| Prothrombin G20210A | |
|---|---|
| Other names | Prothrombin thrombophilia, [1] factor II mutation, prothrombin mutation, rs1799963, factor II G20210A |
| Symptoms | Blood clots [1] |
| Frequency | 2% (Caucasians) [1] |
Prothrombin G20210A is a genetic condition that increases the risk of blood clots including from deep vein thrombosis, and of pulmonary embolism. [1] One copy of the mutation increases the risk of a blood clot from 1 in 1,000 per year to 2.5 in 1,000. [1] Two copies increases the risk to up to 20 in 1,000 per year. [1] Most people never develop a blood clot in their lifetimes. [1]
It is due to a specific gene mutation in which a guanine (G) is changed to an adenine (A) at position 20210 of the DNA of the prothrombin gene. Other blood clotting pathway mutations that increase the risk of clots include factor V Leiden.
Prothrombin G20210A was identified in the 1990s. [2] About 2% of Caucasians carry the variant, while it is less common in other populations. [1] It is estimated to have originated in Caucasians about 20,000 years ago. [3] [ better source needed ]
The variant causes elevated plasma prothrombin levels (hyperprothrombinemia), [4] possibly due to increased pre-mRNA stability. [5] Prothrombin is the precursor to thrombin, which plays a key role in causing blood to clot (blood coagulation). G20210A can thus contribute to a state of hypercoagulability, but not particularly with arterial thrombosis. [4] A 2006 meta-analysis showed only a 1.3-fold increased risk for coronary disease. [6] Deficiencies in the anticoagulants Protein C and Protein S further increase the risk five- to tenfold. [2] Behind non-O blood type [7] and factor V Leiden, prothrombin G20210A is one of the most common genetic risk factors for venous thromboembolism (VTE). [4] Increased production of prothrombin heightens the risk of blood clotting. Moreover, individuals who carry the mutation can pass it on to their offspring. [8]
The mutation increases the risk of developing deep vein thrombosis (DVT), [9] which can cause pain and swelling, and sometimes post-thrombotic syndrome, ulcers, or pulmonary embolism. [10] Most individuals do not require treatment but do need to be cautious during periods when the possibility of blood clotting are increased; for example, during pregnancy, after surgery, or during long flights. Occasionally, blood-thinning medication may be indicated to reduce the risk of clotting. [11]
A 2005 article concluded that heterozygous carriers who take combined birth control pills are at a 15-fold increased risk of VTE, [12] while carriers also heterozygous with factor V Leiden have an approximate 20-fold higher risk. [2] A more recent and larger study in 2023, however, concluded that heterozygous carriers had a 5.23x-increased risk, and those with both factors a 6.35x risk. [13] In a recommendation statement on VTE, genetic testing for G20210A in adults that developed unprovoked VTE [lower-alpha 1] was disadvised, as was testing in asymptomatic family members related to G20210A carriers who developed VTE. [14] In those who develop VTE, the results of thrombophilia tests (wherein the variant can be detected) rarely play a role in the length of treatment. [15]
| SNP: rs1799963 | |
|---|---|
| Gene | F2 |
| Chromosome | 11 |
| External databases | |
| Ensembl | Human SNPView |
| dbSNP | 1799963 |
| HapMap | 1799963 |
| SNPedia | 1799963 |
The polymorphism is located in a noncoding region of the prothrombin gene (3' untranslated region nucleotide 20210 [lower-alpha 2] ), replacing guanine with adenine. [4] [5] The position is at or near where the pre-mRNA will have the poly-A tail attached. [5]
Diagnosis of the prothrombin G20210A mutation is straightforward because the mutation involves a single base change (point mutation) that can be detected by genetic testing, which is unaffected by intercurrent illness or anticoagulant use.[ citation needed ]
Measurement of an elevated plasma prothrombin level cannot be used to screen for the prothrombin G20210A mutation, because there is too great of an overlap between the upper limit of normal and levels in affected patients. [17]
Patients with the prothrombin mutation are treated similarly to those with other types of thrombophilia, with anticoagulation for at least three to six months. Continuing anticoagulation beyond three to six months depends on the circumstances surrounding thrombosis, for example, if the patient experiences a thromboembolic event that was unprovoked, continuing anticoagulation would be recommended. The choice of anticoagulant (warfarin versus a direct oral anticoagulant) is based on a number of different factors (the severity of thrombosis, patient preference, adherence to therapy, and potential drug and dietary interactions). [18]
Patients with the prothrombin G20210A mutation who have not had a thromboembolic event are generally not treated with routine anticoagulation. However, counseling the patient is recommended in situations with increased thrombotic risk is recommended (pregnancy, surgery, and acute illness). Oral contraceptives should generally be avoided in women with the mutation as they increase the thrombotic risk. [19]
Because prothrombin is also known as factor II, the mutation is also sometimes referred to as the factor II mutation or simply the prothrombin mutation; in either case, the names may appear with or without the accompanying G20210A location specifier (unhelpfully, since prothrombin mutations other than G20210A are known).
An anticoagulant, commonly known as a blood thinner, is a chemical substance that prevents or reduces coagulation of blood, prolonging the clotting time. Some of them occur naturally in blood-eating animals such as leeches and mosquitoes, where they help keep the bite area unclotted long enough for the animal to obtain some blood.
Thrombosis is the formation of a blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibrin to form a blood clot to prevent blood loss. Even when a blood vessel is not injured, blood clots may form in the body under certain conditions. A clot, or a piece of the clot, that breaks free and begins to travel around the body is known as an embolus.
A thrombus, colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to stop and prevent further bleeding, but can be harmful in thrombosis, when a clot obstructs blood flow through healthy blood vessels in the circulatory system.
Pulmonary embolism (PE) is a blockage of an artery in the lungs by a substance that has moved from elsewhere in the body through the bloodstream (embolism). Symptoms of a PE may include shortness of breath, chest pain particularly upon breathing in, and coughing up blood. Symptoms of a blood clot in the leg may also be present, such as a red, warm, swollen, and painful leg. Signs of a PE include low blood oxygen levels, rapid breathing, rapid heart rate, and sometimes a mild fever. Severe cases can lead to passing out, abnormally low blood pressure, obstructive shock, and sudden death.
Venous thrombosis is the blockage of a vein caused by a thrombus. A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to lodge there, it becomes a pulmonary embolism (PE), a blood clot in the lungs. The conditions of DVT only, DVT with PE, and PE only, are all captured by the term venous thromboembolism (VTE).
Antiphospholipid syndrome, or antiphospholipid antibody syndrome, is an autoimmune, hypercoagulable state caused by antiphospholipid antibodies. APS can lead to blood clots (thrombosis) in both arteries and veins, pregnancy-related complications, and other symptoms like low platelets, kidney disease, heart disease, and rash. Although the exact etiology of APS is still not clear, genetics is believed to play a key role in the development of the disease. Diagnosis is made based on symptoms and testing, but sometimes research criteria are used to aid in diagnosis. The research criteria for definite APS requires one clinical event and two positive blood test results spaced at least three months apart that detect lupus anticoagulant, anti-apolipoprotein antibodies, and/or anti-cardiolipin antibodies.
Factor V Leiden is a variant of human factor V, which causes an increase in blood clotting (hypercoagulability). Due to this mutation, protein C, an anticoagulant protein that normally inhibits the pro-clotting activity of factor V, is not able to bind normally to factor V, leading to a hypercoagulable state, i.e., an increased tendency for the patient to form abnormal and potentially harmful blood clots. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst ethnic Europeans. It is named after the Dutch city of Leiden, where it was first identified in 1994 by Rogier Maria Bertina under the direction of Pieter Hendrick Reitsma. Despite the increased risk of venous thromboembolisms, people with one copy of this gene have not been found to have shorter lives than the general population. It is an autosomal dominant genetic disorder with incomplete penetrance.
Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene.
Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enlarged veins in the affected area, but some DVTs have no symptoms.
The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the extrinsic pathway and common pathway of coagulation. This blood test is also called protime INR and PT/INR. They are used to determine the clotting tendency of blood, in such things as the measure of warfarin dosage, liver damage, and vitamin K status. PT measures the following coagulation factors: I (fibrinogen), II (prothrombin), V (proaccelerin), VII (proconvertin), and X.
Thromboembolism is a condition in which a blood clot (thrombus) breaks off from its original site and travels through the bloodstream to obstruct a blood vessel, causing tissue ischemia and organ damage. Thromboembolism can affect both the venous and arterial systems, with different clinical manifestations and management strategies.
Protein C, also known as autoprothrombin IIA and blood coagulation factor XIV, is a zymogen, that is, an inactive enzyme. The activated form plays an important role in regulating anticoagulation, inflammation, and cell death and maintaining the permeability of blood vessel walls in humans and other animals. Activated protein C (APC) performs these operations primarily by proteolytically inactivating proteins Factor Va and Factor VIIIa. APC is classified as a serine protease since it contains a residue of serine in its active site. In humans, protein C is encoded by the PROC gene, which is found on chromosome 2.
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.
Factor V is a protein of the coagulation system, rarely referred to as proaccelerin or labile factor. In contrast to most other coagulation factors, it is not enzymatically active but functions as a cofactor. Deficiency leads to predisposition for hemorrhage, while some mutations predispose for thrombosis.
Renal vein thrombosis (RVT) is the formation of a clot in the vein that drains blood from the kidneys, ultimately leading to a reduction in the drainage of one or both kidneys and the possible migration of the clot to other parts of the body. First described by German pathologist Friedrich Daniel von Recklinghausen in 1861, RVT most commonly affects two subpopulations: newly born infants with blood clotting abnormalities or dehydration and adults with nephrotic syndrome.
Activated protein C resistance (APCR) is a hypercoagulability characterized by a lack of a response to activated protein C (APC), which normally helps prevent blood from clotting excessively. This results in an increased risk of venous thrombosis, which resulting in medical conditions such as deep vein thrombosis and pulmonary embolism. The most common cause of hereditary APC resistance is factor V Leiden mutation.
Protein C deficiency is a rare genetic trait that predisposes to thrombotic disease. It was first described in 1981. The disease belongs to a group of genetic disorders known as thrombophilias. Protein C deficiency is associated with an increased incidence of venous thromboembolism, whereas no association with arterial thrombotic disease has been found.
Hypercoagulability in pregnancy is the propensity of pregnant women to develop thrombosis. Pregnancy itself is a factor of hypercoagulability, as a physiologically adaptive mechanism to prevent post partum bleeding. However, when combined with an additional underlying hypercoagulable states, the risk of thrombosis or embolism may become substantial.
Darexaban (YM150) is a direct inhibitor of factor Xa created by Astellas Pharma. It is an experimental drug that acts as an anticoagulant and antithrombotic to prevent venous thromboembolism after a major orthopaedic surgery, stroke in patients with atrial fibrillation and possibly ischemic events in acute coronary syndrome. It is used in form of the maleate. The development of darexaban was discontinued in September 2011.
Thrombosis prevention or thromboprophylaxis is medical treatment to prevent the development of thrombosis in those considered at risk for developing thrombosis. Some people are at a higher risk for the formation of blood clots than others, such as those with cancer undergoing a surgical procedure. Prevention measures or interventions are usually begun after surgery as the associated immobility will increase a person's risk.
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