Haematology

IRON STUDIES IN MICROCYTIC ANEMIA

TIBC % Transferrin
Cause MCV Iron (Fe) Ferritin Reticulocyte Count RDW
(Transferrin) saturation (Iron/TIBC)
Usually ↓
↓ ↓ ↑ ↓ (< 20%) ↓ ↑
(< 15 ng/mL)
Does not typically cause microcytosis until Hb < 10g/dL; Mentzer Index (MCV/RBC) > 13 due to ↓ RBC count
o Infancy – introduction of cow, goat, or soy milk before age 1 and inadequate consumption of iron–rich foods
o Older children & adults – chronic, asymptomatic bleeding (e.g. slow GIT bleed, abnormal menstruation)
Brittle nails, koilonychia , hair loss, Pica (appetite for non–nutritional items e.g. paper products, clay, dirt), dysphagia
Pagophagia is pica for ice (highly specific for iron deficiency anemia)
Angular cheilitis: inflammation and fissuring of the corners of the mouth
Iron Deficiency Atrophic glossitis: erythematous, edematous, painful tongue with loss of tongue papillae (smooth, bald appearance)
Plummer–Vinson syndrome (PVS): triad of post–cricoid dysphagia, upper esophageal webs, & Fe deficiency anemia
Peripheral Blood Smear – Anisocytosis (Different–sized RBCs; often the 1st finding), microcytosis & hypochromia (↑’d
zone of central pallor)
N.B. Low ferritin (< 15 ng/mL) & iron levels in combination with an elevated TIBC are diagnostic of iron deficiency anemia! N.B. Increased ferritin does not
automatically rule in iron deficiency anemia. It can be increased in response to simultaneous inflammation (recall ferritin is an acute phase reactant),
cirrhosis, and ESRD! Serum ferritin values greater than 100 ng per mL (100 mcg per L) may indicate adequate iron stores and a low likelihood of IDA
o ESRD patients can have functional iron deficiency (normal iron stores with inability to mobilize stores in response to erythropoietin)
 Transferrin saturation < 20% with ferritin 100 – 800 ng/mL or higher
Thalassemia ↓↓ ↑* Normal or ↑ ↑* Usually ↑ / Normal Normal (occasionally ↑)
Normal / ↑* ↓* (compensatory bone marrow
(55 – 70 μm ) 3
(RBC turnover) (*> 45%) response to anemia) Normal–to–↑ Total RBCs
 Hereditary disease caused by decreased production of hemoglobin chains; Most common cause of microcytic anemia in Asian Americans (more commonly α
–thalassemia) and African Americans (more commonly β –thalassemia; also more common with Mediterranean or African descent)
o Pathophysiology for Beta–thalassemia: ↓ β globin synthesis → precipitation of unpaired α chains within RBCs causing membrane damage. This
subsequently leads to death of erythroblast in bone marrow (ineffective erythropoiesis) & lysis of circulating erythrocytes (hemolysis)
 Signs of hemolysis (↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes); Mild ↓ Hct (22 – 32%; usually > 28%); Mentzer index (MCV/RBC) < 13
 Profoundly decreased MCV in comparison to a relatively mild anemia
 Disproportionately elevated RBC counts (e.g. normal or high, rather than low; normal 4 – 6 million/mm3)
 PBC smear – Microcytic, hypochromic anemia, Target cells ± Pappeheimer bodies, nRBCs, Polychromatic RBC
(reticulocyte), anisopoikilocytosis (variation in size & shape), basophilic stippling
 Hemoglobin electrophoresis:
o ↑ HbA2 in beta–thalassemia minor (asymptomatic carrier)
o Sickle Beta–thalassemia – predominantly HbS (60 – 90%), HbA (α 2 β 2) < 30%; HbF (1 – 20%) & ↑ HbA2
 Sickle cell – Beta (+) thalassemia (c.f. to HbS trait which is HbA:HbS = 60:40)
 Type I: 3 – 5% HbA present
 Type II: 8 – 14% HbA present
 Type III: 18 – 25% HbA present
  Sickle cell – Beta (0) thalassemia – no HbA observed
o Beta–thalassemia major – increased Hgb A2 (α 2 δ 2), and Hgb F (α 2 γ 2); No Hgb A
 Anemia develops at 6 months (Hgb F declines); Frontal bossing from extramedullary hematopoiesis, & splenomegaly
 Tx – Splenectomy, folate supplementation, & transfusions (improved symptoms usually); patients usually die from transfusion iron overload (heart &
liver failure); N.B. important to implement Fe chelation therapy (e.g. deferoxamine) within 1 – 2 years of commencing RBC transfusions to delay or
prevent iron–induced cardiotoxicity
o Normal in Alpha–thalassemia trait – 1 gene deletion is asymptomatic (α + trait = silent carrier state)
o Alpha–thalassemia minor – 2 gene deletion is associated with a mild anemia with RBC hyperplasia; seen in Asians & Africans
 Asians more commonly have a deletion of two α genes on 1 chromosome (cis deletion = [– – / αα])
 Africans more commonly have a deletion of 1 α gene from each chromosome (trans deletion = [– α/– α])
 Clinically indistinguishable, determined by genealogy
o Hb H disease (α–thalassemia major) – Hgb H (beta tetramer (β4) precipitates; toxic) & Bart's Hgb (gamma tetramer) on Hb electrophoresis
 Inactivation of 3 α Globin Genes, i.e. only 1 gene being transcribed (- - / - α) – 25% of normal α chains
 Moderate anemia develops by 1 year of age with prominent jaundice and hepatosplenomegaly.
 Increased Hb H (ß4), which forms Heinz bodies that can be seen with crystal blue stain
 Hb Bart = 4 gene deletion; Gamma tetramer (γ4): hydrops fetalis
 NO improvement in Hemoglobin with supplemental iron and do not require a specific treatment – Folate, avoid oxidative stress (e.g. sulfonamides)
o Splenectomy should be considered if too frequent transfusions
o Iron chelation therapy for iron overload states (deferoxamine)

Anemia of Low–Normal (early) ↓ Normal / ↓ Normal / ↑ Normal / ↓ (~25%) ↓ Normal

 chronic disease  ↓ (late phase)
 Usually relatively mild anemia, but ~ 20% have Hb < 8 d/dL (In more severe cases, should rule out concurrent causes of anemia, e.g. iron deficiency,
myelodysplasia, and thalassemia)
 Elevated hepcidin, a small peptide released by the liver in response to inflammation. Hepcidin binds to and inactivates iron channels (ferroportin) and
enterocytes and reticuloendothelial (RES) macrophages → reduced iron absorption in the gut and increased iron sequestration in RES macrophages
o Because reticuloendothelial macrophages recycle senescent erythrocytes and provide > 95% of daily iron for erythrocytes, this sequestration dramatically
reduces serum iron concentration
o Normal or slightly reduced TIBC / transferrin due to cytokine – mediated suppression of transferrin
 Address underlying inflammatory disorder
↓ ↑ Normal / ↓ ↑ ↑ ↓ ↑
Anemia caused by defective heme metabolism, which leads to iron trapping inside the mitochondria
Genetic (X–linked δ–ALA–synthase gene defect; rate–limiting enzyme of heme synthesis) or Acquired (Vitamin B6
deficiency, Lead poisoning, Alcohol use disorder (most common cause), chloramphenicol, isoniazid [→ B6 deficiency;
most common drug], linezolid, Copper deficiency, Myelodysplastic syndrome, Malignancy)
Basophilic stippling on peripheral blood smear (non–specific; basophilic stippling also seen in EtOH)
Sideroblastic Ringed Sideroblasts (with iron–laden, Prussian blue–stained mitochondria) in BM – due to inability of iron to form
anemia heme, thus Fe2+ trapped in mitochondria
Treatment
o Cessation of the offending agent if acquired etiology
o Pyridoxine (B6) supplementation (a cofactor for δ–ALA synthase)
o If Lead Poisoning related etiology
 Dimercaprol and EDTA are 1st line of treatment
 Succimer used for chelation for kids
* If iron overload is present (e.g., due to multiple transfusions, ineffective erythropoiesis, ↑ GI iron absorption)

Iron Deficiency Anemia in Young Children

Risk Factors Prematurity
Lead exposure
 Age < 1
o Delayed introduction of solids (i.e. exclusive breastfeeding after 6 months)
o Cow’s, soy, or goat milk
Age > 1
o > 24 oz per day cow’s milk
o < 3 servings / day iron – rich foods (e.g. meats, cereals)
Diagnosis Screening hemoglobin at age 1
Hb < 11 g/dL, ↓ MCV, ↑ RDW
If family history of hemoglobinopathies, screening Hb electrophoresis is indicated
Treatment Empiric trial of iron supplementation

 Lead poisoning in adults

o Risk factors – occupational exposure (e.g. lead paint, battery manufacturing & recycling, ammunition, construction, plumbing, smelting)
 C.f. in children – chips from lead–painted surfaces
 Pica
 Foreign–born children
 Homes built prior to 1978
 Low socioeconomic status
 Painted toys and decorations manufactured before 1976 or outside the United States
o Pathophysiology
 Lead inhibits key enzymes in heme synthesis pathway
 inhibits ferrochelatase and ALA dehydratase → leads to ↓ heme synthesis → results in ↑ RBC protoporhyrin
 Lead inhibits rRNA degradation → causes rRNA to aggregate in RBCs – visualized as basophilic stippling of RBCs
 Lead causes toxicity through the generation of reactive oxygen specie
o Clinical Features
 Gastrointestinal (abdominal pain, constipation, anorexia)
 Neurologic (cognitive deficits / behaviour problems e.g. forgetfulness, cognitive dysfunction, peripheral motor & sensory neuropathy – e.g.
extensor weakness, foot or wrist drop, stocking–glove distribution)
 Levels as low as 10 – 20 μg/dL are associated with cognitive impairment and behavioural problems (e.g. ADHD)
 Cognitive impairments can persist beyond childhood and beyond adolescents
 Acute encephalopathy (e.g. altered mental status, seizures) typically occurs with very severe lead toxicity (> 100 μg/dL)
 Hematologic (microcytic, hypochromic anemia) – fatigue, exertional dyspnea
 MSK (e.g. joint pains, muscle aches)
 Non–specific symptoms (e.g. fatigue, irritability, insomnia) are common
 Chronic lead exposure can also cause hypertension and nephropathy
 Lead lines on gingivae at base of the teeth
o Investigations
 Microcytic Anemia (disruption of heme synthesis) – (N.B. Chronic lead ingestion causes normocytic, hemolytic anemia)
 Elevated venous lead level (> 10 μg/dL)
 Severe (> 70 μg/dL)
 Moderate (45 – 69 μg/dL)
  Mild (< 44 μg/dL)
 ↑ serum iron and ferritin, ↓ TIBC
 Elevated serum zinc protoporphyrin level
 Basophilic stippling on peripheral smear
 Hyperuricemia (due to impaired purine metabolism) is also typical
 Radiographs – lead lines (lead deposition) on metaphyses of long bones in growing children (rarely seen except in cases of severe lead toxicity)
o Management
 Environmental Surveillance (identify & remove lead sources)
 Chelation therapy – indicated if blood lead levels ≥ 45 µg/dL
 modalities
o Succimer (oral agent) – 1st–line
 ADR - hepatotoxicity
o Penicillamine (oral agent) 2nd–line
o Dimercaprol plus EDTA (parenteral) – for severe disease or lead encephalopathy
 crosses blood brain barrier
 ADR of EDTA – hepatotoxicity
 Mild: 5 – ≤ 44 μg/dL → No medication; repeat lead level in 1 month
o Repeating a lead level in 1 year is appropriate for at – risk kids with lead levels < 5 μg/dL
 Moderate: 45 – 69 μg/dL → Meso – 2,3 – dimercaptosuccinic acid (DMSA, succimer)
 Severe: ≥ 70 μg/dL → Dimercaprol (British Anti – Lewisite) + Calcium disodium edetate (EDTA)
 Nutrition counselling
 Notify public health department
o Complications
 Developmental Delay in children
 Lead encephalopathy
 CD55 molecule helps protect cells from complement–mediated destruction, and its absence leads to the hemolytic anemia seen in paroxysmal nocturnal
hemoglobinuria
 Differential Diagnosis for Eosinophilia
o Parasites
o Asthma
o Churg–Strauss
o Chronic Adrenal Insufficiency
o Myeloproliferative Disorders
o Allergy
o Neoplasia

ANAEMIA OF CHRONIC DISEASE

Pathogenesis  ↑ Inflammatory cytokines (e.g. hepcidin)
 Inhibition of ferroportin (iron channels) on enterocytes and macrophages
 ↓ Iron absorption in gut and ↑ Iron sequestration (reduced iron release from reticuloendothelial
system, which scavenges senescent erythrocytes & provides up to 95% of daily iron)
o Dramatic reduction in iron availability for the generation of new erythrocytes (erythrocytosis)
  Reduced circulation → impaired erythropoiesis
Common Etiologies  Malignancy (e.g. Hodgkin Lymphoma)
 Chronic infection
 Rheumatic disease
 Obesity
 Diabetes Mellitus
 Congestive Heart Failure
Laboratory findings  Normocytic (early) / slightly microcytic (late) anemia
 ↓ serum iron, iron–binding capacity (TIBC), reticulocyte count
 ↑ Bone marrow iron
 Lower than expected erythropoietin for degree of anemia
Treatment  Treat underlying condition causing inflammation
 Reticulocyte < 2% = Non-Hemolytic Anemia (Hypoproliferative BM)
 Reticulocyte count ≥ 2% = Hemolytic Anemia (Hyperproliferative BM)
 Signs of hemolysis = ↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes, splenomegaly
 Folate Deficiency Cobalamin (Vitamin B12) Deficiency
 Increased requirements  Intestinal bacterial overgrowth (competes for cobalamin)
o Physiological – Pregnancy and lactation, prematurity o Blind Loop syndrome (intestinal stagnant loop syndrome) – jejunal
o Pathological diverticulosis, blind loop stricture etc
 Haematological diseases: chronic haemolytic anemias (e.g. sickle cell  Decreased dietary intake – vegans, vegetarians
disease), myelofibrosis o Deficiency typically takes 3 – 4 years to develop
o Malignant disease: carcinoma, lymphoma, myeloma o Recall B12 Dietary sources – Animal protein e.g. meat, milk products & egg
o Inflammatory diseases: Crohn’s disease, tuberculosis, rheumatoid arthritis, yolk
psoriasis, exfoliative dermatitis, malaria  Poor absorption –
 Poor dietary intake o Pernicious anemia (PA; autoimmune destruction of parietal cells &/or anti-
o Nutritional sources – diet deficient in leafy green vegetables, fruits intrinsic factor autoantibodies → achlorhydria & lack of intrinsic factor,
 “Tea and toast” diet in elderly, anorexia nervosa, alcoholism predisposition to other autoimmune conditions e.g. Hashimoto’s thyroiditis)
o Body stores of folate are minimal (3 – 4 months to deplete liver stores)  Anti-IF antibody testing: 50 – 84% sensitivity, 100% specificity;
o Patients with severe alcohol abuse and poor nutrition may become  Anti-parietal cell testing much less specific
Etiology deficient in as little as 5 – 6 weeks  Absent rugae in gastric fundus & body on endoscopy
 Malabsorption (e.g. gastric bypass, alcoholism, Celiac disease [gluten–  Autoimmune metaplastic atrophic gastritis – atrophy of gastric body
induced enteropathy], tropical sprue, drugs) and fundus; glandular atrophy, intestinal metaplasia (replaces oxyntic
 Impaired Folate utilization – glands), & inflammation
o Alcoholism, OCP [EtOH inhibits absorption of monoglutamate form in o Chronic PPIs – achlorhydria
jejunum] o Gastrectomy, Ileal disease / Post–Ileal resection, Roux-en-Y gastric bypass
o Folate antagonists o Pancreatic insufficiency – deficiency in pancreatic peptidases responsible for
 Trimethoprim cleaving R–binder B12 complex
 Phenytoin [inhibits intestinal conjugase → no conversion from o Atrophic gastritis (parietal cells in gastric mucosa not producing IF or HCl →
polyglutamate form to monoglutamate form → impaired folate R–binder not properly bound to cobalamin)
absorption in duodenum & jejunum] o Damage to terminal ileum due to Crohn’s disease which normally facilitates
 Methotrexate [inhibits DHF reductase, which is essential for conversion receptor–mediated absorption of IF–vitamin B12 complex
of folic acid to its reduced form, FH4 – folinic acid]  Parasitic infestation – Fish tapeworm (Diphyllobothrium latum) in ileum
 Absence of TCII (transcobalamin II)
Pathogenesis  Folic acid (Vitamin B9) is absorbed in jejunum and ileum  Vitamin B12 (cobalamin) is a water–soluble vitamin that is involved in the
o Used in tetrahydrofolate (THF) as coenzyme formation of hematopoietic cells and maintenance of myelin integrity
o Important for DNA and RNA synthesis  Anemia 2° to insufficient intake may take several years to develop due to
o small reserve pool in liver (can manifest after 4 months) liver’s ability to store B12
 Causes megaloblastic anemia due to impaired DNA synthesis  B12 absorption –
o R–binder (from salivary glands) binds to vitamin B12 (initially protein –
bound and released by pepsin) to prevent its degradation by gastric acid
o Proteases in the duodenum (originating from the pancreas) separate R–
binder and vitamin B12, allowing vitamin B12 to bind to intrinsic factor
(produced by gastric parietal cells)
o Intrinsic factor – vitamin B12 complex is absorbed in the terminal ileum
 DNA synthesis
o B12 serves as a coenzyme for methionine synthase to produce methionine
  Serves a vital role in methylation reactions
o Tetrahydrofolate – serves a vital role in DNA synthesis
 Via reduction of 5-methyltetrahydrofolate [5-methyl-THF] to
tetrahydrofolate[THF])
 Myelin Stabilization
o Methionine is converted to S–adenosylmethionine (associated with myelin
stabilization)
o Vitamin B12 serves as a coenzyme for methylmalonyl–CoA mutase to convert
methylmalonyl–CoA (produced from methylmalonic acid, MMA) to succinyl–
CoA
 Thus in B12 deficiency, build–up of MMA, and lack of myelin stabilization
(c.f. folate deficiency which only causes elevated homocysteine, and does
NNOT cause build–up of MMA)
 Vitamin B12 Deficiency
o Impaired DNA synthesis significantly affects rapidly dividing cells (e.g.,
hematopoietic precursor cells) and leads to
 Megaloblastic changes, which is caused by slowing of nuclear division
 Due to nuclear–cytoplasmic dyssynchrony (nuclear maturation is
immature / delayed relative to cytoplasmic maturity)
 Ineffective erythropoiesis (intramedullary hemolysis)
 Erythropoietic precursor cells within BM prematurely die →
reticulocytopenia
 Impaired neuronal function
 Mechanism is not fully clear but hypothesized to be due to decreased
methylation of neuronal lipids and proteins (e.g., myelin basic protein)

 Dyspnea, Fatigue, Pallor, Weakness, Glossitis

 No neurologic manifestations (c.f. to B12 deficiency)  Neurologic manifestations – Subacute Combined degeneration of the cord
 N.B. Folate is more readily depleted than B12 (due to involvement of B12 in fatty acid pathways and myelin synthesis)
o Peripheral neuropathy with sensorimotor dysfunction (e.g. loss of ankle jerk)
o Dorsal column (loss of vibration / proprioception, gait difficulties)
o Lateral corticospinal (spasticity, hyperreflexia, weakness)
Clinical o Spinocerebellar tracts –
Features  Ataxia, gait difficulties
 Impaired proprioception information from the spinal cord to the
cerebellum
o Dementia (reversible)
o Symptoms & signs more prominent in the lower than upper extremities

Laboratory  Macrocytic anemia (MCV > 100 μm3) with hypersegmented neutrophils (due to ineffective erythropoiesis secondary to defective nucleic acid synthesis)
Investigations  Peripheral blood smear
 o Hypersegmented lobes (≥6 lobes) seen in neutrophils
o Macrocytosis (megalocytes)
 ↓ Reticulocyte count
o Inappropriately low / normal reticulocyte count – poor reticulocyte response / inability to increase RBC production in response to anemia
Hematocrit
o Corrected reticulocyte count=% reticulocytes ×
45 %
 Pancytopenia – if deficiency is severe
 Hyperhomocysteinemia (↑ homocysteine) – decreased metabolism of homocysteine
 N.B. serum homocysteine level is increased in both folate deficiency and vitamin B12 deficiency. However, serum methylmalonic acid levels are only
seen in vitamin B12 deficiency
 Test TSH to rule out Hypothyroidism (particularly if pernicious anemia)
 Low serum folate  Decreased serum B12 levels
 Normal methylmalonic acid  High methylmalonic acid
 Anti–intrinsic factor and parietal antibodies (seen in pernicious anemia)
 Folate supplementation, especially in pregnancy and/or women of child-  Vitamin B12 IM 1mg/day for 1 week, then twice weekly for 1 week, then
bearing age, Sickle cell anemia, or if chronically on drugs such as weekly for 4 weeks, then 1 mg every 3 months or monthly after.
methotrexate  Retics will rise by day 2–3 and peak at 7-10 days
o N.B. Folinic acid (leucovorin) is more potent than folic acid in  Avoid blood transfusion – May cause decompensation & circulatory overload
‘rescuing’ red blood cells from folate deficiency by bypassing the  N.B. Peripheral neuropathy slow to recover but will improve over weeks to
block on DHFR with chronic, high–dose methotrexate deficiency months. Spinal cord damage is sometimes irreversible and although it may
 Alcoholics should be advised to stop drinking improve, this improvement may not be complete.
 Improve diet – more fruits and vegetables  N.B. Administration of folate in B12 deficiency improves blood counts but
Treatment  Measure retics at 7–10 days causes progression of neurologic disease
 Monitor for hypokalemia during 1st 48 hours of tx; patients with moderate to
severe megaloblastic anemia can have severe, life–threatening hypokalemia in
1st 48 hours of treatment
o Hypokalemia results following uptake of potassium by newly–forming RBCs
o Potassium is replaced depending on measured serum potassium levels
o Some physicians transfuse pRBCs in patients with severe megaloblastic
anemia before Vitamin B12 supplementation as a preventative measure for
hypokalemia
 Neural tube defects in infancy if deficient during pregnancy 
 In the setting of a B12 deficiency, the anemia can correct with aggressive
Complications folate supplementation but the may worsen neurological complications of
B12 deficiency including peripheral neuropathy and posterior column defects
due to deficiencies in myelin production

 B12 deficiency most often impacts

o Rapidly dividing haematologic cells – increased apoptosis causes anemia, and mild thrombocytopenia/leukopenia. Slowing of nuclear
maturation usually results in macrocytosis (elevated MCV), but those with concomitant iron deficiency from GI blood loss (as often occurs
in Crohn’s disease) may have minimal ↑ MCV or high-normal MCV
 o Myelinated nerve fibres – patients classically develop subacute combined degeneration of the spinal cord, which is marked by
demyelination of dorsal column (fasciculus gracilis > cuneatus; reduced vibratory sensation), spinocerebellar tracts (e.g. sensory gait ataxia)
& lateral corticospinal tracts (e.g. spastic paresis [symmetric lower extremity paresthesia], enhanced reflexes, positive Babinski reflex).
 However, myelinated nerves in the peripheral nervous system are often affected first, leading to lower extremity paresthesias with
no other neurologic findings
Common Causes of Macrocytic Anemia (MCV > 100 μm3) Causes of Pancytopenia
 Megaloblastic Anemia (impaired DNA synthesis) – typically MCV > 110 μm ,
3
 Aplastic Anemia
hypersegmented neutrophils, anisocytosis, poikilocytosis, macroovalocyte RBCs o N.B. most cases are idiopathic and thought to be due to
o Folate deficiency autoimmune – induced loss of multipotent hematologic
Bone Marrow
o Vitamin B12 Deficiency stem cells
Aplasia
o Drug–induced (e.g. hydroxyurea, antifolate, zidovudine, CTX agents)  Infection (e.g. parvovirus B19, HIV, viral hepatitis)
o Orotic aciduria  Nutritional Deficiency (e.g. vitamin B12 / folate)
 Myelodysplastic Syndrome (especially if MCV > 110 fL)  Cytotoxic Medications (e.g. hydroxyurea)
 Acute Myeloid Leukemias  Cancer (e.g. hematologic, metastatic)
Bone Marrow
 Liver Disease  Myelofibrosis
Infiltration
 Alcohol abuse (mild macrocytosis – MCV < 110 μm3)  Infection (e.g. tuberculosis, fungal infection)
 Hypothyroidism Mature Blood Cell  Intravascular (e.g. DIC, TTP)
 Reticulocytosis Destruction  Extravascular (e.g. hypersplenism)

 Sickle Cell Disease – Autosomal recessive hemoglobinopathy resulting from single nucleotide base change codes for valine instead of glutamic acid
at the 6th position from the N-terminus of the ß-globin chain, on chromosome 11
o Sickle Cell Disease – overarching term including sickle cell anemia, as well as patients with a sickle mutation (HbS) and a different mutation
in the ß-globin gene (e.g., ß-thalassemia or hemoglobin C disease)
o Resulting in hemolytic anemia and vaso-occlusion; HbSS (Homozygous: Sickle cell anemia); heterozygotes (HbSA, sickle cell trait)
o HbSC is a less severe variant of sickle cell disease characterized by mild normochromic anemia
 Hemoglobin electrophoresis showing equal amounts of HbS and HbC is diagnostic
 HbC – point mutation in ß-globin gene where glutamic acid is replaced with lysine
o Sickle Cell Trait – Presence of HbA and HbS in a 60:40 ratio, respectively, on Hb electrophoresis
 Asymptomatic and does not cause anemia or microcytosis
o Hemoglobin F levels are increased in patients with sickle cell anemia, congenital aplastic anemia, and hereditary persistence of fetal
hemoglobin
o Complications
 Vaso-occlusive Pain Episodes / Events – acute painful crisis, CVA’s, Mis, Dactylitis (Hand–Foot syndrome), acute chest syndrome,
Priapism, Renal Infarction, Splenic Infarction → functional asplenia, Venous Thromboembolism, Infection
 Acute, severe pain
 Pain at ≥ 1 site (e.g. dactylitis)
 ± Low grade fever
 May be triggered (e.g. by dehydration, cold temperature, illness, stress)
 X–rays of Dactylitis
o Initial radiographs reveal only soft tissue swelling
 o Recurrent episodes can lead to a mottled appearance of the bones
 Management
o Analgesia, Hydration, warmth / heat packs ± RBC transfusion
 Oral NSAIDs and oral opioids (e.g. oxycodone); IV opioids if pain unresolved
 N.B. oral codeine and tramadol are contraindicated in children < 12 years old because rapid ultra-rapid
metabolism of codeine and tramadol causes an unpredictably high concentration of the active drug in the
body, which can result in respiratory depression and death
 Chronic – pain, hemolytic anemia, stunted growth
 contributing factors to hemolytic anemia include low EPO concentration (can be due to renal disease) and folate deficiency
 Functional asplenia by an early age
 at increased risk for encapsulated bacterial infection (e.g., Streptococcus pneumoniae, Haemophilus Influenza type b,
Neisseria meningitidis, Salmonella)
o S. pneumonia is the most common cause for sepsis and meningitis
o Salmonella is the most common cause for osteomyelitis
 may result in splenic sequestration of RBCs
 Pneumococcal vaccine strongly indicated
 Aplastic crisis
 Chronic lung disease and pulmonary hypertention – secondary to acute chest syndrome
 Renal disease – can present as inability to concentrate urine, resulting in frequent urination
 Painless haematuria due to papillary necrosis
 Retinopathy – secondary to retinal artery occlusion
 Cardiomyopathy – left-sided diastolic dysfunction with or without pulmonary hypertension
 due to pulmonary hypertension, chronic anemia and hypoxemia with increased
cardiac output, transfusion overload, and hypertension
 Cholelithiasis – pigmented gallstones secondary to chronic hemolysis
 Supersaturation of bile with calcium hydrogen bilirubinate
 Acute sickle hepatic crisis
 secondary to occlusion the hepatic sinusoids
 associated with an increased mortality in the mother and fetus
 Hydroxyurea
o Reduces frequency of vaso-occlusive episodes in sickle cell disease but may take several months to take effect. It is not used in treatment of
an acute episode
o Indicated in HbSS with:
 Frequent Recurrent painful crises
 Recurrent or severe Acute Chest Syndrome
 Persistent symptomatic anemia without underlying cause e.g. renal disease
 Cerebrovascular accident (due to an infarct) in absence of chronic transfusion
o MOA:
 increases fetal hemoglobin
  Decreased haemolysis with reduced release of free haemoglobin and increase in total haemoglobin concentration
 Lowering of white cell and reticulocyte counts
 Increased circulating nitric oxide (NO)
o Seek specialist guidance when a non–specialist suggests use in SCD with leg ulcers, priaprism
o ADRs – myelosuppression (e.g. neutropenia, macrocytic anemia, thrombocytopenia; dose–dependent), Acute kidney injury (rare)
 Acute Chest Syndrome in Sickle Cell Disease
o Diagnostic Criteria
 New pulmonary infiltrate on CXR PLUS ≥ 1 of the following:
 Respiratory Distress – Increased work of breathing, cough, tachypnea, wheezing
 Temperature > 38.5 OC (101.3 OF)
 Hypoxemia
 Chest Pain
o Etiology
 Infection (most common cause)
 Asthma exacerbation
 Pulmonary infarction
o Initial Treatment
 Blood Cx, CBC, U&Es, GXM
 IV fluids, Warmth
 Empiric antibiotics – Third generation cephalosporin + macrolide to cover Streptococcus pneumoniae and Mycoplasma pnuemoniae
respectively
 Ceftriaxone (or cefotaxime) plus azithromycin
 Pain control – to prevent splinting and subsequent hypoventilation and atelectasis
 Blood transfusion indicated if hypoxemia < 92%, significant anemia, or worsening symptoms despite initial treatment
 Avoided if possible given the risk of alloimmunization

Acute Severe Anemia in Sickle Cell Disease

Causes Reticulocytes Key Features
 Transient arrest of erythropoiesis
 Secondary to infection (e.g. Parvovirus B19 which preferably attacks erythroid precursors)
Aplastic Crisis (Pure Red Cell o Most children develop immunity against parvovirus by age 15, thus aplastic crisis is rare after
Decreased (< 1%)
Aplasia) early childhood
 Blood transfusions are mainstay of treatment while erythropoiesis recovers
 Supplement with daily folic acid
 Splenic Vaso–occlusion → rapidly enlarging spleen (splenomegaly)
Increased
Splenic Sequestration Crisis  Occurs in children prior to autosplenectomy
(marked reticulocytosis)
 Supplement with daily folic acid

Pure Red Cell Aplasia / Aplastic crises Aplastic Anemia

Pathophysiology normocytic, normochromic anemia characterized by a severe Pancytopenia due to bone marrow insufficiency
reduction in circulating reticulocytes and marked reduction or o diminished, absent, or destructed hematopoietic stem cells
absence of erythroid precursors in the bone marrow o With bone marrow aplasia
Exact mechanism unknown – thought to be related to abnormal T-
cell function and IgG antibodies that target erythroblasts and
erythropoietin
Etiology Acquired: Idiopathic in > 50% of cases; thought to be due to autoimmune – induced loss of
o most often idiopathic, but can be associated with: multipotent hematologic stem cells
 Thymoma o In idiopathic AA, an underlying insult (e.g. mutation, virus) causes alteration of
 Myelodysplastic syndrome surface antigens on multipotent stem cells, making them appear foreign and
 Drugs (e.g., phenytoin, chloramphenicol, azithromycin, co– triggering a cytotoxic T – cell response.
trimoxazole) o Cytokines released by T – helper cells (type 1 cytokines) also contribute to
 Parvovirus B19 (transient [5–10 days] pure red cell aplasias in pathogenesis, most notably IFN–γ , which triggers apoptotic cell death due to the
hemolytic anemias e.g. HbSS, G6PD) stimulation of a destructive cytokine cascade and increased expression of the Fas
 Autoimmune disorders (e.g., T1DM, thyroiditis, rheumatoid receptor on the hematologic stem cell surface
arthritis, SLE) Medication side effects:
Congenital: o Can't Make New Blood Cells Properly =
o Diamond–Blackfan anemia / Syndrome  Carbamazepine
 Congenital erythroid aplasia; Intrinsic defect of erythroid  Methimazole
progenitor cells → increased apoptosis  NSAIDs
 Rapid onset of macrocytic, non–megaloblastic, anemia in  Benzenes
infancy (usually diagnosed within the 1st year of life) &  Chloramphenicol
reticulocytopenia  Propylthiouracil
 Progressive pallor and poor feeding o Sulfa drugs, cytostatic drugs
 Additional clinical features (50%): Toxins: Benzene, cleaning solvents, insecticides, toluene Ionizing radiation
 Short stature, webbed neck Viruses: parvovirus B19, HBV, EBV, CMV, HIV
 Upper extremity malformations (e.g., triphalangeal Fanconi anemia
thumbs) o Autosomal recessive disorder due to a DNA crosslink repair defect
 Microcephaly, micrognathia o Most common congenital cause of aplastic anemia (i.e. Bone Marrow Failure)
 Craniofacial abnormalities – Hypertelorism, flat nasal o Skeletal and organ abnormalities:
bridge, cleft palate  short stature, hypo- and hyperpigmented macules
 Increased risk of malignancy  cafe-au-lait spots, microcephaly
 Normal platelets, WBCs  developmental delay
 Electrophoresis: ↑ HbF levels  thumb and forearm malformations
 Treatment – Corticosteroids, RBC transfusions, Hematopoietic  Radial defects (30%) & usually assoc. with absent or hypoplastic thumbs
stem cell transplantation (HSCT) in patients unresponsive to  Polydactyly, flat thenar eminence
steroids  Strabismus
 Genitourinary malformations
 GI, heart, eye, and ear abnormalities
o Laboratory tests show
 pancytopenia
 normocytic or more typically macrocytic anemia
 o macrocytic due to fetal erythropoiesis that occurs during periods of chronic
hematopoiesis stress
 leukopenia, thrombocytopenia
 Positive chromosomal breakage testing
o Treatment – Hematopoietic stem cell transplant

 ∼ 50% will develop acute myeloid leukemia or myelodysplastic syndromes in

o Prognosis

early adulthood
Clinical Features  insidious onset, but often initial symptoms are due to anemia or bleeding
(often normocytic) anemia – fatigue, malaise, pallor
Thrombocytopenia – mucosal bleeding, petechiae, purpura
Leukopenia – infections
Investigations Low reticulocyte count (<1%) Pancytopenia – anemia, leukopenia, thrombocytopenia
Bone marrow biopsy  ↓ reticulocyte count – helps identify aplastic anemia in sickle cell patients, who usually
o marked reduction or absence of erythroid precursors. have high baseline reticulocyte count
 Bone Marrow biopsy
o normal cell morphology but hypocellular bone marrow with fatty infiltration
Treatment Tx underlying cause (e.g., cessation of possible offending agents, Withdrawal causative agent if applicable
thymectomy) Supportive therapy
Red blood cell transfusion for symptomatic patients – use judiciously o RBC transfusion (leukoreduced)
Immunosuppressive and/or cytotoxic agents (e.g., glucocorticoids, o platelet transfusion
cyclosporine, cyclophosphamide) o Treat infections
Curative – bone marrow transplant for healthy patients < 50 years old
Medical therapy
o immunosuppressive agents for > 50 years old or those with comorbidities
 anti–thymocyte globulin + cyclosporine
 Tacrolimus
 Eltrombopag
 Alemtuzumab
o Hematopoietic growth factors
 G-CSF (filgastrim)
 GM-CSF

 G6PD Deficiency (glucose-6-phosphate dehydrogenase)

o X–linked enzymopathy affecting ~10% of black men in USA; also commonly occurs in the Mediterranean, Middle East, and Asian descent
 May affect female patients if homozygous or have skewed lyonization of heterozygous mutations (i.e. overexpression of
erythrocytes with the mutated X–chromosome)
o Characterized by Hemolytic anemia (e.g. low Hb, reticulocytosis, icterus) after exposure to oxidizing agent (oxidative stress)
 Erythrocyte unable to generate sufficient NADPH, a cofactor required to make glutathione, to counter oxidative injury (e.g.
superoxide anions, hydrogen peroxide) from certain exposures that serve as triggers:
 Medications
 o Avoid – Dapsone (Diaminodiphenyl sulfone), Primaquine, Nitrofurantoin, Isobutyl nitrite, Rasburicase
o Use with caution
 Trimethoprim–sulfamethoxazole (Bactrim)
 Acetaminophen
 Acetylsalicylic acid (aspirin)
 Chloramphenicol
 Chloroquine
 Colchicine
 Diphenhydramine (Benadryl)
 Glyburide
 Isoniazid
 L–dopa
 Quinine
 Vitamin K
 Infections (activated leukocytes release reactive oxygen species)
 Foods (e.g. fava beans metabolized into highly oxidative compounds)
 Oxidative metabolites accumulate in erythrocytes and denature/precipitate hemoglobin into Heinz bodies (dark red erythrocyte
inclusions), which reduce erythrocyte flexibility and lead to read cell damage (bite cells) and lysis in the reticuloendothelial system
o Clinical Manifestations
 Neonatal unconjugated hyperbilirubinemia – Jaundice & anemia day of life 2 – 3
 Acute hemolytic episode – typically self–resolves in 1 – 2 weeks after removal of the offending oxidant
 Secondary to oxidative stress (e.g. fava beans, sulfa drugs [like TMP-SMX], infection)
 Pallor & Fatigue
 Hemoglobinuria – dark–coloured urine with false–positive dipstick for blood due to HgB (N.B no RBCs on urine microscopy)
 Jaundice & Icterus
 Abdominal &/or back pain
o Investigations
 Hemolysis: ↓ Hb, ↓ Haptoglobin, Hyperbilirubinemia (unconjugated), ↑ LDH, ↑ Reticulocytes
 Peripheral Blood Smear – Bite cells (removal of Heinz bodies by splenic macrophages), Heinz Bodies (oxidized / precipitated
hemoglobin)
 Negative Coombs Test – i.e. hemolysis not antibody–mediated
 Low G6PD assay (↓ G6PD activity level; which detects NADPH formation) – may be normal during attack
 As older erythrocytes (lower G6PD activity) have been hemolyzed and young erythrocytes / reticulocytes (higher G6PD
activity) are disproportionately elevated
 Thus if normal, repeat testing after 3 months of acute attack to confirm the diagnosis
o Management
 Remove or treat responsible agent / condition
 Provide supportive care
 Pyruvate Kinase Deficiency
 o Autosomal recessive disorder that causes chronic hemolysis, hepatosplenomegaly, skin ulcers, and pigmented gallstones
o Not episodic hemolysis associated with oxidative stress like G6PD
 Hereditary Spherocytosis
o Epidemiology
 Usually autosomal dominant membranopathy
 Northern European descent
o Pathophysiology
 Inherited defect in RBC membrane proteins (e.g. spectrin, ankyrin) → fragile, sphere–
shaped RBC that become trapped in the fenestrations of the spleen’s red pulp, leading to
chronic extravascular hemolysis in the spleen → splenomegaly
o Clinical Manifestations
 Often asymptomatic
 Haemolytic anemia
 Severe or prolonged neonatal jaundice (> 1 week) despite phototherapy & appropriate
weight gain (i.e. not due to breastfeeding jaundice)
 Splenomegaly (generally seen if severe hemolysis)
 Sphere–shaped RBCs not as deformable as normal biconcave RBCs, and get trapped in the spleen
 Chronic hemolysis causes high hemoglobin turnover and excess bilirubin that overwhelms conjugation and elimination from the
body. Resulting hyperbilirubinemia manifests as jaundice, dark urine, and pigment (calcium bilirubinate) gallstones

o Laboratory Findings
 ↑ MCHC (> 36 g/dL), Reticulocytosis
 Normal to elevated RDW due to various RBC forms (e.g. reticulocytes, spherocytes, normal RBCs)
 Low to normal MCV
 Negative Coombs Test
 Spherocytes on peripheral blood smear
 ↑ Osmotic fragility on acidified glycerol lysis test
 Abnormal eosin–5–maleimide binding test
o Treatment
 Folic acid supplementation
 Blood transfusion or exchange transfusion if severe hemolysis
 Splenectomy in severe cases may be considered to improve anemia and reduce gallstone risk
 Paroxysmal Nocturnal Hemoglobinuria
o Acquired Clonal stem cell defect from mutation in hematopoietic stem cell
 Acquired disorder with an intrinsic defect in the myeloid stem cells membrane; results in absent GPI leading to absence of
protective proteins on membrane
 Characterized by increased sensitivity of red cells to intravascular haemolysis by fully-activated complement
 Characterized by complement-induced intravascular hemolytic anemia, red urine (due to the appearance of hemoglobin in
the urine) and thrombosis
o Pathogenesis
 Mutation in PIGA gene
 Defect / Deficiencies in several glycosylphosphatidylinositol (GPI) anchored mebrane proteins
 CD55 (decay-accelerating factor, DAF) and CD59 on RBC membrane
o these protect RBC from complement
 Membrane inhibitor of reactive lysis (MIRL, CD59)
 Absence of MIRL plays most critical role
 Normally prevents complement from destroying RBCs
o DAF inhibits C3 convertase
 Acetylcholine esterase (AchE)
 Leukocyte alkaline phosphatase (LAP) – on WBCs
 Complement-mediated destruction of RBCs
 Activation of platelets and WBCs
o "PNH Thrombosis"
 Pancytopenia
 Nocturnal build–up of dark urine
 Coombs negative Hemolytic anemia (complement-mediated)
 venous Thrombosis (from pro–coagulant and pro-inflammatory state formed by complement activation)
o Clinical Features
 Episodic dark urine with first urine of the day caused by hemoglobin
 Mild respiratory acidosis develops shallow breathing during sleep and activates complement
 Chronic intravascular hemolytic anemia: pallor, fatigue, tachycardia, jaundice, and gross hematuria
 acute hemolytic episodes from activators of complement
 Surgery
 Infection
 Stress
 Alcohol
 Thrombocytopenia: mucosal bleeding, petechiae, and ecchymoses
 Leukemia: infections
 Thrombosis (prominent feature)
 Abdominal pain, fever, and rectal bleeding (mesenteric vein thrombosis)
 Headache, vomiting, and seizures (cerebral venous sinus thrombosis)
 Fever, jaundice, hepatomegaly (Budd-Chiari syndrome) renal impairment
o Investigations
 CBC – pancytopenia (due to stem cell disorder)
 Anemia may be severe
 Macrocytosis may be present due to mild reticulocytosis
 Hypochromic, microcytic due to iron deficiency (due to iron loss in urine, )
 Macrocytic Anaemia – seen when folate deficiency predominant resulting in megaloblastic change in bone marrow
  Direct Coomb’s Test Negative
 Urine: Hemosiderinuria constant feature; hemoglobinuria sometimes present
 Hemosiderinuria – "brown urine", occurs with chronic intravascular hemolysis, in which hemoglobin is released from RBCs
into the bloodstream in excess of the binding capacity of haptoglobin
o The excess hemoglobin is filtered by the kidney and reabsorbed in the PCT, where the iron portion is removed and
stored in ferritin or hemosiderin. The tubule cells of the proximal tubule slough off with the hemosiderin and are
excreted into the urine, producing a "brownish" color. It is usually seen 3-4 days after the onset of hemolytic
conditions.
 Hemoglobinuria is another indicator of intravascular hemolysis, but disappears more quickly than hemosiderin, which can
remain in the urine for several weeks; therefore, hemosiderinuria is a better marker for intravascular hemolysis.
 Marrow: erythroid hyperplasia during hemolytic phase; may be aplastic during bone marrow failure phase
 Ham’s (acidified serum lysis) test positive – confirmatory test (N.B. negative test does not rule out disease)
 Negative test however does not rule out PNH
 Demonstrates sensitivity of red cells to lysis by complement, activated by acid
 Chemistry – Hemolytic Anemia – jaundice, ↑ Indirect hyperbilirubinemia, ↑ LDH, reticulocytosis & decreased haptoglobin
 Flow cytometry – most accurate test
 CD55/59–negative RBCs [diagnosis to detect absent CD59 (MIRL) or lack of CD55 (DAF); able to quantify PNH clone]
o Treatment
 Best initial therapy – eculizumab (or ravulizumab)
 Inactivates C5 in complement pathway
 Decreases red cell destruction
 Complement inhibitor
 Must vaccinate all against Neisseria, & pnuemococcal due to increased risk
 Best curative therapy – allogeneic bone marrow transplant
 Supportive therapy
 Transfusion of washed packed RBCs (washing removes complement) PRN
 Oral iron therapy for Fe deficiency
 Folate supplements
 Steroids may be of benefit
 Anticoagulation (e.g. warfarin) for thrombotic complications
o Complications
 Renal insufficiency
 Thromboembolism
 5% develop myelodysplasia
 2.5% develop acute leukemias; AML (10%)
 Aplastic anemia
 Red Cell Fragmentation Syndromes – caused by physical damage and shearing of RBCs
o Microangiopathic haemolytic anemia (MAHA):
 Intravascular haemolysis resulting from vascular pathology
  Due to fragmentation of normal red cells passing through abnormal arterioles e.g with microthrombi (TTP-HUS – abnormal
platelet adherence, DIC – abnormal fibrin strand deposition, Pre-eclampsia/HELLP)
 Deposition of platelets and fibrin most common cause of microvascular lesions
 Red cells adhere to fibrin and are fragmented by force of blood flow
 Etiology – Underlying disorders:
o Mucin-producing adenocarcinomas
o Complications of pregnancy:
 Preeclampsia, eclampsia
 Haemolysis, Elevated Liver enzymes, Low Platelets (HELLP)
o Disseminated Intravascular Coagulation (DIC)
o Thrombotic Thrombocytopenic Purpura / Haemolytic Uraemic Syndrome (TTP/HUS)
o Malignant hypertension
o Drugs: mitomycin, bleomycin, cisplatin
o Extracorporeal circulation devices
 Laboratory Findings:
o Peripheral Blood film:
 Schistocytes (fragmented RBCs) prominent
 Spherocytes, Reticulocytes and normoblasts
 Thrombocytopenia
o Coagulopathy in DIC
 Treat underlying disorder
o Traumatic cardiac haemolytic anaemia
 Seen in patients with prosthetic heart valves, cardiac valvular disorders esp. severe aortic stenosis
 Intravascular Haemolysis due to physical damage of red cells from turbulence and high shear stresses against abnormal heart
surfaces
 Haemolytic anaemia usually mild and well compensated


Autoimmune Hemolytic Anemia

Warm agglutin AIHA Cold agglutinin AIHA
Etiology  Drugs (e.g. penicillin, α–methyldopa)  Infections (e.g. Mycoplasma pneumoniae infection & infectious Mononucleosis)
 Viral infections  Lymphoproliferative disorders
 Autoimmune (e.g. SLE)
 Immunodeficiency states
 Lymphoproliferative (e.g. CLL)
Clinical  Asymptomatic to life–threatening anemia  Symptoms of anemia – acute, complement–mediated (intravascular hemolysis)
Manifestations  Chronic hemolytic anemia – extravascular hemolysis  Jaundice, Splenomegaly
 Jaundice, splenomegaly  Livedo reticularis & acral cyanosis with cold exposure that disappear with warming (i.e.
 Antibodies are most reactive to RBC at body temperature predilection for areas below core body temperature)
 o Painful and blue toes/fingers in the cold
o Numbness, mottling
 Antibodies are most reactive to RBC at lower temperature
Investigations  Direct Coomb’s test (DAT; aka direct antiglobulin test) –  Direct Coomb’s test (DAT; aka direct antiglobulin test ) – positive with anti-C3, anti-IgM,
positive with anti-IgG, anti-C3, or both but usually not IgG
 Normal C3 and C4  ↓ C3 and C4
 Hemolytic Normocytic Anemia with evidence of hemolysis (jaundice, ↑ Indirect hyperbilirubinemia, ↑ LDH, reticulocytosis & decreased haptoglobin)
 Peripheral Blood Smear – Polychromatic RBCs, Spherocytes, microspherocytes, eliptocytes, RBC agglutination
 Urinalysis – Haemoglobinuria
 AIHA and thrombocytopenia = Evans syndrome
Treatment  High–dose glucocorticoids (decreases antibody production)  Avoidance of cold temperatures
 IVIG  Rituximab ± fludarabine
 Splenectomy for refractory disease  Plasmapheresis for those refractory to rituximab
 Immunomodulators  Other immunosuppressants – cyclosporine, cyclophosphamide
o Rituximab
o Azathioprine
o Cyclosporine
Complications  Venous thromboembolism  Ischemia & peripheral gangrene
 Lymphoproliferative disorders  Lymphoproliferative disorders, Lymphoma
 Drug–induced Immune–mediated Haemolytic Anemia
Drug coats erythrocytes → IgG binding → identified by Fc receptors on splenic macrophages → splenic
destruction of RBCs by phagocytosis (extravascular hemolysis)
Drug triggers immune complexes → complement–mediated destruction of RBCs (intravascular haemolysis)
Oxidative injury
Pathogenesis Most common triggers
o NSAIDs (e.g. diclofenac)
o Hapten – mediated hemolysis for IgG attachment to surface of erythrocytes:
 Cephalosporins (e.g. ceftriaxone)
 Penicillins (e.g. piperacillin–tazobactam)
Sudden onset (within hours of exposure)
Anemia: fatigue, pallor, dyspnea
Hemolysis: jaundice, dark urine, abdomen or back pain (possibly due to increased erythrocytes in the vertebral
bone marrow)
Clinical Manifestations o ↑ Reticulocytes, indirect bilirubin & LDH
o ↓ Haptoglobin
o Normal coagulation studies
o Spherocytes and immature RBCs (normoblasts) on peripheral blood smear
o Positive Direct Coombs test (anti-IgG [or anti-C3] bound to the erythrocyte surface detected)
Discontinue offending drug
Treatment Transfusion (if severe)
 ± Glucocorticoid, IVIG

Heme Synthesis, Porophyrias, and Lead Poisoning

 Porphyrias are hereditary or acquired conditions of defective heme synthesis that lead to the accumulation of heme precursors. Lead inhibits specific enzymes needed in
heme synthesis, leading to a similar condition.
Condition Porphyria Cutanea Tarda (PCT) Acute Intermittent Porphyria (AIP) Lead Poisoning

Peak incidence: ∼ 30 years

Epidemiology Most common porphyria 2nd most common porphyria Sources of exposure: Battery manufacturing,
Peak incidence: 40–70 years metallurgy, corrosion inhibition; Gun range /
Sex: ♂ > ♀ Sex: ♀ > ♂ (2:1) ammunition; Tableware containing lead; Drinking
water (from lead plumbing or contaminated sources);
Antique or imported toys with lead–containing paint
Etiology / Defective uroporphyrinogen III Autosomal dominant mutation of Ferrochelatase and ALA dehydratase inhibition
Affected Enzyme decarboxylase (UROD) porphobilinogen deaminase (PBG–D), previously Heme synthesis disruption via inhibition of
o Type I: acquired insufficiency (sporadic) of known as uroporphyrinogen I synthase aminolevulinate dehydratase (catalyzes the conversion
UROD in the context of hepatic damage Many patients with enzymatic defects associated of aminolevulinic acid to porphobilinogen)
 Mainly occurs in older men with chronic with AIP remain asymptomatic unless an attack is
alcoholism and hepatic cirrhosis triggered.
o Type II: inherited/familial (autosomal Attacks are triggered by:
dominant) defective UROD o CYP450 inducers: Several enzymes involved in
Enzyme deficiencies in latter steps (after heme biosynthesis are the CYP enzymes of
 condensation of PBG to HMB) cause cytochrome P450. Inducers of CYPs stimulate
photosensitivity heme biosynthesis (stimulates ALA synthase)
Susceptibility factors → accumulation of porphyrin intermediates
o Increased hepatic iron stores,  Anticonvulsants (especially barbiturates,
hemochromatosis benzodiazepines, phenytoin)
o Exacerbated by Alcohol consumption,  Sulfonamides, Rifampin
smoking  Griseofulvin
o Hepatitis C → chronic HCV infection  Anesthetics
o HIV  Hormone therapy
o Estrogen therapy o Alcohol, Smoking
o Sunlight exposure o Sex hormones, especially progesterone
o Fasting: Increased intake of carbohydrates may
alleviate symptoms.
o Stress (e.g., surgery, infection)
Enzyme deficiencies in early steps of porphyrin
synthesis cause neurovisceral symptoms

Pathophysiology Defective UROD → uroporphyrin Defective PBG–D (porphobilinogen deaminase Accumulated substrate – Protoporphyrin, ALA (blood)
accumulation in the skin → sunlight– dysfunction) → Neurotoxic accumulation of
dependent skin damage (chronic porphobilinogen (PBG) & δ–aminolevulinic acid
photosensitivity) (ALA) → neurovisceral (GI & neuro) symptoms
Clinical Features Cutaneous manifestations 5 Ps of AIP: Painful abdomen, Polyneuropathy, Intestinal colic (lead colic)
o Blistering cutaneous hyperpigmentation Psychologic disturbances, Port wine–colored pee, Purple–bluish line on gums (lead line or Burton line)
and photosensitivity P450 inducers; Symptoms of anemia
o Increased fragility of sun–exposed skin → Precipitated by triggers like drugs (see above) Nephropathy
blistering and impaired healing o Fever Nervous System
o Healing results in scarring and milia o GI symptoms: severe colicky abdominal Pain, o Radial or peroneal nerve palsy (wrist/foot drop)
formation nausea, vomiting o Encephalopathy, cognitive impairment (memory
o Hypertrichosis o Neurological abnormalities (Seizures, loss)
o Scleroderma–like changes (especially areflexia) o Headache, fatigue, muscle weakness, demyelination
forehead and scalp) o Polyneuropathy: non–specific pain, (peripheral neuropathy, paresthesias), delirium,
Worsened by alcohol weakness/fatigue, paresthesia, paresis seizures
Commonly occurs on: o Psychiatric symptoms: hallucinations, Children—lead paint exposure
o Dorsum of the hand disorientation, anxiety, insomnia o mental deterioration.
o Face and neck o Autonomic dysfunction: tachycardia, HTN Adults—environmental exposure (e.g., batteries,
o Extensor surface of the forearm o Red–purple (Port–wine coloured) urine ammunition)
In contrast to some porphyrias, the skin is not
involved (i.e. NO photosensitivity)
Diagnosis Urine: ↑ uroporphyrin (tea–colored, pink Initial diagnosis of AIP is based on clinical findings. Microcytic, hypochromic anemia
urine) A high index of suspicion is necessary. Basophilic stippling in peripheral blood smear
Blood tests: ↑ serum porphyrins, possibly Pink Urine (esp. during attacks): ↑ PBG & ↑ ALA Ringed sideroblasts in bone marrow
 abnormal LFTs o Urine may turn brown, dark red, or purple when Pb detectable in blood
exposed to sunlight & air (due to oxidation of Bands of increased density at metaphysis of bones on
excess PBG) X-ray – due to lead deposition in zone of calcification
Management Avoid susceptibility factors and excessive Avoid triggers (no EtOH, no smoking, no CYP450 Chelation Therapies:
sunlight. inducers) Oral Succimer (Dimercaptosuccinic acid, DMSA)
Phlebotomy Hemin / IV Hematin – for severe attacks o Children with BLL ≥ 45 μg/dl
 Antimalarials – low–dose o Fe2+–containing porphyrin that inhibits heme o Asymptomatic adults with BLL ≥ 80 μg/dl
Hydroxychloroquine or chloroquine synthesis; decreases activity of δ– o Symptomatic adults with BLL ≥ 50 μg/dl
aminolevulinate synthase → ↓ heme IM Dimercaprol
biosynthesis → ↓ intermediates o If lead encephalopathy
o Dark, oily solution o BLL ≥ 70 μg/dl
Alternatives:  ± Calcium disodium edetate (CaNa2EDTA)
o Heme arginate
o Glucose loading (Dextrose infusion) → ↓ heme BLL = Blood Lead Levels
synthesis
  Neutropenia / Agranulocytosis
o Definition: absolute neutrophil count (ANC) < 1500
 Mild: ANC between 1500 – 1000
 Moderate: ANC between 1000 – 500
 ANC < 500 = severe; ANC < 200 = agranulocytosis
o Clinical features – fever, infections
o High yield associations
 Chemotherapy – often get support by G–CSF to counteract ADRs of chemotherapuetics
 Very rarely congenital
 Medications
 Antipsychotic – Clozapine
 Anti-epileptic – Carbamezapine
 Antiviral – Ganciclovir
 Thyroid medications – PTU, methimazole

PLASMA CELL DYSCRASIAS

Multiple Myeloma Plasmacytoma
 Most common primary malignancy of bone (N.B. metastatic carcinoma is most common  Solitary mass in the bone or soft tissue
malignancy to involve bone generally-speaking)  ≥ 10% clonal plasma cells confirmed in tissue biopsy
Epidemiology  Sex: ♂ > ♀ (3:2)  No or minimal bone marrow involvement (< 10% plasma cells in
 Peak incidence: 50–70 years, median age 66 years old bone marrow)
 Risk factors – MGUS  No organ damage detectable
 Plasma cell neoplasm produces monoclonal paraprotein (immunoglobulin)
o IgG (50%), IgA (25%) Monoclonal Gammopathy of Undetermined Significance (MGUS)
o Bence Jones myeloma (free light chains [e.g. kappa, lambda] excreted in urine) (20%)
 BM infiltration → suppression of hematopoiesis → leukopenia, thrombocytopenia, anemia  No clinical complications and the proportion of plasma cells in the
 Cell proliferation → net osteolysis & calcium loss from bone → hypercalcemia marrow is normal (<4%) or only slightly raised (4 – 10%)
 ↑ Serum viscosity → hyperviscosity syndrome (more common in Waldenstorm’s  Occurs in 1% of normal population > 50 years; 3% > 70 years
macroglobulinemia)  Benign disorder; Absent underlying lymphoproliferative disorder
 Renal insufficiency 2O to myeloma cast nephropathy (most common cause; monoclonal light or myeloma
chains clog the renal tubules causing intratubular cast formation and toxicity). Other causes  Overproduction of any Ig type
Etiology &
include amyloidosis, monoclonal immunoglobulin deposition disease (MIDD), both of which  Usually asymptomatic. No CRAB findings.
Pathophysiolgy
cause glomerular injury and nephrotic syndrome  Bone marrow analysis shows < 10% monoclonal plasma cells.
 Lytic bone disease in patients with myeloma include:  M–protein < 3g/dl (i.e. 30g/L) & stable (stationary)
o IL-6 – growth factor for plasma cell; may also have direct stimulatory effect on osteoclasts  1–2% risk per year of transitioning to multiple myeloma
o RANKL and Osteoprotegerin (OPG) – RANKL produced by myeloma cells → production of  Diagnostic Criteria for Multiple Myeloma:
osteoclast activating factor (OAF) o Monoclonal protein in serum or urine
o Macrophage inflammatory protein 1a (MIP1) – Although MIP1 can induce osteoclasts o ≥ 10% clonal plasma cells in bone marrow or soft tissue / bone
independent of the effects of RANKL, it also may enhance the effects of both IL–6 & RANKL. plasmacytoma
o IL–3 – stimulates osteoclasts and inhibits osteoblast formation through Activin A, a factor o End – organ damage (CRAB)
produced by marrow macrophages; Osteoblast dysfunction  Hypercalcemia
Clinical Features  Bone Marrow infiltration – bone pain, pathological fractures; N.B. in addition to the classic  Renal Insufficiency
 punched out skeletal lesions, MM may present as rapidly–progressive, generalized bone loss
(due to increased levels of osteoclast–activating factor secreted by neoplastic cells) resembling
primary osteoporosis, and leading to fragility fractures
 Constitutional symptoms (fever, malaise, weight loss)
 Recurrent infections (susceptibility to encapsulated organisms e.g. Strep. Pneumonia,
Haemophilus Influenza) – due to immune dysregulation and hypogammaglobulinemia
o Bacterial URTI and UTIs are common
 Neurologic Symptoms (e.g. peripheral neuropathy, paresthesias) – plasmacytoma infiltration or
paraneoplastic effects and are not usually present at initial diagnosis
 Features of hypercalcemia: polyuria (osmotic diuresis due to Ca in filtrate), polydipsia,
constipation, anorexia, nausea, weakness, confusion, altered sensorium
Investigations  Organ damage (“CRAB”)
o Normochromic normocytic Anemia (<10mg/dL)
o Renal insufficiency (creatinine clearance < 40 mL/min or serum creatinine > 2 mg/dL)
o Hypercalcemia from osteolytic bone lesions (> 11 mg/dL) – 25% of cases @ time of  Anemia (usually normocytic)
diagnosis; may be asymptomatic if < 12 mg/dL; constipation, muscle weakness  Bone Pain (usually due to lytic lesions)
o Bone – “punched out” osteolytic lesions / osteopenia (osteoclast activation) on imaging
(low–dose whole body CT) & skeletal survey with plain X–ray
 Axial skeleton (vertebrae, ribs), long bones (proximal ends)
 Generalized osteopenia (20%)
 Pathological fractures / vertebral compression fracture
 Cross–sectional imaging with whole body CT (without contrast), MRI, or PET scan
preferred & recommended over plain radiographs / skeletal survery because
these studies are far more sensitive
 ± Elevated erythrocyte sedimentation rate (ESR)
 Neutropenia, thrombocytopenia in advanced disease
 Hyperuricaemia Figure 1: 1a. BM in multiple myeloma showing large numbers of
 Hyperproteinemia & Low serum albumin (in advanced disease) plasma cells with abnormal forms (Myeloma cells, one binucleate
 Serum β2 microglobulin – prognostic marker (not important in diagnosis)
 Serum alkaline phosphatase (ALP) – usually normal (except following pathological fractures)
o N.B. In metastatic malignancies (an important differential), ALP usually high
 Serum/Urine protein electrophoresis – Monoclonal paraproteinemia (M–spike)
o M protein > 3g/dl (i.e. 30 g/L) (distinguishes it from MGUS where M protein < 3 g/dl)
o Paraprotein gap (serum protein – serum albumin > 4)
 Peripheral blood smear – rouleaux formation, abnormal plasma cells
 Serum free light chain analysis
 BM biopsy (confirmatory) – ≥ 10% clonal bone marrow plasma cells in biopsy (DIAGNOSTIC)
o N.B. patients with patchy bone marrow involvement can sometimes have normal biopsies
 Urinalysis:
o Patients with cast nephropathy often have normal urinalysis with little proteinuria (UA
detects albumin, but not light chains of myeloma kidney) – may show evidence of granular
casts but typically bland urinalysis
o If glomerular injury from amyloidosis or MIDD (monoclonal Ig deposition disease), may have
hematuria and proteinuria → possible nephrotic syndrome
  24–hour urine collection (protein, creatinine clearance)
 Stage I (median survival > 5 years) Asymptomatic/Smoldering Myeloma:
o β2 microglobulin < 3.5 mg/L AND albumin ≥ 3.5 g/dL  M protein > 3g/dl (i.e. 30 g/L) (distinguishes it from MGUS [< 3 g/dl in MGUS])
 Stage II (median survival 3 – 4 years) And/or:
o β2 microglobulin 3.5–5.5 mg/L + any albumin OR  ± > 10% plasma cells in marrow (Marrow plasmacytosis)
International
o β2 microglobulin < 3.5 mg/L AND albumin < 3.5 g/dL  No CRAB (no evidence of organ damage)
Staging System
 Stage III (median survival 2 – 3 years)  No treatment necessary
o β2 microglobulin > 5.5 mg/L  N.B. MRI more useful than skeletal survey in assessing prognosis in
early/asymptomatic (“smoldering”) myeloma, identifying focal and diffuse BM
involvement amenable for biopsy, and monitoring disease progression
Management  Asymptomatic patients: watch and wait, unless patients have ≥ 60% clonal cells, excessive free light chains or ≥ 1 bone lesion
 Symptomatic patients
o Standard and intermediate risk HSCT eligible: induction therapy followed by autologous HSCT (hematopoietic stem cell transplantation)
o HSCT ineligible: chemotherapy alone (e.g., dexamethasone and lenalidomide)
 Specific:
Newly- diagnosed:
 Intensive therapy:
 Patients < 65 years with good renal function
 Chemotherapy to reduce tumour burden followed by autologous SCT
 Avoid combinations with Melphalan as it will damage stem cells
 Drugs include: thalidomide (useful in 1st line therapy and management of relapsed disease), dexamethasone, bortezomib (Velcade), lenolidamide
(thalidomide analogue), cyclophosphomide, doxorubicin
 Maintenance treatment: thalidomide, lenolidamide, bortezomib (useful in refractory disease; inhibits the cellular proteasome and NF-κB activation)
 Bortezomib MOA – MM cells are particularly susceptible to proteasome inhibition (due to cytotoxic effect of accumulated damaged & mistfolded
proteins), because they generate extremely high quantities of secretory proteins (e.g. monoclonal immunoglobulins), some of which misfold and
aggregate within the endoplasmic reticulum.
 Increased stress on the endoplasmic reticulum triggers an unfolded protein response that eventually leads to activation of caspases and cellular
apoptosis
 Non–intensive therapy:
 Elderly patients
 Melphalan, prednisone, thalidomide (MPT)**
 Thalidomide and dexamethasone
 Thalidomide contraindicated if low number of B & T cells, and pregnancy
 Lenolidamide and dexamethasone
 Cyclophosphamide
 Relapsed disease:
 Time after initial treatment (e.g. 6 months [try different drug therapy] vs. 5 years [can repeat drug therapy])
 Drugs used in initial treatment
 Supportive Therapy – bisphosphonates, blood transfusions, Granulocyte-colony stimulating factor (G-CSF) and erythropoietin (EPO)
o Anaemia – transfusion with pRBC; erythropoietin
o Renal failure – hydration; treat underlying cause
o Spinal cord compression / Compression paraplegia (medical emergency – permanent neurological deficit) – Decompression laminectomy or radiotherapy
o Bone disease & hypercalcaemia – bisphosphonates (pamidronate, clodronate or zoledronic acid);
o Acute hypercalcaemia – saline diuresis + bisphosphonates (helps to reverse bone resorption)
 o Hyperuricaemia – allopurinol (+ hydration as well)
o Bleeding – caused by paraprotein interference with coagulation and hyperviscosity syndrome may be treated by repeated plasmapheresis
Complications  Hypercalcemic Crisis, Hypercalciuria (Nephrocalcinosis)
o Treatment with hydration, & dexamethasone (mild), bisphosphonates (moderate & severe)
 Hyperviscosity Syndrome
o Typically due to increased serum protein content with large molecular size, abnormal polymerization, & abnormal immunoglobulin shape → impaired
microcirculation
o Nasal or oral bleeding (mucosa hemorrhage due to dysfunctional platelet aggregation)
o Blurry vision, neurologic symptoms (e.g. confusion, headache, dizziness, vertigo, nystagmus, hearing loss),
o Severe cases can cause somnolence, coma, seizures, and heart failure
o Plasmapheresis for symptomatic patients
o N.B. more common in Waldenstorm macroglobulinemia (due to elevated IgM)
 Thromboses – ↑ risk of arterial (e.g. stroke / transient ischemic attack, myocardial infarcation) & venous thrombosis
 Light chain–related (AL) amyloidosis: light chains can accumulate as amyloids and may lead to restrictive cardiomyopathy, renal insufficiency, macroglossia,
malabsorption syndromes, polyneuropathy and normocytic anemia
 Infections (e.g. pneumonia, UTI)
o Highest risk during the 1st 3 – 4 months of therapy
o Vaccines, prophylactic antibiotics during therapy to help prevent infections
 Skeletal Lytic Lesions &/or Pathologic Fractures
 Myeloma Light chain Cast Nephropathy (Myeloma Kidney) – most common cause of kidney disease in MM
o Light chains (e.g. kappa, lambda) directly toxic to renal tissue and protein complex (obstructive cast) formation in the distal nephron leads to tubular obstruction
o Fatigue, peripheral edema and dyspnea, oliguria
o ↑ BUN, ↑ Creatinine; dipstick negative for protein but quantitative protein concentrations (spot or 24 – hour turbidimetric assay) will be elevated
o Confirmed by a markedly positive urine sulfosalicylic acid test, urine protein electrophoresis, and/or free light chain immunnoassays
o Treatment:
 Treatment of multiple myeloma (chemotherapy) and hypercalcemia (fluids & bisphosphonates)
 Forced diuresis and removal of offending agents (e.g., NSAIDs)
 If progression to end–stage renal disease (ESRD) occurs: dialysis, plasmapheresis or transplantation.
Monoclonal Immunoglobulin Deposition Disease (less common)
o Intact immunoglobulins or heavy &/or light chains deposit on the kidney basement membranes, resulting in glomerular disease and nephrotic syndrome
o Therefore, large intact immunoglobulins (and heavy chains) can enter the urine; however albumin (which passes through the injured glomerulus) would be
detected on urine dipstick (c.f. to Light chain cast nephropathy [Myeloma kidney] above)

 Waldenstrom’s macroglobulinemia (Lymphoplasmacytoid Lymphoma)

o A type of indolent non-Hodgkin B-cell lymphoma / lymphoproliferative disorder associated with abnormal production of monoclonal IgM paraprotein (M –
protein)
o Peripheral neuropathy; No CRAB findings
o Main risk factor is MGUS
o Overproduction of IgM (macroglobulinemia) with Hyperviscosity syndrome (recall IgM is a pentamer that is mainly intravascular → increased serum
viscosity):
 Headache, Blurry vision
 Raynaud phenomenon
 Retinal hemorrhages
 o Generalized Lymphadenopathy
o Increased risk of bleeding
 Due to dysfunctional platelet aggregation in hyperviscosity (result of macroglobulin interference with coagulation factors and platelet functions)
o Increased serum protein with M spike comprised of IgM (> 3 g/dL or > 30 g/L)
o ↑ ESR, ↑ uric acid, ↑ LDH, and ↑ alkaline phosphatase, ± peripheral blood lymphocytosis
o Bone marrow biopsy and aspirate: abnormal plasma cells with Dutcher bodies (periodic acid–Schiff positive, intranuclear inclusions of IgM deposits)
o Treatment – Median survival is 5 years; generally poor response to therapy
 Rituximab (anti–CD20) + cyclophosphamide, fludarabine (or other purine analogue), bendamustine or bortezomib (but is omitted if there is
hyperviscosity syndrome).
 Acute hyperviscosity syndrome – plasmapheresis
 Langerhans Cell Histiocytosis
o Proliferative disorder of dendritic (Langerhans) cells from monocyte lineage
o Peak incidence: 5 – 10 years
o Pathophysiology – histiocyte (macrophages within tissue) proliferate and infiltrate one or more organ systems
 Cells are functionally immature and do not efficiently stimulate primary T lymphocyte via antigen presentation
o Clinical Findings
 Lytic bone lesions (e.g. skull [most common], jaw, femur) consisting of Langerhans and immune cells
 Asymptomatic lesions; local pain & overlying tender mass; Pathologic fractures
 Skin lesions (purplish papules, eczematous rash)
 Recurrent otitis media and mastoid swelling
 Lymphadenopathy, hepatosplenomegaly
 Pulmonary cysts / nodules
 Central Diabetes Insipidus (polyuria, hypernatremia)
o Diagnosis
 X-rays – “punched out” lytic bone lesions with or without sclerosis in child
 Langerhans cell on bone or skin biopsy
 Cells express S – 100 (mesodermal origin) and CD1a
 Birbeck granules (“tennis rackets” on EM) are characteristic
o Treatment
 Solitary lesions can be observed
 CTX (prednisone ± vinblastine)
 Lesions near the sphenoid, orbital, ethmoid, or temporal bones require CTX
 Desmopressin for Diabetes Insipidus

Common causes of thrombocytopenia

Decreased platelet  Bone Marrow Suppression  Bone Marrow Infiltration
production o Chemotherapy & immunosuppressants o Metastatic Cancer
o Radiotherapy o Hematologic Malignancy
o Chronic Alcohol use o Histiocytosis
o Drug – induced o Sarcoidosis
 Bone Marrow Failure o Myelofibrosis
o Myelodysplasia (especially for age > 60) o Gaucher disease
o Aplastic Anemia o Amyloidosis
o Paroxysmal Nocturnal Hemoglobinuria  Infections (e.g. EBV, HBV, HCV, HIV, CMV, Parvovirus B19, RMSF, Ehrlichiosis, TB,
  Congenital (e.g. Fanconi Syndrome) Tick disease, Histoplasmosis)
 Nutritional – Vitamin B12 or folate deficiency
Increased platelet  Connective Tissue Disorders  Non–immune
destruction o Systemic Lupus Erythematosus o Consumption
o Antiphospholipid Syndrome  vWD 2B
o Rheumatoid Arthritis  Bleeding
 Medications  Kassalbach Merritt (vascular tumour)
o Antiplatelets – o Destruction
 GP llb/llla inhibitors – abciximab (can also cause psuedothrombocytopenia),  Disseminated Intravascular Coagulation
eptifbatide, tirofiban  TTP–HUS (Thrombotic Thrombocytopenic purpura – Haemolytic Uremic
 Clopidogrel (P2Y12 Receptor Blocker) Syndrome)
o Antiarrhythmics – digoxin, dipyridamole  ECMO
o Antibiotics – Bactrim, vancomycin, piperacillin, gentamicin, meropenem,  LVAD
cilastatin/imipenem, fluconazole, quinine  IABP
o Anti–hypertensives – captopril, furosemide, HCTZ / triamterene, spironolactone  Valvulopathy
o Anti–seizure – phenytoin  Dialysis
o Others – drospirenone / ethinylestradiol, famotidine, tonic water (quinine),  Preeclampsia
vaccines (e.g. HBV, influenza)  HELLP Syndrome – T3 (3rd trimester), hemolytic anemia, thrombocytopenia,
 Immune Destruction elevated transaminases
o Idiopathic thrombocytopenic purpura  Acute Fatty Liver of Pregnancy – T3 (3rd trimester), nausea, vomiting,
o Heparin – induced thrombocytopenia epigastric pain, malaise, and elevated transaminases
o Vaccine – Induced thrombotic thrombocytopenia
o Post – transfusion purpura
Other  Dilutional due to:
o Massive red blood cell transfusion
o Physiologic in pregnancy T2 & T3 (gestational thrombocytopenia)
 Splenic sequestration

 Heparin Induced Thrombocytopenia

o New–onset thrombocytopenia in the setting of heparin with normal coagulation studies
 Risk Factors
 Unfractionated heparin (UFH) >> enoxaparin (LMWH) which has a much
lower risk of HIT
 Longer duration of heparin use
o Pathophysiology –
 Heparin induces a conformational change to platelet surface protein (platelet
factor 4), which creates a neoantigen
 Immune system responds by forming an IgG autoantibody (Heparin–PF4 +
antibody immune complex). HIT antibodies then coat platelet surfaceS, causing:
 Thrombocytopenia – the reticuloendothelial system (largely the spleen)
removes HIT antibody–coated platelets → mild–to–moderate
thrombocytopenia (average nadirs of 60,000 /mm3)
 o Additionally thrombus formation causes platelet consumption
o Severe thrombocytopenia (<20,000/mm3) is uncommon
 Thrombus – HIT antibodies activates platelets, resulting in platelet aggregation and the release of procoagulant factors →
high risk (as high as 50%) for arterial and venous thrombosis.
o Venous thrombosis in the leg veins, cardiac vessels, and skin (at the site of heparin injection) is common.
o Arterial thrombosis may occur in the heart, limbs, or CNS
 Type II Hypersensitivity reaction
o Type I HIT – seen in 10% to 30% of patients given heparin, was characterized by a benign thrombocytopenia
 Occurs due to a non–immune direct effect of heparin on platelet activation and usually presents within 2 days of heparin exposure.
 Heparin – induced platelet clumping
 Platelet count nadirs > 100,000 mm3, and then normalizes with continued heparin therapy and there are no clinical consequences
 resolves spontaneously over several days without intervention
 Usually Asymptomatic
o Type II HIT – affects 5% of patients exposed to heparin
 More serious immune–mediated disorder due to antibodies to platelet factor 4 (PF4) complexed with heparin → platelet
aggregation, thrombocytopenia & thrombosis (arterial &/or venous). Suspected with heparin exposure > 5 days & any of the
following:
 Plt usually drop >50% from baseline, with a nadir of 30,000 – 60,000/ μL
 Usually presents 5 – 10 days after initiation of heparin therapy (or ≤1 day after initiation, if prior heparin exposure within
30 days, e.g. from previous hospital admission)
 ± Arterial or Venous thrombosis (as high as 50% in
untreated HIT)
o Life–threatening consequences (e.g. limb
ischemia, stroke)
 Necrotic skin lesions at heparin injection sites
 Acute systemic (anaphylactoid) reactions after IV
heparin bolus – Fever, chills, dyspnea
 Overt bleeding is rare (can see bleeding at injection
sites)
o Diagnosis
 CBC – drop in platelet count by > 30% (irrespective of absolute platelet count)
 ↑ bleeding time
 Normal PT/PTT (PTT may be increased)
 ELISA – Presence of anti-PF4-heparin (antiplatelet factor 4 antibody testing)
 Serotonin release assay – gold standard confirmatory test
 Enzyme immunoassay
 N.B. Start treatment in suspected cases prior to confirmatory test (ELISA will take days to come)
o Therapy
 Stop all heparin products – Platelet count typically normalize 2 – 7 days after stopping heparin
  Start a direct thrombin inhibitor (e.g. argatroban, lepirudin, and bivalirudin) or fondaparinux (synthetic pentasaccharide)
 N.B. Transition to warfarin when platelets are back at baseline
 N.B. Warfarin is used for anticoagulation maintenance in patients with HIT but only after the patient has received another
anticoagulant and Plt > 150,000/mm3 (with the non – heparin anticoagulant continued until INR is therapeutic)
 Initial treatment with warfarin is contraindicated in patients with HIT as it rapidly lowers protein C levels, which may
transiently increase the risk of thrombus
 N.B. Direct Oral Anticoagulants, DOAC (e.g. apixaban) can also be considered
 N.B. Platelet infusion is contraindicated – may worsen thrombosis
o Prognosis – mortality 5–10% in patients with HIT type II from thrombosis
o Prevention – avoid heparin–containing products for life due to risk of recurrence
o Complications – thrombosis
 Warfarin (Coumadin)
o MOA – ↓ hepatic synthesis of vitamin K–dependent clotting factors (II, VII, IX, X; protein C &S)
 Prevents the reduction of vitamin K, a necessary step in the synthesis of clotting factors via inhibition of vitamin K epoxide reductase
→ inhibition of γ-carboxylation of clotting factors
 Affects extrinsic pathway (thus monitor warfarin with PT, INR)
o Risk of bleeding–associated complications, particularly intracranial bleed. ICH requires
urgent warfarin reversal to prevent propagation of hemorrhage. This is achieved by
administering the following:
 Prothrombin complex concentrate (PCC), which contains vitamin K–dependent
clotting factors and normalizes INR in less than 10 minutes after administration
 Intravenous Vitamin K, which results in sustained warfarin reversal but takes 12
– 24 hours for full effect. Because of this delayed effect, vitamin K is always used
with clotting factors replacement
 N.B. FFP (Fresh frozen plasma) is considered 2nd line for replacing vitamin K–
dependent clotting factors due to the large volume (often > 2L) required & the
delay for blood compatibility tests. FFP is typically used when PCC is
unavailable
o Teratogenic – bone dysmorphogenesis
o Drug interactions
 P450 metabolism
 inhibitors → ↑ PT (unchecked warfarin activity)
o decrease in P450 degrades less warfarin and levels rise
o mnemonics SICKFACES.COM
 Sodium valproate, Isoniazid, Cimetidine, Ketoconazole
 Fluconazole, Alcohol (binge drinking), Chloramphenicol, Erythromycin, Sulfonamides
 Ciprofloxacin, Omeprazole, Metronidazole
 P450 inducers → ↓ PT (inhibits activity of warfarin)
o increase in P450 degrades more warfarin and levels fall
 o mnemonics BS CRAP GPS "induces" rage
 Barbiturates, St John's Wort
 Carbamazepine, Rifampin, Alcohol (chronic), Phenytoin
 Griseofulvin, Phenobarbital, Sulfonylureas
 ASA, sulfonamides, and phenytoin – displace warfarin from plasma proteins, leading to increased free fraction → ↑ PT
 Cholestyramine – ↓ oral absorption; due to low pKa

WARFARIN INTERACTIONS
Mechanism Examples
 Metronidazole
Alteration of intestinal flora
 Fluoroquinolones
 Azoles (e.g. ketoconazole)
↑ Warfarin effect
CYP2C9 inhibition  Amiodarone
(↑ INR)
(i.e. Cytochrome P450 2C9 inhibition)  Sodium valproate, Isoniazid, Cimetidine, Ketoconazole, Fluconazole, Alcohol (binge drinking),
Chloramphenicol, Erythromycin, Sulfonamides, Ciprofloxacin, Omeprazole, Metronidazole
↓ Vitamin K recycling  Acetaminophen (aka Paracetamol)
 Rifampin, Phenytoin
CYP2C9 induction
 Barbiturates, St John's Wort, Carbamazepine, Rifampin, Alcohol (chronic), Phenytoin,
↓ Warfarin effect (i.e. Cytochrome P450 2C9 induction)
Griseofulvin, Phenobarbital, Sulfonylureas
(↓ INR)
↑ Coagulation factors  Oral Contraceptives
↑ Vitamin K ingestion  Green leafy vegetables
INR – independent Inhibition of platelet function  NSAIDs, clopidogrel
interaction ↑ Bleeding (unknown mechanism)  Ginkgo biloba

 Superior sagittal sinus thrombosis

o Rare condition
o Risk Factors – Association with:
 Trauma
 Infection
 Hypercoagulation
 Vasculitis
 Nephrotic Syndrome
 Pregnancy
 Severe Dehydration
o Clinical Features
 Severe headache and associated conditions as above
 Hemiparesis with asymmetry in DTRs, Papilledema, Seizures
 Absent meningeal signs
o Investigations
 CT Brain & MRI venography
 Thrombus in superior sagittal sinus
 ± Small hemorrhagic foci in hemispheric white matter, contralateral to side of hemiparesis
o Foci secondary to venous hypertension
o Treatment – Anticoagulation with heparin (irrespective of area of hemorrhagic infarction)
o
 BLEEDING DISORDERS – COAGULATION & PLATELET DISORDERS
Disseminated Intravascular Coagulation (DIC) Primary Thrombotic Microangiopathies (TMAs)

 Primarily adult patients (median age ∼ 40)

Thrombotic Thrombocytopenic Purpura (TTP) Haemolytic Uremic Syndrome (HUS)
Epidemiology  Acquired Coagulation Disorder / consumptive coagulopathy → inappropriate  Mainly children < 5 years of age
widespread clotting activation  More common in women and black
populations
Etiology  Infections  ADAMTS13 deficiency → uncleaved vWF  Bacterial exotoxins
o Sepsis (more commonly gram negative organisms) multimers → platelet trapping & activation o Shiga–like toxin (verotoxin) from
o Viral Infections o Acquired TTP (∼ 95%): enterohemorrhagic E. coli (EHEC
o Rickettsial infections  Autoantibodies against ADAMTS13, a O157:H7 serotype)
o Malaria vWF–cleaving metalloprotease  Usually transmitted via
 Severe traumatic injury o Congenital TTP (∼ 5%): contaminated foods, e.g.,
o Acute traumatic coagulopathy  Gene mutations resulting in deficiency undercooked beef or raw leafy
o Traumatic brain injury of ADAMTS13 vegetables
o Crush injuries  N.B. ADAMTS13 is a plasma metalloprotease  ~15% of children infected with
o Burns responsible for cleaving ultra–large strings of E. coli O157:H7 will develop
o Fat embolism vWF off the vascular endothelial wall HUS!
o Surgery  Risk factors o Shiga toxin produced by Shigella
o Rhabdomyolysis o Drugs (quinine, ticlopidine, clopidogrel, dysenteriae
 Malignancy and cyclosporine)  Streptococcus pneumoniae infection
o Solid Tumours – often non–symptomatic type (i.e. latent DIC / chronic DIC); o Pregnancy
Mucin–producing  Associated with ADAMTS13 deficiency
 e.g. pancreatic, gastric, ovarian, breast, Non–Small Cell Lung Cancer that becomes more pronounced with
 Often secrete tissue factor into blood, which intermittently triggers increasing gestational age & persists
coagulation cascade into postpartum period; may
o Hematological – Leukemia (e.g. acute promyelocytic leukemia [APL], acute precipitate TTP
myelocytic leukemia) o Systemic disease: cancer, HIV, SLE,
 Organ Failure infections
o Acute Pancreatitis o Malignancies
o Fulminant hepatitis
o Liver cirrhosis
o Acute hepatic necrosis
o ARDS (Acute Respiratory Distress Syndrome)
 Obstetric complications (e.g. PPH, placental abruption, amniotic fluid embolism,
retained products of conception, Preeclampsia, HELLP syndrome)
o Significant bleeding → release of tissue factor (thombroplastin) →
uncontrolled activation of coagulation cascade & a consumptive coagulopathy
 Toxins – Snake bites, Amphetamine overdose
 Immunologic – Acute hemolytic transfusion reaction (AHTR), Transplant reaction
(e.g., graft–versus-host disease ), extracorporeal procedures (e.g., dialysis)
 Vascular malformations – Aortic aneurysms, Vasculitis
 Dilution – Massive bleeding, Massive transfusion, Massive volume
repletion/volume overload
 Drug reactions
 Other – Nephrotic syndrome, New thrombus formation, Hemolysis, Acidosis
Pathophysiology  ↑ cytokines in sepsis → procoagulant excessively triggers coagulation cascade  ADAMTS13 deficiency → excess vWF  Complement–mediated
→ formation of fibrin– or platelet–rich thrombi, thus consuming platelets accumulation on endothelial cell surfaces →  E. Coli O157:H7 infection → Shiga–like
(thrombocytopenia), coagulation factors (evidenced by prolonged PT/INR & platelet adhesion & diffuse microthrombus toxin in systemic circulation → toxin–
PTT), and fibrinogen; hypercoagulation with hyperfibrinolysis which is then formation → blockage of small vessels → mediated endothelial injury
triggered to degrade the clots, which elevates D–dimer (a fibrin degradation RBC fragmentation (hemolysis) and end– (especially in renal glomeruli) →
product) & depletes antithrombin and protein C & S → paradoxical organ damage (especially in brain & kidneys, microthrombus formation → blockage
microthrombi (e.g. PE with pleuritic chest pain, dyspnea, tachypnea) → potentially resulting in acute kidney injury or of small vessels → RBC fragmentation
impaired perfusion & tissue necrosis stroke). (hemolysis) & end–organ damage
 Bleeding & organ damage (e.g. kidneys, lungs)
Clinical Features  Thrombosis, embolism, organ dysfunction, &/or bleeding; LIFE - THRETENING A diarrheal illness (usually bloody) for the
 May appear acutely (e.g., following trauma, sepsis), or subacutely (e.g., latent Pentad of Symptoms (“Nasty Fever Ruined My past 5 – 10 days precedes the onset of
DIC following malignancy)! Tubes”): HUS symptoms in many children. Triad of
 Bleeding manifestations  Fever clinical findings:
o Petechiae, purpura, ecchymoses  Microangiopathic Hemolytic Anemia (↑ LDH, ↓  Microangiopathic Hemolytic Anemia
o Blood oozing from surgical, IV, & venipuncture sites haptoglobulin) – Fatigue, dyspnea, & pallor, o Fatigue, dyspnea, & pallor
o Hematuria Jaundice o Jaundice
o Hematemesis, hematochezia  Thrombocytopenia – Petechiae, mucosal  Thrombocytopenia
o Features of hemoperitoneum, hemothorax bleeding o Petechiae & purpura rarely present
 Thrombotic manifestations  Renal Impairment / failure (c.f. TTP)
o Acute renal failure: oliguria o Hematuria, Proteinuria  Renal Impairment
o Hepatic dysfunction: jaundice o Oliguria, Anuria o Hematuria, proteinuria
o ARDS: dyspnea, rales  Neurological symptoms o Oliguria, anuria
o Pulmonary thromboembolism: dyspnea, chest pain, hemoptysis o Altered MS, delirium o Edema
o Deep vein thrombosis: lower limb edema o Seizures, focal deficits, stroke  Splenomegaly
o Neurological dysfunction: altered mentation, stroke o Headache, confusion, dizziness  Complement–mediated
o Purpura fulminans: DIC with extensive skin necrosis  Splenomegaly microangiopathy (non–diarrheal HUS)
o Waterhouse Friderichsen syndrome: adrenal infarcts → adrenal insufficiency – hereditary disorder marked by
unregulated complement activation &
the formation of platelet–rich thrombi
Laboratory Acute DIC  CBC – Thrombocytopenia, Microangiopathic Hemolytic Anemia
findings  Thrombocytopenia o ↓ haptoglobin, ↑ LDH, ↑ indirect bilirubin, ↑ reticulocytes (> 2.5%)
 ↑ ↑ PT/PTT (due to depletion of clotting factors)  Normal PT & aPTT (or mildly ↑)
 ↓ Fibrinogen (due to consumption)  Normal FDPs & D-dimer levels (or mildly ↑)
 ↑ ↑ FDPs & D–dimer (due to accelerated fibrinolysis)  Negative Coombs test
 Peripheral Blood Smear: Microangiopathic hemolytic anemia– evidenced by ↑  Manual Peripheral blood smear –
total bilirubin levels); thrombi in vasculature shears RBCs (schistocytes) o Schistocytes (up to 10% of RBCs), helmet cells, triangle cells
 Bleeding risk – very high o Low number of platelets, RBC with Howell jolly bodies, nRBC
 Thromboembolism risk – mildly increased  Serum chemistry
Chronic DIC o Hemolytic anemia – ↑ LDH, ↑ indirect bilirubin & ↓ Haptoglobin, ↑ aminotransferases
 Platelets – often normal o ↑ BUN & Cr (impaired renal function)
 Fibrinogen – often normal  Urinalysis – Hematuria, proteinuria
 D–dimer elevated  ADAMTS13 activity and inhibitor testing  Diagnosis of etiology – Shiga toxin stool
 Bleeding risk – mildly increased o ↓ ADAMTS13 activity PCR, stool culture, blood culture
 Thromboembolism risk – very high o Not a routinely available test and should be  Leukocytosis with left shift (as high as
used for confirmation only 50,000–60,000/μL)
Treatment  Treatment of the underlying illness (e.g., antibiotics for infectious diseases,  Monitoring and correction  Avoid antibiotics and antimotility
chemotherapy or surgery for malignant disease) o Fluid status abnormalities agents
 Bleeding and consumptive types o Electrolyte disturbances  Fluid & Electrolyte management
o Platelet concentrate indicated if: o Acid–base abnormalities  Monitor and correct
 Plt < 10,000/mm3 in asymptomatic individuals o RBC transfusions o Fluid status abnormalities
 Plt < 50,000/mm3 with active bleeding or if a surgical procedure is planned  Emergent treatment – Prompt initiation of o Electrolyte disturbances
o FFP if PT or aPTT > 1.5x normal o Plasma exchange therapy – replaces with o Acid–base abnormalities
o Cryoprecipitate if fibrinogen < 150 mg/dL donor plasma which replenishes ADAMTS13 o Blood pressure
o Packed RBCs if: from donor serum and removes the  Blood transfusions
 Massive hemorrhage without hemodynamic response to fluid therapy autoantibodies  Dialysis as indicated for AKI: Up to 50%
 Hb < 7 g/dL  Withdrawal via 16-18 gauge IV catheter of HUS patients require dialysis.
o If acute traumatic coagulopathy→ transfuse pRBC, FFP, and Plt concentrate  Return via 18 gauge IV catheter  Only in refractory cases: plasma
in a 1:1:1 ratio  Plasma exchange with Cryosupernate or exchange therapy
o Synthetic protease inhibitor (e.g., Gabexate®, nafamostat®) FFP  Eculizumab : may be beneficial in HUS
o Antifibrinolytic therapy (e.g., tranexamic acid) – generally avoided due to  Cryosupernate (preferred) or Fresh with neurological symptoms
potential thrombotic complications (e.g. MI, renal artery thrombosis), but in Frozen Plasma replace withdrawn fluid  Post–diarrheal HUS is a nationally
patients with massive blood loss following trauma, has been shown to o Glucocorticoids (e.g., prednisone) notifiable condition.
improve survival o Rituximab (anti CD20) – severe cases
 Organ failure type: natural protease inhibitor (e.g., antithrombin, or o Caplicizumab – antibody against vWF
thrombomodulin [rhTM] administration) o Platelet transfusion should only be reserved
 Non–symptomatic type: heparin for patients who are bleeding or require an
invasive procedure.
 Generally not recommended because
additional platelets may worsen the
ongoing intravascular thrombosis
Prognosis   10 – 20% mortality; Tx should be presumptive  With treatment, mortality rate of HUS
in a timely fashion is low: < 5%
 Without emergent plasma exchange, mortality  Long–term renal sequelae occur in 5–
~83 – 90% 25% of children with HUS

Figure 2: Thrombotic Microangiopathies - Pathophysiology

 Primary Thrombotic Microangiopathies (TMAs)
o TTP
o Shiga –toxin mediated HUS (Shiga – toxin stool PCR)
o Atypical HUS = any thrombotic microangiopathy without severe ADAMTS13 deficiency, Shiga–toxin producing bacteria or streptococci
 Extremely rare
 Most cases of aHUS are genetic, although some may be acquired due to autoantibodies or occur for unknown reasons (idiopathic)
o Complement – mediated TMA
 Pathophysiology
 Hereditary deficiency of or acquired autoantibody against Complement factor H or complement factor H–related proteins →
uncontrolled complement system activation on vasculature
 Features
 HTN & AKI often present
 CNS symptoms are the most common extra–renal manifestation
o Drug – induced TMA
 Immune–mediated
 Quinine (most common)
 Gemcitabine & oxaliplatin
 Quetiapine
 Dose–dependent
 Various chemotherapuetic agents
 Immunosuppressive agents (e.g. cyclosporine & tacrolimus)
 VEGF mutations (e.g. bevacizumab)
 Opioids taken inappropriately & cocaine
o Rare hereditary disorders of B12 metabolism or Coagulation
 Cobalamin C deficiency (MMA (methylmalonic acid) /homocysteine)
 Coagulation – mediated (thrombomodulin, plasminogen, DGKE mutations)
 Secondary Thrombotic Microangiopathies
o HELLP & Malignant HTN
o Systemic Infections, Malignancies, & Autoimmune disorders
o Bone Marrow Transplantation (BMT) or Solid Organ Transplant (SOT) – related
 Evans Syndrome
o Thrombocytopenia with Microangiopathic Hemolytic Anemia (MAHA)
o However ADAMTS levels are normal
o No Schistocytes
o Treated with Corticosteroids
o Better prognosis than standard Thrombotic Thrombocytopenic Purpura
 Immune Thrombocytopenic Purpura (Idiopathic) – ITP
o Diagnosis of exclusion in isolated thrombocytopenia (< 150,000/mm3)
o Etiology
 Primary ITP: inciting factor such as preceding viral infection that causes an autoimmune reaction
 Secondary ITP: associated with lymphoma, leukemia, SLE, HIV, HCV
o Epidemiology:
  common disorder, especially in children and women of childbearing age
o Pathophysiology:
 IgG autoantibodies against GP IIb/IIIa membrane proteins on platelets (Anti – G2b3a antibody–mediated platelet destruction ~ 80% of cases) →
opsonization with platelet–antibody complex removed from circulation by spleen → ↓ platelet count → bone marrow megakaryocytes and
compensatory increase in platelet production
 Circulating platelets are rapidly removed by the autoantibodies, limiting the role of platelet transfusions
o Clinical features
 Commonly asymptomatic
 Symptoms depend on platelet counts (e.g. easy bruising, petechiae, bleeding, hematuria, melena); Many patients have minimal bleeding
symptoms despite extremely low platelet counts (<5,000/mL)
 100,000 – 150,000 /mm3 → asymptomatic thrombocytopenia
 50,000 – 99,000 /mm3 → Often asymptomatic, prolonged bleeding may occur following trauma or surgery
 30,000 – 49,999 /mm3 → Prolonged bleeding following trauma or surgery are more likely; scattered petechiae, rarely purpura
 5,000 – 29,999 /mm3 → Spontaneous bleeding, disseminated petechial bleeding in skin and mucosa, easy bruising
 < 5,000 /mm3 → Hematologic emergency
 Acute ITP (typically in children): following a viral infection
 Usually self–limited—80% of cases resolve spontaneously within 3 – 6 months
 Chronic ITP (typically women of childbearing age): insidious onset or incidental finding
 Typically becomes chronic in adults; spontaneous remissions are rare
 N.B. if isolated thrombocytopenia in pregnancy in 1st trimester, usually indicative of ITP with platelet count usually < 70,000/mm3 (c.f.
Gestational Thrombocytopenia which is physiologic & occurs late in pregnancy [i.e. NOT 1 st trimester] with platelet count typically
between 100,000 – 150,000/mm3)
 Spleen is typically normal sized
o Diagnosis
 CBC – isolated thrombocytopenia
 ± prolonged bleeding time
 Peripheral blood smear: Platelets are normal to large (megathrombocytes) in size.
 HIV & HCV screening
 Consider bone marrow biopsy in atypical cases (typical bone marrow biopsy findings in ITP include increased megakaryocytes)
 Additional testing as required to rule out other etiologies of thrombocytopenia
o Treatment
 Children
 If no bleeding or cutaneous symptoms only (e.g. bruising/petechiae) → observation regardless of platelet count
 If mucosal bleeding (e.g. gastrointestinal) or increased risk of bleeding (e.g., contact sports, coagulopathy): glucocorticoids, IVIG or anti–
D (if Rh positive and Coombs–negative)
 Adults
 Observation if no cutaneous symptoms AND platelet count of ≥ 30,000/mm3
 If Bleeding OR Platelets < 30,000 / mm3
o First–line treatment: corticosteroids; majority of adults respond in 1 – 2 weeks
o Alternative (if intolerance to corticosteroids): IVIG or IV Rho immunoglobulin (IV RhIG), or anti–D immunoglobulin
  IV immune globulin (IVIG)—saturates the reticuloendothelial system (RES) binding sites for platelet–bound self–
immunoglobulin, decreasing platelet uptake & destruction by the spleen; typically reserved for patients with active
bleeding
 Anti–D binding to Rh(D)–positive erythrocytes is thought to saturate Fc receptors on macrophages within
reticuloendothelial system, thereby limiting the ability of RES to clear platelets
o Second–line treatment: splenectomy
 Indication: treatment–resistant thrombocytopenia and severe bleeding
 induces remission in 70% to 80% of the cases of chronic, steroid–resistant ITP
 Procedure: minimally invasive, laparoscopic operation is preferred
 Splenectomy removes source of platelet destruction
 Associated risks (e.g. sepsis, thrombosis)
 If splenectomy is contraindicated or ITP remains refractory
o Thrombopoietin receptor agonists: romiplostim, eltrombopag
o Rituximab (anti-CD20)
 In severe cases of ITP (i.e. life–threatening hemorrhage e.g. intracranial bleeding) and platelets < 30,000/mm 3 – platelet transfusion PRN
 Platelet transfusion typically avoided in ITP as it can lead to further platelet destruction by antibodies
 Hypersplenism
o Condition in which spleen becomes increasingly active and then rapidly removes blood cells (either cytopenia of one or multiple cell lines)
 Splenic enlargement due to increased demand of splenic function & excessive splenic sequestration
 Decreased RBC and platelet survival
 Splenomegaly increases the spleen’s mechanical filtering and destruction of red blood cells (RBCs) and often of white blood
cells (WBCs) and platelets.
 Compensatory bone marrow hyperplasia (hyperproliferative state) occurs in those cell lines that are reduced in the
circulation
 May be primary or secondary condition
 Potential for correction of these abnormalities by splenectomy
 Platelets usually remain > 30,000 / μL
o Etiology – essentially any cause of splenomegaly
 Portal Hypertension
 Cirrhosis
 Portal or hepatic vein thrombosis
 Splenic congestion – ?congestive heart failure
 Reticuloendothelial system hyperplasia & Splenic sequestration
 Membrane Defects – spherocytosis, , ovalocytosis, elliptocytosis
 Hemoglobinopathies – early sickle cell anemia, thalassemia major
 Paroxysmal nocturnal hemoglobinuria
 Pernicious anemia
 Hematologic malignancies (lymphomas, leukemias, myeloproliferative disorders): Neoplastic cells cause infiltration of the spleen
leading to splenomegaly.
 Immune hyperplasia – response to infection (viral, bacterial, fungal, parasitic)
  Infectious Mononucleosis
 AIDS
 Viral Hepatitis
 Leishmaniasis
 Trypanosomiasis
 Ehrlichiosis
 Malaria
 Tuberculosis
 Disordered immunoregulation
 Rheumatoid Arthritis (Felty’s Syndrome)
 Systemic Lupus Erythematosus
 Collagen vascular diseases
 Serum sickness
 Immune Hemolytic Anemias
 Immune thrombocytopenia
 Immune neutropenia
 Drug Reactions
 Angioimmunoblastic lymphadenopathy
 Infiltrative disorders (sarcoidosis, amyloidosis, glycogen storage diseases)
 Congenital Coagulation Disorders
Disorder Von Willebrand Disease (vWD) Hemophilia A & B
 Autosomal Dominant  X–linked recessive inheritance (males affected; females usually
 Intrinsic Pathway Coagulation Defect carriers)
 Most common bleeding disorder; usually mild o Haemophila in Females – Possibility of girl with haemophilia
 Due to either quantitative or qualitative deficiency in von Willebrand Factor (vWF) in progeny of carrier female and affected male
 Pathogenesis – impaired platelet adhesion as vWF acts as a bridging glycoprotein  Hyperlyonization
Etiology &
between platelets and endothelial factors at sites of vascular injury  Autosomal dominant inheritance (rare)
Pathophysiology
o vWF also serves as a carrier of factor VIII, preventing its degradation of protein C  Intrinsic pathway coagulation defect
 Most common hereditary clotting factor deficiency to present
clinically
 Hemophilia A – Due to deficiency of Factor VIII:C
 Hemophilia B – Deficiency of factor IX
Clinical Features  Mostly Asymptomatic  Delayed / prolonged bleeding after mild trauma
  Symptom onset variability (e.g. few years after menarche) is based on disease o Hemarthrosis (80%; especially knee), intramuscular
severity hematomas
o Easy bruising & mucocutaneous bleeding (e.g. epistaxis, menorrhagia) o Gastrointestinal or genitourinary tract bleeding
o Ecchymosis (esp. mucosal hemorrhages) → from reduced half–life of factor VIII o Intracranial bleeding
o Excessive bleeding during surgical procedures  Hemophilic Arthropathy (most commonly knee)
 Prolonged bleeding time  ↑ Activated PTT
 Platelet count and PT are normal  Normal Platelet count & PT
 Prolonged aPTT or Normal aPTT (If mild disease or in states of increased vWF Absent or ↓ factor VIII (hemophilia A) or factor IX (hemophilia B)
Investigations synthesis e.g. pregnancy, OCP use, acute stress, thyroid hormone activity
supplementation)
 vWF testing (vWF antigen, ristocetin cofactor activity reduced, factor VIII levels
usually reduced)
 Treatment rarely needed outside of trauma or surgery: only if symptoms occur  Factor replacement (e.g. recombinant Factor VIII for
o Desmopressin – stimulates vWF release from endothelial cells Hemophilia A)
o Recombinant vWF concentrate Desmopressin for mild hemophilia A
Treatment o Other options: Intermediate – purity Factor VIII concentrates (contains vWF + If Factor VIII unavailable, Cryoprecipitate (70–80 units Factor
Factor VIII), cryoprecipitate, OCPs in cases with menorrhagia, antifibrinolytics VIII activity per bag; Factor VIII + Fibrinogen + vWF)
(e.g. aminocaproic acid, tranexamic acid) o Risk of infection with repeated blood product dosage (HTLV–1,
 Avoid aspirin, NSAIDs, and intramuscular injections HIV, Hepatitis B etc.)

 Glanzmann's disease
o Autosomal recessive
o Deficiency of membrane GP IIb/IIIa
o Results in failure of primary platelet aggregation (i.e. no clumping of platelets on peripheral blood film)
 Bernard–Soulier syndrome
o Autosomal Dominant
o Characterized by thrombocytopenia with abnormal giant platelets
o Deficiency of GP Ib
o Defective binding to vWF (i.e. defective platelet adhesion due to absence of GP 1b receptor site)
 Vitamin K deficiency
o Vitamin K is a fat–soluble vitamin that serves an important role in hemostasis, by serving as a cofactor for enzymatic γ –carboxylation of
glutamic acid residues on prothrombin complex proteins
 Body obtains vitamin K exogenously from intestinal absorption of dietary vitamin K and endogenously from bacterial production of
vitamin K in the intestines
 In the liver, epoxide reductase converts vitamin K to activated vitamin K, which acts as a cofactor for the vitamin K–dependent
coagulation proteins (II, VII, IX, X, protein C & S)
 All vitamin K–dependent proteins require calcium as a cofactor.
 Vitamin K deficiency is an acquired bleeding disorder that leads to decreased production of prothrombin complex proteins (factors
II, VII, IX, and X, protein C, and protein S). Neonates require supplemental vitamin K at birth because their bowel lacks the bacteria
that produce vitamin K.
o Etiology – most commonly due to poor dietary intake, intestinal malabsorption, or hepatocellular disease causing loss of storage sites
 Liver normally stores `a 30–day supply of vitamin K, but an acutely ill person with underlying hepatocellular disease causing loss of
storage sites
o Investigations
 Initially increased PT, followed by prolongation of PTT
 Normal platelet count
o Management
 Administration of Vitamin K rapidly replenishes stores with 8 – 10 hours
 Fresh Frozen Plasma may be used for the management of acute hemorrhage in the interim
 Etiologies of Hereditary or Inherited Thrombophilia
o Factor V Leiden mutation (Most common inherited / hereditary thrombophilia – 40 – 50%; 2 – 15% of Caucasians)
 Activated Protein C Resistance – Mutation in factor V makes it resistant to inactivation by APC
  R506Q
 Pathogenesis
 F5 is resistant to inactivation by activated protein C
 Factor V Leiden less severe than inherited mutations in Protein C/S;
o APC can inactivate FVa from two different sites
 Clinical Features
 Venous thrombosis (Heterozygous – 5x; Homozygous – 50x)
 Central retinal vein occlusion
 Hepatic Vein thrombosis
 Recurrent miscarriages (more commonly associated with antiphospholipid antibody syndrome)
 Normal PT/PTT
 Diagnosis
 Coagulation studies
o Screening test on both patient and control plasma. The addition of APC will result in a prolonged activated partial
thromboplastin time (aPTT) in the control plasma, but less prolongation in the patient plasma
 Confirmation via genetic testing
 Tx
 If actively thrombosing – standard heparin → warfarin regimen
 If risk of thrombus anticipated (e.g. pregnancy) – LMWH
 Avoid OCPs
o Prothrombin gene mutation (G20210A)
o Antiphospholipid Syndrome
o Hyperhomocysteinemia
o Protein C & S deficiency
 More likely in cases of unprovoked DVT (i.e. no risk factors such as immobilization, OCP use)
o Antithrombin III Deficiency
 Uremic Platelet Dysfunction – Renal Dysfunction associated with increased tendency to bleed
o Impaired platelet function is the major contributor to this tendency.
o Prolonged bleeding time
o Other coagulation studies (PT, PTT, Plt count) are usually normal
o Correction of platelet dysfunction indicated in patients with active bleed or those who are about to undergo a surgical procedure
 Correction of anemia
 IV Desmopressin
 Simplest and least toxic acute treatment option for prolonged bleeding time in active bleeding
 Acts by increasing release of factor VIII:vMF multimers from endothelium
 Dialysis
 Estrogen Treatment
 Cryoprecipitate infusion
 Associated with infectious complications
 Indicated for cases refractory to desmopressin and blood transfusions
 ACUTE LYMPHOBLASTIC LEUKEMIA ACUTE MYELOID LEUKEMIA
Epidemiology  Peak incidence: 2–5 years  Peak incidence: 65 years

∼ 80% of acute leukemias during childhood are lymphocytic.

 Most common malignant disease in children  80% of acute leukemias during adulthood are myelogenous.

 ♂ > ♀(Male > Female)
Etiology  No identifiable cause or risk factors in most cases  No identifiable cause or risk factors in most cases
 Prior bone marrow damage due to alkylating chemotherapy or ionizing radiation  Pre–existing hematopoietic disorder (most common identifiable cause)
 Adult T–cell leukemia/lymphoma is linked to infection with HTLV. o Myelodysplastic syndromes
 Genetic or chromosomal factors o Aplastic anemia
o Down syndrome o Myeloproliferative disorders (e.g., osteomyelofibrosis, CML)
o Neurofibromatosis type 1  Environmental factors
o Ataxia telangiectasia o Alkylating chemotherapy
o Ionizing radiation
o Benzene exposure
o Tobacco
 Genetic or chromosomal factors
o Down syndrome
o Fanconi anemia
Pathophysiology  Acquired somatic mutations (chromosomal translocations and other genetic abnormalities) in early hematopoietic precursors → clonal proliferation of a lymphoid or
myeloid stem cell line and arrest in cell differentiation and maturation in early stages of hematopoiesis → rapid proliferation of abnormal and dysfunctional blasts
(with impaired apoptosis pathways) → accumulation of leukemic WBCs in bone marrow → disrupted hematopoiesis → leukopenia, thrombocytopenia, & anemia
 Immature blasts enter the bloodstream → infiltration of other organs (particularly liver, spleen, lymph nodes, but also testes, skin, and mediastinum)
Classification  French–American–British (FAB) historical classification of ALL (histopathological  FAB classification for AML
appearance of cells) o M0 – Acute myeloblastic leukemia without maturation
o L1 ALL with small cells (20–30%) o M1 – Acute myeloblastic leukemia with minimal granulocyte maturation
o L2 ALL with heterogeneous large cells (70%) o M2 – Acute myeloblastic leukemia with granulocyte maturation
o L3 ALL with large cells, i.e., Burkitt lymphoma (1–2%) o M3 – Acute promyelocytic leukemia (APML)
 The current WHO Classification (2016) classifies ALL into subtypes of precursor o M4 – Acute myelomonocytic leukemia
lymphoblastic leukemia/lymphoma based on morphologic and genetic factors: o M5 – Acute monocytic leukemia
o B lymphoblastic leukemia with recurrent genetic abnormalities o M6 – Acute erythroid leukemia
 ALL with BCR–ABL o M7 – Acute megakaryoblastic leukemia
 ALL with t(v;11q23)  The WHO classification is based on various factors (e.g., presence of genetic
 ALL with t(1;19)(q23;p13.3) abnormalities or associations to prior chemotherapy/radiation).
 ALL with t(12;21)(p13;q22) o AML with recurrent genetic abnormalities (e.g., translocations)
 Hyperdiploid > 50 o AML with myelodysplasia–related changes
 Hypodiploid t(5;14)(q31;q32) o Therapy–related AML
o B lymphoblastic leukemia, not otherwise specified o AML not otherwise specified
o Precursor T lymphoblastic leukemia/lymphoma o Myeloid sarcoma
 Immunophenotype classification of ALL: based on the origin (B cell or T cell) and o Myeloid leukemia associated with Down syndrome
maturity of the leukemic cells
o B-cell ALL (∼ 80–85% of cases)
 Early (pro–B) ALL
 Common ALL
 Precursor B-ALL
 Mature B-cell ALL (also known as Burkitt leukemia)
 o T–cell ALL (∼ 15–20% of cases)
 Early (pro–T) ALL
 Intermediate–T ALL
 Mature T–cell ALL

 Lymphoblastic proliferation – scant cytoplasm, fine chromatin (N.B. no granules, or  Leukemic Promyelocytes – large basophilic cells with eccentric nuclei and
Auer rods) abundant basophilic cytoplasm containing Auer rods (rod–like
 T–cell ALL – basophilic cell clusters composed of lymphoblasts (large spherical nuclei intracytoplasmic inclusion bodies; present in 50% of cases)
surrounded by thin rim of cytoplasm; nucleus is often indented and shows fine loose o Large blasts (2–4 times the size of RBC)
[non–condensed] chromatin) o Blasts with round or kidney–shaped nuclei, comparatively more
o Large blasts (1.5–3 times the size of RBC) cytoplasm than in ALL
o Blasts with large, irregular nuclei (high nuclear–to–cytoplasm ratio) o Prominent nucleoli
o Inconspicuous nucleoli o Fine granules
o Coarse granules
 The diagnosis of B- or T-cell ALL is confirmed on immunotyping

Clinical Features General Features of Acute Leukemia

 Sudden onset of symptoms and rapid progression (days to weeks)
 Anemia: fatigue, pallor, weakness
 Thrombocytopenia: epistaxis, bleeding gums, petechiae, purpura
 Immature leukocytes: frequent infections, fever
 Hepatomegaly &/or splenomegaly (caused by leukemic infiltration)
 B symptoms – Fever, night sweats, unexplained weight loss  Leukemia cutis (or myeloid sarcoma): nodular skin lesions with a purple or
o Fever in acute leukemia treated as a sign of infection until proven otherwise! gray-blue color
 Painless lymphadenopathy  Fever & lymphadenopathy RARE in AML (c.f. can be common 1st signs in ALL!)
 Bone pain due to leukemic infiltration (presenting as limping or refusal to bear  Gingival hyperplasia (AML subtype M4 and M5)
weight in children)  Signs of CNS involvement, e.g., headache, visual field changes (uncommon)
 Airway obstruction (stridor, difficulty breathing) due to mediastinal or thymic  APML considered medical emergency! – high-risk of pulmonary /
infiltration (primarily in T–cell ALL) cerebrovascular hemorrhage due to consumptive coagulopathy; APL appears
 Meningeal leukemia (or leukemic meningitis) → headache, neck stiffness, visual to promote a bleeding diathesis via activation of tissue factor (DIC) and
field changes, or other CNS symptoms (caused by CNS involvement) increased generation of plasmin (primary hyperfibrinolysis)
  Painless Testicular enlargement (rare finding)
Investigations  CBC –
o Thrombocytopenia, Anemia
o WBC may be elevated, normal, or low (not a reliable diagnostic marker)
 Leukemic hiatus in AML: A gap in the differentiation of WBCs in which there is a high number of blast cells and mature leukocytes but no intermediate forms
 About 50% of patients have significant leukocytosis (> 50,000 / mm3)
 Leukostasis / symptomatic hyperleukocytosis (More common in AML than ALL) –
 Medical emergency most commonly seen in patients with acute myeloid leukemia or chronic myeloid leukemia in blast crisis. It is characterized by an
extremely elevated blast cell count and symptoms of decreased tissue perfusion.
 Hyperleukocytosis more common in patients with myelomonocytic (FAB-M4) leukemia, monocytic (FAB-M5) leukemia, or the microgranular variant of acute
promyelocytic leukemia (FAB-M3)
 Symptoms of leukostasis occur less frequently and typically affect patients with white blood cell (WBC) counts > 100 x 10 9/L (100,000/ μL)
o Main clinical symptoms of leukostasis & causes of early death are related to CNS (~ 40%) and lungs (~ 30%)
o Pulmonary – dyspnea and hypoxia with or without diffuse interstitial or alveolar infiltrates on imaging studies
 Arterial pO2 can be falsely decreased in patients with hyperleukocytosis, since the WBCs in the test tube utilize oxygen.
 Pulse oximetry provides a more accurate assessment of O2 saturation in this setting
o Neurologic – visual changes, headache, dizziness, tinnitus, gait instability, confusion, somnolence, and, occasionally, coma.
 increased risk of intracranial hemorrhage that persists for at least a week after the reduction of white cell count, perhaps from a reperfusion injury as
areas of the brain that were ischemic from leukostasis regain blood flow.
 Non–contrasted CT or MRI is indicated in patients with neurologic abnormalities (caution with IV contrast dye due to possibly impaired renal function
secondary to leukostasis or tumor lysis syndrome, and dehydration)
o Approximately 80% of patients with leukostasis are febrile, which may be due to inflammation associated with leukostasis or concurrent infection.
 Peripheral blood smear:
o presence of circulating blasts (immature lymphocytes) with fine nuclear chromatin, small nucleoli, and scant agranular cytoplasm
o AML: Some subtypes (especially M3, or APL) exhibit Auer rods , which are pink-red, rod-shaped granular cytoplasmic inclusion bodies in malignant immature
lymphocytes (blasts)
 Flow cytometry from the bone marrow distinguishes the cell of origin (B cell or T cell)
 Coagulation studies: rule out DIC (prolonged PT/aPTT, hypofibrinogenemia)
 Electrolytes and metabolic markers: ↑ PO42-, ↓ Ca2+, ↑ K+, ↑ LDH, and ↑ uric acid (increased cell lysis)
 Confirmatory diagnostic tests (Bone Marrow Biopsy)
o AML: > 20% myeloblasts in the bone marrow
o ALL: > 20 – 25% lymphoblasts in the bone marrow
 Additional test
o Cerebrospinal fluid analysis: relevant for diagnosis and treatment of leukemic meningitis
o Chest X–Ray: mediastinal mass in the case of thymic infiltration (occurs primarily in T-cell ALL) or mediastinal lymphadenopathy
o Abdominal ultrasound: organ enlargement (especially the liver and/or spleen)
Histochemistry  Terminal deoxynucleotidyl transferase–positive (TdT+; marker of pre–T & pre–B  Myeloperoxidase – positive
cells)
 Periodic acid-Schiff (PAS) – often positive
Cytogenetics  Philadelphia translocation, t(9,22) – bcr–abl fusion gene (∼ 20–30% of ALL in adults  t(15;17) translocation (particularly acute promyelocytic leukemia (M3 AML)
and only 2–3% of ALL in children)  Philadelphia translocation (< 2% of patients with AML)
 t(12;21): most common specific abnormality in childhood B-ALL
 Hyperdiploidy is common in pre-B-ALL (see prognosis below)
Immunophenotyping  Confirmation (lymphoblast)  The majority of subtypes are positive for CD13, 33, 34, 117, and HLA-DR.
(Flow Cytometry) o TdT+ (lymphoblast marker for precursor T– and B– cell) – both B–ALL & T–ALL
o CD34+ –myeloid / lymphoblast
  B–ALL is usually positive for CD10 (CALLA), CD19, and CD20
 T–ALL is usually positive for CD2–CD8, especially CD3 – usually teenagers
o N.B. most common presentation is a mediastinal mass
Management  Multidrug Chemotherapy – choice of chemotherapeutic agents is based on the cytogenetics of the leukemic cells
o Induction therapy (goal: massive reduction of tumor cell count)
 Duration: 4–6 weeks
 High-dose chemotherapy regimens are effective but usually cause severe side effects.
o Re-induction therapy (goal: massive reduction of tumor cell count)
 Only indicated in case of relapse or failure of primary induction therapy
 Duration: 4–6 weeks
o Consolidation therapy (goal: destruction of remaining tumor cells)
 Begin after complete remission is achieved
 Duration: several months
 Medium doses
 ALL regimen: variable drug regimens (E.g., alkylating agents, anthracyclines, methotrexate)
o Maintenance therapy (goal: maintaining remission)
 Duration: up to 24 months
 Low doses
 ALL regimen: may include methotrexate, vincristine, glucocorticoids
 Allogenic Stem Cell Transplantation if poor prognostic factors (e.g., unfavorable cytogenetics) or patients who do not achieve remission through chemotherapy
 Vincristine  Induction therapy – Anthracyclines antibiotic (e.g., daunorubicin) + Cytarabine
 Glucocorticoids  Addition of ATRA (all–trans–retinoic acid) in APML (promyelocytic leukemia)
 Cyclophosphamide o Works by promoting differentiation of neoplastic cells into mature
 Doxorubicin neutrophils
 L–asparaginase  pRBC transfusion if severe anemia
 CTX – complete remission > 95% of children 985% cured)  Bone marrow transplantation is curative
 Philadelphia translocation – Addition of BCR-ABL tyrosine kinase inhibitor (e.g., imatinib)
Preventative CNS Tx  Intrathecal chemotherapy:
o Immunophenotyped therapy administered directly into the subarachnoid space via spinal tap or a device placed under the scalp
 ALL: indicated for all children to prevent meningeal leukemia (even if no CNS involvement is detected)
 AML: only indicated after diagnostic measures have confirmed CNS involvement
 CNS radiotherapy
o Not routinely used because of associated risk of secondary malignancies, and endocrine (e.g., hypothyroidism, growth hormone deficiency) & neurocognitive (e.g.,
cognitive decline, neuroinflammation) side effects.
o Reserved for patients who do not respond to intrathecal chemotherapy or who develop impingement of important CNS structures (e.g., cranial nerve, spinal cord).
Prognosis  Favourable prognostic Factors  Favourable prognostic Factors
o Low WBC < 50,000/mm3 o t(8;21)
o No CNS involvement o Acute promyelocytic leukemia (APML) with t(15;17)
o Cytogenetics  Unfavourable prognostic factors
 Hyperdiploidy o > 60 years
 t(12;21) → cryptic t(12;21) TEL–AML fusion –N.B. t(12;21) most specific o ↑ LDH
abnormality in childhood B-ALL o FAB M7 (acute megakaryocytic leukemia)
o Hyperploidy o Various translocations, e.g., t(6;9)
o Age 2 – 10 years o Karyotype abnormalities (e.g., trisomy 8, monosomy 5 or 7)
o Pre B–ALL o FLT3 gene mutation
 Unfavourable prognostic factors (easier to memorize) o Complex pattern of aberrations (i.e., > 3 aberrations)
 o Age < 1 year or > 10 years at diagnosis o Immunotyping – CD34, MDR1
o WBC > 50,000/mm3
o CNS or testicular involvement at diagnosis
o Philadelphia chromosome t(9;22) or t(4;11)
o Hypoploidy
o Complex pattern of aberrations (> 3 aberrations)
o Immunotyping – Mature B-cell ALL, Precursor T-cell ALL
Complications  Oncologic Emergencies
o Mediastinal or thymic infiltration (primarily in T-cell ALL) → SVC syndrome, airway compromise
o Febrile neutropenia
o Severe thrombocytopenia or anemia
o Leukostasis
o Tumor Lysis Syndrome
 Tumor lysis syndrome (TLS)
o Rapid destruction of tumor cells leads to a massive release of intracellular components, which subsequently damage the kidneys and may
cause potentially life–threatening renal failure.
o Defined as ≥ 2 of the following:
 Uric acid > 8.0 mg/dL
 Phos > 4.5 mg/dL
 K > 6.0 mmol/L
 Hypocalcemia (iCal < 1.12, corrected < 7.0)
 AKI
o Etiology – most commonly occurs after initiating cytotoxic treatment of ALL, AML, or high-grade lymphomas e.g. NHL
 Risk Factors
 Tumours with high burden or rapid turnover
 Cytotoxic chemotherapy or immunotherapy initiation
 An LDH elevation related to a high cell turnover rate prior to cancer treatment may indicate an increased risk of TLS
o Pathophysiology:
 tumor cell lysis → release of intracellular components (e.g., K+, PO43-, nucleic acid) into the bloodstream → severe electrolyte
disturbances (“PUKe calcium” for the electrolytes affected in tumor lysis syndrome: Phosphorus, Uric acid, and potassium (K+) are
Elevated; Calcium is decreased)
 The breakdown of nucleic acids releases large amounts of uric acid and leads to acute kidney failure, which limits clearance of
potassium, phosphorus, and uric acid.
 Hyperphosphatemia: PO43- binds Ca2+ & forms calcium phosphate crystals that obstruct renal tubules → acute kidney injury
 Hyperkalemia
 ↑ Nucleic acid → conversion to uric acid → hyperuricemia → urate nephropathy & risk of acute renal injury
 ↓ Ca2+ secondary to PO43- binding → secondary hypocalcemia
o Clinical features
 Nausea, vomiting, & diarrhea
 Lethargy
  Hematuria
 Acute Kidney Injury (due to uric acid &/or calcium phosphate stones)
 Seizures
 Cardiac arrhythmias
 Tetany, muscle cramps
 Paresthesia
 Sudden death
o Prophylaxis
 All patients
 Hydration (most effective preventive measure) – IV fluids
 Avoid potentially nephrotoxic drugs
such as NSAIDs
 Possibly in addition to hydration –
Uric acid metabolism inhibition
o In patients with a low to
intermediate risk of TLS:
allopurinol or febuxostat
o In patients with a high risk of
hyperuricemia due to TLS
(e.g., extremely high WBC):
rasburicase
 Recombinant uricase:
catalyzes the
breakdown of uric
acid to allantoin
o Allopurinol and rasburicase
helps moderate the risk of
uric acid–mediated renal
damage; however calcium
phosphate–induced renal injury may still occur
o Consider alkalinization of the urine
o Treatment
 Continuous telemetry
 Aggressive electrolyte monitoring & treatment
 Hyperkalemia
o Calcium Gluconate (cardioprotective) + Glucose and insulin (rapid action)
o Sodium polystyrene sulfonate (delayed action)
o Last resort: hemodialysis or hemofiltration
 Hypocalcemia: calcium administration
  Hyperphosphatemia: hydration and possibly phosphate binding agents
 Rasburicase, if not already given as prophylaxis
 Fluid administration with or without loop diuretics to aid renal excretion of uric acid crystals
 Renal replacement therapy may be necessary

 Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma

o Group of low–grade non–Hodgkin lymphomas (NHL) and is a B–cell lymphoma that presents with lymphocytic leukocytosis
 CLL: low–grade B–cell lymphoma with lymphocytic leukocytosis
 Disease in blood and bone marrow
 Small Lymphocytic Lymphoma (SLL)
 Disease is mainly in lymph nodes
 Chronic lymphocytic T–cell leukemia (T–CLL): now known as T-prolymphocytic leukemia (T–PLL). More aggressive & severe than CLL

 Sex: ♂ > ♀ (M:F ∼ 2:1)

o Epidemiology

 Age > 60 years; median age 70 – 72 years

 incidence of CLL increases with age
 Most common type of leukemia in adults
o Risk Factors
 Advanced age > 60 years
 Environmental factors: organic solvents
 Genetics: positive family history
o Associated conditions – Warm autoimmune hemolytic anemia (IgG)
o Pathophysiology
 Acquired mutations in hematopoietic stem cells → increased proliferation of leukemic B cells with impaired maturation and
differentiation in the bone marrow; Proliferating B cells cannot effectively recognize antigen → immunocompromise /
hypogammaglobulinemia:
 Suppression of the proliferation of normal blood cells
o Immunosuppression – Granulocytopenia
 Hypogammaglobulinemia and irregularities in immune cell signaling and function
o Thrombocytopenia
o Anemia
 Infiltration of the lymph nodes, liver, and spleen
o Clinical features
 Often asymptomatic (50%; results in late or incidental diagnosis)
 Many are diagnosed incidentally with markedly elevated WBC
 Insidious onset of symptoms
 Weight loss, fever, night sweats, fatigue
 Painless lymphadenopathy (cervical, supraclavicular, axillary)
 Lymphadenopathy is a typical finding in lymphomas such as CLL/SLL and helps to differentiate CLL from CML!
 ± Hepatomegaly &/or splenomegaly
 Repeated infections (increased susceptibility)
 Severe bacterial infections (e.g., necrotic erysipelas)
 Mycosis (candidiasis)
 Viral infections (herpes zoster, pneumonia)
 Symptoms of anemia and thrombocytopenia
 Dermatologic symptoms
 Leukemia cutis
 Chronic pruritus
 Chronic urticaria
o Investigations
 CBC
 Persistent lymphocytosis with a high percentage of small mature lymphocytes
o ↑ WBC (> 20,000/μL) with > 80% lymphocytes
 Findings that indicate suppression of normal myelopoiesis:
o Granulocytopenia
 o Anemia
o Thrombocytopenia
 Peripheral Blood smear: Smudge cells (Gumprecht shadows) – mature–appearing lymphocytes that rupture easily due to increased
fragility and appear as artifacts in a blood smear
 N.B. False positive results possible: Smudge cells may also appear if the quality or handling of the blood sample was
inadequate
 Immunotyping with Flow Cytometry (most accurate test) –
 Monoclonal B cell lymphocytes – B–CLL Immunophenotyped (CD19+, CD20+, CD23+, CD5+)
o Increased expression of CD5+ on B–cells is abnormal (recall CD5 is normally a T–cell marker)
 Light chain restriction (kappa or lambda)
 Serum antibody electrophoresis: antibody deficiency (decreased γ globulin fraction)
 ↓ IgG in 50% of patients
 Bone marrow aspiration generally not needed (Not necessary to confirm the diagnosis)
 BM aspiration may be helpful in investigating cytopenia of unknown origin, for instance, during later stages of the disease.
 Bone marrow cytology and histology
o High percentage (> 30%) of small, mature lymphocytes
o Decreased number of myeloid progenitor cells
 Additional Diagnostic Procedures
 Genetics: FISH analysis to detect mutations associated with CLL (e.g., del(17p13))
 Ultrasound: splenomegaly and/or hepatomegaly
 Liver histology: periportal lymphocyte infiltration and centrilobular necrosis
 Lymph node biopsy: A biopsy may be performed if the peripheral blood smear does not yield diagnostic clues, to confirm the
diagnosis, or to differentiate CLL from other diseases (e.g., Hodgkin’s disease).
o Treatment of CLL
 Chemotherapy and monoclonal antibodies, but does not necessarily increase survival time.
 Allogeneic stem cell transplantation, which is the only curative treatment option, is often not viable because of advanced age
Rai Staging System
Stage Risk Finding Median Survival Treatment
0 Low Isolated lymphocytosis > 150 months  Asymptomatic CLL (Rai 0, slow progression) – observe and monitor disease progression
I + Lymphadenopathy 101 months
II Intermediate + Hepatosplenomegaly  Symptomatic CLL or advanced stage (Rai stage > 0, accelerated disease progression)
71 months
and/or splenomegaly o Chemotherapy
III + Anemia (Hb < 11 o If CD 20 positive: rituximab (antibody directed against CD20)
g/dL) o Targeted therapy with ibrutinib [targeted against Bruton's tyrosine kinase (BTK)]
High 19 months
IV + Thrombocytopenia  Refractory CLL or early recurrence in fit, young patients: allogeneic stem cell transplantation
(< 100,000/ μL)
 Regimens
 < 65–70 years
o FCR: fludarabine (1st line; purine analog–based therapy), cyclophosphamide, rituximab
  N.B. Fludarabine may exacerbate warm autoimmune hemolysis
o Stem cell transplantation
 > 65–70 years
o Chlorambucil + monoclonal antibody (e.g., rituximab)
o Possibly a single agent: chlorambucil or rituximab
o Ibrutinib [ADRs – atrial fibrillation]
 del(17p13) positive
o Enrollment in clinical trials is recommended.
o No standard approach; options include:
 Monoclonal antibody (e.g., alemtuzumab – antibody directed against CD52)
o Complications
 Immunosuppression with subsequent infections (most common cause of death)
 Hyperviscosity syndrome
 Autoimmune hemolytic anemia (of both the warm and cold agglutinin type)
 Secondary Malignancies – Richter transformation (~5%)—CLL/SLL transformation into an aggressive lymphoma, most commonly
diffuse large B-cell lymphoma (DLBCL)
 Suggestive Findings / Diagnostic indicators
o Rapidly progressive lymphadenopathy → lymph node biopsy required
o New onset of B symptoms [Night sweats, involuntary weight loss > 10% over 6 months → cachexia, fever > 38°C
(100.4°F)]
o ↑ LDH
o Poor prognosis
 Treatment – similar to symptomatic CLL and advanced stages
o Prognosis
 Median survival 10 years
 Worse prognosis with
 Multiple chain lymphadenopathy
 Hepatosplenomegaly
 Anemia & thrombocytopenia
 Advanced age is associated with a poor overall survival rate
 Genetic abnormalities: e.g., del(17p13) is associated with a poor overall survival rate because of the high risk of disease
progression and poor response to chemotherapy.
 β-2 microglobulin levels: correlate with the severity of the disease
 Blood lymphocyte doubling time: Rapid doubling is associated with a high risk of disease progression.
 Lymphomas are responsible for approximately 15% of all primary mediastinal masses, and 45% of anterior mediastinal masses in children
o Only 10% of lymphomas which involve the mediastinum are primary (i.e. mediastinal involvement not part of systemic disease) and the
majority are Hodgkin lymphomas (~ 60%)
o Primary mediastinal lymphomas are most frequently of three histologic varieties:
  Nodular sclerosing Hodgkin lymphoma
 Primary mediastinal large B-cell lymphoma
 Lymphoblastic lymphoma
 Hodgkin Lymphoma
o Malignant lymphoma typically of B–cell origin.
o Bimodal age distribution
 15 – 35 years
 > 60 years (typically 50 – 70 years)
o Subtype variance with age
 Young adults: nodular sclerosing HL
 Elderly adults: mixed–cellularity HL
o Sex: ♂ > ♀
 Male predominance, especially in pediatric cases
 Exception: ♀ = ♂ in nodular sclerosing HL (most common type)
o Contiguous pattern of spread (c.f. Non–Hodgkin which favours non–contiguous spread)
o WHO classifies HL into two types:
 classical HL (CHL)
 Nodular Sclerosis (most common)
 Mixed Cellularity
 Lymphocyte–Depleted
 Lymphocyte–Rich CHL
 Nodular Lymphocyte Predominant HL (NLPHL)
o Etiology / Risk factors
 Association with Epstein–Barr virus (EBV) in immunodeficiency (e.g., HIV infection)
 50% of cases associated with EBV infection
 Autoimmune diseases (e.g., rheumatoid arthritis, sarcoidosis)
o Clinical Features
 Painless lymphadenopathy
 Cervical lymph nodes (∼ 60–70%) > axillary lymph nodes (∼ 25–35%) > inguinal lymph nodes (∼ 8–15%)
o nontender mass of localized, single group of nodes – rubbery, mobile
 Mediastinal lymphadenopathy (50%) → retrosternal chest pain, dry cough, and shortness of breath
 ± Splenomegaly and/or hepatomegaly
 Mediastinal Mass – predilection for anterior & middle mediastinum (either thymus or lymph node involvement)
 Possible SVC syndrome
 Retrosternal chest pain, dyspnea, cough
 B symptoms (i.e. subacute fever, sweats, weight loss)
 Night sweats, involuntary weight loss > 10% over 6 months, subacute fever > 38°C (100.4°F)
 Can occur in a variety of diseases, such as non–Hodgkin lymphoma, other malignancies, tuberculosis, and various
inflammatory diseases
  The presence of only one of the symptoms – in the case of confirmed HL – is considered positive for B symptoms.
 Pel–Ebstein fevers (Relatively rare but very specific for HL)
 Cyclical fever with periods of high temperature for 1–2 weeks, followed by afebrile periods for 1–2 weeks
 Alcohol–induced pain at affected lymph nodes (Relatively rare but very specific for HL)
 Etiology is unclear but may be due to vasodilation in the lymph node following alcohol exposure causing capsular distension
 Pruritus – paraneoplastic process classically associated with HL and likely due to cytokine and interleukin release
o Cotswold Modified Ann Arbor System (based on both localization of the lymphoma with respect to the diaphragm & the presence of
systemic symptoms)
 Stage I – Involvement of 1 lymph node area (IN), or 1 extra–nodal (IE) focus
 Stage II – Confined to one side of the diaphragm: Involvement of ≥ 2 (IIN) lymph node areas or extra–nodal foci (IIE)
 Stage III – On both sides of the diaphragm: Involvement of ≥ 2 (IIIN) lymph node areas or extra–nodal foci (IIIE)
 Stage IV – Disseminated spread into one or more extra–lymphatic organs independent of lymph node involvement
 Additional modifiers
o Primarily involved tissue: nodal (N) or extra–nodal (E)
o Symptoms
 A: if asymptomatic
 B: if B symptoms present
o Bulky disease (X)
o Complications
 Tumor lysis syndrome
 hypocalcemia (most common)
 hyperkalemia
 hyperphosphatemia
 hyperuricemia
 SVC syndrome
 Minimal change disease
 Paraneoplastic syndromes – calcitriol secretion causes hypercalcemia
 Treatment – related complications (see below)
o Investigations
 CBC –
 Elevated or decreased WBC count (i.e. leukocytosis or leukopenia)
 Anemia
 Eosinophilia (tumour cells secrete cytokines that generate eosinophils)
 Serum chemistry
 ↑ LDH (associated with high tumour burden)
 Hypercalcemia: most commonly due to paraneoplastic production of 1,25-dihydroxyvitamin D
 Excisional Biopsy of suspicious lymph nodes
 Histopathology – pathognomonic Reed–Sternberg cells (malignant B–cells)
o Large cells with binucleate or bi–lobed nuclei with dark centers of chromatin and pale halos (owl–eye appearance)
 o CD15/CD30–positive
 Inflammatory background containing the following cell types in varying numbers: lymphocytes, neutrophils, eosinophils,
macrophages/histiocytes, plasma cells, and fibroblasts
 Granuloma formation
 Imaging – for staging; sometimes employed if no clear evidence of peripheral lymphadenopathy to identify a potential biopsy site
 Chest X–Ray or CT–scan: detection and measurement of anterior mediastinal masses and enlarged lymph nodes (e.g.
mediastinal lymphadenopathy) in chest, abdomen, and pelvis
 Bone scintigraphy or PET–CT with 18–fluorodeoxyglucose (FDG): performed before treatment to assess disease spread
o If no clear evidence of peripheral lymphadenopathy, they usually undergo imaging to identify potential biopsy sites
o Neoplastic cells in lymph nodes have high metabolic rate and readily take up radiotracer on PET scan; however,
radiotracer also pools in healthy organs that have high glucose requirements such as the brain, kidney, and liver;
excretion of radiotracer also leads to enhancement throughout the urinary collecting system
Histological Classification of HL (WHO)
Subtype Characteristics Prognosis Pathology
Nodular sclerosing  Most common: 65 – 75% of HL  Good prognosis.  Nodules of Reed–Sternberg cells within lacunae, separated by collagenous tissue with
classical HL (NSHL) subtype sclerosing appearance (hence the name “nodular sclerosing”)
 Localization: mostly o Diffuse band-like fibrosis with lacunar spaces
mediastinal and cervical  Lymphocyte rich

Mixed–cellularity  Commonly found in  Slightly worse than  Nodules with numerous Reed–Sternberg cells, and increased number of histiocytes,
classical HL (MCHL) immunocompromised patients with nodular eosinophils, and plasma cells (hence the name “mixed–cellularity”)
(e.g., HIV–positive individuals) sclerosing subtype o Large inflammatory infiltrate with many eosinophils
 Localization: mostly abdominal
and splenic

Lymphocyte–rich  Rare  Good Prognosis  Presence of Reed–Sternberg cells, and reactive lymphocytosis that causes distortion of
classical HL (LRHL)  Localization: mostly cervical the lymph node architecture.
and axillary
Lymphocyte–  Very rare (< 1%)  Bad prognosis  Numerous Reed–Sternberg cells, and decreased number of lymphocytes
depleted classical HL  Localization: mostly below the
(LDHL) diaphragm
Nodular lymphocyte  Rare (5%)  Very Good  Decreased number of Reed–Sternberg cells, and abundant lymphocytes
predominant HL Prognosis  Popcorn cells (histiocytes with nuclei that resemble popcorn).
(NLPHL) o Popcorn cells express CD19 and CD20, and negative for CD15 and CD30

o Treatment
 In early stages (I & II) – involved–field radiation and chemotherapy
 chemotherapy approach is ABVD: adriamycin (doxorubicin), bleomycin, vinblastine, dacarbazine
 In later stages (III & IV, & often II with bulky disease) – polychemotherapy (mainstay of treatment) ± radiation therapy (select cases)
 ABVD
 Stanford V: doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, prednisone
 BEACOPP: bleomycin, etoposide, adriamycin (doxorubicin), cyclophosphamide, oncovin (vincristine), procarbazine,
prednisone
 Primary refractory or relapsed disease: trial of alternative chemotherapy or consideration of high–dose chemotherapy and
autologous stem cell transplantation
 Anti–emetics
 Metoclopramide and some other dopaminergic antagonists occasionally used for treatment (and prevention) of
chemotherapy–induced nausea and vomiting
o MOA for metoclopramide – prokinetic drug that acts on central and peripheral D2–receptor blocker
o ADR – extrapyramidal symptoms – akathisia, dystonia, and parkinsonian–like symptoms. Incidence of these ADRs
when high doses are used > 30%
o N.B. metoclopramide has largely been replaced by 5–HT3 serotonin receptor antagonists (e.g. ondansetron) and
aprepitant
o Treatment–related complications
 Secondary malignancy (10 – 20%): Radiation exposure increases risk of solid organ malignancy (e.g. breast, lung, thyroid), and
chemotherapy exposure increases the risk of hematologic malignancy. Most cases arise > 5 years after treatment.
 Secondary malignancies are the leading cause of death in those who have been cured of Hodgkin’s Lymphoma
 Cardiovascular disease – long–term complications due to chemotherapy &/or radiation therapy
 Increased risk of premature coronary artery disease, valve damage, peripheral arterial disease, and cardiomyopathy
o Radiation–induced cardiotoxicity – radiation therapy causes diffuse fibrosis in the interstitium of the myocardium,
along with progressive fibrosis of the pericardial layers, cells in the conduction system, and the cusps and/or leaflets
 of the valves. It also causes injury to the intimal layer, with arterial narrowing typically involving the ostial parts of the
coronary vessels. These effects lead to:
 Myocardial ischemia and/or infarction – due to ostial narrowing of coronary arteries
 Restrictive cardiomyopathy with diastolic dysfunction
 Constrictive pericarditis
 Valvular abnormalities (mitral or aortic stenosis / regurgitation)
 Conduction defects (sick sinus syndrome, variable degrees of heart block)
 Doxorubicin – cardiomyopathy
 Cardiovascular disease is the leading non–malignant cause of death in long–term HL survivors
 Pulmonary disease (e.g. fibrosis, bronchiectasis) 2O to chest radiation
 Bleomycin – lung fibrosis
 Hypothyroidism 2O to chest radiation
 Neuropathy from chemotherapy &/or vincristine
 Risk of infection

 Good prognosis: 5-year survival rate ∼ 80–90% (in children > 90%)
o Prognosis

 ∼ 10–20% of patients will develop secondary malignancies (complications related to radiation therapy and chemotherapy)
 Best prognosis: nodular lymphocyte predominant HL (NLPHL)

 Unfavorable factors for Hodgkin lymphoma (relevant when selecting a treatment regimen)
 High ESR
 Involvement of three or more lymph node areas
 Large mediastinal tumor
 Bulky disease (tumors measuring ≥ 10 cm across)

NON–HODGKIN’S LYMPHOMA
 NHL is the most common hematopoietic neoplasm
 ~ 85% of lymphomas
Epidemiology  Incidence of all NHL increases with age; peak incidence > 50 years
 Subtype variance with age
 High–grade lymphomas more common in children and young adults (20–40 years)
 Chromosomal translocations: most commonly t(14;18)
 Infections
o EBV, HIV, HTLV–1, HCV
Etiology o Helicobacter pylori → gastric lymphoma (e.g., MALT, Diffuse large B-cell lymphoma)
 Autoimmune diseases: Hashimoto thyroiditis, rheumatic disease
 Immunodeficiency: congenital immunodeficiencies, AIDS, history of chemotherapy &/or immunosuppressive therapy
 Environmental factors: aromatic hydrocarbons (e.g., benzene), radiation
Clinical  Insidious onset in low–grade lymphomas
Features  Painless lymphadenopathy
 Splenomegaly, hepatomegaly
 Extra–nodal disease: most commonly involves the gastrointestinal tract, skin, thyroid, and CNS
 B symptoms (weight loss, fever, night sweats)
  Fatigue, weakness, and signs of bone marrow involvement (anemia, bleeding, increased susceptibility to infections)
 Staging: similar to the one used for Hodgkin lymphoma (see the Cotswold modification of Ann Arbor staging system for details), but without B symptoms
 Classification
Staging &
o Limited disease (Stage I + II): lymph node involvement confined to one side of the diaphragm
Classification
o Advanced disease (Stage III + IV): lymph node and/or extra–nodal involvement on both sides of the diaphragm
 N.B. Chronic lymphocytic leukemia and multiple myeloma are classified separately
 CBC
o Elevated or decreased WBC count (leukocytosis or leukopenia)
o Anemia
o Thrombocytopenia
 Serum chemistry –
o ↑ LDH
o Hypercalcemia: secondary to paraneoplastic syndrome in aggressive NHL
o ALP, U&Es, Uric Acid
 Virus serology testing (e.g., HIV, EBV serology)
 Histology
o Confirmatory test: Excisional Lymph Node Biopsy (need to see OVERALL lymphocyte architecture of lymphpocytes): monomorphous, lymphocytic proliferation
 N.B. Needle aspiration not useful because the INDIVIDUAL lymphocyte appears normal
o Bone marrow aspiration and biopsy in all patients for staging
Investigations
o Biopsy samples from extra–nodal sites if extra–nodal disease is suspected
 Imaging
o X–ray and CT (Chest, ABD, Pelvis, Neck) are required in all patients for staging
o Brain MRI for patients with neurologic symptoms
o Possibly PET–CT: initial evaluation for NHL staging, and post–treatment assessment
 Further tests
o Immunohistochemistry
 B–cell lymphomas: CD20 positive
 T–cell lymphomas: CD3 positive
o Lumbar puncture with CSF examination (cytology; detection of EBV DNA) in case of
 Primary CNS lymphoma
 Neurologic signs and symptoms
 HIV–positive patients
 Low-grade NHL
o Limited Stage – Radiation therapy (Curative)
o Advanced Stage – Watch and wait; Polychemotherapy* (Palliative)
Management  High-grade NHL (All Stages) – Polychemothreapy* (Curative)
 * Polychemotherapy
o Most NHL: CHOP regimen – Cyclophosphamide, Hydroxydaunorubicin (doxorubicin), Oncovin (vincristine), Prednisolone)
o B-cell NHL: R-CHOP (combination of CHOP and CD20 antibody Rituximab)
Prognosis  Low–grade lymphomas: median survival of 6–10 years
 High–grade lymphomas: survival typically several months (years in less aggressive variants)
 Indicators of poor prognosis: old age, number of involved nodal and extranodal sites, ↑ LDH, ↑ β 2–microglobulin
o International Prognostic Index (IPI) for aggressive NHL (Max score out of 5)
 Age (>60 associated with poor prognosis)
 Stage (III or IV)
  LDH - elevated
 No of extranodal sites (>1)
 Performance status (2-4)
 Low risk (0-1), Low intermediate (2) and high intermediate (3), High (4,5)
Disease / Lymphoma type Clinical Features
B-CELL LYMPHOMAS (85% OF NHL)
Indolent  Same disease as chronic lymphocytic leukemia (CLL), however, the neoplastic cells are primarily located in lymphatic tissue rather than
Small Lymphocytic Lymphoma
(Low–grade) circulating in peripheral blood
 More common in middle–aged men; Middle–age / older adults
 “Indolent”  Clonal B–cell Neoplasm
lymphomas  BRAF mutation
do not  Similar in appearance to CLL (associated with a better prognosis)
usually  Clinical features
require o Symptomatic cytopenia – Pancytopenia due to bone marrow fibrosis
immediate  Granulocytopenia (infections)
therapy,  Anemia (fatigue, weakness)
but are  Thrombocytopenia (bleeding, bruising)
difficult to  Up to 20% have leukocytosis – Although most patients are
cure luekopenic due to BM infiltration, a minority have mild leukocytosis
due to increased circulating lymphocytes
o Massive Splenomegaly (abdominal fullness & early satiety 2O gastric
compression)
Hairy Cell Leukemia o B symptoms are rare
o Hepatosplenomegaly / Lymphadenopathy (rare; uncommon)
o Hairy cells
 Investigations / Diagnosis
o Peripheral smear – leukocyte cells with “hairy” filamentous, cytoplasmic projections
 Large B Lymphocytes (large round basophilic nuclei; cell membrane consists of cytoplasmic protrusions = hairy cell)
o Stains TRAP+ – Usually positive tartrate-resistant acid phosphatase (TRAP) stain and CD11c marker
o Bone marrow aspiration: often a dry tap
o Bone marrow biopsy with flow cytometry – BM fibrosis with cytopenias
 Management
o Chemotherapy with single agent (moderate/severe) – Cladribine (2CDA) or Pentostatin (DCF; N.B. NOT a cholesterol medication)
o Prognosis – Life-expectancy is often near–normal

 VERY low risk of converting to Acute Leukemia

Waldenstrom’s macroglobulinemia  IgM antibodies
Follicular Lymphoma  Most common low–grade lymphoma in adults
 Slowly progressive / indolent, painless, peripheral lymphadenopathy of alternating size (“waxing and waning”) and splenomegaly
 Hilar and mediastinal lymphadenopathy occurs, however large mediastinal mass is rare
 Generally absent – B symptoms (e.g. night sweats, fever, weight loss) & laboratory abnormalities (e.g. elevated LDH, cytopenia)
 Diagnosis – excisional lymph node biopsy
 Immunophenotyping – Translocation t(14,18) in ~85% of cases: heavy–chain Ig (14) and Bcl–2 (18) are translocated, resulting in an
overexpression of Bcl-2, an oncogene which inhibits apoptosis
 Histopathology – Nodular growth of follicular lymphocytes (small cells with cleaved nuclei)
  Associated with chronic inflammation (e.g., H. pylori associated MALT lymphoma)
Marginal Zone Lymphoma  Translocation t(11;18)
o Translocation of API2 and MALT1 – promotes the continuous activation of the transcription factor NF-κB
Aggressive  Most common in children
(High–grade)  Translocation t(8;14) in 75% of cases
 Translocation of c–myc and heavy–chain Ig; Overactivation of C–MYC proto-oncogene → activation of transcription
 “Starry sky” pattern – Tingible body macrophages (containing many phagocytized tumor cells) are scattered diffusely within a sheet of
Burkitt lymphoma uniform neoplastic cells)
o Sporadic Burkitt: typically located in  Bowel obstruction due to abdominal mass
the abdomen
o Endemic Burkitt lymphoma: EBV–
associated (most often in equatorial
Africa and South America) and
typically located in the maxillary and
mandibular bones
o HIV–associated Burkitt lymphoma

 Most common NHL in adults

 Approx. 90% of primary CNS lymphomas are DLBCL
 ↑ expression of Bcl–2 and Bcl–6 (N.B. ↑ levels of Bcl-2 inhibits apoptosis)

Diffuse large B–cell lymphoma (DLBCL)

Precursor B–cell lymphoblastic  More common in adolescents and young adults

 lymphoma
 More common in older men
 Translocation t(11;14) – translocation of cyclin D1 and heavy-chain Ig
 CD5+

Mantle cell lymphoma

T–CELL LYMPHOMAS (15% OF NHL)

 Cutaneous lymphoma .
 Atypical CD4+ cells
Indolent
Mycosis fungoides  Heterogeneous skin lesions
(Low–grade)
 May progress to Sézary syndrome
 Tx – skin–directed corticosteroids, interferon alfa, chemotherapy, phototherapy, and/or radiation
Aggressive  Occurs almost exclusively adults
(High–grade)  Neoplastic proliferation of mature CD4+ T cells
 Caused by the HTLV – HTLVI associated (Serum has antibodies to HTLV1; virus endemic in Japan and Caribbean)
 Types of ATLL – Defined by LDH level, Number of circulating/abnormal lymphocytes
o Smouldering ATLL – normal WBC, >5% leukaemic cells (abnormal lymphocytes); indolent
o Chronic ATLL – skin rash, lymphocytosis but few abnormal lymphs; <2 years prognosis
 Mild Lymphadenopathy
 Lymphocytosis
o Lymphoma – lymphadenopathy; no leukemia
Adult T–cell Lymphoma o Acute ATLL (most common) – leukemia, skin rash, lymphadenopathy, hypercalcemia
 Hepatosplenomegaly, lymphadenopathy, variable morphology cutaneous lesions
 Hypercalcemia (abdominal pain, nephrocalcinosis, psychosis, bone pain/lesions) + Lytic bone lesions
 Elevated lactate dehydrogenase
 Associated with intravenous drug abuse
 Opportunistic infections in ATLL (due to immunosuprresion)
o Pneumocystis jirovecii
o Strongyloides stercoralis
o Cyptococcal mennigitis
o Crusted scabies
Cutaneous T–cell lymphoma  Mycosis fungoides:
o T– cell lymphoma largely limited to the skin and lymph nodes.
o Typically erythematous & pruritic patches & plaques refractory to standard treatments that develop brownish nodules
 Can also cause erythroderma and alopecia; severe pruritus and psoriasis–like lesions
 Subsequently, systemic spread occurs, including lymphadenopathy and hepatosplenomegaly
  Classically see epidermal collections or aggregates of malignant / atypical CD4+ T cells (Pautrier microabscess In epidermis).

 Sézary syndrome:
o Advanced T-cell lymphoma with cutaneous involvement along with the development of true T-cell leukemia.
 Systemic skin lesions – Dermatitis, erythroderma, generalized lymphadenopathy and circulating T–lymphoma cells
 Erythroderma accompanied by palmar and plantar hyperkeratosis
 Intense pruritus
 Generalized lymphadenopathy
 Leukemic dissemination present in Sézary syndrome distinguishes it from mycosis fungoides.
o Peripheral blood smear shows CD4+ cells with profoundly grooved (cerebriform) nuclei (termed Sézary cells).
 Either progression of mycosis fungoides or as de novo disease
 Characteristic lymphocytes usually CD4+ with folded or cerebriform nuclear chromatin (‘brain-like lobes of nuclei)

 Treatment for early stage disease:

o Topical corticosteroids (first-line)
o Topical nitrogen mustard (second-line)
 Treatment for moderate to late stage disease:
o Total electron skin beam therapy
o Systemic chemotherapy (e.g., bexarotene)
o Topical corticosteroids may also be used.
Precursor T-cell lymphoblastic  Predominantly adolescents and young adults (♂:♀ = 2:1)
lymphoma  Mediastinal mass → shortness of breath and superior vena cava syndrome
 Often T cell
 Often involves mediastinum (massive mediastinal involvement typical)
Lymphoblastic Lymphoma
 Needs prophylactic CNS treatment
 Treat as ALL – weekly / daily treatment; needs maintenance treatment
 MYELOPROLIFERATIVE DISORDERS
Disease Etiology Clinical Features Investigations Treatment
 Sex: ♂>♀ (M>F) Diagnosis
 Peak incidence:  Peripheral blood smear – Extreme leukocytosis
50–60 years (often > 100,000/mm3) & Basophilia
 Idiopathic (in  Philadelphia Chromosome: Abnormal fusion gene BCR–ABL, t(9,22) – leukemogenesis due to o Leukostasis / symptomatic hyperleukocytosis)
Chronic Myeloid most cases) constitutionally active tyrosine kinase – medical emergency most commonly seen in
Leukemia (CML)  Ionizing radiation Chronic phase (Blast count < 10% Peripheral Blood & BM) patients with acute myeloid leukemia or
 Aromatic  Can persist for up to 10 years and is often clinically unremarkable chronic myeloid leukemia in blast crisis. It is
hydrocarbons  Weight loss, fever, night sweats, fatigue characterized by an extremely elevated blast
(especially  Splenomegaly cell count and symptoms of decreased tissue
benzene)  Swollen lymph nodes are not typical in CML perfusion. Symptoms of leukostasis are rare
Accelerated phase (Blast count 10% – 19% Peripheral Blood & BM) unless the WBC count exceeds 400 x 109/L
 Erythrocytopenia: anemia (400,000/microL).
 Thrombocytopenia: petechial bleeding  ↓ LAP
 Neutropenia: infection and fever  Must differentiate from leukemoid reaction (see
 Extreme pleocytosis below)
oInfarctions: splenic and myocardial infarctions, retinal vessel occlusion Treatment
oLeukemic priapism  Targeted therapy: first–line for chronic and
oTerminal phase: myelofibrosis accelerated phase
 Extreme splenomegaly: palpable in lower left quadrant or pelvic cavity o Tyrosine kinase inhibitors: e.g., imatinib
Blast crisis (Blast count ≥ 20% Peripheral Blood & BM) (Glivec®), nilotinib, dasatinib
 Terminal stage of CML  ADRs of EGF receptor blocker – skin rash
 Symptoms resemble acute leukemia o Life – long
 Rapid progression of bone marrow failure → pancytopenia, bone pain  Allogeneic stem cell transplantation: if targeted
 Severe malaise therapy is not successful or in young patients
 Subtypes: without any major comorbidities (the only
o Myeloid blast crisis → AML (⅔ of cases) curative option)
o Lymphoid blast crisis → ALL (⅓ of cases)  Cell count normalization: supportive therapy if
targeted therapy fails
o Hydroxyurea
 Blast phase: acute leukemia treatment
 Thrombocytosis (> 600,000/μL)
Essential  JAK2 mutation  Thromboembolic events  ↑ LAP
Thrombocytosis (50%)  Increased risk of fetal loss  ↑ LDH and uric acid (hyperuricemia)
 Vasomotor symptoms (headache,  BM aspiration: hyperplasia of megakaryocytes
visual disturbances, acral  Rule out causes of reactive thrombocytosis:  Prevent thromboembolisms: low dose aspirin
paresthesias) o Acute blood loss, acute bacterial &/or viral infections  Reduce thrombocyte count: hydroxyurea or
 Acute gouty arthritis o Iron deficiency, asplenia, metastatic cancer / interferon alpha (IFN–α )
 Petechial bleeding lymphoma, chronic inflammatory, or infectious
 Erythromelalgia (acral dysesthesia diseases (e.g. RA, IBD, Sarcoidosis, TB)
and erythema) o Drugs – aztreonam, ceftazidime, ibuprofen,
epinephrine, glucocorticoids
Polycythemia  JAK2 mutation  Often asymptomatic (incidental finding on blood tests!)  Phlebotomy: periodic removal of blood via
  Constitutional symptoms: weight loss, fatigue, sweating
 ↑ Blood Viscosity – Hyperviscosity syndrome (triad of mucosal bleeding, neurological symptoms,
and transient visual disturbances)
o Erythromelalgia – burning pain in feet or hands accompanied by erythema, pallor, or cyanosis, in venipuncture temporarily reduces cell counts and
the presence of palpable pulses; common in essential thrombocytosis & polycythemia rubra vera hyperviscosity.
o Hypertension, HTN o 250–500 mL every 2–3 days until Hct ≤ 0.45 is
 Plethora (Facial flushing, Cyanotic lips, ruddy cyanosis) established
 Aquagenic Pruritus: worsening / aggravated symptoms after bath with warm water  Antiplatelet prophylaxis: aspirin
Vera (95%)  Non–specific neurological symptoms: dizziness, headache, visual disturbances, tinnitus  Cytoreductive therapy: determined on an
 ↑ RBC turnover (gouty arthritis) individual basis; recommended if risk factors are
 Bleeding present
 Splenomegaly; less commonly hepatomegaly o Hydroxyurea
 Peptic ulcer disease o Interferon alpha
 Oxygen Saturation > 92% on room air o JAK2 inhibitor: ruxolitinib
 Thrombotic (e.g. Venous Thrombosis, Budd Chiari Syndrome, Stroke) & hemorrhagic (e.g. epistaxis)
complications
 Complications – Myelofibrosis & acute leukemia
Investigation
 ↑ Hb/Hct, ↑ RBCs, Thrombocytosis (↑ Platelets > 450,000/μL), Leukocytosis (↑ Leukocytes > 12,000/μL) – majority of patients have elevations of all three
major cell lines on presentation
 ↑ Uric acid, ↑ LDH
 ↑ LAP
 ↓ Serum iron levels, ↓ ESR, ↓ EPO
o Low EPO level (c.f. secondary forms of polycythemia, e.g. chronic hypoxia or EPO–secreting tumors, which have high EPO levels)
 JAK2 positive – Peripheral blood screening for JAK2V617F mutation – present in almost 100% of cases
 Arterial O2 saturation: normal
Diagnostic Criteria (WHO, 2016)
 All three major criteria OR The first two major criteria AND the minor criterion
 Major Criteria
o Evidence of increased RBCs
 ↑ Hemoglobin (♂: Hb > 16.5 g/dL / ♀: Hb > 16 g/dL), OR
 ↑ Hematocrit (♂: Hct > 49% / ♀: Hct > 48%), OR
 ↑ Red cell mass (> 25% mean normal predicted value)
o Bone marrow biopsy showing hypercellularity with trilineage growth (increased erythropoiesis, granulopoiesis, and megakaryopoiesis with
pleomorphic, mature megakaryocytes; i.e. panmyelosis)
o Evidence of a genetic mutation in the JAK2 gene (Presence of JAK2 V617F or JAK2 exon 12 mutation)
 Minor Criteria
o ↓ EPO (subnormal serum erythropoietin level)
 Peak incidence
 Weakness, fatigue, weight loss  Curative: allogeneic stem cell transplantation
60–70 years  ↑ leukocyte alkaline phosphatase (LAP), LDH, & uric acid
 Splenomegaly (option for younger patients; < 60 years of age)
Primary  Etiology:  Leukoerythroblastic blood film:
 Hyperproliferative phase (early  Supportive
Myelofibrosis unknown o Teardrop poikilocyte RBCs (dacrocytes) – also seen in
phase): thrombocytosis (→ o Hyperproliferative phase
 JAK2 mutation beta–thalassemia post–splenectomy
thromboembolic events) and  Prevent thromboembolisms: antiplatelet drug
(50%)
 (aspirin 100 mg)
 Control cell count: hydroxyurea, interferon
leukocytosis alpha, cladribine
 Pancytopenic phase (late phase): o Pancytopenic phase
o Erythrocytopenia → anemia  JAK2 inhibitor: ruxolitinib
o Thrombocytopenia → petechial  Periodic transfusions
 Low–dose thalidomide + glucocorticoids
bleeding
o Leukopenia → ↑ susceptibility to o Nucleated RBCs
infection o Immature WBC granulocytes
o Dacrocytes
Poor Prognostic Indicators:  BM aspiration: punctio sicca (Dry aspiration, severely
o Significant weight loss reduced cell count, and extensive BM fibrosis;
o Hb < 10 g/dL alternatively biopsy)
o Leukopenia (WBC < 4,000 / mm3)
o Thrombocytopenia (Plt < 150,000 /
mm3)

Leukemoid Reaction Chronic Myeloid Leukemia (CML)

Leukocyte Count > 30,000 – 50,000 / mm3 Elevated (often > 100,000 / mm3)
Severe infection → Reactive leukocytosis / granulocytosis (early
left shift to granulocytes and band forms); Release of the cells
from the bone marrow under the influence of IL–1 and TNF
Cause BCR–ABL fusion
(N.B. absent BCR–ABL fusion, aka negative for Philadelphia
chromosome)
LAP score
Low (< 10)
(Leukocyte Alkaline High (> 100)
(due to cytochemically abnormal neutrophils)
Phosphatase)
More mature cells with a marked left shift (band forms)
[metamyelocytes & bands > myelocytes, promyelocytes]
Less mature (i.e. all stages)
Neutrophil precursors
(metamyelocytes & bands < myelocytes, promyelocytes)
Toxic granulations & vacuolization + Dohle bodies (± Rouleaux
formation; more typical of Multiple Myeloma)
Absolute basophilia Not present Present
 SECONDARY ERYTHROCYTOSIS / POLYCYTHEMIA
Expected RBC
EPO O2 sat Underlying etiology
Plasma Volume mass
Relative Polycythemia  Severe Dehydration
↔/
↔ ↓ ↔  Excessive Diuresis
↑  Stress Erythrocytosis
Absolute Polycythemia
Appropriate Absolute  SaO2 < 92% (PaO2 < 65 mmHg) → Hypoxemia–induced
Polycythemia (Erythrocytosis) Erythrocytosis
 Hypoxia secondary to:
o High–altitude exposure
o Chronic cardiopulmonary disease
↑ ↔ ↑ ↓
o Cardiac disease (e.g. right–to–left cardiac shunts)
o Obstructive Sleep Apnea
o N.B. carboxyhemoglobin levels should be obtained to
exclude carbon monoxide poisoning in certain
patients, including heavy smokers
Inappropriate (Autonomous)  Paraneoplastic syndrome, especially with:
Absolute Polycythemia o Renal cell carcinoma (RCC)
(Erythrocytosis)
↑↑ ↔ ↑ ↔ o Hepatocellular carcinoma (HCC)
 Polycystic kidney disease (PKD)
 Myelodysplastic Syndrome (MDS)
Epidemiology  Heterogenous group of hematopoietic stem cell malignancies that causes hypercellular marrow & abnormal ineffective
hematopoiesis → peripheral cytopenia
 22 and 45 cases per 100,000 people older than age 70 years
 Risk Factors
o Older age (mean age of onset = 70 years)
o Previous chemotherapy / radiation (t – MDS, therapy related MDS)
o Toxins, genotoxic drugs, immunosuppressive agents
o Genetic defects due to:
 Epigenetic factors, RNA splicing factors, transcription factors
 5q (5q –) deletion most common
 May transform to acute leukemia (MDS = pre–leukemias; high risk of conversion to AML [> 20% blasts]) – 30% of cases

Clinical  Often asymptomatic at diagnosis / in early stages  Subtypes

Manifestations  Cytopenias o MDS with single–lineage dysplasia
o Anemia – weakness, fatigue, SOB, pallor o MDS with multilineage dysplasia
o Leukopenia – frequent infections o MDS with ringed sideroblasts
o Thrombocytopenia – bruising / bleeding, petechiae o MDS with isolated del(5q) chromosome abnormality
 Rarely Hepatosplenomegaly / Lymphadenopathy o MDS with excess blasts
 Progresses slowly → most succumb to bleeding, infections before o MDS, unclassifiable
transformation to AML
Diagnosis  Normocytic or macrocytic anemia with insufficient reticulocytosis
o Normal or mildly elevated MCV, increased RDW
o Low reticulocyte count
 Peripheral Blood Smear – Dysplastic red & white blood cells, normal platelets; 1 – 20% blasts
o Megaloblastoid maturation – Oval macrocytosis & neutrophil hyposegmentation / hypogranulation
o Nucleated RBCs, ringed Sideroblasts (erythroblasts with iron granules accumulated in mitochondria), Howell–Jolly bodies,
basophilic stippling
o Pseudo–Pelger–Huët anomaly
 Neutrophils with hyposegmented nuclei (usually bilobed)
 Seen in peripheral blood smears of patients undergoing CTX
o Large, agranular platelets, and megakaryocytes (in MDS-F)
o Pawn ball megakaryocytes – discrete nuclear lobes / multinucleation
 Bone Marrow biopsy (Diagnostic) – hypercellular marrow & ringed sideroblasts, with numerous cells of all three cell lines with
blasts, megakaryocytes, dysplastic erythroid precursors etc.
Treatment  Transfusions for symptomatic cytopenias
 Chemotherapy
 TNF inhibitors (e.g. lenalidomide, thalidomide), DNA methylation inhibitors (e.g. Azacitidine)
o Azacitidine – a cytidine analogue; reduces DNA methylation and alters gene expression, leading to reduced protein synthesis and increased cellular
differentiation. It is toxic to abnormal hematopoietic cells but is used primarily to treat myelodysplastic syndrome
 Allogeneic Hematopoeitic stem cell transplantation
o Only curative option, for young individuals
 IMMUNOLOGIC BLOOD TRANSFUSION REACTIONS
Transfusion Onset Cause / Pathogenesis Clinical Features Treatment
reaction (time after
transfusion
initiation)
Anaphylactic / Within seconds to Recipient anti–IgA antibodies directed Angioedema / urticaria, Mild reaction – Temporarily stop infusion + give antihistamine
Allergic minutes against donor blood IgA hypotension, respiratory (DPH) (particularly patients with hx of allergic reactions; may
Reaction distress / wheezing, shock restart transfusion once reaction abates)
IgA deficient recipient DISCONTINUE TRANSFUSION FOR MODERATE TO SEVERE
REACTIONS – give epinephrine, O2, steroid; Might require
ventilatory support if reaction severe
Prevention – Pre–transfusion antihistamine; wash RBC
components with 0.9% NaCl (NS)
Acute Within 1 hour ABO incompatibility (often clerical error) Fever, chills, non–specific flank Stop transfusion immediately
Haemolytic (Minutes to hours) Usually IgM Ab activate complement via pain, hemoglobinuria within 1 Aggressive IVF isotonic fluid (normal saline) & supportive care
classical pathway → C5b-9 membrane hour of transfusion (e.g. supplemental O2, vasopressors)
(aka attack complex form → intravascular Hypotension Limit clerical errors
Immediate, hemolysis → hemoglobinemia, Patients may feel anxious or Repeat type and crossmatch confirming a mismatch
Hemolytic hemoglobinuria SOB, but O2 saturation & lung
Transfusion Ag–Ab → activation of coagulation sounds typically normal
Reaction, IHTR) cascade (DIC) → Bradykinin leads to Acute Renal failure (due to
capillary permeability & dilatation, and acute tubular necrosis)
C3a → hypotension → renal failure DIC – e.g. diffuse bleeding at IV
catheter sites, shock
Positive Direct Coombs Test, ↑
plasma free Hb ≥ 25 mg/dL
Hemolysis (e.g. ↑ LDH, ↑
indirect bilirubin)
Febrile non– Within 1 – 6 hours Cytokine accumulation during blood Transient Fever & chills Antipyretic (acetaminophen)
hemolytic storage Rise in temperature >1°C from Avoid aspirin as tendency for patients to have
(most Cytokine release (IL–1, IL–6, TNF) resulting baseline thrombocytopenia or platelet dysfunction
common) in pyrexia; Ab (HLA) to donor Leukocyte Stop transfusion checking to eliminate TAS (transfusion-
Ag (HLA in transfused blood) associated sepsis)
Usually Ab exposure from previous Prevention –pre–storage leukocyte–reduced blood products;
pregnancies or transfusions (e.g. pre–storage leukoreduction can only be achieved by filtration
undergoing regular transfusions). of WBCs [< 5 ×106/l]; less efficient leukoreduction option is
washing with 0.9% saline (isotonic)
o Leukoreduction also reduces risk of human leukocyte
antigen alloimmunization and transmission of CMV (which
typically resides in leukocytes)
o Leukoreduction involves reducing the number of transfused
leukocytes through filtering or other methods such as saline
washing, freezing and deglycerolizing, or buffy coat removal
Urticarial Within 2 – 3 hours Recipient IgE against blood product Urticaria Antihistamines (H1–receptor blocker) e.g. cetirizine,
component diphenhydramine
Glucocorticoids
Transfusion– Within 6 hours Donor anti–leukocyte antibodies (HLA Respiratory distress, dyspnea Stop transfusion
related acute (minutes to hours) usually) to recipient leukocyte antigens Fever, chills, cyanosis Respiratory (ventilatory) support until reaction abates;
lung injury Activated neutrophils → diapedesis/ Hypotension Diuretics of NO VALUE
(TRALI) degranulation → ↑ permeability of No circulatory overload (c.f. to
pulmonary vessels (pulmonary edema) TACO)
Non–cardiogenic pulmonary
edema with diffuse bilateral
pulmonary infiltrates
Transfusion– Within 6 hours Risk factors Respiratory distress (e.g. Respiratory support (e.g. supplemental oxygen)
Associated o Age < 3 and > 60 with chronic anemia dyspnea, tachypnea) Diuresis (e.g. furosemide)
Circulatory  E.g. toddlers with severe, chronic Hypertension In high–risk patients, preventative measures include limiting
Overload iron deficiency anemia due to Tachycardia transfusion volumes, transfusing slowly, and administering
(TACO) excessive milk consumption (>24 Pulmonary edema (e.g., S3 pretransfusion diuretics
oz/day) & poor intake of iron–rich gallop, bilateral crackles / rales,
foods elevated JVP)
o Underlying cardiac or renal condition
o Large transfusion volume or fast
infusion rate
Delayed Within days to Anamnestic antibody response to minor Often asymptomatic Laboratory evidence of haemolytic anemia
haemolytic weeks RBC antigen to which patient was Onset > 24 hours to a month o Indirect hyperbilirubinemia, ↑ LDH, ↑ reticulocyte count
previously sensitized (e.g. pregnancy) after transfusion o ↓ Hb, haptoglobin
(minor blood lgG host antibodies to donor RBC antigens Fatigue, dyspnea, Tachycardia New Positive Coomb’s antiglobulin test
group – Rhesus, Kidd, Duffy, Kell, Lewis Jaundice Positive New antibody screen
incompatibility) Partial activation of complement → Low grade fever o Reduced survival of transfused RBCs so transfusion may be
extravascular destruction (Ab titre rises less clinically effective.
again 5–10 days after) o Extravascular hemolysis in the reticuloendothelial system
days to weeks after transfusion

No treatment per say; mainly supportive (e.g. fluids)

Prevention – review transfusion history & prior antibody
screens
Patient requires antigen–negative (extended antigen cross–
matched) red cell transfusion
Graft Versus Within weeks Donor T–lymphocytes engraft and Rash, fever, GI symptoms No effective treatment
Host proliferate in immunodeficient host and (severe diarrhea, liver
(Transfusion– attack the host tissues dysfunction ~ 10 days post–
associated transfusion)
GVHD; rare) Pancytopenia
High mortality > 90%
Transfusion–  Usually during Contaminated blood products (more Mild to Severe Treat: Discontinue transfusion. Manage septicemia.
associated infusion of first 100 commonly platelet transfusions; platelets Fever, chills, septic shock
sepsis (TAS) ml of contaminated stored at room temperature → Tachycardia, hypotension Appropriate antibiotics to manage underlying organism
pack susceptibility to bacterial growth) More severe than FNHTR.
Transfusion–  Within ~30 min  Yersinia enterocolitica – siderophilic No haemoglobinemia/uria as for Prevention: Donor screening and proper cleansing of
transmitted (Minutes to hours) bacteria requiring iron IHTR antecubital fossa of donor arm to prevent staph contamination
bacterial  Staphylococcus – skin commensal Renal failure, septic shock, DIC
infection (TTBI)  Pseudomonas, asymptomatic donor Very high mortality if high
bacteremia or during lab procedures bacterial count

 Citrate, which binds ionized calcium, is the main anticoagulant used for blood product storage and can cause hypocalcemia if a massive
transfusion is required (e.g. cardiac surgery). Calcium gluconate infusion is used to prevent of treat severe hypocalcemia
 Similarly, warming the blood product is recommended during rapid, massive transfusion, to prevent hypothermia and arrhythmia
 Alloantibodies
o Major problem that leads to difficulties finding cross – matched blood in patients with a history of multiple transfusions (e.g. sickle cell
anemia, myelodysplasia, thalassemia)
 These patients tend to develop multiple alloantibodies that make finding compatible blood even more difficult
o Most commonly implicated RBCs antigens are typically E, L and K
o N.B. autoantibodies are commonly implicated as a cause of incompatible cross – match in patients with autoimmune anemia and taking
certain drugs (e.g. methyldopa, procainamide)
o RBCs do not express HLA antigens
 HLA Allosensitization
o Increases risk of graft rejection in patients awaiting organ or bone marrow transplantation and platelet refractoriness in those requiring
subsequent platelet transfusion support
 Transfusion thresholds
o Any Hb < 7
o Hb 7 – 8: consider if
 Symptomatic
 Cardiac surgery
 Oncology patient in treatment
 Heart Failure
o Hb 8 – 10: consider if
 Non – cardiac surgery
 Ongoing bleeding
 Acute Coronary Syndrome
 Indications for Specialized RBC treatments
 Bone marrow transplant (BMT) recipients
Irradiated  Acquired or congenital cellular immunodeficiency
 Blood components donated by first or second degree relatives
 Chronically transfused patients
 CMV seronegative at – risk patients (e.g. AIDs, transplant patients)
Leukoreduced
 Potential transplant recipients
 Previous febrile nonhemolytic transfusion reaction
 IgA deficiency
Washed  Complement – dependent autoimmune hemolytic anemia
 Continued allergic reactions (e.g. hives) with red cell transfusion despite antihistamine treatment

Palliative Care
Indications Goals & Services
Patient or family request Pain control
Uncontrolled symptoms Improve sense of control
Distress regarding diagnosis & treatment Decreasing family distress / burden
Comorbid physical or psychosocial issues Understanding illness & treatment options
 Concerns regarding prognosis & treatment options Identifying surrogate decision makers, goals of care
Life expectancy < 6 months Assisting arrangement of financial affairs
Spiritual & existential support