CAUSES OF BLEEDING

1. CAUSES OF BLEEDING • Defective clot formation • Platelet plug • Fibrin clot • Excessive fibrinolysis • Vascular fragility

2. PLATELET DEFECTS Thrombocytopenia Increased consumption (ITP, DIC) Decreased production (marrow disease, chemo) Defective platelet function (ASA, other drugs most common cause) Von Willebrand disease (defective platelet adhesion) Most common inherited bleeding disorder?

3. DEFECTS IN FIBRIN CLOT FORMATION Inherited deficiency of single clotting factor (hemophilia A or B) Acquired deficiency of multiple clotting factors Liver disease Vitamin K deficiency/warfarin DIC Circulating inhibitor Antibody to factor VIII Heparin Defective fibrin crosslinking (factor XIII deficiency - very rare)

4. EXCESSIVE FIBRINOLYSIS DIC Thrombolytic drug administration Inherited deficiency of fibrinolytic inhibitor (rare)

5. VASCULAR DISORDERS THAT CAN CAUSE BLEEDING Inherited defect in collagen formation (Ehlers Danlos syndrome) Acquired defect in collagen formation (scurvy) (mainly purpura) Infiltrative disease (amyloidosis) Vasculitis (purpura only)

6. ASSESSMENT OF BLEEDING RISK History & physical exam* Platelet count* Assessment of platelet function Bleeding time Platelet Function Analysis Assessment of fibrin clot formation PT/INR* aPTT Thrombin time Assessment of fibrinolytic system *Part of routine pre-op screen

7. USEFULNESS OF THE HISTORY IN SCREENING FOR BLEEDING DISORDERS Odds ratios for presence/absence of bleeding disorder by multivariate analysis Symptom Odds ratio 95% CI Family members with proven bleeding disorder 50.5 12.5-202.9 Profuse bleeding from small wounds 30 8.1-111.1 Profuse bleeding with tonsillectomy 11.5 1.2-111.9 Easy bruising 9.9 3.0-32.3 Profuse bleeding after surgery 5.8 1.3-26.4 Muscle bleeding 4.8 0.7-31.4 Frequent nosebleeds 3.8 0.9-15.7 Profuse bleeding with tooth extraction 3.2 0.9-11.3 History of blood in stool 2.8 0.7-11.7 Family members with bleeding symptoms 2.5 0.7-9.4 History of joint bleeding 2.5 0.6-10.2 Menorrhagia 2.5 0.6-9.9 Profuse bleeding with childbirth 2.1 0.3-13.5 Frequent gum bleeding 0.7 0.3-2.0 History of hematuria 0.5 0.1-2.3 Arch Intern Med 1995;155:1409

8. FAMILY HISTORY IN BLEEDING DISORDERS • von Willebrand disease: dominant inheritance, variable penetrance • Hemophilia: sex linked inheritance, high penetrance • Other clotting factor deficiencies - recessive inheritance Family tree in hemophilia

9. PATTERNS OF BLEEDING IN HEMOSTATIC DISORDERS Platelet/vascular disorders Coagulation factor deficiency Onset Immediate Delayed Skin, mucosal surfaces Location Deep tissue

10. PLATELET COUNT VS BLEEDING RISK Bleeding risk rises as platelet count falls below 100K Plts > 50K safe for many invasive procedures Higher count may be needed if procedure is “blind” and it would be difficult to achieve hemostasis mechanically Associated platelet function defects (eg, ASA), liver disease or DIC enhance risk Lower bleeding risk at a given platelet count if thrombocytopenia due to consumption (eg, ITP) vs decreased production

11. ASSESSMENT OF PLATELET/VASCULAR FUNCTION: THE BLEEDING TIME Advantages In vivo test; measures vascular as well as platelet function Disadvantages Difficult to standardize Sensitivity and specificity relatively poor Does not predict bleeding risk

12. ASSESSMENT OF PLATELET/VASCULAR FUNCTION: PLATELET FUNCTION ANALYSIS Advantages In vitro test Well-standardized Better sensitivity and specificity Disadvantages Does not assess vascular function No data re: ability to predict bleeding risk Consider testing when clinical picture or family history suggest bleeding disorder, platelet count normal, AND no concurrent disease or drug known to affect platelet function

13. FIBRIN CLOT FORMATION TF VII(a) PL Ca++ VIIIa IXa Xa Va “Contact" system XIa XII, HMWK, PK ? Not physiologically important IIa Fibrin

14. The prothrombin time ASSESSMENT OF FIBRIN CLOT FORMATION Sensitive to changes in factors VII, V, X, II, fibrinogen Best global test of clotting system integrity Magnitude of test abnormality proportional to severity of coagulopathy Abnormal in most acquired coagulopathies (liver disease, vitamin K deficiency, DIC) Will not detect deficiencies of factors VIII, IX, XI TF VII(a) Prothrombin time PL Ca++ VIIIa IXa Xa Va XIa XII, HMWK, PK IIa Fibrin

15. ISI ( ) Patient PT Mean Normal PT INR = ISI (International Sensitivity Index) is reagent- and method-specific; higher number indicates lower sensitivity to changes in clotting factor levels

16. Reagent A: ISI = 1.24, mean normal = 12.6 sec PT = 22 sec 1.24 ) ( 22.0 12.6 INR = = 2.0 Reagent B: ISI = 2.46, mean normal = 12.2 sec PT = 16.2 sec 2.46 ) ( 16.2 12.2 INR = = 2.0

17. INR COMPARISON 10 patients on stable warfarin therapy REAGENT E (ISI 2.98) REAGENT B (ISI 0.96) PATIENT # INR INR 1 3.4 2.7 2 2.8 2.5 3 3.5 2.3 4 2.6 2 5 2.2 1.2 6 2.3 2.4 7 1.9 1.7 8 3 2.8 9 2.2 2.7 10 4 4

18. DOES THE INR SYSTEM WORK IN LIVER DISEASE? Comparison of three reagents Reagent (ISI) A (0.86) B (1.09) C (2.53) Mean INR (warfarin pts) 2.63 2.75 2.67 Mean INR (liver disease) 1.88 2.17 2.63 Thrombosis and Haemostasis 1994;71:727

19. The partial thromboplastin time ASSESSMENT OF FIBRIN CLOT FORMATION Sensitive to changes in factors XI, VIII, IX,, V, X, II, fibrinogen Very sensitive to contact factor levels (XII, etc) - not clinically important Magnitude of test abnormality often not proportional to severity of coagulopathy Used to screen for hemophilia, monitor heparin, detect circulating anticoagulants aPTT TF VII(a) PL Ca++ VIIIa IXa Xa Va XII, HMWK, PK XIa IIa Fibrin

20. RESULTS OF 1025 CONSECUTIVE aPTT MEASUREMENTS (excluding those ordered for monitoring heparin) # abnormal: 143 (14%) # TESTS # PATIENTS Abnormal result 143 97 On anticoagulant 64 37 Liver disease 41 27 No cause found, no bleeding 15 14 Normal on repeat testing 9 9 Known hemophilia 5 4 History of intestinal bypass 5 4 Other malabsorption (CF) 2 1 Technical problem with test 1 1 0 0 Newly dx'd bleeding disorder Robbins and Rose, Ann Intern Med 1979;90:796

21. RESULTS OF PREOPERATIVE SCREENING IN 1603 CHILDREN PT, aPTT, BT, history # with abnormal labs on repeat testing 13 # of those in whom bleeding disorder diagnosed (1 mild hemophilia, 1 VWD) 2 # in which bleeding disorder not apparent from history alone (mild hemophilia A) 1 Burk et al, Pediatrics 1992;89:691

22. The aPTT can help us decide why a patient is bleeding, but is much less useful in predicting whether a patient will bleed To bleed or not to bleed? is that the question for the PTT?

23. The thrombin time ASSESSMENT OF FIBRIN CLOT FORMATION Thrombin time TF VII(a) PL Ca++ Measures only conversion of fibrinogen to fibrin, fibrin polymerization Very sensitive to heparin; normal or near-normal result essentially rules out heparin as cause of prolonged clotting times VIIIa IXa Xa Va XIa XII, HMWK, PK IIa Fibrin

24. FIBRINOLYSIS Platelets Plasminogen Endothelial cell Fibroblasts PAI-1 TPA UK Macrophage Plasmin Liver PI PI 2 2 Fibrin FDP Fibrinogen

25. ASSESSMENT OF THE FIBRINOLYTIC SYSTEM Euglobulin lysis time (not well standardized) Alpha2-antiplasmin level* (depletion implies poor fibrinolytic control) PAI-1 activity Available at UW

26. Bleeding severity vs antiplasmin activity patients with platelets > 30,000 100 80 0-2+ bleeding 60 % of patients 3-4+ bleeding 40 20 0 < 50% 50-75% > 75% Antiplasmin activity

27. VON WILLEBRAND DISEASE Inherited deficiency or dysfunction of von Willebrand factor Type I = partial quantitative deficiency Type II = partial qualitative deficiency Type III = severe deficiency Defective platelet adhesion, (slightly) decreased factor VIII activity Mild or moderate bleeding tendency in most type I and type II pts Diagnosis: von Willebrand antigen, factor VIII, ristocetin cofactor activity, platelet function analysis Treatment: DDAVP (type I); intermediate purity factor VIII concentrate (types II, III)

28. NORMALS TYPE I VWD VARIABILITY IN VON WILLEBRAND FACTOR LEVELS OVER TIME Abildgaard et al, Blood 1980;56:712

29. HEMOPHILIA Inherited deficiency of factor VIII (Hemophilia A) or IX (Hemophilia B) Sex-linked inheritance: almost all patients male Bleeding into joints, soft tissues; mucosal/skin/CNS bleeding rare Severity inversely proportional to factor level: <1% = severe: frequent "spontaneous" bleeds 1-5% = moderate: spontaneous bleeding less common > 5% = mild: bleeding mainly after trauma/surgery; may go undiagnosed until adulthood

30. Treatment of bleeding episodes HEMOPHILIA Unexplained pain in a hemophiliac should be considered a bleed until proven otherwise External signs of bleeding may be absent, particularly early in course Treatment: factor replacement, pain control 1 U/kg factor VIII should increase plasma level by about 2% Test for inhibitor if unexpectedly low response to factor replacement

31. HEMOPHILIA Factor replacement in severe hemophilia A Site of bleed Desired factor level Dose Other Joint 40-50% 20-40 U/kg/day Rest, immobilization, PT Risk of compartment syndrome or neuro compromise Muscle 40-50% 20-40 U/kg/day Follow with antifibrinolytic therapy Oral mucosa 50% initially 25 U/kg x 1 Initially 80-100%, then 30% until healed 40-50 U/kg then 30-40 U/kg daily Pressure, packing, cautery Epistaxis Initially 100%, then 30% until healed 40-50 U/kg then 30-40 U/kg daily Endoscopy to find lesion GI Initially100%, then 30% until healed 40-50 U/kg then 30-40 U/kg daily GU R/O stones, UTI Initially100%, then 50% until healed 50 U/kg then 25 U/kg q 12h infusion CNS Initially100%, then 50% until healed 50 U/kg then 25 U/kg q 12h infusion Test for inhibitor before surgery! Trauma or surgery

32. VITAMIN K DEFICIENCY 200 150 Deficiency of factors II, VII, IX, X, protein C, protein S Causes: Decreased vitamin K intake Decreased production of vitamin by gut flora (antibiotics) Poor absorption - sprue, biliary obstruction, etc Inhibition of vitamn K action (warfarin, certain antibiotics) Bleeding tendency roughly correlated to INR Treatment: vitamin K (oral or parenteral); FFP Bleeding events/100 patient-yr 100 50 0 <2 2.0-2.9 3-4.4 4.5-6.9 >7 INR

33. LIVER DISEASE Pathophysiology: Diminished synthesis of most clotting proteins and inhibitors platelet sequestration low grade intravascular coagulation? Bleeding due to impaired fibrin formation and (in some cases) increased fibrinolytic activity INR, platelet count, antiplasmin level help predict bleeding risk Treatment: FFP, platelets, Amicar

34. COAGULATION INHIBITORS Heparin: prolongs thrombin time, aPTT, high levels prolong PT/INR Factor VIII antibodies: prolong aPTT only Bovine thrombin antibodies: prolong all clotting times, minimal bleeding Lupus anticoagulant (does not cause bleeding) Diagnosis: prolonged clotting time that does not correct after mixing with normal plasma Treatment depends on type of inhibitor

35. THROMBOLYTIC DRUGS t-PA, streptokinase, urokinase, etc Activate plasminogen, initiate fibrinolysis Depletion of plasminogen may limit efficacy Most lysis initially at surface of clot; antiplasmin inhibits plasmin in blood Depletion of antiplasmin increases risk for systemic fibrinolysis Life-threatening bleeding may occur despite normal fibrinogen, clotting times Risk of bleeding greater with higher dose, longer duration of therapy Antidote: antifibrinolytic drug (Amicar)

36. DISSEMINATED INTRAVASCULAR COAGULATION Rapid formation and lysis of intravascular fibrin Consumption of clotting factors, platelets, inhibitors Lifethreatening underlying disease in most pts Bleeding due to uncontrolled fibrinolysis, thrombocytopenia, etc Large vessel thrombosis unusual Tissue necrosis due to microvascular occlusion, hypotension, endothelial damage, direct effects of cytokines Most deaths due to underlying disease

37. DISSEMINATED INTRAVASCULAR COAGULATION ASSESS SEVERITY GUIDE TREATMENT DIAGNOSIS D-Dimer Antithrombin Prothrombin time Fibrinogen Plasminogen Fibrinogen Prothrombin time Alpha2-antiplasmin Platelet count Platelet count Protein C Alpha2-antiplasmin Fibrin monomer

38. TREATMENT OF DIC • TREAT UNDERLYING DISEASE! • Clotting factor & inhibitor replacement IF patient bleeding or at high risk • Fresh frozen plasma (if INR > 1.6) • Cryoprecipitate (if fibrinogen < 50-100) • Platelets (if count < 30-50K) • Pharmacologic inhibitors (selected pts) • Heparin • Antifibrinolytics

39. UWHC/VA TRANSFUSION INDICATIONS PLATELET TRANSFUSION standard adult dose = 5 units Plts < 20K (except ITP, TTP) Most beneficial in marrow failure states 10K trigger safe for most patients Plts < 50K AND significant bleeding OR invasive procedure/surgery planned within six hours Plts < 100K AND major CNS or eye surgery (up to 48 hours postop)

40. Contains: all clotting factors and inhibitors FRESH FROZEN PLASMA UWHC/VA transfusion indications adult dose = 10-15 ml/kg Active bleeding and INR > 1.6 Invasive procedure planned within 6 hours and INR > 1.6 Immediate reversal of warfarin effect for emergency surgery or active bleeding Surgery with massive transfusion (> 10 units RBC/24 hours) Replacement during plasmapheresis TTP

41. Contains: fibrinogen, factor VIII, von Willebrand factor CRYOPRECIPITATE UWHC/VA transfusion indications Fibrinogen deficiency (<100 mg/dl) For DIC: give 1 bag/2-3 Units FFP Factor VIII or VWF deficiency Rarely used for this indication; factor concentrates preferable Fibrin glue

42. (Desmopressin) DDAVP Vasopressin analog; stimulates VWF release from endothelium Intravenous administration (0.3 mcg/kg); intranasal (Stimate) Increased plasma VWF levels for 18-24 hours, enhanced platelet adhesiveness Effective in Type I von Willebrand disease Mild hemophilia A (some cases) Other disorders of primary hemostasis (variable efficacy) Reducing surgical blood loss (conflicting data) Can give q 24 hours with little tachyphylaxis Few side effects in adults (flushing, occasional hyponatremia, rare thromboembolism)

43. (Epsilon-aminocaproic acid) AMICAR Antifibrinolytic: Inhibits plasmin activation by tPA, fibrin degradation by plasmin Short plasma half-life; need frequent dosing, up to 24 gm/day Oral, intravenous, or topical (mouthwash) Uses: Treatment of bleeding due to hyperfibrinolytic states: DIC, thrombolytic drugs, post cardiac bypass, liver disease Prophylaxis in severely thrombocytopenic patients Treatment of GI or urinary tract bleeding Treatment of menorrhagia Prophylaxis after dental extractions in hemophilia (mouthwash) Risks & side effects: GI symptoms, orthostatic hypotension, rhabdomyolysis, rarely thrombosis

44. VITAMIN K Oral, subcutaneous, or iv administration (potential for anaphylaxis with iv form) Indications: Correction of vitamin K deficiency Treatment of warfarin or superwarfarin overdose Treatment of warfarin-induced skin necrosis Prophylactic use in patients on TNA or at high risk for vitamin K deficiency

45. REVERSAL OF WARFARIN ANTICOAGULATION INR ACTION Withhold warfarin until INR therapeutic, restart at lower dose < 6, no bleeding < 6, rapid reversal needed for surgery, etc. Vitamin K 1-2 mg po Vitamin K 1-2 mg iv or 2.5-5 mg po; give additional 0.5-1.0 mg if INR still supratherapeutic at 24 hours 6-10 or significant bleeding Vitamin K 3 mg slow iv, recheck INR q 6h and repeat as needed 10-20 Vitamin K 10 mg slow iv; repeat q 6-12 hours as needed > 20 Add FFP for major bleeding if INR > 2 Avoid subcutaneous Vit K (unreliable absorption)