Factor II

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Factor II
Author: Robert A Schwartz, MD, MPH; Chief Editor: Emmanuel C Besa, MD more... Updated: Jul 12, 2012

Background
Clotting factor II, or prothrombin, is a vitamin Kdependent 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 [1] ; in 1969, Shapiro and colleagues were the first to report a structural prothrombin abnormality.[2] 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.[5] The gene encoding prothrombin is primarily expressed in the liver[6] and is located on chromosome 11 in the region of the centromere.[7] It is composed of 14 exons and contains 24 kilobases of DNA.[7] The gene encodes a signal region, a propeptide region, a glutamic acid domain, 2 kringle regions, and a catalytic domain.[7] 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.[10] 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.[11]

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This mutation alters the polyadenylation site of the gene and results in increased mRNA synthesis, with a subsequent increase in protein expression.[12] Prothrombin 20210a has an estimated prevalence of 2% in whites.[13, 14] The mutation is more prevalent in those of southern European descent than in those of northern European descent, and it is rarely seen in Asians or Africans.[13] A study of patients in Turkey revealed the presence of the prothrombin 20210a mutation in 0.7% of subjects.[15] Individuals carrying the prothrombin 20210a mutation have a 2- to 3-fold increased risk for developing thrombosis.[10, 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.[17] 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.[18] 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. Treatment with oral anticoagulants is useful in preventing recurrence in patients with the mutation who have already experienced a thrombotic event. Additionally, women who are 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.[19, 20] Livedo vasculopathy is associated with immunoglobulin (Ig)M antiphosphatidylserine-prothrombin complex antibody.[21] 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.[20] Chronic urticaria is an autoimmune disease found in one half of cases with circulating histamine-releasing autoantibodies, mainly directed against the high affinity IgE-receptor Fc RI on mast cells and basophils or against IgE. Chronic urticaria may be associated with the activation of coagulation that is due to the involvement of eosinophils and 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 with chronic urticaria.

Pathophysiology
In the blood coagulation cascade, prothrombin is cleaved by factor Xa to form thrombin, an active serine protease.[22] This proteolytic reaction occurs on the phospholipid surfaces of platelets and requires calcium. Thrombin is responsible for inducing platelet aggregation and activating several other mediators in the coagulation cascade. It converts fibrinogen to fibrin, which then polymerizes to form a clot around platelet aggregates. Thrombin also converts factor XIII to factor XIIIa, an enzyme that cross-links and stabilizes fibrin polymers. 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. 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, including smooth muscle, fibroblasts, endothelial cells, and mononuclear phagocytes.[23] Decreased levels or a dysfunctional structure 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 mitosis and chemotaxis in several different cell lines. Several specific missense mutations of the prothrombin gene have been documented.[24, 25, 26, 27] These single amino acid 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 of prothrombin activity.[25] A single guanine-to-adenine mutation was found, which resulted in the substitution of histidine for arginine at residue 320. The arginine 320toisoleucine 321 bond is 1 of 2 sites in prothrombin cleaved by factor Xa 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.[25] Two members of a family from Venezuela were found to have undetectable antigen levels and prothrombin activity levels at 4% of normal.[28] A mutation was identified that had resulted in the substitution of cystine for tyrosine at residue 44. Substitution of a cystine at residue 44, located in the aromatic stack region of the protein, would result in an abnormal folding of the protein and could be the cause for the observed lack of secretion of prothrombin.[28]

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Other mutations, affecting various regions of the prothrombin gene, have also been described. Prothrombin Puerto Rico I involves an arginine to glycine substitution at position 457.[29, 30] Prothrombin Saint-Denis involves an aspartic acid to glutamine substitution at position 552.[31] Acquired factor II deficiency has several possible etiologies. Because prothrombin is synthesized almost exclusively in the liver, severe liver disease can have a dramatic impact on prothrombin levels. Vitamin K deficiency can also result in decreased prothrombin levels. Vitamin K is produced in the gut by enteric flora, and levels can be affected by intestinal malabsorption, bile duct obstruction, or antibiotic administration.[32] Vitamin K deficiency can be iatrogenically induced by the administration of propylthiouracil or vitamin K antagonists such as warfarin. Vitamin K deficiency can also be seen in neonates. Finally, acquired factor II deficiency can sometimes be observed in patients with lupus anticoagulant.[33, 34] These patients can develop specific prothrombin autoantibodies that form a complex with prothrombin and cause excessive clearance of prothrombin from the body.[35, 36] This condition, sometimes referred to as "lupus anticoagulant hypoprothrombinemia syndrome," is most often seen with systemic lupus erythematosus.[34]

Epidemiology
Frequency
United States Both congenital and acquired factor II deficiencies are rare. International Only approximately 30 cases of congenital factor II deficiency have been documented worldwide.[37]

Mortality/Morbidity
Congenital factor II deficiency is a lifelong bleeding disorder. Death can result because of massive hemorrhage from relatively minor accidents or trauma. Hemorrhage can also occur as a result of surgery if precautions are not taken. Intracranial bleeding is another serious sequela of this disorder. Rarely, hemarthroses can occur.[3]

Race
Factor II deficiency has no known racial or ethnic predilection.

Sex
Males and females are affected equally in cases of factor II deficiency.

Age
Patients with severe congenital factor II deficiency present early in life, whereas those with less severe forms can present at any age. Acquired forms can be observed in all age groups.

Contributor Information and Disclosures

Author Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New Jersey-New Jersey Medical School Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi Disclosure: Nothing to disclose. Coauthor(s)

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Christopher J Steen, MD Dermatologist, Private Practice Christopher J Steen, MD is a member of the following medical societies: Alpha Omega Alpha and Sigma Xi Disclosure: Nothing to disclose. Pere Gascon, MD, PhD Professor and Director, Division of Medical Oncology, Institute of Hematology and Medical Oncology, IDIBAPS, University of Barcelona Faculty of Medicine, Spain Pere Gascon, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, New York Academy of Medicine, New York Academy of Sciences, and Sigma Xi Disclosure: Nothing to disclose. Specialty Editor Board Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences Disclosure: Nothing to disclose. Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference Disclosure: Medscape Salary Employment Ronald A Sacher, MB, BCh, MD, FRCPC Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Association for the Advancement of Science, American Association of Blood Banks, American Clinical and Climatological Association, American Society for Clinical Pathology, American Society of Hematology, College of American Pathologists, International Society of Blood Transfusion, International Society on Thrombosis and Haemostasis, and Royal College of Physicians and Surgeons of Canada Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership Rebecca J Schmidt, DO, FACP, FASN Professor of Medicine, Section Chief, Department of Medicine, Section of Nephrology, West Virginia University School of Medicine Rebecca J Schmidt, DO, FACP, FASN is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Nephrology, International Society of Nephrology, National Kidney Foundation, Renal Physicians Association, and West Virginia State Medical Association Disclosure: Renal Ventures Ownership interest Other Chief Editor Emmanuel C Besa, MD Professor, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Clinical Oncology, American Society of Hematology, and New York Academy of Sciences Disclosure: Nothing to disclose.

References

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heterozygote for dys- and hypoprothrombinaemia. Br J Haematol . Jan 2003;120(1):142-4. [Medline]. 41. Girolami A, Scarparo P, Allemand E. Mutations are no substitutes for clotting, chromogenic and immunological assays in patients with congenital prothrombin deficiency. Am J Hematol . Jun 2008;83(6):518; author reply 518-9. [Medline]. 42. HEMEX Laboratories. 'II' be or not 'II' be tested. Prothrombin gene mutation - a new thrombophilia risk. Updated January 23, 2003. Accessed December 2, 2008. [Full Text]. 43. Henriksen RA, Dunham CK, Miller LD, et al. Prothrombin Greenville, Arg517-->Gln, identified in an individual heterozygous for dysprothrombinemia. Blood. Mar 15 1998;91(6):2026-31. [Medline]. [Full Text]. 44. Kearon C, Gent M, Hirsh J, et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. Mar 25 1999;340(12):901-7. [Medline]. [Full Text]. 45. Kearon C, Julian JA, Kovacs MJ, et al. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. Dec 1 2008;112(12):4432-6. [Medline]. 46. McMahon MJ, James AH. Combined deficiency of factors II, VII, IX, and X (Borgschulte-Grigsby deficiency) in pregnancy. Obstet Gynecol . May 2001;97(5 pt 2):808-9. [Medline]. 47. Medline Plus Medical Encyclopedia. Factor II deficiency. Updated March 13, 2007. Available at http://www.nlm.nih.gov/medlineplus/ency/article/000549.htm. Accessed December 2, 2008. 48. National Hemophilia Foundation. Learn about coagulation disorders: factor II deficiency. Available at http://www.hemophilia.org/bdi/bdi_types5.htm. Accessed December 2, 2008. 49. Rossi E, Za T, Ciminello A, Leone G, De Stefano V. The risk of symptomatic pulmonary embolism due to proximal deep venous thrombosis differs in patients with different types of inherited thrombophilia. Thromb Haemost. Jun 2008;99(6):1030-4. [Medline]. 50. Strijks E, Poort SR, Renier WO, Gabreels FJ, Bertina RM. Hereditary prothrombin deficiency presenting as intracranial haematoma in infancy. Neuropediatrics . Dec 1999;30(6):320-4. [Medline]. 51. Sun WY, Burkart MC, Holahan JR, Degen SJ. Prothrombin San Antonio: a single amino acid substitution at a factor Xa activation site (Arg320 to His) results in dysprothrombinemia. Blood. Jan 15 2000;95(2):711-4. [Medline]. [Full Text]. Medscape Reference 2011 WebMD, LLC

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