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.
