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Resistance to activated protein C (APC) is a common inherited risk factor for venous thrombosis, which is associated with a mutation in coagulation factor V (factor V Leiden). We investigated the risk of venous thrombosis in individuals homozygous for this abnormality. We determined the factor V Leiden genotype in 471 consecutive patients aged less than 70 years with a first objectively confirmed deep-vein thrombosis and in 474 healthy controls. We found 85 heterozygous and seven homozygous individuals among the cases with thrombosis and 14 heterozygous individuals among the control subjects. The expected number of homozygous individuals among the controls was calculated from Hardy-Weinberg equilibrium and estimated at 0.107 (allele frequency, 1.5%). Whereas the relative risk was increased sevenfold for heterozygous individuals, it was increased 80-fold for homozygous individuals. These patients experienced their thrombosis at a much younger age (31 v 44 years). The homozygous individuals were predominantly women, most likely due to the effect of oral contraceptives. Because of the increased risk of thrombosis with age, the absolute risk becomes most pronounced in older patients, both for heterozygous and homozygous individuals. For the homozygous individuals, the absolute risk may become several percentage points per year. This implies that most individuals homozygous for factor V Leiden will experience at least one thrombotic event in their lifetime.

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Summary. Venous thrombosis (deep vein thrombosis, pulmonary embolism) is a common and serious disorder, with genetic and acquired risk factors. The genetic risk factors can be subdivided in to those that are strong, moderate and weak. Strong risk factors are deficiencies of antithrombin, protein C and protein S. Moderately strong are factor V Leiden, prothrombin 20210A, non-O blood group and fibrinogen 10034T. There are many weak genetic risk factors, including fibrinogen, factor XIII and factor XI variants. Even for moderately strong risk factors (relative risks 2-5), the majority of carriers will never develop thrombosis.

Objective To provide a comprehensive overview of the risk of venous thrombosis in women using different combined oral contraceptives.Design Systematic review and network meta-analysis.

Summary. Mortality figures were calculated for a group of 717 Dutch haemophiliacs over the period 1973-86. Followup was on average 10-9 years; no patients were lost to followup. The data were compared to the general male population by actuarial methods and patient-year analysis. Forty-three patients died, while 20 deaths were expected in a hypothetical group of non-haemophiliacs of the same age distribution. Hence, overall mortality was 2·l times higher than in the general population. This leads to a calculated life expectancy of 66 years, äs compared to 74 years in the general male population. Mortality did not differ much by severity of haemophilia. A possibly beneflcial effect of prophylaxis on longevity was observed. Haemorrhage occurred in half of all deaths and among these traumatic bleeding was the most prevalent. The number of deaths due to ischaemic heart disease was significantly lower (80% reduction) than expected and therefore the authors conclude that haemophilia offers protection against ischaemic heart disease. Cancer mortality was significantly higher (2-5 times) than expected.

Sununary.We previously reported that mortality due to ischaemic heart disease was lower in haemophilia patients than in the general male population. To support the hypothesis that this could be attributed to a protective effect of the clotting defect in haemophilia and not to differences in cardiovascular risk factors, we performed a second study. We examined 95 haemophilia patients for the presence of major risk factors for ischaemic heart disease and compared their risk factor profile with the data of epidemiologic surveys of the general Dutch population.Haemophilia patients had on average higher blood pressures than the comparison population, were more often hypertensive and used antihypertensive drugs twice äs often.The mean serum cholesterol level of the patients was markedly lower than in the comparison population (4-8 versus 5-6 mmol/1, 95% confidence interval of the difference: 0-5-Mmmol/l).The risk factors were weighted into one theoretical risk raüo for ischaemic heart disease by application of logistic regression coefficients. The theoretical risk ratio based on the risk factor profile was 0-78. This risk ratio can only explain a moderate reduction in the incidence of ischaemic heart disease, much smaller than the mortality ratio of 0-20 we reported previously. Therefore these data support the hypothesis of a direct protective effect of haemophilia on the development of ischaemic heart disease.