Inherited thrombophilia and venous thromboembolism

The term thrombophilia includes any inherited and acquired disorders associated with an increased tendency to venous thromboembolism (VTE). Inherited thrombophilia is one of the main determinants of VTE, and the presence of inherited thrombophilic defects exposed carriers to increased risks for VTE compared with noncarriers. There is no clear relationship between clinical manifestations and the type of underlying thrombophilic defect. Thus, the diagnosis of inherited thrombophilia has to be established on a laboratory basis. Carriers of thrombophilic defects may experience thrombosis at a younger age than noncarriers. However, a first thrombotic manifestation that occurs late in life may also be an expression of thrombophilia and this remains in many cases the only etiopathogenetic explanation for the event. Screening of family members of symptomatic probands has the potential to identify still asymptomatic carriers who may benefit from more appropriate thromboprophylaxis during high-risk situations for VTE. Women of fertile age who belong to these thrombophilic families might receive the greatest advantage from screening. Many inherited thrombophilic disorders can be considered risk factors for recurrent VTE, especially if more than one defect is present in the same patient. More intensive or prolonged duration of VTE treatment might be requested for the prevention of recurrent VTE in the most severe thrombophilic conditions. The availability of new methods for the assessment of thrombin generation in terms of endogenous thrombin potential are very promising tools for the identification of those carriers of inherited thrombophilia who will develop thrombosis or who will encounter recurrence of VTE.     

Inherited thrombophilia and gestational venous thromboembolism

Thromboembolic disease is a leading cause of maternal morbidity and mortality during pregnancy and the puerperium. To reduce the incidence of venous thromboembolism in pregnancy and improve outcomes, an individual risk stratification based on probability of thrombosis as a rationale for an individual risk-adapted prophylaxis is required. Within the past 10 years, a significant improvement in risk estimation has been achieved due to the identification of new genetic risk factors of thrombosis. 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--indicating that pregnancy-associated thrombosis is multicausal, resulting from the interaction of combined defects. 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, for example, surgery or trauma, and no additional genetic risk factor, the probability of a pregnancy-associated thrombosis appears also 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. Despite the remarkable progress in risk stratification, the absolute magnitude of risk in many cases is unknown and current recommendations remain empirical.     

Inherited thrombophilia and gestational venous thromboembolism

Inherited thrombophilias are associated with an increased risk of venous thromboembolism (VTE) and the risk is further increased during pregnancy. However, not all pregnancies or all thrombophilias carry the same risk. Deficiencies in coagulation inhibitors and especially in antithrombin are rare but are associated with a higher risk than the most frequent factor V Leiden or prothrombin (factor II) 20210A mutations. Differences may be observed depending on heterozygosity or homozygosity of the defects and on the presence of combined thrombophilias. Although we now have more information on the global risk of thrombosis in thrombophilia, the magnitude of the risk is unknown in women who do or do not have a history of VTE, and in those who are the propositus or family members. Additional risk factors may be taken into account such as age of the mother, cesarean section, obesity, and immobilization during pregnancy. Recommendations of the American College of Chest Physicians (ACCP) concerning prophylaxis during pregnancy published in 2001 are mostly 1C recommendations; they are based on observational studies and subject to changes when more information becomes available. There is now a consensus about prevention in the postpartum period in women with thrombophilia. In contrast, prophylaxis in the antepartum period is often determined on an individual basis. We give some indications of the appropriate prophylaxis on the basis of the ACCP recommendations and personal experience.     

Travel, venous thromboembolism, and thrombophilia

Current evidence indicates that prolonged air travel predisposes to venous thrombosis and pulmonary embolism. An effect is seen once travel duration exceeds 6 to 9 hours and becomes obvious in long-haul passengers traveling for 12 or more hours. A recent records linkage study found that increase in thrombosis rate among arriving passengers peaked during the first week and was no longer apparent after 2 weeks. Medium- to long-distance travelers have a 2- to 4-fold increase in relative thrombosis risk compared with nontravelers, but the averaged absolute risk is small (approximately one symptomatic event per 2 million arrivals, with a case-fatality rate of approximately 2%) and there is no evidence that thrombosis is more likely in economy class than in business- or first-class passengers. It remains uncertain whether and to what extent thrombosis risk is increased by short-distance air travel or prolonged travel by motorcar, train, or other means. Most travelers who develop venous thrombosis or pulmonary embolism also have one or more other predisposing risk factors that may include older age, obesity, recent injury or surgery, previous thrombosis, venous insufficiency, malignancy, hormonal therapies, or pregnancy. Limited (though theoretically plausible) evidence suggests that factor V Leiden and the prothrombin gene mutation predispose to thrombosis in otherwise healthy travelers. Given that very many passengers with such predispositions do not develop thrombosis, and a lack of prospective studies to link predisposition with disease, it is not now possible to allocate absolute thrombosis risk among intending passengers or to estimate benefit-to-risk ratios or benefit-to-cost ratios for prophylaxis. Randomized comparisons using ultrasound imaging indicate a measurable incidence of subclinical leg vein thrombosis after prolonged air travel, which appears to increase with travel duration and is reduced by graded pressure elastic support stockings. Whether this surrogate outcome measure translates into clinical benefit remains unknown, but support stockings are likely to be more effective and have less adverse effects than the use of aspirin.     

Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review

The 2 most common genetic polymorphisms that predispose to a first episode of venous thromboembolism (VTE) are factor V Leiden (FVL) and prothrombin G20210A. However, the effect of these polymorphisms on the risk of recurrent VTE is unclear. We performed a meta-analysis to obtain best estimates of the relative risk of recurrent VTE associated with these genetic polymorphisms. Electronic and manual searches were used to identify cohort studies of patients with a first episode of VTE that reported the incidence of objectively confirmed recurrence following discontinuation of anticoagulation among those with or without heterozygous FVL or prothrombin G20210A polymorphism. Thirteen reports fulfilled our criteria for inclusion. Pooled results from 10 studies involving 3104 patients with first-ever VTE revealed that FVL was present in 21.4% of patients (95% confidence interval [CI], 20%-23%) and associated with an increased odds of recurrent VTE of 1.41 (95% CI, 1.14-1.75; P = .08 for heterogeneity). Pooled results from 9 studies involving 2903 patients with first-ever VTE revealed that prothrombin G20210A was present in 9.7% of patients (95% CI, 9%-11%) and associated with an increased odds of recurrent VTE of 1.72 (95% CI, 1.27-2.31; P = .19). The estimated population-attributable risk of recurrence for FVL was 9.0% (95% CI, 4.5%-13.2%) and for prothrombin G20210A was 6.7% (95% CI, 3.4%-9.9%). Heterozygous FVL and prothrombin G20210A are each associated with a significantly increased risk of recurrent VTE after a first event, but the magnitude of the increase in risk is modest and by itself is unlikely to merit extended-duration anticoagulation. These data call into question the cost-effectiveness of routine testing for these common inherited thrombophilic polymorphisms among patients with a first episode of VTE.     

Prophylaxis and treatment of venous thromboembolism in individuals with inherited thrombophilia

Venous thromboembolism (VTE) susceptibility genes are widely diffuse in the general population, but clinical penetrance of genotypes is incomplete and has variable expressivity. Therefore, the indiscriminate search for carriers is of doubtful utility and potentially detrimental for screened individuals. A targeted screening in kindreds in which VTE already occurred can be more fruitful in identifying individuals sharing with the proband one or more known susceptibility genes (possibly cosegregating with other ones still unknown). Clinical penetrance is variable, and is higher in the relatively rare deficiencies of antithrombin (AT), protein C (PC), or protein S (PS), and lower in the presence of the common polymorphisms factor V Leiden and prothrombin G20210A. Women with inherited thrombophilia should be warned about the thrombotic risk associated with the use of oral contraceptives or hormonal replacement treatment. Moreover, prophylaxis during puerperium and surgery or after trauma is warranted. The absolute risk associated with such situations is low but not negligible in the presence of deficiencies of AT, PC, or PS, homozygous conditions, and carriership of multiple defects. In such cases primary prophylaxis should be applied also during pregnancy and in general should be more stringent; moreover, in these patients the option for indefinite duration of secondary anticoagulant prophylaxis after VTE should be considered because of the relevant risk of recurrent VTE. In all cases, a careful balance of benefits and risks associated with prophylactic measures should be achieved, and patient preferences should be considered.     

Inherited thrombophilia in children with venous thromboembolism and the familial risk of thromboembolism: an observational study

Screening for inherited thrombophilia (IT) is controversial; persons at high risk for venous thromboembolism (VTE) who benefit from screening need to be identified. We tested 533 first- and second-degree relatives of 206 pediatric VTE patients for IT (antithrombin, protein C, protein S, factor V G1691A, factor II G20210A) and determined the incidence of symptomatic VTE relative to their IT status. The risk for VTE was significantly increased among family members with, versus without, IT (hazard ratio = 7.6; 95% confidence interval [CI], 4.0-14.5; P < .001) and highest among carriers of antithrombin, protein C, or protein S deficiency (hazard ratio = 25.7; 95% CI, 12.2-54.2; P < .001). Annual incidences of VTE were 2.82% (95% CI, 1.63%-4.80%) among family members found to be carriers of antithrombin, protein C, or protein S deficiency, 0.42% (0.12%-0.53%) for factor II G202010A, 0.25% (0.12%-0.53%) for factor V G1691A, and 0.10% (0.06%-0.17%) in relatives with no IT. Given the high absolute risk of VTE in relatives with protein C, protein S, and antithrombin deficiency, we suggest screening for these forms of hereditary thrombophilia in children with VTE and their relatives. Interventional studies are required to assess whether thromboembolism can be prevented in this high-risk population.     

Increased risk of venous thromboembolism among patients with familial Mediterranean fever

Journal of Thrombosis and Thrombolysis - Familial Mediterranean Fever (FMF) is an auto inflammatory disease characterized by acute febrile attacks, serositis, arthritis and skin rash. Previous...     

Impact of screening on thrombophilia for patients with venous thrombosis.

AIM: The epidemiologic importance of thrombophilia on venous thromboembolism (VTE) has been extensively studied. We tried to identify the variables that point to the positive test results for thrombophilia and the impact of these results on clinical decisions. METHODS: Thrombophilia screening was applied to 84 consecutive patients with VTE. After test results, two independent observers evaluated, in a case by case basis, the indication of a change on prophylaxis or special attention, in order to modify the period of anticoagulant intake or have a higher medical surveillance before risk situations or for the extension of the research to the first degree relatives. RESULTS: Thrombophilia was found in 41.66% (35/84), and in 32.12% (27/84) it involved a genetic cause. The factor V Leiden was found in 15.47%, followed by the natural anticoagulant dysfunction (11.9%). There was no significative difference of thrombophilia frequency between ages, nor a difference of age in the onset of the first thrombotic event between thrombophilic and non-thrombophilic patients. There was a higher prevalence of thrombophilia in patients with superficial thrombophlebitis of spontaneous onset and in cases of recurrence. The change on prophylaxis resulted in 7.14% (6/84) and special attention in 40.47% (34/84). CONCLUSIONS: Spontaneous superficial thrombophlebitis, occurrence of VTE related to non surgical causes, and recurrence, were the main findings which suggested thrombophilia. The change of prophylaxis was applied to a small percentage of patients. The special attention for risk situations and the extension of the primary prophylaxis to the asymptomatic family members seems to be the best indication for the laboratory research on thrombophilia.     

The prevalence of risk factors for venous thromboembolism among hospital patients.

BACKGROUND--This study provides an estimate of the prevalence of risk factors for venous thromboembolism among hospital patients. METHODS--The presence of risk factors for venous thromboembolism was determined from a retrospective review of the medical records of 1,000 randomly selected patients in 16 acute care hospitals in central Massachusetts. RESULTS--The most common risk factors for venous thromboembolism were age 40 years (59%) or more, obesity (28%), and major surgery (23%). The average number of risk factors increased with increasing age. One or more risk factors for venous thromboembolism were present in 78% of hospital patients, two or more in 48%, three or more in 19%, four or more in 6%, and five or more in 1%. CONCLUSION--Risk factors for venous thromboembolism are common among hospital patients, suggesting that prophylaxis should be widely employed. The cost-effectiveness and risk benefit of prophylaxis is well established in patients undergoing major surgery. Further studies are needed to confirm the benefit of prophylaxis in patients with nonsurgical risk factors for venous thromboembolism.     

Risk of venous thromboembolism after air travel: interaction with thrombophilia and oral contraceptives

BACKGROUND: Conflicting data are available on air travel as a risk factor for venous thromboembolism. To our knowledge, there are no studies investigating whether individuals with thrombophilia and those taking oral contraceptives are more likely to develop venous thromboembolism during flights than those without these risk factors. PARTICIPANTS AND METHODS: The study sample consisted of 210 patients with venous thromboembolism and 210 healthy controls. DNA analysis for mutations in factor V and prothrombin genes and plasma measurements of antithrombin, protein C, protein S, total homocysteine levels, and antiphsopholipid antibodies were performed. RESULTS: In the month preceding thrombosis for patients, or the visit for controls, air travel was reported by 31 patients (15%) and 16 controls (8%), with an oddsratio of 2.1 (95% confidence interval, 1.1-4.0). Thrombophilia was present in 102 patients (49%) and 26 controls (12%), and oral contraceptives were used by 48 patients and 19 controls (61% and 27% of those of reproductive age, respectively). After stratification for the presence of air travel and thrombophilia, the odds ratio for thrombosis in individuals with both risk factors was 16.1 (95% confidence interval, 3.6-70.9). Stratification for the presence of air travel and oral contraceptive use gave an odds ratio of 13.9 (95% confidence interval, 1.7-117.5) in women with both risk factors. CONCLUSIONS: Air travel is a mild risk factor for venous thromboembolism, doubling the risk of the disease. When thrombophilia or oral contraceptive use is present, the risk increases to 16-fold and 14-fold, respectively, indicating a multiplicative interaction.     

The genetics of venous thromboembolism: a systematic review of thrombophilia families

Journal of Thrombosis and Thrombolysis - Genetic risk factors are important for the occurrence and prognosis of venous thromboembolism (VTE). The studies of thrombophilia families are important for...     

Congenital plasminogen deficiency associated with venous thromboembolism: therapeutic trial with stanozolol

We describe the case of a 34-year-old man with a history of venous thrombotic disease and demonstrate that his plasma plasminogen was reduced to about half-normal levels but was functionally intact. The deficiency was inherited as an autosomal trait and the propositus and his sister are heterozygotes. The propositus, but no other family member, had an associated deficiency of plasminogen activator activity, probably due to heightened plasminogen activator inhibition in his plasma. A therapeutic trial with the anabolic steroid stanozolol transiently normalized plasminogen and plasminogen activator levels.     

Treating venous thromboembolism in patients with cancer

Venous thromboembolism (VTE) is a major cause of morbidity and mortality among patients with cancer. Although much is known about the factors that contribute to VTE risk, pre-emptive therapy in high-risk populations is clearly indicated in only a few clinical situations. Low-molecular-weight heparin is still the recommended class of anticoagulants for cancer-associated VTE. Management of VTE in patients with renal failure, hemorrhagic brain metastases, thrombocytopenia and coagulopathy remains challenging with few safe and effective alternatives. Novel oral agents are currently being investigated and may play a role in the future in the treatment of cancer-associated VTE.     

Prevention of venous thromboembolism in cancer patients.

Thrombosis is a common complication in patients with malignancy and its occurrence is heightened by therapeutic interventions such as operations or the use of chemotherapy. The magnitude of the risk for venous thromboembolism (VTE) is well established for cancer surgery where rates twice that for abdominal surgery in noncancer subjects are described. The case for routine thromboprophylaxis in patients receiving chemotherapy is less clear, and prospective studies investigating rates of thrombosis by tumor type, stage of disease, and chemotherapeutic regimens are required. For thromboprophylaxis in the surgical patient either low-dose heparin or low-molecular-weight (LMW) heparin are effective and safe. For patients receiving chemotherapy in advanced breast cancer, low-dose warfarin is effective. Interestingly, heparin therapy may prolong survival in patients with malignant disease; the mechanism is unclear, and observations from retrospective analysis need to be confirmed in prospective studies.     

Treatment of venous thromboembolism in cancer patients.

The occurrence of venous thromboembolism complicates the management of the patient with malignant disease because of the need for anticoagulant therapy. Cancer patients have an ongoing thrombotic stimulus due to the underlying cancer and its associated treatments, but are also considered to be at increased risk for anticoagulant-related bleeding. In recent years, the results of clinical trials have demonstrated the safety and efficacy of weight-adjusted subcutaneous low molecular weight heparin, administered at home, for patients with acute deep vein thrombosis. This approach is particularly attractive to patients with cancer where quality of life is an important consideration. There are no trials that specifically address the question of the duration of oral anticoagulant therapy in cancer patients. However, data can be extrapolated from trials evaluating the duration of oral anticoagulant therapy in other high-risk patients. Hence, cancer patients should continue oral anticoagulant therapy for as long as the cancer remains active (usually at least 6 months). There still remain a number of unanswered questions about the clinical management of thromboembolism in the cancer patient.