The impact of prothrombin complex concentrates when treating DOAC-associated bleeding: a review

Abstract

BackgroundBleeding complications are a risk associated with all anticoagulants. Currently, the treatment options for the management of direct oral anticoagulant (DOAC)-associated bleeding are limited. Prothrombin complex concentrates (PCCs) have been proposed as a potential therapeutic option, and evidence regarding their use is increasing.ReviewMany studies supporting PCC have used preclinical models and healthy volunteers; however, more recently, observational studies have further improved insight into current DOAC reversal strategies. Multiple clinical practice guidelines now specifically suggest use of PCCs for this indication. Specific reversal agents for Factor Xa inhibitors may become available in the near future, but data on their efficacy are still emerging.ConclusionsUltimately, a multimodal approach may be the optimal strategy to restore haemostasis in patients presenting with DOAC-associated coagulopathy.Electronic supplementary materialThe online version of this article (10.1186/s12245-018-0215-6) contains supplementary material, which is available to authorized users.

Andexanet versus prothrombin complex concentrates: Differences in reversal of factor Xa inhibitors in in vitro thrombin generation

“…As discussed above, anti-FXa levels were not impacted by PCCs in these studies. 17,21,28 Moreover, thrombin generation was not normalized in most cases with 4F-PCCs until the inhibitors had been substantially cleared, 21 a finding consistent with the present study showing that 4F-PCCs did not normalize TF-TG unless FXa inhibitor levels were <35-75 ng/mL (Table 2; Figure 5). Regarding bleeding patients on FXa inhibitors, several observational studies have reported on the use of 4F-PCCs but have shown inconsistent efficacy results.…”

“…Factor replacement therapies, such as four-factor prothrombin complex concentrates (4F-PCCs), are approved for reversal of anticoagulation with vitamin K antagonists (VKA; eg, warfarin) and serve to replace factors VII (FVII), IX (FIX), X (FX), and II (FII) rendered functionally deficient by the anticoagulant. 11 Although 4F-PCCs have been studied for FXa inhibitor reversal in nonclinical in vitro/ex vivo assays, [12][13][14] animal models, 15 healthy volunteers, [16][17][18][19][20][21][22][23] and observational clinical studies in patients taking FXa inhibitors, [24][25][26][27] the effectiveness and clinical benefit of 4F-PCCs on hemostatic efficacy and reversal of key biomarkers are mixed, 7,[28][29][30][31] and their potential mechanism of action has not been critically elucidated. There have been no controlled studies evaluating the effectiveness of 4F-PCCs for reversal of FXa inhibitor-mediated bleeding (or anticoagulation), and they are not approved for this indication.…”

“…Since published data demonstrated no effect of 4F-PCCs on anti-FXa levels in subjects anticoagulated with FXa inhibitors, 17,21,28 we evaluated the hypothesis that PCCs could have an alternative mechanism, such as providing additional enzyme (FX that can be converted to FXa) and substrate (FII) sufficient to overcome FXa inhibition and thereby normalize thrombin generation. 30 A central question is to what degree FXa inhibition needs to be relaxed (via clearance of the anticoagulant) for PCCs to normalize thrombin generation.…”

A review of guidelines on anticoagulation reversal across different clinical scenarios – Is there a general consensus?

“…Various studies have evaluated the safety and efficacy of 4F-PCCs in DOAC reversal, in settings including major bleeding and requirement for urgent surgery [27,44,[55][56][57][58][59][60][61]. 4F-PCC was generally effective in achieving hemostasis in patients with major bleeding, with TEE rates ranging from 0% to 8% [27,44,[56][57][58][59][60]62], and appeared to be associated with a mortality benefit versus no reversal treatment in patients with traumatic ICH [61]. However, one meta-analysis (including 10 case series) reported that it was difficult to assess whether the addition of 4F-PCCs was more effective in managing major bleeding compared with cessation of DOAC therapy alone [63].…”

Reversal of rivaroxaban anticoagulant effect by prothrombin complex concentrates: which dose is sufficient to restore normal thrombin generation?

“…Moreover, some experts suggested that activated PCC (APCC, FEIBA©, Takeda, Japan) could be an effective strategy to improve haemostasis in DOAC-related major bleeding events [7,8]. Although clinical guidelines recommend PCCs for the treatment of DOAC-associated bleeding events [9], some authors suggested that PCCs may not be effective in this situation [10]. In the present study, we assessed the in vitro efficacy and safety of three 4-factor PCCs that contain the human coagulation factors II, VII, IX and X and are commercially available in France for reversing rivaroxaban anticoagulant effect.…”