A HEPARIN-COFACTOR-II MUTATION (HCII RIMINI) COMBINED WITH FACTOR-V LEIDEN OR TYPE-I PROTEIN-C DEFICIENCY IN 2 UNRELATED THROMBOPHILIC SUBJECTS

305 patients with juvenile thromboembolic episodes were screened for t he presence of heparin cofactor II deficiency. The heterozygous deleti on of two bases was found in the exon 5 of the heparin cofactor II gen e in two unrelated patients, very likely due to a founder effect. This molecular lesion, causing a frameshift and elongated translation, aff ects the core of the molecule and should cause the complete unfolding of the protein, which is in accordance with the observed type I defici ency. 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 hep arin cofactor II gene alteration was associated with, in one patient, the factor V Leiden mutation and, in the other, type I protein C defic iency. The tracing of the single defects in several family members ind icated that the mutations became clinically manifest only when present in the doubly heterozygous condition. This study provides two example s, based on molecular findings, of the interplay of risk factors which is potentially useful to define a role for heparin cofactor Il defici ency in inherited thrombophilia.