Low Prevalence of the Factor V Leiden Mutation Among “Severe” Hemophiliacs with a “Milder” Bleeding Diathesis

Arnaldo A Arbini; Pier Mannuccio Mannucci; Kenneth A Bauer

doi:10.1055/s-0038-1649922

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1995; 74(05): 1255-1258
DOI: 10.1055/s-0038-1649922

Original Article

Clinical Studies

Schattauer GmbH Stuttgart

Low Prevalence of the Factor V Leiden Mutation Among “Severe” Hemophiliacs with a “Milder” Bleeding Diathesis

Arnaldo A Arbini

¹The Hematology-Oncology Division, Department of Medicine, Brockton-West Roxbury Department of Veterans Affairs Medical Center, Boston, MA, USA

²The Beth Israel Hospital, Harvard Medical School, Boston, MA, USA

,

Pier Mannuccio Mannucci

³The Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Institute of Internal Medicine IRCCS Ospedale Magglore and University of Milan, Milan, Italy

,

Kenneth A Bauer

¹The Hematology-Oncology Division, Department of Medicine, Brockton-West Roxbury Department of Veterans Affairs Medical Center, Boston, MA, USA

²The Beth Israel Hospital, Harvard Medical School, Boston, MA, USA

› Author Affiliations

Abstract

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Summary

Patients with hemophilia A and B and factor levels less than 1 percent of normal bleed frequently with an average number of spontaneous bleeding episodes of 20–30 or more. However there are patients with equally low levels of factor VIII or factor IX who bleed once or twice per year or not at all. To examine whether the presence of a hereditary defect predisposing to hypercoagulability might play a role in amelio rating the hemorrhagic tendency in these so-called “mild severe” hemophiliacs, we determined the prevalence of prothrombotic defects in 17 patients with hemophilia A and four patients with hemophilia B selected from 295 and 76 individuals with these disorders, respectively, followed at a large Italian hemophilia center. We tested for the presence of the Factor V Leiden mutation by PCR-amplifying a fragment of the factor V gene which contains the mutation site and then digesting the product with the restriction enzyme Mnll. None of the patients with hemophilia A and only one patient with hemophilia B was heterozygous for Factor V Leiden. None of the 21 patients had hereditary deficiencies of antithrombin III, protein C, or protein S. Our results indicate that the milder bleeding diathesis that is occasionally seen among Italian hemophiliacs with factor levels that are less than 1 percent cannot be explained by the concomitant expression of a known prothrombotic defect.

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References

References
1 Walsh PN, Rainsford SG, Biggs R. Platelet coagulant activities and clinical severity in hemophilia. Thromb Diath Haemorrh 1973; 29: 722-729
2 Bauer KA, Mannucci PM, Gringeri A, Tradati F, Barzegar S, Kass BL, ten Cate H, Kestin AS, Brcttler DB, Rosenberg RD. Factor IXa-factor VIIIacell surface complex does not contribute to the basal activation of the coagulation mechanism in vivo. Blood 1992; 79: 2039-2047
3 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008
4 Bertina RM, Koeleman BP C, Rosier T, Rosendaal FR, Dirven RJ, de Ronde H, van der Welden PA, Reitsma PH. Mutation in blood coagulation factor V associated withresistance to activated protein C. Nature 1994; 369: 64-67
5 Dahlbäck B. Physiological anticoagulation. Resistance to activated protein C and venous thromboembolism J Clin Invest 1994; 94: 923-927
6 Dahlbäck B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci USA 1994; 91: 1396-1400
7 Odegaard B, Mann KG. Proteolysis of factor Va by factor Xa and activated protein C. J Biol Chem 1987; 262: 11233-11238
8 Kalafatis M, Bertina RM, Rand MD, Mann KG. Characterization of the molecular defect in Factor V_R506Q . J Biol Chem 1995; 270: 4053-4057
9 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522
10 Ridker PM, Hennekens CH, Lindpainter K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912-917
11 Dahlbäck B. Inherited thrombophilia: Resistance to activated protein C as a pathogenic factor of venous thrombosis. Blood 1995; 85: 607-614
12 Majerus PW. Bad blood by mutation. Nature 1994; 369: 14-15
13 Kunkel LM, Smith KD, Boyer SH, Borgaonkar DS, Wachtel SS, Miller OJ, Breg WR, Jonew HW, Rary JM. Analysis of human Y chromosome-specific reiterated DNAin chromosome variants. Proc Natl Acad Sci USA 1977; 74: 1245-1249
14 Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 1988; 239: 487-491
15 Fleiss JL. Statistical Methods for Rates and Proportions. Second Edition New York: John Wiley & Sons, Inc; 1981: 321 pages
16 Bauer KA, Broekmans AW, Bertina RM, Conard J, Horellou MH, Samama MM, Rosenberg RD. Hemostatic enzyme generation in the blood of patients with hereditary protein C deficiency. Blood 1988; 71: 1418-1426
17 Mannucci PM, Tripodi A, Bottasso B, Baudo F, Finazzi G, De Stefano V, Palareti G, Manotti C, Mazzucconi MG, Castaman G. Markers of procoagulant imbalance in patients with inherited thrombophilic syndromes. Thromb Haemost 1992; 67: 200-202
18 Greengard JS, Eichinger S, Griffin JH, Bauer KA. Variability of thrombosis among homozygous siblings with resistance to activated protein C due to an Arg →;Gin mutation in the gene for factor V. N Engl J Med 1994; 331: 1559-1562
19 Chan J, Weinmann AF, Thompson AR. Factor V Arg/Gln 506 has no dominant influence on the severity of hemophilia when inherited concurrently (Abstract). Thromb Haemost 1995; 73: 1793 a