Mirko Hirschl

HIGH PLASMA LEVELS OF FACTOR VIII AND THE RISK OF RECURRENT VENOUS THROMBOEMBOLISM

BACKGROUND A high plasma level of factor VIII is a risk factor for venous thromboembolism. We evaluated the risk of a recurrence of thrombosis after an initial episode of spontaneous venous thromboembolism among patients with high plasma levels of factor VIII. METHODS We studied 360 patients for an average follow-up period of 30 months after a first episode of venous thromboembolism and discontinuation of oral anticoagulants. Patients who had recurrent or secondary venous thromboembolism, a congenital deficiency of an anticoagulant, the lupus anticoagulant, hyperhomocysteinemia, cancer, or a requirement for long-term treatment with antithrombotic drugs or who were pregnant were excluded. The end point was objectively documented, symptomatic recurrent venous thromboembolism. RESULTS Recurrent venous thromboembolism developed in 38 of the 360 patients (10.6 percent). Patients with recurrence had higher mean (+/-SD) plasma levels of factor VIII than those without recurrence (182+/-66 vs. 157+/-54 IU per deciliter, P=0.009). The relative risk of recurrent venous thrombosis was 1.08 (95 percent confidence interval, 1.04 to 1.12; P<0.001) for each increase of 10 IU per deciliter in the plasma level of factor VIII. Among patients with a factor VIII level above the 90th percentile of the values in the study population, the likelihood of recurrence at two years was 37 percent, as compared with a 5 percent likelihood among patients with lower levels (P<0.001). Among patients with plasma factor VIII levels above the 90th percentile, as compared with those with lower levels, the overall relative risk of recurrence was 6.7 (95 percent confidence interval, 3.0 to 14.8) after adjustment for age, sex, the presence or absence of factor V Leiden or the G20210A prothrombin mutation, and the duration of oral anticoagulation. CONCLUSIONS Patients with a high plasma level of factor VIII have an increased risk of recurrent venous thromboembolism.

Overweight, Obesity, and the Risk of Recurrent Venous Thromboembolism

BACKGROUND Excess body weight is a risk factor for a first venous thromboembolism. The impact of excess body weight on risk of recurrent venous thrombosis is uncertain. METHODS We studied 1107 patients for an average of 46 months after a first unprovoked venous thromboembolism and withdrawal of anticoagulant therapy. Excluded were pregnant patients, those requiring long-term antithrombotic treatment, and those who had a previous or secondary thrombosis, natural coagulation inhibitor deficiency, lupus anticoagulant, or cancer. Our study end point was symptomatic recurrent venous thromboembolism. RESULTS A total of 168 patients had recurrent venous thromboembolism. Mean (SD) body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) was significantly higher among patients with recurrence than among those without recurrence: 28.5 (6.0) vs 26.9 (5.0) (P = .01). The relationship between excess body weight and recurrence was linear; the adjusted hazard ratio for each 1-point increase in BMI was 1.044 (95% confidence interval [CI], 1.013-1.076) (P < .001). Four years after discontinuation of anticoagulant therapy, the probability of recurrence was 9.3% (95% CI, 6.0%-12.7%) among patients of normal weight and 16.7% (95% CI, 11.0%-22.3%) and 17.5% (95% CI, 13.0%-22.0%) among overweight and obese patients, respectively. Compared with patients of normal weight, the hazard ratio of recurrence adjusted for age, sex, factor V Leiden, prothrombin G20210A mutation, high factor VIII levels, and type of initial venous thromboembolic event was 1.3 (95% CI, 0.9-1.9) (P = .20) among overweight patients and 1.6 (95% CI, 1.1-2.4) (P = .02) among obese individuals. The population attributable risk corresponding to excess body weight was 26.8% (95% CI, 5.3%-48.2%). CONCLUSION Excess body weight is a risk factor of recurrent venous thromboembolism.

Clinical Studies and Thrombin Generation in Patients Homozygous or Heterozygous for the G20210A Mutation in the Prothrombin Gene

A genetic variation in the prothrombin gene, the G-->A transition at nucleotide 20210, is a risk factor for venous thrombosis in heterozygotes and is associated with increased prothrombin activity. The homozygous phenotype and the extent of thrombin generation in heterozygous and homozygous subjects are unknown. We investigated a family that included 2 homozygous and 5 heterozygous carriers of the 20210 A allele. The homozygous propositus and his presumably heterozygous father suffered from deep-vein thrombosis. His presumably heterozygous mother and his homozygous sister had recurrent phlebitis at a young age. The remaining 5 affected family members are still asymptomatic. We studied thrombin generation in the family and in 22 unrelated carriers of the 20210 A allele by measuring (1) prothrombin fragment F1+2 (F1+2) as an index of ongoing thrombin generation and (2) the endogenous thrombin potential (ETP) as an index of the possible thrombin-forming capacity. Their F1+2 levels were not different from those of age-matched controls, and thus, ongoing hemostatic system activation was not detectable. A significantly increased ETP was found in the heterozygous carriers of the 20210A allele compared with the controls (527.8+/-114.9 versus 387+/-50.1 nmol/L x min, P<0.0001). In the 2 homozygotes, the ETP was almost twice (639 and 751 nmol/L x min, respectively) as high as in the controls. We conclude that homozygosity for the G20210A mutation in the prothrombin gene is associated with a severe, albeit more benign, thrombotic diathesis compared with homozygosity for deficiencies of antithrombin, protein C, or protein S. In carriers of the 20210 A allele, the pathomechanisms leading to thrombosis should be sought in the higher amounts of thrombin that may be formed once thrombin generation is triggered, rather than in ongoing thrombin generation in vivo.

Tissue factor pathway inhibitor and the risk of recurrent venous thromboembolism

Tissue factor pathway inhibitor (TFPI) regulates factor X activation. Low TFPI is a risk factor for a first venous thrombosis. We evaluated whether low TFPI confers an increased risk of recurrent venous thromboembolism (VTE). TFPI-free antigen was measured in 611 patients with a first spontaneous VTE, and who were prospectively followed after withdrawal of anticoagulation. The endpoint was symptomatic recurrent VTE. The relative risk (RR) of recurrence increased from 1.0 (95% CI 0.4-2.6) in patients with TFPI levels < or = 5th percentile to 2.7 (95% CI 1.0-7.4) in patients with levels < or = 2nd percentile as compared with higher levels. At five years, the probability of recurrence was 48.6% (95th CI 19.0-78.1) among patients with TFPI < or = 2nd percentile and 16.8% (95th CI 13.8-19.8) among those with higher levels (p=0.04). Compared to patients with wild type factor V and high TFPI, the RR of recurrence was 1.1 (95% CI 0.7-1.7) in patients with factor V Leiden and high TFPI, 2.3 (95% CI 0.6-9.5) in patients with wild type factor V and low TFPI and 3.5 (95% CI 0.9-14.3) in patients with factor V Leiden and low TFPI. In a multivariate analysis,the high risk of recurrence in carriers of factor V Leiden and low TFPI slightly decreased [RR 2.8 (95% CI 0.6-9.5)]. We conclude that thrombosis patients with low levels of free TFPI are at an increased risk of recurrent VTE.

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.

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.

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.