Bleeding Disorders

1. Bleeding Disorders Meera Shreedhara 8/25/08

2. What is it? • A bleeding disorder is an acquired or inherited tendency to bleed excessively

5. Mechanisms of bleeding • Vascular Integrity • Platelets • Clotting factors • Fibrinolysis • Derangement of any of these factors can cause abnormal bleeding

6. Key to diagnosis • History • History • History

7. Bleeding history • Epistaxis • Gingival hemorrhage • Mucosal Bleeding • Heavy Menses • Child birth • Easy bruisability • Bleeding following tooth extractions • Hematomas • Bleeding following surgery • Hemarthrosis

8. Medication History • Aspirin • Warfarin • NSAIDS • B- Lactam antibiotics • Clopidogrel and other antiplatelet agents • Herbal medications.

9. Nutritional history • Vit K deficiency • Vit C deficiency • Broad spectrum antibiotics

15. History • Should the pt undergo a limited or extensive workup? • Is this acquired or hereditary? • Is this likely a disorder of clotting factors,platelets, fibrinolysis or vWF? • Do medications or intercurrent illnesses play a role? • What is the immediate cause for which a workup is being done?

16. Hereditary • Deficiency of coagulation factors • Hemophilia • Fibrinogen deficiency • Von Willebrand disease • Platelet disorders • Glanzmann thrombasthenia • Bernard-Soulier syndrome • Platelet granule disorders • Fibrinolytic disorders • Alpha 2 antiplasmin deficiency • PAI 1 deficiency • Structural disorders • Hemorrhagic Telangiectasias • Ehler Danlos syndrome

17. Acquired • Thrombocytopenis • Liver disease • Renal failure • Vit K deficiency • Acquired antibodies to coagulation factors • DIC • Drugs • Vascular

18. Lab testing • Platelet count • Bleeding time-Measure of the interaction of platelets with the blood vessel wall. • Thrombocytopenia (platelet count usually below 50,000/microL), • Qualitative platelet abnormalities (eg, uremia), • von Willebrand disease (VWD), • Vascular purpura, • Severe fibrinogen deficiency

19. Platelet function assay • Expose platelets within citrated whole blood to high shear (5,000 to 6,000/sec) within a capillary tube and monitor the drop in flow rate as the platelets form a hemostatic plug within the center of a membrane coated with collagen and either ADP or epinephrine • Abnormal closure times are an indication of platelet dysfunction, they are not specific for any disorder • The test is coagulation factor independent • PFA-100™ is more sensitive (>70 percent) than the bleeding time (20 to 30 percent) in detecting all subtypes of von Willebrand's disease (vWD) • Exception is type 2N vWD, in which the hemostatic defect resides in the Factor VIII binding site on vWF

20. Platelet function assay • Collagen/epinephrine closure time (CEPI-CT)- Abnormal in Aspirin intake • Collagen/adenosine diphosphate (CADT-CT)-Normal in aspirin intake

21. Prothrombin time • Measure of the extrinsic pathway and common pathway • Bypasses the intrinsic pathway and uses thromboplastins to substitute for platelets • Within the combined pathway, factors VII, X, and prothrombin are vitamin-K dependent and are altered by warfarin

23. Prolonged PT • Vitamin K deficiency • Liver disease, which decreases the synthesis of both vitamin K-dependent and -independent clotting factors. • Deficiency or inhibition of factors VII, X, II (prothrombin), V, or fibrinogen • The infrequent antiphospholipid antibodies (lupus anticoagulant phenomenon) with antiprothrombin activity • Heparin does NOT prolong the PT

24. aPTT • Measures the intrinsic and common pathways of coagulation • Uses partial thromboplastins; they are incapable of activating the extrinsic pathway • Prolonged in deficiency of, or an inhibitor to, any of the clotting factors except for factor VII • Prolonged in the presence of Lupus Anticoagulant. • Used to monitor heparin activity

27. Thrombin time • Measure conversion of fibrinogen to fibrin monomers and the formation of initial clot by thrombin • Hypofibrinogenemia, • Dysfibrinogens • Increased fibrin split products • Heparin increases TT but not RT

29. Factor deficiencies/ inhibitors • A prolonged aPTT can be due to a deficiency (or absence) of a coagulation factor or the presence of a coagulation factor inhibitor • Mixing studies help differentiate this • Lupus anticoagulants can result in a prolonged aPTT that is not correctable by the addition of normal plasma • Overcome by adding excess platelet phospholipid (particularly a hexagonal phase phospholipid) or by assessing the diluted Russell's viper venom time

30. Fibrinolysis • Fibrin and fibrinogen degradation products (FDP) are protein fragments resulting from the action of plasmin on fibrin or fibrinogen

31. Fibrinolysis • FDP assays do not differentiate between fibrin degradation products and fibrinogen degradation products • Fibrin D-dimers are degradation products of cross-linked fibrin • D-dimers specifically reflect fibrinolysis of cross-linked fibrin (ie, the fibrin clot) – so are more reliable indicators of thrombosis

32. Fibrinolysis • Assays for plasminogen, • Tissue plasminogen activator (t-PA), • Alpha-2 antiplasmin, • Plasminogen activator inhibitor-1 (PAI-1), • Thrombin-activatable fibrinolysis inhibitor (TAFI).

33. Normal PT and PTT • Thrombocytopenia • vWD • Factor 13 deficiency • Platelet dysfunction • Vascular purpuras • Psychogenic purpura

34. Normal PT and Prolonged aPTT • Hemophilia A • Hemophilia B • Factor XI deficiency • Factor VIII inhibitor • Malignancy, • Clonal lymphoproliferative disorders, • Pregnancy, • Rheumatologic disorders

35. Prolonged PT and normal aPTT • Factor VII deficiency • Warfarin therapy • Early liver disease • Early DIC

36. Prolonged PT and PTT • Vit K deficiency • Liver disease • Warfarin treatment • Acquired inhibitor to factor V • Factor X deficiency- seen in Amyloidosis • DIC

37. Acute Promyelocytic Leukemia • DIC is often seen at presentation or during treatment • Medical Emergency as Cerebral hemorrhage can occur in upto 4% of untreated pts • Promyelocytes seen on smear • Reciprocal translocation between the long arms of chromosomes 15 and 17, with the creation of a fusion gene, PML/RAR-alpha • Immediate initiation of ATRA induces de deifferentiation

38. Hemophilia • Hemophilia A and B are X-linked recessive diseases • Severe disease <1 % factor activity, • Moderate disease- 1 to 5 % • Mild disease >5 % • The most common sites are into joints and muscles and from the gastrointestinal tract

39. Treatment • The two components to therapy are treatment of active bleeding and inhibitor ablation via immune tolerance induction • Cryoprecipitate has high levels of factor VIII • Porcine Factor VIII • Recombinant human Factor VIII • The choice of factor VIII product usually is based upon safety, purity, and cost.

40. Dosing • One international unit (IU) of clotting factor is that amount present in 1 mL of pooled normal plasma • Dose of F VIII (IU) = Weight (kg) x (Desired % increase) x 0.5 • Depends on the clinical indication and the presence of inhibitors

41. von Willebrand’s disease • Most common of the inherited bleeding disorders • In 1926, Erik von Willebrand described the first patient with the disease • Von Willebrand factor (VWF) binds to both platelets and endothelial components, forming an adhesive bridge between platelets and vascular subendothelial structures and between adjacent platelets at sites of endothelial injury

42. Malignant diseases Monoclonal gammopathy of unknown significance Multiple Myeloma Non-Hodgkin's lymphoma Chronic lymphocytic leukemia Waldenstrom's macroglobulinemia Essential thrombocythemiaPolycythemia vera Chronic myelogenous leukemia Wilms tumor Other carcinomas Immunologic disorders Systemic lupus erythematosus Other autoimmune diseases Other disorders Hypothyroidism Ventricular septal defect Aortic stenosis Mitral valve prolapse Gastrointestinal angiodyplasia Uremia Hemoglobinopathies Drugs and other agents Valproic acid Antibiotics Acquired von Willebrand’s disease

43. Treatment • DDAVP • Replacement of vWF • EACA • Tranexamic acid • Recombinant factor 7

44. Its better to bleed than clot!

45. Therapies other than factor replacement • DDAVP • EACA • Tranexamic Acid • Factor 7 inhibitor- Novoseven

46. Liver disease Vs DIC • Low factor V levels can be used as evidence for either reduced hepatic synthetic function or increased consumption, as in DIC • Factor VIII is not manufactured by hepatocytes; factor VIII levels are usually normal or increased in liver disease