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

The aim of the present study was to examine if soluble thrombomodulin (sTM) and von Willebrand factor (VWF) could predict a first-ever ischemic or hemorrhagic stroke. This study was an incident case-referent study from within a population-based cohort in northern Sweden. Up to 1996 about 44,000 subjects had been screened and stroke cases were classified according to the WHO MONICA criteria. A first-ever stroke occurred in 108 cases. A total of 216 controls were selected from the same cohort. This prospective study found no association with sTM or VWF and the development of a first-ever ischemic stroke (n = 87) in the logistic regression model. For the hemorrhagic stroke cases (n = 18), the multivariate logistic regression model revealed a significant negative association with sTM. When dichotomized, the upper level (>17.3 microg/L) of sTM, as compared with the lower level (<17.3 microg/L), showed one fifth of the risk for hemorrhagic stroke (OR, 0.18; CI, 0.05 to 0.69). No significant association was found for VWF. We suggest that the novel finding of an inverse relation between sTM and hemorrhagic stroke should be investigated in a larger study.
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PMID:Prospective study on soluble thrombomodulin and von Willebrand factor and the risk of ischemic and hemorrhagic stroke. 1185 79

The progress of a stroke concerns the activation of endothelial cells and platelets. We measured the plasma activities of von Willebrand factor (vWf) and the serum levels of soluble thrombomodulin (sTM) as endothelial markers, and the plasma concentrations of soluble P-selectin (sP-selectin) and soluble E-selectin (sE-selectin) as adhesion molecules during the acute (within 48 h from onset) and subacute (after 1 month from the onset) phases of 52 consecutive patients with acute ischemic stroke and 86 age-matched control subjects. The plasma vWf activities and levels of sP-and sE-selectins in stroke patients were significantly elevated compared with those in controls during both the acute and subacute phases. The serum levels of sTM in stroke patients were significantly higher than those in controls only during the subacute phase. In atherothrombotic infarction, the vWf activities and the levels of sP-selectin, markers for endothelial and platelet activation, remained higher until the subacute phase compared with controls, and the concentrations of sTM, a marker for endothelial injury, were increased during the subacute phase compared with during the acute phase. In lacunar infarction, the levels of sTM and sE-selectin of patients were higher only during the acute phase than controls. These findings suggest that the endothelial cell damage might be maintained until the subacute phase in atherothrombotic infarction, whereas it is remarkable only during the acute phase in lacunar infarction. The evaluation of endothelial markers and adhesion molecules would represent the pathophysiological states of stroke and may provide useful information for the treatment of the ischemic infarction.
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PMID:Endothelial markers and adhesion molecules in acute ischemic stroke--sequential change and differences in stroke subtype. 1188 28

Patients with cerebral small vessel disease (SVD) can present as isolated lacunar infarction or with diffuse white matter changes, with the imaging appearance of leukoaraiosis. Endothelial dysfunction, which can lead to breakdown of the blood-brain barrier, impaired cerebral autoregulation and prothrombotic changes, is believed to be important in mediating disease. Circulating levels of intercellular adhesion molecule 1 (ICAM1), thrombomodulin (TM), tissue factor (TF) and tissue factor pathway inhibitor (TFPI) are markers of endothelial activation and damage, and may provide insights into disease pathogenesis or differences between phenotypes. We therefore measured these markers in a prospective series of patients with lacunar stroke. One hundred and ten white Caucasian patients with previous lacunar stroke and 50 community control subjects were studied. Markers of endothelial function were measured on venous blood samples. Patients were classified on brain imaging into two groups: isolated lacunar infarction (n = 47) and ischaemic leukoaraiosis, defined as a clinical lacunar stroke and leukoaraiosis on brain imaging (n = 63). The number of lacunes and severity of leukoaraiosis were also scored on MRI. ICAM1, TM and TFPI were elevated in cerebral SVD subjects compared with controls (P <or= 0.006). The ischaemic leukoaraiosis group had a different endothelial marker profile, with lower levels of TFPI (P = 0.01) and a higher TF/TFPI ratio (P = 0.01) compared with the isolated lacunar infarction group. TM levels were associated with the number of lacunes (P = 0.008) and the leukoaraiosis score (P = 0.03), but TF levels and the TF/TFPI ratio were associated only with the extent of leukoaraiosis (P <or= 0.02). These results suggest that there is evidence of chronic endothelial dysfunction in cerebral SVD, and endothelial prothrombotic changes may be important in mediating the ischaemic leukoaraiosis phenotype. Therapies which help to stabilize the endothelium may have a role in this group of patients.
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PMID:Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. 1253 8

The time course of the concentration of active thrombin in clotting plasma (the thrombogram) was measured by subsampling from platelet-rich plasma (PRP) and continuous chromogenic measurement of platelet-poor plasma (PPP) in 41 stroke patients under the age of 50, in whom stroke could not be attributed to cardioembolic disease, arterial dissection or vasculitis. A significant increase in the area under the thrombogram (endogenous thrombin potential, ETP) was seen in 23 patients. In 9 of them, ETP was increased in PRP but normal in PPP. High ETP in PRP was significantly associated with stroke, both in the middle and in the highest tercile of the ETP (odds ratio 5.1, range 1.8-15.1, and 3.7, range 1.3-10.3, respectively). A decreased sensitivity to the inhibitory action of thrombomodulin (TM) on thrombin generation was observed in 5 of 37 cases. No further definition of the cause of increased thrombin generation or TM resistance was attempted, except for the role of von Willebrand factor (vWF). ETP in PRP, platelet-derived procoagulant activity and vWF were correlated and higher in patients than in controls (p=0.002, p=0.045 and p=0.0006, respectively). This confirms the correlation between vWF level and stroke at young age found in epidemiological studies. It suggests that the role of vWF in thrombin generation, which has been demonstrated in vitro, may be the underlying mechanism of this correlation. In summary, hypercoagulability, defined as an increased capacity of the platelet plasma system to form thrombin, is found in over half of the patients under 50 years with an otherwise unexplained stroke. Sometimes it is due to increased plasma factor activity, sometimes to an increased procoagulant activity of the platelets.
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PMID:Thrombin generation in platelet-rich plasma as a tool for the detection of hypercoagulability in young stroke patients. 1285 13

Since its discovery as a critical cofactor in the initiation of the protein C (PC) anticoagulant pathway [1,2], biochemical and structural investigations, combined with in vivo analyses of genetically engineered mice have revealed new, and in part PC- and thrombin-independent aspects of thrombomodulin (TM) function in fibrinolysis and inflammation, and in embryogenesis. This review summarizes more recent structural and functional investigations of TM, gives an overview of the association of TM gene polymorphisms with human disease, and provides a synopsis of what is know about TM function in disease states of thrombosis, stroke, arteriosclerosis, and cancer. Newly emerging aspects of TM function in inflammation and embryogenesis are presented and discussed in detail.
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PMID:Thrombomodulin. 1287 Dec 87

In type 2 diabetic patients with or without nephropathy, we examined relationships between plasma concentrations of total homocysteine (tHcy) and clinical macroangiopathy, as well as endothelial dysfunction indicated by plasma thrombomodulin (TM) concentrations. We studied 103 type 2 diabetic patients including 26 with macroangiopathy (12 patients with coronary artery disease [CAD], 10 with stroke, and 4 with peripheral vascular disease [PVD]). Plasma tHcy was measured by high-performance liquid chromatography. Plasma TM was determined by enzyme immunoassay. As an index of glomerular filtration rate, creatinine clearance (Ccr) also was determined in a 24-hour urine collection. Considering all diabetic patients, plasma tHcy concentrations were significantly higher in those with macroangiopathy than in those without (10.4 +/- 3.7 v 8.5 +/- 2.8 micromol/L, P=.0077). By univariate and multivariate analyses, plasma tHcy was correlated inversely with Ccr. Plasma tHcy concentrations were significantly higher in the patients with overt albuminuria than in those with normoalbuminuria or microalbuminuria. After exclusion of patients with renal insufficiency (Ccr<60 mL/min), differences in plasma tHcy concentrations between patients with and without macroangiopathy were abolished. By multivariate analysis, total cholesterol, urinary albumin, Ccr, C-peptide, and tHcy retained significant influence on the plasma TM. Even in patients with normal renal function (Ccr > or = 80 mL/min), plasma tHcy was correlated positively with plasma TM. In conclusions, diabetic nephropathy is a main determinant of plasma tHcy elevation in type 2 diabetic patients. Since plasma TM is independently associated with plasma tHcy, in diabetic patients with overt nephropathy, elevation of tHcy reflecting reduced clearance is a likely cause of endothelial dysfunction, resulting in the atherosclerosis underlying development of cardiovascular disease.
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PMID:High plasma homocysteine concentrations are associated with plasma concentrations of thrombomodulin in patients with type 2 diabetes and link diabetic nephropathy to macroangiopathy. 1462 17

Maintaining a delicate balance among anticoagulant, procoagulant, and fibrinolytic pathways in the cerebral microcirculation is of major importance for normal cerebral blood flow. Under physiological conditions and in the absence of provocative stimuli, the anticoagulant and fibrinolytic pathways prevail over procoagulant mechanisms. Blood clotting is essential to minimize bleeding and to achieve hemostasis; however, excessive clotting contributes to thrombosis and may predispose the brain to infarction and ischemic stroke. Conversely, excessive bleeding due to enhanced anticoagulatory and fibrinolytic mechanisms could predispose the brain to hemorrhagic stroke. Recent studies in the author's laboratory indicate that brain capillary endothelium in vivo produces thrombomodulin (TM), a key cofactor in the TM-protein C system that is of major biological significance to the antithrombotic properties of the blood-brain barrier (BBB). The BBB endothelium also expresses tissue plasminogen activator (tPA), a key protein in fibrinolysis, and its rapid inhibitor, plasminogen activator inhibitor (PAI-1). The procoagulant tissue factor is normally dormant at the BBB. There is a vast body of clinical evidence to document the importance of hemostasis in the pathophysiology of brain injury. In particular, functional changes caused by major stroke risk factors in the TM--protein C, tPA/PAI-1, and tissue factor systems at the BBB may result in large and debilitating infarctions following an ischemic insult. Thus, correcting this hemostatic imbalance could ameliorate drastic CBF reductions at the time of ischemic insult, ultimately resulting in brain protection. Delineation of the molecular mechanisms of BBB-mediated hemostasis will likely contribute to future stroke prevention efforts and brain protection strategies.
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PMID:Antithrombotic, procoagulant, and fibrinolytic mechanisms in cerebral circulation: implications for brain injury and protection. 1509 52

The purpose of the present study was to investigate sequential changes in serum soluble thrombomodulin (sTM) concentrations in patients with acute cerebral infarction (ACI), and to correlate sTM concentrations with the severity of ACI evaluated by Japan Stroke Scale. Eighty-three consecutive patients with ACI were enrolled, and blood examinations were carried out soon after admission and 1 month after. sTM concentrations at admission in patients with cardioembolic infarction (3.2 +/- 1.2 ng/ml) were significantly lower than those of lacunar infarction (3.9 +/- 1.2) (P < 0.05). Serial examinations revealed that sTM concentrations increased significantly 1 month after admission (3.8 +/- 1.2), compared with those at admission (3.6 +/- 1.2) (P = 0.02). Of three ACI subtypes, sTM concentrations during 1 month significantly increased in atherothrombotic infarction (P = 0.002) or, not significantly, in cardioembolic infarction (P = 0.09). The sTM concentrations at admission showed a significant inverse correlation with the severity of ACI (P = 0.04). Although sTM concentrations serve as a useful marker for endothelial cell damage, they are decreased in patients with severe ACI, especially in atherothrombotic and cardioembolic infarctions. Lower sTM concentrations may play some important role in disease progression or in the recurrence following ACI, although the exact mechanism of this unique result should be clarified.
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PMID:Significance of serum soluble thrombomodulin level in acute cerebral infarction. 1514 26

The protein C pathway is a major regulator of blood coagulation, since it controls the conversion of prothrombin to thrombin through a feedback inhibition mechanism. Protein C circulates in plasma as an inactive zymogen and is activated on the surface of endothelial cells by the thrombin-thrombomodulin complex, a process that can be further enhanced when protein C binds to its membrane receptor, the endothelial-cell protein C receptor. Activated protein C (APC) is then released from the complex, binds protein S and inhibits thrombin formation by inactivating coagulation factors Va and VIIIa. The importance of the protein C anticoagulant pathway is emphasized by the increased risk of venous thromboembolism (VTE) associated with protein C and protein S deficiencies, the factor V Leiden mutation, and reduced circulating APC levels. The protein C pathway also plays a significant role in inflammatory processes, since it prevents the lethal effects of E. coli-associated sepsis in animal models and improves the outcome of patients with severe sepsis. APC seems to display anti-apoptotic and neuroprotective activities. Thus, it reduces organ damage in animal models of sepsis, ischemic injury, endothelial cell injury, or stroke. Further research will hopefully widen the current therapeutic perspectives in all these illnesses, where these effects might play a crucial role in their treatment. This review will summarize the mechanisms that contribute to these biological activities of the protein C pathway.
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PMID:The multifunctional protein C system. 1585 99

Normal adults have very few circulating endothelial cells (CECs) in their blood, but increased levels have been shown in association with conditions associated with endothelial damage such as myocardial infarction and stroke. As atrial fibrillation (AF) is associated with a hypercoagulable state and abnormalities of plasma indices of endothelial damage/dysfunction, we hypothesised that CECs would also be raised in this condition, and would correlate with these plasma markers. We measured CECs (by immunofluoresence) as an indicator of frank endothelial damage, alongside 3 plasma indices of endothelial perturbation: von Willebrand factor (vWf), soluble E-selectin and soluble thrombomodulin (sTM) (all ELISA) in 28 patients with chronic 'stable' AF, 63 patients with AF plus an acute cardiovascular or cerebrovascular event as positive controls, and 20 healthy subjects in sinus rhythm as negative controls. Chronic 'stable' AF patients had significantly higher levels of plasma vWf (p<0.001 ), but comparable numbers of CECs (p=0.1638) in comparison to healthy controls. In patients with AF associated with an acute cardiovascular or cerebrovascular event, levels of CECs (p<0.0001) and sTM (p=0.004), but not vWf or sEsel, were significantly increased in comparison to chronic 'stable' AF patients. Patients with uncomplicated AF have abnormal systemic endothelial damage/dysfunction, as evident by increased plasma vWf levels, but normal numbers of CECs, compared to subjects in sinus rhythm. However, following clinical complications, such as stroke or significant haemodynamic compromise, further endothelial disturbance (as indicated by high levels of sTM and CECs) suggests additional endothelial damage.
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PMID:Circulating endothelial cells in atrial fibrillation with and without acute cardiovascular disease. 1627 Jun 20


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