Antiplatelet pretreatment does not increase hematoma volume in experimental intracerebral hemorrhage.
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SUBMITTER: Lauer A
PROVIDER: S-EPMC3170939 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hematoma clearance occurs in the days after intracerebral hemorrhage (ICH) and has not been well studied. In the current study, we examined changes in the hematoma in a piglet ICH model. The effect of deferoxamine on hematoma was also examined.The ICH model was induced by an injection of autologous blood into the right frontal lobe of piglets. First, a natural time course of hematoma changes ?7 days was determined. Second, the effect of deferoxamine on hematoma changes was examined. Hemoglobin and membrane attack complex levels in the hematoma were examined by enzyme-linked immunosorbent assay. Immunohistochemistry and Western blotting were used to examine CD47 (a regulator of erythrophagocytosis), CD163 (a hemoglobin scavenger receptor), and heme oxygenase-1 (a heme degradation enzyme) in the clot.After ICH, there was a reduction in red blood cell diameter within the clot with time. This was accompanied by membrane attack complex accumulation and decreased hemoglobin levels. Erythrophagocytosis occurred in the hematoma, and this was associated with reduced clot CD47 levels. Activated macrophages/microglia were CD163 and hemeoxygenase-1 positive, and these accumulated in the clot with time. Deferoxamine treatment attenuated the process of hematoma resolution by reducing member attack complex formation and inhibiting CD47 loss in the clot.These results indicate that membrane attack complex and erythrophagocytosis contribute to hematoma clearance after ICH, which can be altered by deferoxamine treatment.
| S-EPMC5237112 | biostudies-literature
Project description:Hematoma volume is the strongest predictor of outcome in intracerebral hemorrhage (ICH). Despite known differences in the underlying biology between deep and lobar ICHs, limited data are available on location specificity of factors reported to affect hematoma volume.To evaluate whether determinants of ICH volume differ by topography, we sought to estimate location-specific effects for potential predictors of this radiological outcome.Prospective cohort study.Academic medical center.A total of 744 supratentorial primary ICH patients (388 deep and 356 lobar) aged older than 18 years admitted between January 1, 2000, and December 31, 2010.Intracerebral hemorrhage volume measured from the computed tomography scan obtained on presentation to the emergency department. Linear regression analysis, stratified by ICH location, was implemented to identify determinants of log-transformed ICH volume.Median ICH volume was larger in lobar hemorrhages (39 mL; interquartile range, 16-75 mL) than in deep hemorrhages (13 mL; interquartile range, 5-40 mL; P < .001). In multivariable linear regression, independent predictors of deep ICH volume were intensity of anticoagulation (? = 0.32; standard error [SE] = 0.08; P < .001; test for trend across 4 categories of the international normalized ratio), history of coronary artery disease (? = 0.33; SE = 0.17; P = .05), male sex (? = 0.28; SE = 0.14; P = .05), and age (? = -0.02; SE = 0.01; P = .001). Independent predictors of lobar ICH volume were intensity of anticoagulation (? = 0.14; SE = 0.06; P = .02) and antiplatelet treatment (? = 0.27; SE = 0.13; P = .03).Predictors of hematoma volume only partially overlap between deep and lobar ICHs. These findings suggest that the mechanisms that determine the extent of bleeding differ for deep and lobar ICHs. Further studies are needed to characterize the specific biological pathways that underlie the observed associations.
| S-EPMC3808840 | biostudies-literature
Project description:Background and purposeHematoma volume is an important determinant of clinical outcome in spontaneous intracerebral hemorrhage (ICH). We performed a genome-wide association study (GWAS) of hematoma volume with the aim of identifying novel biological pathways involved in the pathophysiology of primary brain injury in ICH.MethodsWe conducted a 2-stage (discovery and replication) case-only genome-wide association study in patients with ICH of European ancestry. We utilized the admission head computed tomography to calculate hematoma volume via semiautomated computer-assisted technique. After quality control and imputation, 7 million genetic variants were available for association testing with ICH volume, which was performed separately in lobar and nonlobar ICH cases using linear regression. Signals with P<5×10-8 were pursued in replication and tested for association with admission Glasgow coma scale and 3-month post-ICH dichotomized (0-2 versus 3-6) modified Rankin Scale using ordinal and logistic regression, respectively.ResultsThe discovery phase included 394 ICH cases (228 lobar and 166 nonlobar) and identified 2 susceptibility loci: a genomic region on 22q13 encompassing PARVB (top single-nucleotide polymorphism rs9614326: β, 1.84; SE, 0.32; P=4.4×10-8) for lobar ICH volume and an intergenic region overlying numerous copy number variants on 17p12 (top single-nucleotide polymorphism rs11655160: β, 0.95; SE, 0.17; P=4.3×10-8) for nonlobar ICH volume. The replication included 240 ICH cases (71 lobar and 169 nonlobar) and corroborated the association for 17p12 (P=0.04; meta-analysis P=2.5×10-9; heterogeneity, P=0.16) but not for 22q13 (P=0.49). In multivariable analysis, rs11655160 was also associated with lower admission Glasgow coma scale (odds ratio, 0.17; P=0.004) and increased risk of poor 3-month modified Rankin Scale (odds ratio, 1.94; P=0.045).ConclusionsWe identified 17p12 as a novel susceptibility risk locus for hematoma volume, clinical severity, and functional outcome in nonlobar ICH. Replication in other ethnicities and follow-up translational studies are needed to elucidate the mechanism mediating the observed association.
| S-EPMC6085089 | biostudies-literature
Project description:Background and Purpose- Enhancement of erythrophagocytosis by macrophages in a timely manner can limit the toxic effects of erythrocyte metabolites and promote brain recovery after intracerebral hemorrhage (ICH). In the current study, we investigated the therapeutic effect of retinoid X receptor agonist, bexarotene, in facilitating erythrophagocytosis and neurobehavioral recovery in 2 mouse models of ICH. Methods- Bone marrow-derived macrophages and fluorescently labeled erythrocytes were used to study erythrophagocytosis in vitro with phenotypic changes quantified by gene expression. ICH was modeled in vivo using intrastriatal autologous blood and collagenase injection in mice with and without bexarotene treatment beginning 3 hours after ICH. In vivo phagocytosis, ability and hematoma clearance were evaluated by erythrophagocytosis assays, flow cytometry, and histological analysis. Neurological deficits and functional recovery were also quantified. Results- Bexarotene increased macrophage expression of phagocytosis receptors and erythrophagocytosis and reduced macrophage TNF (tumor necrosis factor) production in vitro. In vivo, bexarotene treatment enhanced erythrophagocytosis, reduced hematoma volume, and ultimately improved neurological recovery after ICH in 2 distinct models of ICH. Conclusions- Bexarotene administration is beneficial for recovery after ICH by enhancing hemorrhage phagocytosis, modulating macrophage phenotype, and improving functional recovery.
| S-EPMC7135897 | biostudies-literature
Project description:Background Previous studies have shown that cortical superficial siderosis (cSS) can increase hematoma volume and predict poor outcomes following primary intracerebral hemorrhage (ICH). Objective We aimed to determine whether a large hematoma volume was the essential factor contributing to worse outcomes of cSS. Methods Patients with spontaneous ICH underwent a CT scan within 48 h after ictus. Evaluation of cSS was performed using magnetic resonance imaging (MRI) within 7 days. The 90-day outcome was assessed using the modified Rankin Scale (mRS). In addition, we investigated the correlation between cSS, hematoma volume, and 90-day outcomes using multivariate regression and mediation analyses. Results Among the 673 patients with ICH [mean (SD) age, 61 (13) years; 237 female subjects (35.2%); median (IQR) hematoma volume, 9.0 (3.0–17.6) ml], 131 (19.5%) had cSS. There was an association between cSS and larger hematoma volume (β = 4.449, 95% CI 1.890–7.009, p < 0.001) independent of hematoma location and was also related to worse 90-day mRS (β = 0.333, 95% CI 0.008–0.659, p = 0.045) in multivariable regression. In addition, mediation analyses revealed that hematoma volume was an essential factor mediating the effect of cSS on unfavorable 90-day outcomes (proportion mediated:66.04%, p = 0.01). Conclusion Large hematoma volume was the major charge of directing cSS to worse outcomes in patients with mild to moderate ICH, and cSS was related to a larger hematoma in both lobar and non-lobar areas. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT04803292, identifier: NCT04803292.
| S-EPMC10196120 | biostudies-literature
Project description:Background and Purpose- Our previous studies found that erythrocyte CD47 has a role in regulating hematoma resolution following experimental intracerebral hemorrhage (ICH). The current study examined whether or not a CD47 blocking antibody enhances hematoma clearance in a mouse ICH. Methods- ICH was induced by intracaudate injection of autologous blood in adult C57BL/6 mice. Mice had an ICH or ICH with CD47 blocking antibody or IgG coinjection. In subgroups of CD47 blocking antibody-treated mice, clodronate (to deplete microglia/macrophages) or control liposomes were coinjected. The effects of CD47 blocking antibody on ICH-induced brain injury were also tested in both males and females. Mice had magnetic resonance imaging to examine clot volume, iron deposition, brain swelling, and brain tissue loss. Behavioral tests were performed in all mice, and brains were harvested for brain immunohistochemistry. Results- In male mice, CD47 blocking antibody speeded up hematoma/iron clearance by macrophages/microglia and reduced ICH-induced brain swelling, neuronal loss, and neurological deficits. In contrast, clodronate liposome-induced microglia/macrophage depletion caused more severe brain swelling, neuronal loss, and functional deficits. In addition, similar injury severity in males and females was found in IgG control group and CD47 blocking antibody was also effective in females. Conclusions- Blocking CD47 in the hematoma speeded hematoma clearance and reduced brain injury after ICH suggesting it could be a treatment for ICH patients with surgical clot removal.
| S-EPMC6538472 | biostudies-literature
Project description:Microglia/macrophages (MMΦ) are highly plastic phagocytes that can promote both injury and repair in diseased brain through the distinct function of classically activated and alternatively activated subsets. The role of MMΦ polarization in intracerebral hemorrhage (ICH) is unknown. Herein, we comprehensively characterized MMΦ dynamics after ICH in mice and evaluated the relevance of MMΦ polarity to hematoma resolution. MMΦ accumulated within the hematoma territory until at least 14days after ICH induction. Microglia rapidly reacted to the hemorrhagic insult as early as 1-1.5h after ICH and specifically presented a "protective" alternatively activated phenotype. Substantial numbers of activated microglia and newly recruited monocytes also assumed an early alternatively activated phenotype, but the phenotype gradually shifted to a mixed spectrum over time. Ultimately, markers of MMΦ classic activation dominated at the chronic stage of ICH. We enhanced MMΦ alternative activation by administering intraperitoneal injections of rosiglitazone, and subsequently observed elevations in CD206 expression on brain-isolated CD11b+ cells and increases in IL-10 levels in serum and perihematomal tissue. Enhancement of MMΦ alternative activation correlated with hematoma volume reduction and improvement in neurologic deficits. Intraventricular injection of alternative activation signature cytokine IL-10 accelerated hematoma resolution, whereas microglial phagocytic ability was abolished by IL-10 receptor neutralization. Our results suggest that MMΦ respond dynamically to brain hemorrhage by exhibiting diverse phenotypic changes at different stages of ICH. Alternative activation-skewed MMΦ aid in hematoma resolution, and IL-10 signaling might contribute to regulation of MMΦ phagocytosis and hematoma clearance in ICH.
| S-EPMC5540140 | biostudies-literature
Project description:Intracerebral hemorrhage (ICH), the most devastating form of stroke, has no specific therapy proven to improve outcome by randomized controlled trial. Location and baseline hematoma volume are strong predictors of mortality, but are nonmodifiable by the time of diagnosis. Expansion of the initial hematoma is a further marker of poor prognosis that may be at least partly preventable. Several risk factors for hematoma expansion have been identified, including baseline ICH volume, early presentation after symptom onset, anticoagulation, and the CT angiography spot sign. Although the biological mechanisms of hematoma expansion remain unclear, accumulating evidence supports a model of ongoing secondary bleeding from ruptured adjacent vessels surrounding the initial bleeding site. Several large clinical trials testing therapies aimed at preventing hematoma expansion are in progress, including aggressive blood pressure reduction, treatment with recombinant factor VIIa guided by CT angiography findings, and surgical intervention for superficial hematomas without intraventricular extension. Hematoma expansion is so far the only marker of outcome that is amenable to treatment and thus a potentially important therapeutic target.
| S-EPMC3743539 | biostudies-literature
Project description:Background and objectiveThe aim of this study was to evaluate the impact of radiographic cerebral small vessel disease (CSVD) on the severity of acute intracerebral hemorrhage (ICH) as measured by: ICH volume, hematoma expansion, and extension of intraventricular hemorrhage (IVH).MethodsCSVD was determined on baseline computed tomography (CT) scans of patients from the Ethnic and Racial Variations of Intracerebral Hemorrhage study through the extent of leukoaraiosis and cerebral atrophy using visual rating scales. The associations of leukoaraiosis and atrophy with ICH volume, hematoma expansion, IVH presence, and severity of IVH were tested using multivariable regression models. Secondary analyses were stratified by hemorrhage location. Bonferroni correction was applied to correct for multiple testing.ResultsA total of 2579 patients (mean age 61.7 years, 59% male) met inclusion criteria. Median ICH volume was 10.5 (Interquartile range [IQR] 4.0-25.3) mL. IVH was detected in 971 patients (38%). Neither leukoaraiosis nor atrophy was associated with hematoma expansion. Increasing grades of leukoaraiosis were associated with increased risk of IVH in a dose-dependent manner, while cerebral atrophy was inversely associated with IVH (both P for trend < 0.001). Increasing grades of global atrophy were dose-dependently associated with lower ICH volumes (ß (95% Confidence Interval [CI]) - 0.30[- 0.46, - 0.14], - 0.33[- 0.49, - 0.17], - 0.40[- 0.60, - 0.20], and - 0.54[- 0.76, - 0.32], for grades 1, 2, 3 and 4 compared to 0; all P < 0.001). The associations of leukoaraiosis with ICH volume were consistent with those of atrophy, albeit not meeting statistical significance.ConclusionsLeukoaraiosis and cerebral atrophy appear to have opposing associations with ICH severity. Cerebral atrophy correlates with smaller ICH volume and decreased risk and severity of IVH, while leukoaraiosis is associated with increased risk of IVH. Whether these observations reflect overlapping or divergent underlying mechanisms requires further study.
| S-EPMC7082383 | biostudies-literature
Project description:ImportanceIntraventricular thrombolysis reduces intraventricular hemorrhage (IVH) volume in patients with spontaneous intracerebral hemorrhage (ICH), but it is unclear if a similar association with parenchymal ICH volume exists.ObjectiveTo evaluate the association between intraventricular alteplase use and ICH volume as well as the association between a change in parenchymal ICH volume and long-term functional outcomes.Design, setting, and participantsThis cohort study was a post hoc exploratory analysis of data from the Clot Lysis: Evaluating Accelerated Resolution of Intraventricular Hemorrhage phase 3 randomized clinical trial with blinded outcome assessments. Between September 1, 2009, and January 31, 2015, patients with ICH and IVH were randomized to receive either intraventricular alteplase or normal saline via an external ventricular drain. Participants with primary IVH were excluded. Data analyses were performed between January 1 and June 30, 2021.ExposureRandomization to receive intraventricular alteplase.Main outcomes and measuresThe primary outcome was the change in parenchymal ICH volume between the hematoma stability and end-of-treatment computed tomography scans. Secondary outcomes were a modified Rankin Scale score higher than 3 and mortality, both of which were assessed at 6 months. The association between alteplase and change in parenchymal ICH volume was assessed using multiple linear regression, whereas the associations between change in parenchymal ICH volume and 6-month outcomes were assessed using multiple logistic regression. Prespecified subgroup analyses were performed for baseline IVH volume, admission ICH volume, and ICH location.ResultsA total of 454 patients (254 men [55.9%]; mean [SD] age, 59 [11] years) were included in the study. Of these patients, 230 (50.7%) were randomized to receive alteplase and 224 (49.3%) to receive normal saline. The alteplase group had a greater mean (SD) reduction in parenchymal ICH volume compared with the saline group (1.8 [0.2] mL vs 0.4 [0.1] mL; P < .001). In the primary analysis, alteplase use was associated with a change in the parenchymal ICH volume in the unadjusted analysis per 1-mL change (β, 1.37; 95% CI, 0.92-1.81; P < .001) and in multivariable linear regression analysis that was adjusted for demographic characteristics, stability ICH and IVH volumes, ICH location, and time to first dose of study drug per 1-mL change (β, 1.20; 95% CI, 0.79-1.62; P < .001). In the secondary analyses, no association was found between change in parenchymal ICH volume and poor outcome (odds ratio [OR], 0.97; 95% CI 0.87-1.10; P = .64) or mortality (OR, 0.97; 95% CI 0.99-1.08; P = .59). Similar results were observed in the subgroup analyses.Conclusions and relevanceThis study found that intraventricular alteplase use in patients with a large IVH was associated with a small reduction in parenchymal ICH volume, but this association did not translate into improved functional outcomes or mortality. Intraventricular thrombolysis should be examined in patients with moderate to large ICH with IVH, especially in a thalamic location.
| S-EPMC8642781 | biostudies-literature