Module 5

1. Basic Clinician Training Module 5 Introduction TEG Analysis of Hyperfibrinolysis Test Your Knowledge Fibrinolysis and Hyperfibrinolysis TEG Analysis

2. Introduction • Fibrinolysis • Breakdown of clots, and wound healing • Essential component of hemostasis • Protective mechanism that limits clot formation • Abnormal activation of the fibrinolytic pathway, resulting in bleeding • Breakdown of formed fibrin clot • Degradation of coagulation factors (i.e. DIC) • Impairment of clot formation due to excess generation of fibrin degradation products • Interferes with fibrin cross-linking • Inhibits platelet function

3. Physiological Pathophysiological Excess plasma-free plasmin Fibrinolysis:Physiological vs. Pathophysiological Fibrin-bound plasmin Excessive fibrin(ogen) degradation Coagulation factor consumption Accelerated degradation of formed fibrin clot Formation of FDPs Interference with clot formation Bleeding

4. Primary Rapid clot breakdown Increase in circulating tPA binding to fibrin Excess tPA -Decreased hepatic clearance -Decreased fibrinolytic inhibitors α2-antiplasmin PAI-1 Secondary Secondary to systemic hypercoagulability Systemic or microvascular Not localized Commonly associated with DIC Hyperfibrinolysis:Primary vs. Secondary

5. Primary Bleeding Rapid breakdown of clot Diminished clot formation Formation of FDPs Inhibition of platelet function Interference with fibrin cross-linking Secondary Bleeding Degradation of fibrin Consumption of coagulation factors Formation of FDPs Inhibition of platelet function Interference with fibrin cross-linking Hyperfibrinolysis:Primary vs. Secondary

6. Primary Treat consequence of excess circulating tPA Common treatment: Antifibrinolytic agent Secondary Treat hypercoagulability Common treatment: Anticoagulant Heparin LMWH Warfarin Restore endogenous anticoagulation pathways ATIII APC Hyperfibrinolysis:Primary vs. Secondary

7. Hyperfibrinolysis:Treatment and Monitoring • Selection of proper treatment is critical • Wrong treatment can be fatal • TEG analysis helps

8. Decision Tree EPL > 15% No or Yes LY30 > 7.5% C.I. C.I. > 3.0 No Yes Hemorrhagic < 1.0 > 3.0 R > 10min R < 3min No Primary fibrinolysis Yes Secondary fibrinolysis No Yes Fibrinolytic Low clotting factors Platelet hypercoagulability MA < 55mm MA > 73mm No Yes Yes No Low platelet function Enzymatic hypercoagulability Enzymatic & platelet hypercoagulability a < 45º i Yes Hypercoagulable Low fibrinogen level

9. Hyperfibrinolysis LY30 > 7.5% EPL > 15% CI (coagulation index) Distinguish primary and secondary CI = Linear combination of R, K, alpha (α), and MA TEG Analysis:Hyperfibrinolysis

10. TEG Analysis: Primary hyperfibrinolysis Common treatment: Antifibrinolytic agent

11. TEG Analysis: Secondary Hyperfibrinolysis Common treatment: Anticoagulant

12. DIC Characteristics • Disseminated Intravascular Coagulation (DIC) • Bacterial infections/sepsis • Systemic infections • Liver transplants • Vascular disorders • Severe trauma • Solid tumors and hematological malignancies • Obstetrical complications • Placental abruptions • Amniotic fluid emboli • Presence of toxins (snake venom, amphetamines, and other drugs)

13. Disseminated Intravascular Coagulation (DIC) Ongoing systemic activation of coagulation Secondary Fibrinolysis Pro-thrombotic Intravascular deposition of fibrin Depletion of factors and platelets Thrombosis of small and midsize vessels Bleeding Tissue ischemia and organ failure Levi, M & TenCate, H. NEJM. 1999;341:1999

14. DIC:Diagnostic Characteristics • Progressive disease • No single laboratory test • Diagnosis • Clinical presentation • Bleeding and/or disease state • Laboratory tests: • Presence of soluble fibrin monomer complexes • Platelet count < 100,000/dL or rapidly decreasing platelet count • Increased PT, aPTT • Presence of FDPs • Low levels of coagulation inhibitors (ATIII) • TEG analysis to demonstrate progression of DIC

15. Progression of DIC:TEG Analysis Hypercoagulable Secondary to an underlying disorder - Inflammatory state - Down-regulation of anticoagulant mechanisms - Intravascular deposition of fibrin - Activation of fibrinolysis Secondary fibrinolysis Degradation of fibrin and fibrinogen - Increasing FDPs - FDPs compromise clot formation and integrity - Depletion of factors • Hypocoagulable • Consuming factors and platelets • - Bleeding

16. Progression of DIC:Common Treatments • Hypercoagulable • Treat underlying disorder • Restore anticoagulation pathways • - Anticoagulant therapy • - ATIII • - APC • Platelet inhibition • Secondary fibrinolysis • Treat underlying disorder • Restore anticoagulation pathways • - Anticoagulant therapy • - ATIII • - APC Hypocoagulable Replacement therapy (FFP, platelets, cryoprecipitate) Note: May amplify inflammatory response and mediate a hyper- coagulable state, even though patient is bleeding

17. Basic Clinician Training Interpretation Exercises Fibrinolysis

18. Exercise 1 • Using the TEG decision tree, what is a likely cause(s) of bleeding in this patient? • (Select all that apply) • Residual anticoagulant • Surgical bleeding • Primary fibrinolysis • Secondary fibrinolysis • What treatment(s) would you consider for this patient? Answer: page 25

19. Exercise 2 • Using the TEG decision tree, what is a likely cause(s) of bleeding in this patient? • (Select all that apply) • Residual anticoagulant • Surgical bleeding • Primary fibrinolysis • Secondary fibrinolysis • What treatment(s) would you consider for this patient? Answer: page 26

20. Exercise 3 • This patient was brought to the OR for CABGx4, on pump. Due to the initial hyper- • coagulable state (black tracing), no prophylactic antifibrinolytic was administered. The • rewarming TEG (greentracing) indicated development of primary fibrinolysis. • What would be a common treatment plan for this patient? • Consider administering an antifibrinolytic agent before termination of CPB. Repeat TEG. • Consider administering an antifibrinolytic agent after CPB and protamine administration. Repeat TEG. • Consider no treatment. Repeat TEG post-protamine. • Consider administering an antifibrinolytic agent during CPB and platelets post-protamine. Answer: page 27

21. Exercise 4 Kaolin • This patient was brought to the OR for CABGx4, on pump. While opening the chest, • the surgeon commented that the patient was ‘oozy.’ What is the mostly likely cause • of this condition? • Fibrinogen deficiency • Platelet deficiency/defect • Fibrinolysis • Hemodilution • Would treatment with an antifibrinolytic agent be contra-indicated? Yes or No. • If no, which antifibrinolytic agent would you use? Answer: page 28

22. Exercise 5 Kaolin • Using the TEG decision tree, what is a likely cause(s) of bleeding in this patient? • (Select all that apply) • Residual anticoagulant • Surgical bleeding • Primary fibrinolysis • Secondary fibrinolysis • What treatment(s) would you consider for this patient? Answer: page 29

23. Exercise 6 Kaolin • Using the TEG decision tree, what is a likely cause of bleeding in this patient? • (Select all that apply) • Factor deficiency • Platelet deficiency/dysfunction • Primary fibrinolysis • Secondary fibrinolysis • What treatment(s) would you consider for this patient? Answer: page 30

24. Exercise 7 • Using the TEG decision tree, what is your interpretation of this tracing? • (Select all that apply) • Primary fibrinolysis • Secondary fibrinolysis • Fibrinolysis • Surgical bleeding • Platelet adhesion defect Answer: page 31

25. Answer to Exercise 1 • Using the TEG decision tree, what is a likely cause(s) of bleeding in this patient? • (Select all that apply) • Residual anticoagulant • Surgical bleeding • Primary fibrinolysis • Secondary fibrinolysis • What treatment(s) would you consider for this patient? Consider treating • the underlying disorder, plus an antiplatelet agent and an anticoagulant to • inhibit or reduce thrombin generation.

26. Answer to Exercise 2 • Using the TEG decision tree, what is a likely cause(s) of bleeding in this patient? • (Select all that apply) • Residual anticoagulant • Surgical bleeding • Primary fibrinolysis • Secondary fibrinolysis • What treatment(s) would you consider for this patient? • Antifibrinolytic agent

27. Answer to Exercise 3 • This patient was brought to the OR for CABGx4, on pump. Due to the initial hyper- • coagulable state (black tracing), no prophylactic antifibrinolytic was administered. The • rewarming TEG (green tracing) indicated development of primary fibrinolysis. • What would be a common treatment plan for this patient? • Consider administering an antifibrinolytic agent before termination of CPB. Repeat TEG. Since • fibrinolysis on pump can be transient, repeat TEG. If fibrinolysis persists, treat with • antifibrinolytic agent and monitor the effect. • b) Consider administering an antifibrinolytic agent after CPB and protamine administration. Repeat TEG. • c) Consider no treatment. Repeat TEG post-protamine. • d) Consider administering an antifibrinolytic agent during CPB and platelets post-protamine.

28. Answer to Exercise 4 This patient was brought to the OR for CABGx4, on pump. While opening the chest, the surgeon commented that the patient was ‘oozy.’ What is the mostly likely cause of this condition? a) Fibrinogen deficiency b) Platelet deficiency/defect c) Fibrinolysis d) Hemodilution Would treatment with an antifibrinolytic agent be contra-indicated? No If no, which antifibrinolytic agent would you use? Consider aprotinin for potential platelet-protecting effects.

29. Answer to Exercise 5 Kaolin Using the TEG decision tree, what is a likely cause(s) of bleeding in this patient? (Select all that apply) a) Residual anticoagulant b) Surgical bleeding c) Primary fibrinolysis d) Secondary fibrinolysis What treatment(s) would you consider for this patient? Consider treating with antifibrinolytic agent first. If patient continues to bleed, repeat TEG to determine need for platelets or factors.

30. Answer to Exercise 6 Kaolin Using the TEG decision tree, what is a likely cause of bleeding in this patient? (Select all that apply) a) Factor deficiency b) Platelet deficiency/dysfunction c) Primary fibrinolysis d) Secondary fibrinolysis What treatment(s) would you consider for this patient? Consider treating with platelet transfusion. If patient continues to bleed, repeat the TEG to determine possible contribution of fibrinolysis.

31. Answer to Exercise 7 Using the TEG decision tree, what is your interpretation of this tracing? (Select all that apply) a) Primary fibrinolysis (cannot rule out) b) Secondary fibrinolysis (cannot rule out) c) Fibrinolysis d) Surgical bleeding e) Platelet adhesion defect Although fibrinolysis is present, the CI value is outside those given for designation as primary or secondary. Knowledge of patient history, drug history, other laboratory tests, and bleeding status would be required to make a definitive diagnosis. A clinical presentation of DIC would suggest secondary fibrinolysis, and treatment with an anticoagulant. If patient continues to bleed, repeat the TEG and consider treatment with an antifibrinolytic agent.

32. Basic Clinician Training End of Module 5