Results

History of pregnancies and factor V Leiden

Factor V Leiden mutation (Arg506Gln) increases the likelihood of venous thrombosis; it may also have a positive effect through facilitation of embryo implantation. This may manifest itself as a reduced time to pregnancy (increased fecundity) and fewer miscarriages in the first trimester. The first 115 female VT patients with factor V Leiden and 230 age-matched female VT patients without factor V Leiden were included and received a structured questionnaire. Conclusions: Factor V Leiden mutation may support embryo implantation, as factor V Leiden carriers had fewer miscarriages in the first trimester with a similar overall miscarriage rate. Miscarriage of embryos with poor viability may be postponed until the second trimester in factor V Leiden carriers. Fecundity was not influenced by factor V Leiden status.

Malignancies and venous thrombosis.

Venous thrombosis is a common complication in patients with cancer, leading to additional morbidity and compromising quality of life. The objective of this project was: To identify individuals with cancer with an increased thrombotic risk, evaluating different tumor sites, the presence of distant metastases, and carrier status of prothrombotic mutations. Patients with cancer have a highly increased risk of venous thrombosis especially in the first few months after diagnosis and in the presence of distant metastases. Patients with hematological malignancies had the highest risk of venous thrombosis, followed by lung cancer and gastrointestinal cancer. Carriers of the factor V Leiden and prothrombin 20210A mutations appear to have an even higher risk.

Venous thrombosis of the arm

Risk factors for venous thrombosis of the arm have shown to be different compared with risk factors for venous thrombosis of the leg and pulmonary embolisms. For this reason we studied risk factors for arm thrombosis separately. We included the largest group of patients with arm thrombosis ever studied. Out of almost 200 cases, most thrombi were caused by a central venous catheter (32%). We therefore estimated that approximately 1 in 22 patients with a central venous catheter will lead to a thrombosis of the arm. New risk factors for arm thrombosis that had not all been identified previously were prothrombotic mutations, surgery, immobilization of the arm (plaster cast), oral contraceptive use and family history, all increasing the risk two to thirteen-fold. In contrast hormone replacement therapy, unusual exercise, travel and obesity did not increase the risk. In a separate study we showed that sports activities in which the arms were intensively used such as tennis and handball increased the risk of arm thrombosis, while sports activities mainly involving the legs such as running decreased venous thrombosis risk.
Blom JW, Doggen CJM, Osanto S, Rosendaal FR Old and new risk factors for upper extremity deep venous thrombosis; a case-control study of 178 patients. J Thromb Haemost 2005; 3: 2471-8.
van Stralen KJ, Blom JW, Doggen CJM, Rosendaal FR Strenuous sport activities involving the upper extremities increase the risk of venous thrombosis of the arm. J Thromb Haemost 2005; 3: 2110-1.

Prothrombin and venous thrombosis

Prothrombin plays a central role in blood coagulation. Several polymorphisms have been identified in the prothrombin gene. The prothrombin 20210A mutation and elevated prothrombin activity are known to increase the risk of venous thrombosis. In the MEGA study, among prothrombin 20210GG control carriers, homozygous carriers of the prothrombin 19911G polymorphism show a mildly elevated prothrombin activity compared to homozygous wildtype carriers (difference 7.1%). The risk of venous thrombosis was 1.4-fold increased for homozygous versus wildtype carriers. The risk of venous thrombosis for prothrombin19911G carriers is lower than for prothrombin 20210A or factor V Leiden carriers.

MTHFR 677C-T polymorphism and venous thrombosis

Increased homocysteine levels are associated with venous thrombosis, but whether this relation is causal is unclear. The T-variant of the common methylenetetrahydrofolate (MTHFR) 677 C>T polymorphism mildly increases homocysteine levels and has therefore been a candidate risk factor for venous thrombosis. The present study includes 4375 patients and 4856 control subjects from the MEGA study. MTHFR 677 C>T was not associated with the risk of venous thrombosis, and the narrow confidence interval excludes even a small effect (OR (95% CI) 0.99 (0.91-1.08) for the CT genotype and 0.94 (0.81-1.08) for the TT genotype). Mildly elevated homocysteine levels as a result of MTHFR 677TT do therefore not seem to cause venous thrombosis. There is no rationale for measuring the MTHFR 677 C>T variant for clinical purposes.

Travel-related venous thrombosis

In the MEGA study, we examined the effect of all modes of travel on the risk of a first thrombosis. The study included 1906 patients aged less than 70 years, presenting with a first venous thrombosis along with the same number of matched controls (n=3812 in total). The combined effect of travelling and the risk factors for thrombosis (factor V Leiden, prothrombin 20210A mutation, body mass index [BMI] and height) was assessed.
Travelling for more than four hours increased the risk of VT 2-fold (odds ratio 2.1, 95% CI 1.5 to 3.0), compared to not travelling. The risk of flying was similar to the risk of travelling by car, bus or train. Travel by car, bus or train led to a high risk of thrombosis in individuals with the factor V Leiden mutation (relative risk 8.1, 95% CI 2.7 to 24.7), those who were more than 1.90m tall (relative risk 4.7, 95% CI 1.4 to 15.4) and those who used oral contraceptives (estimated relative risk >15). These synergistic effects were more apparent with air travel. In addition, people shorter than 1.60m had an increased risk of VT after air travel only (relative risk 4.9, 95% CI 0.9 to 25.6). Obese individuals with a BMI of more than 30kg/m2 had an increased risk. The more pronounced risk increase observed after air travel compared to ground travel for some of these risk factors may suggest an effect of flight-related factors, which are absent during travel by other modes of transport.

Lifestyle and venous thrombosis: Obesity, smoking and alcohol consumption

Recent studies indicate that obesity increases the risk of venous thrombosis. In accordance with these studies we found that relative to those with a normal body mass index (BMI<25 kg/m2), overweight (BMI≥25 and BMI<30 kg/m2) increased the risk of venous thrombosis 1.7-fold and obesity (BMI≥30 kg/m2) 2.4-fold. The effect of obesity was more pronounced in women than men, with a 24-fold increased risk for women using oral contraceptives compared to normal weight women who did not use oral contraceptives.
The results of studies investigating the relationship of smoking with venous thrombosis are inconsistent. In the MEGA study, smoking was associated with a moderately increased risk of venous thrombosis; in current smokers the risk was 1.4-fold increased and former smokers had a 1.2-fold increased risk compared to individuals who had never smoked. In current smokers the risk increased with the amount of smoking. No dose response relation was found for the number of smoking-years in either current or former smokers. Again the effect of smoking was more pronounced in women than men.
Moderate alcohol consumption is an established protective factor for cardiovascular disease, however the effect on venous thrombosis is unknown. In the MEGA study, alcohol consumption was associated with a decreased risk of venous thrombosis, with two to four glasses per day resulting in the strongest effect compared to abstainers. In our study, levels of fibrinogen, a protein that plays a role in blood clotting, were decreased in individuals who consumed alcohol compared to abstainers. This reduced level of fibrinogen may in part explain the relationship between alcohol consumption and the reduced risk of venous thrombosis.