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Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Atherosclerotic cardiovascular disease (CVD), which includes coronary heart disease (CHD) and stroke, is now the most common cause of death in the middle aged and elderly in all parts of the world except subSaharan Africa. The direct cause of death is frequently an acute thrombotic arterial occlusion. Because atherosclerosis is a diffuse disease, patients with CHD also have a high risk of ischemic stroke. The hemostatic process is a needed defense mechanism to control hemorrhage after injury but at same time, if overactive, may have the potential to precipitate diseases such as myocardial infarction or stroke in the setting of atherosclerosis. In approximately 1% of all patients with ischemic stroke, and in up to 4% of young adults with stroke, the major precipitant of brain ischemia is a hematologic disorder or coagulopathy that predisposes to thrombosis. von Willebrand factor (vWF) plays an important role in platelet adhesion to subendothelial structures and in the intrinsic pathway of coagulation. It is regarded as an indirect measure of endothelial dysfunction. Deficiency of vWF in von Willebrand's disease is well established. However, much less is known regarding the pathophysiologic implications of an elevated level of vWF, particularly in relation to CVD and cerebrovascular disease. The importance of vWF in the pathogenesis of this disease is poorly defined and information is limited and inconsistent. Elevated levels of vWF have been variably linked with risk of CHD; causal criteria are not fully met. Relationships with stroke risk are even less well established. Measurement of vWF adds little to risk prediction after considering the major risk factors--age, sex, smoking, raised blood cholesterol, and hypertension. vWF may have a greater role in predicting outcome in subjects with acute coronary syndromes (ACS), stroke, and perhaps atrial fibrillation. Investigation of the use of vWF level to guide treatment of ACS or stroke is ongoing; however, there is no compelling evidence to date.
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PMID:von Willebrand Factor in CHD and stroke: relationships and therapeutic implications. 1760 81

Fabry disease is an inborn error of glycosphingolipid catabolism resulting from a deficiency of lysosomal enzyme alpha-galactosidase A. The major clinical manifestations of the disease, such as stroke, cardiac dysfunction, and renal impairment, are thought to be caused by vasculopathy due to progressive accumulation of globotriaosylceramide in vascular endothelial cells. The pathogenesis of the vasculopathy has not been elucidated. Since in vitro studies using primary endothelial cells are hampered by the limited lifespan of these cells, the availability of cultured endothelial cells with an extended lifespan is critical for the study of the vasculopathy of Fabry disease. We therefore generated an endothelial cell line from a Fabry hemizygote by introduction of human telomerase reverse transcriptase gene. The cell line has markedly extended lifespan compared to parental primary cells. The cells stably express many key markers of endothelial cells such as von Willebrand factor, CD31, CD34, and endothelial nitric oxide synthase (eNOS) and retain functional characteristics such as uptake of acetylated low-density lipoprotein, responsiveness to angiogenic growth factors, up-regulation of eNOS production upon extracellular stimuli, and formation of tube-like structures on Matrigel basement membrane matrix. The cells show significantly reduced activity of alpha-galactosidase A compared with primary endothelial cells from normal individuals and accumulate globotriaosylceramide in lysosomes. This cell line will provide a useful in vitro model of Fabry disease and will facilitate systematic studies to investigate pathogenic mechanisms and explore new therapeutic approaches for Fabry disease.
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PMID:Establishment and characterization of Fabry disease endothelial cells with an extended lifespan. 1764 84

The administration of an adenosine diphosphate (ADP) receptor antagonist, such as clopidogrel, is recommended for recurrent stroke patients under aspirin treatment. However, up to 25% of vascular patients have an inadequate response to clopidogrel treatment, which could be associated with increased reinfarction rates. This study investigated whether the platelet function analyzer (PFA-100) system represents an appropriate tool for monitoring clopidogrel's antiplatelet effects in stroke patients. Sixteen stroke patients on clopidogrel therapy (75 mg/day) were included in a prospective analyst-blinded, cross-sectional study. Platelet function was assayed by collagen/epinephrine (CEPI)- and collagen/ADP (CADP)-induced closure times (CTs) using the PFA-100 system. von Willebrand factor antigen (vWF-Ag) levels were measured by enzyme immunoassay. CEPI-CT and CADP-CT values averaged 160 +/- 15 seconds and 102 +/- 10 seconds, respectively, and were in the normal range. vWF-Ag concentrations averaged 153 +/- 17% and correlated inversely with CTs (r = .71; P < .002 for CEPI-CT, r = .54; P < .04 for CADP-CT). Our data indicate that the current PFA-100 cartridges are not sufficiently sensitive to detect clopidogrel-induced platelet inhibition in stroke patients.
J Stroke Cerebrovasc Dis
PMID:Clopidogrel-induced platelet inhibition cannot be detected by the platelet function analyzer-100 system in stroke patients. 1784 16

We measured the level of plasma von Willebrand factor (vWF), a marker of vascular endothelial damage, in patients with vascular parkinsonism (VP) to clarify whether the level of plasma vWF is useful in the diagnosis of VP. We examined 26 patients with VP, 26 with Parkinson's disease (PD), 26 with cerebral infarct (CI), and 26 age-matched normal controls (NC). The vWF was measured by the ristocetin cofactor assay. The level of plasma vWF in the VP group was significantly higher than that in the PD or in the NC groups (P < .01). However, there was no difference between the VP group and the CI group. These findings suggest marked endothelial cell damage in patients suffering from VP and CI. Thus, the level of plasma vWF may be useful in diagnosing VP.
J Stroke Cerebrovasc Dis
PMID:Plasma von Willebrand factor activities in vascular Parkinsonism: comparison with Parkinson's disease. 1790 29

The purposes of the present study were to investigate sequential changes in plasma von Willebrand factor (vWf) activities and serum soluble thrombomodulin (sTM) concentrations, compared with white blood cell (WBC) counts, and to disclose the different roles of vWf and sTM in acute ischemic stroke. Forty-three acute ischemic stroke patients admitted to our hospital within 48 hours from onset were enrolled. Plasma vWf activities, serum sTM concentrations, and WBC counts were measured at the acute stage and 1 and 6 months after admission. The time course study revealed that vWf activities increased more markedly 1 month after admission than at the acute stage. However, sTM concentrations were low at the acute stage and increased sequentially at 1 month (not significantly) and 6 months (significantly) after admission. In contrast, elevated WBC counts at the acute stage decreased significantly at 1 and 6 months after admission. Raised vWf activities 1 month after admission were suggested to occur through continuous endothelial dysfunction or repair and platelet activation, compared with the acute stage, and decreased sTM at the acute stage through down-regulation of sTM synthesis by acute inflammatory response after acute ischemic stroke, compared with the chronic stage.
J Stroke Cerebrovasc Dis
PMID:Sequential changes in von Willebrand factor and soluble thrombomodulin in acute ischemic stroke. 1790 36

Plasma level of von Willebrand factor (vWF) is a useful marker not only for endothelial dysfunction, but also for left atrial thrombogenesis. We measured plasma levels of vWF antigen and other coagulation and fibrinolysis markers in 183 consecutive patients with acute ischemic stroke and compared these data between patients with and without atrial fibrillation (AF). vWF correlated with severity, outcome, and infarct size and were significantly higher in the AF group than in the non-AF group. The positive correlations of vWF with plasmin-alpha2 plasmin inhibitor complex and soluble fibrin monomer complex, and higher levels of vWF in patients with than without spontaneous echo contrast, indicate thrombogenesis in the left atrium. Plasma levels of vWF may reflect thrombogenesis in patients with AF.
J Stroke Cerebrovasc Dis
PMID:Increased von Willebrand factor in acute stroke patients with atrial fibrillation. 1790 39

Photochemically induced cerebral infarction has been considered a clinically relevant model for ischemic stroke. We evaluated various transgenic mice to study the role of platelet adhesion molecules in this model. Infarction to the sensorimotoric cortex was induced by erythrosin B and laser light. Infarct volumes were calculated from triphenyltetrazolium chloride stained brain slices. Thrombus formation and vessel leakage were observed in vivo by multiphoton microscopy. Mice mutant in VWF, GPIbalpha, beta3 integrin, and P-selectin did not show any significant differences in infarct volume compared to wild type (WT). This is in contrast to the intraluminal middle cerebral artery occlusion model in which alphaIIbbeta3 integrin, GPIbalpha, and P-selectin are known to modulate infarct size. Multiphoton microscopy showed that small, non-occlusive embolizing platelet thrombi formed in the photochemically injured brains. Massive vessel leakage was observed within 25 min of laser injury. Interestingly, we observed a significant increase in infarct size with aging, accordant with heightened fragility of the blood brain barrier (BBB) in older mice. This model of photochemically induced stroke is closer to a BBB injury model than a thrombotic stroke model in which platelets and their adhesion molecules are crucial. This model will be useful to study mechanisms regulating BBB permeability.
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PMID:Platelet adhesion receptors do not modulate infarct volume after a photochemically induced stroke in mice. 1799 53

At sites of vascular injury, platelets come into contact with the subendothelial extracellular matrix which triggers their activation and the formation of a hemostatic plug. This process is crucial for normal hemostasis, but may also lead to pathological thrombus formation causing diseases such as myocardial infarction or stroke. The initial capture of flowing platelets is mediated by the interaction of the glycoprotein (GP) Ib-V-IX complex with von Willebrand factor (vWF) immobilized on exposed collagens. This interaction allows the binding of the collagen receptor GPVI to its ligand and to initiate cellular activation, a process that is reinforced by locally produced thrombin and soluble mediators released from platelets. These events lead to the shift of beta1 and beta3 integrins on the platelet surface from a low to a high affinity state, thereby enabling them to bind their ligands and to mediate firm adhesion, spreading, coagulant activity, and aggregation. This review summarizes the most important structural and functional properties of these adhesion receptors and briefly discusses their potential as targets for antithrombotic therapy.
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PMID:Cell adhesion mechanisms in platelets. 1817 60

Engagement of the adhesion receptor glycoprotein (GP) Ib-IX-V by von Willebrand factor (VWF) mediates platelet adhesion to damaged vessels and triggers platelet activation and thrombus formation in heart attack and stroke. GPIb-IX-V contains distinct 14-3-3zeta-binding sites at the GPIb alpha C-terminus involving phosphorylation of Ser609, an upstream site involving phosphorylated Ser587/Ser590, and a protein kinase A (PKA)-dependent site on GPIb beta involving Ser166. 14-3-3zeta regulates the VWF-binding affinity of GPIb-IX-V and inhibiting 14-3-3zeta association blocks receptor signaling, suggesting a key functional role for 14-3-3zeta. We used deletion mutants of GPIb alpha expressed in Chinese hamster ovary (CHO) cells to define the relationship of 14-3-3zeta binding to another GPIb-IX-V-associated signaling protein, phosphoinositide 3-kinase (PI3-kinase). Pull-down experiments involving glutathione S-transferase (GST)-PI3-kinase/p85-subunit and GST-14-3-3zeta indicated that both proteins interacted with contiguous GPIb alpha sequences 580 to 590/591 to 610. Deleting these, but not upstream sequences of GPIb alpha expressed in CHO cells, inhibited VWF/ristocetin-dependent Akt phosphorylation, relative to wild-type receptor, confirming this region encompassed a functional PI3-kinase-binding site. Pull-down experiments with GST-p85 truncates indicated the GPIb alpha-binding region involved the p85 breakpoint cluster region (BCR) domain, containing RSXSXP. However, pull-down of GPIb-IX was unaltered by mutation/deletion/phosphorylation of this potential 14-3-3zeta-binding sequence in mutant constructs of GST-p85, suggesting PI3-kinase bound GPIb alpha independently of 14-3-3zeta; 14-3-3zeta inhibitor peptide R18 also blocked pull-down of receptor by GST-14-3-3zeta but not GST-p85, and GST-p85 pull-downs were unaffected by excess 14-3-3zeta. Together, these data suggest the GPIb alpha C-terminus regulates signaling through independent association of 14-3-3zeta and PI3-kinase.
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PMID:A functional 14-3-3zeta-independent association of PI3-kinase with glycoprotein Ib alpha, the major ligand-binding subunit of the platelet glycoprotein Ib-IX-V complex. 1829 48

Thrombotic microangiopathy (TMA) is a rare disorder characterized by microvascular thrombosis. TMA has been reported in patients with antiphospholipid antibodies and/or antiphospholipid syndrome but its pathogenesis is not clarified. We present two patients with TMA associated with IgG phosphatidylserine dependent antiprothrombin antibodies (aPS/PT). CASE 1: A 44-year-old Japanese female with systemic lupus erythematosus (SLE) and positive lupus anticoagulant (LA) was started on ticlopidine after having stroke. Four weeks later she developed TMA. IgG/M/A anticardiolipin antibodies (aCL) were negative, but strong positive IgG aPS/PT were detected. CASE 2: A 32-year-old Russian female with SLE was admitted because of hypertension, renal insufficiency and proteinuria at 14 weeks of pregnancy. She developed TMA after surgical abortion. IgG aPS/PT and LA were strongly positive but IgG/M/A aCL were negative. Neither case had von Willebrand factor cleaving protease (ADAMTS-13), suggesting that TMA in those patients was associated with thrombophilia rather than insufficient ADAMTS-13. Both patients were successfully treated with a series of plasma exchange.
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PMID:Thrombotic microangiopathy in patients with phosphatidylserine dependent antiprothrombin antibodies and antiphospholipid syndrome. 1832 60


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