Endothelial dysfunction, nitric oxide and platelet activation in hypertensive and diabetic type II patients

Alterations in the synthesis or enhanced inactivation of nitric oxide (NO) and an increase in endothelin-1 production lead to an imbalance that can induce arterial hypertension. Type II diabetes is characterized by impaired endothelium-dependent vasodilation and vascular disease. NO is produced through L-arginine pathway by three different isoforms of nitric oxide synthase (NOS), an inducible form that can be activated by cytokines such as tumor necrosis factor alpha (TNFalpha). We evaluated NO plasmatic levels, endothelial damage markers such as von Willebrand factor (vWF), platelet activation, soluble P-selectin (sP-Sel), TNFalpha levels, insulinaemia (I), glycosylated haemoglobin (HbA1c), glycaemia and blood pressure in 32 hypertensive diabetic type II patients (Group A), 37 hypertensive patients (Group B) and 35 healthy subjects (Group C) matched in sex, age, body mass index and dietary habits. The level of I was increased in patients compared to the controls and correlated with their NO levels. vWF plasmatic levels were increased in Group A compared to Groups B and C. We also found significant differences in platelet activation among all the groups. In diabetic patients, increased NO levels correlated with TNFalpha, HbA1c and platelet activation showed greater endothelial damage than in Group B. These parameters described a prothrombotic state associated with an insulin resistance state, an increased vWF release, raised sP-Sel and TNFalpha levels and, maybe, low NO bioavailability, which could lead to a higher risk of development of thrombotic events in hypertensive diabetic patients (Group A) than in the hypertensive patients in Group B.     

Association of cardiovascular risk factors with markers of endothelial dysfunction in middle-aged men and women. Results from the MONICA/KORA Augsburg Study

Endothelial dysfunction plays an important role in the pathogenesis of cardiovascular diseases and diabetes mellitus. However, the causes underlying endothelial dysfunction are not fully understood. Therefore, the aim of the present study was to investigate associations of cardiovascular risk factors with soluble adhesion molecules (sE-Selectin, sICAM-1), soluble thrombomodulin (sTM) and von Willebrand factor (vWF) as markers of endothelial dysfunction. The study population consisted of a subcohort of 2,168 men and women aged 35 to 74 years randomly drawn from three cross-sectional population-based MONICA/KORA Augsburg surveys conducted between 1984 and 1995. In multivariable linear regression analysis, current smoking, high (versus moderate) alcohol consumption, ratio of total cholesterol/HDL-cholesterol (TC/HDL-C) and C-reactive protein (CRP) were significantly associated with elevated levels of sE-selectin and sICAM-1. Increased levels of sE-selectin were also found in subjects with actual hypertension, high body mass index and prevalent diabetes mellitus. In addition, low physical activity and no (versus moderate) alcohol consumption were significantly associated with elevated concentrations of sICAM-1. Levels of sTM were higher in subjects with actual hypertension, no or high amounts of alcohol intake and a high ratio of TC/HDL-C, but were lower in subjects with a history of myocardial infarction. VWF was significantly associated with CRP only. In conclusion, sE-selectin and sICAM-1 are more strongly associated with traditional cardiovascular risk factors than sTM and vWF.     

Experimental thrombosis I: relation with fibrinogen and other haemostatic parameters

Epidemiological studies have shown that the haemostatic parameters Fibrinogen (Fg), Factor VII (F VII), Factor VIII (F VIII), von Willebrand factor (vWF), Tissue Plasminogen Activator (t-PA), Plasminogen Activator Inhibitors (PAI) are risk factors/markers of ischemic cardiovascular disease. Ferritin (sFER) and Leukocytosis have also been implicated. In the present study we have followed the levels of fibrinogen, von Willebrand factor and thrombomodulin in relation to lipids, iron and the appearance of atherosclerotic lesions in New Zealand rabbits fed with a cholesterol enriched diet for a two-month period compared with a group of control rabbits. Hematocrit and white blood cell count (WBC) were measured in parallel. In hyperchlesterolemic rabbits the levels of fibrinogen and von Willebrand factor increased progressively, showing a positive correlation with the increasing cholesterol levels. There was an increase in soluble thrombomodulin beginning at the eighth week of study. In addition, these animals showed gross intimal atherosclerotic lesions in the whole extension of their aortas. Immunohistochemical studies showed the presence of fibrin(ogen) related antigen throughout the arterial wall and in the central portions of the atheromas. In the control group there was no formation of atherosclerotic plaques and all haemostatic, haematological and biochemical parameters were within the normal range. WBC and sFER levels were unaffected in both groups. Our results show that increased levels of fibrinogen and von Willebrand factor, known coronary risk factors, are strongly associated with the formation of atherosclerotic plaques in rabbits. The plaques contain a considerable amount of fibrinogen related antigen.     

Effects of antioxidant vitamins C and E on endothelial function and thrombosis/fibrinolysis system in smokers

Smoking is associated with endothelial dysfunction and abnormalities in thrombosis/fibrinolysis system, possibly through increased oxidative stress. In this study we investigated the effect of combined antioxidant treatment with vitamins C and E on endothelial function and plasma levels of plasminogen activator inhibitor (PAI-1), von Willebrand factor (vWF), tissue plasminogen activator (tPA) and factor VII (fVII), in smokers. Forty-one healthy smokers were randomly divided into 4 groups receiving vitamin C 2g/day (group A), vitamin C 2g/day plus vitamin E 400 IU/day (group B), vitamin C 2g/day plus vitamin E 800 IU/day (group C) or no antioxidants (controls, group D), for 4 weeks. Forearm blood flow was measured using venous occlusion strain-gauge plethysmography. Forearm vasodilatory response to reactive hyperemia (RH%) or to sublingual nitroglycerin administration (NTG%) were considered as indexes of endothelium dependent or independent dilation respectively. After treatment, RH% was increased only in groups B (p <0.05) and C (p <0.001) but not in groups A and D. Plasma levels of PAI-1 and vWF were decreased only in group C (p <0.05 for both), while PAI-1/tPA ratio was significantly decreased in both groups B and C (p <0.05 for both). NTG% and plasma levels of tPA and fVII remained invariable in all groups. In conclusion, combined administration of vitamin C and vitamin E at high dosages, improved endothelial function and decreased plasma levels of PAI-1, vWF and PAI-1/tPA ratio in chronic smokers.     

Endothelial cell and hemostatic activation in relation to cytokines in patients with sepsis

Sepsis is commonly associated with disturbances of the hemostatic balance. Most of the pathophysiological changes in sepsis are caused by endotoxin acting directly through endothelial injury or indirectly through release of cytokines with procoagulant effects. The relation between cytokines and hemostatic parameters was assessed in 32 patients with sepsis. Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin III complexes (TAT), tissue type plasminogen activator (t-PA) functional and antigen, plasminogen activator inhibitor-1 (PAI-1), plasminalpha2-antiplasmin complexes (PAP), D-Dimer, thrombomodulin (TM) and von Willebrand factor (vWF) were measured in patients and in 30 healthy subjects. The levels of cytokines TNF-alpha and interleukin-6 (IL-6) also were determined. A significant increase of F1+2, TAT, PAI-1, PAP, and D-Dimer was observed in septic patients as compared with controls (p<0.0001), whereas t-PA activity was significantly reduced (p<0.01). The markers of endothelial cell activation TM, vWF, and t-PA antigen also were elevated significantly as compared with the control group (p<0.01). Finally, we found a marked increase of TNF-alpha and IL-6 (p<0.0001). Whereas the increase of cytokine levels could be partially responsible for the hemostatic activation, it did not correlate with markers of endothelial activation in patients with sepsis.     

Association between increased homocysteine levels and impaired fibrinolytic potential: potential mechanism for cardiovascular risk

BACKGROUND: Elevated homocysteine levels increase cardiovascular risk although the mechanism is not well understood. Since thrombosis plays an important role in plaque development and acute coronary syndromes, hyperhomocysteinemia may increase risk by increasing the thrombotic potential. METHODS AND RESULTS: Hemostatic risk factors were measured in 3,216 individuals (1,451 men and 1,765 women) free of cardiovascular disease who participated in cycle 5 of the Framingham Offspring Study. An increase in homocysteine level was associated with a rise in plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (TPA) antigen, von Willebrand factor and fibrinogen level. After regression analyses adjusting for covariates, there remained significant associations between homocysteine and PAI-1 and TPA antigen. CONCLUSION: Increasing homocysteine levels are associated with impaired fibrinolytic potential, as indicated by increased PAI-1 and TPA antigen levels. These data suggest that folic acid and other homocysteine lowering therapies may decrease cardiac events through a reduction in thrombotic tendency.     

Studies on the pathogenesis of coagulopathy in patients with arterial thromboembolism and malignancy

Plasma levels of thrombin-antithrombin III complex(TAT), plasmin-₂-plasmin inhibitor complex(PAP), von Willebrand factor antigen (vWF:Ag) plasminogen activator antigen(PA) and plasminogen activator inhibitor-1 antigen(PAI-1), were determined in 110 patients with arterial thromboembolic diseases within 4 weeks after attack (Th; 41 cases with myocardial infarction and 69 with cerebral infarction), 67 patients with various types of carcinoma(Ca; 31 cases without metastasis and 36 with metastasis)and 50 age-matched healthy individuals(Co). The following results were obtained: 1) Mean plasma levels of TAT, PAP, vWF:Ag, PA and PAI-1 were significantly higher in Th than Co. 2) Mean plasma levels of TAT, PA and PAI-1 were significantly higher in Ca than Co regardless of metastasis but those of PAP and vWF:Ag were significantly higher only in Ca with metastasis than Co. 3) Significant relationship was observed between plasma levels of TAT and PAP both in Th and Ca. 4) Significant relationship was also observed between plasma levels of TAT and vWF:Ag, PA or PAI-1 in Th, but not in Ca. It is suggested from these results that the coagulopathies observed in these patients result from the activation of intravascular blood coagulation and fibrinolysis, and that vascular endothelial cell damage may play an important role in the activation in Th.     

Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers

OBJECTIVE: Increased circulating levels of hemostatic factors have been associated with arterial and venous thrombosis. Although in vitro evidence suggests that glucocorticoids may activate hemostasis and inhibit thrombolysis, no controlled in vivo studies have examined the effects of glucocorticoids on hemostatic factors. We hypothesized that a 5-day treatment course of dexamethasone would increase circulating levels of hemostatic and anti-fibrinolytic factors. METHODS: We randomized 24 healthy men ages 19-39 to receive either dexamethasone 3 mg twice daily versus placebo for 5 days. Parameters examined before and after the intervention included: clotting factors VII, VIII, and XI, von Willebrand factor (vWF), D-dimer, PAI-1, soluble CD40-ligand (sCD40-ligand), and fibrinogen. RESULTS: Dexamethasone tended to modestly increase clotting factors levels and fibrinogen without significantly affecting PAI-1, D-dimer or sCD40-ligand. Factor VII increased by a mean of 13% (p = 0.04 versus placebo), factor VIII by 27% (p = 0.0008), factor XI by 6% (p = 0.01), and fibrinogen by 13% (p = 0.05). CONCLUSIONS: Glucocorticoids may increase the activity of clotting factors in vivo. This may contribute to the reported increased risk of thrombosis in patients with sustained exposure to glucocorticoids.     

High levels of plasma FVIII and vWF in the toxic epidemic syndrome patients

Factor VIII and von Willebrand factor proteins were evaluated in 115 patients having the chronic phase of the Toxic Epidemic Syndrome (TES), a new multisystemic disease probably caused by the ingestion of denatured rapeseed oil, and in 50 control volunteers. Higher circulating levels of factor VIII procoagulant activity (VIII:C) (158 +/- 58.4 U/dl), von Willebrand factor antigen (vWF:Ag) (166.1 +/- 55.5 U/dl) and von Willebrand factor ristocetin cofactor activity (vWF:RCo) (178.7 +/- 55.2 U/dl) were seen in TES patients (p less than 0.001, TES patients versus control subjects, for each parameter). The increased levels of vWF:Ag and vWF:RCo observed in TES patients correlated with the scleroderma like lesion of the skin, with the sicca syndrome and with Raynaud's phenomenon (p less than 0.01), but not with other clinical manifestations. The multimeric analysis of vWF in 92% of the TES patients was similar to that found in normal plasma, but in the remaining 8% a very slight increase of larger vWF multimers in plasma were observed. The raised levels of vWF found in TES patients in the chronic phase may reflect an "in vivo" vascular injury.     

Fluvastatin decreases soluble thrombomodulin in cardiac transplant recipients

We conducted a randomized, placebo controlled, double-blind, cross-over study, to assess the effects of a 4-week fluvastatin therapy on plasma markers of endothelial activation or injury in 20 transplanted heart recipients. The levels of thrombomodulin and von Willebrand factor antigen were higher at baseline in cardiac transplant recipients than in age and sex-matched healthy controls. Plasma total cholesterol showed a 21% reduction on fluvastatin therapy (p = 0.0001). Fluvastatin treatment had no significant effect on creatininemia, plasma cyclosporine, PAI-1 antigen, PAI-1 activity, tPA antigen, and Von Willebrand factor. However, fluvastatin produced a significant decrease of plasma thrombomodulin (66.7 ng/ml on placebo versus 58.8 ng/ml on fluvastatin, p <0.001), suggesting a rapid improvement of endothelial injury in these patients.     

Effects on coagulation and fibrinolysis of desmopressin in patients undergoing total hip replacement.

Twelve patients undergoing total hip replacement, with regional anaesthesia and with dextran infusion for plasma expansion and thromboprophylaxis, were given the vasopressin analogue desmopressin (DDAVP) or placebo in a randomized, double-blind prospective study. In controls (n = 6) we found a prolongation of the bleeding time, low factor VIII (FVIII) and von Willebrand factor (vWF) and a decrease in antithrombin III to levels known to be at risk for venous thrombosis. Desmopressin shortened postoperative bleeding time, gave an early FVIII/vWF complex increase, prevented antithrombin III from falling to critically low values and appeared to activate the fibrinolytic system, both by tPA increase and PAI-1 decrease. Thus in the controls we found changes in both coagulation and fibrinolysis indicating a haemorrhagic diathesis as well as a risk for thromboembolism. Desmopressin induced factor changes that possibly reduce both risks.     

Increased levels of endothelial haemostatic markers in patients with coronary heart disease

von Willebrand factor (vWF), thrombomodulin and tissue plasminogen activator antigen (tPAag) are regarded as markers of endothelial activation and/or damage. Elevated levels have been associated with atherosclerotic disease states. The aim of the present study was to compare the levels of vWF, thrombomodulin and tPAag in patients with coronary heart disease (CHD) and matched healthy individuals to see if they discriminated significantly between the study groups also after adjustment for established CHD risk factors. Patients (n=193) in various stages of CHD and matched controls (n=193) were included. To evaluate possible influence of acute phase reaction, reinvestigation was performed after 6 months. We observed elevated levels of vWF (P<.001) and tPAag (P<.001) but not thrombomodulin (P=.082) in CHD patients when compared to controls, still statistically significant after 6 months and also after adjustment for established risk factors. Our results indicate that vWF and tPAag but not thrombomodulin in the present population are independent markers of atherosclerosis.     

A new animal model of thrombophilia confirms that high plasma factor VIII levels are thrombogenic

The thrombotic risk associated with elevated plasma levels of clotting factor VIII (FVIII) was investigated in a mouse model of thrombophilia. After the intravenous injection of recombinant human FVIII and/or of purified FVIII-free human von Willebrand factor (vWF), a controlled mild injury was inflicted on the carotid artery of FVB mice by irradiation with filtered green light in combination with intravenous injection of the dye rose bengal. Formation of a platelet-rich thrombus was continuously monitored for 40 min via transillumination and the thrombus size was measured via image analysis. Administration of recombinant human FVIII at 40 microg/kg led to initial FVIII plasma activities equivalent to 250% of normal human plasma FVIII activity and significantly enhanced thrombus size. Immunohistochemical staining illustrated the accumulation of FVIII within the thrombi. Human vWF, even at 10 mg/kg, had no effect on thrombus formation. The thrombotic tendency induced by FVIII was significantly inhibited by the administration of human vWF in a dose-dependent manner. Separate plasma measurements revealed that human FVIII has comparable affinities for human and murine vWF but that human vWF does not effectively bind murine platelets. The inhibition by human vWF of the thrombotic tendency induced by human FVIII could therefore be explained by a lack of accumulation of FVIII within the developing thrombus because of the reduced affinity of human vWF for murine platelets and the reduced occupancy of murine von Willebrand factor by human FVIII after injection of human vWF. These results show that vWF actively participates in FVIII accumulation in the arterial thrombus and provide experimental evidence for epidemiological findings that elevated plasma FVIII levels are associated with an increased thrombotic risk, also in arteries.     

The effects of different alcoholic drinks on lipids, insulin and haemostatic and inflammatory markers in older men

Light to moderate drinking is associated with lower risk of coronary heart (CHD) than non-drinkers. We have examined the relationships between total alcohol intake and type of alcoholic beverage and several potential biological mechanisms. We carried out the study in 3158 men aged 60-79 years drawn from general practices in 24 British towns with no history of myocardial infarction, stroke or diabetes and who were not on warfarin. Total alcohol consumption showed a significant positive dose-response relationship with high density lipoprotein cholesterol (HDL-C), coagulation factor IX, haematocrit, blood viscosity, and tissue plasminogen (t-PA) antigen, and an inverse dose-response relationship with insulin, fibrinogen, von Willebrand factor (vWF) and triglycerides after adjustment for possible confounders. Total alcohol consumption showed weak associations with plasma viscosity and fibrin D-dimer, and no association with factors VII, VIII, or C-reactive protein (CRP). Wine was specifically associated with lower CRP, plasma viscosity, factor VIII and triglycerides. The findings are consistent with the suggestion that HDL-C in particular but also insulin and haemostatic factors may contribute to the beneficial effect of light to moderate drinking on risk of CHD. Wine has effects that may confer greater protection than other alcoholic beverages.     

Hemostatic parameters and platelet activation marker expression in cyanotic and acyanotic pediatric patients undergoing cardiac surgery in the presence of tranexamic acid

We have investigated hemostatic parameters including platelet activation in 56 pediatric patients with or without cyanosis undergoing cardiopulmonary bypass (CPB) and cardiac surgery to repair congenital defects. Patients were participants in a study assessing the effects of tranexamic acid on surgery-related blood loss. Parameters monitored included blood loss, prothrombin F1.2, thrombin-antithrombin complexes, t-PA, PAI-1, plasminogen, fibrin D-dimer, and plasma factor XIII. Additionally, flow cytometry monitored platelet degranulation (P-selectin or CD63), as well as surface-bound fibrinogen, von Willebrand factor and factor XIIIa. Cyanotic patients had evidence of supranormal coagulation activation as both fibrin D-dimer and PAI-1 levels were elevated prior to surgery. While the extent of expression of P-selectin or CD63 was not informative, platelet-associated factor XIIIa was elevated in cyanotic patients at baseline. In both patient groups, CPB altered platelet activation state and coagulation status irrespective of the use of tranexamic acid.     

Venous thromboembolism and transient thrombocytopenia in a patient with diabetes insipidus treated with desmopressin acetate (DDAVP)

A 22 year-old woman with diabetes insipidus on chronic therapy with desmopressin acetate (DDAVP) developed recurrent venous thromboembolism and transient thrombocytopenia temporally related to the administration of DDAVP. Large increases in plasma von Willebrand factor (vWF), vWF-activity, and relative increases in the concentrations of the larger multimeric forms of vWF-antigen were observed, as well as a plasma factor which sensitized normal platelets to undergo spontaneous aggregation in vitro. Additional studies showed that the patient's plasma retained the platelet aggregation inducing activity after selective removal of vWF by immunoabsorption. The nature of the platelet activating factor and the relationship of this factor and the excessively increased and transiently abnormal vWF to the recurrent venous thromboembolism in this patient remain uncertain. Although the findings do not implicate definitively DDAVP in the elevation of vWF in this patient, it is suggested that its use be considered with caution in patients with diabetes mellitus and increased levels of vWF.     

Activation of endothelial cells, coagulation and fibrinolysis in children with Dengue virus infection

Dengue virus causes a febrile illness: Dengue fever (DF), and less frequently a life-threatening illness: Dengue hemorrhagic fever (DHF). Although severe bleeding remains a major cause of death in DHF, the pathogenesis of bleeding is poorly understood. This prospective cohort study was designed to determine the extent of activation of endothelial cells and the hemostatic system in correlation with clinical severity, and also to detect the best prognostic factor(s) for DHF. Endothelial cell activation, coagulation, anticoagulant and fibrinolysis parameters were measured in 42 children with Dengue infections (20 with DF and 22 with DHF) during three phases of illness. In DHF patients, during the febrile phase, von Willebrand factor antigen (vWF:Ag), tissue factor (TF) and plasminogen activator inhibitor (PAI-1) were significantly elevated, while platelet counts and ADAMTS 13 (a disintegrin and metalloprotease with thrombospondin repeats) were significantly low compared to DF patients. During the toxic phase, soluble thrombomodulin (sTM), tissue plasminogen activator (t-PA) and PAI-1 were also significantly increased, while ADAMTS 13 and thrombin activatable fibrinolysis inhibitor (TAFIa) were significantly low compared to DF patients. Abnormal vWF multimers were seen only in DHF patients. For endothelial cell injury and release of procoagulant components, activation of the coagulation cascade with thrombin generation, increased antifibrinolytic factors and consumption of natural anticoagulants, each appeared to play an important role in the development of hemorrhage in Dengue patients. Using logistic regression analysis, we found plasma VWF:Ag to be the best indicator of progression to DHF.     

Endothelial markers and HIV infection in the era of highly active antiretroviral treatment

Many circumstances can induce activation and/or injury of the endothelium that plays a role in the development of vascular complications. Raised plasma levels of endothelial markers such as von Willebrand factor (vWF), soluble thrombomodulin (sTM) and soluble vascular cell adhesion molecule-1 (sVCAM-1) have a prognostic and/or diagnostic value. Human immunodeficiency virus-infected patients (HIV+) have a clustering of conditions that activate or injure the endothelium. Highly active antiretroviral treatment produces adverse effects such as dyslipemia, insulin resistance (IR) and body fat changes (named lipodystrophy syndrome) which may contribute to aggravate their endothelial perturbation. The aim of this study was to measure lipid profile, insulin resistance status, and endothelial markers in 38 HIV+ naive of antiretroviral treatment and 63 HIV+ under highly active antiretroviral treatment (33 with lipodystrophy syndrome and 30 without it). Body fat distribution was also evaluated by dual-energy X-ray absorptiometry (DEXA) analysis. Thirty-one HIV negative subjects were used as controls. We looked for association between variables. Insulin resistance status was a common finding in the four groups. Lipodystrophic patients presented an atherothrombotic lipid profile [elevated levels of triglycerides (TG), low-density lipoprotein cholesterol (LDL-chol) and apolipoprotein-B (APO-B)] and a strong loss of fat in legs and arms (lipoatrophy). All endothelial markers evaluated in our naive patients were higher as compared to control group. sVCAM-1 in HIV+ under therapy without lipodystrophy syndrome showed significantly decreased levels as compared to naive group (487 vs. 666 ng/ml) and vWF and sTM tended to diminish although they did not show a significant difference (130% vs. 170%, 41 vs. 45 ng/ml, respectively). Lipodystrophic patients showed a tendency to increased levels of endothelial activation markers (sVCAM-1: 500 ng/ml and vWF: 154%) together with significantly increased levels of an endothelial injury marker (sTM: 50 ng/ml) with respect to HIV+ under therapy without lipodystrophy syndrome. Plasma levels of sTM, as an endothelial injury marker, correlated with peripheral lipoatrophy (rho = -0.357) in lipodystrophic patients. In conclusion, despite the beneficial immunology effect of highly active antiretroviral treatment and the apparent decrease in the endothelial perturbation, the patients who develop lipodystrophy present altered endothelial markers and other risk factors, such as IR and dyslipemia, which turn them into a high atherothrombotic risk group.     

血浆止血标志物与静止性腔隙性梗死的关系

目的探讨血浆止血标志物浓度与静止性腔隙性梗死间的关系。方法选择131例核磁共振(MRI)检查发现腔隙性梗死而无临床症状的患者,与143例年龄和性别相匹配、MRI检查无腔隙性梗死的对照组,观察血浆止血标志物与腔隙性梗死间的关系。结果在调整年龄、性别等因素后,静止性腔隙性梗死患者的血管性血友病因子(vWF)、纤维蛋白原、D二聚体和β血小板球蛋白(β-TG)浓度明显高于对照组,而纤溶酶原、组织纤溶酶原激活物(tPA)抗原、纤溶酶原激活物抑制剂-1(PAI-1)抗原、可溶性血栓调节蛋白(sTM)和C反应蛋白浓度与对照组相比无明显变化。结论 vWF、纤维蛋白原、D二聚体和纤维蛋白原与静止性腔隙性梗死明显相关,提示止血因子改变参与腔隙性梗死的发生,为腔隙性梗死的临床预防提供理论依据。     

Effects of toll-like receptor-4 gene polymorphisms on soluble P-selectin and von Willebrand factor levels in hypercholesterolemic patients

Toll-like receptor-4 (TLR-4) gene polymorphisms have been associated with a lower risk of atherosclerosis. High levels of soluble P-selectin (sP-selectin) and von Willebrand factor predict an increased risk for cardiovascular events and correlate to atherosclerotic risk factors. The relationship between these markers and TLR-4 gene polymorphisms was evaluated in a cohort of consecutive hypercholesterolemic outpatients. TLR-4 gene polymorphisms were detected in 48 out of 330 (14%) patients with hypercholesterolemia. Lipid and inflammatory markers, sP-selectin and von Willebrand were evaluated in carriers and in 96 (ratio 2:1 to cases) age- and sex-matched TLR-4 wild-type patients randomly selected from the same population. A cohort of normocholesterolemic outpatients (n = 262) served as the control group. sP-selectin was sensibly lower in carriers of TLR-4 variants as compared to wild-types and controls (89 ng/ml vs. 162 ng/ml and 163 ng/dl, respectively, p = 0.0001). Similarly, carriers showed lower von Willebrand factor values (683 mU/ml) than wild-types (910 mU/ml; p = 0.001). In multivariate analysis, TLR-4 gene polymorphisms were positively associated with sP-selectin, whereas the relationship with von Willebrand factor was no longer significant. HMG-CoA reductase inhibitors reduced sP-selectin and von Willebrand factor levels independently of TLR-4 gene variants. Plasma concentrations of these markers, however, remained lower in carriers of TLR-4 gene polymorphisms even after cholesterol lowering. In conclusion, carriership of Asp299 and Thr399Ile TLR-4 gene polymorphisms is associated with lower levels of sP-selectin and von Willebrand factor among hypercholesterolemic patients. While the underlying mechanisms remain to be investigated, such an association may indicate a protective effect of TLR-4 variants for atherosclerosis.