Evaluation of the bleeding patient

1. Evaluation of the bleeding patient V. Kinsella M.D. January,27 2006

2. MILD bleeding • Platelets secretion disorders • vW deficiency • Platelets dense granules deficiency 4. Unknown

3. Hemostasis and thrombosis • Dependent on 3 factors: • Vascular endothelium • Platelets • Coagulation system

4. 1.Clinical aspects of bleeding

5. 1.Clinical aspects of bleeding Evaluation of patients with bleeding is a multi-step process: • Complete history • Detailed physical exam • Laboratory evaluation

6. history • Is there a personal or family history of bleeding after surgical procedures, dental procedures, childbirth, or trauma? • When the bleeding episode started? • Has the patient received medications that can cause or make worse a bleeding problem?

7. history Many drugs can contribute to bleeding; semisynthetic penicillins cephalosporins calcium channel blocker dipyridamole thiazides alcohol quinine, quinidine chlorpromazine, sulfonamides INH, rifampin methyldopa phenytoin, barbiturates, warfarin, heparin, thrombolytic agents NSAIDs, ASA allopurinol TMP/SMX

8. physical exam 1. Assess volume status (correct shock if present) 2. Look for hepatosplenomegaly 3. Do a rectal exam for evidence of GI bleeding 4. Examine oropharynx for evidence of petechiae

9. Clinical aspects of bleeding

10. physical exam • Look for physical signs and symptoms of diseases related to capillary fragility: • Cushing’s syndrome, Marfan syndrome or exogenous steroids • "senile purpura” • Petechiae secondary to coughing, sneezing, Valsalva maneuver, blood pressure measurement • vasculitis ("palpable purpura") • Telangiectasias (Osler-Weber-Rendu syndrome) (HHT)

11. petechiae (typical of platelet disorders) Do not blanch with pressure (angiomas)Not palpable (vasculitis)

12. vasculitis (palpable rash)

13. 2. Hematologic disorders causing bleeding • Platelet disorders • Coagulation factor disorders

14. Clinical differentiation Platelets x Coagulation Defects

15. Platelets Defects • Generally have immediate onset of bleeding after trauma • Bleeding is predominantly in skin, mucous membranes, nose, GI tract, and urinary tract • Bleeding may be observed as petechiae (<3 mm) or ecchymoses (>3 mm

16. Clinical aspects of bleeding

17. Coagulation Defects • "Deep" bleeding (in the joint spaces, muscles, and retroperitoneal spaces) is common. Observed on exam as hematomas and hemarthroses.

18. Hematoma (typical of coagulation factor disorders)

19. Hemarthrosis (acute)

20. Laboratory Evaluation of Bleeding CBC and smear Platelet count Thrombocytopenia RBC and platelet morphology TTP, DIC, etc. Coagulation PT extrinsic/common pathways PTT Intrinsic/common pathways Coag. factor assays Specific factor deficiencies 50:50 mix Inhibitors (e.g., antibodies) Fibrinogen assay Decreased fibrinogen Thrombin time Qualitative/quantitative fibrinogen defects D-dimer Fibrinolysis (DIC)

21. Laboratory Evaluation of Bleeding Platelet function von Willebrand factor vWD Bleeding time In vivo test (non-specific) Platelet function analyzer (PFA) Qualitative platelet disorders

22. Laboratory Evaluation of the Coagulation Pathways Partial thromboplastin time (PTT) Prothrombin time (PT) Surface activating agent (Ellagic acid, kaolin) Phospholipid Calcium Thromboplastin Tissue factor Phospholipid Calcium Intrinsic pathway Extrinsic pathway Common pathway Thrombin time Thrombin Fibrin clot

23. Coagulation cascade Intrinsic system (surface contact) Extrinsic system (tissue damage) XII XIIa Tissue factor XIa XI IX IXa VIIa VII VIII VIIIa X Vitamin K dependant factors Xa V Va (Thrombin) IIa IIa II Fibrinogen Fibrin

24. Initial Evaluation of a Bleeding Patient Normal PT Normal PTT Consider evaluating for: Platelet disorder Mild factor deficiency Factor XIII Monoclonal gammopathy Abnormal fibrinolysis a2 anti-plasmin deficiency Vascular disorders Dysfibrinogenemia

25. Initial Evaluation of a Bleeding Patient Elevated PT Normal PTT 50:50 mix is abnormal Repeat with 50:50 mix Test for inhibitor activity: 1.Specific: Factor VII (rare) 2.Non-specific: Anti-phospholipid 50:50 mix is normal Test for factor deficiency: 1.Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC) 2. Deficiency of factor VII (rare)

26. Initial Evaluation of a Bleeding Patient Normal PT Abnormal PTT 50:50 mix is abnormal Repeat with 50:50 mix Test for inhibitor activity: Specific factors: VIII, IX, XI Non-specific (anti-phospholipid) 50:50 mix is normal Test for factor deficiency: Isolated deficiency in intrinsic pathway (factors VIII, IX, XI) Multiple factor deficiencies (rare)

27. Initial Evaluation of a Bleeding Patient Abnormal PT Abnormal PTT 50:50 mix is abnormal Repeat with 50:50 mix Test for inhibitor activity: Specific : Factors V, X, prothrombin, fibrinogen (rare) Non-specific: anti-phospholipid (common) 50:50 mix is normal Test for factor deficiency: Isolated deficiency in common pathway: Factors V, X, Prothrombin, Fibrinogen Multiple factor deficiencies (common) (Liver disease, vitamin K deficiency, warfarin, DIC)

28. Bleeding time • 5-10% of patients hospitalized patients have a prolonged bleeding time • Most of the prolonged bleeding times are due to aspirin or drug ingestion • Prolonged bleeding time does not predict excess surgical blood loss • Not recommended for routine testing in preoperative patients

29. Thrombin Time • Measures rate of fibrinogen conversion to fibrin • Procedure: • Add thrombin with patient plasma • Measure time to clot • Variables: • Source and quantity of thrombin

30. Causes of prolonged Thrombin Time • Heparin • Hypofibrinogenemia • Dysfibrinogenemia • Paraprotein • Thrombin inhibitors (Hirudin) • Thrombin antibodies

31. PLATELETS

32. Approach to the thrombocytopenic patient • History • Is the patient bleeding? 2. Are there symptoms of a secondary illness? (neoplasm, infection, autoimmune disease) 3. Is there a history of medications, alcohol use, or recent transfusion?

33. Approach to the thrombocytopenic patient • History 4. Are there risk factors for viral infection? 5.Is there a family history of thrombocytopenia? 6. Do the sites of bleeding suggest a platelet defect?

34. Approach to the thrombocytopenic patient • Assess the number and function of platelets • CBC with peripheral smear • Bleeding time • Platelet aggregation study • PFA

35. Quantitative disorders Abnormal distribution Dilution effect Decreased production Increased destruction Classification of platelet disorders

36. Qualitative disorders Inherited disorders (rare) Acquired disorders Immune Medications Chronic renal failure Cardiopulmonary bypass Liver disease Classification of platelet disorders

37. Inherited platelet disorders Rare congenital abnormalities on synthesis or release of secretory granules

38. Inherited platelet disorders • Gray platelets syndrome: No alpha granules

39. Inherited platelet disorders • May-Hegglin: Thrombocytopenia Large platelets Neutrophils – Dohle bodies

40. Inherited platelet disorders • Glazmann’s thrombasthenia: Congenital deficiency or abnormality of GP IIb-IIIa • Bernard-Solier syndrome: Congenital deficiency or abnormality of GP Ib

41. Acquired platelet disorders • Decreased production: Ineffective thrombopoiesis - MDS • Increased destruction: Immune Non-immune • Poor aggregation

42. Increased platelets destruction 1. Immune-mediated Idiopathic - ITP Drug-induced Collagen vascular disease Lymphoproliferative disease Sarcoidosis 2.Non-immune mediated DIC Microangiopathic hemolytic anemia

43. ITP is a diagnosis of exclusion !

44. Initial Treatment of ITP Platelet count Symptoms Treatment >50,000 None 20-50,000 Not bleeding None Bleeding Glucocorticoids IVIG <20,000 Not bleeding Glucocorticoids Bleeding Glucocorticoids IVIG Hospitalization Rituximab

45. COAGULATION FACTOR DEFECTS

46. vonWillebrand’s disease Hemophilia (A and B) Inherited Coagulation factor bleeding disorders

47. vonWillebrand disease • Most common hereditary coagulation disorder • Autossomal dominant • Incidence 1:1000 Erik A. vonWillenbrand M.D. (1870-1949)

48. vonWillebrand factor • Synthesis in endothelium and megakaryocytes • Forms large multimers • Carrier of factor VIII • Anchors platelets to subendothelium • Bridge between platelets

49. vonWillebrand disease • Abnormal synthesis of von Willebrand factor (vWF) causes decreased platelet adhesion and decreased serum levels of factor VIII

50. vonWillebrand disease Classification • Type 1 Partial quantitative deficiency (“decreased”) • Type 2 Qualitative deficiency (“abnormal”) • Type 3 Total quantitative deficiency (“absent”)