1. Management of Bleeding in Cardiac Surgical Patients Jerrold H. Levy, MD, FAHA Professor and Deputy Chair for Research Emory University School of Medicine Director, Cardiothoracic Anesthesiology and Critical Care Emory Healthcare Atlanta, Georgia

2. Adapted from Hoffman M, et al. Blood Coag Fibrinol. 1998;9(suppl 1):S61-S65. TF-Bearing Cell Activated Platelet Platelet TF VIIIa Va VIIIa Va VIIa TF VIIa Xa X II IIa IX VVa II VIII/vWF VIIIa II IXa X IX X IXa VIIa Xa IIa Xa Normal Hemostasis

3. Perioperative Impairment of Hemostasis Inhibition of hemostasis or platelets  Hypothermia  Mechanical and inflammatory injury  Heparin or protamine  Preoperative drug therapies Extrinsic pathway activation  Tissue or vascular injury  Reperfusion of ischemic tissues  Local thrombin generation Dilutional coagulopathy Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27–S86; Disorders of hemostasis. In: Harrison’s Internal Medicine. New York, NY: Mc-Graw Hill; 2007. Available at: http://www. accessmedicine.com/resourceToc.aspx?resourceID=4. Accessed January 4, 2008. CT = cardiothoracic; RBC = red blood cell; CPB = cardiopulmonary bypass; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; PVD = peripheral vascular disease.

4. Predictors of Postoperative Bleeding: CT Surgery Advanced age Small body size or preoperative anemia (low RBC volume) Antiplatelet, antithrombotic drugs Prolonged operation  CPB time – high correlation with surgery type Emergency surgery Other comorbidities  CHF  COPD  Hypertension  PVD  Renal failure Ferraris VA, et al. Ann Thorac Surg. 2005;79:1454-1461. Ferraris VA, et al. Ann Surg. 2002;235:820-827.. Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86. CT = cardiothoracic; RBC = red blood cell; CPB = cardiopulmonary bypass; CHF = congestive heart failure; COPD = chronic obstructive pulmonary disease; PVD = peripheral vascular disease.

5. Clopidogrel and Other Thienopyridines Also AHA/ACC, STS guidelines note “if possible” Product Insert: “If a patient is to undergo elective surgery and an antiplatelet effect is not desired, [the drug] should be discontinued 5 days prior to surgery.” ACC = American College of Cardiology; AHA = American Heart Association; STS = Society of Thoracic Surgeons. Plavix (clopidogrel bisulfate) [package insert]. Bridgewater, NJ: Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership; 2007. Braunwald E, et al. J Am Coll Cardiol. 2002;40:1366-1374. Ferraris VA, et al. Ann Thorac Surg. 2007;83:S27-S86.

6. Clopidogrel and CABG: Reoperation for Bleeding* *Need for reexploration secondary to bleeding; † P=.01; ‡ P=.018. Yende S, et al. Crit Care Med. 2001;29:2271-2275. Hongo RH, et al. J Am Coll Cardiol. 2002;40:231-237. 1.5 0.6 9.8 6.9 0 2 4 6 8 10 12 Yende † Hongo ‡ % No clopidogrel Clopidogrel

7. Prohemostatic Agents Aprotinin Lysine analogs Protamine DDAVP (desmopressin) Recombinant factor VIIa (rVIIa) FEIBA/PCCs DDAVP = 1,desamino-8-D-arginine vasopressin; FEIBA = factor VIII inhibitor bypassing activity; PCC = prothrombin complex concentrate.

8. Reports of rVIIa in Cardiac Surgery Diprose P, Herbertson MJ, D ’ Shaughnessy D, Gill RS. Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non- coronary cardiac surgery: randomized double-blind placebo-controlled pilot study. Br J Anaesth. 2005;95:596-602. Goodnough LT, Lublin DM, Zhang L, Depois G, Eby C. Transfusion medicine service policies for recombinant factor VIIa administration. Transfusion. 2004;44:1325- 1331. Halkos ME, Levy JH, Chen E, et al. Early experience with activated recombinant factor VII for intractable hemorrhage after cardiovascular surgery. Ann Thorac Surg. 2005;79:1303-1306. Hendriks HG, van der Maaten JMAA, de Wolf J, Waterbolk TW, Sloof MJH, van der Meer J. An effective treatment of severe intractable bleeding after valve repair by one single dose of activated recombinant factor VII. Anesth Analg. 2001;93:287- 289. Stratmann G, Russell IA, Merrick SH. Use of recombinant factor VIIa as a rescue treatment for intractable bleeding following repeat aortic arch repair. Ann Thorac Surg. 2003;76:2094-2097. Tanaka KA, Waly AA, Cooper WA, Levy JH. Treatment of excessive bleeding in Jehovah ’ s Witnesses following cardiac surgery with recombinant factor VIIa (NovoSeven ® ). Anesthesiology. 2003;98:1513-1515.

9. Perioperative Thrombosis/Hypercoagulability: Potential Causes Premature cessation of heparin therapy Heparin-induced thrombocytopenia Inadequate heparin during CPB Low ATIII/APC/factor V Leiden Preoperative thrombocytosis Transfused platelets Vascular disease Technical issues All of the above Levy JH, Hursting MJ. Hematol Oncol Clin North Am. 2007;21:65-88. Levy JH, et al. Anesth Analg. 2007;105:570-582. Spiess BD, et al. Transfusion. 2004;44:1143-1148. ATIII = antithrombin III; APC = activated protein C.