Search

Background: Patients with venous thromboembolic disease may present with different clinical manifestations. Factor V Leiden mutation leading to resistance to activated protein C is associated with a sevenfold increased risk for presenting with deep-vein thrombosis. It is not yet established whether carriers of the mutation have a similarly increased risk for manifesting with pulmonary embolism., Methods: From an Anticoagulation Clinic monitoring coumarin therapy, a consecutive series of patients with a first thromboembolic event (objectively proven by current radiological methods) were enrolled. All patients were interviewed and blood was drawn for genotyping. From the hospital charts and the personal interview, information was obtained on acquired risk factors and the signs and symptoms on hospital admission., Results: 45 patients presented with symptoms of pulmonary embolism only, 211 had only symptoms of deep-vein thrombosis whereas 23 had clinical features of both. In about half of the patients acquired risk factors for venous thromboembolism were present which did not differ between the three groups of patients. Recent surgery had been performed more often in patients presenting with pulmonary embolism than in other patients (33.3% vs. 18.5%, p < 0.05). Factor V Leiden was present in 9% of the patients presenting with pulmonary embolism (relative risk: 3.3 95% CI: 1.0-10.6) and 17% of the patients presenting with deep-vein thrombosis (relative risk: 6.9 95% CI: 3.6-12.8). The prevalence of factor V Leiden was intermediate in patients with both clinical characteristics., Conclusion: These data suggest that patients with venous thromboembolism have different clinical presentation depending on the risk factor profile. Factor V Leiden may preferentially lead to manifest deep-vein thrombosis. Differences in structure of venous thrombi could underlie differences in embolic tendency.

Background: Previous studies have suggested that hyperhomocysteinemia may be a risk factor for venous thrombosis. To assess the risk of venous thrombosis associated with hyperhomocysteinemia, we studied plasma homocysteine levels in patients with a first episode of deep-vein thrombosis and in normal control subjects., Methods: We measured plasma homocysteine levels in 269 patients with a first, objectively diagnosed episode of deep-vein thrombosis and in 269 healthy controls matched to the patients according to age and sex. Hyperhomocysteinemia was defined as a plasma homocysteine level above the 95th percentile in the control group (18.5 micromol per liter)., Results: Of the 269 patients, 28 (10 percent) had plasma homocysteine levels above the 95th percentile for the controls, as compared with 13 of the controls (matched odds ratio, 2.5; 95 percent confidence interval, 1.2 to 5.2). The association between elevated homocysteine levels and venous thrombosis was stronger among women than among men and increased with age. The exclusion of subjects with other established risk factors for thrombosis (e.g., a deficiency of protein C, protein S, or antithrombin; resistance to activated protein C; pregnancy or recent childbirth; or oral-contraceptive use) did not materially affect the risk estimates., Conclusions: High plasma homocysteine levels are a risk factor for deep-vein thrombosis in the general population.

Protein C is a vitamin K-dependent zymogen of a serine protease that inhibits blood coagulation by proteolytic inactivation of factors Va and VIIIa. Individuals with protein C deficiency are at risk for thrombophlebitis, deep-vein thrombosis, and pulmonary embolism. Genetic analysis of a number of randomly chosen healthy individuals revealed three polymorphisms, C/T at -654, A/G at -641, and A/T at -476, in the protein C promoter region. To investigate whether these genetic variations associate with the plasma protein C level, we determined the genotype for the three polymorphisms and measured plasma protein C levels in 240 individuals not deficient in protein C. The mean protein C level of these individuals was 103%. Interestingly, individuals with the homozygous CGT genotype (n = 40) had a mean protein C level of 94%, whereas individuals with a homozygous TAA genotype (n = 28) had a mean protein C level of 116%. This difference in mean protein C levels between the CGT and TAA groups (P < .001) could not be explained by environmental factors known to influence protein C levels in the normal population. Plasma factor II and factor X levels did not differ between the two groups, which makes a difference in liver function an unlikely cause. Finally, we tested whether the genotype associated with lower protein C levels is associated with higher thrombotic risks. This analysis showed that compared with the genetic variant associated with higher protein C levels (TT/AA/AA), the genetic variant associated with lower protein C levels (CC/GG/TT genotype) is indeed a risk factor for thrombosis (OR, 1.6; 95% confidence interval, 1.0 to 2.5).

Because the relationship between factor XII deficiency and venous thrombosis is unclear and study results seem contradictory, we undertook a population-based case-control study. Among 350 unselected patients younger than 70 years, with a first, objectively confirmed, episode of deep-vein thrombosis and without underlying malignant disease we detected a 6% frequency (21/350 patients) of factor XII deficiency (activity level < 57%). Among 350 healthy control subjects, matched for age and sex, the frequency was 5% (18 subjects). Thus there is no increase in prevalence of factor XII deficiency among thrombosis patients and no increase in thrombosis risk for subjects with low factor XII levels (matched odds ratio 1.2 (95% CI 0.6-2.4)). In addition, there was no relation between strata of factor XII levels and thrombosis risk. In conclusion, we do not consider factor XII to be a determinant of deep-vein thrombosis.

Activated protein C (APC) is a serine protease with potent anticoagulant properties, which is formed in blood on the endothelium from an inactive precursor. During normal haemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa (ref. 2). To do this efficiently the enzyme needs a nonenzymatic cofactor, protein S (ref. 3). Recently it was found that the anticoagulant response to APC (APC resistance) was very weak in the plasma of 21% of unselected consecutive patients with thrombosis and about 50% of selected patients with a personal or family history of thrombosis; moreover, 5% of healthy individuals show APC resistance, which is associated with a sevenfold increase in the risk for deep vein thrombosis. Here we demonstrate that the phenotype of APC resistance is associated with heterozygosity or homozygosity for a single point mutation in the factor V gene (at nucleotide position 1,691, G-->A substitution) which predicts the synthesis of a factor V molecule (FV Q506, or FV Leiden) that is not properly inactivated by APC. The allelic frequency of the mutation in the Dutch population is approximately 2% and is at least tenfold higher than that of all other known genetic risk factors for thrombosis (protein C (ref. 8), protein S (ref. 9), antithrombin10 deficiency) together.

The literature on Helicobacter pylori has become enormous, but the epidemiology of the infection remains an enigma. Guided by epidemiologic principles we have tried to interpret the available data on the epidemiologic aspects of H. pylori. We conclude that conflicting results on familial clustering and seroprevalence curves might have logical explanations. However, the exact way this organism spreads among humans remains to be solved.

The clinical diagnosis of deep venous thrombosis is non-specific, i.e. suffers from a large number of false-positive diagnoses. Therefore, the use of objective tests is emphasized. We have investigated retrospectively the increase, if any, in the use of objective tests over a three year period in the Leiden area (1986-1989). We found that the percentage of patients on whom objective tests were used was more than doubled, from 21% to 55%; this increase was accompanied by a 29% decrease in the incidence of venous thromboembolic disease. These opposing trends are to be expected if more objective tests are used.

The authors compared the sensitivity and the reproducibility of the bleeding time techniques according to Ivy and Simplate II. The sensitivity was studied in two groups: one group of 64 healthy volunteers and another group of 40 patients with various disorders of hemostasis, including 28 patients with Von Willebrand's disease. Ivy and Simplate II bleeding times were performed on each subject. The reproducibility was studied in 48 patients with mildly or moderately prolonged bleeding times that resulted from various disorders who had a duplicate Ivy or a duplicate Simplate II bleeding time. All subjects were randomized over the technologists and they were blinded for each other's results. By a receiver operating characteristic analysis, the Ivy method appeared to offer greater overall detection efficacy than the Simplate II method. For the Ivy method, the standard deviation of the ratios of the duplicate bleeding times was 0.37 and for the Simplate II method it was 0.33. The authors conclude that the Simplate II method is not superior in sensitivity or reproducibility to the Ivy method, which is cheaper, takes less time, and does not leave scars.

The bleeding time in healthy volunteers was determined according to both the Ivy and the Simplate II techniques. A significantly longer bleeding time in people with blood group O than in people with non-O blood groups was demonstrated with both techniques. This difference could not be attributed to a difference in sex ratio, platelet count or haematocrit. The mean level of von Willebrand factor in blood group O is lower than in non-O blood groups, but we found no association between the level of von Willebrand factor and the bleeding time, despite the very broad range of von Willebrand factor levels in the subjects examined.