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

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Presentation on theme: "Inflammation, Thrombosis, and Bleeding Jerrold H. Levy, MD Professor of Anesthesiology Deputy Chair for Research Emory University School of Medicine Director,"— Presentation transcript:

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

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

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 Group 1 Group 2 X ± SEM Activity - % Zaidan JR et al, Anesth Analg 1986;65: Normal Activity HeparinProtamine Measurement Period ANTITHROMBIN ACTIVITY

14 PATIENTS ON HEPARIN THERAPY Baseline ACT Heparin 4.1 u/ml Heparin 5.4 u/ml Heparin 6.8 u/ml ACT (sec) AT III No AT III 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 Lemmer et al J Thorac Cardiovasc Surg 1994;107: Donor-Blood-Product Requirements Levy et al Circulation 1995;92: P <.001

17 Neurologic Deficit (Stroke) Levy et al, Circulation 1995;92: Number of Patients% Placebo5 / 727 AprotininPump Prime1 / 721 Low Dose0 / 700 High Dose 0 / 730 P = 0.01 Incidence of Stroke in Repeat CABG Surgery

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

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

21 IMAGE Study Adverse OutcomePlaceboAprotinin Death 1.6% 1.4% (6/434)(5/436) Myocardial Infarction Definite 3.8% 2.9% Definite 3.8% 2.9% (16/421) (12/410) (16/421) (12/410) Def+probable 9.1% 8.6% (38/418) (35/407) (38/418) (35/407) Def+prob+possible 12.0% 12.3% (50/418) (50/408) (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 Inhibition of Thrombin PAR-1 Activation by Aprotinin Cell Membrane G protein Protease (Thrombin) (Irreversible) Coughlin SR, Proc Natl Acad Sci USA 1999;96: Coughlin SR, Proc Natl Acad Sci USA 1999;96: APROTININ X

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: Samama CM: Aprotinin vs placebo in major ortho surgery: a randomized/DB/, dose-ranging study. Anesth Analg 95: , 2002.

26 APROTININ FOR HIGH RISK PATIENTS Repeat sternotomy Jehovahs 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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