Secondary Hematoma Expansion and Perihemorrhagic Edema after Intracerebral Hemorrhage: From Bench Work to Practical Aspects.

Intracerebral hemorrhages (ICH) represent about 10-15% of all strokes per year in the United States alone. Key variables influencing the long-term outcome after ICH are hematoma size and growth. Although death may occur at the time of the hemorrhage, delayed neurologic deterioration frequently occurs with hematoma growth and neuronal injury of the surrounding tissue. Perihematoma edema has also been implicated as a contributing factor for delayed neurologic deterioration after ICH. Cerebral edema results from both blood-brain barrier disruption and local generation of osmotically active substances. Inflammatory cellular mediators, activation of the complement, by-products of coagulation and hemolysis such as thrombin and fibrin, and hemoglobin enter the brain and induce a local and systemic inflammatory reaction. These complex cascades lead to apoptosis or neuronal injury. By identifying the major modulators of cerebral edema after ICH, a therapeutic target to counter degenerative events may be forthcoming

Intravenous tPA therapy does not worsen acute intracerebral hemorrhage in mice

Tissue plasminogen activator (tPA) is the only FDA-approved treatment for reperfusing ischemic strokes. But widespread use of tPA is still limited by fears of inadvertently administering tPA in patients with intracerebral hemorrhage (ICH). Surprisingly, however, the assumption that tPA will worsen ICH has never been biologically tested. Here, we assessed the effects of tPA in two models of ICH. In a mouse model of collagenase-induced ICH, hemorrhage volumes and neurological deficits after 24 hrs were similar in saline controls and tPA-treated mice, whereas heparin-treated mice had 3-fold larger hematomas. In a model of laser-induced vessel rupture, tPA also did not worsen hemorrhage volumes, while heparin did. tPA is known to worsen neurovascular injury by amplifying matrix metalloproteinases during cerebral ischemia. In contrast, tPA did not upregulate matrix metalloproteinases in our mouse ICH models. In summary, our experimental data do not support the assumption that intravenous tPA has a deleterious effect in acute ICH. However, due to potential species differences and the inability of models to fully capture the dynamics of human ICH, caution is warranted when considering the implications of these findings for human therapy

Targeting the Nrf2-Heme Oxygenase-1 Axis after Intracerebral Hemorrhage.

BACKGROUND: Injury to cells adjacent to an intracerebral hemorrhage (ICH) is likely mediated at least in part by toxins released from the hematoma that initiate complex and interacting injury cascades. Pharmacotherapies targeting a single toxin or pathway, even if consistently effective in controlled experimental models, have a high likelihood of failure in a variable clinical setting. Nuclear factor erythroid-2 related factor 2 (Nrf2) regulates the expression of heme oxygenase-1 (HO-1) and multiple other proteins with antioxidant and antiinflammatory effects, and may be a target of interest after ICH. METHODS: Studies that tested the effect of HO and Nrf2 in models relevant to ICH are summarized, with an effort to reconcile conflicting data by consideration of methodological limitations. RESULTS: In vitro studies demonstrated that Nrf2 activators rapidly increased HO-1 expression in astrocytes, and reduced their vulnerability to hemoglobin or hemin. Modulating HO-1 expression via genetic approaches yielded similar results. Systemic treatment with small molecule Nrf2 activators increased HO-1 expression in perivascular cells, particularly astrocytes. When tested in mouse or rat ICH models, Nrf2 activators were consistently protective, improving barrier function and attenuating edema, inflammation, neuronal loss and neurological deficits. These effects were mimicked by selective astrocyte HO-1 overexpression in transgenic mice. CONCLUSION: Systemic treatment with Nrf2 activators after ICH is protective in rodents. Two compounds, dimethyl fumarate and hemin, are currently approved for treatment of multiple sclerosis and acute porphyria, respectively, and have acceptable safety profiles over years of clinical use. Further development of these drugs as ICH therapeutics seems warranted

Bolus administration of tranexamic acid with a maintenance dose via infusion and strict blood pressure control for non-traumatic intracerebral hemorrhages

Introduction Spontaneous intracerebral hemorrhages (ICH) account for 10–15% of all strokes with an incidence of 10–30 cases per 100,000 people/year, and their incidences are expected to double in the next 30 years. Mortality and morbidity associated with ICHs is still high. Until recently, there were no effective evidence-based treatments for acute ICH. ICH growth remains an important predictor of patient outcomes. Tranexamic acid (TXA), an anti-fibrinolytic drug, is known to reduce hemorrhaging in other conditions. The purpose of this study was to assess the effect of TXA compared to a placebo on the growth of hematomas in patients with spontaneous ICH. Methodology A single-blinded randomized placebo-controlled trial was conducted using TXA (intravenous 1 g bolus followed by an infusion of TXA at 1g/h for 8 h) in acute (<8 h) cases of primary ICH. Strict blood pressure control (target systolic blood pressure [SBP], 140–160 mmHg) was achieved using labetalol infusion. A repeat brain computed tomography (CT) was performed in the next 24 h to reassess the hematoma growth. The primary objective was to test the effect of TXA on hematoma growth. The secondary objective was to test the feasibility, tolerability, and adverse events of TXA in cases of primary ICH. Results Thirty patients were recruited between September 2012 and October 2013. The patients’ mean age was 49 with male predominance (70%). The baseline SBP was 150 mmHg), mean Glasgow Coma Scale score was 13–15/15), and median time from stroke to the 1st CT scan was 5.5 h. The hematoma locations were as follows: internal capsule, 80%; thalamus, 13.3%; and head of caudate, 6.66%. The mean total hemorrhage growth was 0.16 mL and 3.07 mL in the treatment and placebo groups, respectively. Statistical analysis showed a reduction in the total hemorrhage growth in the TXA group in comparison to the control (p < 0.05). Conclusions Patients who present with spontaneous ICH secondary to uncontrolled hypertension should be treated with a combination of a bolus administration of TXA (1 g) and a maintenance dose via infusion (1 g/8 h) with strict blood pressure control, rather than blood pressure control alone. However, a double-blinded randomized study with multicenter involvement is needed for further evaluation of the significance of this finding

Management of anticoagulant-related intracranial hemorrhage: An evidence-based review

The increased use of anticoagulants for the prevention and treatment of thromboembolic diseases has led to a rising incidence of anticoagulant-related intracranial hemorrhage (AICH) in the aging western population. High mortality accompanies this form of hemorrhagic stroke, and significant and debilitating long-term consequences plague survivors. Although management guidelines for such hemorrhages are available for the older generation anticoagulants, they are still lacking for newer agents, which are becoming popular among physicians. Supportive care, including blood pressure control, and reversal of anticoagulation remain the cornerstone of acute management of AICH. Prothrombin complex concentrates are gaining popularity over fresh frozen plasma, and reversal agents for newer anticoagulation agents are being developed. Surgical interventions are options fraught with complications, and are decided on a case-by-case basis. Our current state of understanding of this condition and its management is insufficient. This deficit calls for more population-based studies and therapeutic trials to better evaluate risk factors for, and to prevent and treat AICH

Matrix metalloproteinases in human spontaneous intracerebral hemorrhage: an update

Background: In default of a plausible and satisfactory causal treatment for hemorrhagic stroke, a role of matrix metalloproteinases (MMPs) in the pathogenesis of cerebrovascular diseases has recently been widely discussed. The well-known impact of MMPs on extracellular matrix destruction triggered by inflammation as a foundation for several diseases, including stroke, is very much in evidence. Newly, some additional aspects of MMP function considering their intracellular activity crucial for neuronal death following ischemic brain damage have emerged. The effect of blood-brain barrier disruption caused by MMPs on the prognosis in patients suffering from spontaneous intracerebral hemorrhage (ICH) has been of interest since it throws a new light upon the pathogenesis, course and possible therapeutic approaches for this least treatable and at the same time most life-threatening form of stroke. Hence, we primarily aimed to review the current clinical knowledge on the significance of metalloproteinase activation in the course of spontaneous intracranial hemorrhage in humans. We also provide a brief characterization of the MMP enzyme family and report on the latest findings on issues arising from experimental studies. Methods: A Medline search using the following key words was performed: matrix metalloproteinases + spontaneous intracerebral hemorrhage/intracranial hemorrhage/bleeding/hemorrhagic stroke. We accepted studies reporting on MMP expression in adult patients with spontaneous ICH, as well as its relation to radiological and clinical features and patients’ outcome. For the final review, 18 clinical studies were considered. MMP inhibition was reviewed on the basis of 11 relevant experimental studies. Also, some relevant reports on the biology of MMPs and their pathophysiology in ICH were reviewed. Results and Conclusions: Many studies provide convincing evidence of a detrimental role of MMPs in ICH, stressing their association with neuroinflammation. The role of MMPs in hemorrhagic stroke appears critical for hematoma and brain edema growth as well as for neuronal death, which are understood as secondary brain injury and may have a considerable clinical impact. Although data on human spontaneous ICH are scarce and mostly based on small populations, they reveal the apparent correlation between MMPs and clinical and radiological ICH features as well as the functional outcome, which might rationalize future therapeutic strategies. However, attempts at MMP inhibition in spontaneous ICH have solely been made under experimental conditions and were associated with a wide range of possible side effects. Therefore, further comprehensive, elucidating investigations in this field are vital before any conclusions could be translated to humans. Copyright (C) 2012 S. Karger AG, Base

Vascular disruption and blood–brain barrier dysfunction in intracerebral hemorrhage

Abstract This article reviews current knowledge of the mechanisms underlying the initial hemorrhage and secondary blood–brain barrier (BBB) dysfunction in primary spontaneous intracerebral hemorrhage (ICH) in adults. Multiple etiologies are associated with ICH, for example, hypertension, Alzheimer’s disease, vascular malformations and coagulopathies (genetic or drug-induced). After the initial bleed, there can be continued bleeding over the first 24 hours, so-called hematoma expansion, which is associated with adverse outcomes. A number of clinical trials are focused on trying to limit such expansion. Significant progress has been made on the causes of BBB dysfunction after ICH at the molecular and cell signaling level. Blood components (e.g. thrombin, hemoglobin, iron) and the inflammatory response to those components play a large role in ICH-induced BBB dysfunction. There are current clinical trials of minimally invasive hematoma removal and iron chelation which may limit such dysfunction. Understanding the mechanisms underlying the initial hemorrhage and secondary BBB dysfunction in ICH is vital for developing methods to prevent and treat this devastating form of stroke.http://deepblue.lib.umich.edu/bitstream/2027.42/134526/1/12987_2014_Article_103.pd

Hemorrhagic transformation of ischemic stroke

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