THU0178 Circulating free protein S levels may be linked to cardiovascular events and venous thrombosis in SLE

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.

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FAMILIAL TYPE I PROTEIN S DEFICIENCY ASSOCIATED WITH SEVERE VENOUS THROMBOSIS. A STUDY OF FIVE CASES

10.1055/s-0038-1642943 ◽

1987 ◽

Author(s):

C Boyer-Neumann ◽

M Wolf ◽

J Amiral ◽

A M Guyager ◽

D Meyer ◽

...

Keyword(s):

Venous Thrombosis ◽

Plasma Protein ◽

Active Form ◽

Vena Cava ◽

Protein S ◽

Immunological Methods ◽

Type I ◽

Protein S Deficiency ◽

Free Protein ◽

S Deficiency

Protein S deficiency has been demonstrated in 5 members from the same family with a history of severe recurrent venous thrombosis over three generations. The propositus, a 16 year old female, had a first spontaneous thrombotic episode at age 15. Phlebography revealed a total obstruction of her left ilio-femoral vein with an extension to the vena cava. She was treated with heparin followed by oral anticoagulant therapy. The four other affected members (mother, aunts and uncle of the propositus) had also presented recurrent thrombosis with onset at a young age. The grandfather, not tested, had died from massive pulmonary embolism at age 54. The immunological assay of protein S was performed in plasma by Laurell, using a monospecific antiserum to human protein S, or by an ELISA, using a kit from Diagnostica Stago (Asserachrom Protein S). In order to separate free protein S, the functionally active form, from protein S complexed with C4-binding protein, plasma was adsorbed with 3.75 % polyethyleneglycol (PEG 6000). Following PEG precipitation, the levels of free protein S antigen remaining in the supernatant were quantitated by the usual immunological methods. In addition, two-dimensional immunoelectrophoresis (DDIE) also provided information on the distribution of both forms. In plasma protein S levels were decreased (40 to 55 % of the normal range) in two untreated patients and lower levels (17 to 20 96) were observed in the three others, including the propositus, who were under dicoumarol therapy. In PEG treated-plasma, protein S was undetectable (less than 5 %) in all patients, indicating a lack of free protein S. This was confirmed by DDIE : whereas protein S migrated as two distinct peaks, corresponding to free and complexed protein S in normal plasma, only a single peak of complexed protein S was observed in all affected patients. These results clearly demonstrate a total lack of free protein S which appears to be responsible for the thromboembolic disorder in this family as there was no deficiency of the other plasma inhibitors (antithrombin III, heparin cofactor II and protein C). According to the classification recently proposed by Comp et al., this family belongs to type I protein S deficiency, with an autosomal dominant mode of inheritance.

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Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S

Blood ◽

10.1182/blood.v95.6.1935 ◽

2000 ◽

Vol 95 (6) ◽

pp. 1935-1941 ◽

Cited By ~ 82

Author(s):

Michael Makris ◽

Michael Leach ◽

Nick J. Beauchamp ◽

Martina E. Daly ◽

Peter C. Cooper ◽

...

Keyword(s):

Venous Thrombosis ◽

Protein S ◽

Structural Defects ◽

Protein S Deficiency ◽

Gene Defect ◽

Thrombotic Risk ◽

Free Protein ◽

First Degree Relatives ◽

S Deficiency ◽

Increased Risk

Abstract 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 PROS1gene 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 withPROS1 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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The effect of different hormonal contraceptives on plasma levels of free protein S and free TFPI

Thrombosis and Haemostasis ◽

10.1160/th12-10-0771 ◽

2013 ◽

Vol 109 (04) ◽

pp. 606-613 ◽

Cited By ~ 19

Author(s):

Frans M. Helmerhorst ◽

Kathrin Fleischer ◽

Anders E. A. Dahm ◽

Frits R. Rosendaal ◽

Jan Rosing ◽

...

Keyword(s):

Venous Thrombosis ◽

Oral Contraceptives ◽

Acquired Resistance ◽

Activated Protein C ◽

Protein S ◽

Hormonal Contraceptives ◽

Free Protein ◽

Routes Of Administration ◽

Apc Resistance ◽

Increased Risk

SummaryUse of combined oral contraceptives is associated with a three- to sixfold increased risk of venous thrombosis. Hormonal contraceptives induce acquired resistance to activated protein C (APC), which predicts the risk of venous thrombosis. The biological basis of the acquired APC resistance is unknown. Free protein S (PS) and free tissue factor pathway inhibitor (TFPI) are the two main determinants of APC. Our objective was to assess the effect of both hormonal and non-hormonal contraceptives with different routes of administration on free TFPI and free PS levels. We conducted an observational study in 243 users of different contraceptives and measured APC sensitivity ratios (nAPCsr), free TFPI and free PS levels. Users of contraceptives with the highest risk of venous thrombosis as reported in recent literature, had the lowest free TFPI and free PS levels, and vice versa, women who used contraceptives with the lowest risk of venous thrombosis had the highest free TFPI and free PS levels. An association was observed between levels of free TFPI and nAPCsr, and between free PS and nAPCsr. The effect of oral contraceptives on TFPI and PS is a possible explanation for the increased risk of venous thrombosis associated with oral contraceptives.

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Coagulation Factors, Postmenopausal Hormone Replacement Therapy and the Risk of Venous Thrombosis: The WHI Clinical Trials of Postmenopausal Hormone Therapy.

Blood ◽

10.1182/blood.v110.11.127.127 ◽

2007 ◽

Vol 110 (11) ◽

pp. 127-127 ◽

Cited By ~ 1

Author(s):

Mary Cushman ◽

Joseph Larson ◽

Frits R. Rosendaal ◽

Lawrence S. Phillips ◽

Barbara V. Howard ◽

...

Keyword(s):

Risk Factors ◽

Relative Risk ◽

Venous Thrombosis ◽

Protein C ◽

Coagulation Factor ◽

Protein S ◽

Postmenopausal Hormone ◽

Free Protein ◽

Coagulation Marker ◽

D Dimer

Abstract Background. Postmenopausal estrogen (E) therapy, especially in combination with progestin (P) doubles the relative risk of venous thrombosis (VTE). Risk with hormones is higher with increasing age, obesity and with factor V Leiden. We studied coagulation markers as susceptibility factors for postmenopausal hormone-related VTE. Methods. The Women’s Health Initiative program included two placebo-controlled double-blind randomized trials of two E regimens, E (conjugated equine estrogens) or E+P (E + medroxyprogesterone acetate), in 16,608 postmenopausal women aged 50–79. We performed a nested case control study that measured baseline levels of coagulation markers in 215 women who developed VTE during follow up and 867 age-matched controls. The joint effects of treatment assignment to either E regimen vs placebo and prespecified abnormal levels of each coagulation factor on relative risk of VTE were estimated by logistic regression adjusting for age, race, body-mass index and type of E regimen. Results. Low levels of protein C and free protein S (<5th percentile), high D-dimer (top quartile), and high plasmin antiplasmin complex (PAP) and prothrombin fragment 1–2 (top decile) were all associated with risk of VTE with adjusted odds ratios (95% CI) of 2.0 (1.0–4.1), 2.9 (1.5–5.6), 2.8 (2.0–4.0), 2.5 (1.6–4.0) and 1.9 (1.2–3.1), respectively. Elevated factors II, VIII, IX and fibrinogen were not VTE risk factors. Compared to women with normal coagulation marker levels assigned to placebo, the joint odds of VTE with either E regimen plus an abnormal coagulation marker were more than additive compared to the separate effects of hormones and coagulation abnormalities for low protein C, low free protein S, and elevated D-dimer, PAP and F1–2. The odds ratios of VTE with the combination of an abnormal coagulation factor and assignment to hormones were (in order listed in prior sentence), 4.5 (95% CI 2.0–10.2), 6.7 (3.0–14.5), 6.1 (3.7–10), 5.8 (3.2–10.5) and 4.4 (2.4–7.7). Conclusions. We report new findings of elevated F1-2 and PAP as VTE risk factors in women in this prospective study nested in trials of E or E+P versus placebo. Protein C or S values below the 5th percentile were also clinically relevant even though they do not represent inherited deficiency. Lower protein C and free protein S, and higher D-dimer, F1-2 and PAP all identified women at increased risk of VTE with hormones. If our findings are confirmed in management studies, measurement of these factors might assist women with decision-making on safety of E or E+P.

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Free protein S deficiency in a family with venous thrombosis

Journal of Vascular Surgery ◽

10.1016/0741-5214(90)90007-w ◽

1990 ◽

Vol 12 (5) ◽

pp. 541-544 ◽

Cited By ~ 4

Author(s):

Carl G. Lauer ◽

Thomas J. Reid ◽

Carol S. Wideman ◽

Bruce L. Evatt ◽

Barbara M. Alving

Keyword(s):

Venous Thrombosis ◽

Protein S ◽

Protein S Deficiency ◽

Free Protein ◽

S Deficiency

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Clinical relevance of decreased free protein S levels: results from a retrospective family cohort study involving 1143 relatives

Blood ◽

10.1182/blood-2008-08-174128 ◽

2009 ◽

Vol 113 (6) ◽

pp. 1225-1230 ◽

Cited By ~ 39

Author(s):

Willem M. Lijfering ◽

Rene Mulder ◽

Min Ki ten Kate ◽

Nic J. G. M. Veeger ◽

Andre B. Mulder ◽

...

Keyword(s):

At Risk ◽

Venous Thrombosis ◽

Protein S ◽

Normal Range ◽

Recurrence Rates ◽

Free Protein ◽

Post Hoc Analysis ◽

Hazard Ratios ◽

Young Subjects ◽

Post Hoc

AbstractConflicting data have been reported on the risk for venous thrombosis in subjects with low free protein S levels. We performed a post-hoc analysis in a single-center retrospective thrombophilic family cohort, to define the optimal free protein S level that can identify subjects at risk for venous thrombosis. Relatives (1143) were analyzed. Relatives with venous thrombosis (mean age 39 years) had lower free protein S levels than relatives without venous thrombosis (P < .001), which was most pronounced in the lowest quartile. Only relatives with free protein S levels less than the 5th percentile (< 41 IU/dL) or less than the 2.5th percentile (< 33 IU/dL) were at higher risk of first venous thrombosis compared with the upper quartile (> 91 IU/dL); annual incidence 1.20% (95% confidence interval [CI], 0.72–1.87) and 1.81% (95% CI, 1.01–2.99), respectively; adjusted hazard ratios 5.6, (95% CI, 2.7–11.5) and 11.3 (95% CI, 5.4–23.6). Recurrence rates were 12.12% (95 CI, 5.23–23.88) and 12.73% (95% CI, 5.12–26.22) per year; adjusted hazard ratios were 3.0 (95% CI, 1.03–8.5) and 3.4 (95% CI, 1.1–10.3). In conclusion, free protein S level can identify young subjects at risk for venous thrombosis in thrombophilic families, although the cutoff level lies far below the normal range in healthy volunteers.

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