Management of the Bleeding Patient Receiving New Oral Anticoagulants: A Role for Prothrombin Complex Concentrates

Abstract

Ease of dosing and simplicity of monitoring make new oral anticoagulants an attractive therapy in a growing range of clinical conditions. However, newer oral anticoagulants interact with the coagulation cascade in different ways than traditional warfarin therapy. Replacement of clotting factors will not reverse the effects of dabigatran, rivaroxaban, or apixaban. Currently, antidotes for these drugs are not widely available. Fortunately, withholding the anticoagulant and dialysis are freqnently effective treatments, particularly with rivaroxaban and dabigatran. Emergent bleeding, however, requires utilization of Prothrombin Complex Concentrates (PCCs). PCCs, in addition to recombinant factor VIIa, are used to activate the clotting system to reverse the effects of the new oral anticoagulants. In cases of refractory or emergent bleeding, the recommended factor concentrate in our protocols differs between the new oral anticoagulants. In patients taking dabigatran, we administer an activated PCC (aPCC) [FELBA] due to reported benefit in human in vitro studies. Based on human clinical trial evidence, the 4-factor PCC (Kcentra) is suggested for patients with refractory rivaroxaban- or apixaban-associated hemorrhage. If bleeding continues, recombinant factor VIIa may be employed. With all of these new procoagulant agents, the risk of thrombosis associated with administration of factor concentrates must be weighed against the relative risk of hemorrhage.

Current knowledge on assessing the effects of and managing bleeding and urgent procedures with direct oral anticoagulants

“…62 The aPCC FEIBA has been documented in a series of case reports to successfully and rapidly resolve dabigatran-related life-threatening bleeding complications. 39,[63][64][65] In a porcine polytrauma model with supratherapeutic dabigatran concentrations, FEIBA in doses ranging from 25 to 50 IU/kg was found to reduce blood loss in a dose-dependent manner, with the 50-IU/kg dose effectively reducing blood loss without inducing a procoagulant state. 66 In a case series of four patients who experienced bleeding while receiving dabigatran (intracranial hemorrhage [ICH], n = 2; pericardiocentesis, n = 1; gastrointestinal, n = 1), FEIBA doses ranging from 42 to 100 IU/kg were successful in stabilizing the patients' condition without any subsequent thrombosis observed.…”

“…S18 [39][40][41][42][43][44][45][46][47][48][49][50] One analysis, however, suggested that activated PCCs (aPCCs) and rFVIIa were more likely to produce partial dabigatran reversal than nonactivated PCCs. 51 Beyond FFP and rFVIIa, three types of PCC products are currently available.…”

“…53 Studies of the various products in vitro and ex vivo primarily evaluated thrombin generation using variable doses and have yielded inconsistent results. 39,45 As such, the ideal agent and dose to reverse the anticoagulation effects of DOACs, in the absence of a specific reversal agent, remains unclear. Given the availability of different types of PCCs, it is important to make sure that the specific agent to be used is identified in the prescription order.…”

Direct Oral Anticoagulants in Emergency Trauma Admissions

“…In the presence of circulatory instability the usual vasopressors are used, while patients receiving massive transfusions may require plasma/plate let products and fibrinogen concentrates (5,6). Should conventional measures prove inadequate, offlabel administration of prothrombin complex concentrates or activated prothrombin complex concentrate and/or recombinant factor VIIa (rFVIIa) in the recommended dosages can be considered (5,6,22,23,(27)(28)(29)(30) (Figure 2). In experimental studies (dabigatran) and tests on healthy volunteers (apixaban, edoxaban, and rivaroxaban), the best effect has been documented for prothrombin complex concentrate (29-32, e27-e33); no prospective randomized trials have been conducted.…”

Optimizing the safety of treatment for venous thromboembolism in the era of the direct oral anticoagulants

“…47 Furthermore, in volunteers given edoxaban, 4-factor PCC attenuated bleeding from punch biopsy sites in a concentration-dependent manner. 48 With 50 U/kg, PCC restored bleeding duration to background levels and enhanced thrombin generation.…”