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Medscape Reference Reference
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Author: Robert A Schwartz, MD, MPH; Chief Editor: Emmanuel C Besa, MD more... Updated: Jul 12, 2012
Clotting factor II, or prothrombin, is a vitamin K–dependent proenzyme that functions in the blood coagulation cascade. Factor II deficiency is a rare, inherited or acquired bleeding disorder. In 1947, Quick and colleagues were the first to describe a deficiency of factor II  ; in 1969, Shapiro and colleagues were the first to report a structural prothrombin abnormality. Inherited factor II deficiency is an autosomal recessive disorder that can manifest as hypoprothrombinemia, a decrease in the overall synthesis of prothrombin, or as dysprothrombinemia, the synthesis of dysfunctional prothrombin.[3, 4] Homozygous individuals are generally asymptomatic and have functional prothrombin levels of 2-25%. However, symptomatic individuals may experience easy bruising, epistaxis, soft-tissue hemorrhage, excessive postoperative bleeding, and/or menorrhagia. In true hypoprothrombinemia, immunologic assays correlate well with functional assays in that both reveal low prothrombin values. Heterozygous patients are generally asymptomatic and have prothrombin levels of 50% or greater on both immunologic and functional assays. In dysprothrombinemia, only the functional assay for prothrombin returns significantly reduced values, whereas the immunologic assay reveals normal values. Acquired factor II deficiency can be caused by severe liver disease, vitamin K deficiency, anticoagulant drugs (eg, warfarin), or the presence of an antibody directed against the protein. The gene encoding prothrombin is primarily expressed in the liver and is located on chromosome 11 in the region of the centromere. It is composed of 14 exons and contains 24 kilobases of DNA. The gene encodes a signal region, a propeptide region, a glutamic acid domain, 2 kringle regions, and a catalytic domain. The enzyme gammaglutamyl carboxylase, in the presence of vitamin K, converts the N- terminal glutamic acid residues to gammacarboxyglutamic acid residues. These gamma-carboxyglutamic acid residues are necessary for the binding of prothrombin to phospholipids on platelet membranes. Because measurable prothrombin is present in all individuals with hypoprothrombinemia or dysprothrombinemia, authorities believe that the complete absence of prothrombin is incompatible with postnatal life. Studies of transgenic mice with a complete deficiency of prothrombin reveal embryonic lethality and neonatal death.[8, 9] Aside from the prothrombin deficiencies, another disorder of prothrombin is the prothrombin 20210a mutation. First reported in 1996 as a familial cause of venous thromboembolism, the prothrombin 20210a mutation results in increased levels of plasma prothrombin and a concurrent increased risk for the development of thrombosis. Although the exact mechanism of this disorder has not been elucidated, the prothrombin 20210a mutation involves the substitution of an adenine for a guanine at position 20210 within the 3' untranslated region of the prothrombin gene.
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 Prothrombin 20210a has an estimated prevalence of 2% in whites. Additionally. but also as a cytokine and growth factor capable of inducing mitosis and chemotaxis in several different cell lines. located in the aromatic stack region of the protein. A family in San Antonio. Protein C then degrades factors Va and VIIIa to inhibit the coagulation cascade. an enzyme that cross-links and stabilizes fibrin polymers. Thrombin is responsible for inducing platelet aggregation and activating several other mediators in the coagulation cascade. would result in an abnormal folding of the protein and could be the cause for the observed lack of secretion of prothrombin. Substitution of a cystine at residue 44. This may provide the rationale for clinical trials on the use of anticoagulant drugs as adjuvant treatment in patients with chronic urticaria. A study of patients in Turkey revealed the presence of the prothrombin 20210a mutation in 0. mainly directed against the high affinity IgE-receptor Fc ε RI on mast cells and basophils or against IgE. 14] The mutation is more prevalent in those of southern European descent than in those of northern European descent. Thus. was found to have normal antigenic levels of prothrombin but half the normal levels of prothrombin activity. Thrombin also converts factor XIII to factor XIIIa. Several specific missense mutations of the prothrombin gene have been documented. with a subsequent increase in protein expression. Treatment with oral anticoagulants is useful in preventing recurrence in patients with the mutation who have already experienced a thrombotic event. Pathophysiology In the blood coagulation cascade. 25.medscape. A study of cancer patients in the Netherlands found that the presence of the prothrombin 20210a mutation in these patients may increase the risk of venous thrombosis to a level greater than that attributable to the malignancy alone. This proteolytic reaction occurs on the phospholipid surfaces of platelets and requires calcium.[24. an active serine protease. Prothrombin plays a role in a role in chronic urticaria and various vascular disorders.7% of subjects. which resulted in the substitution of histidine for arginine at residue 320. It converts fibrinogen to fibrin.[13. women who are known to carry the mutation may want to avoid oral contraceptives because of the additional risk of thrombosis. 16] One case-control study found evidence of an increased risk of developing an ischemic cerebrovascular event in men aged younger than 60 years with the prothrombin 20210a mutation. prothrombin is cleaved by factor Xa to form thrombin. Decreased levels or a dysfunctional structure of factor II can lead to absent or defective clot formation and dysfunctional platelet aggregation. Chronic urticaria may be associated with the activation of coagulation that is due to the involvement of eosinophils and a tissue factor pathway.[19. and it is rarely seen in Asians or Africans. inducing mitosis and chemotaxis in cell lines. A single guanine-to-adenine mutation was found. 27] These single amino acid substitutions can cause hypoprothrombinemia and/or dysprothrombinemia. 26.com/article/209742-overview This mutation alters the polyadenylation site of the gene and results in increased mRNA synthesis. Two members of a family from Venezuela were found to have undetectable antigen levels and prothrombin activity levels at 4% of normal. and mononuclear phagocytes. Substitution of histidine for arginine at this site resulted in the blockage of factor Xa cleavage. endothelial cells.Factor II http://emedicine. The prothrombin 20210a mutation can be identified without DNA analysis and should be considered in any patient experiencing a thrombotic event without other risk factors. forming a dysfunctional molecule and resulting in dysprothrombinemia. Texas. thrombin functions not only in the clotting cascade. 2 dari 7 3/16/2013 6:14 AM .[10. including smooth muscle. Chronic urticaria is an autoimmune disease found in one half of cases with circulating histamine-releasing autoantibodies. The presence of antiphosphatidylserine-prothrombin complex antibodies and histopathological necrotizing vasculitis in the upperto-middle dermis indicates cutaneous leukocytoclastic angiitis rather than cutaneous polyarteritis nodosa. Individuals carrying the prothrombin 20210a mutation have a 2. with generation of thrombin potentially contributing to an increased vascular permeability. which then polymerizes to form a clot around platelet aggregates. A mutation was identified that had resulted in the substitution of cystine for tyrosine at residue 44.to 3-fold increased risk for developing thrombosis. fibroblasts. Thrombin also has cytokine and growth-factor functions. The prothrombotic effects of thrombin are ultimately suppressed by the binding of thrombin to thrombomodulin on endothelial cell surfaces to form a complex that activates protein C. The arginine 320–to–isoleucine 321 bond is 1 of 2 sites in prothrombin cleaved by factor Xa to form thrombin. 20] Livedo vasculopathy is associated with immunoglobulin (Ig)M antiphosphatidylserine-prothrombin complex antibody.
whereas those with less severe forms can present at any age. MD. Age Patients with severe congenital factor II deficiency present early in life. Acquired forms can be observed in all age groups.[29. Vitamin K deficiency can also be seen in neonates. Contributor Information and Disclosures Author Robert A Schwartz. Sex Males and females are affected equally in cases of factor II deficiency. Acquired factor II deficiency has several possible etiologies. and Sigma Xi Disclosure: Nothing to disclose. Pediatrics.medscape. American College of Physicians. severe liver disease can have a dramatic impact on prothrombin levels. American Academy of Dermatology. Coauthor(s) 3 dari 7 3/16/2013 6:14 AM . MD." is most often seen with systemic lupus erythematosus. bile duct obstruction.com/article/209742-overview Other mutations. University of Medicine and Dentistry of New Jersey-New Jersey Medical School Robert A Schwartz. Vitamin K deficiency can also result in decreased prothrombin levels. 30] Prothrombin Saint-Denis involves an aspartic acid to glutamine substitution at position 552.[35. hemarthroses can occur. Vitamin K is produced in the gut by enteric flora.Factor II http://emedicine. Epidemiology Frequency United States Both congenital and acquired factor II deficiencies are rare. Prothrombin Puerto Rico I involves an arginine to glycine substitution at position 457. International Only approximately 30 cases of congenital factor II deficiency have been documented worldwide. Intracranial bleeding is another serious sequela of this disorder. and levels can be affected by intestinal malabsorption. Professor of Pathology. Death can result because of massive hemorrhage from relatively minor accidents or trauma. sometimes referred to as "lupus anticoagulant hypoprothrombinemia syndrome.[33. Dermatology. affecting various regions of the prothrombin gene. Medicine. and Preventive Medicine and Community Health. Race Factor II deficiency has no known racial or ethnic predilection. MPH is a member of the following medical societies: Alpha Omega Alpha. Rarely. 36] This condition. acquired factor II deficiency can sometimes be observed in patients with lupus anticoagulant. MPH Professor and Head. 34] These patients can develop specific prothrombin autoantibodies that form a complex with prothrombin and cause excessive clearance of prothrombin from the body. Finally. or antibiotic administration. Mortality/Morbidity Congenital factor II deficiency is a lifelong bleeding disorder. Because prothrombin is synthesized almost exclusively in the liver. Hemorrhage can also occur as a result of surgery if precautions are not taken. Vitamin K deficiency can be iatrogenically induced by the administration of propylthiouracil or vitamin K antagonists such as warfarin. have also been described.
FRCPC Professor. MB. American Society of Hematology. University of Nebraska Medical Center College of Pharmacy. MD is a member of the following medical societies: American Association for Cancer Education. University of Barcelona Faculty of Medicine. New York Academy of Sciences. Editor-in-Chief. DO. Department of Internal Medicine. Talecris Honoraria Board membership Rebecca J Schmidt. University of Cincinnati Academic Health Center Ronald A Sacher. American Association of Blood Banks. Department of Internal Medicine. MD Emeritus Professor. PhD Professor and Director. Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa. Hoxworth Blood Center. American Society of Hematology. Department of Medicine. and New York Academy of Sciences Disclosure: Nothing to disclose. PharmD. MD.medscape. National Kidney Foundation. New York Academy of Medicine. PhD is a member of the following medical societies: Alpha Omega Alpha. FASN is a member of the following medical societies: American College of Physicians. and Royal College of Physicians and Surgeons of Canada Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching. American Society of Clinical Oncology. College of American Pathologists. BCh. Renal Physicians Association. Francisco Talavera. Kimmel Cancer Center. FRCPC is a member of the following medical societies: American Association for the Advancement of Science. Private Practice Christopher J Steen. American College of Physicians. International Society on Thrombosis and Haemostasis. FACP. Medscape Drug Reference Disclosure: Medscape Salary Employment Ronald A Sacher. MD. Spain Pere Gascon. American Society of Nephrology. FACP. Drexel University College of Medicine. MD is a member of the following medical societies: Alpha Omega Alpha and Sigma Xi Disclosure: Nothing to disclose. American Federation for Medical Research.com/article/209742-overview Christopher J Steen. Adjunct Professor of Medicine. and New York Academy of Sciences Disclosure: Nothing to disclose. American Society of Hematology. MB. West Virginia University School of Medicine Rebecca J Schmidt. American College of Clinical Pharmacology. and West Virginia State Medical Association Disclosure: Renal Ventures Ownership interest Other Chief Editor Emmanuel C Besa. Pere Gascon. Internal Medicine and Pathology. BCh. Section of Nephrology. DO. FASN Professor of Medicine. Department of Medicine. Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation. Institute of Hematology and Medical Oncology. MD. Specialty Editor Board Paul Schick. IDIBAPS. American Heart Association. MD is a member of the following medical societies: American College of Physicians. PhD Adjunct Assistant Professor. Lankenau Hospital Paul Schick. References 4 dari 7 3/16/2013 6:14 AM . American Medical Association. American Society for Clinical Pathology. International Society on Thrombosis and Haemostasis. International Society of Nephrology. MD. American Clinical and Climatological Association. Jefferson Medical College of Thomas Jefferson University. MD Professor. Section Chief. Research Professor. Director. Division of Medical Oncology.Factor II http://emedicine. and Sigma Xi Disclosure: Nothing to disclose. MD Dermatologist. International Society of Blood Transfusion.
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