Use of prothrombin complex concentrate containing heparin for emergency reversal of bivalirudin anticoagulation: a word of caution:

TLDR: Considering the absence of safety data in bleeding patients and the risk of ‘delayed onset HIT’, the administration of heparin-containing PCC should not be recommended for bleeding management in patients treated with bivalirudin.

Abstract: We read with great interest the case reported by Dr. Hassen and colleagues describing the management of severe bleeding associated with bivalirudin in a patient with acute heparin-induced thrombocytopenia (HIT) undergoing emergent complex cardiac surgery.1 Acute renal failure serves as an explanation for the persisting anticoagulant effect observed in this case as, in dialysis patients, the half-life of bivalirudin can be prolonged up to 3.5 hours.2 Uncontrollable diffuse bleeding is a challenging scenario for cardiac surgical teams. In this case report, Hassan et al. used a multimodal approach to manage haemorrhage, which also included the administration of 4-factor prothrombin complex concentrate (PCC) containing heparin. Based on this single-case experience, the authors suggested an algorithm for the management of patients with comparable clinical conditions. Although the long-term course of the patient was fortunately uneventful, the management strategy promoted by the authors should be interpreted with caution. It is well accepted that even small amounts of heparin may trigger HIT reactions. Refaai et al. reported a case of HIT-associated venous thromboembolism and cerebral venous thrombosis as the consequence of heparin ‘flushes’.3 As thrombin plays a pivotal role in HITassociated thromboembolism (TE), it can be speculated that high intraoperative concentrations of bivalirudin may have prevented/attenuated any potential manifestations of HIT that could have been induced by the heparin contained in the PCC. However, a not rare phenomenon known as ‘late onset HIT’ has also been described in the case published by Refaai et al., meaning that HIT can occur even days following heparin exposure.3 In addition, the administration of PCC itself may be considered as a risk factor for TE complications. The halflife of the pro-coagulant factors contained in the PCC ranges from approximately 6 hours for factor VII to more than 10 days for factor II, while it is approximately 2 days for the antithrombotic proteins C and S.4 The safety profile of these powerful drugs has only been assessed in small randomized or retrospective trials, most of them for the reversal of vitamin k antagonist (VKA) therapy (only approved indication).5 The incidence of TE reported in the prospective studies for VKA reversal was approximately 4%.5 However, incidences as high as 20% have been reported following the administration of PCC for major bleeding outside the context of VKA reversal.6 Considering the absence of safety data in bleeding patients and the risk of ‘delayed onset HIT’, the administration of heparin-containing PCC should not be recommended for bleeding management in patients treated with bivalirudin. Viewing the dilemma of currently available approaches in cases of diffuse microvascular bleeding in patients treated with bivalirudin, we prefer to cautiously tamponade the thorax, leave the chest open (which also prevents the bleeding associated with the placement of sternal wires during anticoagulation) and start continuous haemofiltration immediately after intensive care unit admission. Using such a strategy, the chest can usually be closed within 24 hours when laboratory parameters have normalized and diffuse bleeding has stopped. The underlying risk for preoperative TE complications is not increased. As outlined by Dr. Hassan et al., our experience with bivalirudin anticoagulation during cardiac surgery and, Use of prothrombin complex concentrate containing heparin for emergency reversal of bivalirudin anticoagulation: a word of caution