Activation of the Hemostatic System During Cardiopulmonary Bypass

Normal hemostasis

circulating platelets adhere to the subendothelium that is exposed when the vascular lining is broken. Adhesion of platelets to the endothelial bed is mediated through the surface proteins that are produced and stored in platelets and endothelial cells such as von Willebrand Factor (VWF). *** Leads to: platelet shape changes Assembly of the glycoprotein IIb/IIIa (GPIIb/IIIA) receptor release of secondary aggregators as ADP and thromboxane A2.

At the same time of platelet plug formation, the coagulation system is activated.

Anticoagulant mechanisms tissue factor pathway inhibitor (TFPI) inactivates factor VIIa bound to tissue factor antithrombin III It neutralizes factor Xa, thrombin (factor IIa), factor IXa and factor VIIa bound to tissue factor. All these actions are thought to be accelerated when antithrombin is bound to heparin or vascular heparin-like proteoglycans. protein C anticoagulant pathway inactivates factors Va and VIIIa.

Cardiopulmonary bypass (CPB)  is a technique that temporarily takes over the function of the heart and lungs during surgery, maintaining the circulation of blood and the oxygen content of the patient's body. The CPB pump itself is often referred to as a heart–lung machine . Results in widespread activation of the hemostatic system. However, surgery also results in normal increases in coagulation activation, platelet activation, and fibrinolysis that are associated with normal wound hemostasis.

MECHANISMS OF ACTIVATION Hemostatic system activation occurs via several mechanisms including: Activation of coagulation fibrinolysis, inflammation, platelets.

Activation of coagulation it has been thought that contact activation via factor XII was the trigger for extensive activation of the hemostatic system during CPB. Factor XII becomes activated when blood interacts with a foreign surface, such as the CPB circuit, thus activating the intrinsic clotting pathway. Boisclair et al. showed no change in factor XIIa levels during CPB, despite significant thrombin generation, indicating that contact activation was not the initial trigger for coagulation.

This suggests a role for the extrinsic pathway as the primary stimulus with subsequent activation of factor IX and the intrinsic system via the extrinsic pathway. TF is released by the endothelial cells due to the surgical trauma and the retransfusion of pericardial blood and TF-expression on the surface of activated monocytes are also sources for VIIa/TF activation during CPB. Together, the contact activation and tissue factor pathway result in the immense formation of thrombin during CPB.

The Fibrinolytic System Activation of fibrinolysis occurs simultaneously and by several mechanisms. t-PA release contributes to fibrinolysis and is promoted by: CPB-mediated contact activation of factor XII Thrombin Hypothermia traumatized endothelial cells returned blood from the cardiotomy suction.

The activation of these cascades may lead to a consumptive coagulopathy Thrombin mediates the conversion of fibrinogen to fibrin, and also activates factor V, VII, XIII, and platelets. It also activates complement in the inflammatory system, which may further enhance coagulation activation. thrombin also downregulates hemostasis by releasing TFPI and in combination with thrombomodulin, it activates protein C, which inhibits the previously generated factors Va and VIIIa Thrombin also initiates fibrinolysis by mediating release of t-PA which activates plasmin. If the effects of thrombin and plasmin are not attenuated, unrestricted thrombin and plasmin activity will lead to consumption of coagulation factors and platelets (i.e. a disseminated intravascular coagulation state during CPB) and this may result in both bleeding and thrombo-embolic complications.

Inflammation A sepsis-like clinical picture that often results from CPB, termed the systemic inflammatory response syndrome, can be linked to “crosstalk” with the coagulation system. Leukocytes, including neutrophils and monocytes, bind to and are activated by the surface of the bypass circuit, which leads to an increase in TF expression, procoagulant activation, and thrombin generation on these cells. Shed blood contains increased numbers of activated leukocytes and levels of TF bound to cells and microparticles, as well as soluble TF.

Platelet CPB activates platelets with resultant structural and biochemical changes. These include physical factors (such as hypothermia and high shear stresses), exposure to artificial surfaces, the use of exogenous drugs (such as heparin and protamine), and the release of endogenous chemical mediators (such as thrombin, complement, cytokines and adrenaline)

several platelet surface molecules such as GPIb and GPIIb/IIIa are downregulated during CPB. expression of P-selectin is increased by activated platelets All these changes can lead to both the formation of platelet conjugates by activated platelets and hemostatic defects due to impaired platelet function. Thrombocytopenia.

Use of heparin and protamine To prevent thromboembolic complications due tot the use of CPB, heparin is administered before the patient is connected to the CPB system. Heparin binds to the enzyme inhibitor antithrombin III (AT-III) causing rapid interaction with thrombin. Next to the neutralization of thrombin, heparin also leads to increased plasmin generation. This results in increased fibrinolysis and also platelet activation, as plasmin binds to their surface. protamine sulfate is used for reversal of heparin anticoagulation The administration of protamine may also cause a transient thrombocytopenia, which is associated with platelet activation and the formation of transient aggregates that appear to sequestrate in the lungs.

Strategies to attenuate hemostatic activation during cardiac surgery Pharmacological strategies Platelet inhibition: Aspirin, Clopidogrel, dipyridamole, short-acting GPIIb/IIIa antagonist Fibrinolysis inhibitors: Tranexaminic acid (TA), ε-aminocaproic acid (EACA) and aprotinine Thrombin inhibitors: Several newly developed antithrombotic agents have been studied as alternatives to heparin when heparin cannot be used (eg, heparin-induced thrombocytopenia with thrombosis)

Non-pharmacological strategies Heparin-coated CPB circuit Cardiotomy suction: blood in the pericardial cavity is highly activated and contains high concentrations of thrombin and plasmin. This blood is usually collected by cardiotomy suction and rerouted to the patient without processing. Normothermia: platelet aggregation and endothelial cell related coagulation Plasma levels of soluble thrombomodulin were more increased in hypothermic than in normothermic more extensive endothelial damage or activation

References S.F. KHURI, et al.: EFFECTS OF CARDIOPULMONARY BYPASS ON HEMOSTASIS,1997 Roman M. Sniecinski, et al.: Activation of the Hemostatic System During Cardiopulmonary Bypass,2011 A Practical Approach to Cardiac Anesthesia,2007, Chapter two