Secondary Bleeding During Acute Experimental Intracerebral Hemorrhage

Schlunk, Frieder; Böhm, Myriam; Boulouis, Grégoire; Qin, Tao; Arbel, Michal; Tamim, Isra; Fischer, Paul; Bacskai, Brian J.; Frosch, Matthew P.; Endres, Matthias; Greenberg, Steven M.; Ayata, Cenk

doi:10.1161/strokeaha.118.021732

Cited by 11 publications

(12 citation statements)

References 30 publications

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“…Although we did not attempt to measure local pressures in order to avoid invasive instrumentation, mass effect and tissue distortion by expanding hematoma are characteristic of ICH 36 and can even shear local arterioles causing secondary hemorrhage. 37 Collagenase itself did not directly trigger SD because SDs occurred with a latency of 30 min or more and coincided with rapid hematoma growth. Moreover, perihematomal edema and inflammation occur many hours to days after ICH and are unlikely to have contributed to SD occurrence in our study.…”

Section: Discussionmentioning

confidence: 99%

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage

Fischer

Sugimoto

Chung

et al. 2020

J Cereb Blood Flow Metab

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Recurrent waves of spreading depolarization (SD) occur in brain injury and are thought to affect outcomes. What triggers SD in intracerebral hemorrhage is poorly understood. We employed intrinsic optical signaling, laser speckle flowmetry, and electrocorticography to elucidate the mechanisms triggering SD in a collagenase model of intracortical hemorrhage in mice. Hematoma growth, SD occurrence, and cortical blood flow changes were tracked. During early hemorrhage (0–4 h), 17 out of 38 mice developed SDs, which always originated from the hematoma. No SD was detected at late time points (8–52 h). Neither hematoma size, nor peri-hematoma perfusion were associated with SD occurrence. Further, arguing against ischemia as a trigger factor, normobaric hyperoxia did not inhibit SD occurrence. Instead, SDs always occurred during periods of rapid hematoma growth, which was two-fold faster immediately preceding an SD compared with the peak growth rates in animals that did not develop any SDs. Induced hypertension accelerated hematoma growth and resulted in a four-fold increase in SD occurrence compared with normotensive animals. Altogether, our data suggest that spontaneous SDs in this intracortical hemorrhage model are triggered by the mechanical distortion of tissue by rapidly growing hematomas.

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Section: Discussionmentioning

confidence: 99%

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage

Fischer

Sugimoto

Chung

et al. 2020

J Cereb Blood Flow Metab

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“…Spontaneous intracerebral microhemorrhages (CMHs) are defined as small foci of hemorrhages in the cerebrum [ 30 – 32 ]. These atraumatic CMHs are due to the rupture of small arteries, arterioles, and/or capillaries.…”

Section: Introductionmentioning

confidence: 99%

Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

Chang

Drelich

et al. 2020

PLoS Negl Trop Dis

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Intracerebral microhemorrhages (CMHs) are small foci of hemorrhages in the cerebrum. Acute infections induced by some intracellular pathogens, including rickettsia, can result in CMHs. Annexin a2 (ANXA2) has been documented to play a functional role during intracellular bacterial adhesion. Here we report that ANXA2-knockout (KO) mice are more susceptible to CMHs in response to rickettsia and Ebola virus infections, suggesting an essential role of ANXA2 in protecting vascular integrity during these intracellular pathogen infections. Proteomic analysis via mass spectrometry of whole brain lysates and brain-derived endosomes from ANXA2-KO and wild-type (WT) mice post-infection with R. australis revealed that a variety of significant proteins were differentially expressed, and the follow-up function enrichment analysis had identified several relevant cell-cell junction functions. Immunohistology study confirmed that both infected WT and infected ANXA2-KO mice were subjected to adherens junctional protein (VE-cadherin) damages. However, key blood-brain barrier (BBB) components, tight junctional proteins ZO-1 and occludin, were disorganized in the brains from R. australis-infected ANXA2-KO mice, but not those of infected WT mice. Similar ANXA2-KO dependent CMHs and fragments of ZO-1 and occludin were also observed in Ebola virus-infected ANXA2-KO mice, but not found in infected WT mice. Overall, our study revealed a novel role of ANXA2 in the formation of CMHs during R. australis and Ebola virus infections; and the underlying mechanism is relevant to the role of ANXA2-regulated tight junctions and its role in stabilizing the BBB in these deadly infections.

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“…Lauer et al [90] also found that the pretreatment with dabigatran etexilate, a new oral specific thrombin inhibitor, did not increase hematoma volume in both collagenase-induced and laser-induced ICH models, in contrast to warfarin. In contrast, another study suggested both warfarin and dabigatran exacerbated secondary hemorrhage in two kinds of mouse ICH model (intrastriatal liquid polymer injection and intrastriatal blood injection) [91]. Further investigation is needed for a better understanding of the pathophysiology of thrombin-induced brain injury after ICH to determine how and when to target it (or downstream pathways) without impacting hematoma growth.…”

Section: Thrombin In Intracerebral Hemorrhagementioning

confidence: 99%

The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke

Garton

Hua

et al. 2020

Transl. Stroke Res.

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Thrombin is increased in the brain after hemorrhagic and ischemic stroke primarily due to the prothrombin entry from blood either with a hemorrhage or following blood-brain barrier disruption. Increasing evidence indicates that thrombin and its receptors (protease-activated receptors (PARs)) play a major role in brain pathology following ischemic and hemorrhagic stroke (including intracerebral, intraventricular, and subarachnoid hemorrhage). Thrombin and PARs affect brain injury via multiple mechanisms that can be detrimental or protective. The cleavage of prothrombin into thrombin is the key step of hemostasis and thrombosis which takes place in every stroke and subsequent brain injury. The extravascular effects and direct cellular interactions of thrombin are mediated by PARs (PAR-1, PAR-3, and PAR-4) and their downstream signaling in multiple brain cell types. Such effects include inducing blood-brain-barrier disruption, brain edema, neuroinflammation, and neuronal death, although low thrombin concentrations can promote cell survival. Also, thrombin directly links the coagulation system to the immune system by activating interleukin-1α. Such effects of thrombin can result in both short-term brain injury and longterm functional deficits, making extravascular thrombin an understudied therapeutic target for stroke. This review examines the role of thrombin and PARs in brain injury following hemorrhagic and ischemic stroke and the potential treatment strategies which are complicated by their role in both hemostasis and brain.

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Secondary Bleeding During Acute Experimental Intracerebral Hemorrhage

Cited by 11 publications

References 30 publications

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage

Rapid hematoma growth triggers spreading depolarizations in experimental intracortical hemorrhage

Annexin A2 depletion exacerbates the intracerebral microhemorrhage induced by acute rickettsia and Ebola virus infections

The Role of Thrombin in Brain Injury After Hemorrhagic and Ischemic Stroke

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