Factor II Deficiency
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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 disorder with an estimated incidence of one case per 2 million population. [1] } Affected individuals are a homozygote for a defective prothrombin gene or a compound heterozygote with different mutated prothrombin genes inherited from each parent. [2] Accordingly, they usually have either little normal prothrombin or a near-normal output of dysfunctional prothrombin.
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, 5] Homozygous individuals are generally asymptomatic and have functional prothrombin levels of 2-25%. However, symptomatic individuals may experience one or more of the following [1] :
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. [6]
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. [7]
Prothrombin 20210a has an estimated prevalence of 2% in whites. [8, 9] 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. [8] A study of patients in Turkey revealed the presence of the prothrombin 20210a mutation in 0.7% of subjects. [10]
Individuals carrying the prothrombin 20210a mutation have a 2- to 3-fold increased risk for developing thrombosis. [7, 11] 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. [12] 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. [13]
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.
Laboratory studies for factor II deficiency include coagulation studies and clotting factor assays (see Workup). Coagulation study results are as follows:
Prothrombin time (PT) is prolonged
Activated partial thromboplastin time (aPTT) is prolonged
Bleeding time is within reference range
Treatment of factor II deficiency is aimed at restoring circulating factor II to levels sufficient for hemostasis. Levels greater than 30% of normal are usually adequate. Treatment measures include fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), and vitamin K. Additionally, in patients with acquired factor II deficiency, the underlying cause should be found and treated. (See Treatment and Medication.)
In 1947, Quick and colleagues were the first to describe a deficiency of factor II. [14] In 1969, Shapiro and colleagues were the first to report a structural prothrombin abnormality. [15]
The gene encoding prothrombin is primarily expressed in the liver [16] and is located on chromosome 11 in the region of the centromere. [17] It is composed of 14 exons and contains 24 kilobases of DNA. [17] The gene encodes a signal region, a propeptide region, a glutamic acid domain, two kringle regions, and a catalytic domain. [17] The enzyme gamma-glutamyl carboxylase, in the presence of vitamin K, converts the N- terminal glutamic acid residues to gamma-carboxyglutamic acid residues. These gamma-carboxyglutamic acid residues are necessary for the binding of prothrombin to phospholipids on platelet membranes.
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. [18] This mutation alters the polyadenylation site of the gene and results in increased mRNA synthesis, with a subsequent increase in protein expression. [19]
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. [20, 21]
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. In fact, most hypoprothrombinemia-associated mutations are missense ones. [5]
A family in San Antonio, Texas, was found to have normal antigenic levels of prothrombin but half the normal levels of prothrombin activity. [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]
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] Two novel mutations in the prothrombin gene were delineated in association with compound heterozygous type 1/2 prothrombin deficiency. [32]
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. [33]
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. [34, 35] These patients can develop specific prothrombin autoantibodies that form a complex with prothrombin and cause excessive clearance of prothrombin from the body. [36, 37] This condition, sometimes referred to as “lupus anticoagulant hypoprothrombinemia syndrome,” is most often seen with systemic lupus erythematosus (SLE). [35] It is a rare cause of intracranial bleeding [38] and may be associated with severe thrombocytopenia. [39]
The lupus anticoagulant hypoprothrombinemia syndrome may also occur in individuals without SLE. Bleeding attibuted to acquired hypoprothrombinemia caused by antiphospholipid antibodies may follow acute adenovirus gastroenteritis and mycoplasma pneumonia. [40] The lupus anticoagulant hypoprothrombinemia syndrome is associated with a high mortality. [41]
Both congenital and acquired factor II deficiencies are rare. The prevalence of congenital factor II deficiency is approximately 1 per 1 to 2 million population. [42]
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]
Myocardial infarction is a rare complication in young people, with coronary thrombosis due to hypercoagulable states being one cause. A heterozygote prothrombin gene mutation (G-20210-A) and protein S deficiency were described in a 19-year-old with a myocardial infarction with normal coronary arteries. [43]
Factor II deficiency has no known racial or ethnic predilection. Males and females are affected equally. 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.
Harel R, Shani D, Donohoe K. A case of congenital prothrombin deficiency and idiopathic thrombocytopenic purpura in a pregnant female. Blood Coagul Fibrinolysis. 2016 Feb 15. [Medline].
Watson H, Perez A, Ayesu K, Musa F, Sarriera J, Madruga M, et al. Inherited factor II deficiency with paradoxical hypercoagulability: a case report. Blood Coagul Fibrinolysis. 2018 Mar. 29 (2):223-226. [Medline].
Baudo F, de Cataldo F, Josso F, Silvello L. Hereditary hypoprothrombinaemia. True deficiency of factor II. Acta Haematol. 1972. 47(4):243-9. [Medline].
Girolami A, Scarano L, Saggiorato G, et al. Congenital deficiencies and abnormalities of prothrombin. Blood Coagul Fibrinolysis. 1998 Oct. 9(7):557-69. [Medline].
Lancellotti S, Basso M, De Cristofaro R. Congenital prothrombin deficiency: an update. Semin Thromb Hemost. 2013 Sep. 39(6):596-606. [Medline].
Bajaj SP, Rapaport SI, Barclay S, Herbst KD. Acquired hypoprothrombinemia due to non-neutralizing antibodies to prothrombin: mechanism and management. Blood. 1985 Jun. 65(6):1538-43. [Medline]. [Full Text].
Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3′-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood. 1996 Nov 15. 88(10):3698-703. [Medline]. [Full Text].
Rosendaal FR, Doggen CJ, Zivelin A, et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost. 1998 Apr. 79(4):706-8. [Medline].
Atasay B, Arsan S, Gunlemez A, Kemahli S, Akar N. Factor V Leiden and prothrombin gene 20210A variant in neonatal thromboembolism and in healthy neonates and adults: a study in a single center. Pediatr Hematol Oncol. 2003 Dec. 20(8):627-34. [Medline].
Irdem A, Devecioglu C, Batun S, Soker M, Sucakli IA. Prevalence of factor V Leiden and prothrombin G20210A gene mutation. Saudi Med J. 2005 Apr. 26(4):580-3. [Medline].
Margaglione M, Brancaccio V, Giuliani N, et al. Increased risk for venous thrombosis in carriers of the prothrombin G–>A20210 gene variant. Ann Intern Med. 1998 Jul 15. 129(2):89-93. [Medline]. [Full Text].
Lalouschek W, Schillinger M, Hsieh K, et al. Matched case-control study on factor V Leiden and the prothrombin G20210A mutation in patients with ischemic stroke/transient ischemic attack up to the age of 60 years. Stroke. 2005 Jul. 36(7):1405-9. [Medline]. [Full Text].
Blom JW, Doggen CJ, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA. 2005 Feb 9. 293(6):715-22. [Medline]. [Full Text].
Quick AJ. Congenital hypoprothrombinemia and pseudo-hypoprothrombinemia. Lancet. 1947. ii:379-82.
Shapiro SS, Martinez J, Holburn RR. Congenital dysprothrombinemia: an inherited structural disorder of human prothrombin. J Clin Invest. 1969 Dec. 48(12):2251-9. [Medline]. [Full Text].
Royle NJ, Irwin DM, Koschinsky ML, MacGillivray RT, Hamerton JL. Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively. Somat Cell Mol Genet. 1987 May. 13(3):285-92. [Medline].
Degen SJ. The prothrombin gene and its liver-specific expression. Semin Thromb Hemost. 1992. 18(2):230-42. [Medline].
Pollak ES, Lam HS, Russell JE. The G20210A mutation does not affect the stability of prothrombin mRNA in vivo. Blood. 2002 Jul 1. 100(1):359-62. [Medline]. [Full Text].
Ceelie H, Spaargaren-van Riel CC, Bertina RM, Vos HL. G20210A is a functional mutation in the prothrombin gene; effect on protein levels and 3′-end formation. J Thromb Haemost. 2004 Jan. 2(1):119-27. [Medline].
Sun WY, Witte DP, Degen JL, Colbert MC, Burkart MC, Holmbäck K, et al. Prothrombin deficiency results in embryonic and neonatal lethality in mice. Proc Natl Acad Sci U S A. 1998 Jun 23. 95(13):7597-602. [Medline]. [Full Text].
Sun WY, Coleman MJ, Witte DP, Degen SJ. Rescue of prothrombin-deficiency by transgene expression in mice. Thromb Haemost. 2002 Dec. 88(6):984-91. [Medline].
Narayanan S. Multifunctional roles of thrombin. Ann Clin Lab Sci. 1999 Oct-Dec. 29(4):275-80. [Medline].
Zhou H, Gabazza EC, Takeya H, et al. Prothrombin and its derivatives stimulate motility of melanoma cells. Thromb Haemost. 1998 Sep. 80(3):407-12. [Medline].
Akhavan S, Mannucci PM, Lak M, et al. Identification and three-dimensional structural analysis of nine novel mutations in patients with prothrombin deficiency. Thromb Haemost. 2000 Dec. 84(6):989-97. [Medline].
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. 2000 Jan 15. 95(2):711-4. [Medline]. [Full Text].
Wang W, Fu Q, Zhou R, et al. Prothrombin Shanghai: hypoprothrombinaemia caused by substitution of Gla29 by Gly. Haemophilia. 2004 Jan. 10(1):94-7. [Medline].
Jayandharan G, Viswabandya A, Baidya S, et al. Molecular genetics of hereditary prothrombin deficiency in Indian patients: identification of a novel Ala362 –> Thr (Prothrombin Vellore 1) mutation. J Thromb Haemost. 2005 Jul. 3(7):1446-53. [Medline]. [Full Text].
Sun WY, Smirnow D, Jenkins ML, Degen SJ. Prothrombin Scranton: substitution of an amino acid residue involved in the binding of Na+ (LYS-556 to THR) leads to dysprothrombinemia. Thromb Haemost. 2001 Apr. 85(4):651-4. [Medline].
Lefkowitz JB, Weller A, Nuss R, et al. A common mutation, Arg457–>Gln, links prothrombin deficiencies in the Puerto Rican population. J Thromb Haemost. 2003 Nov. 1(11):2381-8. [Medline].
Kling SJ, Jones KA, Rodgers GM. A second case of prothrombin Puerto Rico I in the United States. Am J Hematol. 2007 Jul. 82(7):661-2. [Medline]. [Full Text].
Rouy S, Vidaud D, Alessandri JL, et al. Prothrombin Saint-Denis: a natural variant with a point mutation resulting in Asp to Glu substitution at position 552 in prothrombin. Br J Haematol. 2006 Mar. 132(6):770-3. [Medline].
Kuijper PH, Schellings MW, van de Kerkhof D, Nicolaes GA, Reitsma P, Halbertsma F, et al. Two novel mutations in the prothrombin gene identified in a patient with compound heterozygous type 1/2 prothrombin deficiency. Haemophilia. 2013 Sep. 19(5):e304-6. [Medline].
Bhat RV, Deshmukh CT. A study of Vitamin K status in children on prolonged antibiotic therapy. Indian Pediatr. 2003 Jan. 40(1):36-40. [Medline]. [Full Text].
Baudo F, Redaelli R, Pezzetti L, et al. Prothrombin-antibody coexistent with lupus anticoagulant (LA): clinical study and immunochemical characterization. Thromb Res. 1990 Jan 15. 57(2):279-87. [Medline].
Taddio A, Brescia AC, Lepore L, Rose CD. Steady improvement of prothrombin levels after cyclophosphamide therapy in pediatric lupus anticoagulant hypoprothrombinemia syndrome (LAHPS). Clin Rheumatol. 2007 Dec. 26(12):2167-9. [Medline].
Cote HC, Huntsman DG, Wu J, Wadsworth LD, MacGillivray RT. A new method for characterization and epitope determination of a lupus anticoagulant-associated neutralizing antiprothrombin antibody. Am J Clin Pathol. 1997 Feb. 107(2):197-205. [Medline].
Vivaldi P, Rossetti G, Galli M, Finazzi G. Severe bleeding due to acquired hypoprothrombinemia-lupus anticoagulant syndrome. Case report and review of literature. Haematologica. 1997 May-Jun. 82(3):345-7. [Medline]. [Full Text].
Sreedharanunni S, Ahluwalia J, Kumar N, Bose SK, Dhawan R, Malhotra P. Lupus anticoagulant – hypoprothrombinemia syndrome: a rare cause of intracranial bleeding. Blood Coagul Fibrinolysis. 2016 Dec 22. [Medline].
Foord A, Baca N, Buchbinder D, Mahajerin A. Lupus anticoagulant hypoprothrombinemia syndrome associated with severe thrombocytopenia in a child. Pediatr Blood Cancer. 2016 Nov 15. [Medline].
Shimizu T, Ishiguro A, Takayanagi T, Matsui T, Tonegawa N, Maekawa T, et al. [A case of lupus anticoagulant hypoprothrombinemia syndrome following adenovirus gastroenteritis and mycoplasma pneumonia]. Nihon Rinsho Meneki Gakkai Kaishi. 2014. 37(1):55-60. [Medline].
Nayer A, Ortega LM. Catastrophic antiphospholipid syndrome: a clinical review. J Nephropathol. 2014 Jan. 3(1):9-17. [Medline]. [Full Text].
Meeks SL, Abshire TC. Abnormalities of prothrombin: a review of the pathophysiology, diagnosis, and treatment. Haemophilia. 2008 Nov. 14 (6):1159-63. [Medline].
Klincheva M, Vilarova EA, Angjusheva T, Milev I, Idoski E, Mitrev Z. Endothelial Nitric Oxide Synthase T-786C Mutation, Prothrombin Gene Mutation (G-20210-A) and Protein S Deficiency Could Lead to Myocardial Infarction in a Very Young Male Adult. Open Access Maced J Med Sci. 2016 Mar 15. 4 (1):142-5. [Medline].
Miyawaki Y, Suzuki A, Fujita J, et al. Thrombosis from a prothrombin mutation conveying antithrombin resistance. N Engl J Med. 2012 Jun 21. 366(25):2390-6. [Medline].
Lechler E. Use of prothrombin complex concentrates for prophylaxis and treatment of bleeding episodes in patients with hereditary deficiency of prothrombin, factor VII, factor X, protein C protein S, or protein Z. Thromb Res. 1999 Aug 15. 95(4 suppl 1):S39-50. [Medline].
Robert A Schwartz, MD, MPH Professor and Head of Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School; Visiting Professor, Rutgers University School of Public Affairs and Administration
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, New York Academy of Medicine, American Academy of Dermatology, American College of Physicians, Sigma Xi
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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, Sigma Xi
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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, Sigma Xi
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Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
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Ronald A Sacher, MBBCh, FRCPC, DTM&H Professor of Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center
Ronald A Sacher, MBBCh, FRCPC, DTM&H 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, Royal College of Physicians and Surgeons of Canada
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Perumal Thiagarajan, MD Professor, Department of Pathology and Medicine, Baylor College of Medicine; Director, Transfusion Medicine and Hematology Laboratory, Michael E DeBakey Veterans Affairs Medical Center
Perumal Thiagarajan, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society for Biochemistry and Molecular Biology, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Royal College of Physicians
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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 Society of Hematology
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Factor II Deficiency
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