Free Protein S Deficiency Is a Risk Factor for Venous Thrombosis

Abstract

SummaryA recent study suggests that protein S deficiency is not a risk factor for venous thrombosis. Since this unexpected finding would have important clinical implications if confirmed, we performed a case-control study with the aim to determine the prevalence of protein S deficiency in patients with thrombosis and in healthy individuals taken from the general population and the relative risk of thrombosis in protein S-deficient patients. Free protein S concentration was measured in 327 consecutive patients with at least one venous thrombotic episode and in 317 age- and sex-matched control individuals. Different normal reference ranges were obtained and adopted for men and women. Protein S deficiency was found in 3.1% (95% Cl: 1.5-5.2) of patients and in 1.3% of controls (95% Cl: 0.3-2.8). Ten patients and 4 control subjects had protein S deficiency, which determined a relative risk of thrombosis (sex- and age-adjusted odds ratio) of 2.4 (95% Cl: 0.8-7.9). When men and women were analyzed separately, the risk was 5.0 (95% CI: 0.6-43.6) and 1.6 (95% Cl: 0.4-6.7) respectively. PS-deficient men had more thrombotic episodes than women and later in life. Multivariate analysis established that sex was an independent determinant of the number of episodes, as was age, while PS deficiency was not. However sex and PS deficiency status were both determinants of age at first thrombotic episode.

Cleaved Protein S (PS), Total PS, Free PS, and Activated Protein C Cofactor Activity as Risk Factors for Venous Thromboembolism

“…However, in contrast to the observation that the risk of VTE increases with decreasing protein C concentrations (16 ), the implication of phenotypic PS deficiency in VTE has not been clearly established. Actually, both case-control studies performed showed no involvement of total PS concentrations, whereas free PS gave contradictory results (17,18 ).…”

“…Factors known to influence PS concentrations were taken into account by matching the healthy controls for age, sex, and hormone treatment and by excluding patients receiving oral anticoagulants or with acute thrombosis. In addition to total and free PS measurements using ELISAs as in previous studies (17,18 ), we measured free PS by an ELSA, APC cofactor activity, and cleaved PS to determine which assay(s) would be the most relevant to evaluate the thrombotic risk. Our study had enough power (␤ ϭ 0.2, Plasma cleaved PS was first evaluated in healthy controls to define the physiologic variations of this PS form.…”

Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency

“…This type of PS deficiency is often, but not always, 16 associated with the PROS1 Ser 460 →Pro (Heerlen) mutation. 17 Although PS deficiency and, particularly, low levels of free PS 18,19 are an established risk factor for venous thrombosis, risk estimates differ widely among studies, possibly reflecting the different severity of the underlying molecular defects. 20 Moreover, the few epidemiological studies that distinguish between type I and type III deficiencies are rather contradictory with respect to the risk of thrombosis associated with type III deficiency, which was found to be none, 21 the same as in type I deficiency 22 or intermediate.…”

Functional characterization of twelve natural PROS1 mutations associated with anticoagulant protein S deficiency

“…1 It is an autosomal dominant trait with incomplete penetrance and variable clinical and biochemical expression which affects 2% to 8% of patients with thrombosis in Caucasian populations. 6 According to plasma levels of total and free PS antigen and to the functional activity of PS, three types of PS deficiency have been proposed. Type I is a quantitative deficiency characterized by reduced levels of total and free PS antigen, as well as anticoagulant activity; type II is a qualitative deficiency characterized by normal levels of PS antigen but reduced anticoagulant activity; type III PS deficiency, which may be considered as a mild quantitative deficiency, 7 is characterized by normal levels of total PS antigen but reduced levels of free PS antigen and activity.…”

“…The thrombotic risk associated with heterozygous type I PS deficiency is between 2.5 and 10-fold higher than in the general population. 6,8 The PS gene (PROS1; Gene ID: 5627) spans 101 Kb of genomic DNA in the centromeric region of chromosome3. It is composed of 15 exons that are transcribed in 3.5 Kb of mRNA (NM_000313).…”