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The Biology of Bleeding and Clotting to Death Jeffrey H. Lawson, MD, PhD Director, Vascular Surgery Research Lab Director of Clinical Trials in Vascular Surgery Duke University Medical Center Durham, North Carolina What Are the Challenges of Hemostasis in Surgery? 1. Who is likely to bleed or clot too much? 2. How do we optimize the physiology of the patient? 3. Which topical agents are effective? 4. Which biologic agents are effective? When? How much? How not to overshoot? Thrombosis Clotting Surgery Post-op Recovery Bleeding Hemorrhage 2 Bleeding, Clotting, and Surgery • D&C for 2 years at Duke University = 358 complications • Total bleeding and thrombosis complications: 197/358 = 55% • 114 of 358 cases could not be well adjudicated with respect to complications Well-documented data reveal 197/244 = 81% • Total perioperative bleeding complications: 131/244 = 54% • Total perioperative thrombosis complications: 75/244 = 31% • Total deaths: 67 • Bleeding as cause of death: 18/67 = 27% • Thrombosis as cause of death: 22/67 = 33% D&C=dilation and curettage. 3 Coagulation Cascade: Tissue Factor Pathway VII(VIIa) XIII II X IIa XIIIa Xa TF·VII(VIIa) IXaß VIIa TF·VIIa Ca2:PL Va·Xa Ca2:PL Xa (IXα) TF VIIIa-IXaß Ca2:PL XIa XI IIa IX Xa PL IXaß VIII IIa IIa V FN (cross-linked) IIa Fn Fg Xa 4 The Problem Most complications are at the dark interface between: • Biology • Clinical skill • Medical therapy • Sick patients 5 Hemostasis “The arrest of bleeding” Stedman’s Medical Dictionary But is hemostasis more than that? 6 Hemostasis In surgery—hemostasis is … • About bleeding • About clotting • About timing • About balance 7 Hemostasis “Life in the Balance” Bleeding to Death Clotting to Death Trauma Major Surgery Hemophilia Stroke MI Thrombosis Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64. 8 Hemostasis “Too thick or too thin” Dr. Richard McCann Hemostasis in cardiovascular surgery “Knowing when to be thick and when to be thin” 9 Hemostasis • Blood coagulation • Anticoagulation • Fibrinolysis • Antifibrinolysis • Vascular tone and blood flow • Endothelial cells and platelets 10 Keeping on Center Antifibrinolytic Activity Procoagulant Activity Bleeding Clotting Normal Hemostasis Fibrinolytic Activity Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64. Anticoagulant Activity 11 What About Hemostatic Swings During Surgery? Thrombosis Clotting Surgery Post-op Recovery Bleeding Hemorrhage Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64. 12 Keeping on Center Factor V falls IIase increase Procoagulant Activity Bleeding Clotting Fibrinolytic Activity TF increase Antifibrinolytic Activity PAI-1 increase Normal Hemostasis Inflammatory Cytokines t-PA increase Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64. Anticoagulant Activity Heparin falls 13 Keeping on Center Topical Hemostatics Purified Factors, FFP, Cryo, PLTs Antifibrinolytic Activity Procoagulant Activity Bleeding Clotting Aminocaproic acid, Aprotinin Normal Hemostasis Fibrinolytic Activity t-PA, SK, UPA FFP=fresh frozen plasma; Cryo=cryoprecipitate; PLTs=platelets; SK=streptokinase; UPA=urinary-type plasminogen activator; LMWH=low-molecular-weight heparin. Anticoagulant Activity Heparin, Warfarin LMWH, Argatroban 14 Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64. Operative Management Thrombosis Clotting Physiology and Good Surgery Bleeding Hemorrhage Topical Hemostatic Agents Systemic Biologic Therapies Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64. 15