Heparin Resistance During Cardiopulmonary Bypass in Adult Cardiac Surgery

Abstract

The use of heparin for anticoagulation has changed the face of cardiac surgery by allowing a bloodless and motionless surgical field throughout the introduction of cardiopulmonary bypass (CPB). However, heparin is a drug with complex pharmacologic properties that can cause significant interpatient differences in terms of responsiveness. Heparin resistance during CPB is a weighty issue due to the catastrophic consequences stemming from inadequate anticoagulation, and the treatment of it necessitates a rationalized stepwise approach due to the multifactorial contributions toward this entity. The widespread use of activated clotting time (ACT) as a measurement of anticoagulation during CPB is examined, as it may be a false indicator of heparin resistance. Heparin resistance also has been repeatedly reported in patients infected with COVID-19, which deserves further exploration in this pandemic era. This review aims to examine the variability in heparin potency, underlying mechanisms, and limitations of using ACT for monitoring, as well as provide a framework towards the current management of heparin resistance.

Keywords: COVID-19; activated clotting time; albumin; anticoagulation; antithrombin.

Fig 1

Interactions among antithrombin (AT), heparin, and activated coagulation factors (thrombin in C and factor IXa or Xa in D and E). (A and B) Binding of AT to a specific pentasaccharide sulfation sequence within the heparin polymer induces a conformational change in the binding sites of AT for activated coagulation factors. (C) Both AT and thrombin bind to the same heparin chain. The ability of heparin to act as a template for AT and thrombin depends on its length and, thus, on its molecular weight. Approximately 18 monosaccharide units are minimal to bridge AT to thrombin. (D) Factors IXa and Xa bind to an allosteric site on the pentasaccharide-activated AT without simultaneous binding to the same heparin chain. The inhibition of factors IXa and Xa can occur with heparin lengths <18 monosaccharide units. (E) The binding and inhibition of factors IXa or Xa by AT in the presence of low-molecular-weight heparin.

Fig 2

Algorithm for treatment of heparin resistance. Flow chart adapted from Finley and Greenberg. ACT, activated clotting time; AT, antithrombin; CABG, coronary bypass graft surgery; CPB, cardiopulmonary bypass; FFP, fresh frozen plasma; HiTT, high-dose thrombin time; MiECC, minimally invasive extracorporeal circulation.