Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis

Single-point mutations in the gene coding for prothrombin (factor II:A20210) or factor V (factor V:A1691) are associated with an increased risk of venous thromboembolism. The use of oral contraceptives is also a strong and independent risk factor for the disease, and the interaction between factor V:A1691 and oral contraceptives greatly increases the risk. No information is available about the interaction between oral contraceptives and mutant prothrombin. We investigated 148 women with a first, objectively confirmed episode of deep vein thrombosis and 277 healthy women as controls. Fourteen patients (9.4%) were carriers of factor II:A20210, 24 (16.2%) of factor V:A1691, and 4 (2.7%) of both defects. Among controls, the prevalence was 2.5% for either factor II:A20210 or factor V:A1691, and there was no carrier of both the mutations. The relative risk of thrombosis was 6-fold for factor II:A20210 and 9-fold for factor V:A1691. The most prevalent circumstantial risk factor in patients and the only one observed in controls was oral contraceptive use, which per se conferred a 6-fold increased risk of thrombosis. The risk increased to 16.3 and 20.0 when women with factor II:A20210 or factor V:A1691 who used oral contraceptives were compared with noncarriers and nonusers. These figures indicate a multiplicative interaction between the genetic risk factors and oral contraceptives. No difference in the type of oral contraceptives was observed between patients and controls, those of third generation being the most frequently used (73% and 80%). We conclude that carriers of the prothrombin mutation who use oral contraceptives have a markedly increased risk of deep vein thrombosis, much higher than the risk conferred by either factor alone.     

Budd-Chiari syndrome: combination of genetic defects and the use of oral contraceptives leading to hypercoagulability

A young female, who had been in excellent health and had used third-generation oral contraceptives, was admitted to hospital because of abdominal pain and ascites. Budd-Chiari syndrome (BCS) was diagnosed by radiographic and histological examination. Tests for myeloproliferative disease, deficiency of coagulation inhibitors and paroxysmal nocturnal haemoglobinuria were negative. DNA investigation showed a double heterozygous defect: the Arg506Gln mutation in the factor V gene (factor V Leiden) and G20210A nucleotide substitution in the prothrombin gene. This double defect was also found in the patient's father, who had never experienced an episode of venous thromboembolism. Genetic and acquired thrombogenic risk factors are being detected increasingly in patients with BCS. With the discovery of new genetic defects leading to hypercoagulabiulity an increasing number of patients with serious thrombotic manifestations, such as BCS, will exhibit concurrence of hereditary and acquired risk factors for thrombosis.     

Higher risk of venous thrombosis during early use of oral contraceptives in women with inherited clotting defects

BACKGROUND: Results of recent studies show that the risk for venous thrombosis is highest during initial oral contraceptive use. This suggests a subgroup of females who are at immediate risk of thrombosis when exposed to oral contraceptives. OBJECTIVE: To determine whether women with inherited clotting defects who use oral contraceptives develop venous thrombosis at an earlier stage than do those without inherited clotting defects. METHODS: Analysis of the data from the Leiden Thrombophilia Study, a population-based case-control study with data on duration of oral contraceptive use and recently detected genetic coagulation disorders. Patients had a first episode of objectively proven deep vein thrombosis. Patients and controls were considered thrombophilic when they had protein C deficiency, protein S deficiency, antithrombin deficiency, factor V Leiden mutation, or prothrombin 20210 A mutation. RESULTS: Risk of developing deep vein thrombosis was greatest in the first 6 months and the first year of oral contraceptive use. Compared with prolonged use, the risk of developing deep vein thrombosis was 3-fold higher in the first 6 months of use (95% confidence interval [CI], 0.6-14.8) and 2-fold higher in the first year of use (95% CI, 0.6-6.1). Patients who developed venous thrombosis in the early periods of use were more often thrombophilic. Among women with thrombophilia, the risk of developing deep vein thrombosis during the first 6 months of oral contraceptive use (compared with prolonged use) was increased 19-fold (95% CI, 1.9-175.7), and in the first year of use, it was increased 11-fold (95% CI, 2.1-57.3). CONCLUSIONS: Women with inherited clotting defects who use oral contraceptives develop venous thrombosis not only more often but also sooner than do those without inherited clotting defects. Venous thrombosis in the first period of oral contraceptive use might indicate the presence of an inherited clotting defect.     

Evidence of jak2 val617phe positive essential thrombocythemia with splanchnic thrombosis during estroprogestinic treatment.

The discovery of the Janus kinase 2 Val617Phe mutation has brought new insights into the development of myeloproliferative disorders; however, the pathogenesis of essential thrombocythemia and its related thrombotic complications has not been completely understood. Although the Janus kinase 2 Val617Phe mutation confirms the initially suspected clonal character of the disease, factors influencing clonal transformation and expansion in the bone marrow have not been fully detected. Furthermore, patients affected by essential thrombocythemia who are carriers of the Janus kinase 2 Val617Phe mutation show a higher incidence of venous thromboembolism both before, and at the time of diagnosis, compared with noncarriers, and recent evidence of splanchnic and cerebral vein thrombosis in carriers of the Janus kinase 2 Val617Phe mutation has been reported. The intake of oral contraceptives is a strong and independent risk factor for venous thromboembolism. In addition, in-vitro tests showed both an altered primary haemostatic plug formation and enhanced platelet aggregation in patients taking such drugs. Little is known, though, about the influence of steroid hormones on both megakaryopoiesis and platelet function in patients with the Janus kinase 2 Val617Phe mutation. Herewith, we report the case of a 30-year-old woman who took a third generation oral contraceptive for 5 months and developed an essential thrombocythemia with spleno-portal axis and superior mesenteric vein thrombosis. She was found to carry the kinase gene Janus kinase 2 mutation.     

Smoking increases the risk of venous thrombosis and acts synergistically with oral contraceptive use

The results of studies investigating the relationship of smoking with venous thrombosis are inconsistent. Therefore, in the MEGA study, a large population-based case-control study, we evaluated smoking as a risk factor for venous thrombosis and the joint effect with oral contraceptive use and the factor V Leiden mutation. Consecutive patients with a first venous thrombosis were included from six anticoagulation clinics. Partners of patients were asked to participate and additional controls were recruited using a random digit dialing method. Participants completed a standardized questionnaire. Individuals with known malignancies were excluded from the analyses, leaving a total of 3,989 patients and 4,900 controls. Current and former smoking resulted in a moderately increased risk of venous thrombosis (odds ratio (OR)(current) 1.43, 95% confidence interval (CI95) 1.28-1.60, OR(former) 1.23, CI95 1.09-1.38) compared with nonsmoking. Adjustment for fibrinogen levels did not substantially change these risk estimates. A high number of pack-years resulted in the highest risk among young current smokers (OR(>or=20 pack-years) 4.30, CI95 2.59-7.14) compared with young nonsmokers. Women who were current smokers and used oral contraceptives had an 8.8-fold higher risk (OR 8.79, CI95 5.73-13.49) than nonsmoking women who did not use oral contraceptives. Relative to nonsmoking noncarriers, the joint effect of factor V Leiden and current smoking led to a 5.0-fold increased risk; for the prothrombin 20210A mutation this was a 6.0-fold increased risk. In conclusion, smoking appears to be a risk factor for venous thrombosis with the greatest relative effect among young women using oral contraceptives.     

Benefits and risks of third-generation oral contraceptives

OBJECTIVE: To evaluate the risks and benefits of third-generation oral contraceptives. DATA SOURCES: A MEDLINE search was done for English language articles published from 1985 through 1998 relating to the side-effect profile of third-generation oral contraceptives or their association with cardiovascular or thromboembolic disease. All articles containing original data were included. DATA SYNTHESIS: The risk of venous thromboembolism appears to be 1.5- to 2.7-fold greater in users of third-generation, compared with second-generation, oral contraceptives. Compared with nonusers, women who use third-generation oral contraceptives may have a 4.8- to 9.4-fold greater risk of venous thromboembolism. Users of third-generation oral contraceptives do not appear to have an increased risk of myocardial infarction compared with nonusers and may have risk of myocardial infarction of 0.26 to 0.7 compared with second-generation users. Whether third-generation oral contraceptives are associated with a decreased stroke risk is still not clear. CONCLUSIONS: Although third-generation oral contraceptives most likely increase a user's risk of venous thromboembolism, their improved side-effect profile and their possible decreased association with myocardial infarction and stroke may make them a useful new class of oral contraceptives for most women except those at increased risk of venous thrombosis.     

The genetics of venous and arterial thromboembolism

There is substantial evidence to indicate that the pathologic processes of venous and arterial thromboembolism involve both genetic and environmental influences. Scientific progress over the past decade has revealed a growing number of genetic factors, such as factor V Leiden and the prothrombin gene variant, that are present in more than 1% of the population and increase the relative risk of venous thrombosis between two- and sevenfold. Furthermore, several of these factors have been demonstrated to interact adversely with environmental influences, such as oral contraceptives and smoking. Although these traits are present at relatively high prevalence in the population, the magnitude of the increased thrombotic risk associated with these factors is substantially less than that related to inherited deficiency of the natural anticoagulant protein antithrombin, and somewhat less than the elevated risk with protein C and protein S deficiencies. In contrast to the progress that has been made in understanding the genetic contributions to venous thromboembolism, much still remains to be learned about the genetic basis of arterial thrombosis. Despite the documentation of associations between several genetic polymorphisms with plasma procoagulant levels, consistent associations with arterial thrombotic disease have not been found.     

Therapy insight: Vascular complications in patients with inflammatory bowel disease

Inflammatory bowel disease (IBD) is associated with an increased risk of vascular complications. The most important of these complications are arterial and venous thromboembolism, which represent a significant cause of morbidity and mortality in IBD patients. Recent data suggest that thromboembolism is a disease-specific extraintestinal manifestation of IBD. The most common thrombotic manifestations in IBD are deep vein thrombosis of the leg and pulmonary emboli. It has been suggested that disease activity and the extent of colonic localization are correlated with the risk of developing thromboembolism. The occurrence of thrombosis in patients with IBD is partially attributed to the existing hypercoagulable state in IBD. Both coagulation and fibrinolysis are activated in patients with IBD; this is especially true for those with active disease. The most common risk factors for thrombophilia in IBD patients with venous thromboembolism are Leiden mutation in the gene encoding factor V, hyperhomocysteinemia, and antiphospholipid antibodies. The main genetic defects that have been established as risk factors for venous thrombosis are rather uncommon in IBD, but when present increase the risk of thromboembolism. Screening for coagulation defects seems justified only in IBD patients with a history of thrombosis or a family history of venous thromboembolic events. Antithrombotic treatment of IBD patients with venous thromboembolism is similar to that of thrombotic non-IBD patients.     

Laboratory thrombophilias and venous thromboembolism

Inherited abnormalities of coagulation are increasingly recognized in patients with venous thromboembolism. Common causes of hypercoagulability, also known as thrombophilia, include factor V Leiden, the prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies. Thrombophilia should be suspected in patients who develop idiopathic venous thromboembolism at a young age, recurrent thrombosis, thromboses at unusual sites, recurrent unexplained pregnancy loss, or if there is a family history of thrombotic disorders. The most cost-effective approach is to initially screen for factor V Leiden, the prothrombin gene mutation, hyperhomocysteinemia, and antiphospholipid antibodies because these are the most common defects causing thrombophilia. Long-term anticoagulation is controversial but should be considered if unprovoked venous thromboembolism recurs.     

Cardiovascular Risks of Hormonal Contraceptives

In 2012, new information about arterial thrombosis (thrombotic stroke and myocardial infarction) and venous thromboembolism in users of hormonal contraceptives was published. A Danish study representing the experience of more than 1.6 million women reported only small, and statistically indistinguishable, differences in the relative risks of thrombotic stroke and acute myocardial infarction between current users of combined estrogen/progestin oral hormonal contraceptives containing different progestins and low (30–40 microgram) or very low (20–40 micrograms) doses of ethinyl estradiol. A United States study also found no differences in the risks of arterial thrombosis between users of low estrogen dose oral contraceptives containing levonorgestrel, norethrindrone, or norgestimate and formulations that deliver hormones transdermally or vaginally. The United States study provided further evidence about the risk of venous thromboembolism in users drosperinone-containing oral contraceptives and the norelgestromin—containing transdermal patch compared with other low estrogen hormonal contraceptives, although the aggregate of data remains inconclusive.     

Risk of venous thrombosis: obesity and its joint effect with oral contraceptive use and prothrombotic mutations

In the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA study), body weight, height and body mass index (BMI) were evaluated as risk factors. Additionally, the joint effect of obesity together with oral contraceptive use and prothrombotic mutations on the risk of venous thrombosis were analysed. Three-thousand eight-hundred and thirty-four patients with a first venous thrombosis and 4683 control subjects were included, all non-pregnant and without active malignancies. Relative to those with a normal BMI (<25 kg/m(2)), overweight (BMI > or = 25 and BMI < 30 kg/m(2)) increased the risk of venous thrombosis 1.7-fold [odds ratio (OR)(adj(age and sex)) 1.70, 95% confidence interval (CI) 1.55-1.87] and obesity (BMI > or = 30 kg/m(2)) 2.4-fold (OR(adj) 2.44, 95% CI 2.15-2.78). An increase in body weight and body height also individually increased thrombotic risk. Obese women who used oral contraceptives had a 24-fold higher thrombotic risk (OR(adj) 23.78, 95% CI 13.35-42.34) than women with a normal BMI who did not use oral contraceptives. Relative to non-carriers of normal BMI, the joint effect of factor V Leiden and obesity led to a 7.9-fold increased risk (OR(adj) 7.86, 95% CI 4.70-13.15); for prothrombin 20210A this was a 6.6-fold increased risk (OR(adj) 6.58, 95% CI 2.31-18.69). Body height, weight and obesity increase the risk of venous thrombosis, especially obesity in women using oral contraceptives.     

Mutations at the activated protein C cleavage sites Arg336 and Arg562 of factor VIII in Thai patients with venous thrombosis

Venous thrombosis is a multicausal disease, more than one genetic risk factor may cooperate to effect thrombotic risk. Factor V Leiden is found to be an important hereditary risk factor for venous thromboembolism. Analogous to factor V Leiden, a point mutation at amino acid positions Arg336 and Arg562 in factor VIII may predispose patients to thrombosis. Eighty-one Thai patients with venous thrombosis and 100 Thai healthy volunteers have been studied. Neither heterozygous nor homozygous mutations were detected both thrombosis patients or normal volunteers. However, further studies with larger samples of venous thrombosis patients are recommended.     

Risk of venous thrombosis in carriers of the prothrombin G20210A variant and factor V Leiden and their interaction with oral contraceptives

BACKGROUND AND OBJECTIVES: The prothrombin G20210A mutation and factor V Leiden have been found to be associated with an increased risk of venous thrombosis, but the reported prevalences of the prothrombin gene variant both in the normal population and in patients with deep venous thrombosis (DVT) vary greatly in the literature. Moreover, the influence of oral contraceptives (OC) on thrombotic events in patients with the prothrombin G20210A variant has not been well established. In this study we evaluate both circumstances. DESIGN AND METHODS: A case-control study was run on 229 patients with DVT and 246 healthy controls. The patients' history of thrombosis and acquired thrombotic risk factors, especially OC, were recorded. Prothrombin G20210A mutation, factor V Leiden, antithrombin, heparin II cofactor, plasminogen and proteins C and S were evaluated. RESULTS: Seven and a half percent of the patients and 2.9% of the controls were carriers of the prothrombin mutation, while 12.2% of the patients and 1.6% of the controls had factor V Leiden. Among the 229 DVT patients there were 130 patients with clinically suspected thrombophilia (first thrombotic event occurring before the age of 45 years or positive family history of thrombosis or recurrent venous thrombosis). Ten percent of these 130 patients were carriers of the prothrombin G20210A mutation and 18.5% had the factor V Leiden mutation. The odds ratios (OR) for DVT risk were: 2.4 (95% CI, 1.0-6.3) for the total DVT patients and 5.2 (95% CI, 1.4-19.5) for the patients with clinically suspected thrombophilia with the prothrombin mutation. The risk of thrombosis was 6.9 (95% CI, 2.3-20.6) for the DVT patients and 14.3 (95% CI, 3.3-64.6) for the patients with clinically suspected thrombophilia with factor V Leiden. Fifty-five percent of the patients with combined congenital defects (prothrombin mutation G20210A plus another congenital defect) had recurrent thrombosis. In women receiving OC the risk of DVT was 3.5 (95% CI, 1.5-8.2) that of the patients not receiving OC. When women with combined defects were also taking OC, the risk of thrombosis increased significantly. INTERPRETATION AND CONCLUSIONS: The prevalence of the prothrombin G20210A mutation in the healthy population in our study is similar to that observed in other southern European countries. The prothrombin G20210A mutation does not by itself seem to be a high thrombotic risk factor. However, when it is present together with other thrombotic risk factors, the predicted risk of thrombotic events increases. The use of OC by women with the prothrombin G20210A variant or FV Leiden, either alone or combined with other thrombotic risk factors, was associated with a significant increase in the risk of venous thrombosis.     

Evidence-based indications for thrombophilia screening

Thrombophilic defects have been shown to be associated with an increased risk of venous thrombosis, fetal loss, and gestational complications. The knowledge about the clinical relevance of thrombophilic defects is increasing, and evidence-based indications for thrombophilia screening are therefore discussed in this review. Selective thrombophilia screening based on previous personal and/or family history of venous thromboembolism is more cost-effective than universal screening in all patient groups evaluated. In the majority of patients with acute venous thrombosis, the results of thrombophilia screening do not influence the duration of oral anticoagulation. The only patient population who clearly profits from thrombophilia screening in this situation are patients with a newly diagnosed antiphospholipid syndrome, because prolonged anticoagulation can avoid the high incidence of recurrence in this patient population. Because of the increased risk of venous thrombosis during pregnancy and the puerperium, thrombophilia screening is indicated in selected patients with a previous history of venous thrombosis or a positive family history. Significant associations with early and late pregnancy loss are observed for carriers of the heterozygous factor V Leiden mutation, the heterozygous prothrombin-mutation G20210A and anticardiolipin antibodies, while protein S deficiency is significantly associated with late pregnancy loss. Antithrombotic drugs like UFH, LMWH or low-dose aspirin may have a potential therapeutic benefit in patients with recurrent pregnancy loss and thrombophilia, but placebo-controlled, multicenter trials are urgently needed to clarify this issue. Although a supra-additive effect for the risk of venous thrombosis is observed between oral contraceptives and some thrombophilias, the absolute incidence of venous thromboembolism is low in premenopausal women and mass screening strategies are therefore unlikely to be effective. While antiphospholipid antibodies are known to be associated with arterial thrombosis, screening for heritable thrombophilias is not useful in arterial thrombosis, although subgroup analysis indicates that they may play a role particularly in young patients and children.     

Prothrombotic inherited abnormalities other than factor V Leiden mutation do not play a role in venous thrombosis in inflammatory bowel disease

OBJECTIVES: Because the incidence of thromboembolism is increased in patients with inflammatory bowel disease, we attempted to assess the role of prothrombotic inherited coagulation abnormalities in the development of thrombosis. METHODS: Four populations were compared: 15 patients with inflammatory bowel disease and a previous venous thrombosis, 58 control patients with inflammatory bowel disease but without thrombosis, 110 patients without inflammatory bowel disease but with previous deep venous thrombosis, and 84 healthy subjects. Inherited and acquired risk factors of venous thrombosis, e.g., factor V Leiden and prothrombin 20210A mutations, C677T methylenetetrahydrofolate reductase polymorphism, a polymorphism located in exon 13 of factor V gene, inflammatory and hypercoagulability markers were studied in each population. RESULTS: In the study, 14.3% of thrombotic patients with inflammatory bowel disease had factor V Leiden mutation versus 0% of control patients with inflammatory bowel disease (p = 0.04), 15.5% of thrombotic patients without inflammatory bowel disease (NS) and 3.6% of the healthy controls. A total of 14% of thrombotic patients with inflammatory bowel disease and 11.8% of thrombotic patients without inflammatory bowel disease carried prothrombin 20210A mutation, compared to 1.7% of control patients with inflammatory bowel disease; however, the difference was just below significance. Other inherited coagulation abnormalities were not statistically significantly different among the four populations. CONCLUSIONS: Our study confirms that factor V Leiden mutation increases the risk for thrombotic events but is not more frequent in patients with inflammatory bowel disease. Our results do not support the role of other thrombotic risk factors.     

Prediction,prevention, and treatment of venous thromboembolic disease in pregnancy

Pregnancy is recognized as an independent risk factor for venous thromboembolism leading to thromboembolic events, particularly in women with prior venous thrombosis, family history of thrombosis, or additional thrombophilic risk factors. To reduce the incidence of venous thromboembolism in pregnancy and improve outcomes, an individual risk stratification on the basis of probability of thrombosis as a rationale for an individual risk-adapted prophylaxis is required. In women without prior thrombosis, the presence of a heterozygous factor V Leiden or heterozygous G20210A mutation in the prothrombin gene is associated with a pregnancy-associated thrombotic risk of approximately 1 in 400. Thus, in pregnant carriers of either one of these mutations the risk of venous thromboembolism is low. For this reason, routine thrombophilia screening of all pregnant women is not recommended. However, a combination of the two genetic risk factors can increase the risk to a modest level (risk 1 in 25). In women with a single episode of prior thrombosis associated with a transient risk factor (such as surgery or trauma) and no additional genetic risk factor, the probability of a pregnancy-associated thrombosis also appears to be low. In contrast, in women with a prior idiopathic venous thrombosis who carry an additional hereditary risk factor or who have a positive family history of thrombosis, a high risk (> 10%) can be expected, supporting the indication for active antepartum and postpartum heparin prophylaxis. In many cases, the absolute magnitude of risk is unknown or estimated, and recommendations are often empiric.     

The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation

The G20210A mutation in the prothrombin gene is associated with an increased risk of a first venous thromboembolic episode; few data are available about the long-term risk for recurrent venous thromboembolism and it is not known whether or not carriers of the mutation should be recommended lifelong anticoagulant treatment after the first thrombosis. We investigated 624 patients, referred for previous objectively documented deep venous thrombosis of the legs or pulmonary embolism, to determine the risk of recurrent thromboembolism in heterozygous carriers of the G20210A mutation in the prothrombin gene after the first episode of venous thromboembolism. After exclusion of other inherited (anti-thrombin, protein C, protein S deficiency and factor V Leiden) or acquired (anti-phospholipid antibody syndrome) causes of thrombophilia, 52 heterozygous carriers of the prothrombin mutation were compared with 283 patients with normal genotype. The relative risk for recurrent venous thromboembolism was calculated between groups using a Cox's proportional hazard model. The patients with the prothrombin mutation had a risk for spontaneous recurrent venous thromboembolism similar to that of patients with normal genotype (hazard ratio 1.3; 95% CI, 0.7-2.3). The circumstances of the first event (spontaneous or secondary) did not produce any substantial variation in the risk for recurrence. In conclusion, the carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype.     

Acquired activated protein C resistance is common in cancer patients and is associated with venous thromboembolism

PURPOSE: Cancer patients have an increased risk for venous thromboembolism. Because activated protein C resistance is a common risk factor for venous thromboembolism, we prospectively evaluated the activated protein C sensitivity ratio and factor V Leiden mutation in cancer patients with and without venous thromboembolism. SUBJECTS AND METHODS: We studied 55 consecutive cancer patients with deep vein thrombosis, 58 cancer patients with no history of venous thromboembolism, 54 patients with venous thromboembolism without malignancy, and 56 healthy controls. The presence of factor V Leiden mutation was determined by polymerase chain reaction and allele specific restriction digestion. The activated protein C sensitivity ratio was expressed as the ratio of activated partial thromboplastin times measured in the presence and absence of activated protein C; a ratio <2.0 in patients who did not have factor V Leiden was considered to indicate acquired activated protein C resistance. RESULTS: The prevalence of factor V Leiden mutation in cancer patients with thromboembolism (1 of 55, 2%) did not differ significantly from those in cancer patients without thromboembolism (4 of 58, 7%) or normal controls (2 of 56, 4%), but was significantly lower than that of patients with thromboembolism without cancer (18 of 54, 33%, P <0.001). The prevalence of acquired activated protein C resistance was significantly greater in cancer patients with thromboembolism (29 of 54, 54%, P = 0.001) compared with the other groups: 9 of 54 (17%) in cancer patients without thromboembolism, 7 of 36 (19%) in patients with thromboembolism without cancer, and none of the normal controls. CONCLUSION: Although factor V Leiden is not a major risk factor for thrombosis in cancer patients, acquired activated protein C resistance is common and may contribute to the thrombotic tendency in these patients.     

Recurrent venous thromboembolism: diagnosis and management

A diagnosis of recurrent venous thromboembolism is commonly suspected by physicians in the clinical setting. Many do not realize that recurrent venous thromboembolism may mimic the first venous thromboembolic event (VTE) and that only 20 to 30% of patients who have had a first VTE actually have objective recurrent thrombotic disease. Objective testing is necessary to prevent the misdiagnosis of thrombophilia in patients and the associated exposure to prolonged anticoagulant treatment that accompanies that diagnosis. In patients with clinically suspected recurrent venous thrombosis, compression ultrasonography in a new venous segment is the preferred diagnostic approach and contrast venography is an alternative test. There is insufficient evidence to know whether D-dimer testing is an effective approach to the diagnosis of thrombophilia. In patients with suspected recurrent pulmonary embolism, the diagnostic method should begin with ventilation/perfusion lung-imaging and a complementary pulmonary angiography when the results of initial tests are equivocal. Patients with recurrent venous thromboembolism should be treated with anticoagulants for longer than 6 months but the precise period depends on the patient's risk of bleeding as a result of the treatment. Finally, there is currently a lack of evidence that risk for recurrent VTE is increased in patients with a first episode of venous thromboembolism and heterozygous factor V Leiden mutation or the G2021OA prothrombin mutation.