Thrombophilia

Thrombophilia or hypercoagulability is the propensity to develop thrombosis (blood clots) due to an abnormality in the system of coagulation.^[1][2] Hereditary defects in one or more of the clotting factors can cause the formation of potentially dangerous blood clots (thrombosis). Approximately 5-8% of the U.S. population has one of these clotting disorders collectively called thrombophilia, a propensity for blood clotting in which a genetic or acquired defect can be identified that may result in thrombosis.^[2] Nevertheless, most of these only develop thrombosis in the presence of an additional risk factor.^[2] There is no specific treatment for most thrombophilias, but recurrent episodes of thrombosis may be an indication for long-term preventative anticoagulation.^[2]

Signs and symptoms

The most common symptoms of thrombophilia are deep vein thrombosis (DVT) and pulmonary embolism (PE), two conditions referred to together as venous thromboembolism (VTE). DVT usually occurs in the legs, and is characterized by pain, swelling and redness of the limb. It may lead to long-term swelling and heaviness in a proportion of cases due to damage to valves in the veins. The clot may also break off and migrate (embolism) to the lungs. Depending on the size and the location of the embolus this may lead to sudden-onset shortness of breath, chest pain, palpitations and may be complicated by collapse, shock and cardiac arrest.^[2] Venous thrombosis may also occur in more unusual places: in the brain (cerebral venous sinus thrombosis), liver (portal vein thrombosis and hepatic vein thrombosis), mesenteric vein, kidney (renal vein thrombosis) and possibly the veins of the arms.^[2] Whether thrombophilia also increases the risk of arterial thrombosis is less well established; myocardial infarction (heart attack) and stroke are caused by arterial thrombosis.^[2]

Protein C deficiency may cause purpura fulminans, a severe clotting disorder in the newborn that leads to both tissue death and bleeding into the skin and other organs. The condition has also been described in adults. Protein C and protein S deficiency have also been associated with an increased risk of skin necrosis on commencing anticoagulant treatment with warfarin or related drugs.^[2]

Thrombophilia has been linked to both recurrent miscarriage and possibly various complications of pregnancy such as intrauterine growth restriction, stillbirth, severe pre-eclampsia and abruptio placentae.^[2]

Diagnosis

Tests for thrombophilia include complete blood count (with examination of the blood smear), prothrombin time, partial thromboplastin time, 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.^[2] Testing may be more or less extensive depending on clinical judgement.^[2] There is substantial variation in the tests ordered,^[3] and many laboratories add on various other tests, depending on local policy and guidelines.

There are divergent views as to whether everyone with an unprovoked episode of thrombosis should be investigated for thrombophilia. Even those with a form of thrombophilia may not necessarily be at risk of further thrombosis, while recurrent thrombosis is more likely even in those who have no detectable thrombophilic abnormalities.^[4][5] 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.^[6] In contrast, the combination of thrombophilia with other risk factors may provide an indication for preventative treatment, which is why thrombophilia testing may be performed even in those who would not meet the strict criteria for these tests.^[4] Searching for a coagulation abnormality is not normally undertaken in patients in whom thrombosis has an obvious other cause. For example, if the thrombosis is due to immobilisation after recent orthopedic surgery, it is unlikely that an underlying cause is found.^[4] Increasingly, recurrent miscarriage is seen as an indication for thrombophilia screening.^[7]

Thrombophilia screening in people with arterial thrombosis is generally unrewarding, except for unusually young patients—especially when precipitated by smoking or use of estrogen-containing hormonal contraceptives—and those in whom revascularization (e.g. arterial bypass) fails because of rapid occlusion of the graft.^[8]

Causes

Causes of thrombophilia can be acquired or congenital.

• Acquired refers to transient or acquired conditions that increase the tendency to clot. This might include antiphospholipid antibodies or a temporary hypercoagulable state such as pregnancy. Also, advanced carcinomas of the pancreas or lung may produce Trousseau syndrome, which creates a hypercoagulable state.
• Congenital refers to hereditary conditions that increase the tendency to clot. These include Factor V Leiden (see below); prothrombin G20210A; protein C, protein S and antithrombin deficiencies.

Congenital

Common types; most common causes are hyperactivity of procoagulants or type II,^[9] which are more severe than type I:

• Factor V Leiden^[1] (5% of the population are heterozygous for FVL).
• Prothrombin mutation^[1] (G20210A, 5'UTR).
• High homocysteine levels due to MTHFR mutation^[1] or vitamin deficiency (vitamins B6, B12 and folic acid).
• Sickle-cell disease (only small risk)^[1]

Rare forms, most being deficiency of anticoagulants or type I^[9] (less severe):

• Antithrombin III deficiency.^[1]
• Protein C deficiency.^[1]
• Protein S deficiency.^[1]
• Plasminogen and fibrinolysis disorders (very rare)^[1]

Acquired

Causes posing high risk for thrombosis:

• Antiphospholipid antibodies^[1]
  • anti-cardiolipin antibodies and/or
  • lupus anticoagulants
• Heparin-induced thrombocytopenia^[1]
• Paroxysmal nocturnal hemoglobinuria

Lower risk for thrombosis:

• Nephrotic syndrome^[1]
• Hyperestrogenemia^[1]
• Estrogen-containing hormonal contraceptives^[1]
• Tobacco smoking^[1]

History

Rudolf Virchow categorized abnormalities in the consistency of the blood as a factor in the development of thrombosis. The exact nature of these abnormalities remained elusive until the first form of thrombophilia, antithrombin deficiency, was recognized in 1965. Protein C deficiency followed in 1981 and protein S deficiency in 1984. These are highly uncommon abnormalities. The most common hereditary thrombophilia, factor V Leiden, was reported in 1994. A common mutation in factor II (prothrombin) followed in 1996.^[10]

References

External links

• National Association for Thrombosis and Thrombophilia - USA patients' association