Coagulation factor VII and inflammatory markers in patients with coronary heart disease.

To further elucidate the connection between inflammation and factor VII (FVII) taking genetic variation in the FVII locus into account, we have examined 387 patients after myocardial infarction and 387 age-matched and sex-matched healthy control individuals. Circulating levels of C-reactive protein, FVII antigen (FVIIag), activated FVII (FVIIa), fibrinogen and interleukin-6 were analysed and all subjects were genotyped for the Arg353Gln polymorphism in the FVII locus. Plasma concentrations of C-reactive protein, fibrinogen, and interleukin-6 were higher among patients than control individuals. FVIIag was lower in the patient group, but for FVIIa there was no difference between the two groups. Among the inflammatory markers, only C-reactive protein indicated a weak nonlinear association with FVII. No significant difference in frequency of the Gln allele was observed between patients and control individuals but the presence of the Gln allele was associated with lower plasma levels of FVIIag and FVIIa in both groups. The low-grade chronic inflammation seen 3 months after myocardial infarction is not of major importance for the variation in plasma concentration of FVII. The presence of the Gln allele in the Arg353Gln polymorphism in the FVII locus did not differ between patients and control individuals but was associated with lower plasma levels of FVIIag and FVIIa that could have a protective effect against myocardial infarction. To further elucidate these facts, a prospective study should be performed to reduce the risk of a possible selection bias due to coronary heart disease death seen in retrospective case-control studies.     

A protective contribution of the Q allele of the R353Q polymorphism of the Factor VII gene in individuals with chronic stable angina?

BACKGROUND: Factor VII polymorphisms have been suggested in some studies to show an association with some aspects of coronary disease, and there is a known association between FVII levels and polymorphic variants in the gene. The aim of the study was to assess whether Factor VII polymorphism R353Q is associated with the extent of coronary artery disease in patients with chronic stable angina. METHODS AND RESULTS: There is evidence that Factor VII polymorphisms are markers of susceptibility to coronary artery disease (CAD), but two studies have suggested that there is no association between the degree of vessel disease and these polymorphisms. One of these studies did not exclude patients with unstable angina or MI. We therefore set up a prospective cohort study to determine Factor VIIa, VIIc and VIIAg levels, genotype for R353Q, lipid status, smoking history and the degree of vessel disease, in patients attending the hospital for routine day case angiography over a 20 month period. From 519 cases, 400 had no previous MI or revascularisation, including 153 with zero vessel disease, and were successfully genotyped: 9 (2%) QQ, 78 (20%) RQ and 313 (78%) RR. Compared with RR subjects, heterozygotes were 2.7 years older (95% CI: 0.3, 5.0; p=0.027), but were not significantly different regarding gender, cholesterol, extent of vessel disease or smoking history. If those with vessel disease were considered, then the heterozygotes were 3.5 years older than the RR homozygotes (95% CI: 0.6-6.4, p=0.016). There was a significant association between all measures of Factor VII and the R353Q polymorphism, with the Q allele associating with lower levels. There was no significant association between the degree of vessel disease and genotype. CONCLUSIONS: The degree of vessel disease as seen at day case angiography is independent of polymorphism status, but there appears nonetheless to be a moderate protective effect of the Q allele against stable angina, in that angiographic investigation occurs a few years later for RQ heterozygotes than RR homozygotes. The effect may be mediated by reduced levels of Factor VII.     

Reduction in coagulation factor VII plasma levels by R353Q but not the -323P0/10 promoter polymorphism in healthy Tunisians

The association between the R353Q and -323P0/10 (10-bp insertion in the promoter region at position -323) factor VII mutations and plasma factor VII levels was investigated in a group of 214 healthy Tunisians. The frequency for the Q allele was 0.253 and that for the 10-bp allele was 0.206, and their distribution was variable, with a high prevalence of the 10-bp allele (0.306) seen in North Tunisia and a high prevalence of the Q allele (0.288) see in the Sahel region. No significant linkage disequilibrium was observed between the two mutations, and the most prevalent haplotype was -323P0/353R (0.589 +/- 0.054). Carriers of the R353Q (P < 0.001), but not -323P0/10 (P = 0.088), factor VII mutations had lower mean factor VII serum concentrations. This reduction in mean serum factor VII was more pronounced among homozygous (Q/Q) carriers and among males (49.9%) compared to females (32.7%). Adjusting for all other variables in the linear regression analysis (sex, age, region, smoking, and R353Q and -323P0/10 mutations), heterozygous carriers of the -323P0/10 and R353Q mutation had on average reductions of 10 units (P = 0.005) and 30 units (P < 0.001) in plasma factor VII, respectively, compared to noncarriers, while homozygote carriers of the R353Q (-43.3, P < 0.001), but not carriers of the -323P0/10 (-6.30, P = 0.356), had significantly lower levels of mean plasma factor VII. These data suggest that part of the previously described effects on FVIIc levels associated with the R/Q polymorphism may be explained by genetic variation in the promoter region of the FVII gene.     

Modulation of factor VII levels by intron 7 polymorphisms: population and in vitro studies

Previous studies have established that factor VII gene (F7) polymorphisms (5'F7 and R353Q) contribute about one-third of factor VII (FVII) level variation in plasma. However, F7 genotyping in patients with cardiovascular disease has produced conflicting results. Population and expression studies were used to investigate the role of intron 7 (IVS7 ) polymorphisms, including repeat and sequence variations, in controlling activated FVII (FVIIa) and antigen (FVIIag) levels. Genotype-phenotype studies performed in 438 Italian subjects suggested a positive relation between the IVS7 repeat number and FVII levels. The lowest values were associated with the IVS7 + 7G allele. The screening of 52 patients with mild FVII deficiency showed an 8-fold increase in frequency (8%) of this allele, and among heterozygotes for identical mutations, lower FVII levels were observed in the IVS7 + 7G carriers. This frequent genetic component participates in the phenotypic heterogeneity of FVII deficiency. The evaluation of the individual contribution of polymorphisms was assisted by the expression of each IVS7 variant, as a minigene, in eukaryotic cells. The novel quantitative analysis revealed that higher numbers of repeats were associated with higher mRNA expression levels and that the IVS7 + 7G allele, previously defined as a functionally silent polymorphism, was responsible for the lowest relative mRNA expression. Taken together, these findings indicate that the IVS7 polymorphisms contribute to the plasmatic variance of FVII levels via differential efficiency of mRNA splicing. These studies provide further elements to understand the control of FVII levels, which could be of importance to ensure the hemostatic balance under pathologic conditions.     

Prolonged prothrombin time, Factor VII and activated FVII levels in chronic liver disease are partly dependent on Factor VII gene polymorphisms

BACKGROUND: Prothrombin time is a benchmark for functional assessment in cirrhosis and Factor VII levels (FVII), crucial in determining the prothrombin time, are genetically determined. METHODS: We have evaluated the prothrombin time, a number of haemostatic variables synthesised by the liver (FII, FV, FVII and activated FVII, AT and fibrinogen) and two polymorphisms of the FVII gene (5'F7 and 353R/Q) in: (a) patients with liver cirrhosis (n=118), (b) patients with chronic hepatitis (n=102) and (c) controls (n=100). RESULTS: By one-way analyses of variance, the prothrombin time and the mean levels of the FII, FV, FVIIc, FVIIa, and AT were statistically different between cirrhotics, chronic hepatitis patients and controls. The allele frequency of the FVII polymorphisms did not differ between the three groups. Those rare patients (4.6%) who were homozygous for the type 2 alleles had markedly reduced FVIIc and FVIIa levels. The analysis carried out taking into account Child class versus FVII genotype showed that the mean FVIIc levels were comparable for different genotypes within each Child's class, with the exception of the patients homozygous for the type 1 allele. CONCLUSION: Our findings help to explain the not infrequent finding of a severely prolonged prothrombin time in patients who are otherwise in a good functional class.     

Reduced procedural risk for coronary catheter interventions in carriers of the coagulation factor VII-Gln353 gene

OBJECTIVES: We have focused on the role of coagulation factor VII (FVII) Arg353Gln polymorphism as a risk predictor of complications following percutaneous transluminal coronary angioplasty (PTCA), directional coronary atherectomy (DCA), and stenting. BACKGROUND: The FVII Arg353Gln mutation decreases FVII activity, and presence of the Gln353 allele could be protective against thrombus formation during catheter interventions. METHODS: A total of 666 consecutive patients with coronary artery disease who had undergone PTCA (n = 280), DCA (n = 104), or stenting (n = 282) were followed up for a 30-day composite end point, which included need for target vessel revascularization, myocardial infarction, and death. The Arg353Gln polymorphism of FVII was determined by PCR/RFLP assay. RESULTS: Carriers of the Gln353 allele had significantly lower levels of total FVII activity (FVIIc, -20.7%, p < 0.001) and of activated circulating FVII (FVIIa, -32.7%, p = 0.03) compared with Arg353/Arg353. The composite end point occurred in 43 patients: 4 were heterozygous Arg353/Gln353, and 39 were homozygous Arg353/Arg353. The incidence of the composite end point was 2.5% in carriers of the Gln353 allele and 7.7% in Arg353/Arg353 homozygotes (p = 0.013). This corresponds to a 72% risk reduction in carriers of the Gln353 allele (relative risk: 0.28; 95% confidence interval: 0.09-0.81; p = 0.02). CONCLUSIONS: The Gln353 allele of FVII is associated with substantial risk reduction in adverse events that complicate coronary catheter interventions. With the perspective of active site-blocked activated FVII (FVIIai) as conjunctive medication, the results suggest that the FVII genotype should be taken into due consideration in assessment of FVIIai medication and of its dosage.     

Atorvastatin reduces plasma levels of factor VII activity and factor VII antigen in patients with hyperlipidemia

Atorvastatin is a powerful new synthetic 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor currently in clinical use. Its effects on plasma levels of factor VII were examined in 30 hyperlipidemic patients. After 12 weeks of atorvastatin treatment, factor VII activity (FVIIc) and factor VII antigen (FVIIag) levels had decreased by 13% (p < 0.0001) and 12% (p < 0.0001), respectively. The decreased concentrations of serum triglycerides correlated with decreases in FVIIc levels (r = 0.54, p = 0.0023) and FVIIag levels (r = 0.59, p = 0.0006) at 12 weeks of treatment with atorvastatin. No significant changes were seen in activated factor VII (FVIIa) levels. Plasma concentrations of fibrinogen were slightly, but not significantly, increased at 12 weeks. No significant changes were seen in plasminogen activator inhibitor-1 levels. The effects of atorvastatin on FVII may contribute to a decreased thrombotic potential, resulting in fewer thromboembolic events, including a reduction in coronary heart disease.     

Variation of the factor VII gene and ischemic heart disease in Japanese subjects

BACKGROUND: Polymorphisms of the 5' region (5'FT), an intronic mutation (IVS7), and the 353Arg-Gln (R353Q) substitution of the factor VII gene have been reported to be associated with the plasma level of factor VII. Greater than normal levels of factor VII have also been reported to be associated with atherothrombotic events. However, the significance of factor VII gene polymorphism in the pathogenesis of ischemic heart diseases (IHD) has not been confirmed. OBJECTIVE: To determine whether these three factor VII gene polymorphisms are associated with levels of factor VII in Japanese subjects, and whether these three polymorphisms of the factor VII gene are associated with the risk of myocardial infarction. METHODS: We studied three polymorphisms of the factor VII gene, 5'FT, IVS7, and R353Q polymorphisms, for 493 Japanese subjects consisting of 285 subjects without clinical evidence of ischemic heart disease (non-IHD group) and 208 myocardial infarction patients (myocardial infarction group). We also assessed the plasma levels of factor VII antigen (FVIIag) in 103 subjects in the non-IHD group. RESULTS: Multiple regression analysis revealed that the level of FVIIag was significantly associated with age, body mass index, cholesterol level and a polymorphism of the factor VII gene (5'FT). Logistic analysis of 493 subjects revealed that cholesterol level [P = 0.0036, odds ratio 1.010, 95% confidence interval (CI) 1.003-1.017], smoking (P = 0.0001, odds ratio 5.522, (95% CI 2.684-11.364) and diabetes mellitus (P = 0.0001, odds ratio 6.450, (95% CI 2.953-14.088) were risk factors for myocardial infarction. However, the three polymorphisms of factor VII gene were not associated with risk of myocardial infarction. CONCLUSION: The polymorphisms of the factor VII gene influenced the levels of factor VII but were not significantly associated with risk of myocardial infarction in Japanese subjects.     

Oral contraceptives highlight the genotype-specific association between serum phospholipids and activated factor VII.

The present analysis was undertaken to study the effect of oral contraceptive (OC) use on activated factor VII (FVIIa) in subjects characterized by FVII genotypes, with the further aim of evaluating the role of lipids in this pharmacological interaction. In OC users (n=42) and nonusers (n=130) of comparable age, we examined the FVII phenotypic variables (FVII coagulant activity [FVIIc], FVII antigen, and FVIIa), FVII genotypes (the 353R/Q and 5'F7 polymorphisms analyzed in combination; alleles M1/M2 and A1/A2, respectively), and a number of lipid and lipoprotein parameters: serum concentrations of total cholesterol (chol), low density lipoprotein and high density lipoprotein-chol, triglycerides, phospholipids (PhLs), apolipoprotein A1, and lipoprotein(a). PhLs, triglycerides, apolipoprotein A1, chol, FVII antigen, FVIIc, and high density lipoprotein-chol levels were shown to be statistically higher in users than nonusers. FVII levels, particularly those of FVIIa and FVIIc, were much higher in homozygotes for the A1 and M1 alleles (A11 M11), especially in OC users. A strong association was found between PhL and FVIIa: in the multiple regression analysis, women taking OCs who had elevated PhL concentrations also had very high levels of FVIIa, but only if their genotype was A11 M11. These results indicate that the increased FVII levels in OC users depend on the FVII genotype and that high PhL concentrations predict very high levels of FVIIa and FVIIc.     

Serum phospholipids are the main environmental determinants of activated factor VII in the most common FVII genotype. European Union Concerted Action "Clotart".

BACKGROUND AND OBJECTIVE: Numerous studies have emphasized the role of triglyceride-rich lipoproteins and of Factor VII (FVII) polymorphisms in determining levels of FVII activity. DESIGN AND METHODS: This study was undertaken to evaluate the role of other lipid fractions and the interaction between lipids and FVII in subjects with recognised genotypes. Volunteer subjects (n=459) from 5 European countries were studied. Blood samples were drawn irrespective of the time of day or fasting status. Levels of FVII activity (FVIIc), activated FVII (FVIIa) and FVII antigen (FVIIAg) were evaluated with reference to a number of lipid parameters (HDL-, LDL- and total cholesterol, triglycerides, phospholipids, lipoprotein(a), and apoliproptein A1). The two most common FVII polymorphisms were analyzed in combination (353R/Q and 5'F7; alleles M1/M2 and A1/A2, respectively). RESULTS: Homozygotes for the A1 and M1 alleles (M11/A11) had significantly higher FVII levels. At multiple regression analysis the strongest predictor of FVIIa and FVIIc was the concentration of phospholipids. This interaction was confined to the A11M11 genotype subjects. INTERPRETATION AND CONCLUSIONS: These data indicate that lipids contribute mainly to FVIIa levels through their phospholipid content, and that the degree of this contribution is strictly dependent on FVII genotypes.     

Angiotensin-converting enzyme insertion/deletion genotype is associated with the activities of plasma coagulation factor VII and X independent of triglyceride metabolism

BACKGROUND: The D allele of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and coagulation activity play important roles in cardiovascular events, however, the precise association between these two risk factors remains unclear. METHODS: We identified the ACE I/D genotype and measured the plasma coagulation factor VII and X (FVII and FX) activities and serum lipids in 172 patients (110 men and 62 women, mean age 56.7+/-13.3 years) undergoing coronary angiography. RESULTS: The frequency of the D allele was significantly higher in those with a history of myocardial infarction (MI) than in those with normal coronary arteries, but there was no significant association between FVII and FX activities and the stage of coronary disease. Plasma coagulation factor VII and FX activities were significantly lower in the DD genotype (n=42) than in the II genotype (n=67, P<0.001 and P<0.001, respectively) or the ID genotype (n=63, P<0.01 and P<0.05, respectively). The association of the ACE D allele with lower activities of FVII and FX was also seen in patients with coronary artery disease (CAD). There was a significant association between serum triglyceride levels with FVII and FX, but not with the ACE I/D genotype. CONCLUSION: We concluded that the ACE I/D polymorphism may contribute more to the onset of MI than the activities of FVII and FX and that the ACE D allele might be associated with lower plasma activities of FVII and FX. The potential link between ACE I/D polymorphism and the plasma activities of FVII and FX is probably independent of triglyceride metabolism.     

Expression of factor VII in the liver of patients with liver disease: correlations with the disease severity and impairment in the hemostasis.

Factor VII (FVII) plasma levels in patients with liver disease may be below the normal range. However, no data are available on FVII expression in liver biopsies from patients with liver diseases other than cirrhosis. We have analyzed the expression of FVII by in situ hybridization in liver biopsies from 50 patients in comparison with the procoagulant activity of FVII, and with the plasma levels as activated FVII (FVIIa) and FVII antigen. The level of FVIIa was significantly lower in stage 4 liver fibrosis patients than in the remaining ones (P < 0.05). The percentage of hepatocytes expressing FVII was significantly lower in stage 4 liver fibrosis patients (4.1+/-1.3%) than in stage 3 (22.7+/-6.1%), stage 2 (31.5+/-6.1%), stage 1 (43.7+/-8.2%) and stage 0 patients (63.8+/-4.4%) (P < 0.001). These percentages correlated inversely in a statistically significant way with the histological activity index and the liver function tests. We have demonstrated that the FVIIa plasma levels in patients with chronic liver disease other than cirrhosis may be below the normal range in the absence of blood coagulation impairment. The percentage of hepatocytes expressing FVII decreases as the severity of liver damage increases.     

缺血性心脏病患者血浆凝血因子Ⅶ与血脂的关系

目的研究各种类型缺血性心脏病(IHD)患者血浆凝血因子Ⅶ(FⅦ)水平的改变并探讨其与血浆脂质的关系。方法活化凝血因子Ⅶ(FⅦa)测定采用重组可溶性组织因子一期法,凝血因子Ⅶ活性(FⅦc)测定采用凝血一期法,凝血因子Ⅶ总抗原(FⅦag)采用ELISA法。结果稳定型心绞痛(SA)组、不稳定型心绞痛(UA)组、陈旧性心肌梗死后心绞痛(OMI)组、急性心肌梗死(AMI)组的FⅦa均显著高于正常组,各组间差异均有统计学意义,UA、OMI、AMI组的FⅦag与正常组和SA组的FⅦag间差异有统计学意义。FⅦa与血浆甘油三酯(TG)水平、FⅦa与FⅦc、FⅦc与FⅦag均呈正相关。结论各种不同类型IHD均可出现程度不等的外源性凝血途径的激活。FⅦa是IHD发病的危险因素,可能较FⅦc或FⅦag更敏感。OMI组的FⅦa水平增高,可能是再梗死发作的危险因素之一。TG可能通过引起FⅦa增高间接影响IHD的病理过程。     

冠心病患者血浆组织因子活性及凝血因子VII水平改变

目的研究汉族冠心病患者血浆中组织因子活性（aTF）、活化凝血因子VII（FVIIa）和凝血因子VII抗原（FVII:Ag）水平并探讨其与冠脉病变支数之间的关系。方法aTF采用发色底物法,FVIIa和FVII:Ag采用ELISA法。结果与对照组相比,冠心病患者血浆中aTF（P<0.05）、FVIIa（P<0.01）及FVII:Ag（P<0.05）水平均显著升高;急性冠状动脉综合征（ACS）患者中aTF高于稳定型心绞痛（SAP）组（P<0.05）和对照组（P<0.01）,后两者之间无显著差异;ACS和SAP患者之间血浆中FVIIa水平无显著差异,但均高于对照组;ACS组中FVII:Ag水平明显高于对照组。在不同冠脉病变支数的患者之间,aTF、FVIIa及FVII:Ag水平没有差异。结论SAP和ACS患者均可出现外源性凝血途径的激活,血浆中aTF增强可能预示了急性冠脉事件的发生;FVIIa可能可以作为冠心病的早期分子标志物;冠脉病变支数可能不能反映凝血激活的程度。     

Plasma factor VII, triglyceride concentration and fibrin degradation products in primary hyperlipidemia: a clinical and laboratory study

There is evidence that the increase in coagulation factor VII (FVII) represents a predictive risk factor of arterial thrombosis in coronary heart disease. Its relative contribution to this multifactorial process and its relationship to other risk factors, namely cholesterol and triglycerides, is yet a matter of investigation. In this study we aimed to clarify whether FVII synthesis or activation correlated with plasma lipid concentrations. For this, we assayed the plasma levels of FVII antigen (FVII:ag) and FVII coagulant activity (FVIIc) in types IIa, IIb and IV hyperlipidemic individuals, together with the levels of cholesterol, triglycerides, high-density lipoproteins and apolipoprotein B. FVII activation state (FVIIa) was then assessed by FVIIc/FVII:ag. In order to assess the possible correlation of FVII levels with the generation of thrombin and formation of fibrin, we also assayed the plasma concentration of fibrin degradation products (D-dimers) in these patients. Considering all the patients studied, there was a fair correlation between FVIIc and FVII:ag (r = 0.704; p less than 0.01). The mean levels of FVIIc and FVII:ag were significantly higher in type IV hyperlipidemia than in controls (t = 4.260; p less than 0.001 and t = 3.015; p less than 0.01, respectively) and other types of hyperlipidemia. We also found that FVIIc and FVII:ag significantly correlated to triglyceride concentration. We could not detect an evident activation of FVII in these patients since FVIIc/FVII:ag was not elevated in comparison with controls, nor did it correlate with any of the lipid determinations in any of the types of hyperlipidemia studied.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of factor VIIa generation and prothrombin activation by treatment with enoxaparin in patients with unstable angina

Factor VIIa (FVIIa) and thrombin generation occur in patients suffering an acute coronary event. We studied the effect of treatment with enoxaparin on FVIIa and prothrombin activation in patients with unstable angina. Anti-Xa activity, FVIIa, FVII coagulant activity (FVII:C) and FVII antigen (FVII:Ag), free tissue factor pathway inhibitor (TFPI), and prothrombin fragments 1 + 2 (F1+2) were measured in patients' plasma, over a 24-h treatment period with enoxaparin. All 14 patients recruited in the study (mean age 68 years) were treated with a subcutaneous injection of enoxaparin, 1 mg/kg twice daily. Blood was drawn just before, and at different time intervals after, the first injection. Before enoxaparin administration, the levels of FVIIa (4.02 +/- 0.8 ng/ml) and F1+2 (2.68 +/- 0.2 nmol/l) were significantly increased as compared with control subjects (2.3 +/- 0.3 ng/ml and 0.9 +/- 0.1 nmol/l respectively, P < 0.05). Free TFPI, FVII:C and FVII:Ag were within normal ranges. One hour after the first injection of enoxaparin, FVIIa and F1+2 levels decreased by 65% and 50%, respectively, and no significant fluctuations were noted throughout the observation period. The concentrations of FVII:C and FVII:Ag were not modified as compared with baseline values. After each injection, the peak concentrations of free TFPI and anti-Xa activity were observed at 2 and 4 h respectively. The kinetics of FVIIa and F1+2 inhibition did not follow those of anti-Xa activity and TFPI release.     

Interaction between the C-260T polymorphism of the CD14 gene and the plasma IL-6 concentration on the risk of myocardial infarction: the HIFMECH study

Experimental and clinical observations suggest that innate immunity plays a major role in the pathogenesis and progression of atherosclerosis. A common C-260T polymorphism in the promoter of the CD14 gene, the trans-membrane receptor of lipopolysaccharides, has been inconsistently associated with coronary heart disease. Our objective was to evaluate the contribution of the CD14 polymorphism to the inflammatory response and to the risk of myocardial infarction (MI). We used an European case-control study, the HIFMECH study, comparing 533 men with MI and 575 sex- and age-matched controls. Associations between genotype and disease outcome, according to interleukin-6 (IL-6) and C-reactive protein (CRP) levels, were assessed using conditional logistic regression. The CD14/C-260T polymorphism was associated with plasma IL-6 levels, T/T subjects having higher plasma levels than C/C in cases but not in controls (mean+/-S.D.: 2.04+/-1.37 versus 1.70+/-1.15, p=0.01; 1.20+/-0.75 versus 1.35+/-0.88, p=0.31, respectively). Overall, the CD14/C-260T polymorphism was not associated with the risk of MI. However, in individuals with IL-6 plasma levels in the highest tertile, T allele carriers had a higher risk of MI than C/C (OR: 1.85; CI 95 1.05-3.25). IL-6 increased the risk of MI in carriers of the T allele (OR for first versus third IL-6 tertile: 4.02; CI 95 2.24-7.21), but not in C/C (OR: 0.75; CI 95 0.32-1.74, p=0.004 for interaction). The data indicate a role for CD14/C-260T in MI. The risk mediated by the polymorphism is highly dependent on IL-6 plasma levels.     

Standardization of factor VII/activated factor VII measurement in plasma of patients treated with recombinant factor activated VII.

To improve the standardization of the factor VII clotting activity (FVII:C) assay in patients treated with recombinant activated factor VII (rFVIIa), we conducted a multicentre study on plasma samples from four patients with haemophilia A, before and at various times after injection of a single dose of rFVIIa. FVII:C and prothrombin time were measured with the methods and reagents routinely used in each laboratory. Strong inter-laboratory variability of FVII:C values was found. The main source of variability was the type of thromboplastin. FVII:C values measured using rabbit thromboplastin were very close to activated factor VII clotting activity values (FVIIa:C) measured with a commercial assay (Staclot VIIa-TF). FVII:C values obtained with human placental thromboplastin were about three times lower than those obtained with rabbit and recombinant thromboplastins, and with the FVIIa:C assay. There was a good relationship between FVIIa:C and activated factor VII antigen values measured using a commercial immunoassay (Imubind FVIIa ELISA). In conclusion, rFVIIa at pharmacological concentrations can be easily monitored on the basis of FVII:C, using rabbit and probably also recombinant thromboplastin; equivalent results are obtained with a specific activated factor VII bioassay.     

Activation of coagulation factor VII by tissue-type plasminogen activator.

To investigate the effect of tissue-type plasminogen activator (t-PA) on blood coagulation, we examined the effects of the addition of t-PA to normal pool plasma (NPP) on clotting times such as diluted prothrombin time (PT) and kaolin clotting time (KCT). The diluted PT but not the KCT was significantly shortened by the addition of t-PA to NPP compared with the normal controls, suggesting a t-PA-induced activation of blood coagulation through factor VII (FVII) activation. The activated factor VII (FVIIa) concentration in the NPP was significantly increased by the addition of t-PA. Although the FVIIa formation was not observed following the incubation of purified FVII with only t-PA or plasminogen, an increase in the FVIIa level was observed after the incubation of purified FVII with t-PA together with plasminogen, or only plasmin. This plasmin-mediated FVIIa formation was also confirmed by Western blotting. These findings suggest that t-PA enhances the activation of the coagulation system through FVII activation.