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Early platelet transfusion improves platelet activity and may improve outcomes after intracerebral hemorrhage.

ABSTRACT: BACKGROUND:In patients with acute intracerebral hemorrhage (ICH), reduced platelet activity on admission predicts hemorrhage growth and poor outcomes. We tested the hypotheses that platelet transfusion improves measured platelet activity. Further, we hypothesized that earlier treatment in patients at high risk for hemorrhage growth and poor outcome would reduce follow-up hemorrhage size and poor clinical outcomes. METHODS:We prospectively identified consecutive patients with ICH who had reduced platelet activity on admission and received a platelet transfusion. We defined high-risk patients as per a previous publication, reduced platelet activity, or known anti-platelet therapy (APT) and the diagnostic CT within 12 h of symptom onset. Platelet activity was measured with the VerifyNow-ASA (Accumetrics, CA), ICH volumes on CT with computerized quantitative techniques, and functional outcomes with the modified Rankin Scale (mRS) at 3 months. RESULTS:Forty-five patients received a platelet transfusion with an increase in platelet activity from 472 ± 50 (consistent with an aspirin effect) to 561 ± 92 aspirin reaction units (consistent with no aspirin effect, P < 0.001). For high-risk patients, platelet transfusion within 12 h of symptom onset, as opposed to >12 h, was associated with smaller follow-up hemorrhage size (8.4 [3-17.4] vs. 13.8 [12.3-62.5] ml, P = 0.04) and increased odds of independence (mRS < 4) at 3 months (11 of 20 vs. 0 of 7, P = 0.01). There were similar results for patients with known APT. CONCLUSIONS:In patients at high risk for hemorrhage growth and poor outcome, early platelet transfusion improved platelet activity assay results and was associated with smaller final hemorrhage size and more independence at 3 months.

SUBMITTER: Naidech AM

PROVIDER: S-EPMC6211165 | biostudies-other | 2012 Feb

REPOSITORIES: biostudies-other

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Early platelet transfusion improves platelet activity and may improve outcomes after intracerebral hemorrhage.

Naidech Andrew M AM Liebling Storm M SM Rosenberg Neil F NF Lindholm Paul F PF Bernstein Richard A RA Batjer H Hunt HH Alberts Mark J MJ Kwaan Hau C HC

Neurocritical care 20120201 1

<h4>Background</h4>In patients with acute intracerebral hemorrhage (ICH), reduced platelet activity on admission predicts hemorrhage growth and poor outcomes. We tested the hypotheses that platelet transfusion improves measured platelet activity. Further, we hypothesized that earlier treatment in patients at high risk for hemorrhage growth and poor outcome would reduce follow-up hemorrhage size and poor clinical outcomes.<h4>Methods</h4>We prospectively identified consecutive patients with ICH w ...[more]

PMID: 21837536

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Project description:BackgroundExacerbated blood-brain barrier (BBB) damage is related with tissue plasminogen activator (tPA)-induced brain hemorrhage after stroke. Platelets have long been recognized as the cellular orchestrators of primary haemostasis. Recent studies have demonstrated further that platelets are required for supporting intact mature blood vessels and play a crucial role in maintaining vascular integrity during inflammation. Therefore, we sought to investigate whether platelets could reduce tPA-induced deterioration of cerebrovascular integrity and lead to less hemorrhagic transformation.MethodsMice were subjected to models of collagenase-induced intracerebral hemorrhage (ICH) and transient middle cerebral artery (MCA) occlusion. After 2 h of MCA occlusion, tPA (10 mg/kg) was administered as an intravenous bolus injection of 1 mg/kg followed by a 9 mg/kg infusion for 30 min. Immediately after tPA treatment, mice were transfused with platelets. Hemorrhagic volume, infarct size, neurological deficit, tight junction and basal membrane damages, endothelial cell apoptosis, and extravascular accumulation of circulating dextran and IgG, and Evans blue were quantified at 24 h.ResultsPlatelet transfusion resulted in a significant decrease in hematoma volume after ICH. In mice after ischemia, tPA administration increased brain hemorrhage transformation and this was reversed by resting but not activated platelets. Consistent with this, we observed that tPA-induced brain hemorrhage was dramatically exacerbated in thrombocytopenic mice. Transfusion of resting platelets ameliorated tPA-induced loss of cerebrovascular integrity and reduced extravascular accumulation of circulating serum proteins and Evans blue, associated with improved neurological functions after ischemia. No changes were found for infarct volume. Inhibition of platelet receptor glycoprotein VI (GPVI) blunted the ability of platelets to attenuate tPA-induced BBB disruption and hemorrhage after ischemia.ConclusionOur findings demonstrate the importance of platelets in safeguarding BBB integrity and suggest that transfusion of resting platelets may be useful to improve the safety of tPA thrombolysis in ischemic stroke.

Project description:OBJECTIVES:Impaired oxygen delivery due to reduced cerebral blood flow is the hallmark of delayed cerebral ischemia following subarachnoid hemorrhage. Since anemia reduces arterial oxygen content, it further threatens oxygen delivery increasing the risk of cerebral infarction. Thus, subarachnoid hemorrhage may constitute an important exception to current restrictive transfusion practices, wherein raising hemoglobin could reduce the risk of ischemia in a critically hypoperfused organ. In this physiologic proof-of-principle study, we determined whether transfusion could augment cerebral oxygen delivery, particularly in vulnerable brain regions, across a broad range of hemoglobin values. DESIGN:Prospective study measuring cerebral blood flow and oxygen extraction fraction using O-PET. Vulnerable brain regions were defined as those with baseline oxygen delivery less than 4.5?mL/100?g/min. SETTING:PET facility located within the Neurology/Neurosurgery ICU. PATIENTS:Fifty-two patients at risk for delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage with hemoglobin 7-13?g/dL. INTERVENTIONS:Transfusion of one unit of RBCs over 1 hour. MEASUREMENTS AND MAIN RESULTS:Baseline hemoglobin was 9.7?g/dL (range, 6.9-12.9), and cerebral blood flow was 43?±?11?mL/100?g/min. After transfusion, hemoglobin rose from 9.6?±?1.4 to 10.8?±?1.4?g/dL (12%; p < 0.001) and oxygen delivery from 5.0 (interquartile range, 4.4-6.6) to 5.5?mL/100?g/min (interquartile range, 4.8-7.0) (10%; p = 0.001); the response was comparable across the range of hemoglobin values. In vulnerable brain regions, transfusion resulted in a greater (16%) rise in oxygen delivery associated with reduction in oxygen extraction fraction, independent of Hgb level (p = 0.002 vs normal regions). CONCLUSIONS:This study demonstrates that RBC transfusion improves cerebral oxygen delivery globally and particularly to vulnerable regions in subarachnoid hemorrhage patients at risk for delayed cerebral ischemia across a wide range of hemoglobin values and suggests that restrictive transfusion practices may not be appropriate in this population. Large prospective trials are necessary to determine if these physiologic benefits translate into clinical improvement and outweigh the risk of transfusion.

Project description:Modulators of the sphingosine-1-phosphate receptor (S1PR) have been proposed as a promising strategy for treating stroke. However, the detailed mechanisms and the potential translational value of S1PR modulators for intracerebral hemorrhage (ICH) therapy warrant exploration. Using collagenase VII-S-induced ICH in the left striatum of mice, we investigated the effects of siponimod on cellular and molecular immunoinflammatory responses in the hemorrhagic brain in the presence or absence of anti-CD3 monoclonal antibodies (Abs). We also assessed the severity of short- and long-term brain injury and evaluated the efficacy of siponimod in long-term neurologic function. Siponimod treatment significantly decreased brain lesion volume and brain water content on day 3 and the volume of the residual lesion and brain atrophy on day 28. It also inhibited neuronal degeneration on day 3 and improved long-term neurologic function. These protective effects may be associated with a reduction in the expression of lymphotactin (XCL1) and T-helper 1 (Th1)-type cytokines (interleukin 1β and interferon-γ). It may also be associated with inhibition of neutrophil and lymphocyte infiltration and alleviation of T lymphocyte activation in perihematomal tissues on day 3. However, siponimod did not affect the infiltration of natural killer cells (NK) or the activation of CD3-negative immunocytes in perihematomal tissues. Furthermore, it did not influence the activation or proliferation of microglia or astrocytes around the hematoma on day 3. Siponimod appears to have a profound impact on infiltration and activation of T lymphocytes after ICH. The effects of neutralized anti-CD3 Abs-induced T-lymphocyte tolerance on siponimod immunomodulation further confirmed that siponimod alleviated the cellular and molecular Th1 response in the hemorrhagic brain. This study provides preclinical evidence that encourages future investigation of immunomodulators, including siponimod, which target the lymphocyte-related immunoinflammatory reaction in ICH therapy.

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Early platelet transfusion improves platelet activity and may improve outcomes after intracerebral hemorrhage.

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Early platelet transfusion improves platelet activity and may improve outcomes after intracerebral hemorrhage.

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