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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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including smooth muscle. endothelial cells. located in the aromatic stack region of the protein.[24. 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. Treatment with oral anticoagulants is useful in preventing recurrence in patients with the mutation who have already experienced a thrombotic event. Several specific missense mutations of the prothrombin gene have been documented. Prothrombin plays a role in a role in chronic urticaria and various vascular disorders. Two members of a family from Venezuela were found to have undetectable antigen levels and prothrombin activity levels at 4% of normal.to 3-fold increased risk for developing thrombosis. Prothrombin 20210a has an estimated prevalence of 2% in whites. This proteolytic reaction occurs on the phospholipid surfaces of platelets and requires calcium. which then polymerizes to form a clot around platelet aggregates. and it is rarely seen in Asians or Africans. It converts fibrinogen to fibrin. 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. Chronic urticaria is an autoimmune disease found in one half of cases with circulating histamine-releasing autoantibodies. Texas. with a subsequent increase in protein expression. The arginine 320–to–isoleucine 321 bond is 1 of 2 sites in prothrombin cleaved by factor Xa to form thrombin. mainly directed against the high affinity IgE-receptor Fc ε RI on mast cells and basophils or against IgE. which resulted in the substitution of histidine for arginine at residue 320. 14] The mutation is more prevalent in those of southern European descent than in those of northern European descent. Chronic urticaria may be associated with the activation of coagulation that is due to the involvement of eosinophils and a tissue factor pathway. Thrombin also has cytokine and growth-factor functions. fibroblasts. Substitution of a cystine at residue 44.medscape. Pathophysiology In the blood coagulation cascade. Individuals carrying the prothrombin 20210a mutation have a 2. This may provide the rationale for clinical trials on the use of anticoagulant drugs as adjuvant treatment in patients with chronic urticaria. A family in San Antonio. inducing mitosis and chemotaxis in cell lines. A study of patients in Turkey revealed the presence of the prothrombin 20210a mutation in 0. forming a dysfunctional molecule and resulting in dysprothrombinemia. women who are known to carry the mutation may want to avoid oral contraceptives because of the additional risk of thrombosis. A single guanine-to-adenine mutation was found. and mononuclear phagocytes. 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.[10. A mutation was identified that had resulted in the substitution of cystine for tyrosine at residue 44. but also as a cytokine and growth factor capable of inducing mitosis and chemotaxis in several different cell lines. 27] These single amino acid substitutions can cause hypoprothrombinemia and/or dysprothrombinemia. 25. an enzyme that cross-links and stabilizes fibrin polymers. with generation of thrombin potentially contributing to an increased vascular permeability. thrombin functions not only in the clotting cascade. prothrombin is cleaved by factor Xa to form thrombin.[13. 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. Decreased levels or a dysfunctional structure of factor II can lead to absent or defective clot formation and dysfunctional platelet aggregation. 2 dari 7 3/16/2013 6:14 AM . 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. Thus.com/article/209742-overview This mutation alters the polyadenylation site of the gene and results in increased mRNA synthesis. Additionally. an active serine protease. Thrombin also converts factor XIII to factor XIIIa.Factor II http://emedicine. Protein C then degrades factors Va and VIIIa to inhibit the coagulation cascade.7% of subjects. was found to have normal antigenic levels of prothrombin but half the normal levels of prothrombin activity. Substitution of histidine for arginine at this site resulted in the blockage of factor Xa cleavage. 26.[19. 20] Livedo vasculopathy is associated with immunoglobulin (Ig)M antiphosphatidylserine-prothrombin complex antibody. 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.
Vitamin K deficiency can also be seen in neonates. or antibiotic administration. Epidemiology Frequency United States Both congenital and acquired factor II deficiencies are rare. Coauthor(s) 3 dari 7 3/16/2013 6:14 AM . Dermatology. MD. 36] This condition. University of Medicine and Dentistry of New Jersey-New Jersey Medical School Robert A Schwartz. acquired factor II deficiency can sometimes be observed in patients with lupus anticoagulant. whereas those with less severe forms can present at any age. International Only approximately 30 cases of congenital factor II deficiency have been documented worldwide. Acquired forms can be observed in all age groups. Professor of Pathology. Acquired factor II deficiency has several possible etiologies. Vitamin K deficiency can also result in decreased prothrombin levels. sometimes referred to as "lupus anticoagulant hypoprothrombinemia syndrome. Pediatrics.[29. Vitamin K is produced in the gut by enteric flora. have also been described. and Sigma Xi Disclosure: Nothing to disclose. 30] Prothrombin Saint-Denis involves an aspartic acid to glutamine substitution at position 552. MPH is a member of the following medical societies: Alpha Omega Alpha. Mortality/Morbidity Congenital factor II deficiency is a lifelong bleeding disorder. Age Patients with severe congenital factor II deficiency present early in life. and Preventive Medicine and Community Health. and levels can be affected by intestinal malabsorption.medscape. Vitamin K deficiency can be iatrogenically induced by the administration of propylthiouracil or vitamin K antagonists such as warfarin. affecting various regions of the prothrombin gene. Race Factor II deficiency has no known racial or ethnic predilection. Hemorrhage can also occur as a result of surgery if precautions are not taken." is most often seen with systemic lupus erythematosus.[33.com/article/209742-overview Other mutations. American College of Physicians. severe liver disease can have a dramatic impact on prothrombin levels. Finally. Intracranial bleeding is another serious sequela of this disorder. Sex Males and females are affected equally in cases of factor II deficiency. Prothrombin Puerto Rico I involves an arginine to glycine substitution at position 457.[35. MPH Professor and Head. bile duct obstruction. hemarthroses can occur. MD. Because prothrombin is synthesized almost exclusively in the liver. Contributor Information and Disclosures Author Robert A Schwartz. American Academy of Dermatology. Death can result because of massive hemorrhage from relatively minor accidents or trauma. 34] These patients can develop specific prothrombin autoantibodies that form a complex with prothrombin and cause excessive clearance of prothrombin from the body.Factor II http://emedicine. Medicine. Rarely.
Specialty Editor Board Paul Schick. and New York Academy of Sciences Disclosure: Nothing to disclose. American Society for Clinical Pathology. Private Practice Christopher J Steen. New York Academy of Medicine. Talecris Honoraria Board membership Rebecca J Schmidt. MD. International Society on Thrombosis and Haemostasis. References 4 dari 7 3/16/2013 6:14 AM . University of Cincinnati Academic Health Center Ronald A Sacher. American Medical Association. FRCPC Professor. MD. American Clinical and Climatological Association. DO. MB. Francisco Talavera. Kimmel Cancer Center. Department of Medicine. Adjunct Professor of Medicine. Medscape Drug Reference Disclosure: Medscape Salary Employment Ronald A Sacher. International Society of Nephrology. Research Professor. FASN is a member of the following medical societies: American College of Physicians. Drexel University College of Medicine. Section Chief. International Society on Thrombosis and Haemostasis. American College of Physicians. American College of Clinical Pharmacology. Renal Physicians Association.com/article/209742-overview Christopher J Steen. American Society of Hematology. FASN Professor of Medicine. MB. MD Professor. Institute of Hematology and Medical Oncology. Spain Pere Gascon. PhD is a member of the following medical societies: Alpha Omega Alpha. American Society of Clinical Oncology. Department of Internal Medicine. MD. DO. American Society of Hematology. PhD Professor and Director. MD is a member of the following medical societies: American College of Physicians. PhD Adjunct Assistant Professor. and Sigma Xi Disclosure: Nothing to disclose. and Royal College of Physicians and Surgeons of Canada Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching. and West Virginia State Medical Association Disclosure: Renal Ventures Ownership interest Other Chief Editor Emmanuel C Besa. Hoxworth Blood Center.Factor II http://emedicine. and New York Academy of Sciences Disclosure: Nothing to disclose. College of American Pathologists. National Kidney Foundation. Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation. MD. PharmD. Lankenau Hospital Paul Schick. Department of Medicine. American Society of Hematology. Jefferson Medical College of Thomas Jefferson University. American Federation for Medical Research. BCh. University of Nebraska Medical Center College of Pharmacy. Director. MD is a member of the following medical societies: Alpha Omega Alpha and Sigma Xi Disclosure: Nothing to disclose. FACP. Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa. MD Emeritus Professor. FACP. BCh. American Heart Association. American Association of Blood Banks. West Virginia University School of Medicine Rebecca J Schmidt. Internal Medicine and Pathology. University of Barcelona Faculty of Medicine. IDIBAPS. International Society of Blood Transfusion. American Society of Nephrology. Department of Internal Medicine.medscape. MD is a member of the following medical societies: American Association for Cancer Education. MD Dermatologist. Pere Gascon. FRCPC is a member of the following medical societies: American Association for the Advancement of Science. Editor-in-Chief. Section of Nephrology. Division of Medical Oncology. New York Academy of Sciences.
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