Factor VII-activating protease in patients with acute deep venous thrombosis

Factor VII-activating protease (FSAP) is involved in haemostasis and inflammation. FSAP cleaves single chain urokinase-type plasminogen activator (scu-PA). The 1601GA genotype of the 1601G/A polymorphism in the FSAP gene leads to the expression of a FSAP variant with reduced ability to activate scu-PA, without affecting the ability to activate coagulation Factor VII (FVII). Previous studies have investigated the association of the 1601GA genotype with incidence and progression of carotid stenosis and deep venous thrombosis (DVT). The present study is the first to evaluate the potential association between the FSAP phenotype and DVT.We studied the association between the 1601G/A polymorphism, FSAP activity, FSAP antigen, Factor VIIa (FVIIa), prothrombin fragment 1 + 2 (F1 + 2), and C-reactive protein (CRP) in plasmas of 170 patients suspected for DVT. FSAP genotypes were equally distributed in patients with (n = 64) and without DVT (n = 106), (P = 0.94). The 1601GA genotype was associated with significant reduction of FSAP activity (P < 0.001) and FSAP antigen levels (P = 0.04). Patients with DVT showed significantly higher FSAP activity (P = 0.008), FSAP antigen (P = 0.003), and F1 + 2 levels (P < 0.001) than patients without DVT. The association between the FSAP measures and DVT disappeared when adjusted for CRP levels. F1 + 2 correlated positively to FSAP antigen (P = 0.01), while FVIIa-levels were comparable in patients with and without DVT.We conclude that even though FSAP measures are significantly increased in patients with acute DVT, alterations in the scu-PA activating properties of FSAP are presumably not markedly involved in the development of acute DVT, and that the association between FSAP and DVT disappears after adjustment for CRP.     

The G79A polymorphism of protein Z gene is an independent risk factor for cerebral venous thrombosis

Background and purpose   Protein Z (PZ), a vitamin Kdependent protein, plays a role in inhibiting coagulation. Its plasma level or PZ gene polymorphisms have been discussed as risk factors for stroke with conflicting results reported between various studies. Only one of these polymorphisms was studied in a cohort of patients suffering from cerebral venous thrombosis (CVT). Methods   We performed a retrospective genetic study comparing 100 healthy controls to 54 patients referred to our hemostasis unit after CVT occurrence. We compared the distribution of three PZ gene polymorphisms that may influence PZ plasma levels: A-13G in the promoter and G79A in intron F were tested using previously described techniques, and we developed a technique to evaluate the G-103A in intron A. Results   The G79A polymorphism was significantly more frequent in patients than in controls (p = 0.012): the presence of at least one A allele led to an odds ratio of 2.57 with a 95 % confidence interval of 1.23–5.34. The A-13G polymorphism also showed a nonsignificant trend towards a higher prevalence in patients. Conclusion   The G79A polymorphism of the PZ gene was shown to be a new independent risk factor for cerebral venous thrombosis. Nevertheless, these results have to be confirmed by a prospective study including plasma PZ evaluation.     

A negative personal and family history for venous thrombotic events is not sufficient to exclude thrombophilia in patients with cerebral venous thrombosis

A hereditary thrombophilia is found in 20-30% of patients with cerebral venous thrombosis (CVT). These patients might have an increased rate of a positive personal or family history of venous thrombotic events. We investigated the diagnostic value of a structured personal and family history for venous thrombotic events in 56 consecutive cases of CVT. Fourteen of 56 patients (25%) had a hereditary thrombophilia, mostly factor V Leiden. Patients with both CVT and hereditary thrombophilia had more frequently a positive family and personal history than patients affected by CVT only but the difference was not strong enough to differ from the 42 CVT patients without thrombophilia (43% vs. 31%; P = 0.52 and 14% vs. 10 %; P = 0.63). We conclude that a negative personal and family history of venous thrombotic events is not sufficient to exclude thrombophilia and patients with CVT should be tested for inherited thrombophilia regardless of the patient's past personal and family history for venous thrombotic events.     

Hormonal contraceptives as a risk factor for cerebral venous and sinus thrombosis

This review will focus on recent developments in our understanding of cerebral venous and sinus thrombosis (CVST), as a side effect of combined oral contraceptives (COCs) use. Case-control studies have shown an increased risk of CVST in women who use COCs, especially third-generation contraceptives that contain gestodene or desogestrel. Several studies have indicated that the combination of COCs and thrombophilia greatly increased the risk of CVST, particularly in women with hyperhomocysteinaemia, factor V Leiden and the prothrombin-gene mutation. Women with thrombophilia who developed CVST while taking oral contraceptives should be definitively advised to stop using COCs. These patients should be considered for preventive therapy with low doses of heparin in prothrombotic situations such as bed rest or pregnancy, and the duration of anticoagulation should be considered on a case-by-case basis. Patients may be considered candidates for chronic treatment with antiplatelet agents. The best and most cost-effective screening method for thrombophilia in women who are planning to conceive is selective screening based on the presence of previous personal or family history of either prior extracerebral or cerebral venous thromboembolism events.     

Abdominal obesity and the risk of recurrent deep vein thrombosis

BACKGROUND: Abdominal obesity has been found to be associated with an increased risk of deep vein thrombosis (DVT). Whether patients with abdominal obesity have an increased risk of recurrence is currently unknown. METHODS: Patients with objective diagnosis of DVT and a life expectancy of greater than 6 months underwent measurement of the circumference of the waist. A waist circumference of greater than 102 cm for men and greater than 88 cm for women defined abdominal obesity. Information on age, gender, and on the presence of risk factors for DVT was collected. At follow-up, all patients underwent serial compression ultrasound of the lower limbs and were clinically evaluated every 6 months. RESULTS: One hundred patients were enrolled, 58 with abdominal obesity and 42 without. Mean age was 64.5 and 57.3 years, respectively (p<0.05). Percentage of male patients was 32.8% and 81.0% (p<0.01). Unprovoked DVT and transient risk factors rates were similar in both groups. Overall, recurrent DVT was documented in 29 patients, 16 in patients with abdominal obesity (27.6%) and 13 in patients without (31.0%). At the multivariate regression analysis HR for VTE recurrence in abdominal obese patients was 1.26 (95% confidence interval=0.47-3.4). CONCLUSIONS: Abdominal obesity does not seem to modify the risk of recurrent DVT.     

Recurrent venous thrombosis including cerebral venous sinus thrombosis in a patient taking sildenafil for erectile dysfunction

Acquired or hereditary prothrombotic risk factors may lead to cerebral venous sinus thrombosis (CVST), particularly when other predisposing factors coexist. A 57-year-old man experienced right leg deep venous thrombosis, severe thrombosis of the haemorrhoid plexus and CVST over a 12-month period during which he was taking sildenafil regularly twice a week. Sildenafil is a phosphodiesterase 5 (PDE5)-inhibitor used for erectile dysfunction (ED). A slight reduction in antithrombin III and free protein S levels was demonstrated. After suspension of sildenafil and six months on oral anticoagulants, clinical improvement was obtained. Recurrent venous thrombosis, including CVST, may complicate prolonged treatment with PDE5-inhibitors in subjects at risk. Periodic monitoring of clotting factors is recommended in these subjects.     

Coagulation factor VII R353Q polymorphism and the risk of puerperal cerebral venous thrombosis

Puerperal cerebral venous thrombosis (CVT) is a relatively common form of stroke in young women in India. The blood coagulation factor VII (FVII) R353Q polymorphism increases the risk for venous thrombosis. Our aim was to investigate the association of FVII R353Q polymorphism with the risk of puerperal CVT. A total of 100 women with puerperal CVT and 102 age-matched women without postpartum complications were investigated. FVII R353Q genotypes were identified using restriction fragment length polymorphism analysis. Our results showed that the homozygous FVII 353QQ genotype was present in 9% and 8% of patients and controls, respectively; and 42% of patients and 31.4% of controls had the heterozygous 353RQ genotype (odds ratio = 1.55, 95% confidence interval = 0.89-2.70; p = 0.243). Our findings suggest that the FVII R353Q polymorphism is not associated with increased risk for CVT occurring during the puerperal period in Indian women.     

Past provoking venous thrombosis risk situations on the risk of a recurrent thrombotic event: a cohort study

Objective

Strategies that can classify the risk for recurrent venous thrombosis are needed. Some patients may have experienced many risk situations during their life time without developing venous thrombosis (VT), while others may have experienced few of such risk factors and then develop VT idiopathically or after a single provoked risk factor. We hypothesized that those who had 'survived' many risk situations without developing VT would, after a first VT, have a low recurrence risk.

Methods

Brazilian tertiary hospital cohort was followed for an average of 30 months after anticoagulation withdrawal for a first VT. Patients with indication for indefinite anticoagulation were not included. The primary end point was objective recurrent VT.

Results

Recurrent VT was recorded in 7% of 378 eligible patients. Patients with a provoked first event and positive past risk situations for VT had an incidence rate of recurrence of 1.16 (95% confidence interval [CI], 0.47-2.39) per 100 patient-years. The incidence rate ratio (IRR) of this subgroup compared to patients with a provoked event without other past risk situations for VT was 1.1 (95% CI, 0.3-4.4). This IRR was 3.3 (95% CI, 1.3-8.7) in patients with an unprovoked event and positive past risk situations and 5.1 (95% CI, 1.6-16.1) in patients with an unprovoked event and no past risk situations.

Conclusions

Asking a patient about past exposure of venous thrombosis risk factors long before the occurrence of a first venous thrombosis occurred, does not provide information to classify patients at lower risk for recurrence of venous thrombosis.     

Effect of prothrombin 19911 A>G polymorphism on the risk of cerebral sinus‐venous thrombosis

Background and Purpose: The A>G polymorphism at position 19911 of the prothrombin gene is associated with a mildly increased risk of venous thromboembolism, alone or in association with such common thrombophilia mutations as factor V Leiden and prothrombin 20210 GA. Its role in cerebral sinus‐venous thrombosis (CSVT) is not known. Methods: The presence of prothrombin 19911 A>G was investigated in a case–control study of 107 patients with cerebral thrombosis and factor V Leiden (n = 25), prothrombin 20210 GA (n = 47), without known thrombophilia (n = 35) and 842 healthy individuals with the corresponding coagulation profile. Results: Prothrombin 19911 A>G did not increase the risk of CSVT in carriers of factor V Leiden (adjusted odds ratio 1.6, 95%CI 0.6–4.7), prothrombin 20210 GA (odds ratio 1.1, 95%CI 0.6–2.2), nor in patients without known thrombophilia (odds ratio 1.3, 95%CI 0.5–3.1). Conclusions: Prothrombin 19911 A>G polymorphism does not appear to be a risk factor for CSVT, alone or in association with factor V Leiden or prothrombin 20210GA.     

脑卒中患者早期下肢深静脉血栓形成的研究

目的探讨脑卒中患者早期下肢深静脉血栓形成(DVT)的危险因素。方法对144例发病48 hrs内的脑卒中住院患者于入院后24 h内行D-二聚体(DD)、纤维蛋白原(FIB)、C-反应蛋白(CRP)水平测定,并于发病后3d和14d进行双下肢深静脉超声检测,确定下肢早期DVT的发生率;通过比较脑卒中后早发DVT组与非DVT组患者相关临床信息,筛选脑卒中后下肢DVT发生的危险因素。结果脑卒中后患者早期下肢DVT发生率为6.3%。Logistic回归分析显示中重度脑卒中、CPR及FIB升高是脑卒中患者早期DVT的独立危险因素。结论脑卒中患者是发生DVT的高危人群,对CRP、FIB升高的严重脑卒中患者进行DVT监测和预防是十分必要的。     

重型颅脑损伤并发下肢深静脉血栓形成的诊治

目的 探讨重型颅脑损伤术后并发下肢深静脉血栓形成的诊治. 方法 回顾性分析解放军第一六三医院自2003年12月至2008年12月收治的37例重型颅脑损伤并发下肢深静脉血栓形成的患者的临床资料. 结果 37例患者均行抗凝治疗,其中溶栓治疗18例,下腔静脉滤器置入14例.1例患者死亡,其余36例患者下肢肿胀疼痛症状均缓解,其中治愈11例,显效21例,有效4例. 结论 重型颅脑损伤患者容易发生下肢深静脉血栓形成,彩色多普勒超声、静脉造影及数字减影血管造影能够有效地诊断深静脉血栓形成.深静脉血栓形成主要治疗方法 为抗凝治疗,下腔静脉滤器置入对防止肺栓塞发生有重要作用,早期预防至关重要.     

Circulating tissue factor positive microparticles in patients with acute recurrent deep venous thrombosis

Introduction

Circulating tissue factor positive microparticles (MPTF) were reported in a wide range of diseases with thrombotic tendency. Though D-dimer assay had a high negative predictive value for deep venous thrombosis (DVT) recurrence, there are currently no reliable positive predictors for recurrent DVT. We therefore quantified MPTF in patients with acute recurrent DVT to determine whether MPTF levels could be used to predict recurrent DVT.

Materials and Methods

Microparticles (MPs) were isolated from plasma of initial DVT patients (n = 25), recurrent DVT patients (n = 25) and sex- and age-matched healthy individuals (n = 25), stained with annexin V, cell-specific monoclonal antibodies (MoAbs) and a MoAb directed against tissue factor (TF), and analyzed by flow cytometry. We also determined the plasma procoagulant activity with a Human TF Chromogenic Activity Assay Kit.

Results

We found total MPTF to be elevated in recurrent DVT patients versus normal individuals (P = 0.001). The number of monocyte-derived MPTF in both initial and recurrent DVT was higher than in normal individuals (P < 0.01, respectively). The platelet and endothelial cell derived MPTF in recurrent DVT were significantly increased relative to other MPTF (P < 0.05), although there was no difference between initial DVT patients and normal individuals. We demonstrated elevated procoagulant activity of platelet-free plasma in DVT patients relative to normal individuals, and a positive correlation with MPTF.

Conclusions

The elevated MPTF could be a potentially predictor for DVT recurrence. Further studies are needed to validate its sensitivity and specificity.     

The risk of occurrence of venous thrombosis: focus on protein Z

Protein Z (PZ) is a vitamin K-dependent factor identified in human plasma in 1984 characterized by an homology with other vitamin K-dependent factors. PZ acts as the cofactor of the PZ dependent inhibitor (ZPI), in the inhibition of activated factor X bound on phospholipid surface. In humans, PZ is characterized by an unusual wide distribution in plasma partly explained by a genetic control. Several PZ gene polymorphisms influencing plasma concentration have been described. In mice, the disruption of PZ gene is asymptomatic, but in association with homozygous FV Leiden produced a severe prothrombotic phenotype. This review analyzes the results obtained from different studies so far published in order to understand whether PZ deficiency could be considered as a risk factor for venous thrombosis.The roles of PZ plasma level and PZ gene polymorphisms remain debated with conflicting results. Many of these studies reported low PZ levels in association with an increased risk of venous thrombosis. On the other side, some studies did not observe an association between low levels of PZ and thrombotic events. A relationship between PZ deficiency and pregnancy complications was also described but not confirmed by all studies.These discrepancies can be explained by the heterogeneity of populations chosen as control, by the PZ interindividual variability and by the small size of the cohorts in mainly retrospective studies. Large prospective studies remain to be done to investigate its possible role in thrombosis.     

Individual propensity for thrombosis: comparison of venous and arterial circulations

Introduction

The pathogenesis of venous thrombosis has been attributed to complex interaction between environmental and inherited variables. A basal predisposition for venous thrombophilia independent of environmental variables has not been previously defined experimentally. Both to address the existence of an individual propensity to venous thrombosis and to establish an animal model in which variables governing this propensity could be tested, we provoked venous thrombi in a cohort of pigs of uniform size and age. We furthermore sought to determine whether the thrombotic propensity in the venous circulation is associated with similar propensity for arterial thrombosis.

Materials and methods

Bilateral iliac venous stents were deployed and 2 h later, thrombi were harvested and weighed. The thrombotic response was compared to carotid arterial thrombi generated by crush injury within the same pig. Venous and arterial thrombus platelet deposition were measured by scintillation detection of autologous ¹¹¹In-platelet content.

Results

In a cohort of 27 pigs, venous thrombus weights and platelet content varied over greater trrhan 10-fold range from least to greatest responders. There was strong intra-individual correlation of thrombus platelet deposition (r = 0.86; p = 0.008) and thrombus weights (r = 0.68; p = 0.015) between stented iliac vein pairs. Venous thrombosis correlated with whole blood platelet counts but not carotid platelet-rich thrombus formation.

Conclusions

The wide variation in venous thrombotic response to a standardized injury appears to represent an intrinsic propensity of the individual. The poor correlation with arterial thrombosis implies unique mechanisms responsible for this propensity in arteries and veins.     

Haplotypes of TAFI gene and the risk of cerebral venous thrombosis - a case-control study

Introduction

Cerebral venous thrombosis (CVT) is an uncommon disease with some differences compared to other-site thrombosis, including a higher frequency in young people, female sex and oral contraceptive users. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a regulator of fibrinolysis, whose levels are genetically controlled and its increase is associated to thrombosis. Our objective was to investigate in a case-control study the association between CVT and TAFI single nucleotide polymorphisms (SNPs) and its haplotypes in comparison to other-site venous thrombosis and controls.

Materials and Methods

Seventy two patients with CVT were compared to 143 individuals with no history of thromboembolic events (control group) and to 128 patients with deep vein thrombosis in the limbs and/or pulmonary embolism (venous thromboembolism-VTE group). SNPs were genotyped by restriction fragment length polymorphism or allele-specific PCR for F2 20210G > A, F5 1691G > A, TAFI (-1053C > T, -438G > A, 505G > A, 1040C > T and + 1542C > G).

Results

The GTC haplotype for TAFI 505G > A/1040C > T/+ 1542C > G SNPs was associated with an increased risk of CVT compared to controls [odds ratio (OR) 2.67, 95% confidence interval (CI): 1.13 - 6.34) and VTE group (OR 2.51, 95%CI: 1.07 - 8.06). The CVT risk became even more pronounced when evaluating unprovoked or hormone-related thrombosis cases: CVT compared to controls (OR 3.24, 95%CI: 1.19 - 8.82) and VTE group (OR 4.32, 95%CI: 1.27 - 14.63).

Conclusions

Our data indicate that the GTC haplotype for TAFI 505G > A/1040C > T/+ 1542C > G SNPs increased the risk of CVT in comparison to controls and VTE cases. Further studies are required to confirm our findings.     

Antipsychotic drugs as a risk factor for venous thromboembolism

Objective. We assessed whether antipsychotic drugs represent a risk factor for venous thromboembolism by comparing the prevalence of antipsychotic drugs use in a population of patients with venous thromboembolism versus a group of individuals treated for hypertension. Methods. We identified 266 patients (141 women) diagnosed as having venous thromboembolism at the average age of 43.1±11 years who had been hospitalized in the University Hospital in Hradec Králové from 1 January 1996 to 31 December 2004. Two hundred and seventy-four patients (140 women) with arterial hypertension, with an average age of 48.3±8.8 years, represented the control population. Results. Use of antipsychotic drugs was moderately more frequent in the group of patients with venous thromboembolism as compared with the control group subjects (4.89 vs. 1.82%; odds ratio 2.76; 95% confidence interval=1.01–7.55). Discussion. We discuss the possible mechanisms of venous thromboembolism induced by antipsychotic agents – hypoactivity, blood status, obesity, abnormal coagulation, autoimmune mechanisms, and hyperhomocysteinemia. Conclusion. Our results indicate the possibility of an increased risk for venous thromboembolism in patients using antipsychotic drugs. It is necessary to seriously consider this possible adverse effect owing to its potentially fatal consequences.     

The factor V gene A4070G mutation and the risk of venous thrombosis

The A4070G polymorphism in exon 13 of the factor V (FV) gene, which replaces His by Arg at position 1299 of the B domain, was recently shown to influence circulating FV levels and to contribute to the activated protein C (APC) resistance phenotype. We examined the impact of this polymorphism in a population of unselected patients with venous thromboembolic disease (VTE). The prevalence of the G4070 (R2) allele was determined in 205 patients and 394 healthy subjects of similar age and sex distribution. Thirty-seven patients (18%) were heterozygous for the R2 allele and 1 (0.5%) was homozygous. Forty-four controls (11.2%) were heterozygous for the R2 allele and 1 (0.2%) was homozygous. Thus, the allelic frequency was significantly higher in the patients with VTE than in the healthy controls, with respective values of 9.5% and 5.8%. The odds ratio was 1.8 (95% CI: 1.1-2.8, p = 0.02), pointing to an increased risk of VTE in carriers of the R2 allele. After excluding subjects with putative or confirmed gene defects (mainly the FV R506Q mutation), the R2 allele was still a risk factor for VTE in the remaining patients, with an odds ratio of 2.0 (95% CI: 1.2-3.5, p = 0.01), demonstrating that this polymorphism is itself a risk factor. This study also confirms that the R2 allele influences APC resistance (APCR) in the absence of the FV R506Q mutation.