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Venous thromboembolism associated with double heterozygosity for R506Q
mutation of factor V and for T298M mutation of protein C in a large family
of a previously described homozygous protein C-deficient newborn with
massive thrombosis
B Brenner, A Zivelin, N Lanir, JS Greengard, JH Griffin and U Seligsohn
Department of Hematology, Rambam Medical Center, Haifa, Israel.
It is remarkable that certain patients with heterozygous protein C (PC)
deficiency manifest venous thromboembolism (VTE), whereas others,
particularly those belonging to families with homozygous PC deficiency,
remain asymptomatic. The goals of the present study of a family, in which
the proband had homozygous PC deficiency, were to identify members with and
without VTE, to determine the mutation causing PC deficiency, and to search
for the R506Q mutation of factor V (FV) causing activated PC resistance.
Heterozygosity for a T298M mutation in exon 9 of the PC gene was found in
the father of the homozygous proband who died of massive thrombosis. Based
on analysis of a three- dimensional molecular model of PC, we speculate
that this mutation causes type I deficiency due to disruption of packing of
hydrophobic side chains and loss of an H-bond between Q184 and T298.
Forty-six family members were examined for the T298M mutation by polymerase
chain reaction (PCR) amplification of exon 9 and restriction analysis using
Mae III and for the FV R506Q mutation by PCR amplification of exon 10 and
restriction analysis using Mnl I. VTE was observed in five of 11 members
who were heterozygous for both PC and FV mutations. In contrast, VTE was
not observed for the PC mutation in 13 heterozygotes who had normal FV,
including the parents of the deceased proband, 10 heterozygotes for the FV
mutation who had normal PC, and 12 individuals bearing neither mutation.
These observations extend recent evidence of an increased thrombotic risk
conferred by the coexistence of heterozygous PC deficiency and heterozygous
activated PC resistance and support the paradigm in which hereditary
thrombophilia is often a multigenic disease.
Volume 88,
Issue 3,
pp. 877-880,
08/01/1996
Copyright © 1996 by The American Society of Hematology
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