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

2 Surgery Post-op Recovery 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 Bleeding Hemorrhage

3 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.

4 VII(VIIa) TF TF·VII(VIIa) TF·VIIa Ca 2 :PL IIaXa IXa ß VIIa X XI XIa IX IIa Va·Xa Ca 2 :PL IIa FN (cross-linked) VIIIa-IXa ß Ca 2 :PL Xa PL (IX α ) VIII Fg Fn XIIIa XIII II IIa Xa IXa ß XaIIa V Coagulation Cascade: Tissue Factor Pathway

5 The Problem Most complications are at the dark interface between: Biology Clinical skill Medical therapy Sick patients

6 Hemostasis “The arrest of bleeding”  Stedman’s Medical Dictionary But is hemostasis more than that?

7 Hemostasis In surgery—hemostasis is … About bleeding About clotting About timing About balance

8 Hemostasis “Life in the Balance” Bleeding to Death Trauma Major Surgery Hemophilia Clotting to Death Stroke MI Thrombosis Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.

9 Hemostasis “Too thick or too thin”  Dr. Richard McCann Hemostasis in cardiovascular surgery “Knowing when to be thick and when to be thin”

10 Hemostasis Blood coagulation Anticoagulation Fibrinolysis Antifibrinolysis Vascular tone and blood flow Endothelial cells and platelets

11 Keeping on Center Normal Hemostasis Procoagulant Activity Anticoagulant Activity Fibrinolytic Activity Antifibrinolytic Activity Bleeding Clotting Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

12 Surgery Post-op Recovery Thrombosis Clotting Bleeding Hemorrhage What About Hemostatic Swings During Surgery? Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl 1):55-64.

13 Keeping on Center Normal Hemostasis Procoagulant Activity Anticoagulant Activity Fibrinolytic Activity Antifibrinolytic Activity Bleeding Clotting Factor V falls t-PA increase IIase increase TF increase PAI-1 increase Heparin falls InflammatoryCytokines Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

14 Keeping on Center Topical Hemostatics Purified Factors, FFP, Cryo, PLTs Aminocaproic acid, Aprotinin Heparin, Warfarin LMWH, Argatroban t-PA, SK, UPA Normal Hemostasis Procoagulant Activity Anticoagulant Activity Fibrinolytic Activity Antifibrinolytic Activity Bleeding Clotting FFP=fresh frozen plasma; Cryo=cryoprecipitate; PLTs=platelets; SK=streptokinase; UPA=urinary-type plasminogen activator; LMWH=low-molecular-weight heparin. Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.

15 Thrombosis Clotting Bleeding Hemorrhage Physiology and Good Surgery Topical Hemostatic Agents Systemic Biologic Therapies Operative Management Adapted from Lawson JH, et al. Semin Hematol. 2004;41(suppl):55-64.