Hematology

RED CELL DISORDERS BONE MARROW FAILURE SYNDROMES BLEEDING DISORDERS HEMATOLOGY PRIMARY DECREASE PRODUCTION INCREASED DESTRUCTION POLYCYTHEMIA ANEMIA SECONDARY LEUKEMIAS CHRONIC ACUTE MYELOID MYELOID LYMPHOID LYMPHOID DIAMOND BLACKFAN APLASTIC ANEMIA PLATELET DISORDERS COAGULATION DEFECTS VASCULAR BLOOD LOSS

PRIMARY DECREASED PRODUCTION INCREASED DESTRUCTION POLYCYTHEMIA ANEMIA SECONDARY BLOOD LOSS NUTRITIONAL ANEMIAS FOLIC ACID DEF IRON VITAMIN B12 DEF HEMOLYTIC ANEMIAS MEMBRANE DEFECTS INFECTION IMMUNE RED CELL DISORDERS

ANEMIA Definition: Reduction of the RBC volume (Hematocrit) or hemoglobin concentration below the range of values occurring in healthy persons.

Etiopathogenesis of Anemia Iron, folic acid, proteins . . . Bone Marrow DEFICIENCY ANEMIA MARROW FAILURE Circulation BLOOD LOSS HEMOLYSIS Acute Chronic Intravascular Extravascular 1 2 4 3

Hematologic Values During Infancy and Childhood 47 (42-52) 16 (14.0-18.0) Adult male 42 (37-47) 14 (12.0-16.0) Adult female 38 (34-40) 13 (11.0-16.0) 7-12 yr 37 (33-42) 12.0 (10.5-14.0) 6 mo -6 yr 36 (31-41) 12.0 (9.5-14.5) 3 months 50 (42-66) 16.5 (13-20.0) 2 weeks 55 (45-65) 16.8 (13.7-21.1) Cord Blood HEMATOCRIT HEMOGLOBIN AGE

Classification of Anemia based on Red Cell MCV Aplastic anemia Leukemia Folate deficiency Vitamin B12 deficiency Liver disease Normal Chronic Disease Hereditary Spherocytosis Blood loss Early iron deficiency Marrow infiltration Thalassemias Iron Deficiency Lead poisoning Chronic Diseases MCV High MCV Normal MCV low

Which of the RBC’s in the foll. blood smears is considered- 1. Normocytic, normochromic 2. hypochromic, microcytic 3. macrocytic B A C

Physiologic Anemia of Infancy Anemia during the first 6 to 8 weeks of life Etiopathophysiology: Abrupt cessation of erythropoiesis at birth with the onset of respiration Low erythropoietin levels (EPO still from the liver, not very sensitive to hypoxia Shortened survival of fetal RBC Expansion of the blood volume that accompanies weight gain Erythropoiesis resumes when the hemoglobin level falls to about 9-11 g/dl at 2-3 months of age Not due to iron deficiency Usually do not require treatment

FUNCTIONS OF IRON Vital to animals the oxygen carrying component of hemoglobin electron carrier for some enzymes Daily, a normal adult, destroys 15 ml of senescent red cells and produces an equal quantity of new red cells. For the daily production of erythrocytes, about 15 mg of iron is required.

Almost all of the iron needed is drawn from stores, which was recycled from the destruction of old red cells. The vast majority of the iron is retained in the body as it is moved from one compartment to another. Very little is iron is obtained from the diet.

If the body is capable of recycling iron, then why is there iron deficiency? IRON FACT : Recycling of the iron by the body is not a tight system. A normal healthy person loses around 1 to 2 mg of iron everyday.

Iron losses has to be replaced by absorption of iron from the diet The amount of iron in the normal diet is only slightly greater than the amount necessary to replace those lost from normal processes. An increase in iron requirements may lead to iron deficiency even on a normal diet.

Physiologic increase in iron requirements FEMALE infancy menopause Adolescence pregnancy childhood male

Pathologic causes of iron deficiency anemia Gastrointestinal bleeding: the most common Peptic ulcer Gastritis Parasitism Inflammatory bowel disease cancer Menometrorrhagia Chronic loss from the urine or sputum Iatrogenic

IRON DEPLETION IRON DEFICIENT ERYTHROPOIESIS IRON DEFICIENCY ANEMIA

Pallor In infants (0-12 months) and preschool children (1-5 years) developmental delays behavioral disturbances (e.g., decreased motor activity, social interaction, and attention to tasks) These developmental delays may persist past school age (i.e., 5 years) if the iron deficiency is not fully reversed.

Iron-deficiency anemia also contributes to lead poisoning in children by increasing the gastrointestinal tract's ability to absorb heavy metals, including lead.

In adults (>/= to 18 years) Impaired work capacity Fatigue and lethargy Pregnant women Increased risk of preterm delivery In the first two trimesters of pregnancy threefold increased risk for delivering a low-birthweight baby

Low Hemoglobin and Hematocrit Low Serum ferritin concentration Low Serum iron concentration Increased Total Iron Binding Capacity (TIBC) Low Transferrin saturation LABORATORY DIAGNOSIS

Iron deficiency may be defined as absent bone marrow iron stores (as described on bone marrow iron smears) or an increase in Hb concentration of greater than 1.0 g/dL after iron treatment or abnormal values on certain other biochemical tests (serum iron, TIBC)

Treatment Iron therapy 4 to 6 mg/kg/day Based on the elemental iron content Should be given on an empty stomach Diagnostic and therapeutic Reduction of the consumption of milk to 500 ml or less/24 hours Increase the intake of iron-rich foods Less blood loss sec to cow’s milk intolerance

Repletion of iron stores 1-3 mo Increase in hemoglobin level 4-30 days Reticulocytosis (peak at 5-7 days) 48-72 hour Initial bone marrow response: erythroid hyperplasia 36-48 hour Replacement of intracellular iron enzyme 12-24 hour Response Time after iron administration Response to iron therapy in iron deficiency anemia

RBC’s are larger than normal Precursors have an open, finely dispersed nuclear chromatin pattern Asynchrony between maturation of nucleus and cytoplasm Megaloblastic Anemias

Folic acid is absorbed throughout the entire small intestine Normal adult daily requirement: 100 ug/24 hours Clinical manifestations: signs and symptoms of anemia, failure to weight gain, irritability, diarrhea Treatment: Folic acid 1-5 mg/day Hematologic response noted within 24 hours Continue for 3-4 wks Folic Acid Deficiencies Megaloblastic Anemias

Humans cannot synthesize Vit B12 Derived from food May result from Inadequate intake Surgery involving the stomach or ileum Lack of secretion of IF by the stomach Consumption or inhibition of the Vit B12-IF complex Abnormalities involving the receptor sites in the terminal ileum VITAMIN B 12 DEFICIENCIES Megaloblastic Anemias

HEMOLYTIC ANEMIAS DEF’N: Accelerated destruction of red cells wherein destruction exceeds production HEMOLYTIC ANEMIAS INTRAVASCULAR EXTRAVASCULAR

HEMOLYTIC ANEMIAS Main division: Extravascular hemolysis – red cells are coated with antibodies and are destroyed by tissue macrophages in the spleen Autoimmune hemolysis Hereditary microspherocytosis Unstable hemoglobin disease Intravascular hemolysis – destruction of the red cells occur in the circulation G6PD deficiency Traumatic hemolysis Malaria

IMMUNE HEMOLYTIC ANEMIAS Sine qua non for diagnosis: (+) Coomb’s test Classification: Rh, ABO incompatibilities Idiopathic Secondary: drugs, infections, neoplasms, connective tissue disorders

Immune Hemolytic Anemia Secondary type: Drugs: streptomycin, PAS, Chlorpromazine, quinidine, quinine, tolbutamide, alpha-methyldopa, stibophen, penicillin Infections: Mycoplasma, measles, varicella, influenza, coxsackie Neoplasms: lymphomas, carcinomas Connective tissue diseases: SLE, RA

DISORDERS OF HEMOGLOBIN SYNTHESIS HEMOGLOBIN HEME GLOBIN Cong. Erythropoietic porphyria Thalassemia Syndromes Beta thalassemia Alpha thalassemia

THE HEMOGLOBINS 2 α 2 γ Hemoglobin F (Fetal) 2 α 2 δ Hemoglobin A2 2 α 2 β Hemoglobin A1 (Adult) Polypeptides Hemoglobin

Thalassemia syndromes Clinical manifestations Hypochromic-microcytic anemia of varying severity Growth failure, hepatosplenomegaly Massive expansion of the marrow of the face and skull: chipmunk facies Bone marrow is hypercellular with marked erythroid hyperplasia Radiologic features: hair on end appearance of the skull x-ray, thinning of the cortices and widening of the medullary cavities of the long bones Diagnosis: Hemoglobin electrophoresis

Alpha Thalassemia 4 alpha globin genes code for the production of the alpha polypeptides of the hemoglobin 4 distinct forms: Single gene deletion- silent carrier Two gene deletion-mild anemia Three gene deletion- Hb H disease ( β 4) Four gene deletion – incompatible with life; hydrops fetalis Thalassemia syndromes

Beta Thalassemia Several forms Homozygous (Cooley’s anemia) Severe form Starts to manifest after the 6 th month of life Heterozygous (Thalassemia minor) Asymptomatic/mild anemia Often misdiagnosed and treated for IDA Thalassemia syndromes

Management Blood transfusion: ideally using washed frozen packed red cells Hypertransfusion: maintain the hemoglobin level greater than 10 g/dl Splenectomy: When there is hypersplenism Increased in transfusion requirement Thalassemia syndromes

Complications Cardiac complications Diabetes mellitus Delayed or absent puberty Thalassemia syndromes

Hereditary Spherocytosis Autosomal dominant Occas. autosomal recessive Most common molecular defects: abnormalities of spectrin or ankyrin

Hereditary Spherocytosis CLINICAL MANIFESTATIONS Newborn: anemia and hyperbilirubinemia Maybe asymptomatic Severe anemia, pallor, jaundice, fatigue, exercise intolerance, splenomegaly Expansion of the diploe of the skull Increased tendency for gallstone formation

Hereditary Spherocytosis LABORATORY FINDINGS Evidence for hemolysis: reticulocytosis and hyperbilirubinemia Anemia: 6-10 g/dL Reticulocyte: 6-20% Normal MCV, increased MCHC RBCs on blood film: 15-20% spherocytes (small RBC with a less conspicuous central pallor)

Hereditary Spherocytosis DIAGNOSIS Clinical Family history Characteristic blood film picture Splenomegaly Increased osmotic fragility

Function of Red Cells Normal function of Red Cells: To transport oxygen without undergoing any chemical changes Occasionally, an oxygen will be converted to a more reactive oxidizing species: O 2 - (superoxide) H 2 O 2 G6PD Deficiency

Oxidant Defenses in the Red Cell Oxidant Defenses in the Red Cell Superoxide dismutase: converts O 2 - to O 2 and H 2 O Catalase: converts H 2 O 2 to O 2 and H 2 O Glutathione antioxidant system: most important G6PD Deficiency

Glutathione anti-oxidant system 2GSH + H2O2 GSSG + 2 H2O Reaction 1 GSSG + NADPH 2 GSH + NADP Reaction 2 GLU PEROXIDASE GLU REDUCTASE G6PD Deficiency

Role of Gluc 6 Phosphate Dehydrogenase NADPH is consumed by the glutathione antioxidant system The sole source of NADPH is the hexosemonophosphate shunt which is catalyzed by Gluc6 PO4 dehydrogenase Gluc 6 PO4 + NADP 6 Phosphogluconate + NADPH G6PO4 dehydrogenase G6PD Deficiency

Damage to the Red Cell in G6PD deficiency brought about by oxidant stress Damage to Hemoglobin (denaturation) Extravascular hemolysis Membrane destruction Intravascular hemolysis Main mechanism for the anemia in G6PD G6PD Deficiency

CHRONIC ACUTE MYELOID MYELOID LYMPHOID LYMPHOID LEUKEMIAS AML M0-M7 ALL L1-L2 CML CLL

CLASSIFICATION OF ACUTE LEUKEMIAS (FAB) assoc. with difficulty in aspirating the marrow megakaryoblastic AML M7 Erythroleukemia AML M6 Monocytic AML M5 Granulocytic and monocytic AML M4 Commonly associated with DIC Promyelocytic AML M3 With granulocytic maturation AML M2 Without maturation AML M1 Undifferentiated AML M0 ACUTE MYELOGENOUS LEUKEMIA

CLASSIFICATION OF ACUTE LEUKEMIAS (FAB) LEUKEMIAS Mature B cell (burkitt’s lymphoma)-bad prognosis T-cells (bad prognosis) Best prognosis (pre-B cell lineage) Large, finely stippled chromatin, mod. cytoplasm, deeply basophilic cytoplasm with vacuolations ALL L3 Large cells, cleft nucleus, prominent nucleoli, mod. cytoplasm ALL L2 Small cells predominate, homogenous nuclear chromatin, inconspicuous nucleoli, scanty basophilic cytoplasm ALL L1 ACUTE LYMPHOCYTIC LEUKEMIA

Generalities ALL is more common in children AML is more common among the elderly Good prognostic factors for ALL: Female sex Age 2 to 8 years old WBC count < 50,000/cumm Presence of anemia Hyperdiploid DNA CD 10 positivity LEUKEMIAS

PLATELET DISORDERS COAGULATION DEFECTS VITA K DEF BLEEDING DISORDERS HEMOPHILIAS QUALITATIVE QUANTITATIVE TRAUMA VASCULAR PURPURA VITAMIN DEF VASCULAR VWD CONN. TISS. DSE ITP INFECTIOUS SCURVY EHLER DANLOS SYNDROME DIC DIC THROMBASTHENIAS

Hemostasis - the sum total of those specialized functions within the circulating blood and its vessels that are intended to stop hemorrhage.

Normal hemostasis Vessel injury Collagen exposure TXA2, ADP Platelet aggregation 1  hemostatic plug Stable hemostatic plug Vasoconstriction  blood flow Tissue thromboplastin Blood coag. Fibrin

Screening Tests of Hemostasis the most critical screening for hemostatic abnormality is the history screening tests are performed in the face of a history suggestive of a bleeding diathesis and not a substitute for history

Clinical manif typically assoc with specific hemostatic disorder MUCOCUTANEOUS BLEEDING (Epistaxis, petechiae, purpura, ecchymosis, GI hemorrhage Menorrhagia, Bleeding from superficial cuts and abrasions) Thrombocytopenias platelet dysfunction vWD

Clinical manif typically assoc with specific hemostatic disorder Severe hemophilias A/B severe FVII FX or FXIII def severe Type 3 vWD afibrinogenemia Cephalhematomas in NB Hemarthrosis Hematuria IM, intracerebral, retroperitoneal bleeding

Hemostatic Screening Tests CBC, platelet count and peripheral blood smear Bleeding time PT, aPTT, TCT Fibrinogen

Prothrombin Time Intrinsic Surface XII Prekallikrein HMW -K XI XIa IX IXa VIIIa Phospoholipid Ca++ Extrinsic VII-VIIa Tissue Factor Phospholipid Ca++ X Xa Va Phospholipid Ca++ Prothrombin(II) Thrombin(IIa) Fibrinogen(I) Fibrin

Activated Partial Thromboplastin Time Intrinsic Surface XII Prekallikrein HMW -K XI XIa IX IXa VIIIa Phospoholipid Ca++ Extrinsic VII-VIIa Tissue Factor Phospholipid Ca++ X Xa Va Phospholipid Ca++ Prothrombin(II) Thrombin(IIa) Fibrinogen(I) Fibrin

Acquired platelet dysfunction with eosinophilia (APDE) Etiology: unknown Clinical manifestations - occurs mostly in children 1-12 y/o (5-8 y/o) - affects both sexes - symptoms: spontaneous bruising on the extremities, on and off for weeks or months - some with mucosal bleeding: epistaxis, gum bleeding

APDE Laboratory findings 1. Eosinophilia (3-69% of total WBC) in 83% of cases 2. Mild leukocytosis (5,600-35,000/mm3) in 80% of the cases 3. Platelet count - normal; 3% show mild transient thrombocytopenia 4. Platelet morphology: 30-80% of platelets are pale-staining, fewer cytoplasmic granules, good cell membrane appearance and  or no clumping in PBS

APDE Laboratory findings 5. BT-prolonged in 60% of patients. 6. Clot retraction is normal in all cases. 7. Platelet adhesiveness - abn low in 60% of patients. 8. PF 3 release - abn in 50% of patients 9. Platelet aggregation - decreased, Ricof- normal 10. IgG, IgA, IgM- normal; IgE - increased 11. Stool exam -common parasites, e.g. ascaris, hookworm, enterobius, etc. in 50-60% of cases

APDE Treatment 1. Patient education to avoid trauma and injury 2. Antihelminthic drugs for the common intestinal parasites Course and prognosis Course usually lasts for 2-6 months, but sometimes for 2-3 years. Bleeding symptoms may recur. Prognosis Good

Henoch-Schonlein purpura Clinical features 1. Characteristic cutaneous purpura – symmetric purpura involving buttocks and LE, sometimes on extensor surfaces of UE, sparing the trunk above the waist 2. Joint involvement – from asymptomatic swelling to painful involvement of one or more joints 3. Visceral involvement - GIT and kidneys

Henoch-Schonlein purpura Laboratory evaluation 1. To determine normal hemostatic function by screening tests: PC, PBS, BT, PT and aPTT 2. To determine existence and degree of visceral involvement, particularly GI and renal disease. Tests: Hgb/Hct, retic count, guiac testing of the stool, WBC and diff.’l count, urinalysis, serum creatinine or BUN

Immune thrombocytopenic purpura Incidence: unknown, largely affects infants and young children Pathogenesis: platelet antibodies Clinical features: 1. Occurs mostly in children 2-8 years old 2. Both sexes affected 3. 50-80% of cases - history of preceding infection, usually viral, within the preceding 3 weeks

Immune thrombocytopenic purpura Criteria for diagnosis 1. Clinical: purpura with an otherwise essentially normal PE 2. Platelet count low with no evidence of red cell or white cell abnormality 3. BMA:  megakaryocytes with normal myeloid and erythroid elements 4. Exclusion of 2  causes of thrombocytopenia

Drug-induced thrombocytopenia Some drugs considered to cause destructive thrombocytopenia: Quinidine Penicillin Anticonvulsants Quinine Sulfonamides Digoxin Heparin Treatment Discontinue and avoid the drug

ACQUIRED PROTHROMBIN COMPLEX DEFICIENCY Prevalent among breastfed infants Common bleeding sites: intracranial hemorrhage, skin and muscle ecchymoses, GI bleeding Both PT and PTT are elevated Treatment: Vitamin K1 1 to 5 mg IV for 1 to 3 days or until coagulation tests become normal Fresh plasma for serious, life threatening bleeding

HEMOPHILIAS Hemophilia A : deficiency of Factor VIII Hemophilia B: deficiency of Factor IX X-linked recessive May manifest in the neonates as post-vaccination hematomas Hemarthrosis usually involves the big joints Prolonged aPTT and normal PT Treatment: Factor replacement therapy

BLACKFAN-DIAMOND ACQUIRED APLASTIC ANEMIA BONE MARROW FAILURE FANCONI’S ANEMIA CONGENITAL APLASTIC ANEMIA TRANSIENT ERYTHOBLASTOPENIA OF CHILDHOOD (TEC)

Hematology

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