the immobilization and the surgery and it is less likely that investigations will yield clinically important results. when venous thromboembolism occurs when a patient is experiencing transient major risk factors such as prolonged immobility, surgery, or trauma, testing for thrombophilia is not appropriate because the outcome of the test would not change a patient's indicated treatment. in 2013, the american society of hematology, as part of recommendations in the choosing wisely campaign, cautioned against overuse of thrombophilia screening; false positive results of testing would lead to people inappropriately being labeled as having thrombophilia, and being treated with anticoagulants without clinical need in the united kingdom, professional guidelines give specific indications for thrombophilia testing. it is recommended that testing be done only after appropriate counseling, and hence the investigations are usually not performed at the time when thrombosis is diagnosed but at a later time. in particular situations, such as retinal vein thrombosis, testing is discouraged altogether because thrombophilia is not regarded as a major risk factor. in other rare conditions generally linked with hypercoagulability, such as cerebral venous thrombosis and portal vein thrombosis, there is insufficient data to state for certain whether thrombophilia screening is helpful, and decisions on thrombophilia screening in these conditions are therefore not regarded as evidence-based. if cost-effectiveness (quality-adjusted life years in return for expenditure) is taken as a guide, it is generally unclear whether thrombophilia investigations justify the often high cost, unless the testing is restricted to selected situations. recurrent miscarriage is an indication for thrombophilia screening, particularly antiphospholipid antibodies (anti-cardiolipin igg and igm, as well as lupus anticoagulant), factor v leiden and prothrombin mutation, activated protein c resistance and a general assessment of coagulation through an investigation known as thromboelastography. women who are planning to use oral contraceptives do not benefit from routine screening for thrombophilias, as the absolute risk of thrombotic events is low. if either the woman or a first-degree relative has had thrombosis, the risk of developing thrombosis is increased. screening this selected group may be beneficial, but even when negative may still indicate residual risk. professional guidelines therefore suggest that alternative forms of contraception be used rather than relying on screening. thrombophilia screening in people with arterial thrombosis is generally regarded as unrewarding and is generally discouraged, except possibly for unusually young patients (especially when precipitated by smoking or use of estrogen-containing hormonal contraceptives) and those in whom revascularization, such as coronary arterial bypass, fails because of rapid occlusion of the graft. treatment people considered to be at a high risk of repeated thrombosis due to thrombophilia are often advised to take warfarin for prolonged periods of time or even indefinitely. there is no specific treatment for thrombophilia, unless it is caused by an underlying medical illness (such as nephrotic syndrome), where the treatment of the underlying disease is needed. in those with unprovoked and/or recurrent thrombosis, or those with a high-risk form of thrombophilia, the most important decision is whether to use anticoagulation medications, such as warfarin, on a long-term basis to reduce the risk of further episodes. this risk needs to weighed against the risk that the treatment will cause significant bleeding, as the reported risk of major bleeding is over 3% per year, and 11% of those with major bleeding may die as a result. apart from the abovementioned forms of thrombophilia, the risk of recurrence after an episode of thrombosis is determined by factors such as the extent and severity of the original thrombosis, whether it was provoked (such as by immobilization or pregnancy), the number of previous thrombotic events, male sex, the presence of an inferior vena cava filter, the presence of cancer, symptoms of post-thrombotic syndrome, and obesity. these factors tend to be more important in the decision than the presence or absence of a detectable thrombophilia. those with antiphospholipid syndrome may be offered long-term anticoagulation after a first unprovoked episode of thrombosis. the risk is determined by the subtype of antibody detected, by the antibody titer (amount of antibodies), whether multiple antibodies are detected, and whether it is detected repeatedly or only on a single occasion. women with a thrombophilia who are contemplating pregnancy or are pregnant usually require alternatives to warfarin during pregnancy, especially in the first 13 weeks, when it may produce abnormalities in the unborn child. low molecular weight heparin (lmwh, such as enoxaparin) is generally used as an alternative. warfarin and lmwh may safely be used in breastfeeding. when women experience recurrent pregnancy loss secondary to thrombophilia, some studies have suggested that low molecular weight heparin reduces the risk of miscarriage. when the results of all studies are analysed together, no statistically significant benefit could be demonstrated. prognosis in people without a detectable thrombophilia, the cumulative risk of developing thrombosis by the age of 60 is about 12%. about 60% of people who are deficient in antithrombin will have experienced thrombosis at least once by age 60, as will about 50% of people with protein c deficiency and about a third of those with protein s deficiency. people with activated protein c resistance (usually resulting from factor v leiden), in contrast, have a slightly raised absolute risk of thrombosis, with 15% having had at least one thrombotic event by the age of sixty. in general, men are more likely than women to experience repeated episodes of venous thrombosis. people with factor v leiden are at a relatively low risk of thrombosis, but may develop thrombosis in the presence of an additional risk factor, such as immobilization. most people with the prothrombin mutation (g20210a) never develop thrombosis. epidemiology the major ("type 1") thrombophilias are rare. antithrombin deficiency is present in 0.2% of the general population and 0.5–7.5% of people with venous thrombosis. protein c deficiency, too, is present in 0.2% of the population, and can be found in 2.5–6% of people with thrombosis. the exact prevalence of protein s deficiency in the population is unknown; it is found 1.3–5% of people with thrombosis. the minor ("type 2") thrombophilias are much more common. factor v leiden is present in 5% of the population of northern european descent, but much rarer in those of asian or african extraction. in people with thrombosis, 10% have factor v leiden. in those who are referred for thrombophilia testing, 30–50% have the defect. the prothrombin mutation occurs at rates of 1–4% in the general population, 5–10% of people with thrombosis, and 15% of people referred for thrombophilia testing. like factor v leiden, this abnormality is uncommon in africans and asians. the exact prevalence of antiphospholipid syndrome is not well known, as different studies employ different definitions of the condition. antiphospholipid antibodies are detected in 24% of those referred to thrombophilia testing. history rudolf virchow, the german pathologist who distinguished the various causes of thrombosis, and whose work led to the development of thrombophilia as a concept german physician rudolf virchow categorized abnormalities in the consistency of the blood as a factor in the development of thrombosis in 1856. the exact nature of these abnormalities remained elusive until the first form of thrombophilia, antithrombin deficiency, was recognized in 1965 by the norwegian hematologist olav egeberg. protein c deficiency followed in 1981, when described by researchers from the scripps research institute and the u.s. centers of disease control. protein s deficiency followed in 1984, described by researchers at the university of oklahoma. antiphospholipid syndrome was described in full in the 1980s, after various previous reports of specific antibodies in people with systemic lupus erythematosus and thrombosis. the syndrome is often attributed to the british rheumatologist graham r.v. hughes, and is often referred to as hughes syndrome for that reason. the more common genetic thrombophilias were described in the 1990s. many studies had previously indicated that many people with thrombosis showed resistance activated protein c. in 1994 a group in leiden, the netherlands, identified the most common underlying defect—a mutation in factor v that made it resistant to the action of activated protein c. the defect was called factor v leiden, as genetic abnormalities are typically named after the place where they are discovered. two years later, the same group described a common mutation in the prothrombin gene that caused elevation of prothrombin levels and a mild increase in thrombosis risk. it is suspected that other genetic abnormalities underlying familial thrombosis will in future be discovered through studies of the entire genetic code, looking for small alternations in genes.