Mechanisms and attenuation of hemostatic activation during extracorporeal circulation  George J. Despotis, MD, Michael S. Avidan, MD, Charles W. Hogue, MD  The Annals of Thoracic Surgery  Volume 72, Issue 5, Pages S1821-S1831 (November 2001) DOI: 10.1016/S0003-4975(01)03211-8

Fig 1 Pathophysiology of hemostasis abnormalities with extracorporeal circulation. CPB crystalloid prime refers to crystalloid solution required to prime the cardiopulmonary bypass circuit whereas cardioplegia volume refers to volume of crystalloid required for cardioplegic myocardial arrest. Contact activation via extracorporeal circulation (ECC) refers to contact activation related to interface of blood with nonendothelial surface of extracorporeal circuit. Pericardial activation refers to activation of the hemostatic system via the tissue factor pathway mediated by transfusion pericardial blood containing tissue thromboplastin, tPA = tissue plasminogen activator; Gp = platelet glycoprotein receptors (e.g., IIb/IIIa or Ib), Mechanical (i.e., as related to ECC) refers to shear forces imposed by some of the components of the ECC circuit as listed. The Annals of Thoracic Surgery 2001 72, S1821-S1831DOI: (10.1016/S0003-4975(01)03211-8)

Fig 2 Mechanisms and effects of excessive hemostatic activation with cardiac surgery. The coagulation system is subdivided into three pathways intrinsic or contact, extrinsic or tissue factor and common (i.e., below conversion of X to Xa); the conversion of factor X to Xa is within all three pathways. Dashed line designates release of protein cleavage by-products. Abbreviations (activated factors are designated using a small “a” whereas inactivated factors are designated using a small “i”): Factor XII = XII; Factor VII = VII; Factor X = X; Factor VIII = VIII; Factor IX = IX; Factor V = V; Factor XIII = XIII; prothrombin fragment 1.2 = PT 1.2; calcium ions = Ca++; fibrinopeptide A = FPA; PL = phospholipid; PAP = plasmin-antiplasmin complexes; EC = endothelial cells; tPA:PAI1= tPA PAI1 complexes; fibrin monomer = fibrin (m); fibrin polymer = fibrin (p); fibrin cross-linked polymer = fibrin (L); plasminogen activator inhibitor = PAI1; tissue plasminogen activator = tPA; fibrinogen/fibrin degradation products = FDP; polymerized fibrin degradation products = D-dimers; * designates endothelial cell related. The Annals of Thoracic Surgery 2001 72, S1821-S1831DOI: (10.1016/S0003-4975(01)03211-8)

Fig 3 Agents that preserve hemostasis. Dashed line designates release of protein cleavage by-products. The following coagulation factors, hemostatic mediators and by-products are abbreviated using the following (activated factors are designated using a small “a”): Factor XII = XII; Factor VII = VII; Factor X = X; Factor VIII = VIII; Factor IX = IX; Factor V = V; Factor XIII = XIII; prothrombin fragment 1.2 = PT 1.2; calcium ions = Ca++; fibrinopeptide A = FPA; fibrin monomer = fibrin (m); fibrin polymer = fibrin (p); plasminogen activator inhibitor = PAI1; tissue plasminogen activator = tPA; fibrinogen/fibrin degradation products = FDP; polymerized fibrin degradation products = D-dimers; EACA = epsilon-amino caproic acid; TA = tranexamic acid; vWF = von Willebrand Factor; Gp = glycoprotein receptors. The Annals of Thoracic Surgery 2001 72, S1821-S1831DOI: (10.1016/S0003-4975(01)03211-8)

Fig 4 Effects of aprotinin on blood loss and transfusion requirements in patients undergoing cardiac surgery involving CPB: A summary from four large, recent, multi-center US trials [50–53]. A = aprotinin-treated patients; P = placebo-treated patients; Blood loss = cumulative 24 hours blood loss; CTD = chest tube drainage; U = units; Primary = first cardiac surgical procedure; Repeat = one or more previous cardiac procedures. Percentage of patients reexplored for each cohort within the box labeled “Reexploration.” The Annals of Thoracic Surgery 2001 72, S1821-S1831DOI: (10.1016/S0003-4975(01)03211-8)

Fig 5 Relationship between hemostatic changes in platelets and coagulation factors with cardiopulmonary bypass (CPB) and excessive microvascular bleeding. Percent decreases were compared in patients without microvascular bleeding (nonbleeders) who averaged two hours on CPB as compared to patients with excessive microvascular bleeding who averaged over three hours on CPB. Percent decreases were calculated using Pre-CPB and Post-CPB values in the following equation: ([post-CPB/pre-CPB] - 1) x 100. Average absolute values for hemostatic variables are also indicated. Coagulation Factors V, VII, VIII, IX, X and XII are expressed as % activity, fibrinogen concentration is expressed as mg/dl and platelet count is expressed in 1,000/μl. * p <0.05. (Reprinted with permission from Despotis et al [74].) The Annals of Thoracic Surgery 2001 72, S1821-S1831DOI: (10.1016/S0003-4975(01)03211-8)

Fig 6 Inhibition of thrombin activity. Left panel depicts normal physiologic inhibition of fluid phase thrombin by high molecular weight (HMW) heparin molecules and the limitations of heparin in inhibiting clot-bound thrombin. The thrombin molecule has three major binding sites: the fibrinogen binding site (Exo I); the fibrinogen catalytic site (Cat Site); and the fibrin binding site (Exo II). After binding of heparin to the ATIII molecule via a critical pentasaccharide sequence, a conformational change in the C-terminal portion of the ATIII molecule is induced. Inhibition of the thrombin molecule requires heparin molecules with a critical oligosaccharide chain length of 18 units that serve as a template for the binding of antithrombin III (ATIII) with thrombin. However, thrombin inhibition via the ATIII-heparin mechanism is limited by availability of the Exo II site which can also be occupied by fibrin. Although low molecular weight fractions (LMW) of heparin induce a conformational change in the C-terminal portion of the ATIII molecule, they cannot serve as a template for ATIII and thrombin due to their short chain length. The right panel depicts the normal inhibition of clot-bound thrombin by the heparin cofactor II (HCII) - heparin complex and the sites of action of various direct thrombin inhibitors. A minimum chain length of six units for the heparin oligosaccacharide is required to activate HCII however 20-24 unit chain lengths result in a substantially greater thrombin inhibition via HCII. Direct thrombin inhibitors such as hirudin and hirulog bind to both the Exo I and catalytic sites of the thrombin molecule. In contrast, polypeptide aptamers and hirugen bind to the Exo I site whereas PPACK and argatroban bind to the fibrinogen catalytic site of thrombin. (As modified from Tollefson D, et al. Thromb Hemostas 1995;96:120-129. Reprinted with permission). The Annals of Thoracic Surgery 2001 72, S1821-S1831DOI: (10.1016/S0003-4975(01)03211-8)