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.     

Lipoprotein (a) in patients with spontaneous venous thromboembolism

INTRODUCTION: Elevated lipoprotein (a) (Lp (a)) has been established as a risk factor of coronary heart disease and stroke. Findings concerning the risk of venous thromboembolism (VTE) in adults are contradictory. The aim of our study was to investigate, whether elevated Lp (a) levels are an independent risk factor of spontaneous symptomatic venous thromboembolism (VTE). Our study was further designed to detect differences in risk profiles between thrombosis patients with and without symptomatic PE. MATERIALS AND METHODS: We investigated Lp (a) in 128 patients with spontaneous symptomatic deep vein thrombosis (DVT, group 1), 105 with spontaneous symptomatic pulmonary embolism with or without DVT (PE, group 2) and 122 healthy controls. Lp (a) was measured with an immunoturbidimetric assay (Tina-quant(R), Roche, Grenzach-Wyhlen, Germany) on a Hitachi-Modular system. RESULTS: Lp (a) levels (mg/L) were not significantly different among groups, median levels (25th-75th percentiles) were 170 (51-386) in group 1, 140 (<20-427) in group 2 and 126 (54-331) in controls, respectively. As continuous variable, odds ratios for VTE for a 100 mg/L increase of Lp (a) were 1.1 [95% confidence interval 0.98-1.2] for group 1 versus controls and 1.1 [0.95-1.2] for group 2 versus controls. The prevalence of Lp (a) above 300 mg/L was not significantly different among patients and controls (group 1: 30%, group 2: 32% and controls: 25%, p=0.4, p=0.2, respectively). CONCLUSIONS: In conclusion we found no association between Lp (a) and VTE regardless whether DVT occurred together with PE or not.     

Predictive factors for concurrent deep-vein thrombosis and symptomatic venous thromboembolic recurrence in case of superficial venous thrombosis. The OPTIMEV study

Superficial venous thrombosis (SVT) prognosis is debated and its management is highly variable. It was the objective of this study to assess predictive risk factors for concurrent deep-vein thrombosis (DVT) at presentation and for three-month adverse outcome. Using data from the prospective multicentre OPTIMEV study, we analysed SVT predictive factors associated with concurrent DVT and three-month adverse outcome. Out of 788 SVT included, 227 (28.8%) exhibited a concurrent DVT at presentation. Age >75years (odds ratio [OR]=2.9 [1.5-5.9]), active cancer (OR=2.6 [1.3-5.2]), inpatient status (OR=2.3 [1.2-4.4]) and SVT on non-varicose veins (OR=1.8 [1.1-2.7]) were significantly and independently associated with an increased risk of concurrent DVT. 39.4% of SVT on non-varicose veins presented a concurrent DVT. However, varicose vein status did not influence the three-month prognosis as rates of death, symptomatic venous thromboembolic (VTE) recurrence and major bleeding were equivalent in both non-varicose and varicose SVTs (1.4% vs. 1.1%; 3.4% vs. 2.8%; 0.7% vs. 0.3%). Only male gender (OR=3.5 [1.1-11.3]) and inpatient status (OR=4.5 [1.3-15.3]) were independent predictive factors for symptomatic VTE recurrence but the number of events was low (n=15, 3.0%). Three-month numbers of deaths (n=6, 1.2%) and of major bleedings (n=2, 0.4%) were even lower, precluding any relevant interpretation. In conclusion, SVT on non-varicose veins and some classical risk factors for DVT were predictive factors for concurrent DVT at presentation. As SVT remains mostly a clinical diagnosis, these data may help selecting patients deserving an ultrasound examination or needing anticoagulation while waiting for diagnostic tests. Larger studies are needed to evaluate predictive factors for adverse outcome.     

Influence of lipids and obesity on haemorheological parameters in patients with deep vein thrombosis

It is not well established whether haemorheological alterations constitute independent risk factors for deep vein thrombosis (DVT). We have determined in 149 DVT patients and in 185 control subjects the body mass index (BMI), the haemorheological profile: blood viscosity (BV), plasma viscosity (PV), fibrinogen (Fg), erythrocyte aggregation (EA), erythrocyte deformability (ED) and plasma lipids. In the crude analysis BMI, Fg, PV, EA, triglycerides (TG) and ApoB were statistically higher and HDL cholesterol (HDL-Chol) statistically lower in DVT patients than in controls. No differences in BV and ED were observed. After BMI adjustment, Fg, PV and EA remained statistically higher in DVT cases than in controls (P = 0.013; P = 0.012; P = 0.013; P = 0.028, respectively). When the risk of DVT associated with these variables (using cut-offs that corresponded to the mean plus one SD of the control group) was estimated, EA > 8.2 and PV > 1.28 mPa . s were significantly associated with DVT even further adjustment for lipids and obesity (OR = 2.78, P = 0.004; OR = 1.91, P = 0.024, respectively). However, PV did not remain statistically significant after additional adjustment for Fg. When we consider together all the analyzed variables in order to control every variable for each other, TG > 175 mg/dl (OR = 3,2, P = 0.004) and BMI > 30 kg/m(2) (OR = 3.5, P = 0.003), were also independently associated with a greater risk of DVT. Our results suggest that increased EA constitute an independent risk factor for DVT. However, when associated to hyperlipidaemia and obesity it further increases thrombotic risk.     

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.     

The risk of recurrent venous thromboembolism in patients with unprovoked symptomatic deep vein thrombosis and asymptomatic pulmonary embolism

Patients with a first episode of symptomatic pulmonary embolism (PE) have a higher risk of recurrent venous thromboembolism (VTE) than patients with a first episode of proximal lower extremity deep vein thrombosis (DVT). Patients with symptomatic DVT and silent PE may have a different risk of VTE recurrence than patients that have symptomatic DVT without PE. Therefore, it was the aim of this prospective cohort study to compare the risk of recurrent symptomatic VTE in patients with proximal lower extremity DVT and silent PE to the risk in patients that only have proximal lower extremity DVT. Ninety-one consecutive outpatients presenting to the emergency department of a university hospital subsequently hospitalised with a first episode of unprovoked symptomatic proximal lower extremity DVT, and without new pulmonary symptoms were included. Standard initial treatment consisted of intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin for 5-7 days, overlapped with oral vitamin-K antagonist therapy, with long-term oral vitamin-K antagonist therapy (goal INR 2.5 [2.0-3.0]). Study endpoints were: symptomatic recurrent DVT, new PE, and recurrent PE, evaluated by standard objective testing. At enrollment, 28 of 91 (31%) patients with DVT had silent PE. In the patients with DVT and silent PE, there were 3 VTE recurrences during 20 person-years of follow-up, while there were no VTE recurrences during 61 person-years of follow- up in the patients with isolated DVT. The Kaplan-Meier estimated VTE recurrence rate at 1 year after the diagnosis of DVT was 11% (95% CI: 2-28%) for patients with symptomatic DVT and silent PE, compared to 0% in patients with isolated symptomatic DVT (p=0.0045). In patients with a first episode of unprovoked symptomatic acute proximal lower extremity DVT, the risk of recurrent VTE was significantly higher in those with silent PE compared to those without PE.     

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.     

The risk of symptomatic pulmonary embolism due to proximal deep venous thrombosis differs in patients with different types of inherited thrombophilia

It is uncertain whether the presence of inherited thrombophilia influences the risk of developing symptomatic pulmonary embolism (PE) and whether different thrombophilic alterations are associated with different risks of symptomatic PE. To investigate such issue, we retrospectively studied 920 patients with proximal deep vein thrombosis (DVT) of the legs with or without symptomatic PE referred for thrombophilia screening; patients with overt cancer or antiphospholipid antibodies had been excluded. Three hundred fifty-four patients (38.5%) had deficiency of antithrombin (AT, n = 16), protein C (PC, n = 26), protein S (PS, n = 22), factor V Leiden (FVL, n = 168), prothrombin G20210A (PT-GA, n = 87), or multiple abnormalities (n = 35), and 566 had none of the studied thrombophilic abnormalities. Symptomatic PE complicated the first DVT in 242 patients (26%); the risk of PE was increased in patients with AT deficiency (relative risk [RR] 2.4, 95% confidence interval [CI] 1.6-3.6) or with PT-GA (RR 1.5, 95%CI 1.1-2.0) and decreased in those with FVL (RR 0.7, 95%CI 0.5-1.0) in comparison with those with unknown inherited defect. These data suggest that patients with proximal DVT have different risks of symptomatic PE according to the type of inherited thrombophilia.     

Interleukin-6 and interleukin-6 promoter polymorphism (-174) G > C in patients with spontaneous venous thromboembolism

Increased levels of interleukin-6 (IL-6) have been reported in patients with a history of venous thromboembolism (VTE); however, prospective studies did not confirm an association between inflammatory markers that are highly correlated with IL-6 and the risk ofVTE. It was the aim of our study to investigate the association of IL-6 and its promoter polymorphism (-174) G > C with the risk of spontaneousVTE. IL-6 was measured in 128 patients with deep venous thrombosis (DVT,70 w/58 m),105 with pulmonary embolism (PE, 58 w/47 m) and 122 healthy controls (60 w/62 m) with a highly sensitive ELISA (Quantikine HS Human IL-6 Immunoassay, RnDSystems). The promoter polymorphism was determined by genotyping, allele specific PCR was followed by high resolution gel-electrophoresis. Median concentrations [interquartile ranges] were 2.37 [1.51-3.89] (pg/ml) in patients with DVT, 2.83 [1.83-4.87] in those with PE and 2.51 [1.71-4.78] in controls (p = 0.6, p = 0.4). Hetero- or homozygous carriers of the C allele (71% in DVT, 67% in PE and 59% among controls) did not have higher IL-6 levels than homozygous carriers of the G allele (median 2.60 vs. 2.59 pg/ml, p = 0.7). In conclusion, we found no association of IL-6 and its promoter polymorphism (-174) G > C with the risk of spontaneous VTE.     

Elevated factor VIII is a risk factor for idiopathic venous thromboembolism in Canada - is it necessary to define a new upper reference range for factor VIII?

Previous studies suggest elevated factor VIII is a common, independent risk factor for venous thromboembolism (VTE); however, these studies included secondary and idiopathic VTE. We sought to explore the association between elevated factor VIII and VTE in Canadian patients with idiopathic thrombosis, and confirm the current upper factor VIII reference range was appropriate. We enrolled 300 consecutive patients with idiopathic VTE who were matched to friend controls by age, sex and ethnicity. Factor VIII levels were measured and compared between cases and controls. The optimal cut-off value to designate factor VIII levels as elevated was determined using a variety of methods. The optimal upper cut-off value for factor VIII levels was 270 IU/dl. In the logistic regression analysis, cases were more likely to have elevated factor VIII levels (OR:8.76), as were females (OR:1.93) and older subjects (OR: 1.05). Factor VIII cutoffs for a 95% specificity by age were 238 IU/dl for subjects <40 years, 248 IU/dl age 40-55 years, 261 IU/dl age 56-70 years, and 313 IU/dl age >70. Our findings confirm that elevated factor VIII is associated with an increased risk of idiopathic VTE. In our patients and matched controls, the current upper limit of normal (150 IU/dl) for factor VIII is not of clinical use. We propose that the upper limit be increased to 270 IU/dl or individual labs should establish their upper limit if they wish their assays to be discriminatory in patients with VTE. Age specific cut-offs may be clinically relevant.     

The association of alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism in the LITE study

INTRODUCTION: The alpha-fibrinogen Thr312Ala variant has been shown to influence clot structure through increased factor XIII cross-linking and formation of thicker fibrin fibers. However, the effect of this common variant on risk of venous thromboembolism (VTE) is unclear. This paper reports the association between the Thr312Ala variant and VTE in the LITE study. MATERIALS AND METHODS: 506 cases and 1014 controls frequency matched on age, sex, race, and study were drawn from two prospective studies and included in the analysis. Logistic regression was used to examine the association between Thr312Ala and VTE. RESULTS: In a logistic regression model minimally adjusted for the matching variables, the Thr312Ala TA and AA genotypes were associated with a significantly higher risk of VTE than the TT genotype (TA OR and 95% confidence interval 1.27 [1.01-1.60], AA OR 1.49 [1.00-2.22]). Associations were similar in analyses of PE and DVT considered separately and across racial and study subgroups. The association between alpha-fibrinogen Thr312Ala and VTE was modified by both BMI and the FXIII Val34Leu variant; the combination of elevated BMI or FXIII Val34Leu with alpha-fibrinogen Thr312Ala conveyed lower odds of VTE than would be expected by an additive or multiplicative model of individual risk factors. CONCLUSIONS: These results suggest that alpha-fibrinogen Thr312Ala is involved in the pathogenesis of VTE and that its action may be modified by other VTE risk factors.     

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.     

Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c. A prospective family cohort study

Elevated levels of factor VIII:c (elevated FVIII:c) are associated with an increased risk for venous thromboembolism (VTE) and arterial vascular events, and are at least in part determined genetically. We prospectively followed 192 asymptomatic individuals with elevated FVIII:c (>150%) and 340 with normal levels for an average duration of 31 months (range 7 to 56 months) to investigate the risk of VTE and arterial vascular events. Participants were first degree relatives of consecutive patients with elevated FVIII:c and VTE or arterial vascular events before the age of 50 years. The incidences of VTE were 1.25% (0.46-2.73) per year in the subjects with elevated FVIII:c, versus 0.23% (0.03-0.82) in those with normal levels (OR 5.5 [1.1-27.3]). The annual incidences of arterial vascular events were 1.04% (0.34-2.42) and 0.23% (0.03-0.82) in relatives with and without elevated levels of FVIII:c, respectively (OR: 4.5 [0.9-23.5]). After adjustment for age, smoking, known diabetes mellitus, hyperlipidemia, and hypertension, the odds ratio for any event was 3.7 (1.1-13.1). In conclusion, asymptomatic individuals with elevated FVIII:c levels and a positive family history of VTE or arterial vascular events before the age of 50 appear to have a high annual incidence of first VTE and arterial vascular events. Elevated FVIII:c may be a common risk factor for both clinical entities.     

Unprovoked proximal venous thrombosis is associated with an increased risk of asymptomatic pulmonary embolism

Introduction

Pulmonary embolism (PE) is common in patients with deep venous thrombosis (DVT). The outcome of DVT with concomitant symptomatic PE is worse than the outcome of isolated DVT. The risk factors for DVT and simultaneous asymptomatic PE have not been systematically studied yet.

Aim

To evaluate the frequency and risk factors for asymptomatic PE in patients with DVT.

Patients/methods

In 155 consecutive patients with a first episode of DVT and no PE symptoms, a ventilation-perfusion lung scan was performed. Body mass index (BMI) and waist-to-hip ratio (WHR) were calculated and concentrations of D-dimer, high-sensitivity CRP (hsCRP), tissue plasminogen activator (t-PA) and troponin were measured. Laboratory tests for thrombophilia were performed.

Results

Asymptomatic PE was present in 36% of patients. No differences in gender, age, BMI and WHR were found between the patients with and without PE. PE was more common in patients with proximal DVT than in those with distal DVT (42% vs. 17%, p < 0.01), and in patients with unprovoked DVT compared to patients with provoked DVT (51% vs. 28%, p < 0.01). The risk of silent PE was the highest in patients with unprovoked proximal DVT (OR, 6.9; 95% CI, 2.3–21.0). Patients with asymptomatic PE had significantly higher values of D-dimer, hsCRP, t-PA and troponin than patients with isolated DVT.

Conclusions

Asymptomatic PE affected more than one third of patients with a first DVT. Unprovoked proximal DVT is the most important risk factor for the occurrence of silent PE.     

Incidence and risk factors associated with in-hospital venous thromboembolism after aneurysmal subarachnoid hemorrhage

Our purpose was to determine the incidence and risk factors associated with in-hospital venous thromboembolism (VTE) in patients with aneurysmal subarachnoid hemorrhage (aSAH). The Nationwide Inpatient Sample database was queried from 2002 to 2010 for hospital admissions for subarachnoid hemorrhage or intracerebral hemorrhage and either aneurysm clipping or coiling. Exclusion criteria were age <18, arteriovenous malformation/fistula diagnosis or repair, or radiosurgery. Primary outcome was VTE (deep vein thrombosis [DVT] or pulmonary embolus [PE]). Multivariate logistic regression was used to assess association between risk factors and VTE. Secondary outcomes were in-hospital mortality, discharge disposition, length of stay and hospital charges. A total of 15,968 hospital admissions were included. Overall rates of VTE (DVT or PE), DVT, and PE were 4.4%, 3.5%, and 1.2%, respectively. On multivariate analysis, the following factors were associated with increased VTE risk: increasing age, black race, male sex, teaching hospital, congestive heart failure, coagulopathy, neurologic disorders, paralysis, fluid and electrolyte disorders, obesity, and weight loss. Patients that underwent clipping versus coiling had similar VTE rates. VTE was associated with pulmonary/cardiac complication (odds ratio [OR] 2.8), infectious complication (OR 2.8), ventriculostomy (OR 1.8), and vasospasm (OR 1.3). Patients with VTE experienced increased non-routine discharge (OR 3.3), and had nearly double the mean length of stay (p < 0.001) and total inflation-adjusted hospital charges (p < 0.001). To our knowledge, this is the largest study evaluating the incidence and risk factors associated with the development of VTE after aSAH. The presence of one or more of these factors may necessitate more aggressive VTE prophylaxis.     

The G20210A mutation of the prothrombin gene in patients with previous first episodes of deep-vein thrombosis: prevalence and association with factor V G1691A, methylenetetrahydrofolate reductase C677T and plasma prothrombin levels

A common G to A transition at nucleotide 20210 of the prothrombin gene is associated with an increased risk for deep-vein thrombosis (DVT) and high plasma levels of prothrombin. We calculated the prevalences of prothrombin G20210A, factor V G1691A (also associated with high risk for DVT) and homozygous methylenetetrahydrofolate reductase (MTHFR) C677T (associated with increased susceptibility to develop hyperhomocysteinemia) in 118 patients with a first episode of DVT and in 416 healthy controls. 15.9% of the patients and 2.3% of the controls had prothrombin G20210A (odds ratio [OR]: 8.7, 95% C.I.: 3.8-21.4); 21.1% of the patients and 3.2% of the controls had factor V G1691A (OR 7.8, 3.9-17.1); 20.5% of the patients and 21% of the controls had homozygous MTHFR C677T (OR: 1.0, 0.7-1.2). Exclusion of patients with other hereditary risk factors for DVT did not substantially modify the results. Mutant factor V and prothrombin coexisted in three patients but in no control. The concomitant presence of the MTHFR mutation did not increase the thrombotic risk associated with prothrombin G20210A. 63.2% of individuals with prothrombin G20210A had plasma levels of prothrombin in the upper quartile of distribution. After adjustment for age and sex, subjects with prothrombin levels in the upper quartile carried a slightly higher risk for thrombosis than those with lower prothrombin concentrations (OR: 1.9, 1.1-3.2). In conclusion, we found that prothrombin G20210A is relatively common in Italy and is associated with high prothrombin levels and an 8.7-fold increase in the risk for DVT. Such risk is independent of the coexistence of other known inherited risk factors for thrombosis and increases in patients with associated mutant factor V. Whether it is due to the associated increase in plasma prothrombin levels remains to be established.     

Circulating P-selectin and the risk of recurrent venous thromboembolism

The clinical relevance of high P-selectin levels in venous thrombosis is unknown. We prospectively followed 544 patients with first unprovoked venous thromboembolism (VTE) after cessation of anticoagulation and evaluated P-selectin as a risk factor of recurrent VTE. VTE recurred in 63 (12%) patients. Patients with recurrence had significantly higher P-selectin levels than those without (45.8 mg/dl +/- 16.4 vs. 40.1 mg/dl +/- 13.3; p = 0.006). After four years, the probability of recurrence was 20.6% (95% confidence interval [CI] 12.6-28.5) among patients with P-selectin values above the 75(th) percentile of the patient population and was 10.8% (95% CI 7.2-14.3) among patients with lower values (p = 0.046). Compared to patients with low P-selectin, adjusted risk of recurrence was 1.7-fold (95% CI 1.0-2.9, p = 0.045) increased among patients with P-selectin levels exceeding the 75(th) percentile. We conclude that high circulating P-selectin is a risk factor of recurrent VTE.     

Prospective analysis of risk factors and distribution of venous thromboembolism in the population-based Malmö Thrombophilia Study (MATS)

Background

Despite venous thromboembolism (VTE) being a major cause of morbidity and mortality, there is still limited information on its prevalence and incidence in the general population.

Objective

To evaluate risk factors, distribution and epidemiology of VTE in the Malmö area with 280 000 inhabitants.

Methods

Patients diagnosed with VTE at Malmö University Hospital in 1998–2006 were invited to a prospective population-based study. Blood sampling and a questionnaire study could be performed in 70% of patients. Remaining 30% were excluded due to language problems, dementia, other severe disease, or unwillingness to participate.

Results

During 1998–2006 1140 VTE patients (559 men [49%, age 62 ± 16 years] and 581 women [51%, age 61 ± 20 years]) were included. Deep venous thrombosis (DVT) occurred in 882 (77%), pulmonary embolism (PE) in 330 (29%), and both DVT and PE in 72 (6%). The most common acquired risk factors among VTE patients were hormone therapy (24% of female DVT patients and 19% of female PE patients), immobilisation (17% of DVT patients and 18% of PE patients), previous surgery (13% of DVT patients and 19% of PE patients), and concomitant malignant disease (12% of DVT patients and 11% of PE patients). A positive family history for VTE was obtained from 25% of DVT patients and 22% of PE patients.Yearly incidences of VTE, DVT and PE in Malmö were 66, 51, and 19/100.000, respectively.

Conclusion

Hormone therapy, immobilisation, previous surgery and concomitant malignancy were the most common acquired risk factors among VTE patients in this population-based study. The VTE-incidence was lower than in earlier epidemiological studies.     

Frequency of the TAFI -438 G/A and factor XIIIA Val34Leu polymorphisms in patients with objectively proven pulmonary embolism

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are considered to be two forms of the same disease, however it is not fully understood what determines their clinical presentation. Proteins encoded by the FXIIIA and TAFI genes are involved in stabilizing the fibrin clot and in making it more lysis resistant. The FXIIIA 34Leu and TAFI -438A alleles might protect against DVT. Information on such an association with PE is either contradictory or missing. We hypothesized that both polymorphisms might influence the formation and fate of emboli and accordingly the risk of PE. We determined the frequencies of both polymorphisms in patients with objectively demonstrated PE. The frequency of FXIIIA Leu34Leu in PE patients and non-PE patients was 4.5% and 8.8%, [OR 0.5 (95% CI: 0.1 to 1.9)], respectively. For -438 A/A TAFI genotype the frequency was 1.5% and 8.1% [OR 0.1 (95% CI: 0.02 to 1.1)], respectively.     

Elevated plasma fibronectin levels associated with venous thromboembolism

Elevated plasma fibronectin levels occur in various clinical states including arterial disease. Increasing evidence suggests that atherothrombosis and venous thromboembolism (VTE) share common risk factors. To assess the hypothesis that high plasma fibronectin levels are associated with VTE, we compared plasma fibronectin levels in the Scripps Venous Thrombosis Registry for 113 VTE cases vs. age and sex matched controls. VTE cases had significantly higher mean fibronectin concentration compared to controls (127% vs. 103%, p < 0.0001); the difference was greater for idiopathic VTE cases compared to secondary VTE cases (133% vs. 120%, respectively). Using a cut-off of >90% of the control values, the odds ratio (OR) for association of VTE for fibronectin plasma levels above the 90(th) percentile were 9.37 (95% CI 2.73-32.2; p < 0.001) and this OR remained significant after adjustment for sex, age, body mass index (BMI), factor V Leiden and prothrombin nt20210A (OR 7.60, 95% CI 2.14-27.0; p = 0.002). In particular, the OR was statistically significant for idiopathic VTE before and after these statistical adjustments. For the total male cohort, the OR was significant before and after statistical adjustments and was not significant for the total female cohort. In summary, our results suggest that elevated plasma fibronectin levels are associated with VTE especially in males, and extend the potential association between biomarkers and risk factors for arterial atherothrombosis and VTE.