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Hemostasis
- 1. Hemostasis Cynthia J. Rutherford,M.D. Hematology-Oncology Division January 28, 2015
- 2. Phases of hemostasis •Primary hemostasis – platelet adhesion and aggregation • platelet number and function • von Willebrand factor • Secondary hemostasis – activation of the coagulation system • extrinsic • intrinsic • common pathway
- 3. The bleeding patient Cluesfrom the history • Life long history of bleeding • Family history of bleeding • History of liver disease • History of hematologic disorder – ITP, leukemia • Medication history – ASA, NSAIDS . . .
- 4. The bleeding patient Cluesfrom the physical exam • Pattern of skin and mucosal bleeding seen in defects of primary hemostasis - suggest thrombocytopenia, platelet defect or vWD • Pattern of muscle/deep bleeding suggesting defect in secondary hemostasis - coagulopathy • Stigmata of liver disease – arterial nevi, splenomegaly, palmar erythema • Pattern and clinical scenario of DIC
- 5. Clues from thephysical exam Primary hemostatic defects PetechiaeBruising
- 6. Clues from thephysical exam Severe primary hemostatic defects Mucosal bleeding = “wet” purpura
- 7. Clues from thephysical exam Secondary hemostatic defects Hemophiliac joint bleed Deep muscle bleed r/o compartment syndrome
- 8. Clues from thephysical examination Acute DIC
- 9. Patient with hemostaticdefect Iatrogenic bleeding from IM injection
- 10. Laboratory evaluation ofthe bleeding patient • Hemoglobin/hematocrit – to assess effect of bleeding • Platelet count – bruising below 50K – bleeding below 10-20K • Platelet function – PFA-100 – Replaces “bleeding time” • Basic tests of coagulation – PT, PTT – Use these to guide specific factor testing
- 11. PFA-100 testing Platelet FunctionAnalyzer Tests 1º hemostasis with collagen-ADP and collagen- epinephrine agonists Very sensitive (90%) for - vWD diagnosis - platelet dysfunction Useful in monitoring DDAVP therapy
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- 13. Common causes ofcoagulopathy • Advanced liver disease – especially low factor VII – liver makes all coagulation factors, except factor VIII • Anticoagulants – Warfarin inhibits factor II, VII, IX and X – “new” oral anticoagulants – anti-Xa and anti thrombin inhibitors • DIC • Von Willebrand disease • Hemophilia • Other inherited factor deficiencies – afibrinogenemia, factor VII deficiency, etc. • Coagulation inhibitors
- 14. Treating the commoncauses of coagulopathy • Advanced liver disease – especially low factor VII Treat only with bleeding • Disseminated intravascular coagulation (DIC) – Treat cause – Maintain circulation – Transfuse platelets if platelets <50K and patient is bleeding, aiming to maintain platelets 50-75K – Transfuse cryoprecipitate to keep fibrinogen >50mg/dL Note: Plasma infusion not often needed as other coagulation factors not as depleted as fibrinogen
- 15. Cryoprecipitate • Contains only –Fibrinogen – VIII and vWD factor – Factor XIII • Cryoprecipitate packs pooled from 5 donors • Short shelf life after thawing – 4 hours
- 16. Von Willebrand disease •Autosomal dominant inherited condition • Reduced or dysfunctional von Willebrand factor affects: – Platelet adhesion and aggregation – Initiation of secondary hemostasis – Transport of factor VIII
- 17. Primary hemostasis •vWF •Factor VIII •EndothelialCell •Endothelial •Cell •Unactivated •gpIIb/IIIa •Circulating •Platelet •Subendothelium •(Exposed Collagen) •gpIb/IX •Ligand
- 18. Primary hemostasis Aggregation ofactivated platelets •Fibrinogen •Activated Platelet •Activated gpIIb/IIIa
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- 20. Classification of von Willebrand’sDisease Type 1 Quantitative deficiency of vWF 75-80% Autosomal dominant Type 2 Qualitative deficiency of vWF 15-20% Autosomal dominant Type 3 Absence of vWF 1:1,000,000 Autosomal recessive
- 21. Laboratory Diagnosis of vonWillebrand Disease • General screening tests – PFA – 100 (replaces bleeding time) – Activated partial thromboplastin time • Tests specific to vWD – Factor VIII coagulant function – vW factor antigen – vW factor (Ristocetin co-factor) assay – Ristocetin-induced platelet aggregation – vW factor Multimer analysis
- 22. Type 2 vWD: QualitativeAbnormalities in vWF Type 2A Impaired secretion or increased proteolysis Absence of large and intermediate multimers Type 2B Increased affinity for gpIb Absence of large multimers Type 2M Decreased platelet-dependent function Normal multimer pattern Type 2N Decreased affinity for factor VIII Normal multimers
- 23. Patterns of multimersin von Willebrand disease subtypes •Largest Multimers •Intermediate •Multimers •Small Multimers •Normal •Type I •Type IIA •Type IIB •Type III
- 24. Treatment of von WillebrandDisease • DDAVP to release vWF from endothelial cells and platelets • Replacement of vWF with plasma-derived products - Humate-P, Alphanate or Wilate • Prevention of fibrinolysis – mucous membrane bleeding only – e-amino caproic acid (Amicar® ) • General measures – estrogens, topical agents
- 25. DDAVP in von Willebrand’sDisease Releases stored DDAVP from endothelial cells Increases vWF 2-3 fold – need therapeutic trial Route Dose Time to Peak Intravenous 0.3 µg/Kg 30 minutes Intranasal 300 µg 60 minutes • Side effects: flushing, headache, hyponatremia, ? myocardial infarction • Modest tachyphylaxis
- 26. Hemophilia Inherited deficiency ordysfunction of factor: VIII Hemophilia A 85% (Classic hemophilia) IX Hemophilia B 15% (Christmas disease)
- 27. Types of Hemophilia #in # in TYPE FACTOR INCIDENCE USA TEXAS Hemophilia A VIII 1:7000 17,500 1100 (Classical hemophilia) Hemophilia B IX 1:30,000 4000 250 (Christmas disease)
- 28. Signs and Symptomsof Hemophilia • Hemarthroses – joint bleeding • Muscle hemorrhage • Soft tissue hematomas • CNS bleeding • Uncommon: epistaxis, other mucosal bleeding, prolonged bleeding from cuts, petechiae
- 29. Hemophilia Genetics • X-linkedrecessive inheritance • Disease almost exclusively in males • High rate of spontaneous mutation – one third new cases have negative family history • Carrier testing & pre-natal diagnosis available (RFLP)
- 30. Degrees of Severityof Hemophilia Factor level Frequency and Severity Type (Normal 50-150%) of bleeding of bleeding Severe <1% 30-50 times per year Spontaneous Moderate 1-5% 3-10 times per year Occ spontaneous, usually post trauma Mild 5-30% <1 per year Post-trauma or surgery only
- 31. Signs and Symptomsof Hemophilia • Soft tissue hematomas • Hemarthroses • Muscle hemorrhage • CNS bleeding • Uncommon: epistaxis, other mucosal bleeding, prolonged bleeding from cuts, petechiae
- 32. Spontaneous Head “Bump” SevereHemophilia
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- 35. Forearm Compartment Bleed •Volkman’sischemic contracture•Compartment syndrome
- 36. Iatrogenic Complications in hemophilia •Circumcision •i.m.injection •i.j. stick
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- 38. Laboratory Diagnosis ofHemophilia • aPTT Prolonged • Prothrombin time - INR Normal • (Bleeding time) Normal • PFA-100 Normal • Platelet count Normal • von Willebrand factor Normal • Factor VIII One or the other • Factor IX reduced•}
- 39. Treatment in hemophilia •For mild hemophilia A – always consider DDAVP – will raise factor level 2-3X • Factor replacement in doses related to the severity of the bleed or procedure
- 40. Hemophilia Factor VIII andIX Concentrates • Heat or solvent-detergent treated – “intermediate” purity factors, e.g. Humate-P • Purified with – Monoclonal antibodies – Chromatography • Recombinant factors • In 2014 – factors with longer T1/2
- 41. Major Emergencies inHemophilia • Intra-cranial hemorrhage • Iliopsoas hemorrhage • Bleeding around airway • Uncontrolled external bleeding
- 42. Management “pearls” for hemophiliacsin the ER • Most patients are very knowledgeable about their disease, its treatment with concentrate and which veins are best for infusion • Laboratory testing (PT/PTT, factor assays, CBC, etc.) or x-rays (e.g, of joints) not routinely necessary • Following trauma or when any serious illness is suspected, treat with factor concentrates first and then do laboratory tests and x-rays
- 43. The bleeding patient •Don’t panic! • Try to figure the cause from history and physical examination • Order laboratory tests before blood or other products given • Ask for help – there’s a lot of it around!
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