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