This mutation alters the polyadenylation site of the gene and results in increased mRNA synthesis, with a subsequentincrease in protein expression.
Prothrombin 20210a has an estimated prevalence of 2% in whites.
The mutation is more prevalent in those ofsouthern European descent than in those of northern European descent, and it is rarely seen in Asians or Africans.
A study of patients in Turkey revealed the presence of the prothrombin 20210a mutation in 0.7% of subjects.
Individuals carrying the prothrombin 20210a mutation have a 2- to 3-fold increased risk for developing thrombosis.
One case-control study found evidence of an increased risk of developing an ischemic cerebrovascular event inmen aged younger than 60 years with the prothrombin 20210a mutation.
A study of cancer patients in theNetherlands found that the presence of the prothrombin 20210a mutation in these patients may increase the risk ofvenous thrombosisto a level greater than that attributable to the malignancy alone.
The prothrombin 20210a mutation can be identified without DNA analysis and should be considered in any patientexperiencing a thrombotic event without other risk factors. Treatment with oral anticoagulants is useful in preventingrecurrence in patients with the mutation who have already experienced a thrombotic event. Additionally, women whoare known to carry the mutation may want to avoid oral contraceptives because of the additional risk of thrombosis.Prothrombin plays a role in a role in chronic urticaria and various vascular disorders.
Livedo vasculopathy isassociated with immunoglobulin (Ig)M antiphosphatidylserine-prothrombin complex antibody.
The presence ofantiphosphatidylserine-prothrombin complex antibodies and histopathological necrotizing vasculitis in the upper-to-middle dermis indicates cutaneous leukocytoclastic angiitis rather than cutaneouspolyarteritis nodosa.
Chronic urticaria is an autoimmune disease found in one half of cases with circulating histamine-releasingautoantibodies, mainly directed against the high affinity IgE-receptor Fc
RI on mast cells and basophils or againstIgE. Chronic urticaria may be associated with the activation of coagulation that is due to the involvement of eosinophilsand a tissue factor pathway, with generation of thrombin potentially contributing to an increased vascular permeability.This may provide the rationale for clinical trials on the use of anticoagulant drugs as adjuvant treatment in patients withchronic urticaria.
In the blood coagulation cascade, prothrombin is cleaved by factor Xa to form thrombin, an active serine protease.
This proteolytic reaction occurs on the phospholipid surfaces of platelets and requires calcium. Thrombin isresponsible for inducing platelet aggregation and activating several other mediators in the coagulation cascade. Itconverts fibrinogen to fibrin, which then polymerizes to form a clot around platelet aggregates. Thrombin also convertsfactor XIIIto factor XIIIa, an enzyme that cross-links and stabilizes fibrin polymers. The prothrombotic effects ofthrombin are ultimately suppressed by the binding of thrombin to thrombomodulin on endothelial cell surfaces to forma complex that activatesprotein C. Protein C then degrades factors Va and VIIIa to inhibit the coagulation cascade.Thrombin also has cytokine and growth-factor functions, inducing mitosis and chemotaxis in cell lines, includingsmooth muscle, fibroblasts, endothelial cells, and mononuclear phagocytes.
Decreased levels or a dysfunctionalstructure of factor II can lead to absent or defective clot formation and dysfunctional platelet aggregation. Thus,thrombin functions not only in the clotting cascade, but also as a cytokine and growth factor capable of inducing mitosisand chemotaxis in several different cell lines.Several specific missense mutations of the prothrombin gene have been documented.
[24, 25, 26, 27]
These single aminoacid substitutions can cause hypoprothrombinemia and/or dysprothrombinemia.A family in San Antonio, Texas, was found to have normal antigenic levels of prothrombin but half the normal levels ofprothrombin activity.
A single guanine-to-adenine mutation was found, which resulted in the substitution of histidinefor arginine at residue 320. The arginine 320–to–isoleucine 321 bond is 1 of 2 sites in prothrombin cleaved by factorXa to form thrombin. Substitution of histidine for arginine at this site resulted in the blockage of factor Xa cleavage,forming a dysfunctional molecule and resulting in dysprothrombinemia.
Two members of a family from Venezuela were found to have undetectable antigen levels and prothrombin activitylevels at 4% of normal.
A mutation was identified that had resulted in the substitution of cystine for tyrosine atresidue 44. Substitution of a cystine at residue 44, located in the aromatic stack region of the protein, would result in anabnormal folding of the protein and could be the cause for the observed lack of secretion of prothrombin.
Factor IIhttp://emedicine.medscape.com/article/209742-overview2 dari 73/16/2013 6:14 AM