Basic Clinician Training Module 1

1. Basic Clinician TrainingModule 1 Thrombelastography and Hemostasis Introduction and Overview

2. Administrative Improve patient care Reduce costs Blood product Re-operations Length of stay Reduce demand on dwindling blood product supplies Clinical Assess risk for surgical bleeding Personalize hemostatic therapy Assess therapeutic efficacy Monitor hemostatic therapy Why monitor hemostasis?

3. Administrative Reduce blood product utilization Reduce pharmaceutical use Reduce complications associated with blood product transfusions Reduce hospital stays Clinical Reduce bleeding Reduce re-operations for bleeding Reduce thrombotic events Make better therapeutic decisions Desired monitoring outcomes

4. Overview of hemostasis • Overview of concepts • Cell-based model • Components of hemostasis • Monitoring hemostasis: In vivo vs. in vitro hemostasis

5. Definition of hemostasis “Normal hemostasis … controlled activation of clot formationand lysis to prevent hemorrhage without [inappropriate] thrombosis” (Laposata et al.)

6. Components of hemostasis Interactive

7. Components of hemostasis • Endothelium • Subendothelium • Extra-vascular tissue • (tissue factor (TF)) • Extrinsic and intrinsic pathways • Fibrinolytic pathway

8. Components: vascular Intact endothelium: Non-thrombogenic (-) (-)

9. Components: vascular Stress hormones Trauma Surgery Plaque rupture Inflammation… Endothelial damage: • Exposes collagen (+) • Exposes TF (+)

10. Components: platelets Adhesion Activation Aggregation Secretion Procoagulant activity

11. Procoagulant activity of platelets • Platelets play a major role in localizing and controlling the generation of thrombin that leads to fibrin clot formation • Alterations in phospholipid composition • Binding proteins • Glycoprotein receptors [Monroe, DM et al. Arterioscler Thromb Vasc Biol. 2002;22:1381]

12. Components: coagulation pathways Pivotal point of coagulation Thrombin Intrinsic Extrinsic (TF) Amplification Initiation

13. Normal hemostasis Activities and interactions are in BALANCE

14. Abnormal hemostasis Activities and interactions are OUT of BALANCE

15. Clot:The end product of hemostasis

16. Clot • Consists of fibrin and activated platelets • Mechanical device to impede blood loss from the vasculature • Physical properties determine effectiveness • Temporary - dissolves during vascular recovery

17. Hemostasis video • Insert if permission obtained in time

18. The hemostatic process • Hemostasis is a tightly regulated process consisting of three separate, but interrelated, steps: • Platelet plug formation • Fibrin clot formation • Fibrinolysis

19. Endothelial damage:Platelet plug formation • Endothelial damage  exposure to collagen: • Promotes platelet adherence and activation • Activated platelets secrete ADP and TxA2 • ADP  promotes platelet recruitment • TxA2  promotes platelet aggregation • Result: formation of platelet plug (white clot)

20. Endothelial damage:Initiation of thrombin generation Endothelial damage Exposure to tissue factor Initiation of extrinsic pathway Initiate thrombin generation Activate FXI (intrinsic pathway) Amplify thrombin generation

21. Thrombin generation to fibrin-platelet clot formation • Thrombin generation: the pivotal point of the coagulation process • Thrombin actions: • Activates FXI, amplifying thrombin generation • Converts fibrinogen to fibrin • Activates FXIII • Activates platelets • Result: fibrin-platelet clot (red clot)

22. Fibrin formation:Initiation of fibrinolysis • tPA is continually released into plasma by endothelial cells • tPA lacks plasminogen activating effect in absence of fibrin • Fibrin formation  tPA binds to fibrin  enhances plasminogen activation  plasmin generation  fibrin breakdown  formation of FDP (fibrin(ogen) degradation products)

23. The hemostatic process

24. Hemostasis:Another perspective • Consists of at least 6 systems (56+ proteins) • Platelets • Coagulation pathways • Fibrinolytic pathway • Endothelium • Subendothelium • Inflammatory cells • Highly regulated to maintain balance • Highly integrated • Dynamic

25. Monitoring hemostasis

26. Monitoring hemostasisCascade vs. cell-based model[Monroe, DM. et al. Arterioscler Thromb Vasc Biol. 2002;22:1381] Cascade model • Hemostasis represented as two somewhat independent protein activation pathways that converge at the common final pathway and the generation of fibrin. • The routine coagulation tests, PT and aPTT, are based on the cascade model • Measure how coagulation factors interact in solution • Determine if adequate levels of coagulation factors are present for clot formation aPTT PT Platelet counts D-dimers, FDPs

27. Monitoring hemostasisCascade vs. cell-based model Cell-based model • Hemostasis represented as: • Occurring on two cell surfaces • Tissue factor bearing cells • Platelets • Three overlapping phases: • Initiation (TF bearing cells) • Amplification (platelets) • Propagation (platelets) • The coagulation cascades are still important, but are cell-based • The extrinsic pathway works on the surface of the tissue factor bearing cells • The intrinsic pathway works on the surface of platelets • Routine coagulation tests do not represent the cell-based model of hemostasis. Tissue factor bearing cells 1. Initiation IIa 2. Amplification Platelets 3. Propagation IIa Activated platelets

28. Monitoring hemostasisCascade vs. cell-based model Cell-based model • Whole blood tests that measure the interaction of platelets, coagulation factors, and other cellular or plasma factors present during clot formation are required to examine hemostasis in the cell-based model. • The TEG is one such test. Cascade model • Common coagulation tests (PT, aPTT, platelet counts) do not reflect the roles of cells or contributions of local vascular and tissue conditions • Plasma-based assays miss the impact of platelets and platelet activation on thrombin generation. • Plasma-based assays use static endpoints (e.g. fibrin formation) - miss impact of altered thrombin generation on platelet function and clot structure.

29. Whole blood hemostasis analyzer Point of care or laboratory Provides real-time results Monitors all phases of hemostasis from initial fibrin formation through clot lysis Shows the net effect of most of the components of hemostasis: Enzymatic factors Fibrinogen Platelets Fibrinolytic system The TEG® System

30. Monitoring hemostasis with the TEG system • TEG system measures: • Time to initial fibrin formation • Rate of clot formation • Platelet function • Clot quality/strength • Clot lysis

31. Platelet Mapping™ assaysIdentifying platelet inhibitor effects • GPIIb/IIIa inhibitors • Abciximab • Eptifibatide • Tirofiban • Platelet activation inhibitors • Aspirin • Clopidogrel • Ticlopidene • Pathologic platelet inhibition

32. Application of TEG analysis • Used within the clinical context and considering: • Patient clinical condition (bleeding/ not bleeding) • Phase in medical intervention • Type and dose of drug therapy • Patient history • TEG testing shows net effect “whole picture” hemostasis at that point in time • Identifies a “factor deficiency”, but not which factor • Identifies a platelet defect, but cannot distinguish between platelet deficiency and platelet dysfunction.

33. Trend analysis with the TEG • Many clinical procedures cause shifts in the hemostatic state • Not all patients will respond to a clinical procedure in exactly the same way, relative to hemostasis. • Optimal outcomes are achieved when treatments are personalized. • Since the TEG is a point-of-care analyzer, monitoring changes in the hemostatic status of a patient can be accomplished.

34. Trend example: CABG Example?

35. Detects hemorrhagic and prothrombotic states Reduces blood product usage, re-operations, hospital stays Provides guidance for proper therapy Monitors level of platelet inhibition Provides guidance for personalized drug therapies Improves clinical outcomes Lowers costs TEG analysis and clinical outcomes

36. Overview exercises Hemostasis Hemostatic monitoring

37. #1 Normal hemostasis is characterized by a functional _________ between the procoagulant pathways/components and the antithrombotic and anticoagulant pathways/components. Answer Next

38. #2 What is the typical initiating event of the hemostatic process? • Platelet activation • Thrombin generation • Endothelial damage • Plasmin generation Answer Next

39. #3 What is the pivotal point in the activation of the coagulation pathways? • Tissue factor expression • FXII activation • FXa generation • Thrombin generation • Fibrin formation Answer Next

40. #4 Which coagulation pathway is responsible for the initiation of thrombin generation: Intrinsic or Extrinsic? Which coagulation pathway is responsible for the amplification of thrombin generation: Intrinsic or Extrinsic? Answer Next

41. #5 According to the cell-based model of hemostasis, the location and control of thrombin generation is primarily regulated at what level? • Intrinsic pathway • Extrinsic pathway • Fibrinolytic pathway • Platelets • Endothelial cells Answer Next

42. #6 In the cell-based model of coagulation, what is the location where the intrinsic and extrinsic pathways occur? • On any phospholipid surface • On the tissue-factor bearing cells and platelets • In the plasma • On endothelial cells and neutrophils Answer Next

43. #7 Which of the following statements does not describe the PT and aPTT? • They both measure how coagulation factors interact in solution • They both use fibrin formation as a static end point • They both demonstrate the effect of thrombin generation on platelet function • They demonstrate the function of the extrinsic and intrinsic pathways, respectively. Answer Next

44. #8 The TEG is a whole blood hemostasis analyzer that can measure the contribution of which of the following hemostatic components? (select all that apply) • Enzymatic factor • Fibrinogen • Platelets • Fibrinolytic pathway • Endothelial cells Answer Next

45. #9 Which of the following coagulopathies can not be directly assessed with the TEG? • Factor deficiency • Platelet aggregation defect • Platelet adhesion defect • Fibrinolysis • Hypercoagulability Answer Next

46. #10 The TEG can distinguish between surgical bleeding and bleeding due to a coagulopathy. True or False? Answer Next

47. #1 Normal hemostasis is characterized by a functional balance between the procoagulant pathways/components and the antithrombotic and anticoagulant pathways/components. Next

48. #2 What is the typical initiating event of the hemostatic process? • Platelet activation • Thrombin generation • Endothelial damage • Plasmin generation Next

49. #3 What is the pivotal point in the activation of the coagulation pathways? • Tissue factor expression • FXII activation • FXa generation • Thrombin generation • Fibrin formation Next

50. #4 Which coagulation pathway is responsible for the initiation of thrombin generation: Intrinsic or Extrinsic? Which coagulation pathway is responsible for the amplification of thrombin generation: Intrinsic or Extrinsic? Next