Difference in absolute risk of venous and arterial thrombosis between familial protein S deficiency type I and type III. Results from a family cohort study to assess the clinical impact of a laboratory test‐based classification

Abstract

SummaryHereditary protein S (PS) deficiency type I is an established risk factor for venous thromboembolism. Contradictionary data on type III deficiency suggests a difference in risk between both types. We studied 156 first degree relatives (90% of eligible relatives) from type I deficient probands (cohort 1) and 268 (88%) from type III deficient probands (cohort 2) to determine the absolute risk of venous and arterial thromboembolism. Annual incidences of venous thromboembolism were 1AE47 and 0AE17 per 100 person-years in deficient and non-deficient relatives in cohort 1 [relative risk (RR) 8AE9; 95% confidence interval (CI) 2AE6-30AE0], and 0AE27 vs. 0AE24 in cohort 2 (RR 0AE9; 95% CI 0AE4-2AE2). Type III deficiency was demonstrated in 20% of non-deficient relatives in cohort 1 and the annual incidence in this subgroup was 0AE70 (RR 4AE3;0AE95-19AE0). The cut-off level of free PS to identify subjects at risk was 30%, the lower limit of its normal range (65%). PS deficiency was not a risk factor for arterial thromboembolism. In conclusion, type I deficiency was found to be a strong risk factor for venous thromboembolism, in contrast with type III deficiency. This was because of lower free PS levels in type I deficient subjects and a free PS cut-off level far below the lower limit of its normal range. of arterial thromboembolism (Sacco et al, 1989;Mayer et al, 1993;Rudnicka et al, 2001). We present the results of a large family cohort study designed to assess the absolute risk of venous and arterial thromboembolism, respectively, in relatives from type I and type III PS deficient families. Keywords Materials and methods Study populationThe study contained two cohorts of PS deficient families, registered in our hospital from 1987 to 2003. Probands were consecutive patients with documented venous thromboembolism or premature atherosclerosis, i.e. any arterial thromboembolic event before the age of 50 years, in whom PS deficiency type I or type III were established. Their firstdegree relatives older than 15 years of age were identified by pedigree analysis and enrolled in the study after informed consent was obtained. Cohort 1 contained families with inherited PS deficiency type I and cohort 2 families with inherited PS deficiency type III.Detailed information about previous episodes of venous and arterial thromboembolism, exposure to exogenous risk factors for venous thromboembolism, risk factors for atherosclerosis, and anticoagulant prophylaxis or treatment were collected, using a standard questionnaire and reviewing medical records when appropriate. In women, the use of oral contraceptives and their obstetric history were documented. Blood samples for PS measurements were taken after clinical data had been collected. The study was approved by the institutional review board of our hospital. DefinitionsVenous thromboembolism was considered established if deep vein thrombosis was confirmed by compression ultrasound or venography, and pulmonary embolism by ventilation/perfusion lung scanning, spiral computed tomog...

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

“…32 As the nAPCsr is a marker of the risk of venous thrombosis, 36 the data presented in Figure 3C support the outcome of the Kaplan-Meier analysis and confirm that type I and type III PS deficiencies confer similar risks of thrombosis. This finding is in line with that from a previous study, 22 but contrasts with data from other studies in which the risk of thrombosis associated with type III PS deficiency was found to be half that associated with type I deficiency 23 or not elevated at all. 21 A possible explanation for these discrepancies may be the population selection criteria, as it has been reported that type III deficient individuals from families with pure type III deficiency are not at risk of thrombosis, while those from mixed type I/type III deficient families are.…”

“…Currently, type I PS deficiency is generally considered a risk factor for venous thrombosis, while conflicting results have been reported for type III deficiency. [21][22][23] In the present study we re-evaluated the thrombosis risk associated with type I and type III PS deficiencies by Kaplan-Meier analysis of a large cohort of PS-deficient families. Our data indicate that hereditary type III PS deficiency is a risk factor for venous thrombosis and that it confers a similar risk as type I PS deficiency (Figure 1).…”

“…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. 23 To clarify this issue, we re-evaluated the risk of thrombosis associated with type I and type III PS deficiencies by Kaplan-Meier analysis of a large cohort of PS-deficient families. In support of our findings, we present a detailed characterization of type I and type III PS-deficient plasma based on the measurement of coagulation factor levels and ad hoc thrombin generation assays.…”

Different risk of deep vein thrombosis and pulmonary embolism in carriers with factor V Leiden compared with non-carriers, but not in other thrombophilic defects. Results from a large retrospective family cohort study

“…Relatives were tested for factor V Leiden, prothrombin G20210A, and hereditary deficiencies of antithrombin, protein C and protein S by methods described previously. [15][16][17] To avoid bias, probands were excluded from the analyses. The study was approved by the institutional review boards of the participating hospitals.…”

“…[13][14][15][16][17] Between May 1998 and July 2004, first-degree relatives aged 15 ABSTRACT years or older of consecutive patients (probands) with documented venous thrombosis (i.e. deep vein thrombosis or pulmonary embolism) or any documented arterial thrombosis before the age of 50 years, were enrolled after obtaining informed consent.…”