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    • Senger et al performed a retrospective review of patients

    2022-09-29

    Senger et al. performed a retrospective review of 17 patients with ICH on dabigatran or rivaroxaban who received 4F-PCC. Eight patients had a traumatic Amphotericin B injury (TBI) and nine patients had a spontaneous ICH. Nine patients had a devastating outcome, including severe neurologic deficits, comatose status, or death [15]. Hedges et al. performed a relatively larger retrospective review of 193 patients who received either 4F-PCC or three-factor PCC for the reversal of rivaroxaban, dabigatran, apixaban, warfarin, or unknown anticoagulant. The majority of patients were taking warfarin prior to admission, while only 18 patients were taking a DOAC. The efficacy results were not specific for the type of anticoagulant, limiting the external validity of the study [16]. Finally, Grandhi et al. performed a retrospective, observational study of 18 patients who received 4F-PCC for the reversal of rivaroxaban or apixaban for ICH. Eight patients had a TBI and ten patients had a spontaneous ICH. One patient demonstrated hemorrhage progression on head CT, one patient had a VTE, six patients died in the hospital, and six patients had favorable outcomes at 90 days [17]. Recently, Engelbart et al. performed a case series of 42 patients assessing activated PCC (aPCC) for the reversal of DOAC-associated hemorrhage and prevention of hemorrhagic complications in patients requiring urgent procedures [19]. The ACC recommends aPCC as an alternative to 4F-PCC in patients taking a factor Xa inhibitor with a critical site or life threatening bleed [5]. The in-hospital mortality rate was 29% in all patients and 33% among patients with ICH. Thromboembolic complications occurred in 10% of patients [19]. The mortality rate in this study was 14.5% overall and 22.9% in the 4F-PCC group. This is consistent with previous studies that demonstrated mortality ranging from 17.6% to 33% in patients with ICH who received 4F-PCC for the reversal of DOACs [15,17]. Mortality was significantly higher in the 4F-PCC group compared to the no reversal group. This finding was contrary to our expectation that 4F-PCC would improve outcomes and is explained by the significant difference in ISS at baseline. After controlling for ISS, there was no significant difference in mortality between the groups. The primary safety concern with the use of 4F-PCC is thrombosis. In eyespot study, only one patient in the 4F-PCC group had a VTE and no patients in the 4F-PCC group had an ischemic stroke, TIA, or MI, demonstrating a low risk of thrombosis with 4F-PCC. It is possible that more thromboembolic events would have occurred in the 4F-PCC if the mortality rate were lower, as some of the patients died early in their hospital stay and did not have time to develop a thrombotic complication. Andexanet alfa was recently approved by the FDA for the reversal of rivaroxaban and apixaban in the setting of life-threatening or uncontrolled bleeding [3]. While this is the first FDA approved reversal agent for factor Xa inhibitors, 4F-PCC will likely continue to be used off-label for this indication. Given the recent approval of andexanet alfa, the product will not be immediately available to all hospitals. Pharmacy and Therapeutics committees will assess the cost effectiveness, efficacy, and safety of the agent prior to adding andexanet alfa to formulary. Furthermore, thrombotic events occurred in 18% of patients who received andexanet alfa, which could deter prescribers from routine use, especially given the low incidence of thrombosis associated with 4F-PCC in this study [4]. Additionally, guidelines continue to support the use of 4F-PCC for the reversal of factor Xa inhibitors [5]. This study provides effectiveness and safety data to compare 4F-PCC to andexanet alfa in the future.
    Conclusion
    Conflict of interest
    Introduction In the process of thrombus formation, two main pathways, blood coagulation and platelet aggregation, play pivotal roles [1], [2]. Therefore anticoagulants and antiplatelet agents are used to block these pathways for the prevention and treatment of thrombotic diseases. The blood coagulation and platelet aggregation do not act independently and there are cross talks between the two pathways. For example, thrombin, which is a final product of the coagulation pathway and forms fibrin, is a physiological platelet agonist and induces platelet aggregation via its platelet receptors, PAR-1 and PAR-4 [3], [4]. Both thrombin-induced fibrin formation and thrombin-induced platelet aggregation contribute to the thrombus formation.