Management of the Bleeding Patient

1. Management of the Bleeding Patient Dr. Alan Tinmouth Director, Adult Regional Hemophilia and Bleeding Disorders Clinic February 1st, 2005

2. Outline • Review the mechanism of blood coagulation • Understand the tests used in the investigation of bleeding disorders • Understand the therapeutic options in the management of bleeding patients • “Hemostasis” Poker

3. Overview of Hemostasis

4. Primary Hemostasis: Platelets • Adhesion • Platelet glycoprotein Ib/V/IX adheres to subendothelium  binding is primarily to vWF • Activation • Shape change  formation of pseudopods • Anionic phospholipids (phospatidylserine and phosphoethanolamine) exposed on external membrane • Glycoprotein IIb/IIIa exposed on surface • Secretion of platelet granules • Aggregation • Platelets bind to each other via Gp IIb/IIIa receptor and soluble fibrinogen and vWF  FORMATION OF HEMOSTATIC PLUG

5. Platelet Adhesion and Activation

6. Platelet Aggregation

7. Secondary Hemostasis: Coagulation Factors • Coagulation factors are proteins that circulate primarily in inactive state (proenzyme), which are converted to active enzyme • Activation of coagulation factors is a stepwise process of one activated factor activating subsequent factor(s) • Historically separated into the intrinsic pathway and extrinsic pathway • Intrinsic and extrinsic pathways believed to act independently and lead to formation of fibrin clot through separate “coagulation cascades” • Model fails to explain many coagulation abnormalities seen clinically

8. Coagulation in a test tube XII XIIa XI XIa VIIa VII IX IXa +TF INTRINSIC EXTRINSIC +VIIIa X Xa +Va II IIa Fibrinogen Fibrin COMMON

9. Tissue factor is spark initiating coagulation cascade Exposed TF activates factor VII Factor VIIa:TF activates Factor VII*,Factor X*, Factor IX* Factor Xa with Va generates a small amount of thrombin II Xa IIa Initiation Phase X TF VIIa Va TF-Bearing Cell TF VIIa IX IXa * Vitamin K dependent clotting factors

10. II IIa Amplification Phase • Factor VIIa:TF inactivated by Tissue Factor Pathway Inhibitor (TFPI):Factor Xa complex • Thrombin* (II) generated on TF-bearing cell activates platelets and coagulation factors (V, VII*, XI) VIII/vWF TFPI Xa Xa TF VIIa VIIIa Va TF-Bearing Cell XI XIa V Va Platelet VIIIa Va XIa Activated Platelet * Vitamin K dependent clotting factors

11. Activated platelets serve as phospholipid platform for generation of large amounts of thrombin Factor IXa with VIIIa (+ Ca2+) [tenase] activates factor X Factor Xa with Va (+ Ca2+) [pro-thrombinase]produces large thrombin burst Thrombin then generates fibrin and fibrin clot Propagation Phase TF-Bearing Cell TF VIIa IX II IXa X Xa IIa VIIIa IXa Va XIa Activated Platelet IX

12. Formation of Fibrin Clot: Fibrin Deposition • Thrombin binds to fibrinogen and forms fibrin • Cleaves fibrinopeptide A and B to leave fibrin monomer • Thrombin activates factor XIII to XIIIa, • Factor XIIIa catalyzes cross-linking of fibrin monomers to produce stable clot IIa IIa

13. Coagulation Factor Pathway in Vivo

14. Fibrinolysis • Fibrin clots are temporary scaffolding that allow for cellular wound healing • Dissolution of clots needed to maintain vessel patency • Plasmin (converted from plasminogen) is primary agent of fibrinolysis • Fibrinolysis is controlled by • Activators of plasminogen activation • Inhibitors of plasminogen activation • Inhibitors of plasmin

15. Fibrinolysis and Plasmin Inhibition Fibrinolysis • Plasminogen and t-PA bind to fibrin lysine sites • Activated plasmin protected from degradation by alpha2-antiplasmin • Plasmin optimally positioned to degrade fibrin Plasmin Inhibition • Circulating plasmin is rapidly inactivated by alpha2-antiplasmin • Prevents systemic (widespread) fibrinolysis • Thrombin activated fibrinolytic inhibitor (TAFI) removes lysine sites from fibrin to • downregulates fibrinolysis during initial clot formation

16. Fibrinolytic System

17. Laboratory Investigations

18. Platelet Disorders • Platelet Count • Platelet Morphology (blood film) • Platelet Aggregation / Release • von Willebrand Studies • von Willebrand Antigen • Ristocetin Cofactor • von Willebrand Multimers • Bleeding Time

19. Coagulation Factor Disorders • Prothrombin Time / International Normalized Ratio • Activated Partial Thromboplastin Time • Thrombin Time • 50:50 Mixing Studies • Coagulation Factor Assays

20. Activated Partial Thromboplastin Time XII XIIa XI XIa VIIa VII IX IXa +TF INTRINSIC EXTRINSIC +VIIIa X Xa +Va II IIa Fibrinogen Fibrin COMMON

21. Activated Partial Thromboplastin Time XII XIIa XI XIa VIIa VII IX IXa +TF INTRINSIC EXTRINSIC +VIIIa X Xa +Va II IIa Fibrinogen Fibrin COMMON

22. Thrombin Time (TT) XII XIIa XI XIa VIIa VII IX IXa +TF INTRINSIC EXTRINSIC +VIIIa X Xa +Va II IIa Fibrinogen Fibrin COMMON

23. Fibrinolytic System • Euglobulin Lysis • Alpha 2 Antiplasmin • Factor XIII levels

24. Therapy

25. Platelet Transfusions - Products Random Donor Platelets • Separated from whole blood donations • Dose = 5 units (250-300 mls) • ABO matched preferable but not mandatory • Increases platelet ct by 5-10 x 109/L per unit Single Donor Platelets • Collected from 1 donor by apheresis • Equivalent to 5-6 random donor platelets • Decrease donor exposure • Can be matched if patient has identified antibodies to platelets (alloimmune platelet refractoriness)

26. Thrombocytopenia Platelet Dysfunction Congenital Acquired Therapeutic Plat ct < 50x109/L Plat dysfunction Prophylactic Prior to invasive procedures Plat ct < 50-100x109/L Prevent spontaneous bleeding Plat ct  10x109/L Indications for Platelet Transfusions

27. Fresh Frozen Plasma • Made from whole blood within 8 hrs of collection • Contains all coagulation factors • Minimum factor VIII level of 0.7 IU/ml • 200-250 mls / unit • Effect may only last 4 hrs (t1/2 of factor VII) Indications: INR / PTT > 1.5 x normal and • Bleeding or • Emergency procedure or operation

28. Fresh Frozen Plasma Dose: • 10-15 ml/kg for bleeding patients • Sufficient to increase all individual coagulation factors by 30% (minimum hemostatic level) • 5-7 ml/kg may be sufficient for warfarin reversal Alternatives • Vitamin K • 2 mg will correct INR in 12 -24 hrs • No effect on PTT (factors VIII, IX, XI) • Oral dose more effective than subcutaneous • Intravenous associated with anaphylactic reactions

29. Cryoprecipitate • Precipitate collected from plasma thawed at 40C • 10-15 mls/unit • Contains specific clotting factors from plasma • Factor VIII • Fibrinogen • von Willebrand’s Factor • Factor XIII Indications • Fibrinogen < 1.0 g/L • Dysfibrinogenemia

30. Cryoprecipitate Dose • 1 unit / 5-10 kg body weight (total 8-10 units) • t ½ of 3-5 days Alternatives • Factor VIII or IX Deficiency • recombinant factor VIII or IX • Von Willebrand’s Disease • virally inactivated plasma derived factor concentrates • Other factor deficiencies • recombinant factor concentrates • virally inactivated plasma derived factor concentrates

31. DDAVP • Synthetic vasopressin • Release of VIII and vWF from endothelium • May also help with platelet dysfunction • 2-3 fold rise in levels • Dose – 0.3 ug/kg q 12-24 hours • Tachyphylaxis may occur after 2-3 doses

32. Antifibrinolytics • Tranexamic acid (Cyclokapron) • 20-25 mg/kg po or 10 mg/kg IV q8h • Epsilon aminocaproic acid (Amicar) • 50-60 mg/kg po q6h • Competitive inhibition with plaminogen activator (t-PA) • Prevents fibrinolysis (clot breakdown) • Promotes thrombosis • Relative contraindication in renal bleeding

33. Recombinant Factor VIIa • Initiates coagulation by interaction with TF • Only approved for treatment of hemophilia with inhibitors • Treat/prevent bleeding in other patient groups? • Efficacy not proven • Risk of thrombosis? • Primary use is bleeding patients refractory to other treatments • Dose for hemophilia 90 ug/kg q2-3h • Lower dose often effective in other patients 30-40 ug/kg • Vials of 1.2 mg, 2.4mg, 4.8mg • Cost ~ $1000/mg

34. “Hemostasis” Poker

35. One-of-a-Kind

36. Pair

37. Three-of-a-Kind

38. Full House

39. Nothing • Von Willebrand’s Disease • Mild Hemophilia A or B • Mild Factor XI deficiency • Platelet Function Disorder • Factor XIII deficiency • Alpha 2 antiplasmin deficiency • Plasminogen Activator Inhibitor deficiency