Phenotypic Heterogeneity in Patients with Homozygous Prothrombin 20210AA Genotype
2006; Elsevier BV; Volume: 8; Issue: 4 Linguagem: Inglês
10.2353/jmoldx.2006.060014
ISSN1943-7811
AutoresDavid Bosler, Joan C. Mattson, Domnita Crisan,
Tópico(s)Coagulation, Bradykinin, Polyphosphates, and Angioedema
ResumoVenous thromboembolic events (VTEs) affect an estimated 1 in 1000 people annually, resulting in ∼50,000 deaths, with prevalence increasing with age. The genetic contributors to thrombosis have been described and further explored within the last 15 years as molecular diagnostic techniques have become more widely used. The prothrombin G20210A mutation is the second most common inherited thrombotic risk factor after factor V Leiden. Generally present in less than 5% of the population, the mutation's prevalence varies greatly with ethnicity. The G20210A mutation confers a mildly increased thrombotic risk that is compounded by the presence of other risk factors. One striking characteristic of the G20210A mutation is the phenotypic heterogeneity of the rare homozygous cases. Forty percent of the reported homozygous cases are asymptomatic. Many of the symptomatic patients have additional risk factors that might compound the thrombotic risk. We present here a review of the literature for the homozygous prothrombin G20210A mutation and describe additional cases that exemplify the heterogeneous nature of this entity. Venous thromboembolic events (VTEs) affect an estimated 1 in 1000 people annually, resulting in ∼50,000 deaths, with prevalence increasing with age. The genetic contributors to thrombosis have been described and further explored within the last 15 years as molecular diagnostic techniques have become more widely used. The prothrombin G20210A mutation is the second most common inherited thrombotic risk factor after factor V Leiden. Generally present in less than 5% of the population, the mutation's prevalence varies greatly with ethnicity. The G20210A mutation confers a mildly increased thrombotic risk that is compounded by the presence of other risk factors. One striking characteristic of the G20210A mutation is the phenotypic heterogeneity of the rare homozygous cases. Forty percent of the reported homozygous cases are asymptomatic. Many of the symptomatic patients have additional risk factors that might compound the thrombotic risk. We present here a review of the literature for the homozygous prothrombin G20210A mutation and describe additional cases that exemplify the heterogeneous nature of this entity. Venous thromboembolic events (VTEs) affect an estimated 1 in 1000 people annually, resulting in ∼50,000 deaths.1Van Cott EM Laposata M Laboratory evaluation of hypercoagulable states.Hematol Oncol Clin North Am. 1998; 12: 1141-1166Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar The prevalence increases with age, demonstrated by one large prospective study of men, followed from 50 to 80 years of age, with an overall incidence of VTE of 387 per 100,000 observation-years, with 107 fatal events per 100,000.2Hansson PO Welin L Tibblin G Eriksson H Deep vein thrombosis and pulmonary embolism in the general population. The Study of Men Born in 1913.Arch Intern Med. 1997; 157: 1665-1670Crossref PubMed Google Scholar A variety of well-established acquired risk factors exist for these events, including recent surgery, cancer, immobility, obesity, and current or former smoking.1Van Cott EM Laposata M Laboratory evaluation of hypercoagulable states.Hematol Oncol Clin North Am. 1998; 12: 1141-1166Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar,3Goldhaber SZ Tapson VF A prospective registry of 5,451 patients with ultrasound-confirmed deep vein thrombosis.Am J Cardiol. 2004; 93: 259-262Abstract Full Text Full Text PDF PubMed Scopus (456) Google Scholar Use of oral contraceptives has also been identified as an acquired risk factor.1Van Cott EM Laposata M Laboratory evaluation of hypercoagulable states.Hematol Oncol Clin North Am. 1998; 12: 1141-1166Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar,4Martinelli I Taioli E Bucciarelli P Akhavan S Mannucci PM Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis.Arterioscler Thromb Vasc Biol. 1999; 19: 700-703Crossref PubMed Scopus (180) Google Scholar The contribution of inheritance to VTEs has long been noted but is still incompletely understood.5Nguyen A Review and management of patients with the prothrombin G20210A polymorphism.Clin Appl Thromb Hemost. 2000; 6: 94-99Crossref PubMed Scopus (8) Google Scholar,6Mannucci PM Laboratory detection of inherited thrombophilia: a historical perspective.Semin Thromb Hemost. 2005; 31: 5-10Crossref PubMed Scopus (31) Google Scholar Although the first description of a biochemical basis for inherited thrombophilia, antithrombin deficiency, was 40 years ago, the most prevalent genetic contributors to VTE have been described and further explored only within the last 15 years as molecular diagnostic techniques have become more widely used in the effort.6Mannucci PM Laboratory detection of inherited thrombophilia: a historical perspective.Semin Thromb Hemost. 2005; 31: 5-10Crossref PubMed Scopus (31) Google Scholar The most prevalent hereditary risk factor, factor V Leiden, is the most common cause of resistance to activated protein C. The mutation for factor V Leiden was first described in 1994 as a single nucleotide substitution in the factor V gene G1691A.7Bertina RM Koeleman BP Koster T Rosendaal FR Dirven RJ de Ronde H van der Velden PA Reitsma PH Mutation in blood coagulation factor V associated with resistance to activated protein C.Nature. 1994; 369: 64-67Crossref PubMed Scopus (3842) Google Scholar8van der Meer FJ Koster T Vandenbroucke JP Briet E Rosendaal FR The Leiden Thrombophilia Study (LETS).Thromb Haemost. 1997; 78: 631-635PubMed Google Scholar9Dahlback B Resistance to activated protein C caused by the factor VR506Q mutation is a common risk factor for venous thrombosis.Thromb Haemost. 1997; 78: 483-488PubMed Google Scholar The prothrombin gene mutation, G20210A, is the second most prevalent hereditary risk factor for VTE. Prothrombin, or factor II, is the precursor for thrombin, the vitamin K-dependent factor in the coagulation cascade that converts fibrinogen to fibrin. The prothrombin gene, located on chromosome 11 (11p11-q12), is a 21-kb gene containing 14 exons.10Degen SJ Davie EW Nucleotide sequence of the gene for human prothrombin.Biochemistry. 1987; 26: 6165-6177Crossref PubMed Scopus (226) Google Scholar First described by Poort and colleagues in 1996,11Poort 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; 88: 3698-3703Crossref PubMed Google Scholar the G20210A prothrombin gene mutation is a single nucleotide substitution of adenine for guanine in the 3′-untranslated region of the gene. The prothrombin G20210A mutation is thought to elevate prothrombotic risk through a gain of function, resulting in an increased level of prothrombin. Many studies have shown elevated prothrombin levels in patients with mutations, which are generally more pronounced in homozygous cases.11Poort 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; 88: 3698-3703Crossref PubMed Google Scholar12Simioni P Tormene D Manfrin D Gavasso S Luni S Stocco D Girolami A Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant.Br J Haematol. 1998; 103: 1045-1050Crossref PubMed Scopus (61) Google Scholar13Kyrle PA Mannhalter C Beguin S Stumpflen A Hirschl M Weltermann A Stain M Brenner B Speiser W Pabinger I Lechner K Eichinger S Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene.Arterioscler Thromb Vasc Biol. 1998; 18: 1287-1291Crossref PubMed Scopus (155) Google Scholar14Zawadzki C Gaveriaux V Trillot N Bauters A Watel A Alhenc-Gelas M Preudhomme C Jude B Homozygous G20210A transition in the prothrombin gene associated with severe venous thrombotic disease: two cases in a French family.Thromb Haemost. 1998; 80: 1027-1028PubMed Google Scholar15Morange PE Barthet MC Henry M Fontanet H Aillaud MF Alessi MC Juhan-Vague I A three-generation family presenting five cases of homozygosity for the 20210 G to A prothrombin variant.Thromb Haemost. 1998; 80: 859-860PubMed Google Scholar16Eikelboom JW Ivey L Ivey J Baker RI Familial thrombophilia and the prothrombin 20210A mutation: association with increased thrombin generation and unusual thrombosis.Blood Coagul Fibrinolysis. 1999; 10: 1-5Crossref PubMed Scopus (22) Google Scholar17Corral J Zuazu-Jausoro I Rivera J Gonzalez-Conejero R Ferrer F Vicente V Clinical and analytical relevance of the combination of prothrombin 20210A/A and factor V Leiden: results from a large family.Br J Haematol. 1999; 105: 560-563Crossref PubMed Scopus (32) Google Scholar In addition to finding elevated prothrombin levels in patients with the 20210A allele, Poort and colleagues11Poort 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; 88: 3698-3703Crossref PubMed Google Scholar found that the prothrombin level itself was a risk factor for thrombosis. The G20210A mutation has been shown to increase the efficiency of the 3′ end cleavage signal, resulting in increased cleavage site recognition, improved processing, and a more effective poly(A) site.18Ceelie 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; 2: 119-127Crossref PubMed Scopus (80) Google Scholar,19Gehring NH Frede U Neu-Yilik G Hundsdoerfer P Vetter B Hentze MW Kulozik AE Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia.Nat Genet. 2001; 28: 389-392Crossref PubMed Scopus (239) Google Scholar The end result is accumulation of mRNA and increased protein synthesis, and the resulting increase in prothrombin level is thought to confer the increased risk of thrombosis.18Ceelie 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; 2: 119-127Crossref PubMed Scopus (80) Google Scholar,19Gehring NH Frede U Neu-Yilik G Hundsdoerfer P Vetter B Hentze MW Kulozik AE Increased efficiency of mRNA 3′ end formation: a new genetic mechanism contributing to hereditary thrombophilia.Nat Genet. 2001; 28: 389-392Crossref PubMed Scopus (239) Google Scholar The initial Poort and colleagues11Poort 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; 88: 3698-3703Crossref PubMed Google Scholar study found that the mutation was present in 18% of patients with a personal and family history of VTE and 6.2% of unselected patients with first time VTE, compared to 2.3% of healthy controls. Subsequent studies show prevalence in healthy European and American patients ranging from 1.2 to 4.6%.20Zivelin A Rosenberg N Faier S Kornbrot N Peretz H Mannhalter C Horellou MH Seligsohn U A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene.Blood. 1998; 92: 1119-1124PubMed Google Scholar21Ridker PM Hennekens CH Miletich JP G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men.Circulation. 1999; 99: 999-1004Crossref PubMed Scopus (275) Google Scholar22Kapur RK Mills LA Spitzer SG Hultin MB A prothrombin gene mutation is significantly associated with venous thrombosis.Arterioscler Thromb Vasc Biol. 1997; 17: 2875-2879Crossref PubMed Scopus (70) Google Scholar23Margaglione M Brancaccio V Giuliani N D'Andrea G Cappucci G Iannaccone L Vecchione G Grandone E Di Minno G Increased risk for venous thrombosis in carriers of the prothrombin G–>A20210 gene variant.Ann Intern Med. 1998; 129: 89-93Crossref PubMed Scopus (221) Google Scholar24Alhenc-Gelas M Arnaud E Nicaud V Aubry ML Fiessinger JN Aiach M Emmerich J Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes.Thromb Haemost. 1999; 81: 506-510PubMed Google Scholar25Nowak-Gottl U Junker R Kreuz W von Eckardstein A Kosch A Nohe N Schobess R Ehrenforth S Risk of recurrent venous thrombosis in children with combined prothrombotic risk factors.Blood. 2001; 97: 858-862Crossref PubMed Scopus (228) Google Scholar In one large Jewish study, Zivelin and colleagues20Zivelin A Rosenberg N Faier S Kornbrot N Peretz H Mannhalter C Horellou MH Seligsohn U A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene.Blood. 1998; 92: 1119-1124PubMed Google Scholar found a prevalence of 6.7% of 464 Ashkenazi Jews, 5.5% of 273 Sephardic Jews, 4% of 247 Iraqi Jews, 2% of 199 Iranian Jews, 1% of 310 Yemeni Jews, and none of 177 Ethiopian Jews. The mutation is less prevalent in non-Jewish, non-European populations.20Zivelin A Rosenberg N Faier S Kornbrot N Peretz H Mannhalter C Horellou MH Seligsohn U A single genetic origin for the common prothrombotic G20210A polymorphism in the prothrombin gene.Blood. 1998; 92: 1119-1124PubMed Google Scholar,26Arruda VR Annichino-Bizzacchi JM Goncalves MS Costa FF Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease.Thromb Haemost. 1997; 78: 1430-1433PubMed Google Scholar27Gurgey A Kudayarov DK Tuncer M Parlak H Altay C The factor V Leiden and prothrombin G20210A mutations in Kirghiz population.Thromb Haemost. 2000; 84: 356PubMed Google Scholar28Dilley A Austin H Hooper WC El-Jamil M Whitsett C Wenger NK Benson J Evatt B Prevalence of the prothrombin 20210 G-to-A variant in blacks: infants, patients with venous thrombosis, patients with myocardial infarction, and control subjects.J Lab Clin Med. 1998; 132: 452-455Abstract Full Text PDF PubMed Scopus (59) Google Scholar29Ho CH Prevalence of prothrombin 20210A allele and methylenetetrahydrofolate reductase C677T genetic mutations in the Chinese population.Ann Hematol. 2000; 79: 239-242Crossref PubMed Scopus (23) Google Scholar Dilley and colleagues28Dilley A Austin H Hooper WC El-Jamil M Whitsett C Wenger NK Benson J Evatt B Prevalence of the prothrombin 20210 G-to-A variant in blacks: infants, patients with venous thrombosis, patients with myocardial infarction, and control subjects.J Lab Clin Med. 1998; 132: 452-455Abstract Full Text PDF PubMed Scopus (59) Google Scholar found the mutation in only 1 of 318 black infants (0.2%) and no mutations in an additional 185 black control patients. In their study of Brazilians, Arruda and colleagues26Arruda VR Annichino-Bizzacchi JM Goncalves MS Costa FF Prevalence of the prothrombin gene variant (nt20210A) in venous thrombosis and arterial disease.Thromb Haemost. 1997; 78: 1430-1433PubMed Google Scholar found no prothrombin G20210A mutations within their Brazilian Indian population, whereas ∼2% of their cases of African descent carried the mutation. The mutation has been described in 1% of Kirghiz, 1.2% of Azerbaijani, 1.1% of Turkish, 0.3% of Indian, and 0% of other central and southeast Asian populations.27Gurgey A Kudayarov DK Tuncer M Parlak H Altay C The factor V Leiden and prothrombin G20210A mutations in Kirghiz population.Thromb Haemost. 2000; 84: 356PubMed Google Scholar One Chinese study did not find the mutation in any of 1323 patients.29Ho CH Prevalence of prothrombin 20210A allele and methylenetetrahydrofolate reductase C677T genetic mutations in the Chinese population.Ann Hematol. 2000; 79: 239-242Crossref PubMed Scopus (23) Google Scholar Although some studies have found no evidence that the G20210A mutation is a risk factor for VTE,21Ridker PM Hennekens CH Miletich JP G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men.Circulation. 1999; 99: 999-1004Crossref PubMed Scopus (275) Google Scholar the general consensus is that presence of the mutation is associated with mildly increased risk. The reported odds ratios range from 1.9 to 11.5, with most falling between 2 and 4.5Nguyen A Review and management of patients with the prothrombin G20210A polymorphism.Clin Appl Thromb Hemost. 2000; 6: 94-99Crossref PubMed Scopus (8) Google Scholar,8van der Meer FJ Koster T Vandenbroucke JP Briet E Rosendaal FR The Leiden Thrombophilia Study (LETS).Thromb Haemost. 1997; 78: 631-635PubMed Google Scholar,11Poort 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; 88: 3698-3703Crossref PubMed Google Scholar,22Kapur RK Mills LA Spitzer SG Hultin MB A prothrombin gene mutation is significantly associated with venous thrombosis.Arterioscler Thromb Vasc Biol. 1997; 17: 2875-2879Crossref PubMed Scopus (70) Google Scholar23Margaglione M Brancaccio V Giuliani N D'Andrea G Cappucci G Iannaccone L Vecchione G Grandone E Di Minno G Increased risk for venous thrombosis in carriers of the prothrombin G–>A20210 gene variant.Ann Intern Med. 1998; 129: 89-93Crossref PubMed Scopus (221) Google Scholar24Alhenc-Gelas M Arnaud E Nicaud V Aubry ML Fiessinger JN Aiach M Emmerich J Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes.Thromb Haemost. 1999; 81: 506-510PubMed Google Scholar,30McGlennen RC Key NS Clinical and laboratory management of the prothrombin G20210A mutation.Arch Pathol Lab Med. 2002; 126: 1319-1325PubMed Google Scholar,31Bank I Libourel EJ Middeldorp S Van Pampus EC Koopman MM Hamulyak K Prins MH van der Meer J Buller HR Prothrombin 20210A mutation: a mild risk factor for venous thromboembolism but not for arterial thrombotic disease and pregnancy-related complications in a family study.Arch Intern Med. 2004; 164: 1932-1937Crossref PubMed Scopus (92) Google Scholar The homozygous mutation is rare, with 67 reported cases in the literature.11Poort 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; 88: 3698-3703Crossref PubMed Google Scholar12Simioni P Tormene D Manfrin D Gavasso S Luni S Stocco D Girolami A Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant.Br J Haematol. 1998; 103: 1045-1050Crossref PubMed Scopus (61) Google Scholar13Kyrle PA Mannhalter C Beguin S Stumpflen A Hirschl M Weltermann A Stain M Brenner B Speiser W Pabinger I Lechner K Eichinger S Clinical studies and thrombin generation in patients homozygous or heterozygous for the G20210A mutation in the prothrombin gene.Arterioscler Thromb Vasc Biol. 1998; 18: 1287-1291Crossref PubMed Scopus (155) Google Scholar14Zawadzki C Gaveriaux V Trillot N Bauters A Watel A Alhenc-Gelas M Preudhomme C Jude B Homozygous G20210A transition in the prothrombin gene associated with severe venous thrombotic disease: two cases in a French family.Thromb Haemost. 1998; 80: 1027-1028PubMed Google Scholar15Morange PE Barthet MC Henry M Fontanet H Aillaud MF Alessi MC Juhan-Vague I A three-generation family presenting five cases of homozygosity for the 20210 G to A prothrombin variant.Thromb Haemost. 1998; 80: 859-860PubMed Google Scholar16Eikelboom JW Ivey L Ivey J Baker RI Familial thrombophilia and the prothrombin 20210A mutation: association with increased thrombin generation and unusual thrombosis.Blood Coagul Fibrinolysis. 1999; 10: 1-5Crossref PubMed Scopus (22) Google Scholar17Corral J Zuazu-Jausoro I Rivera J Gonzalez-Conejero R Ferrer F Vicente V Clinical and analytical relevance of the combination of prothrombin 20210A/A and factor V Leiden: results from a large family.Br J Haematol. 1999; 105: 560-563Crossref PubMed Scopus (32) Google Scholar,21Ridker PM Hennekens CH Miletich JP G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke, and venous thrombosis in a large cohort of US men.Circulation. 1999; 99: 999-1004Crossref PubMed Scopus (275) Google Scholar22Kapur RK Mills LA Spitzer SG Hultin MB A prothrombin gene mutation is significantly associated with venous thrombosis.Arterioscler Thromb Vasc Biol. 1997; 17: 2875-2879Crossref PubMed Scopus (70) Google Scholar23Margaglione M Brancaccio V Giuliani N D'Andrea G Cappucci G Iannaccone L Vecchione G Grandone E Di Minno G Increased risk for venous thrombosis in carriers of the prothrombin G–>A20210 gene variant.Ann Intern Med. 1998; 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10: 297-302Crossref PubMed Scopus (10) Google Scholar,57Klein L Bhardwaj V Gebara B Cerebral venous sinus thrombosis in a neonate with homozygous prothrombin G20210A genotype.J Perinatol. 2004; 24: 797-799Crossref PubMed Scopus (9) Google Scholar No single current review including all published cases of homozygous prothrombin G20210A mutation exists. Three published reviews of the literature, however, do provide overlapping summaries of most reported cases.32Boinot C Borgel D Kitzis A Guicheteau M Aiach M Alhenc-Gelas M Familial thrombophilia is an oligogenetic disease: involvement of the prothrombin G20210A, PROC and PROS gene mutations.Blood Coagul Fibrinolysis. 2003; 14: 191-196Crossref PubMed Scopus (12) Google Scholar,43Souto JC Mateo J Soria JM Llobet D Coll I Borrell M Fontcuberta J Homozygotes for prothrombin gene 20210 A allele in a thrombophilic family without clinical manifestations of venous thromboembolism.Haematologica. 1999; 84: 627-632PubMed Google Sc
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