Contact of heparinized blood with synthetic surfaces of the heart-lung machine initiates complex chemical and cellular reactions within the blood that result in thrombotic and bleeding problems and in a """"""""whole body inflammatory response."""""""" This proposal seeks to identify and to selectively inhibit the initial reactions and agonists that activate blood coagulation, fibrinolysis and immunochemical defense mechanisms during cardiopulmonary bypass (CPB). The proposal will utilize several newly developed immunochemical assays to decipher the mechanisms whereby platelets$ neutrophils and complement and fibrinolytic and contact system proteins are activated during CPB in patients, in our well-established in vitro model of simulated extracorporeal circulation (SECC) and in a new in vivo baboon model. Newly developed murine antibodies against Factor XII, prekallikrein and high molecular weight kininogen, and specific peptides such as a boroarginine kallikrein inhibitor, will first be tested in our in vitro model and then in the baboon. The project also seeks alternatives to heparin, such as hirudin and boroarginine peptides, and to protamine, such as platelet factor 4, since heparin and protamine are known blood agonists. The role of fibrinolysis by both plasmin and neutrophil elastase during and after CPB will be studied using new specific assays for fibrin and fibrinogen fragments. Fibrinolytic inhibitors - tranexemic acid, epsilon amino caproic acid and aprotonin - will be evaluated in patients and baboons. The project seeks to use specific peptides and combination strategies to reversibly block neutrophil and platelet activation. Patient studies will be done to, discover and quantitate activation of contact system and fibrinolytic system proteins, and platelets and neutrophils. Unapproved drugs, specific peptides and monoclonal antibiotics will be studied in vitro, first using human blood and then in baboons, since most human immunochemical assays cross-react with baboon blood. Recent advances in hematology and immunochemistry offer realistic prospects that selective inhibition of surface-activated blood constituents can be achieved and that the morbidity and mortality of CPB in the very young and very old can be reduced.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (SRC (MM))
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University of Pennsylvania
Schools of Medicine
United States
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Khan, Mohammad M H; Hattori, Takashi; Niewiarowski, Stefan et al. (2006) Truncated and microparticle-free soluble tissue factor bound to peripheral monocytes preferentially activate factor VII. Thromb Haemost 95:462-8
Hattori, Takashi; Khan, Mohammad M H; Colman, Robert W et al. (2005) Plasma tissue factor plus activated peripheral mononuclear cells activate factors VII and X in cardiac surgical wounds. J Am Coll Cardiol 46:707-13
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Edmunds Jr, L Henry (2002) The evolution of cardiopulmonary bypass: lessons to be learned. Perfusion 17:243-51
Edmunds Jr, L H (2001) Evolution of prosthetic heart valves. Am Heart J 141:849-55
Selim, T E; Ghoneim, H R; Abdel Ghaffar, H A et al. (2001) High molecular mass kininogen inhibits cathepsin G-induced platelet activation by forming a complex with cathepsin G. Hematol J 2:371-7
Soulika, A M; Khan, M M; Hattori, T et al. (2000) Inhibition of heparin/protamine complex-induced complement activation by Compstatin in baboons. Clin Immunol 96:212-21
Suzuki, Y; Malekan, R; Hanson 3rd, C W et al. (1999) Platelet anesthesia with nitric oxide with or without eptifibatide during cardiopulmonary bypass in baboons. J Thorac Cardiovasc Surg 117:987-93
Khan, M M; Gikakis, N; Miyamoto, S et al. (1999) Aprotinin inhibits thrombin formation and monocyte tissue factor in simulated cardiopulmonary bypass. Ann Thorac Surg 68:473-8
Rao, A K; Sun, L; Hiramatsu, Y et al. (1999) Glycoprotein IIb/IIIa receptor antagonist tirofiban inhibits thrombin generation during cardiopulmonary bypass in baboons. Thromb Haemost 82:140-4

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