Thrombophilia

Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.
There is no specific treatment for most thrombophilias, but recurrent episodes of thrombosis may be an indication for long-term preventive anticoagulation. The first major form of thrombophilia to be identified by medical science, antithrombin deficiency, was identified in 1965, while the most common abnormalities were described in the 1990s.

Signs and symptoms

The most common conditions associated with thrombophilia are deep vein thrombosis and pulmonary embolism, which are referred to collectively as venous thromboembolism. 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. The clot may also break off and migrate 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, mesenteric vein, kidney and the veins of the arms. Whether thrombophilia also increases the risk of arterial thrombosis is less well established. 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.
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.

Causes

Thrombophilia can be congenital or acquired. Congenital thrombophilia refers to inborn conditions 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 and prothrombin G20210A, a mutation in prothrombin. Compound heterozygotes and homozygotes, while rare, are at significant risk of thrombosis.
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. It is unclear whether congenital disorders of fibrinolysis are major contributors to thrombosis risk. 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.
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, which is caused by antibodies against constituents of the cell membrane, particularly lupus anticoagulant, 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.
Heparin-induced thrombocytopenia is due to an immune system reaction against the anticoagulant drug heparin. Though it is named for associated low platelet counts, HIT is strongly associated with risk of venous and arterial thrombosis. Paroxysmal nocturnal hemoglobinuria 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. Both HIT and PNH require particular treatment.
Hematologic conditions associated with sluggish blood flow can increase risk for thrombosis. For example, sickle-cell disease is regarded as a mild prothrombotic state induced by impaired flow. Similarly, myeloproliferative disorders, in which the bone marrow produces too many blood cells, predispose to thrombosis, particularly in polycythemia vera and essential thrombocytosis. Again, these conditions usually warrant specific treatment when identified.
Cancer, particularly when metastatic, is a recognised risk factor for thrombosis. A number of mechanisms have been proposed, such as activation of the coagulation system by cancer cells or secretion of procoagulant substances. Furthermore, particular cancer treatments may increase the risk of thrombosis further.
Nephrotic syndrome, in which protein from the bloodstream is released into the urine due to kidney diseases, can predispose to thrombosis; this is particularly the case in more severe cases and if the syndrome is caused by the condition membranous nephropathy. Inflammatory bowel 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, 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 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. These include: elevated levels of factor VIII, factor IX, factor XI, fibrinogen and
thrombin-activatable fibrinolysis inhibitor, and decreased levels of tissue factor pathway inhibitor. Activated protein C resistance that is not attributable to factor V mutations is probably caused by other factors and remains a risk factor for thrombosis.
There is an association between the blood levels of homocysteine and thrombosis, although this has not been reported consistently in all studies. Homocysteine levels are determined by mutations in the MTHFR and CBS genes, but also by levels of folic acid, vitamin B₆ and vitamin B₁₂, which depend on diet.

Mechanism

Thrombosis is a multifactorial problem because there are often multiple reasons why a person might develop thrombosis. These risk factors may include any combination of abnormalities in the blood vessel wall, abnormalities in the blood flow, and abnormalities in the consistency of the blood. 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".
Normal coagulation is initiated by the release of tissue factor from damaged tissue. Tissue factor binds to circulating factor VIIa. The combination activates factor X to factor Xa and factor IX to factor IXa. Factor Xa activates prothrombin into thrombin. Thrombin is a central enzyme in the coagulation process: it generates fibrin from fibrinogen, and activates a number of other enzymes and cofactors that enhance the fibrin clot. The process is inhibited by TFPI, antithrombin, protein C, and protein Z.
In thrombophilia, the balance between "procoagulant" and "anticoagulant" activity is disturbed. The severity of the imbalance determines the likelihood that someone develops thrombosis. Even small perturbances of proteins, such as the reduction of antithrombin to only 70–80% of the normal level, can increase the thrombosis risk; this is in contrast with hemophilia, which only arises if levels of coagulation factors are markedly decreased.
In addition to its effects on thrombosis, hypercoagulable states may accelerate the development of atherosclerosis, the arterial disease that underlies myocardial infarction and other forms of cardiovascular disease.