Hemostatic Therapy in Experimental Intracerebral Hemorrhage Associated With Rivaroxaban

Abstract

T hromboembolism in atrial fibrillation is a major cause of stroke.1 Oral anticoagulation (OAC) with the vitamin K antagonist warfarin or one of the new direct oral anticoagulants (nOAC) is highly effective for stroke prevention in atrial fibrillation. [2][3][4][5] The most severe complication of long-term anticoagulation is intracranial hemorrhage. Indeed, intracerebral hemorrhage (ICH) during therapy with vitamin K antagonist is responsible for 88% of all hemorrhage-associated deaths caused by anticoagulation. 6 Moreover, vitamin K antagonistassociated ICH expands more frequently and over a longer time period than spontaneous ICH. [7][8][9] To prevent hematoma expansion-a major therapeutic goal in ICH therapyreplacement of coagulation factors is recommended. 10 Although nOAC appear to carry a substantially lower risk of ICH compared with warfarin, [3][4][5] ICH during nOAC therapy remains a life-threatening complication. Currently, no specific antidote is available, and the effect of administering hemostatic coagulation factors is dubious. 11,12 Recently, an experimental murine model of ICH during OAC has been established in which ICH is induced by injection of collagenase into the striatum during anticoagulation. 13,14 This model shows early hematoma expansion exceeding that of nonanticoagulated mice, during anticoagulation with either warfarin or a high dose of the direct thrombin inhibitor dabigatran. [13][14][15] Excess hematoma expansion in this model could be prevented most effectively by infusing prothrombin complex concentrate (PCC), whereas the effect of recombinant human factor factor VIIa (FVIIa) and fresh frozen plasma (FFP) was less consistent. 15,16 Rivaroxaban is another nOAC that directly inhibits the central coagulation factor Xa. Its widespread clinical use beyond stroke prevention in atrial fibrillation is expected because it has been proven effective and safe for additional indications, including acute coronary syndrome and venous thromboembolism. 17,18 So far, no specific antidote for rivaroxaban is available, and the efficacy of hemostatic factors in the setting of ICH is unknown. 11,12 The purpose of the present study was to establish a murine model of ICH associated with rivaroxaban, and to evaluate the effect of different hemostatic agents on excess hematoma Background and Purpose-Rivaroxaban has recently been approved for stroke prevention in atrial fibrillation. However, lack of an effective antidote represents a major concern in the event of intracerebral hemorrhage (ICH). The aims of the present study were to establish a murine model of ICH associated with rivaroxaban, and to examine the effectiveness of different hemostatic factors in preventing excess hematoma expansion. Methods-In C57BL/6 mice receiving 10 or 30 mg/kg rivaroxaban by gastric gavage, plasma concentration, prothrombin time, and coagulation factor activities were measured repeatedly. Thirty minutes after inducing ICH by intrastriatal collagenase-injection, mice received an intravenous injection of either saline, pro...

Rivaroxaban Does Not Increase Hemorrhage after Thrombolysis in Experimental Ischemic Stroke

“…32,33 Using the Neoplastin prothrombin time assay that is sensitive to rivaroxaban, 34 30 mg/kg rivaroxaban prolong the prothrombin time two-to threefold for at least 4 hours. 17 In the present study, rivaroxaban reduced the activity of coagulation factors II and X ( Figure 1A). Elevated values of rivaroxaban concentration and anti-factor Xa activity remain detectable even 24 hours after rivaroxaban application ( Figures 1E and 1F).…”

“…4,6 Although present and previous data justify withholding thrombolytic treatment in patients with warfarin in the therapeutic INR range, our findings may suggest that hemorrhagic adverse events do not occur more frequently in patients anticoagulated with rivaroxaban than in nonanticoagulated stroke patients. Interestingly, high doses of rivaroxaban 17 and dabigatran 42 are necessary to increase intracerebral hemorrhage volume in murine intracerebral hemorrhage that is induced by striatal collagenase injection. In contrast, the same high dose (30 mg/kg) of rivaroxaban did not cause excess secondary hemorrhagic transformation after thrombolysis in the present study.…”

Volume and functional outcome of intracerebral hemorrhage according to oral anticoagulant type

“…6 Data on NOAC-associated ICH (NOAC-ICH) outside randomized trials are limited, and there is widespread concern that, without any currently available specific antidotes, those who have ICH while on NOACs might have larger ICH volumes and worse clinical outcomes than patients with warfarin-associated ICH (warfarin-ICH). 7,8 Although experimental models show that dabigatran 9 and rivaroxaban 10 -unlike warfarindo not increase ICH volume unless given at supratherapeutic doses, few data are available on the clinical and radiologic characteristics of NOAC-ICH. A small study from Japan recently reported that in 5 patients with ICH associated with the NOAC rivaroxaban, the mean hematoma volume was smaller than in a comparison group of ICH associated with warfarin, 11 and that functional outcomes were better in the NOAC group.…”

Reversal Agents: What We Have and What We Can Expect

“…PCCs are the preferred nonspecific hemostatic agent for NOAC reversal; they are plasma-derived products that contain three (factors II, IX, and X) or four (factors II, IX, X, and VII) clotting factors, in addition to variable amounts of heparin and the natural coagulation inhibitors protein C and protein S. Animal studies have demonstrated that PPCs have a variable ability to normalize anticoagulation parameters and to prevent or attenuate bleeding seen with NOAC usage. 14,[19][20][21][22][23][24][25] The limited data available in humans are restricted to healthy volunteers only. In three small, randomized, placebo-controlled studies involving between 12 and 93 patients, PCC use reversed the anticoagulant effects of rivaroxaban and edoxaban, but not of dabigatran.…”