Prothrombin 20210 (Mutation)
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- The G20210A is a gain of function mutation where adenine is substituted for a guanine at the 20210 noncoding position of the prothrombin (a.k.a. factor II) gene.
- Prothrombin 20210 mutation is the second most common venous thrombophilia after the factor V Leiden mutation.
- The mechanism of increasing the risk of thrombosis is incompletely understood but has been attributed to increased prothrombin or factor II levels in circulation by increased prothrombin protein translation without changing the levels of prothrombin mRNA transcription.
- Autosomal dominant condition, where heterozygotes have a 30% higher prothrombin level and a 3- to 4-fold increased risk of venous thromboembolism (VTE)
- System(s) affected: cardiovascular, hematologic/lymphatic/immunologic, nervous, pulmonary, reproductive, and hepatic
- Synonym(s): prothrombin G20210A mutation; prothrombin G20210A gene polymorphism; prothrombin gene mutation; and FII A20210 mutation
- Found largely in Caucasian population with a prevalence ranging between 1% and 6%, but overall, it is about 2%
- In patients presenting with a VTE, prothrombin 20210 mutation has a prevalence that ranges from 4.6% to 18% with increased prevalence attributed to highly thrombophilic families.
- Mean age of first thrombosis is in the 2nd decade of life.
- Inheritance is similar between both genders (autosomal).
Etiology and Pathophysiology
- Noncoding substitution of adenine for guanine at the 20210 position at the terminal nucleotide of the 3′ resulting in a gain of function of prothrombin gene, leading to increased levels of prothrombin (factor II), by increased translation of prothrombin mRNA but not transcription
- The base change location is in the 3′ terminal nucleotide of the untranslated region associated with the mRNA sequence for polyadenylation. The gain of function is possible due to increased rate of processing, alteration of the site of cleavage, or increased mRNA stability.
- In the coagulation cascade, prothrombin (factor II) is the precursor of thrombin, which cleaves fibrinogen to fibrin. Elevated prothrombin activity leads to elevated thrombin levels and subsequent clot formation.
- The majority of thrombus formation occurs in the venous circulation: deep venous thrombosis (DVT)/PE, mesenteric, and cerebral. Recent studies have shown that prothrombin 20210 mutation did not correlate with Budd-Chiari syndrome or a portal or hepatic vein thrombosis.
- G20210A mutation is not known to be a risk factor for some arterial thrombotic events (myocardial infarction or acute ischemic stroke); however, studies have shown an increased prevalence of the mutation in patients with critical limb ischemia (1).
- Caused by the G20210A mutation of the F2 gene (prothrombin gene) located in the short (p) arm of chromosome 11 that causes a gain of function
- Heterozygotes have a 30% increased levels of prothrombin levels, with a 3- to 4-fold increase of VTE events. Homozygotes are at an even greater risk.
- There are three other prothrombin mutations not related to the G20210A area:
- Yukuhashi: missense mutation G1787T, arginine for leucine at amino acid 596, leading to prolonged procoagulant activity
- C20209T: adjacent to G20210A mutation, primarily found in African individuals; newer studies have suggested a possible relationship between this mutation and recurrent pregnancy loss, although it is not fully understood.
- A19911G: located in the intron of the prothrombin gene; may affect the G20210A mutation by increasing the odds ratio of the venous thromboembolic event. Mechanism is still unknown.
- Being a hereditary condition, the presence of such mutation in the parents poses risk of transmission to offspring.
- Regarding the risk of developing VTE:
- Patients with both the prothrombin 20210 mutation and factor V Leiden mutation increases the odds ratio of VTE by 20-fold.
- Virchow triad of thrombogenesis consists of stasis, endothelial injury, and thrombophilia. Any condition that promotes stasis and endothelial injury will consequently increase the risk of VTE, for example, oral contraceptive, pregnancy, malignancy, orthopedic surgery, congestive heart failure, cerebrovascular accident in the past 3 months, air travel, obesity, and smoking.
- Increased thrombotic risk in patients with prothrombin 20210 mutation during pregnancy and in the postpartum state is attributed to relative stasis.
- Anticoagulation should begin in the 1st trimester because the risk of VTE increases early in pregnancy and should be discontinued at onset of labor or before scheduled induction/cesarean delivery. Postpartum risk of VTE is usually greater, and anticoagulation can resume 4 to 6 hours after a vaginal delivery or 6 to 12 hours after surgery. Warfarin may begin immediately due to slow onset of action.
- C20209T mutation may have some relation with recurrent pregnancy loss; however, it is not well studied (2).
Asymptomatic individuals with the mutation do not require any prophylactic anticoagulation. Exceptions are generally made for pregnant women with very high-risk thrombophilic mutations (usually factor V Leiden) with a strong family history. After the first VTE, lifelong prophylaxis may be warranted if some features are present: unprovoked or in a nontraditional area like hepatic, portal, mesenteric, or cerebral.
Commonly Associated Conditions
- Factor V Leiden