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Inflammation, Thrombosis, and Bleeding

Inflammation, Thrombosis, and Bleeding Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair for Research Emory University School of Medicine Director, Cardiothoracic Anesthesiology Emory Healthcare Atlanta, Georgia LOVE=COAGULATION

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Inflammation, Thrombosis, and Bleeding

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  1. Inflammation, Thrombosis, and Bleeding Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair for Research Emory University School of Medicine Director, Cardiothoracic Anesthesiology Emory Healthcare Atlanta, Georgia

  2. LOVE=COAGULATION Everybody talks about it, only a few people seem to understand it.

  3. Normal Hemostasis II X VIII/vWF VIIa TF Xa IIa Va VIIIa TF-Bearing Cell TF V Va VIIa IX Platelet II IXa X Xa IIa VIIIa IXa Va Activated Platelet VIIa IXa Va IIa Xa VIIIa II IX X Hoffman et al, Blood Coagul Fibrinolysis 1998;9(Suppl 1):S61

  4. CAVEATS REGARDING INFLAMMATION • Inflammation has multiple humoral, cellular components, and undergoes amplification. • Defining clinical outcomes from inflammation is difficult. • Hemostatic activation/thrombin generation is an inflammatory response, and tissue injury is key.

  5. MANIFESTATION OF INFLAMMATION • Bleeding • Ischemia/reperfusion injury • Infection • MOS dysfunction • CNS dysfunction

  6. HEMOSTASIS The stoppage of bleeding, hemorrhage, or blood flow through a blood vessel or body part.

  7. COMPONENTS OF HEMOSTASIS • Vasculature • Coagulation proteins • Platelets

  8. CAVEATS REGARDING COAGULATION/THROMBOSIS • Arterial clot is due to platelet-fibrinogen interactions. Heparin does not completely block this. • Venous clot and venous thromboembolic phenomenon are prevented by thrombin inhibitors

  9. THROMBIN: Proinflammatory mediator • Chemotactic for PMNs, monocytes • Mast cell activator • Stimulates endothelium • Formed via endothelial injury by TF expression, induces cytokine expression

  10. * Thrombomodulin XIIIa THROMBIN GENERATION/EFFECTS * BTG, PF4 Contact (XIIa) Tissue Factor (TF:VIIa) activation/consumption Platelets IX * FV, FVIII, FXI FXIa, FVa/FVIIIa TFPI IXa FVi, FVIIIi X Xa Protein C VIIIa, Ca++ , PL Va, Ca++ , PL APC THROMBIN Prothrombin XIII FPA bradykinin PT fragment 1.2 ATIII Fibrin (M) EC Fibrinogen * tPA tPA:PAI1 Fibrin (Ps) FSP TAT * PAI1 Plasminogen PLASMIN -2-antiplasmin D-dimer Fibrin (Pi) Platelet GP1b PAP complexes * Despotis GJ et al, Anesthesiology 1999;91:1122-51 Endothelial-associated

  11. VASCULAR ENDOTHELIUM Huraux C et al: Circulation 1999;99:53-59

  12. DIC • Triggered by TF/endothelial injury • Produces fibrin deposition in microvasculature and MOS dysfunction • Path: Microangiopathic hemolytic anemia • Lab: platelets, fibrinogen, PT, PTT, D-dimers, ATIII

  13. 120 100 80 60 40 X ± SEM 20 Group 1 Group 2 0 1 2 3 4 5 6 7 8 9 10 11 12 13 ANTITHROMBIN ACTIVITY Normal Activity Activity - % Heparin Protamine Measurement Period Zaidan JR et al, Anesth Analg 1986;65:377-80

  14. PATIENTS ON HEPARIN THERAPY 900 800 678 700 612 600 ACT (sec) 567 500 496 478 453 400 AT III 300 No AT III 200 160 160 100 0 Baseline Heparin Heparin Heparin ACT 4.1 u/ml 5.4 u/ml 6.8 u/ml Levy JH et al, Anesth Analg 2000;90:1076-9

  15. FACTORS AFFECTING ACT • Factor deficiency: fibrinogen, XII, VIII • Contact activation inhibitors: aprotinin • Warfarin therapy • Heparin therapy • Hypothermia • Thrombocytopenia/cytosis • Platelet inhibitors

  16. Aprotinin Use in CABG Reoperations Donor-Blood-Product Requirements P < .001 P < .001 Lemmer et al J Thorac Cardiovasc Surg 1994;107:543-53 Levy et al Circulation 1995;92:2236-44

  17. Incidence of Stroke in Repeat CABG Surgery Number of Patients % Placebo 5 / 72 7 Aprotinin Pump Prime 1 / 72 1 Low Dose 0 / 70 0 High Dose 0 / 73 0 P = 0.01 Neurologic Deficit (Stroke) Levy et al, Circulation 1995;92:2236-44

  18. International Multicenter Aprotinin Graft Patency Experience • 796 (91%) Patients assessable for blood loss, usage • 703 (81%) Patients assessable by angiography for saphenous vein-graft patency (at mean of 10.8 days postop) • 831 (95%) Patients assessable for MI by ECG and cardiac enzyme evaluation

  19. IMAGE Study Blood Loss and Blood Product Replacement Drainage and Transfusion Patients Requiring Any Blood Product P <.001 P <.001 Alderman, Levy, Rich et al, JTCS 1998;116:716-30

  20. IMAGE Study P = .01 P = .03 P = .72 Alderman et al, J Thorac Cardiovasc Surg 1998;116:716-30

  21. IMAGE Study • Adverse Outcome Placebo Aprotinin • Death1.6%1.4% (6/434) (5/436) • Myocardial Infarction • Definite3.8% 2.9% • (16/421) (12/410) • Def+probable 9.1% 8.6% • (38/418) (35/407) • Def+prob+possible 12.0% 12.3% • (50/418) (50/408) Alderman et al, J Thorac Cardiovasc Surg 1998;116:716-30

  22. Role of the Tissue Factor – Thrombin Pathway in Myocardial Ischemia-Reperfusion Injury

  23. X APROTININ Inhibition of Thrombin PAR-1 Activation by Aprotinin Protease (Thrombin) (Irreversible) Cell Membrane G protein Coughlin SR, Proc Natl Acad Sci USA 1999;96:11023-7

  24. APROTININ: Use in Orthopedic Surgery (1) • Janssens M: High-dose aprotinin reduces blood loss in pts undergoing THR surgery. Anesthesiology 1994; 80: 23–9. • Murkin JM: Aprotinin decreases blood loss in patients undergoing revision or bilateral total hip arthroplasty. Anesth Analg 1995; 80: 343–8. • Murkin JM: Aprotinin decreases exposure to allog blood during primary unilateral THR. J Bone Joint Surg Am 2000; 82: 675–84. • Capdevila X Aprotinin decreases blood loss and transfusions in pts undergoing major orthopedic surgery. Anesthesiology 1998; 88: 50–7.

  25. APROTININ: Use in Orthopedic Surgery (2) • Hayes A The efficacy of single-dose aprotinin 2 million KIU in reducing blood loss and DVTs in THR surgery. J Clin Anesth 1996; 8: 357–60. • Kasper SM A retrospective study of the effects of small-dose aprotinin on blood loss and transfusion needs during total hip arthroplasty. Eur J Anaesthesiol 1998; 15: 669–75. • Amar D: Antifibrinolytic therapy and periop blood loss in cancer pts undergoing major orthopedic surgery. Anesthesiology 2003;98:337-42. • Samama CM: Aprotinin vs placebo in major ortho surgery: a randomized/DB/, dose-ranging study. Anesth Analg 95:287-93, 2002.

  26. APROTININ FOR HIGH RISK PATIENTS • Repeat sternotomy • Jehovah’s witnesses • Valve surgery/combined procedures • Aortic root surgery/DHCA • Dialysis patient • Endocarditis • Minimally invasive valve surgery • Transplants/VADs • Recent Plavix

  27. SUMMARY • Thrombin generation modulates the thrombotic effects of vascular injury and pharmacologic intervention • Thrombin activation of PAR-1 receptors activates pathologic mechanism of injury • Aprotinin inhibits pathologic hemostatic activation by blocking PAR-1 receptors • Safety data from clinical studies including orthopedic surgery have not demonstrated a prothrombotic effect of aprotinin

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