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

Abstract

Summary305 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.

Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders

“…This postulate is supported by additional reports that characterize the involvement of other genes. For example, co-heterozygosity for heparin cofactor II ( SERPIND1 ) and factor V Leiden or protein C deficiency was observed in subjects who experienced juvenile thromboembolic episodes (Bernardi et al 1996), as well as in other families with thrombosis tested for these variants (Lane et al 1996; Sansores-Garcia and Majluf-Cruz 1998). Two sisters in one family study were found to be homozygous for a factor XII deficiency-associated mutation ( F12 ) and heterozygous for factor V Leiden; one sister exhibited multiple thrombotic events, whereas the other was asymptomatic (Girolami et al 2010) suggesting that there is significantly greater complexity underlying disease predisposition than just the presence of two or three variants.…”

Homozygous Deficiency of Heparin Cofactor II

“…A similar prothrombotic synergism has been suggested between heterozygous HCII deficiency and mild (factor V Leiden) or strong (protein C deficiency) prothrombotic genetic risk factors. 7 The murine model, however, suggests that HCII might protect against thrombosis in the arterial circulation. 21 It is of interest that 2 other deficiency variants of HCII have been associated with coronary artery disease 6 and multiple atherosclerotic lesions.…”

“…As shown in Table 2, comparison of the proband sequence with previously reported cDNA 12,13 and genomic HCII sequences [5][6][7]14 showed 6 nucleotide differences: G-181A, A36C, T5718C (Gly149), A5924G (Lys218Arg), G12809A (Glu428Lys), and T12915C (His463) (nucleotide numbering according to Herzog et al). 5 The genetic change T12915C (His463), found in heterozygous state in the proband, has been previously described as a common polymorphism.…”

“…5 The genetic change T12915C (His463), found in heterozygous state in the proband, has been previously described as a common polymorphism. 7 The proband presented a homozygous genotype at positions 36A, 5718T (Gly149), and 5924A (Lys218). These alleles were also identified by other authors.…”

Genetic Heterogeneity in Hereditary Thrombophilia

“…One, insertion of a T in exon 2, was discovered in a Japanese patient who suffered from coronary artery disease [28]. The second mutation, a deletion of two nucleotides in exon 5, was found in two apparently unrelated Italian patients with thrombophilia [29].…”