Thrombophilia

Thrombophilic disorders encompass a diverse group of coagulation disorders that potentiate a predisposition for thrombotic events. Such abnormalities can be identified in 50% of people who have an episode of thrombosis (such as deep vein thrombosis in the leg) that was not provoked by other causes. Thrombophilia is caused by abnormalities in blood consistency, which is determined by the levels of coagulation factors and other circulating blood proteins that participate in the "coagulation cascade". A significant proportion of the population has a detectable abnormality, but most of these only develop thrombosis in the presence of an additional risk factor. 

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.

1. Congenital
   The most common types of congenital thrombophilia are those that arise as a result of overactivity of coagulation factors. They are relatively mild, 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).
   The rare forms of congenital thrombophilia are typically caused by a deficiency of natural anticoagulants. They are classified as "type I" and are more severe in their propensity to cause thrombosis. The main ones are antithrombin III deficiency, protein C deficiency and protein S deficiency.
   Milder rare congenital thrombophilias are factor XIII mutation and familial dysfibrinogenemia (an abnormal fibrinogen). Congenital deficiency of plasminogen, for instance, mainly causes eye symptoms and sometimes problems in other organs, but the link with thrombosis has been more uncertain.
   
2. Acquired
   A number of acquired conditions augment the risk of thrombosis. A prominent example is antiphospholipid syndrome, which is caused by antibodies against constituents of the cell membrane, particularly lupus anticoagulant (first found in people with the disease systemic lupus erythematosus but often detected in people without the disease), anti-cardiolipin antibodies, and anti-β2-glycoprotein 1 antibodies; it is therefore regarded as an autoimmune disease.             In some cases antiphospholipid syndrome can cause arterial as well as venous thrombosis. It is also more strongly associated with miscarriage, and can cause a number of other symptoms (such as livedo reticularis of the skin and migraine).

The overall impact of the inherited and acquired thrombophilias is low in the non-pregnant population, and the majority of patients never experience a thrombotic event. During pregnancy, however, the increased risk of thromboses in patients with inherited and acquired thrombophilias can be substantial and warrants consideration, especially as thrombosis is the leading cause of mortality during pregnancy. Fifty percent of the patients with thrombosis during pregnancy will be found to have an underlying thrombophilia.

Diagnosis
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.Testing may be more or less extensive depending on clinical judgement and abnormalities detected on initial evaluation.

Treatment

There is no specific treatment for thrombophilia, unless it is caused by an underlying medical illness (such as nephrotic syndrome), in which case the treatment of the underlying disease is needed. In those with unprovoked and/or recurrent thrombosis, or those with a high-risk 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.

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.

Symptoms

The most common conditions associated with thrombophilia are deep vein thrombosis (DVT) and pulmonary embolism (PE), which are referred to collectively 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 due to damage to valves in the veins. 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) arteries in the lungs, and the veins of the arms. 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.

Associated diseases

The association between thrombophilia and recurrent pregnancy loss or poor pregnancy outcome is well known. It may act by impairing the initial vascularization process occurring at implantation, which is necessary for a successful pregnancy. Hereditary thrombophilia can cause in placentation failure, it may have a role in recurrent IVF failure.
The overall impact of the inherited and acquired thrombophilias is low in the non-pregnant population, and the majority of patients never experience a thrombotic event. During pregnancy, however, the increased risk of thromboses in patients with inherited and acquired thrombophilias can be substantial and warrants consideration, especially as thrombosis is the leading cause of mortality during pregnancy. Fifty percent of the patients with thrombosis during pregnancy will be found to have an underlying thrombophilia.

The management of thrombophilia in the setting of pregnancy remains controversial. Anticoagulation may provide benefit for women both as prophylaxis and as treatment for venous thromboembolism during pregnancy. Women with inherited thrombophilias should be counseled that although their condition may increase the risk of adverse outcomes in pregnancy, the associations are not clear and that there are no definitive studies linking the use of anticoagulation to pregnancy success in this setting. The largest percentage of failed invitro fertilization (IVF) cycles, are due to lack of implantation. As hereditary thrombophilia can cause in placentation failure, it may have a role in recurrent IVF failure. Inherited thrombophilia is more prevalent in women with recurrent IVF failure compared with healthy women. 

Having at least one: thrombophilia, mutation of factor V Leiden and homozygote form of MTHFR mutation were risk factors for recurrent IVF failure.