Abstract
The timing of anti-coagulation therapy initiation after acute cardioembolic stroke remains controversial. We investigated the effects of post-stroke administration of a factor Xa inhibitor in mice, focusing on tissue repair and functional restoration outcomes. We initiated administration of rivaroxaban, a Xa inhibitor, immediately after permanent distal middle cerebral artery occlusion (pMCAO) in CB-17 mice harboring few leptomeningeal anastomoses at baseline. Rivaroxaban initiated immediately after pMCAO hindered the recovery of blood flow in ischemic areas by inhibiting leptomeningeal anastomosis development, and led to impaired restoration of neurologic functions with less extensive peri-infarct astrogliosis. Within infarct areas, angiogenesis and fibrotic responses were attenuated in rivaroxaban-fed mice. Furthermore, inflammatory responses, including the accumulation of neutrophils and monocytes/macrophages, local secretion of pro-inflammatory cytokines, and breakdown of the blood–brain barrier, were enhanced in infarct areas in mice treated immediately with rivaroxaban following pMCAO. The detrimental effects were not found when rivaroxaban was initiated after transient MCAO or on day 7 after pMCAO. Collectively, early post-stroke initiation of a factor Xa inhibitor may suppress leptomeningeal anastomosis development and blood flow recovery in ischemic areas, thereby resulting in attenuated tissue repair and functional restoration unless occluded large arteries are successfully recanalized.
Highlights
Stroke is a leading cause of death and disability worldwide
Rivaroxaban initiated immediately after permanent distal middle cerebral artery occlusion (pMCAO) hindered the recovery of blood flow in ischemic areas by inhibiting leptomeningeal anastomosis development, and led to impaired restoration of neurologic functions with less extensive peri-infarct astrogliosis
Immunohistochemical results demonstrated that the extent of glial fibrillary acidic protein (GFAP)-positive astrogliosis in peri-infarct areas was significantly attenuated in rivaroxaban-fed mice (Fig. 1D and E)
Summary
Stroke is a leading cause of death and disability worldwide. Cardioembolic stroke is the most severe stroke subtype and often occurs in elderly subjects with atrial fibrillation, and can render elderly subjects bedridden and requiring care. When physicians identify atrial fibrillation, in elderly subjects, they should initiate anti-coagulation therapy for the primary prevention of cardioembolic stroke (Gage et al, 2001). When physicians encounter patients with acute cardioembolic stroke with atrial fibrillation, they need to initiate anti-coagulation therapy at an appropriate time to prevent the recurrence of cardioembolism and to avoid massive hemorrhagic transformation that may worsen neurologic symptoms (Berger et al, 2001). In clinical settings, it is unusual that anti-coagulation therapy can be initiated just before or immediately after successful thrombolysis with such a short period of ischemic time
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