Rapid Reversal of Anticoagulation Prevents Excessive Secondary Hemorrhage After Thrombolysis in a Thromboembolic Model in Rats

Abstract

Background and Purpose-Thrombolysis is the only approved therapy for ischemic stroke, but secondary hemorrhage is a severe complication. Because oral anticoagulants are believed to increase the risk of hemorrhage, thrombolysis is usually contraindicated in patients on vitamin K antagonists. We studied whether thrombolysis in a thromboembolic middle cerebral artery occlusion model in rats pretreated with warfarin increases secondary hemorrhage, and whether substitution of coagulation factors before thrombolysis prevents hemorrhagic complications. Methods-Wistar rats were anticoagulated using warfarin in drinking water (0.4 mg/kg per 24 hours). Strength of anticoagulation was monitored using benchside international normalized ratio (INR) coagulometry. Two hours after middle cerebral artery occlusion, recombinant tissue-type plasminogen activator (9 mg/kg) was administered. Two of 5 groups of animals received prothrombin complex concentrate (PCC, 50 U/kg) 15 minutes before thrombolysis. Serial magnetic resonance imaging was performed 20 minutes, 2.5 hours, and 24 hours after middle cerebral artery occlusion. Secondary hemorrhage was quantified on T2* magnetic resonance images as previously established. Results-Severity of hypoperfusion on initial perfusion-weighted imaging -magnetic resonance did not differ among groups. Thrombolysis resulted in successful reperfusion in all groups. Anticoagulated animals had significantly more secondary hemorrhage and a higher mortality rate compared with nonanticoagulated animals. PCC rapidly reversed the increased international normalized ratio. Although PCC failed to prevent hemorrhage in the strongly anticoagulated, it reduced the incidence of severe hemorrhage in moderately anticoagulated rats (INR, 2-3) to the level of nonanticoagulated controls. Conclusions-Preceding

Rivaroxaban Does Not Increase Hemorrhage after Thrombolysis in Experimental Ischemic Stroke

“…10,11,22 This is in accordance with an increased risk of hemorrhagic complications of thrombolysis in stroke patients during therapeutic anticoagulation with VKA. 12 The present study is the first to establish a model of ischemic stroke and thrombolysis during oral anticoagulation with rivaroxaban.…”

“…9 Effective longterm oral anticoagulation with vitamin K antagonists (i.e., international normalized ratio (INR) 42) increases the risk of intracerebral hemorrhage after thrombolytic therapy in patients and cerebral ischemia models. 10,11 The risk of thrombolysis in patients with subtherapeutic warfarin use is controversial. [12][13][14] Current guidelines recommend excluding stroke patients with INR exceeding 1.7 from thrombolytic therapy with rtPA.…”

Prehospital stroke care

“…Hemorrhage: as growth of intracerebral hematoma is aggravated in patients under oral anticoagulation 53 and rapid reversal of anticoagulation has been shown to attenuate this effect in animal experiments, 54 immediate prehospital application of prothrombin complex concentrate may improve outcome of this subset of patients with otherwise poor prognosis. The same applies to blood pressure management in patients with intracerebral hemorrhage.…”

Reversal of Warfarin Anticoagulation with Prothrombin Complex Concentrate before Thrombolysis for Acute Stroke

“…However, proximal MCA occlusions are unlikely to recanalize spontaneously, and outcome following persistent occlusion is poor. PCC has been used to reverse warfarin-associated coagulopathy prior to tPA in animal models [3] and may reduce secondary hemorrhagic transformation [4]. Recombinant factor VIIa has been used in similar situations in humans [5], but carries a greater thrombotic risk [6] and is less effective for hemostasis [7], making PCC a potentially favorable option.…”