Secondary Intracerebral Hemorrhage Due to Early Initiation of Oral Anticoagulation After Ischemic Stroke

Abstract

Background and Purpose-The uncertain risk of secondary intracerebral hemorrhage (sICH) frequently keeps clinicians from initiating oral anticoagulation (OAC) early after ischemic cardioembolic stroke. The goal of this experimental study was to determine the risk of sICH depending on the timing of OAC initiation relative to stroke onset and to address the role of hematogenous macrophages for repair processes preventing OAC-associated sICH. Methods-C57BL/6 mice were subjected to transient middle cerebral artery occlusion. Subgroups were treated with either the vitamin K antagonist (VKA) phenprocoumon or the direct thrombin inhibitor dabigatran etexilate. Hematogenous macrophages were depleted using intraperitoneal injections of clodronate-filled liposomes. Results-Time to therapeutic OAC was 48 hours with VKA and 0.5 hours with dabigatran etexilate treatment. In VKAtreated mice, the risk of sICH was high if effective OAC was already present at stroke onset or achieved within 48 hours after ischemia. With more delayed OAC, the risk of sICH rapidly decreased. Compared with VKA treatment, effective anticoagulation with dabigatran etexilate was associated with a significantly reduced extent of sICH, either if present at stroke onset or if achieved 48 hours later. Partial depletion of macrophages greatly increased the extent of OACassociated sICH in the subacute stage of 3 to 4 days after ischemia. Conclusions-Our findings suggest that repair mechanisms involving hematogenous macrophages rapidly decrease the risk of OAC-associated sICH in the first days after ischemic stroke.

Neuroimmune Response in Ischemic Preconditioning

“…Unprimed T cells contribute to tissue damage in an antigen-independent manner, through unknown signaling mechanisms that may involve IFN-γ and/or release of reactive oxygen species [19]. γδT cells respond swiftly to ischemia and are regarded as detrimental, largely through their production of cytotoxic cytokines, including IL-17 [19,150]. There is also a possibility that CD4…”

Hyperglycemia and PPARγ Antagonistically Influence Macrophage Polarization and Infarct Healing After Ischemic Stroke

“…Mice were anticoagulated by oral administration of phenprocoumon. 17 To provoke hyperglycemia, streptozotocin (10 mmol/L in citrate buffer, pH 4.6; Sigma-Aldrich, Steinheim, Germany) was injected intraperitoneally 6 weeks before tMCAO induction for 5 consecutive days. Infarct volumes and hemorrhages were visualized by staining with 2,3,5-triphenyltetrazolium chloride.…”

“…Infarct volumes and hemorrhages were visualized by staining with 2,3,5-triphenyltetrazolium chloride. 17 LysM-PPARγ(KO) or LysM-PPARγ(WT) mice were used to study the effect of proinflammatory macrophage skewing. Pharmacological PPARγ activation was achieved by oral administration of pioglitazone (20 mg/kg body weight; Takeda Pharmaceutical, Osaka, Japan) starting directly after tMCAO (d0).…”

“…[13][14][15] We recently showed that inflammatory monocytes invade ischemic brain parenchyma within 24 h of stroke onset and subsequently differentiate within the ischemic brain tissue toward noninflammatory macrophages, which promote early lesion repair, in particular vascular remodeling essential for the prevention of sICH. 16,17 Thus, the hematogenous recruitment of monocytes and their appropriate differentiation into macrophages seems critical for the net effect of strokeinduced brain inflammation.…”

Correction to: Neuroimmune Response in Ischemic Preconditioning

“…Macrophages infiltrate the infarct border zone within hours of stroke onset and they undergo differentiation from a proinflammatory to a noninflammatory profile, which facilitates tissue repair [74,152]. Macrophages are the primary producers of osteopontin, which may have neuroprotective and repair-promoting effects in CNS injury, including ischemia [58].…”