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Blood, Vol. 95 No. 6 (March 15), 2000:
pp. 1935-1941
Genetic analysis, phenotypic diagnosis, and risk of venous
thrombosis in families with inherited deficiencies of protein S
Michael Makris,
Michael Leach,
Nick J. Beauchamp,
Martina E. Daly,
Peter C. Cooper,
Kingsley K. Hampton,
Pauline Bayliss,
Ian R. Peake,
George J. Miller, and
F. Eric Preston
From the Division of Molecular and Genetic Medicine, University of
Sheffield, Royal Hallamshire Hospital, Sheffield, United Kingdom; and
MRC Epidemiology and Medical Care Unit, Wolfson Institute of Preventive
Medicine, London, United Kingdom.
Protein S deficiency is a recognized risk factor for venous
thrombosis. Of all the inherited thrombophilic conditions, it remains
the most difficult to diagnose because of phenotypic variability, which
can lead to inconclusive results. We have overcome this problem by
studying a cohort of patients from a single center where the diagnosis
was confirmed at the genetic level. Twenty-eight index patients with
protein S deficiency and a PROS1 gene defect were studied,
together with 109 first-degree relatives. To avoid selection bias, we
confined analysis of total and free protein S levels and thrombotic
risk to the patients' relatives. In this group of relatives, a low
free protein S level was the most reliable predictor of a PROS1
gene defect (sensitivity 97.7%, specificity 100%). First-degree
relatives with a PROS1 gene defect had a 5.0-fold higher risk
of thrombosis (95% confidence interval, 1.5-16.8) than those with a
normal PROS1 gene and no other recognized thrombophilic defect.
Although pregnancy/puerperium and immobility/trauma were important
precipitating factors for thrombosis, almost half of the events were
spontaneous. Relatives with splice-site or major structural defects in
the PROS1 gene were more likely to have had a thrombotic event
and had significantly lower total and free protein S levels than those
relatives having missense mutations. We conclude that persons with
PROS1 gene defects and protein S deficiency are at increased
risk of thrombosis and that free protein S estimation offers the most
reliable way of diagnosing the deficiency.
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