Statins were shown to increase hemorrhagic stroke (HS) in patients with a first cerebrovascular event in 2006 (SPARCL), likely due to off-target antithrombotic effects, but continued to sometimes be ...used in patients with elevated HS risk due to absence of alternative medications. Recently, the PCSK9Is (proprotein convertase subtilisin kexin 9 inhibitors) have become available as a potent lipid-lowering class with potentially less hemorrhagic propensity.
We performed a systematic comparative meta-analysis assessing HS rates across all completed statin and PCSK9I randomized clinical trials with treatment >3 months, following PRISMA guidelines. In addition to HS rates across all trials, causal relation was probed by evaluating for dose-response relationships by medication (low versus high medication dose/potency) and by presence and type of preceding brain vascular events at inception (none versus ischemic stroke/transient ischemic attack versus HS).
The systematic review identified 36 statin randomized clinical trials (204 918 patients) and 5 PCSK9I randomized clinical trials (76 140 patients). Across all patient types and all medication doses/potencies, statins were associated with increased HS: relative risk 1.15, P=0.04; PCSK9Is were not (P=0.77). In the medication dose/potency analysis, higher dose/potency statins (7 trials, 62 204 patients) were associated with magnified HS risk: relative risk, 1.53; P=0.002; higher dose/potency PCSK9Is (1 trial, 27 564 patients) were not (P=0.99). In the type of index brain vascular injury analysis for statins (5 trials, 9772 patients), prior ischemic stroke/transient ischemic attack was associated with a magnified risk of HS: relative risk, 1.43; P=0.04; and index intracerebral hemorrhage was associated with an extremely high effect estimate of risk of recurrent HS: hazard ratio, 4.06. For PCSK9Is, prior ischemic stroke/transient ischemic attack (1 trial, 5337 patients) was not associated with increased HS risk (P=0.97).
Statins increase the risk of HS in a medication dose- and type of index brain vascular injury-dependent manner; PCSK9Is do not increase HS risk. PCSK9Is may be a preferred lipid-lowering medication class in patients with elevated HS risk, including patients with prior HS.
In the United States, Black, Hispanic, and Asian Americans experience excessively high incidence rates of hemorrhagic stroke compared with White Americans. Women experience higher rates of ...subarachnoid hemorrhage than men. Previous reviews detailing racial, ethnic, and sex disparities in stroke have focused on ischemic stroke. We performed a scoping review of disparities in the diagnosis and management of hemorrhagic stroke in the United States to identify areas of disparities, research gaps, and evidence to inform efforts aimed at health equity.
We included studies published after 2010 that assessed racial and ethnic or sex disparities in the diagnosis or management of patients aged 18 years or older in the United States with a primary diagnosis of spontaneous intracerebral hemorrhage or aneurysmal subarachnoid hemorrhage. We did not include studies assessing disparities in incidence, risks, or mortality and functional outcomes of hemorrhagic stroke.
After reviewing 6,161 abstracts and 441 full texts, 59 studies met our inclusion criteria. Four themes emerged. First, few data address disparities in acute hemorrhagic stroke. Second, racial and ethnic disparities in blood pressure control after intracerebral hemorrhage exist and likely contribute to disparities in recurrence rates. Third, racial and ethnic differences in end-of-life care exist, but further work is required to understand whether these differences represent true disparities in care. Fourth, very few studies specifically address sex disparities in hemorrhagic stroke care.
Further efforts are necessary to delineate and correct racial, ethnic, and sex disparities in the diagnosis and management of hemorrhagic stroke.
Clonal hematopoiesis of indeterminate potential (CHIP) is a novel age-related risk factor for cardiovascular disease-related morbidity and mortality. The association of CHIP with risk of incident ...ischemic stroke was reported previously in an exploratory analysis including a small number of incident stroke cases without replication and lack of stroke subphenotyping. The purpose of this study was to discover whether CHIP is a risk factor for ischemic or hemorrhagic stroke.
We utilized plasma genome sequence data of blood DNA to identify CHIP in 78 752 individuals from 8 prospective cohorts and biobanks. We then assessed the association of CHIP and commonly mutated individual CHIP driver genes (
,
, and
) with any stroke, ischemic stroke, and hemorrhagic stroke.
CHIP was associated with an increased risk of total stroke (hazard ratio, 1.14 95% CI, 1.03-1.27;
=0.01) after adjustment for age, sex, and race. We observed associations with CHIP with risk of hemorrhagic stroke (hazard ratio, 1.24 95% CI, 1.01-1.51;
=0.04) and with small vessel ischemic stroke subtypes. In gene-specific association results,
showed the strongest association with total stroke and ischemic stroke, whereas
and
were each associated with increased risk of hemorrhagic stroke.
CHIP is associated with an increased risk of stroke, particularly with hemorrhagic and small vessel ischemic stroke. Future studies clarifying the relationship between CHIP and subtypes of stroke are needed.
Hemorrhagic stroke (HS) could damage human health and impose heavy social and economic burden around the world. An accumulating number of studies revealed the effect of lipid levels on HS, whereas ...the results were inconsistent. Therefore, we conducted a dose–response meta-analysis to evaluate the relationship between lipid levels and HS.
We searched the databases for relative cohort studies, which were published before April 2020. We pooled adjusted effect size and performed the dose–response analysis by random-effect model. 31 eligible studies with 2,291,643 participants and 12,147 hemorrhagic stroke cases were included. An inverse association was observed between the risk of hemorrhagic stroke and total cholesterol (TC) (RR: 0.72; 95% CI: 0.64–0.82) or low-density lipoprotein cholesterol (LDL-C) (RR: 0.69; 95% CI: 0.53–0.89). Additionally, in dose–response analysis, the non-linear trend was also found between TC, high-density lipoprotein cholesterol (HDL-C), and risk of HS. When the level of TC and HDL-C was about 6 and 1.3 mmol/L separately, the risk of HS was decreased to the lowest. And we found a linear trend that for every 1 mmol/L triglyceride (TG) increase, the risk of HS decreased by 7%.
TC and LDL-C were both inversely related to the risk of HS. In dose–response analysis of TG, we also found the inverse linear trend. Furthermore, the non-linear trend suggested the level of TC and HDL-C was about 6 and 1.3 mmol/L separately could lead to the lowest risk of HS.
•Focused on the relationship between multiple types of lipids and the risk of HS.•We observed an inverse association between the risk of HS and TC or LDL-C.•In dose–response analysis, we found for every 1 mmol/L TG increase, the risk of HS decreased by 7%.•The non-linear trend suggested TC and HDL-C cholesterol was about 6 and 1.3 mmol/L separately could lead to the lowest risk of HS.
Background and Purpose
While the thrombotic complications of COVID-19 have been well described, there are limited data on clinically significant bleeding complications including hemorrhagic stroke. ...The clinical characteristics, underlying stroke mechanism, and outcomes in this particular subset of patients are especially salient as therapeutic anticoagulation becomes increasingly common in the treatment and prevention of thrombotic complications of COVID-19.
Methods
We conducted a retrospective cohort study of patients with hemorrhagic stroke (both non-traumatic intracerebral hemorrhage and spontaneous non-aneurysmal subarachnoid hemorrhage) who were hospitalized between March 1, 2020, and May 15, 2020, within a major healthcare system in New York, during the coronavirus pandemic. Patients with hemorrhagic stroke on admission and who developed hemorrhage during hospitalization were both included. We compared the clinical characteristics of patients with hemorrhagic stroke and COVID-19 to those without COVID-19 admitted to our hospital system between March 1, 2020, and May 15, 2020 (contemporary controls), and March 1, 2019, and May 15, 2019 (historical controls). Demographic variables and clinical characteristics between the individual groups were compared using Fischer’s exact test for categorical variables and nonparametric test for continuous variables. We adjusted for multiple comparisons using the Bonferroni method.
Results
During the study period in 2020, out of 4071 patients who were hospitalized with COVID-19, we identified 19 (0.5%) with hemorrhagic stroke. Of all COVID-19 with hemorrhagic stroke, only three had isolated non-aneurysmal SAH with no associated intraparenchymal hemorrhage. Among hemorrhagic stroke in patients with COVID-19, coagulopathy was the most common etiology (73.7%); empiric anticoagulation was started in 89.5% of these patients versus 4.2% in contemporary controls (
p
≤ .001) and 10.0% in historical controls (
p
≤ .001). Compared to contemporary and historical controls, patients with COVID-19 had higher initial NIHSS scores, INR, PTT, and fibrinogen levels. Patients with COVID-19 also had higher rates of in-hospital mortality (84.6% vs. 4.6%,
p
≤ 0.001). Sensitivity analyses excluding patients with strictly subarachnoid hemorrhage yielded similar results.
Conclusion
We observed an overall low rate of imaging-confirmed hemorrhagic stroke among patients hospitalized with COVID-19. Most hemorrhages in patients with COVID-19 infection occurred in the setting of therapeutic anticoagulation and were associated with increased mortality. Further studies are needed to evaluate the safety and efficacy of therapeutic anticoagulation in patients with COVID-19.
Intracerebral hemorrhage (ICH) is a devastating form of stroke affecting millions of people worldwide. Parenchymal hematoma triggers a series of reactions leading to primary and secondary brain ...injuries and permanent neurological deficits. Microglia and macrophages carry out hematoma clearance, thereby facilitating functional recovery after ICH. Here, we elucidate a pivotal role for the interleukin (IL)-4)/signal transducer and activator of transcription 6 (STAT6) axis in promoting long-term recovery in both blood- and collagenase-injection mouse models of ICH, through modulation of microglia/macrophage functions. In both ICH models, STAT6 was activated in microglia/macrophages (i.e., enhanced expression of phospho-STAT6 in Iba1⁺ cells). Intranasal delivery of IL-4 nanoparticles after ICH hastened STAT6 activation and facilitated hematoma resolution. IL-4 treatment improved long-term functional recovery in young and aged male and young female mice. In contrast, STAT6 knockout (KO) mice exhibited worse outcomes than WT mice in both ICH models and were less responsive to IL-4 treatment. The construction of bone marrow chimera mice demonstrated that STAT6 KO in either the CNS or periphery exacerbated ICH outcomes. STAT6 KO impaired the capacity of phagocytes to engulf red blood cells in the ICH brain and in primary cultures. Transcriptional analyses identified lower level of IL-1 receptor-like 1 (ST2) expression in microglia/macrophages of STAT6 KO mice after ICH. ST2 KO diminished the beneficial effects of IL-4 after ICH. Collectively, these data confirm the importance of IL-4/STAT6/ST2 signaling in hematoma resolution and functional recovery after ICH. Intranasal IL-4 treatment warrants further investigation as a clinically feasible therapy for ICH.
Stroke is commonly reported in patients receiving venovenous extracorporeal membrane oxygenation, but risk factors are not well described. We sought to determine preextracorporeal membrane ...oxygenation and on-extracorporeal membrane oxygenation risk factors for both ischemic and hemorrhagic strokes in patients with venovenous extracorporeal membrane oxygenation support.
Retrospective analysis.
Data reported to the Extracorporeal Life Support Organization by 366 extracorporeal membrane oxygenation centers from 2013 to 2019.
Patients older than 18 years supported with a single run of venovenous extracorporeal membrane oxygenation.
None.
Of 15,872 venovenous extracorporeal membrane oxygenation patients, 812 (5.1%) had at least one type of acute brain injury, defined as ischemic stroke, hemorrhagic stroke, or brain death. Overall, 215 (1.4%) experienced ischemic stroke and 484 (3.1%) experienced hemorrhagic stroke. Overall inhospital mortality was 36%, but rates were higher in those with ischemic or hemorrhagic stroke (68% and 73%, respectively). In multivariable analysis, preextracorporeal membrane oxygenation pH (adjusted odds ratio = 0.10; 95% CI, 0.03-0.35; p < 0.001), hemolysis (adjusted odds ratio = 2.27; 95% CI, 1.22-4.24; p = 0.010), gastrointestinal hemorrhage (adjusted odds ratio = 2.01; 95% CI 1.12-3.59; p = 0.019), and disseminated intravascular coagulation (adjusted odds ratio = 3.61; 95% CI, 1.51-8.66; p = 0.004) were independently associated with ischemic stroke. Pre-extracorporeal membrane oxygenation pH (adjusted odds ratio = 0.28; 95% CI, 0.12-0.65; p = 0.003), preextracorporeal membrane oxygenation Po2 (adjusted odds ratio = 0.96; 95% CI, 0.93-0.99; p = 0.021), gastrointestinal hemorrhage (adjusted odds ratio = 1.70; 95% CI, 1.15-2.51; p = 0.008), and renal replacement therapy (adjusted odds ratio=1.57; 95% CI, 1.22-2.02; p < 0.001) were independently associated with hemorrhagic stroke.
Among venovenous extracorporeal membrane oxygenation patients in the Extracorporeal Life Support Organization registry, approximately 5% had acute brain injury. Mortality rates increased two-fold when ischemic or hemorrhagic strokes occurred. Risk factors such as lower pH and hypoxemia during the pericannulation period and markers of coagulation disturbances were associated with acute brain injury. Further research on understanding preextracorporeal membrane oxygenation and on-extracorporeal membrane oxygenation risk factors and the timing of acute brain injury is necessary to develop appropriate prevention and management strategies.
Pediatric stroke is an event caused by disturbance of cerebral circulation that occurs in individuals between 28 days and 18 years of age. Although an uncommon event, pediatric stroke still carries ...significant morbidity and mortality. Unlike adults, causes of pediatric stroke are various and include vascular, infectious, hematologic, neoplastic, and toxic etiologies. Clinical presentation of nontraumatic intracerebral hemorrhages in older children is similar to adults, however in neonates and infants signs and symptoms can be more subtle, especially with smaller hemorrhages. Management of nontraumatic intracerebral hemorrhage consists of stabilizing the patient, management of the hemorrhage itself, and reduction of the rebleeding risk. Even so, when child reaches a medical care, morbidity and mortality rates are still high. We described a case series of pediatric patients with intracerebral nontraumatic hemorrhagic stroke from different etiologies. Although increasingly recognized, such situations are still poorly described in children and our report offers a good overview on this topic.
Perinatal hemorrhagic stroke in late preterm and term neonates is understudied. We describe two-month and two-year neurological outcomes in a prospective cohort.
Neonates ≥36 weeks’ gestation with ...spontaneous hemorrhagic stroke (parenchymal and intraventricular) presenting at age ≤28 days were enrolled between March 2007 and May 2015 at three tertiary pediatric centers. Hemorrhagic transformation of arterial ischemic stroke or cerebral sinovenous thrombosis was excluded. The Pediatric Stroke Outcome Measure (PSOM) assessed outcomes. Wilcoxon signed-rank tests evaluated change over time.
Twenty-six neonates were included (median age: 1 day, interquartile range IQR 0 to 16; median gestational age: 38.3 weeks, IQR 37.0 to 39.0). Hemorrhage was isolated intraventricular in seven (27%), isolated intraparenchymal in six (23%), and a combination in 10 (39%). Three neonates (12%) died during hospitalization; one died later due to cardiac disease. Among 22 survivors, outcomes were assessed at a median of 2.1 months (IQR 1.7 to 3.3) in 96% and 1.9 years (IQR 1.3 to 2.0) in 73%. Median PSOM scores were 0.0 (IQR 0.0 to 1.0) and 0.25 (IQR 0.0 to 1.3), respectively. At two years, 45% of patients had no or nonimpairing deficits (PSOM <1.0), 30% had mild deficits (PSOM 1.0 to 2.0), and 5% had moderate deficits (PSOM 2.5 to 4.5). Over time, 31% worsened and 6% improved. Although total PSOM scores did not change significantly (P = 0.08), language subscores worsened (P = 0.009). No child developed epilepsy.
Perinatal hemorrhagic stroke survivors had favorable outcomes in early childhood; at two years moderate to severe deficits occurred in 5%. Language deficits may emerge over time, warranting close follow-up.
Spontaneous intracerebral hemorrhage (ICH) accounts for 10–30% of all strokes and affects more than one million people every year worldwide, and it is the stroke subtype associated with the highest ...rates of mortality and residual disability. So far, clinical trials have mainly targeted primary cerebral injury and have substantially failed to improve clinical outcomes. The understanding of the pathophysiology of early and delayed injury after ICH is, hence, of paramount importance to identify potential targets of intervention and develop effective therapeutic strategies. Matrix metalloproteinases (MMPs) represent a ubiquitous superfamily of structurally related zinc-dependent endopeptidases able to degrade any component of the extracellular matrix. They are upregulated after ICH, in which different cell types, including leukocytes, activated microglia, neurons, and endothelial cells, are involved in their synthesis and secretion. The aim of this review is to summarize the available experimental and clinical evidence about the role of MMPs in brain injury following spontaneous ICH and provide critical insights into the underlying mechanisms.
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