Alternatives to unfractioned heparin for anticoagulation in cardiopulmonary bypass

Abstract

Despite the progress made in the development of cardiopulmonary bypass (CPB) equipment, systemic anticoagulation with unfractionated heparin and post-bypass neutralization with protamine are still used in most perfusion procedures. However, there are a number of situations where unfractionated heparin, protamine or both cannot be used for various reasons. Intolerance of protamine can be addressed with extracorporeal heparin removal devices, perfusion with (no) low systemic heparinization and, to some degree, by perfusion with alternative anticoagulants. Various alternative anticoagulation regimens have been used in cases of intolerance to unfractionated heparin, including extreme hemodilution, low molecular weight heparins, danaparoid, ancrod, r-hirudin, abciximab, tirofiban, argatroban and others. In the presence of heparin-induced thrombocytopenia (HIT) and thrombosis, the use of r-hirudin appears to be an acceptable solution which has been well studied. The main issue with r-hirudin is the difficulty in monitoring its activity during CPB, despite the fact that ecarin coagulation time assessment is now available. A more recent approach is based on selective blockage of platelet aggregation by means of monoclonal antibodies directed to GPIIb/IIIa receptors (abciximab) or the use of a GPIIb/IIIa inhibitor (tirofiban). An 80% blockage of the GPIIb/IIIa receptors and suppression of platelet aggregation to less than 20% allows the giving of unfractionated heparin and running CPB in a standard fashion despite HIT and thrombosis. Likewise, at the end of the procedure, unfractionated heparin is neutralized with protamine as usual and donor platelets are transfused if necessary. GPIIb/IIIa inhibitors are frequently used in interventional cardiology and, therefore, are available in most hospitals.

Thrombin and cardiopulmonary bypass – A paradigm for evaluation of the regulation of hemostasis

“…Heparin also causes some harmful side-effects including platelet dysfunction and increased fibrinolysis [102]. For these reasons and others, heparin has been questioned as the ideal anticoagulant for use during CPB [29,80,102,205]. It is not surprising that multiple alternatives to the use of heparin during CPB have been proposed.…”

Anticoagulant therapy during cardiopulmonary bypass

“…UFH is highly antigenic, provoking an antibody response in approximately 30-50% of patients undergoing CPB, and precipitating heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) in 1-3% of patients [13,14,20,[23][24][25][26]. HIT is a limb and life-threatening complication of therapy with a mortality rate approaching 40%, [25] and though venous thrombosis is the most common clinical presentation, arterial thrombosis, including ischemic stroke and acute graft closure is not rare [26].…”

“…Protamine administration may itself contribute to perioperative morbidity and adverse reactions in up to 10% of patients, including life-threatening reactions with circulatory collapse, systemic hypotension, pulmonary hypertension, myocardial suppression and overt anaphylaxis [2,13,19,27,31].…”

“…Because of a shorter chain length, LMWHs inhibit factor Xa to a greater extent than factor IIa [13]. However, due to their antithrombin-dependent mechanism of action, LMWHs as with UFH, cannot inactive fibrin-bound thrombin or FXa bound to activated platelets within a developing thrombus [32].…”

“…Unfractionated heparin (UFH), administered to maintain a state of anticoagulation and attenuate the highly prothrombotic environment of CPB, and post-bypass neutralization with protamine sulfate are mainstays of therapy worldwide, and despite clear limitations have been difficult to replace in contemporary practice [13][14][15].…”