Thrombophilia (sometimes called hypercoagulability or a prothrombotic state) is an abnormality of blood coagulation that increases the risk of thrombosis (blood clots in blood vessels). The clot may also break off and migrate (embolize) to arteries in the lungs. Depending on the size and the location of the clot, this may lead to sudden-onset shortness of breath, chest pain, palpitations and may be complicated by collapse, shock and cardiac arrest.
Venous thrombosis may also occur in more unusual places: in the veins of the brain, liver (portal vein thrombosis and hepatic vein thrombosis), mesenteric vein, kidney (renal vein thrombosis) and the veins of the arms. However, more recent data suggest some forms of inherited thrombophilia are associated with increased risk for arterial ischemic stroke.
Thrombophilia has been linked to recurrent miscarriage, and possibly various complications of pregnancy such as intrauterine growth restriction, stillbirth, severe pre-eclampsia and abruptio placentae.
Causes
Thrombophilia can be congenital or acquired. Congenital thrombophilia refers to inborn conditions (and usually hereditary, in which case "hereditary thrombophilia" may be used) that increase the tendency to develop thrombosis, while, on the other hand, acquired thrombophilia refers to conditions that arise later in life.
Congenital
The most common types of congenital thrombophilia are those that arise as a result of overactivity of coagulation factors; hence they are considered "gain-of-function" alterations. They are relatively mild in the usual heterozygous state, and are therefore classified as "type II" defects. The most common ones are factor V Leiden (a mutation in the F5 gene at position 1691) and prothrombin G20210A, a mutation in prothrombin (at position 20210 in the 3' untranslated region of the gene). Compound heterozygotes and homozygotes, while rare, are at significant risk of thrombosis.
Blood group determines thrombosis risk to a significant extent. Those with blood groups other than type O are at a 2- to 4-fold relative risk. O blood group is associated with reduced levels of von Willebrand factor — because of increased clearance — and factor VIII, which is related to thrombotic risk .
Acquired
A number of acquired conditions augment the risk of thrombosis. A prominent example is antiphospholipid syndrome,
Heparin-induced thrombocytopenia (HIT) is due to an immune system reaction against the anticoagulant drug heparin (or its derivatives). Paroxysmal nocturnal hemoglobinuria (PNH) is a rare condition resulting from acquired alterations in the PIGA gene, which plays a role in the protection of blood cells from the complement system. PNH increases the risk of venous thrombosis but is also associated with hemolytic anemia (anemia resulting from destruction of red blood cells). Both HIT and PNH require particular treatment.
Cancer, particularly when metastatic (spread to other places in the body), is a recognised risk factor for thrombosis.
Nephrotic syndrome, in which protein from the bloodstream is released into the urine due to kidney diseases, can predispose to thrombosis; Inflammatory bowel disease (ulcerative colitis and Crohn's disease) predispose to thrombosis, particularly when the disease is active. Various mechanisms have been proposed.
Pregnancy is associated with an increased risk of thrombosis of 2- to 7-fold. This probably results from a physiological hypercoagulability in pregnancy that protects against postpartum hemorrhage. This hypercoagulability in turn is likely related to the high levels of estradiol and progesterone that occur during pregnancy.
Estrogens, when used in combined hormonal birth control and in menopausal hormone therapy (in combination with progestogens), have been associated with a 2- to 6-fold increased risk of venous thrombosis. The risk depends on the types of hormones used, the dose of estrogen, and the presence of other thrombophilic risk factors. Various mechanisms, such as deficiency of protein S and tissue factor pathway inhibitor, are said to be responsible.
Obesity has long been regarded as a risk factor for venous thrombosis. It more than doubles the risk in numerous studies, particularly in combination with the use of oral contraceptives or in the period after surgery. Various coagulation abnormalities have been described in the obese. Plasminogen activator inhibitor-1, an inhibitor of fibrinolysis, is present in higher levels in people with obesity. Obese people also have larger numbers of circulating microvesicles (fragments of damaged cells) that bear tissue factor. Platelet aggregation may be increased, and there are higher levels of coagulation proteins such as von Willebrand factor, fibrinogen, factor VII and factor VIII. Obesity also increases the risk of recurrence after an initial episode of thrombosis.
Unclear
A number of conditions that have been linked with venous thrombosis are possibly genetic and possibly acquired.
Diagnosis
thumb|right | A mutation of coagulation factor V (schematic representation drawn here) is much more common in people with thrombosis than in those without, but is only regarded as a weak risk factor.
Tests for thrombophilia include complete blood count (with examination of the blood film), prothrombin time, partial thromboplastin time, thrombodynamics test, thrombin time and reptilase time, lupus anticoagulant, anti-cardiolipin antibody, anti-β2 glycoprotein 1 antibody, activated protein C resistance, fibrinogen tests, factor V Leiden and prothrombin mutation, and basal homocysteine levels. Recurrent thromboembolism, or thrombosis in unusual sites (e.g. the hepatic vein in Budd-Chiari syndrome), is a generally accepted indication for screening. It is more likely to be cost-effective in people with a strong personal or family history of thrombosis. In contrast, the combination of thrombophilia with other risk factors may provide an indication for preventive treatment, which is why thrombophilia testing may be performed even in those who would not meet the strict criteria for these tests. 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. A 2016 study estimated that more than $1 million was wasted on inappropriate thrombophilia testing in a year at one academic medical center.
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. unless the testing is restricted to selected situations.
In 2021, the American College of Chest Physicians offered one testing-related recommendation in its venous thromboembolism guidelines. They recommended to consider positive D-dimer in the decision to continue or discontinue anticoagulation. Positive D-dimer may suggest that the ongoing thrombotic tendency has not fully resolved.
In 2023, the American Society of Hematology issued new guidelines for thrombophilia testing. One departure from their previous guidelines relates to patients with nonsurgical major transient risk factors; testing may be appropriate. Thrombophilia testing after venous thromboembolism(VTE) provoked by surgery, on the other hand, is not recommended, because the risk of recurrence is low. Some experts argue that unprovoked VTE requires indefinite (lifelong) anticoagulation and therefore performing thrombophilia testing will not affect management. Nearly all recommendations in the guidelines were based on "very low certainty" evidence. may prove helpful in this regard.
Molecular tests such as Factor V Leiden and Prothrombin G20210A are unaffected by the physiologic state of the patient.
Treatment
right|thumb|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.
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. Warfarin and LMWH may safely be used in breastfeeding.
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. 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.