Prospective Study of Markers of Hemostatic Function With Risk of Ischemic Stroke

Folsom, Aaron R.; Rosamond, Wayne D.; Shahar, Eyal; Cooper, Lawton S.; Aleksic, Nena; Nieto, F. Javier; Rasmussen, Mandy L.; Wu, Kenneth K.

doi:10.1161/01.cir.100.7.736

Cited by 377 publications

(300 citation statements)

References 37 publications

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“…23,34,35 In humans, the antithrombotic factor protein C is protective in ischemic stroke. 36 The present study confirms that a deficiency of tPA favors fibrin deposition in brains challenged by a thrombotic ischemic insult, which in turn enhances ischemic brain injury. These findings provide direct evidence for a causal relationship between reduced fibrinolytic activity and ischemic neuronal damage, suggesting that endogenous tPA promotes desirable thrombolytic and protective effects in cerebral ischemia, and that factors other than tPA must be responsible for ischemic neuronal damage.…”

Section: Discussionsupporting

confidence: 83%

Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model

Tabrizi

Wang

Seeds

et al. 1999

ATVB

118

105

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Abstract-Although the serine protease, tissue plasminogen activator (tPA), is approved by the US Food and Drug Administration for therapy to combat focal cerebral infarction, the basic concept of thrombolytic tPA therapy for stroke was challenged by recent studies that used genetically manipulated tPA-deficient (tPAϪ/Ϫ) mice, which suggested that tPA mediates ischemic neuronal damage. However, those studies were potentially flawed because the genotypes of tPAϪ/Ϫ and wild-type control mice were not entirely clear, and ischemic neuronal injury was evaluated in isolation of tPA effects on brain thrombosis. Using mice with appropriate genetic backgrounds and a middle cerebral artery occlusion stroke model with nonsiliconized thread, which does lead to microvascular thrombus formation, in the present study we determined the risk for cerebrovascular thrombosis and neuronal injury in tPAϪ/Ϫ and genetically matched tPAϩ/ϩ mice subjected to transient focal ischemia. Cerebrovascular fibrin deposition and the infarction volume were increased by 8.2-and 6.7-fold in tPAϪ/Ϫ versus tPAϩ/ϩ mice, respectively, and these variables were correlated with reduced cerebral blood flow up to 58% (PϽ0.05) and impaired motor neurological score by 70% (PϽ0.05). Our findings indicate that tPA deficiency exacerbates ischemia-induced cerebrovascular thrombosis and that endogenous tPA protects the brain from an ischemic insult, presumably through its thrombolytic action. In addition, our study emphasizes the importance of appropriate genetic controls in murine stroke research. (Arterioscler Thromb Vasc Biol.

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Section: Discussionsupporting

confidence: 83%

Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model

Tabrizi

Wang

Seeds

et al. 1999

ATVB

118

105

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“…Accordingly, our findings stand against the notion that the beneficial CV effects of MD) are mediated through by a decrease in platelet reactivity. We also found that plasma vWF, considered a HCVRF (Folsom et al, 1999;Smith et al, 2000), did not change significantly with MD. This result suggests that the CV benefit of MD would not be mediated by a decrease in plasma vWF levels.…”

Section: Discussionmentioning

confidence: 49%

Mediterranean diet, but not red wine, is associated with beneficial changes in primary haemostasis

et al. 2003

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Objective: (1) To compare the effect of an alcohol-free Mediterranean-type diet (MD) and a high-fat diet (HFD) on variables of primary haemostasis (bleeding time, plasma von Willebrand factor and platelet aggregation=secretion). (2) To test whether red wine supplementation modified these variables, independently of the diet. Design, subjects and intervention: Controlled prospective intervention study. Two groups, each consisting of 21 healthy male university students (22 AE 3.4 y), received either MD or HFD during 90 days. Between days 30 and 60, both diets were supplemented with 240 ml=day of red wine. Baseline (T0) and T30, T60 and T90-day samples were drawn. Bleeding time was measured before (day 30) and after (day 60) wine supplementation. No drop out from the study was experienced. Setting: University campus and outpatient nutrition clinic. Results: All baseline (day 0) variables did not differ significantly between study groups. On day 30, individuals on MD had significantly higher levels of plasma b-carotene, folate, ascorbate, and eicosapentaenoic acid in plasma lipid fractions, than those on HFD. Total plasma cholesterol, HDL and LDL did not change significantly in either study group at any time point. After 30 days on each diet, individuals on MD had longer bleeding time (BT) than those on HFD (7.6 AE 2.8 vs 5.8 AE 1.7 min; P ¼ 0.017). BT did not change significantly after I month of wine supplementation (7.1 AE 2.0 vs 5.5 AE 2.0 min, respectively). Plasma von Willebrand factor (vWF : Ag) on day 0 was 89 AE 40 and 111 AE 70% in MD and HFD groups, respectively (P ¼ 0.21). These values did not change significantly at 30, 60 or 90 days. MD intake was associated with an increase in platelet serotonin secretion (P ¼ 0.02) and a marginal increase in platelet aggregation after stimulation with epinephrine (P ¼ 0.07). Wine intake resulted in a marginal decrease in platelet 14 C-5-HT secretion with 4 mM ADP (P ¼ 0.07). However, both platelet aggregation and secretion were consistently increased when using collagen as agonist (1 and 2 mg=ml, P ¼ 0.01). Conclusion: The longer BT in individuals on MD, obtained independently of red wine, denotes less interaction of platelets with the vascular wall, which could be beneficial from the point of view of cardiovascular (CV) risk. This effect is not explained by changes in the measured haemostatic determinants of BT (plasma vWF, ex vivo platelet function), and might be attributed to other as yet unknown vascular factors. Moderate consumption of red wine results in a significant increase in ex vivo platelet aggregation and secretion after stimulation with collagen. This observation contradicts previous reports, although further studies are required to elucidate the influence of this finding on CV risk.

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“…25 As well as being a risk factor for coronary artery disease, von Willebrand factor is also a risk factor for stroke, which is a particular concern in hypertensive patients. For example, in the Atherosclerosis Risk in Communities Study, 26 the risk of stroke rose significantly for each standard deviation increase in von Willebrand factor.…”

Section: Discussionmentioning

confidence: 99%

Von Willebrand Factor, Soluble P-Selectin, and Target Organ Damage in Hypertension

et al. 2002

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Abstract-To investigate the relationship between soluble markers of platelet, endothelial and rheological function, and target organ damage and their response to intensified management in a population of middle-age hypertensive patients at high risk of cardiovascular complications, we studied 382 consecutive patients (308 men; mean age, 63 years, SD 8) along with 60 normotensive controls free of cardiovascular disease. Patients were divided into those with target organ damage (TOD; nϭ107) and those free of end-organ damage. Plasma levels of soluble P-selectin (sP-sel), a marker of platelet activation, and von Willebrand factor (vWF), an index of endothelial damage/dysfunction (both enzyme-linked immunosorbent assay), and the rheological indices fibrinogen, plasma viscosity, hematocrit, platelet, and white cell count were measured. In 53 patients, variables were further measured after 6 months of intensified cardiovascular risk management. Patients with TOD had significantly higher vWF, 137 (SD 33) versus 125 (SD 33) IU/dL (Pϭ0.002,) and a greater proportion of smokers, 31% versus 16% (Pϭ0.002). There were no statistically significant differences in plasma viscosity, fibrinogen, hematocrit, white blood cell count, platelet count, or sP-sel between the 2 subgroups. In multivariate analysis, vWF was a significant independent predictor for TOD. After 6 months of intensified management in 53 patients who entered the trial, there were significant reductions in systolic blood pressure, total cholesterol, hematocrit, plasma viscosity, sP-sel, and vWF (all PϽ0.01) but no significant change in fibrinogen.

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Prospective Study of Markers of Hemostatic Function With Risk of Ischemic Stroke

Cited by 377 publications

References 37 publications

Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model

Tissue Plasminogen Activator (tPA) Deficiency Exacerbates Cerebrovascular Fibrin Deposition and Brain Injury in a Murine Stroke Model

Mediterranean diet, but not red wine, is associated with beneficial changes in primary haemostasis

Von Willebrand Factor, Soluble P-Selectin, and Target Organ Damage in Hypertension

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