Prevalence of factor V Leiden,FII G20210A,FXIII Val34Leu and MTHFR C677T polymorphisms in cancer patients with and without venous thrombosis

Venous thromboembolism (VTE) is a common complication in patients with malignant disease. In addition to well-established acquired risk factors for VTE, several genetic risk factors, mainly related to the haemostatic system, are known to influence thrombotic risk. However, the contribution of gene abnormalities to thrombotic tendency in cancer patients remains poorly explored. We performed a prospective study to evaluate the prevalence and clinical significance of four gene variations (factor V Leiden [FVL], factor II G20210A, factor XIII Val34Leu and MTHFR C677T) in cancer patients, with and without VTE. Enrolled were 211 unrelated and unselected patients (M/F ratio 0.5, mean age 57 years, range 12-91 years) with a diagnosis of cancer, admitted to two University Oncology Clinics in the city of S?o Paulo, Southeastern Brazil. After admission, all patients were evaluated for the presence of symptoms and signs of VTE. Sixty-four patients (30.3%) had an episode of deep venous thrombosis (DVT) or pulmonary embolism (PE), which has been objectively verified; 147 patients (69.7%) had no evidence of VTE. FVL was found with a frequency of 1.5% and 2.7% in the VTE and non-VTE group, respectively (odds ratio [OR] for VTE 0.6, 95% CI: 0.06-5.3). FII G20210A was found in 1.5% and 1.3% of thrombotic and nonthrombotic patients, respectively, yielding an OR of 1.2 (95% CI: 0.1-13.1). FXIII Val34Leu was detected in 29.6% of the thrombotic patients and in 28.5% of the non-thrombotic patients (OR 1.1, 95% CI: 0.5-2). MTHFR 677T was present in 53.1% and 60.5% of patients with and without thrombosis, respectively (OR 0.8, 95% CI: 0.4-1.4). The present data do not point to an association between the four polymorphisms here investigated and the risk of VTE in cancer patients.     

Venous thromboembolism and bleeding after total knee and hip arthroplasty. Findings from the Spanish National Discharge Database

The impact of venous thromboembolism (VTE) and bleeding in patients undergoing major joint surgery has not been thoroughly studied. The Spanish National Discharge Database during the years 2005-2006 was used to assess the frequency and clinical impact of VTE and bleeding after elective total knee (TKA) or hip (THA) arthroplasty. Of 58,037 patients undergoing TKA, 0.18% (95% confidence interval [CI]: 0.15-0.22) were diagnosed with pulmonary embolism (PE), 0.57% (95% CI: 0.51-0.63) with deep-vein thrombosis (DVT), 1.20% (95% CI: 1.12-1.30) had bleeding complications, and 0.09% (95% CI: 0.07-0.12) died. Of 54 patients who died, 20.4% (95% CI: 10.7-35.4) had been diagnosed with PE, 3.70% (95% CI: 0.63-11.7) with DVT, and 13.0% (95% CI: 5.67-25.6) had bled. Of 31,769 patients undergoing elective THA, 0.23% (95% CI: 0.18-0.29) were diagnosed with PE, 0.44% (95% CI: 0.37-0.52) with DVT, 1.21% (95% CI: 1.10-1.34) bled, and 0.16% (95% CI: 0.12-0.21) died. Of 52 patients who died, 13.5% (95% CI: 6.08-24.8) had been diagnosed with PE, and 9.61% (95% CI: 3.52-21.3) had bled. On multivariable analysis, PE (odds ratio [OR]: 157; 95% CI: 75-328), DVT (OR: 6.3; 95% CI: 1.5-27) and bleeding (OR: 8.5; 95% CI: 3.6-20) were independent predictors for death after TKA. After THA, only PE (OR: 65; 95% CI: 26-160) and bleeding (OR: 6.4; 95% CI: 2.3-17) predicted the risk for death. Bleeding, DVT, and PE, arising after TKA were all independent predictors for death. Their increase in risk was, however, substantially higher for PE. After THA, only PE and bleeding independently predicted death.     

Risk of cerebral venous thrombosis and novel gene polymorphisms of the coagulation and fibrinolytic systems

BACKGROUND AND PURPOSE: Genetic thrombophilic conditions such as those associated with Factor V Leiden (FVL) and the prothrombin mutant (PT G20210A) have been identified as risk factors for cerebral venous thrombosis (CVT). Recently, a single nucleotide polymorphism (SNP) of the thrombin activatable fibrinolysis inhibitor (TAFI G-438A) has been shown to be associated with lower TAFI levels and to decrease the risk for peripheral venous thrombosis. Furthermore, a protective role in juvenile stroke was shown for a SNP of the vitamin K dependent protein Z (PZ Intron F G79A) which is linked with low PZ levels. PATIENTS AND METHODS: In 77 consecutive patients with CVT and in 203 randomly selected population controls from the same region of Southern Germany, we investigated the following functional SNPs using PCR and restriction fragment analysis techniques: TAFI G-438A, PZ Intron F G79A, FVL and PT G20210A. RESULTS: The prevalence of FVL tended to be higher (OR 2.08, 95 % CI 0.91-4.75, p = 0.06) and that of PT G20210A (OR 4.57, 95 % CI 1.45-14.44, p = 0.007) was significantly higher in patients with CVT than in controls. The A-allele frequency of the TAFI G-438A polymorphism did not significantly differ between patients (21.3 %) and controls (26.9%; OR 0.71, 95 % CI 0.45-1.12; p = 0.17). For the PZ G79A SNP, the frequency of the A-allele was 19.5% in CVT and 24.6% in controls (OR 0.77, 95 % CI 0.49-1.21; p = 0.31). CONCLUSIONS: In this large series of CVT patients, a positive association with established thrombophilic risk factors FVL and especially the PT G20210A mutation was confirmed. In contrast, our study found no significant association of CVT with SNPs of the TAFI and the PZ genes. Other than testing for FVL and the PT G20210A mutation, exploration of these potential thrombophilic variants seems to be of limited value in the investigation of CVT.     

Genetic variation in thrombin-activatable fibrinolysis inhibitor (TAFI) is associated with the risk of splanchnic vein thrombosis

Splanchnic vein thrombosis (SVT) has been associated with a hypercoagulable state. Thrombin-activatable fibrinolysis inhibitor (TAFI) may contribute to a hypercoagulable state, and therefore we were interested in the role of TAFI in SVT. Since the disease is frequently associated with liver insufficiency, which affects plasma levels of TAFI, we studied the role of variation in the TAFI gene in SVT. In a multicenter case-control study on 118 patients with SVT (39 Budd-Chiari syndrome and 85 portal vein thrombosis) and 118 population-based controls, the relationship of SVT with single nucleotide polymorphisms (SNPs) and haplotypes in the TAFI gene (-438G/A, Ala147Thr, Thr325Ile and 1583A/T) was determined. The risk for SVT was decreased (OR 0.2, 95% CI 0.1-0.7) in 147Thr/Thr homozygotes and slightly, but not significantly, increased in carriers of the 325Ile allele (OR 1.6, 95%CI 0.9-2.7). Haplotype analysis confirmed that the Ala147Thr SNP has the strongest association with risk of SVT. In conclusion, genetic variation in the TAFI gene is associated with risk of SVT, suggesting a role for TAFI in the pathogenetic mechanism of SVT.     

Risk factors associated with symptomatic pulmonary embolism in a large cohort of deep vein thrombosis patients

In patients with deep vein thrombosis (DVT), the factors which predispose to concomitant symptomatic pulmonary embolism (PE) have remained uncertain. From a prospective cohort of 5,451 consecutive patients with ultrasound-confirmed DVT, we analyzed 4,211 patients with a known status for presence (n=639) or absence (n=3572) of symptomatic PE. Age and gender were similar in DVT plus PE (63.7+/-15.6 years; 49% men) and DVT patients (63.4+/-17.3 years; 46% men). Body mass index (BMI) was higher in patients with DVT plus PE (median 29.0, range 15.4-67.0 kg/m2) than in patients with DVT (median 26.8, range 9.7-64.4 kg/m2; p<0.001). Chronic lung disease (17% vs. 12%; p<0.001), a personal history of PE (11% vs. 6%; p<0.001), and a family history of DVT or PE (8% vs. 4%; p<0.001) were more frequent in DVT plus PE patients. Twenty-seven percent of DVT plus PE patients received prophylaxis prior to the thromboembolic event compared with 32% of DVT patients (p=0.002). Proximal DVT (OR 1.84, 95% CI 1.39-2.43), prior PE (OR 1.68, 95% CI 1.20-2.35), obesity (BMI >30 kg/m2) (OR 1.65, 95% CI 1.33-2.04), chronic lung disease (OR 1.51, 95% CI 1.13-2.01), as well as omission of prophylaxis (OR 1.30, 95% CI 1.04-1.64) emerged as independent predictors of concomitant symptomatic PE.     

Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry

Cancer patients with acute venous thromboembolism (VTE) have an increased incidence of recurrences and bleeding complications while on anticoagulant therapy. Methods RIETE is an ongoing registry of consecutive patients with acute VTE. We tried to identify which cancer patients are at a higher risk for recurrent pulmonary embolism (PE), deep vein thrombosis (DVT) or major bleeding. Up to May 2007, 3,805 cancer patients had been enrolled in RIETE. During the first three months of follow-up after the acute, index VTE event, 90 (2.4%) patients developed recurrent PE, 100 (2.6%) recurrent DVT, 156 (4.1%) had major bleeding. Forty patients (44%) died of the recurrent PE,46 (29%) of bleeding. On multivariate analysis, patients aged <65 years (odds ratio [OR]: 3.0; 95% confidence interval [CI]: 1.9-4.9), with PE at entry (OR: 1.9; 95% CI: 1.2-3.1), or with <3 months from cancer diagnosis to VTE (OR: 2.0; 95% CI: 1.2-3.2) had an increased incidence of recurrent PE. Those aged <65 years (OR: 1.6; 95% CI: 1.0-2.4) or with <3 months from cancer diagnosis (OR: 2.4; 95% CI: 1.5-3.6) had an increased incidence of recurrent DVT. Finally, patients with immobility (OR: 1.8; 95% CI: 1.2-2.7), metastases (OR: 1.6; 95% CI: 1.1-2.3), recent bleeding (OR: 2.4; 95% CI: 1.1-5.1), or with creatinine clearance <30 ml/min (OR: 2.2; 95% CI: 1.5-3.4), had an increased incidence of major bleeding. With some variables available at entry we may identify those cancer patients withVTE at a higher risk for recurrences or major bleeding.     

Fibrinogen Aalpha-Thr312Ala and factor XIII-A Val34Leu polymorphisms in idiopathic venous thromboembolism

INTRODUCTION: Fibrinogen Aalpha-Thr312Ala and Factor XIII Val34Leu polymorphisms have been shown to modify fibrin clot structure and function. However, clinical studies have yielded conflicting results on their possible association with venous thromboembolism (VTE). METHODS: We studied the association between these two polymorphisms and VTE in a hospital-based case-control study. We also assessed whether an independent or interactive association exists between Aalpha-fibrinogen Thr312Ala and FXIII Val34Leu polymorphisms and VTE. Fibrinogen Aalpha-Thr312Ala and FXIII Val34Leu polymorphisms were determined after PCR and restriction endonuclease digestion in 286 patients with idiopathic VTE and 286 age- and gender-matched controls. Results were analysed using a conditional logistic regression model for matched series. RESULTS: The Fg-Aalpha 312Ala allele was associated with higher risk of VTE (OR 1.5; 95% CI: 1.1 to 2.2, p=0.01) while the FXIII 34Leu allele appeared protective (OR 0.7; 95% CI: 0.6 to 0.9, p=0.02). Both alleles demonstrated an independent association with idiopathic VTE after adjustment for Factor V Leiden and G20210A prothrombin polymorphisms. There was no interaction between the fibrinogen Aalpha-Thr312Ala and FXIII Val34Leu polymorphisms for the risk of VTE. CONCLUSION: In this case-control study, the fibrinogen Fg-Aalpha 312Ala allele was associated with an increased risk of VTE. The FXIII 34Leu allele was also significantly associated with a lower risk of VTE without any interaction between the two polymorphisms studied.     

Factor XIII Val34Leu variant and the risk of myocardial infarction: a meta-analysis

Genetic factors are thought to contribute to the pathogenesis of acute myocardial infarction (AMI). A common variant of factor XIII (FXIII), FXIII Val34Leu, may be protective against developing an AMI, but various studies show conflicting results. We performed a meta-analysis to determine whether the FXIII Val34Leu variant is associated with a decreased risk of AMI. One hundred ninety-five articles were reviewed and 12 case-control studies were selected. We included studies involving patients with objectively diagnosed AMIs (WHO criteria), provided that FXIII Val34Leu genotyping data were available. Inclusion decisions, quality assessment, and data extraction were conducted by two reviewers. Hypothesizing that the Leu allele was protective, we performed three analyses with the Val/Val genotype as the reference group. Pooled odds ratios (OR) and their 95% confidence intervals (95% CI) were determined. Prior to pooling, heterogeneity testing was performed using the I(2) statistic. These studies included a total of 8,743 patients, of which 3,663 were AMI patients and 5,080 were healthy controls. Using the random effects methods, protective effects were seen with the Leu/Val genotype alone (OR 0.79, 95% CI 0.68-0.93) and with Leu/Val and Leu/Leu genotypes combined (OR 0.79, 95% CI 0.66-0.93). There was also a protective effect with the Leu/Leu genotype alone, (not statistically significant: OR 0.83, 95% CI 0.61-1.12), likely due to the low frequency of this genotype. These results suggest that there is an association between the factor XIII Leu allele and a modest protective effect against AMI and may provide useful information in profiling susceptibility to myocardial infarction.     

Association between genotype and plasma levels of thrombin-activated fibrinolysis inhibitor (TAFI) in the development of preeclampsia

Introduction

The objective was to evaluate if thrombin-activated fibrinolysis inhibitor (TAFI) polymorphisms (G505A, C1040T, and G-438A), and TAFIa plasma levels are associated with preeclampsia.

Materials and Methods

In a case-control study design, we evaluated preeclampsia patients and women with uncomplicated pregnancies. The TAFI polymorphisms were determined by real-time PCR method, and TAFIa plasma levels were established with a chromogenic assay.

Results

We included 87 women in each group. The TAFIa levels in the preeclampsia group were 20.4 μg/mL (CI 95% 17.3-23.5), while in the control group, they were significantly lower: 13.3 μg/mL (12.0-14.5, p 0.003). There were no differences in the genotype distribution or allelic frequency of TAFI polymorphisms between the two groups. In preeclampsia patients and controls heterozygous for the G505A polymorphism, the TAFIa values were 22.8 (16.7-28.9 μg/mL) and 13.2 (11.3-15.0 μg/mL, p 0.019), respectively. In G505A homozygous polymorphism the TAFIa values were 25.7 (18.7-32.6 μg/mL) and 13.5 (1.6-21.9 μg/mL, p 0.041), respectively. In the C1040T and G-438A TAFI wild type polymorphisms, the TAFIa values were 18.3 (12.5-23.9 μg/mL) and 11.5 (9.9-35.0, p 0.033), and 19.4 (10.9-27.9 μg/mL) and 12.5 (10.8-14.2 μg/mL, p 0.006), respectively, without differences in other genotypes.

Conclusions

Preeclampsia by itself may be responsible for the increase in TAFIa values rather than the presence of polymorphisms.     

卒中后深静脉血栓形成调查及危险因素探讨

目的 调查卒中后急性期和随访期深静脉血栓形成(DVT)发生率,并探讨DVT发生的危险因素.方法 采用多中心、前瞻性研究设计.所有患者于发病后10～14 d进行双下肢静脉超声检查,出院后继续随访6个月.计算出卒中后急性期和随访期DVT发生率.通过比较卒中后并发DVT与卒中后无DVT的患者多种相关因素,筛选出卒中后DVT发生的危险因素.结果 卒中急性期DVT发生率为4.49%,其中有DVT症状者为51.6%,无症状者为48.4%;多因素Logistic分析显示:年龄(≥70岁,OR=1.63,95%CI 1.08～2.84)、卧床(OR=4.85,95%CI 2.65～9.68)、Wells评分≥2(OR=3.96,95%CI 1.86～7.86)、下肢NIHSS评分≥3分(OR=4.56,95%CI 2.07～8.85)、D-二聚体水平高(OR=3.45,95%CI 2.01～8.52)、Barthel指数(BI)评分低(OR=2.98,95%CI 1.52～6.47)、是否康复治疗(OR=1.82,95%CI 1.22～3.43)、是否抗凝治疗(OR=1.91,95%CI 1.34～4.92)是急性期卒中患者DVT发生的独立危险因素,其中康复治疗和抗凝治疗是保护因素;卒中随访期DVT发生率为1.51%,年龄(≥70岁,OR=1.82,95%CI 1.21～3.98)、出院后仍卧床(OR=5.12,95% CI 2.82～11.32)、出院时下肢NIHSS评分≥3分(OR=4.25,95%CI 2.11～7.87)、出院时BI评分低(OR=2.18,95%CI 1.18～6.23)、急性期有DVT(OR=3.81,95% CI 1.87～7.48)是随访期卒中患者DVT发生的独立危险因素.结论 卒中后DVT多发生于老年患者,48.4%DVT无症状,卒中患者发生DVT的独立危险因素多,对有上述危险因素卒中患者进行DVT监测和预防干预十分必要,康复治疗和抗凝治疗可能能降低DVT的发生.     

Factor XIII Val34Leu is a genetic factor involved in the etiology of venous thrombosis.

A mutation in the factor XIII gene (FXIII Val34Leu) gene was recently reported to confer protection against myocardial infarction, but its relationship with venous thrombosis is unknown. In addition, a mutation in the 5'-untranslated region of the FXII gene (46 C->T) was identified which is associated with low plasma levels of the protein. Its prevalence in patients with venous thrombosis is also unknown. We investigated the frequency of the FXIII Val34Leu and FXII 46 C->T mutations in 189 patients with deep venous thrombosis and in 187 age-, gender- and race-matched controls. FXIII Val34Leu was detected in 38.6% of the patients and in 41.2% of the controls. Interestingly, homozygosity for the FXIII mutation was found in 1.6% of the patients and in 9.6% of the controls, yielding an odds ratio (OR) for venous thrombosis of 0.16 (95% CI: 0.05-0.5). The OR for heterozygotes was 1.1 (95% CI: 0.7-1.7). The FXII 46 C->T mutation was detected in 46.0% of the patients and in 48.6% of the controls. The OR for heterozygotes was 0.9 (95% CI: 0.6-1.4) and for homozygotes the OR was 0.8 (95% CI: 0.3-1.9). Our data indicate that the FXII 46 C->T mutation is unlikely to be a major risk factor for venous thrombotic disease. In contrast, the homozygous state for FXIII Val34Leu is a strong protective factor against venous thrombosis, which emerges as a novel genetic factor involved in the aetiology of thrombophilia.     

Venous thromboembolism in acutely ill hospitalized medical patients

Background

Acute and chronic illness, immobility, and procedural and pharmacologic interventions may predispose patients in the Internal Medicine Wards to venous thromboembolic disease (VTE). The purpose of this study was to determine the incidence of VTE in these patients.

Materials and Methods

A retrospective chart review of cohort of consecutive patients admitted to Internal Medicine wards in Spain between January 1st 2005 and December 31st 2007 was performed. For each patient, demographic data, risk factors for VTE and the diagnosis of VTE during hospitalization was recorded.

Results

We analyzed 1,567,659 patients, excluding 28,226 patients who had DVT or PE before admission, and 196,555 who were discharged in the first 48 hours. We identify 12,458 new diagnosed VTE events among 1,344,959 patients (incidence 0.93%) hospitalized more than two days. Hospitalized-acquired VTE risk factors were feminine gender (odds ratio [OR] 1.31; CI95% 1.26-1.35), age > 70 (OR 1.08 CI95% 1.04-1.13), acute infectious disease (OR 1.27 CI95% 1.17-1.38), acute respiratory disease (OR 1.23 CI95% 1.17-1.28), dementia (OR 1.22 CI95% 1.14-1.31), neoplasic disease (OR 2.29, CI95% 2.19-2.49), and hemiplegia (OR 1.49, CI95% 1.31-1.69).

Conclusions

The number of patients with VTE in an Internal Medicine ward is higher than expected. Several independent risk factors for VTE were identified. Based on the large number of patients who developed a VTE during hospitalization, our data add strength to the argument that VTE prevention should be high on the list of priorities when health care policies are being formed.     

Association between thrombin-activatable fibrinolysis inhibitor (TAFI) and clinical outcome in patients with unstable angina pectoris

Decrease of fibrinolytic potential is considered to be a risk factor for arterial thrombosis. The recently described thrombin-activatable fibrinolysis inhibitor (TAFI) attenuates fibrinolysis by cleaving of the C-terminal lysine residues from fibrin, thereby inhibiting tPA mediated plasminogen activation. The role of plasma TAFI antigen (Ag) levels and gene polymorphisms in arterial thrombosis is still not elucidated. In this prospective study, the association between plasma TAFI Ag levels and the TAFI gene polymorphisms, Ala147Thr, Thr325Ile and -438A/G, with refractory unstable angina pectoris (UAP) was determined. The study population consisted of 209 patients with UAP of whom 76 were refractory and 133 non-refractory to medical treatment. In the same study population the contribution of these polymorphisms to plasma TAFI Ag levels was determined. Plasma TAFI Ag levels were significantly higher in non-refractory patients compared to refractory patients (geometric mean 114.4 and 105.6 U/dl respectively, p=0.042). Plasma TAFI Ag levels in the lowest quartile resulted in a 2.6 fold (95% confidence interval 1.2-5.9) increased risk for refractory UAP compared to plasma TAFI Ag levels in the upper quartile. The three studied TAFI polymorphisms had an independent and additive effect on plasma TAFI Ag levels. However, no significant association between the individual TAFI polymorphisms and refractiveness was observed. In conclusion, in this study population plasma TAFI Ag levels are significantly correlated with refractiveness in patients with UAP. Furthermore, all three polymorphisms contribute independently to plasma TAFI Ag levels, but not to refractiveness.     

Thrombin-activatable fibrinolysis inhibitor genetic polymorphisms as markers of the type of acute coronary syndrome

Introduction

In patients with coronary disease at risk of acute coronary events it is unclear which biological factors could predict the type of acute coronary syndrome clinical presentation. The aim of the study was to investigate the role of genetic polymorphisms in key proteins in fibrinolysis in the type of acute coronary syndrome.

Materials and methods

248 patients with acute coronary syndrome (unstable angina or myocardial infarction) (77% male, mean age 60.75 SD 13.30 years) were prospectively recruited. PAI-1 (type-1 plasminogen activator inhibitor) 4G/5G and TAFI (thrombin-activatable fibrinolysis inhibitor) Ala147Thr, C+1542G, and Thr325Ile polymorphisms were determined by PCR.

Results

147 (59.3%) patients presented with ST-segment elevation acute coronary syndrome (all Q-wave myocardial infarction), and 101 (40.7%) with non-ST-elevation acute coronary syndrome (52 non-Q wave myocardial infarction, and 49 unstable angina). Homozygous TAFI + 1542G and TAFI 325Ile genotypes were less prevalent in patients with ST elevation acute coronary syndrome (p < 0.001, OR: 0.22, 95% CI 0.10-0.50 and p < 0.001, OR: 0.25, 95% CI 0.11-0.55, respectively). There were no differences in TAFI Ala147Thr or PAI genotype distribution between ST elevation and non-ST elevation acute coronary syndrome. In the multivariate analysis including clinical variables, the best model for ST elevation acute coronary syndrome included TAFI + 1542GG (p < 0.001, OR: 0.17, 95% CI 0.07-0.30), age (in years, p < 0.005, OR: 0.97, 95% CI 0.94-0.98) and dyslipidemia (p < 0.005, OR: 2.33, 95% CI 1.42-3.80).

Conclusion

TAFI polymorphism C+1542G and Thr325/Ile are related to the type of acute coronary syndrome. Patients with coronary disease would benefit from individualized cardiovascular prophylaxis based on genetic risk.     

Appropriateness of diagnostic strategies for evaluating suspected venous thromboembolism

It was the objective of this study to determine the proportion of patients who undergo an appropriate diagnostic work-up following a D-dimer test performed to evaluate suspected pulmonary embolism (PE) or deep vein thrombosis (DVT). We performed a retrospective cohort study at a tertiary care hospital. We included patients if they underwent D-dimer testing between 2002 and 2005, if the D-dimer was performed for evaluation of VTE, and if the D-dimer test was successful. We classified: the patients' clinical probability of DVT or PE according to the Wells models, the imaging results, and the appropriateness of the testing algorithm. Of 1,000 randomly selected patients, 863 met our study criteria. Seven hundred nineteen patients (83%) had testing during an emergency department visit, while 144 were tested as inpatients (17%). Physicians performed the D-dimer test to evaluate DVT and PE in 238 (28%) and 625 (72%) patients, respectively. Overall, the testing strategy was appropriate in 69% (95% confidence interval [CI]: 66%-72%) of cases. The testing strategy was more likely to be appropriate for emergency department versus inpatients (75% vs. 39%, p < 0.05) and for DVT versus PE patients (84% vs. 63%, p < 0.05). Of all in-appropriately tested patients, under-utilization of diagnostic imaging was more common than over-utilization (90% vs. 10%, p < 0.05). VTE was confirmed in 37 of 138 'DVT patients' and 35 of 625 'PE patients' (16% [95% CI: 11%-21%] and 6% [95% CI: 4%-8%], respectively). In conclusion, physicians often fail to use diagnostic testing strategies for VTE correctly following a D-dimer test.     

Polymorphisms of haemostasis genes as risk factors for preterm delivery

Clinical trials evaluating the potential benefit of anticoagulant treatment in pregnant women with inherited thrombophilia are based on the observation that a genetic predisposition to thrombosis is associated with frequent abortions and preterm birth. It was the aim of our study to delineate the impact of genetic polymorphisms with prothrombotic and antithrombotic effects on the occurrence of preterm birth in a large cohort of very-low-birth-weight (VLBW)-infants and their mothers. We examined the factor V Leiden and the prothrombin G20210A mutation, the factor VII 121del/ins and the factor XIII Val34Leu polymorphism in preterm very-low-birth-weight (VLBW, n=593) and term-born-infants (n=278) and their mothers (n=785). The primary outcome was preterm vs.term birth. From all polymorphisms tested, the maternal factor VII-121del/ins polymorphism (26.2 vs. 17.6 %; p=0.009) and the infant's factor VII-121del/ins polymorphism (29.0 vs. 20.0 %; p=0.009) were more frequent in singleton VLBW and their mothers compared to term infants and their mothers. Furthermore, the frequency of the factor XIII-Val34Leu polymorphism was significantly lower in singleton VLBW than in term infant controls (5.1 vs. 9.6%, p=0.025). In a multivariate regression analysis, previous preterm delivery (OR=3.8, 95% CI: 1.7-8.4), the maternal carrier status of the factor-VII-121del/ins polymorphism (OR=1.7, 95% CI: 1.12-2.5, p=0.007) and the lower frequency of infant's factor-XIII-Val34Leu polymorphism (OR=0.53; 95% CI: 0.29-0.96; p=0.038) were found to be independently associated with preterm delivery. InVLBW mothers with pathological CTG as cause of preterm delivery, the frequency of factor V Leiden mutation was significantly increased compared to VLBW mothers without pathological CTG (14.1 vs. 6.1%, p=0.01). The investigated haemostasis gene polymorphisms have a much lower impact on subsequent preterm delivery than known risk factors such as previous preterm birth. The reported association of the factor-VII-121del/ins polymorphism on preterm delivery and its clinical relevance needs to be further elucidated.     

Factor XIII Val34Leu polymorphism and the risk of myocardial infarction under the age of 36 years

There are limited and controversial data regarding the impact of factor XIII (FXIII) Val34Leu polymorphism in the pathogenesis of premature myocardial infarction (MI). We examined whether FXIII Val34Leu polymorphism is associated with the development of early MI. We recruited 159 consecutive patients who had survived their first acute MI under the age of 36 years (mean age = 32.1 +/- 3.6 years, 138 were men). The control group consisted of 121 healthy individuals matched with cases for age and sex, without a family history of premature coronary heart disease (CHD). FXIII Val34Leu polymorphism was tested with polymerase chain reaction and reverse hybridization. There was a lower prevalence of carriers of the Leu34 allele in patients than in controls (30.2 vs. 47.1%, p = 0.006). FXIII Val34Leu polymorphism was associated with lower risk for acute MI after adjusting for major cardiovascular risk factors (odds ratio [OR] = 0.51, 95% confidence interval [CI] 0.27-0.95, p = 0.03). Subgroup analysis according to angiographic findings ("normal" coronary arteries [n = 29] or significant CHD [n = 130]) showed that only patients with MI and significant CHD had lower prevalence of carriers of the Leu34 allele compared to controls after adjusting for major cardiovascular risk factors (OR = 0.42, 95% CI 0.22-0.83, p = 0.01). Our data indicate that FXIII Val34Leu polymorphism has a protective effect against the development of MI under the age of 36 years, particularly in the setting of significant CHD.     

High utilization rate of vena cava filters in deep vein thrombosis

The objective was to investigate newly diagnosed patients with deep vein thrombosis (DVT) who received inferior vena cava filters (IVCFs). A prospective registry enrolled 5451 patients from 183 US study sites. In all patients, examination by venous duplex ultrasound confirmed the diagnosis of DVT. We collected and analyzed data on 781 patients who received an IVCF. The most frequently prescribed treatments were low-molecular-weight heparin and unfractionated heparin, which were used as a bridge to warfarin in 39% (n=2143) and 35% (n=1926) of patients, respectively. Of the total population, 781 (14%) (235 outpatients, 546 inpatients) underwent IVCF placement. The most common reasons for IVCF placement were contraindication to anticoagulation (n = 271), prophylaxis (n = 259), major bleeding related to anticoagulation therapy (n = 92), and anticoagulation failure (n = 73). Multivariate analysis revealed that patients were more likely to undergo IVCF insertion with multiple system organ failure (odds ratio [OR], 3.6; 95% CI, 1.48-8.60), previous stroke (OR,3.2;95% CI,2.11-4.74), or history of pulmonary embolism (OR,2.4; 95% CI, 1.95-2.91). In conclusion, a surprisingly high 14% (781) of patients with confirmed DVT received an IVCF. Many of these patients may have warranted less invasive methods of venous thromboembolism prophylaxis. Improved physician education regarding mechanical and pharmacologic prophylaxis alternatives might reduce the use of IVCFs.     

Basal high-sensitivity-C-reactive protein levels in patients with spontaneous venous thromboembolism

The role of C-reactive protein (CRP) in venous thromboembolism (VTE) is still under discussion because of controversial results in the literature. Conflicting data may have partly been due to bias by exogenous factors altering CRP levels. We investigated CRP concentrations in patients with spontaneous VTE applying a study design that allowed the measurement of basal high sensitivity (hs)-CRP levels. Patients with a history of deep vein thrombosis (DVT, n=117) and pulmonary embolism (PE, n=97) were compared to healthy individuals (n=104). Hs-CRP levels (mg/dl) were significantly higher in patients (n=214, median/interquartile range: 0.171/0.082-0.366) than in controls (0.099/0.053-0.245, p=0.001). The unadjusted odds ratio (OR) for VTE per 1 mg/dl increase of CRP was 2.8 [95% confidence interval (CI): 1.1-6.8, p=0.03]. This association remained significant after adjustment for factor V Leiden, prothrombin G20210A and factor VIII activity above 230% (OR = 2.9, 95% CI [1.1-7.5]), but became remarkably attenuated and lost its statistical significance after adjustment for BMI alone (OR = 1.7 [0.7-4.0]). CRP was also not independently associated with VTE in subgroups of patients (those with DVT without symptomatic PE, those with PE and patients without established risk factor) in multiple regression analysis. In summary, we observed significantly higher basal hs-CRP levels in patients with spontaneous VTE compared to healthy controls. This association was independent of hereditary and laboratory risk factors for VTE, but lost its significance after adjustment for BMI. Increased basal CRP levels do not appear to represent an independent risk factor for VTE.     

FXIIIA3种基因多态性与脑血管疾病的关系

目的　探讨在汉族人群中凝血因子XIII的A亚单位(FXIIIA)上的3种基因多态性,即Val34L eu、Tyr2 0 4 Phe、Pro5 6 4 L eu基因多态性与脑血管疾病的关系。方法　临床筛选14 9例实验病例,分为3组:对照组6 8例,脑梗死组5 9例,脑出血组2 2例。应用PCR和单链构象多态性法(PCR- SSCP)检测3组人群的FXIIIA上是否存在Val34L eu、Tyr2 0 4 Phe、Pro5 6 4 L eu基因多态性,并做统计学检验。结果　在3组病例中均检测到Pro5 6 4 L eu基因多态性,并有显著性差异。3组病例均未检测到Val34L eu和Tyr2 0 4 Phe基因多态性存在。结论　在汉族人群中携带有Pro5 6 4 L eu基因多态性者可能会增加脑出血的危险性。所以在汉族人群中开展Pro5 6 4 L eu基因多态性的检测有利于脑血管疾病的防治。