Presentation on theme: "Inflammation, Thrombosis, and Bleeding"— Presentation transcript:
1 Inflammation, Thrombosis, and Bleeding Jerrold H. Levy, MDProfessor of AnesthesiologyDeputy Chair for ResearchEmory University School of MedicineDirector, Cardiothoracic AnesthesiologyEmory HealthcareAtlanta, Georgia
2 Everybody talks about it, only a few people seem to understand it. LOVE=COAGULATIONEverybody talks about it, only a few people seem to understand it.
3 Normal Hemostasis II TF-Bearing Cell II II Platelet IIa IIa VIIa XVIII/vWFTFVIIaXaVaIIaTF-Bearing CellVIIIaTFVIIaVVaIXPlateletIIIXaXNormal HemostasisThis slide represents a schematic model of normal hemostasis that requires activation of both FX and FIX. FVIIa/tissue factor (TF)-activated FXa and FIXa play distinct roles in coagulation. FXa cannot move to the platelet surface because of the presence of normal plasma inhibitors, but instead remains on the TF-bearing cell and activates a small amount of thrombin. This thrombin is not sufficient for fibrinogen cleavage but is critical for hemostasis since it can activate platelets, activate and release FVIII from von Willebrand factor (vWF), activate platelet and plasma FV, and activate FXI. FIXa moves to the platelet surface, where it forms a complex with FVIIIa and activates FX on the platelet surface. This platelet surface FXa is relatively protected from normal plasma inhibitors and can complex with platelet surface FVa, where it activates thrombin in quantities sufficient to provide for fibrinogen cleavage.Hoffman M et al. Blood Coagul Fibrinolysis 1998;9(suppl 1):S61–S65.XaIIaIXaVIIIaVaActivated PlateletVIIaIXaVaVIIIaXaIIaIXIIXHoffman 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 BleedingIschemia/reperfusion injuryInfectionMOS dysfunctionCNS dysfunction
6 HEMOSTASISThe stoppage of bleeding, hemorrhage, or blood flow through a blood vessel or body part.
7 COMPONENTS OF HEMOSTASIS VasculatureCoagulation proteinsPlatelets
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, monocytesMast cell activatorStimulates endotheliumFormed via endothelial injury by TF expression, induces cytokine expression
16 Aprotinin Use in CABG Reoperations Donor-Blood-Product RequirementsP < .001P < .001Lemmer et alJ Thorac Cardiovasc Surg 1994;107:543-53Levy et alCirculation 1995;92:
17 Neurologic Deficit (Stroke) Number of Patients %Placebo 5 /Aprotinin Pump Prime 1 /Low Dose 0 /High Dose 0 /P = 0.01Incidence of Stroke in Repeat CABG SurgeryLevy et al, Circulation 1995;92:
18 International Multicenter Aprotinin Graft Patency Experience 796 (91%) Patients assessable for blood loss, usage703 (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 evaluationFDA rules for investigational study reporting requires that any protocol deviation must have the data excluded from analysis of drug efficacy. However, all data, including protocol violations are included in assessment for drug safety.870 patients were randomized in this study (aprotinin = 436; placebo = 434). 74 patients were excluded from analysis of blood loss and replacement, for reasons that included protocol violation (n = 21), and exclusion for a confounding postop event (n = 53), the most common of which were re-exploration for surgical bleeding (n = 30) and an additional postop surgical procedure (n = 14).However, the data from patients in whom there had been a protocol violation were included in the angiographic analysis of graft patency. Assessment was not available in 167 patients, the majority of whom (n = 117) did not consent to the investigation.
19 IMAGE Study Blood Loss and Blood Product Replacement Drainage and TransfusionPatients Requiring Any Blood ProductP <.001P <.001Alderman, Levy, Rich et al, JTCS 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 Protease (Thrombin)APROTININX(Irreversible)Cell MembraneG proteinCoughlin SR, Proc Natl Acad Sci USA 1999;96:
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 95:287-93,
26 APROTININ FOR HIGH RISK PATIENTS Repeat sternotomyJehovah’s witnessesValve surgery/combined proceduresAortic root surgery/DHCADialysis patientEndocarditisMinimally invasive valve surgeryTransplants/VADsRecent Plavix
27 SUMMARYThrombin generation modulates the thrombotic effects of vascular injury and pharmacologic interventionThrombin activation of PAR-1 receptors activates pathologic mechanism of injuryAprotinin inhibits pathologic hemostatic activation by blocking PAR-1 receptorsSafety data from clinical studies including orthopedic surgery have not demonstrated a prothrombotic effect of aprotinin