C. Y. Vossen

Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT)

Summary.  Background: Reliable risk estimates for venous thrombosis in families with inherited thrombophilia are scarce but necessary for determining optimal screening and treatment policies. Objectives: In the present analysis, we determined the risk of a first venous thrombotic event in carriers of a thrombophilic defect (i.e. antithrombin‐, protein C‐ or protein S deficiency, or factor V Leiden). Patients and methods: The asymptomatic carriers had been tested prior to this study in nine European thrombosis centers because of a symptomatic carrier in the family, and were followed prospectively for 5.7 years on average between March 1994 and January 2001. Annually, data were recorded on the occurrence of risk situations for venous thrombosis and events (e.g. venous thrombosis, death). Results: Twenty‐six of the 575 asymptomatic carriers (4.5%) and seven of the 1118 controls (0.6%) experienced a first deep venous thrombosis or pulmonary embolism during follow‐up. Of these events, 58% occurred spontaneously in the carriers compared with 43% in the controls. The incidence of first events was 0.8% per year (95% CI 0.5–1.2) in the carriers compared with 0.1% per year (95% CI 0.0–0.2) in the controls. The highest incidence was associated with antithrombin deficiency or combined defects, and the lowest incidence with factor V Leiden. Conclusions: The incidence of venous events in asymptomatic individuals from thrombophilic families does not exceed the risk of bleeding associated with long‐term anticoagulant treatment in the literature (1–3%).

Thrombin generation profiles in deep venous thrombosis.

Summary.  Background: Reliable markers and methods to predict risk for thrombosis are essential to clinical management. Objective: Using an integrated approach that defines an individuals comprehensive coagulation phenotype might prove valuable in identifying individuals at risk for experiencing a thrombotic event. Methods: Using a numerical simulation model, we generated tissue factor (TF) initiated thrombin curves using coagulation factor levels from the Leiden Thrombophilia Study population and evaluated thrombotic risk, by sex, age, smoking, alcohol consumption, body mass index (BMI) and oral contraceptive (OC) use. We quantitated the initiation, propagation and termination phases of each individuals’ comprehensive TF‐initiated thrombin generation curve by the parameters: time to 10 nm of thrombin, maximum time, level and rate (MaxR) of thrombin generated and total thrombin. Results: The greatest risk association was obtained using MaxR; with a 2.6‐fold increased risk at MaxR exceeding the 90th percentile. The odds ratio (OR) for MaxR was 3.9 in men, 2.1 in women, and 2.9 in women on OCs. The association of risk with thrombin generation did not differ by age (OR:2.8 ≤ 45 years>OR:2.5), BMI (OR:2.9 ≤ 26 kg m−2>OR:2.3) or alcohol use. In both numerical simulations and empirical synthetic plasma, OC use created extreme shifts in thrombin generation in both control women and women with a prior thrombosis, with a larger shift in thrombin generation in control women. This suggests an interaction of OC use with underlying prothrombotic abnormalities. Conclusions: Thrombin generation based upon the individuals blood composition is associated with the risk for thrombosis and may be useful as a predictive marker for evaluating thrombosis on an individual basis.

Recurrence Rate After a First Venous Thrombosis in Patients With Familial Thrombophilia

Objective—Few comprehensive data are available on the recurrence rate of venous thrombosis in carriers of thrombophilic defects from thrombophilic families. We prospectively determined the recurrence rate after a first venous thrombotic event in patients with familial thrombophilia attributable to factor V Leiden or deficiencies of protein C, S, or antithrombin. Methods and Results—Data were gathered during follow-up on the occurrence of risk situations, anticoagulation treatment, and events (eg, venous thrombosis, hemorrhage). Over a mean follow-up period of 5.6 years, 44 of the 180 patients with familial thrombophilia who did not use long-term anticoagulation experienced a recurrent venous thromboembolic event (5.0%/year; 95% CI 3.6 to 6.7) compared with 7 of the 124 patients on long-term anticoagulation (1.1%/year; 95% CI 0.4 to 2.2). Spontaneous events occurred less often in patients on long-term anticoagulation (57%) than in patients without long-term anticoagulation (75%). The highest recurrence rate was found among men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency. Although long-term anticoagulation treatment decreased the incidence of recurrent events by 80%, it also resulted in a risk of major hemorrhage of 0.8% per year. Conclusions—Extra care after a first event is required for men with a deficiency in natural anticoagulants or multiple defects and women with antithrombin deficiency.

Familial thrombophilia and lifetime risk of venous thrombosis

Summary  Background : We started a large multicenter prospective follow‐up study to provide reliable risk estimates of venous thrombosis in families with various thrombophilic defects.

The plasma hemostatic proteome: thrombin generation in healthy individuals

Summary.  Background and objectives: The range of plasma concentrations of hemostatic analytes in the population is wide. In this study these components of blood coagulation phenotype are integrated in an attempt to predict clinical risk. Methods: We modeled tissue factor (TF)‐induced thrombin generation in the control population (N = 473) from the Leiden Thrombophilia Study utilizing a numerical simulation model. Hypothetical thrombin generation curves were established by modeling pro‐ and anticoagulant factor levels for each individual. These curves were evaluated using parameters which describe the initiation, propagation and termination phases of thrombin generation, i.e. time to 10 nm thrombin (approximate clot time), total thrombin and the maximum rates and levels of thrombin generated. Results and conclusions: The time to 10 nm thrombin varied over a 3‐fold range (2.9–9.5 min), maximum levels varied over a ∼ 4‐fold range (200–800 nm), maximum rates varied ∼ 4.8‐fold (90–435 nm min−1) and total thrombin varied ∼ 4.5‐fold (39–177 µm s−1) within this control population. Thrombin generation curves, defined by the clotting factor concentrations, were distinguished by sex, age, alcohol consumption, body mass index (BMI) and oral contraceptive (OC) use (OC > sex > BMI > age). Our results show that the capacity for thrombin generation in response to a TF challenge may represent a method to identify an individuals propensity for developing thrombosis.

Association between type II secretory phospholipase A2 plasma concentrations and activity and cardiovascular events in patients with coronary heart disease

AIMS Type II secretory phospholipase A(2) (sPLA(2)-IIA) is widely expressed in various cell types and may trigger local inflammatory responses. We sought to evaluate whether systemic sPLA(2) is associated with prognosis in patients with coronary heart disease (CHD). METHODS AND RESULTS Plasma concentrations of sPLA(2) (ELISA) and sPLA(2) activity (selective fluorometric assay) were measured at baseline in a cohort of 1024 patients aged 30-70 years with CHD. The Cox-proportional hazards model was used to determine the prognostic value of sPLA(2) on a combined cardiovascular disease (CVD) endpoint after adjustment for covariates. During a mean follow-up of 4.1 years, 93 patients (9.1%) experienced a secondary CVD event. In a multivariable model, sPLA(2) mass and activity were associated with hazard ratios of secondary CVD events of 2.07 (95% CI, 1.17-3.66) and 1.65 (95% CI 0.96-2.84) for mass and activity, respectively, when extreme tertiles were compared. Further adjustment for cystatin C, N-terminal-probrain natriuretic peptide, C-reactive protein, and lipoprotein-associated phospholipase A(2) attenuated the associations, still showing a positive trend for mass but a less clear pattern for activity. However, when sPLA(2) mass and activity were analysed as continuous variables both still showed a statistically significant increase in risk in all models. CONCLUSION Secretory phospholipase A(2) mass and activity appear to be predictive of secondary CVD events in patients with CHD.

Hereditary thrombophilia and fetal loss: a prospective follow-up study

Summary.  Background: As the placental vessels are dependent on the normal balance of procoagulant and anticoagulant mechanisms, inherited thrombophilia may be associated with fetal loss. Objectives: We performed a prospective study to investigate the relation between inherited thrombophilia and fetal loss, and the influence of thromboprophylaxis on pregnancy outcome. Patients and methods: Women were enrolled in the European Prospective Cohort on Thrombophilia (EPCOT). These included women with factor (F)V Leiden or a deficiency of antithrombin, protein C or protein S. Controls were partners or acquaintances of thrombophilic individuals. A total of 191 women (131 with thrombophilia, 60 controls) had a pregnancy outcome during prospective follow‐up. Risk of fetal loss and effect of thromboprophylaxis were estimated by frequency calculation and Cox regression modelling. Results: The risk of fetal loss appeared slightly increased in women with thrombophilia without a previous history of fetal loss who did not use any anticoagulants during pregnancy (7/39 vs. 7/51; relative risk 1.4; 95% confidence interval 0.4, 4.7). Per type of defect the relative risk varied only minimally from 1.4 for FV Leiden to 1.6 for antithrombin deficiency compared with control women. Prophylactic anticoagulant treatment during pregnancy in 83 women with thrombophilia differed greatly in type, dose and duration, precluding solid conclusions on the effect of thromboprophylaxis on fetal loss. No clear benefit of anticoagulant prophylaxis was apparent. Conclusions: Women with thrombophilia appear to have an increased risk of fetal loss, although the likelihood of a positive outcome is high in both women with thrombophilia and in controls.

Multiple SNP testing improves risk prediction of first venous thrombosis

There are no risk models available yet that accurately predict a persons risk for developing venous thrombosis. Our aim was therefore to explore whether inclusion of established thrombosis-associated single nucleotide polymorphisms (SNPs) in a venous thrombosis risk model improves the risk prediction. We calculated genetic risk scores by counting risk-increasing alleles from 31 venous thrombosis-associated SNPs for subjects of a large case-control study, including 2712 patients and 4634 controls (Multiple Environmental and Genetic Assessment). Genetic risk scores based on all 31 SNPs or on the 5 most strongly associated SNPs performed similarly (areas under receiver-operating characteristic curves [AUCs] of 0.70 and 0.69, respectively). For the 5-SNP risk score, the odds ratios for venous thrombosis ranged from 0.37 (95% confidence interval [CI], 0.25-0.53) for persons with 0 risk alleles to 7.48 (95% CI, 4.49-12.46) for persons with more than or equal to 6 risk alleles. The AUC of a risk model based on known nongenetic risk factors was 0.77 (95% CI, 0.76-0.78). Combining the nongenetic and genetic risk models improved the AUC to 0.82 (95% CI, 0.81-0.83), indicating good diagnostic accuracy. To become clinically useful, subgroups of high-risk persons must be identified in whom genetic profiling will also be cost-effective.

Evaluating chronic venous disease with a new venous severity scoring system

BACKGROUND The Venous Clinical Severity Score (VCSS) has been proposed by the American Venous Forum as an objective means to clinically assess venous disease more completely than with the clinical CEAP classification. However, validation of the VCSS against an objective test is lacking. The purpose of this study was to test the VCSS against abnormalities found on venous ultrasound (US) scans. METHODS As part of a screening project in a large kindred population with protein C deficiency, VCSS and venous US scanning were performed in 210 patients (420 limbs). A single examiner scored the VCSS (0-3) clinically for pain, varicose veins, edema, skin pigmentation, inflammation, induration, ulcer duration and size, and compressive therapy. Another experienced examiner, blinded to the subjects medical history, performed a US examination of the deep and superficial venous system, with a hand-carried US system. The relationship between US and VCSS scores was analyzed by calculating an odds ratio (OR) and its 95% confidence interval (CI). RESULTS Of the 420 limbs screened, VCSS was 0 in 283 limbs, and VCSS was 1 or greater in the following categories: pain, 63 limbs; varicose veins, 70 limbs; edema, 51 limbs; skin pigmentation, 17 limbs; inflammation, 2 limbs; induration, 8 limbs; and compressive therapy, 9 limbs. The highest total score in any limb was 8. A clear association was seen with the VCSS and abnormalities found on US scans. When the score was dichotomized (0 = normal, 1 = any abnormality), it was a strong predictor of US scan abnormalities; limbs with VCSS greater than 0 had a 26-fold greater chance of US scan abnormalities than did limbs with VCSS = 0 (OR, 26.5; 95% CI, 11-64). With ultrasonography as the standard, sensitivity of VCSS compared with US scans was 89.3%, and specificity was 76.1%. Negative predictive value of VCSS = 0 was 97.9%, and positive predictive value for any positive score was 36.5% CONCLUSIONS The results of this study are based on a large kindred population with a higher risk for venous disease than found in the general population. Though the VCSS was devised to quantify the severity of chronic venous disease, this study found it a useful screening tool. The VCSS showed good association with abnormalities on US scans, and when VCSS = 0 there is a high likelihood that the patient does not have venous disease. This simple test may prove valuable in clinical practice.

Using the common-sense model to predict risk perception and disease-related worry in individuals at increased risk for venous thrombosis.

OBJECTIVE This study applied the Common-Sense Model (CSM) to predict risk perception and disease-related worry in 174 individuals with a genetic predisposition to venous thrombosis (thrombophilia). DESIGN Participants completed an adapted version of the Illness Perception Questionnaire-Revised (IPQ-R) and measures assessing risk perception and worry. RESULTS Regression analyses revealed that illness perceptions were predictors of risk perception and thrombosis worry. The hypothesis that illness perceptions mediate the relationship between a persons experience of venous thrombosis and perceived risk and thrombosis worry could not be confirmed. CONCLUSIONS Further research should refine the IPQ-R for populations at risk of a disease and examine the value of the CSM in explaining the relationship between risk perception, worry, and health behavior.