A Heparin Cofactor II Mutation (HCII Rimini) Combined with Factor V Leiden or Type I Protein C Deficiency in Two Unrelated Thrombophilic Subjects

Summary

305 patients with juvenile thromboembolic episodes were screened for the presence of heparin cofactor II deficiency. The heterozygous deletion of two bases was found in the exon 5 of the heparin cofactor II gene in two unrelated patients, very likely due to a founder effect. This molecular lesion, causing a frameshift and elongated translation, affects the core of the molecule and should cause the complete unfolding of the protein, which is in accordance with the observed type I deficiency. The corresponding region of antithrombin III gene is affected by a cluster of frameshift mutations suggesting that heparin cofactor II and antithrombin III could share similar mutational patterns.

The heparin cofactor II gene alteration was associated with, in one patient, the factor V Leiden mutation and, in the other, type I protein C deficiency. The tracing of the single defects in several family members indicated that the mutations became clinically manifest only when present in the doubly heterozygous condition. This study provides two examples, based on molecular findings, of the interplay of risk factors which is potentially useful to define a role for heparin cofactor II deficiency in inherited thrombophilia.

• References

• 1 Parker KA, Tollefsen DM. The protease specificity of heparin cofactor II. Inhibition of thrombin generated during coagulation. J Biol Chem 1985; 260: 3501-3505
• 2 Tollefsen DM. Insight into the mechanism of action of heparin cofactor II. Thromb Haemost 1995; 74: 1209-1214
• 3 Pratt CW, Church FC. General features of the heparin-binding serpin antithrombin, heparin cofactor II and protein C inhibitor. Blood Coag Fibrinol 1993; 4: 479-490
• 4 Blinder AM, Marasa JC, Reynolds CH, Deaven LL, Tollefsen DM. Heparin cofactor II: cDNA sequence, chromosome localization, restriction fragment length polymorphism, and expression in Escherichia coli. Biochemistry 1988; 27: 752-759
• 5 Herzog R, Lutz S, Blin N, Marasa CJ, Blinder MA, Tollefsen DM. Complete nucleotide sequence of the gene for human heparin cofactor II and mapping to cromosomal band 22q11. Biochemistry 1991; 30: 1350-1357
• 6 Ragg H, Preibisch G. Structure and expression of the gene coding for the human serpin hLS2. J Biol Chem 1988; 263: 12129-12134
• 7 Sié P, Dupuoy D, Pichon J, Boneu B. Constitutional heparin cofactor II deficiency associated with recurrent thrombosis. Lancet 1985; ii: 414-416
• 8 Tran TH, Marbet GA, Duckert F. Association of hereditary heparin cofactor II deficiency with thrombosis. Lancet 1985; ii: 413-414
• 9 Simioni P, Lazzaro AR, Coser E, Salmistraro G, Girolami A. Hereditary heparin cofactor II deficiency and thrombosis: report of six patients belonging to two separate kindreds. Blood Coag Fibrinol 1990; 1: 351-356
• 10 Weisdorf DJ, Edson JR. Recurrent venous thrombosis associated with inherited deficiency of heparin cofactor II. Br J Haematol 1990; 77: 125-126
• 11 Bertina RM, van der Linden IK, Engesser L, Muller HP, Brommer JP. Hereditary heparin cofactor II deficiency and the risk of development of thrombosis. Thromb Haemost 1987; 57: 196-200
• 12 Lane DA, Olds RJ, Boisclair M, Chowdhury V, Thein SL, Cooper DN, Blajchman M, Perry D, Emmerich J, Aiach M. Antithrombin III mutation database: first update. Thromb Haemost 1993; 70: 361-369
• 13 Blinder MA, Andersson TR, Abildgaard U, Tollefsen DM. Heparin cofactor II Oslo. Mutation of Arg-189 to His decreases the affinity for dermatan sulfate. J Biol Chem 1989; 264: 5128-5133
• 14 Gandrille S, Aiach M, Lane DA, Vidaut D, Mohlo-Sabatier P, Caso R, de Moerloose P, Fiessinger JN, Clauser E. Important role of Arg 129 in heparin binding site of antithrombin III: identification of novel mutation Arg 129 to Gin. J Biol Chem 1990; 265: 18997-19001
• 15 Turner J, Grundy CB, Kakkar VV, Cooper DN. MspI RFLP in the human heparin cofactor II (HCF2) gene. Nucleic Acids Res 1990; 18: 1664
• 16 Marchetti G, Patracchini P, Gemmati D, Castaman G, Rodeghiero F, Bernardi F. Symptomatic type I protein C deficiency caused by a missense mutation (Gly 381 Ser) in the substrate binding pocket of serine protease. BrJ Haematol 1993; 84: 285-289
• 17 Bertina RM, Koeleman BPC, 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: 64-67
• 18 Peitsch MC. Protein modeling by E-mail. Bio/technology 1995; 13: 258
• 19 Dahlbäck B. Inherited thrombophilia: resistance to activated protein C as a pathogenetic factor for venous thrombosis. Blood 1995; 85: 607-614
• 20 Miletich J, Sherman L, Broze G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-996
• 21 Tait RC, Walker ID, Reitsma PH, Islam SIAM, McCall F, Poort SR, Conkie JA, Bertina RM. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995; 73: 87-93
• 22 Emmerich J, Chadeuf G, Alhenc-Gelas M, Gouault-Heilman G-H, Toulon P, Fiessinger JN, Aiach M. Molecular basis of antithrombin type I deficiency: the first large in-frame deletion and two novel mutations in exon 6. Thromb Haemost 1994; 72: 534-539
• 23 Kondo S, Tokunaga F, Kario K, Matsuo T, Koide T. Molecular and cellular basis for type I heparin cofactor II deficiency (heparin cofactor II Awaji). Blood 1996; 87: 1006-1012
• 24 Huber R, Carrell RW. Implications of the three-dimensional structure of 1-Antitrypsin for structure and function of serpins. Biochemistry 1989; 28: 8951-8966
• 25 Miura O, Hirosawa S, Kato A, Aoki N. Molecular basis for congenital deficiency of a2-plasmin inhibitor. J Clin Invest 1989; 83: 1598-1604
• 26 Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C deficient families. Blood 1994; 84: 1031-1035