Spontaneous Venous Thromboembolism Research Articles

Congenital Anomalies of Inferior Vena Cava in Young Patients with Iliac Deep Venous Thrombosis

Venous thromboembolism (VTE) in young patients is frequently associated with hereditary biological thrombophilia, autoimmune disorders, or neoplasia. Advances in venous ultrasound and contrast-enhanced computed tomography have allowed for the identification of inferior vena cava (IVC) anomalies as newly considered etiologic factor. We present two cases of VTE in young patients: the first case involves left IVC in a 22-year-old man and the second involves IVC atresia in a 39-year-old man. IVC anomalies should be identified in young patients with spontaneous VTE involving the iliac veins because they are at a high risk for thrombotic recurrence and adaptation to long periods of antithrombotic therapy.

Long-term prospective study of recurrent venous thromboembolism in a Hispanic population

The aim of this study was to assess the incidence and risk factors for recurrent venous thromboembolism (VTE) in a Hispanic population. We prospectively followed 343 patients after a first episode of objectively proven VTE. We excluded all patients with VTE at unusual sites, older than 70 years old, with neoplasia, liver or renal chronic disease and antiphospholipid syndrome. Predictors for recurrence were evaluated by Cox model. The probability of recurrent VTE was estimated by the method of Kaplan-Meier. The cumulative probability of recurrent VTE was 19.1% in 5 years and 30.0% in 10 years. Male sex [relative risk (RR) 1.7, 95% confidence interval (CI) 1.0-2.8], spontaneous first VTE (RR 2.9, 95% CI 1.7-5.0) and FII G20210A mutation (RR 4.2, 95% CI 1.9-9.4) were independent risk factors for recurrent VTE. The fibrinogen, coagulation factors VIII, IX, X and XI were measured in 200 patients and were not associated to thrombotic recurrence risk. This study indicates that the incidence of recurrent VTE is high in Hispanics and depends on clinical and laboratory findings. In this population, FII G20210A mutation may represent a specific risk factor for recurrence. The inclusion of different ethnic populations in epidemiological studies of VTE as well as new approaches to the management of anticoagulation therapy in Hispanics is warranted.

Risk Stratification of Recurrent Venous Thromboembolism.

Abstract 2981Poster Board II-956 Background:A better risk stratification for recurrent venous thromboembolism (VTE) in patients with a first episode of idiopathic venous thromboembolism (VTE) is urgently needed. Methods:Retrospective study covering more than 20 years after a first venous thromboembolic event in a group of 1,440 patients with VTE. Results:In the subgroup of patients (n=515) with a first spontaneous VTE, the yearly incidence of a recurrent spontaneous VTE was 8% for the time period 0-2 years and 4-6% in the following 8 years, after a first VTE, triggered by a transient risk factor (oral contraceptives, surgery or immobilization, pregnancy), the yearly incidence of a recurrent spontaneous VTE was 2% (first 2 years) and 1.3-3% (following 8 years). The hazard ratio for recurrent spontaneous VTE in patients with a first spontaneous VTE for specific predictors were as follows: prothrombin mutation heterozygous 1.2 (95% CI 0.9-1.7), FVL heterozygous 1.3 (95% CI 0.92-1.8), male sex 1.9 (95% CI 1.4-2.7), D-Dimer 2.3 (0.9-6.4), protein C (<60% activity) 2.6 (95% CI 1.2-5.7), FVL homozygous 3.0 (1.3-7.7), AT (<60% activity) 3.0 (95% CI 0.96-9.6). In Conclusion, in patients with a first spontaneous VTE the yearly recurrence rate of 5% is more than doubled in the presence of relevant thrombophilic risk factors supporting the need of long-term oral anticoagulant therapy after a first idiopathic VTE. In contrast to current ACCP recommendations, thrombophilic risk factors are of clinical relevance. Disclosures:No relevant conflicts of interest to declare.

Prevalence of FACTOR IX-R338L (FACTOR IX PADUA) IN A COHORT of PATIENTS with Venous Thromboembolism and Mild Elevation of FACTOR IX LEVELS.

Abstract 5057 IntroductionElevated plasma levels of blood coagulation factor IX (FIX) have been associated with increased risk of venous thromboembolism (VTE) in humans. However, the molecular mechanisms underlying elevated FIX have not been elucidated. Recently, a mutation in the FIX gene resulting in a FIX molecule with Arginine Leucine substitution at position 338 (FIX-R338L or Factor IX Padua) has been associated with very high levels of FIX (776%) in a patient with spontaneous VTE. Recombinant expression of FIX-R338L confirmed the gain-of-function mutation. ObjectiveHere we evaluated the levels of FIX and the prevalence of Factor IX Padua in a cohort of patients with VTE followed at our center. The prevalence of FIX Padua was evaluated by using a PCR-RFLP strategy by which PCR with specific primers was followed by digestion with the enzyme TaqI. ResultsThe prevalence of FIX Padua was evaluated in a population of 192 patients with spontaneous VTE (69 males and 123 females; median age 36-yo). A population of 192 healthy individuals matched for age, sex and ethnicity was used as a control group for the determination of FIX levels. Median FIX levels was 128.0% (61.0-207.0%) in patients with VTE. Twenty-nine patients presented FIX levels above the 90th percentile (160.2%). Factor IX Padua was not identified in any patients or controls, even in those with elevated FIX levels. Conclusionin the present study FIX Padua was not identified in any of our patients, indicating that this mutation is not associated with mild elevations of FIX levels frequently observed in patients with VTE. DisclosuresNo relevant conflicts of interest to declare.

Prediction of Recurrent Venous Thromboembolism by Endogenous Thrombin Potential and D-Dimer

Increased thrombin generation is associated with an increased risk of recurrent venous thromboembolism. We investigated the relation between endogenous thrombin potential (ETP) and risk of recurrent venous thromboembolism and evaluated whether prediction of recurrence can be improved by a combined analysis of ETP and D-dimer. We followed 861 patients with first spontaneous venous thromboembolism and determined ETP and D-dimer after discontinuation of anticoagulation. Patients with natural inhibitor deficiency, lupus anticoagulant, or cancer were excluded. The study endpoint was symptomatic recurrent venous thromboembolism. One hundred thirty patients (15.1%) had recurrence. High ETP (> or = 100%) conferred a 1.6-fold increased risk of recurrence (95% CI 1.1-2.3) after adjustment for age, sex, factor V Leiden, factor II G20210A, and duration of anticoagulation. After adjustment for D-dimer, risk of recurrence remained significantly higher among patients with high ETP [hazard ratio 1.6 (95% CI 1.01-2.4)]. After adjustment for ETP, high D-dimer (> or = 0.5 mg/L) conferred a 1.8-fold (95% CI 1.1-2.8) increased risk of recurrence. Compared with patients with low ETP and low D-dimer, risk of recurrence was 2.8-fold (95% CI 1.5-5.3) higher among patients with both high ETP and high D-dimer after adjustment for potential confounders. ETP and D-dimer are independent predictors of recurrent venous thromboembolism. Assessing risk of recurrence can be optimized by combining these indicators of thrombin generation.

Serial D-Dimer Measurements Are Useful in Predicting the Recurrence of Venous Thromboembolism after Discontinuation of Anticoagulation

The optimal duration of anticoagulation following a venous thromboembolism (VTE) is influenced by the site of the event and the presence of risk factors. After anticoagulation is discontinued, approximately 10% of patients will have a recurrent event. At present, there is no accurate method of identifying this group of patients, in whom the benefits of reanticoagulation may outweigh the bleeding risks. In 2006, Palaretti et al reported the use of a single qualitative d-dimer measurement, 4 weeks after stopping anticoagulation for a spontaneous VTE, to identify patients at increased risk of a recurrent VTE. Our observational study investigates whether serial quantitative d-dimer measurements, after the discontinuation of anticoagulation for VTE, are of use in identifying patients at higher risk of VTE recurrence. We followed an unselected group of patients attending a hospital based Thrombosis Clinic in whom anticoagulation for VTE was stopped. Over a 2 year period from July 2005 to July 2007, anticoagulation was discontinued in 216 patients (112 females, 104 males) after a median period of 6 months' treatment (range 2–324 months). The patients ranged in age from 16–88 years, with a mean age of 54 years. Of the group, 146 had been anticoagulated for a deep vein thrombosis (DVT), 59 for pulmonary embolism (PE) +/− DVT, and 11 had been anticoagulated for VTE at other sites. Major risk factors for VTE (recent surgical procedure, malignancy, pregnancy) were present at diagnosis in 80 patients. Minor risk factors (minor trauma, prolonged travel or immobility, hormone therapy) were present in 61 patients, while no risk factors were identified in 69 patients. Presence of risk factors was unknown in the remaining 6 patients. After discontinuation of their anticoagulation, patients were followed up in the Thrombosis Clinic for a median of 14.5 months (range 0–41 months). D-dimer measurements were recorded at the point of stopping anticoagulation, 4 weeks later, and then on subsequent clinic visits. Quantitative d-dimer results were obtained using an automated latex immunoassay (Instrumentation Laboratories, d-dimers HS) on an ACL TOP CTS analyser. Recurrence of VTE occurred in 23 of the 216 (10.7%) patients. D-dimer results off anticoagulation were available in 207 patients. Forty six patients had repeatedly high d-dimer measurements (> 300ng/ml) off anticoagulation. D-dimers remained within the normal range in 112 patients. In 33 patients, d-dimers were initially normal, but subsequently became high, while the opposite was true in 16 patients, where initially high d-dimers later fell into the normal range. Of the recurrences, 8 occurred in the group who had repeatedly high d-dimers after anticoagulation was stopped (17.4%), whilst only 3 recurrences occurred in patients whose d-dimers were consistently normal (2.7%). In the group whose d-dimers were initially normal, but subsequently became high during follow up, there were 6 recurrences (18.2%). There was 1 recurrence in the group whose d-dimers were initially high, but then became normal. In the 9 patients in whom serial d-dimer results were not available, 5 recurrent VTE were observed: 4 of these occurred within 4 weeks of the patient stopping anticoagulation. After statistical analysis of the data, taking into account the nature of the original event, age, gender and d-dimer measurements, a high d-dimer off anticoagulation was the only significant independent variable predicting for recurrence of VTE (Chi-square 13.1 p<0.00001). This data supports a role for monitoring d-dimer measurements in identifying patients at increased risk of VTE recurrence. Further investigation is needed to establish the benefits of reanticoagulation in these patients.

6 versus 30 months anticoagulation for recurrent venous thrombosis in patients with high factor VIII

Patients with first venous thromboembolism (VTE) and high factor VIII (FVIII) are at increased risk of recurrence. It is unknown whether these patients benefit from prolonged secondary thrombophrophylaxis. In a prospective trial patients with first spontaneous VTE and FVIII levels >230 IU/dl were randomized to discontinue vitamin K Antagonist (VKA) after 6 months or to continue VKA for additional 24 months. Patients were excluded if they had a natural inhibitor deficiency, lupus anticoagulant, cancer, were pregnant, required long-term antithrombotic therapy or had acute-phase reaction. Primary study endpoints were symptomatic recurrent VTE or major bleeding within 2 years. Follow-up was continued beyond 2 years. Of 3,219 screened patients 34 met the inclusion criteria. Mean observation time was 37 months. Two of 17 patients allocated to discontinue VKA and two of 17 patients randomized to prolonged anticoagulation had recurrent VTE within 2 years. In the prolonged treatment group, one patient had recurrence during VKA therapy and one patient 4 weeks after voluntary discontinuation of VKA. One major nonfatal bleeding (severe epistaxis) after 10 months of VKA occurred in the prolonged treatment group. Five patients allocated to prolonged anticoagulation had recurrent VTE after discontinuation of VKA. The probability of recurrence at 2 years after discontinuation of VKA was 30% (95% CI 13-46%). Patients with high FVIII are at increased risk of recurrence. Our findings in a small number of patients indicate that prolonged anticoagulation seems to be effective but that the benefit is not maintained after discontinuation of anticoagulation.

Association of venous thromboembolism and olanzapine

Aims:Venous thromboembolism (VTE) has been associated with the diagnosis of a psychiatric disease, as well as with the treatment with psychotropic drugs. Recent reports suggest an association between several atypical antipsychotics agents (eg. olanzapine) and an increased risk for VTE.Methods:We prospectively analysed and consequently followed-up olanzapine users in a cohort of 138 consecutive patients under 60 years of age (male=72, mean age 45 years) suffering from objectively confirmed VTE over a three-year period (2004 - 2006). Data on known acquired or genetic risk factors for VTE were recorded for each patient.Results:Four Caucasian patients (one female, three males; mean age 49 years, range 37-55 years) with spontaneous VTE treated with olanzapine were registered. Two patients were obese. The hospitalization was extended in the female patient. We found coagulation abnormalities in all our subjects (elevated levels of factor VIII:C, mild hyperhomocysteinemia, FV Leiden and prothrombin gene G20210A mutations).Conclusions:These cases indicate that VTE might be associated with the use of olanzapine, at least in the presence of several acquired or inherited risk factors such as immobilization, obesity and disorders of coagulation homeostasis including factor V Leiden, prothrombin gene G20210A mutations, high levels of factor VIII and hyperhomocysteinemia. Subjects treated with olanzapine should be monitored clinically for VTE. Interestingly, in three patients symptoms occurred in the first six months of olanzapine treatment.

A Clinical Perspective of Venous Thromboembolism

A large number of individuals develop venous thromboembolism (VTE) every year.1 Each patient’s episode of DVT or PE is, naturally, unique. To highlight a variety of aspects about VTE a compilation case is presented that is composed of clinical data and images from several real patients. ### History of Present Illness A 36-year-old woman presents to the Emergency Department with severe shortness of breath and moderately intense anterior chest pain, worse on deep inspiration, which had started suddenly that morning. She also reports a 6-wk history of mild shortness of breath, for which she had been seen 4 wk earlier by her primary care physician who diagnosed her with “asthma.” Bronchodilators and steroids were prescribed but led to no significant improvement in her symptoms. She also gives a history of mild left calf pain that had started about 2 months earlier without preceding trauma, immobilization, or surgery. Her primary care physician had seen her and prescribed Ibuprofen for a “pulled muscle.” However, in the 1 week before her present presentation her leg symptoms worsened, and she had increased diffuse leg pain and swelling and slightly bluish discoloration of the whole leg. Her past medical history is only significant for an appendectomy at age 16. She has never been pregnant. She is on no medications, except for an estrogen and progestin-containing oral contraceptive, started 10 months earlier. She does not smoke. There is no family history of venous thromboembolism, although the patient reports that her paternal grandmother had a “swollen leg for many years” until she died in her 70’s, but no further details are known of the patient. ### Physical Examination The patient’s weight is 86 kg and her height 165 cm, calculating to a body mass index (weight divided by [height in meters]2) of 31.6 kg/m2, ie, she has grade 1 obesity. Her …

Abstract 3611: Cardiovascular risk factors and venous thromboembolism: A meta-analysis

Background: The concept that venous thromboembolism (VTE) and atherosclerosis are two distinct entities has recently been challenged. Patients with spontaneous VTE had more asymptomatic carotid atherosclerotic lesions and a higher incidence of cardiovascular disease than patients with VTE secondary to known risk factors and controls. However, no clear relationship between cardiovascular risk factors and VTE has ever been determined. We performed a meta-analysis to assess the potential association between well known cardiovascular risk factors and VTE. Methods: Medline and EMBASE databases were searched to identify studies that evaluated the prevalence of major cardiovascular risk factors in VTE patients and in controls. The studies were selected using a priori defined criteria and each study was reviewed by two authors who abstracted data on study characteristics, study quality and outcomes. Odds Ratio (OR) or weighted mean differences and 95% confidence intervals (CI) were calculated and pooled using a random-effects model. Statistical heterogeneity was evaluated using the I 2 statistic. Results: Twenty-one case-control and cohort studies with a total of 63.552 patients met the inclusion criteria. Compared to controls, the risk of VTE was 2.33 for obesity (95% CI 1.68 –3.24), 1.51 for hypertension (1.23–1.85), 1.42 for diabetes (1.12–1.77), 1.18 for smoking (0.95–1.46), and 1.16 for hypercholesterolemia (0.67–2.02). Weighted mean HDL cholesterol levels were significantly lower in VTE patients compared to controls, whereas no difference was observed in total cholesterol and LDL cholesterol levels. Significant heterogeneity among studies was detected in all subgroups, except for diabetes. Higher quality studies were more homogeneous and, except for hypertension, the significant associations remained unchanged. Discussion: Common cardiovascular risk factors are associated with an increased risk of VTE. This association between VTE and atherothrombosis has obvious clinical implications with respect to screening, risk factor modification and future therapy. Future prospective studies could investigate underlying mechanisms of this two-way relation.

Endothelial dysfunction in patients with spontaneous venous thromboembolism

A high incidence of atherosclerotic lesions and cardiovascular events has been reported in patients with spontaneous venous thromboembolism. Endothelial dysfunction is an early marker of atherosclerosis and has predictive value for ischemic events. We have evaluated endothelial function in patients with a history of spontaneous venous thromboembolism. Patients with a history of symptomatic, objectively confirmed, spontaneous venous thromboembolism were included in a case-control study. Exclusion criteria were any known risk factors for cardiovascular diseases, other conditions associated with endothelial dysfunction, estro-progestinic therapy or pregnancy. Controls were age- (+/-5 years) and sex-matched subjects with the same exclusion criteria but without previous venous thromboembolism. Endothelial function was evaluated by the non-invasive measurement of flow-mediated vasodilation of the brachial artery and of plasma markers of endothelium activation; platelet activation parameters were also measured. Twenty-eight cases (8 females; mean age 59+/-15 years) and 28 controls (8 females; mean age 58+/-15) were studied. Flow-mediated vasodilation was 3.5+/-0.6% in cases (95% CIs: 2.2 to 4.8) and 5.7+/-0.6% (4.2 to 6.8) in controls (p=0.015). Brachial artery blood flow and hyperemic blood flow did not differ between the two groups. Plasma von Willebrand factor and soluble P-selectin levels were significantly higher in patients with venous thromboembolism, while plasma soluble CD40 ligand and urinary 11-dehydro-TxB2 levels were similar in cases and controls. Patients with spontaneous venous thromboembolism have endothelial dysfunction, unlike age- and sex- matched controls. This finding suggests that spontaneous venous thromboembolism may be a condition associated with an enhanced risk of atherosclerosis.

High-Density Lipoprotein and the Risk of Recurrent Venous Thromboembolism

High-density lipoprotein (HDL) protects against arterial atherothrombosis, but it is unknown whether it protects against recurrent venous thromboembolism. We studied 772 patients after a first spontaneous venous thromboembolism (average follow-up 48 months) and recorded the end point of symptomatic recurrent venous thromboembolism, which developed in 100 of the 772 patients. The relationship between plasma lipoprotein parameters and recurrence was evaluated. Plasma apolipoproteins AI and B were measured by immunoassays for all subjects. Compared with those without recurrence, patients with recurrence had lower mean (+/-SD) levels of apolipoprotein AI (1.12+/-0.22 versus 1.23+/-0.27 mg/mL, P<0.001) but similar apolipoprotein B levels. The relative risk of recurrence was 0.87 (95% CI, 0.80 to 0.94) for each increase of 0.1 mg/mL in plasma apolipoprotein AI. Compared with patients with apolipoprotein AI levels in the lowest tertile (<1.07 mg/mL), the relative risk of recurrence was 0.46 (95% CI, 0.27 to 0.77) for the highest-tertile patients (apolipoprotein AI >1.30 mg/mL) and 0.78 (95% CI, 0.50 to 1.22) for midtertile patients (apolipoprotein AI of 1.07 to 1.30 mg/mL). Using nuclear magnetic resonance, we determined the levels of 10 major lipoprotein subclasses and HDL cholesterol for 71 patients with recurrence and 142 matched patients without recurrence. We found a strong trend for association between recurrence and low levels of HDL particles and HDL cholesterol. Patients with high levels of apolipoprotein AI and HDL have a decreased risk of recurrent venous thromboembolism.

Prediction of recurrent venous thromboembolism by measuring ProC Global

In patients with venous thromboembolism (VTE) a laboratory assay that globally measures the overall thrombophilic tendency is not available. We hypothesized that determination of ProC((R)) Global, a plasma assay which tests the global function of the protein C pathway, could be used to stratify patients according to their risk of recurrent VTE. We prospectively followed 774 patients with first spontaneousVTE for a mean time of 52 months. ProC Global normalized ratio (NR) was measured in plasma by use of a commercially available assay based on activated partial thromboplastin time. Ninety-eight of the 774 patients had recurrentVTE. Patients with ProC Global NR > or = 0.75 had a relative risk of recurrence of 0.59 (95% CI 0.40-0.87) as compared with those with lower ratio. After four years, cumulative probability of recurrence was 8.6% in patients with ProC Global NR > or = 0.75 and 17.4% in patients with a lower ratio (p = 0.006). Patients with a high ProC Global NR have a low risk of recurrent VTE. ProC Global NR can be used to stratify patients with a first unprovoked VTE according to their risk of recurrence.

Identification Of Patients At Low Risk For Recurrent Venous Thromboembolism By Measuring Thrombin Generation

Conclusion: Patients at low risk for recurrent venous thromboembolism (VTE) can be identified by measurement of thrombin generation. Summary: Patients with VTE are often investigated for thrombophilic risk factors. The large number of potential thrombophilic risk factors makes this complex and expensive. The authors sought to determine whether the risk of recurrent VTE could be assessed by a global coagulation assay that measures thrombin generation. This was a prospective cohort study of 914 patients. All patients had a spontaneous VTE and were followed for an average of 47 months after discontinuation of oral anticoagulant therapy. The study period was from July 1992 to July 2005. A commercially available assay was used to measure thrombin generation. Excluded patients included those with secondary VTE, those with recurrent VTE, or those with a known thrombophilic risk factor such as antithrombin, protein C or protein S deficiencies, the presence of lupus anticoagulant, or cancer or pregnancy. The primary outcome measure was an objectively documented episode of recurrent VTE. VTE recurred in 100 patients (11%). There was lower thrombin generation in the patients without recurrent VTE compared with those with recurrent VTE (349.2 ± 108 nN vs 415 ± 110.5 nN, P < .001). In patients with thrombin generation values between 400 nN and 300 nN, the relative risk of recurrence compared to patients with thrombin generations >400 nN was 0.42 (95% confidence interval [CI], 0.26 to 0.67, P < .001). In patients with measured thrombin generations <300 nN relative risk was 0.37 (95% CI, 0.21 to 0.66, P = .001). For 4 years, the probability of VTE recurrence in patients with thrombin generation <400 nN was 6.5% (95% CI, 4.0% to 8.9%). In those patients with thrombin generation values >400, the probability of VTE recurrence was 20.0% (95% CI, 14.9% to 25.1%, P < .001). Patients with thrombin generation <400 nN had a 60% lower recurrence of VTE than those with greater values of thrombin generation (relative risk, 0.40; 95% CI, 0.27 to 0.60; P < .001. Comment: There are data to suggest that patients with idiopathic VTE benefit from longer periods of anticoagulation than those with VTE and a recognizable risk factor such as surgery or trauma. Given the implications of long-term anticoagulant therapy, it is desirable to identify which patients with idiopathic VTE are particularly prone to recurrence. If this study can be confirmed by others, measurement of thrombin generation may prove to be a relatively simple method of stratifying patients for their length of anticoagulation after a first time episode of idiopathic VTE.

Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) Polymorphism 663 C>T Affects Clotting Factor VIII Activity and Increases the Risk of Venous Thromboembolism.

Clotting factor VIII (FVIII) is an independent risk factor for primary and recurrent venous thromboembolism (VTE). Various causes for high plasma FVIII levels have been identified and an involvement of genetic factors has been demonstrated. Currently, the underlying genetic components have not been fully elucidated. A multifunctional endocytic receptor, low-density lipoprotein receptor-related protein 1 (LRP1), mediates cellular uptake and subsequent degradation of factor VIII, and seems to contribute to variations in FVIII levels. We assessed the effect of a genetic variation in the coding region of the LRP1 gene (LRP1 663C>T) on basal FVIII levels and the risk of venous thrombosis in a high risk group of patients and healthy controls. One-hundred-fifty-two patients with a history of recurrent VTE (median age = 56 years, 25th – 75th percentile: 44 – 63, 47% women) were compared with 198 age- and sex-matched healthy controls (median age = 53 years, 25th – 75th percentile: 44–59, 50% women) in a case-control study. All patients had at least one spontaneous VTE. The LRP1 663C>T genotype was analysed by mutagenic separated polymerase chain reaction assay. Heterozygosity was confirmed by sequence analysis in all cases. The LRP1 663CC genotype was found in 138 patients and 190 controls, LRP1 663CT in 14 patients and 8 controls, respectively. No homozygous individuals were identified. Genotype distributions did not significantly deviate from Hardy-Weinberg-equilibrium in patients (p=0.6) and controls (p=0.8). Heterozygous individuals were approximately twice as frequent among patients as controls (9% versus 4%, p=0.048). LRP1 663CT was associated with increased odds for VTE in multivariate analysis adjusted for blood group 0, factor V Leiden and the prothrombin variation 20210G>A (OR=3.3, 95% CI [1.3–8.5]). In all study participants (n=350) LRP1 663CT carriers (n=22) had significantly higher factor VIII activity (median=193%, 25th − 75th percentile: 158 – 222) than LRP1 663CC carriers (n=328, median=160%, 25th – 75th percentile: 125 – 195, p=0.01). Blood group 0 was significantly less frequent among patients (18 %) than controls (32 %, p = 0.002) and was associated with significantly lower factor VIII activity levels (n=91, median: 118%, 25th – 75th percentile: 95 – 155) compared to blood group non-0 (n=259, median: 175%, 25th – 75th percentile: 143 – 212, p < 0.001). Particularly high factor VIII activity levels were found in persons with a combination of LRP1 663CT and an AB0 blood group non-0 (n=16, median: 209%, 25th – 75th percentile: 192 – 231). In conclusion, we present evidence that the LRP1 663C>T polymorphism is associated with higher factor VIII plasma levels. Our study is the first report of a significantly increased thrombosis risk in heterozygous carriers of the LRP1 663C>T polymorphism. Prospective studies will have to prove, whether this parameter could serve as predictive marker for risk of venous thrombosis.

Risk of Recurrent Venous Thromboembolism Reduced by High Density Lipoproteins.

Venous thrombosis is clinically distinct from arterial thrombosis, with notable differences in thrombus appearance, pathogenic mechanisms, and therapeutic approaches. High-density lipoprotein (HDL) protects against arterial atherothrombosis, but it is not known if HDL protects against recurrent venous thromboembolism. We hypothesized that HDL protects against recurrent venous thrombosis because of its multiple antithrombotic and anti-inflammatory actions. These protective activities include down-regulation of thrombin generation by acting as an anticoagulant cofactor for activated protein C/protein S, enhancement of protective endothelial nitric oxide synthase activity, reduction of leukocyte adhesion to endothelium, and anti-apoptotic effects on endothelium. To test our hypothesis, we prospectively studied 772 patients who had a first episode of spontaneous venous thromboembolism. During an average follow-up observation period of 48 months we recorded the end point of objectively documented, symptomatic recurrent venous thromboembolism. Patients with a genetic deficiency of a plasma coagulation inhibitor deficiency, with a lupus anticoagulant, or with cancer as well as those who required long-term antithrombotic treatment or were on statin therapy were excluded. The relationship between plasma lipoprotein parameters and recurrence of venous thrombosis was evaluated. Plasma apolipoproteins AI and B were measured by immunoassays for all subjects. Using NMR, we determined the levels of ten major lipoprotein subclasses in plasma for 99 patients with venous thrombosis recurrence and for 297 matched patients without recurrence. Recurrent venous thromboembolism developed in 100 of the 772 patients (12.8%). Patients with recurrence compared to those without recurrence had lower mean (±SD) plasma levels of apolipoprotein AI (1.12±0.22 vs. 1.23±0.27 mg/ml, P<0.001) but similar apolipoprotein B levels. The relative risk of recurrence was 0.87 (95% CI, 0.80 to 0.94) for each increase of 0.1 mg/ml in plasma apolipoprotein AI. For patients with apolipoprotein AI above the 67th percentile of the study population values compared with those with lower levels, the relative risk of recurrence was 0.51 (95% CI 0.32–0.83). Comparisons of plasma lipoprotein particle levels from subjects with recurrence versus those without recurrence gave similar results showing that HDL particle concentrations were lower in subjects with recurrence. Patients with high levels of apolipoprotein AI, HDL-cholesterol, and large HDL particles had decreased risk of recurrent venous thromboembolism. In summary, these novel findings that HDL appears to protect against recurrent venous thrombosis may have implications for testing HDL parameters to predict risk and may imply that lipid-altering drugs that increase HDL might reduce the risk for first or recurrent venous thrombotic events.

Identification of Patients at Low Risk for Recurrent Venous Thromboembolism by Measuring Thrombin Generation

Screening of patients with venous thromboembolism (VTE) for thrombophilic risk factors is common clinical practice. Because of the large number of risk factors, assessing the risk of recurrence in an individual patient is complex. A method covering multicausal thrombophilia is therefore required. To investigate the relationship between recurrence of VTE and a simple global coagulation assay measuring thrombin generation. Prospective cohort study of 914 patients with first spontaneous VTE who were followed up for an average of 47 months after discontinuation of vitamin K antagonist therapy. The study was conducted at the Department of Internal Medicine I, Medical University of Vienna, Vienna, Austria, between July 1992 and July 2005. Thrombin generation was measured by a commercially available assay system. Patients with a previous or secondary VTE; antithrombin, protein C, or protein S deficiencies; presence of lupus anticoagulant; cancer; or pregnancy were excluded. Objectively documented symptomatic recurrent VTE. Venous thromboembolism recurred in 100 patients (11%). Patients without recurrent VTE had lower thrombin generation than patients with recurrence (mean [SD], 349.2 [108.0] nM vs 419.5 [110.5] nM, respectively; P<.001). Compared with patients who had thrombin generation greater than 400 nM, the relative risk (RR) of recurrence was 0.42 (95% confidence interval [CI], 0.26-0.67; P<.001) in patients with values between 400 nM and 300 nM; for patients with lower values, the RR was 0.37 (95% CI, 0.21-0.66; P = .001). After 4 years, the probability of recurrence was 6.5% (95% CI, 4.0%-8.9%) among patients with thrombin generation less than 400 nM compared with 20.0% (95% CI, 14.9%-25.1%) among patients with higher values (P<.001). Patients with thrombin generation less than 400 nM, representing two thirds of patients, had a 60% lower RR of recurrence than those with greater values (RR, 0.40; 95% CI, 0.27-0.60; P<.001). Measurement of thrombin generation identifies patients at low risk for recurrent VTE.

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®, 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.

The Standard is Still the Standard or Why an INR of 2–3 is Still the Optimal Intensity for Secondary Prevention of Venous Thromboembolism

The optimal intensity of warfarin anticoagulation for secondary prevention of venous thromboembolism is debatable. Recent studies have shed light on the issue. The two pivotal studies, ELATE and PREVENT, are reviewed and discussed. Although the ELATE and PREVENT studies offer different conclusions, the results of the two studies are consistent with each other. Low intensity warfarin is more efficacious than placebo, although it is less efficacious than standard intensity and offers no safety advantage. For long term secondary prophylaxis of spontaneous venous thromboembolism, the optimal INR intensity of warfarin remains 2.0-3.0.

Interleukin-6 and interleukin-6 promoter polymorphism (−174) G&gt;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.