Hyperhomocysteinemia Is Not a Risk Factor for Venous and Arterial Thrombosis, but an Epiphenomenon: Results From a Large Retrospective Family Cohort Study

Lijfering, W.M.; Coppens, Magali; Veeger, Nic J. G. M.; Hamulyák, Karly; Prins, MH; Büller, Harry R.; Meer, J. van der

doi:10.1111/j.1538-7836.2007.tb00837.x

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“…[23][24][25][26] It should be noted, however, that relatives with first venous thrombosis were relatively young (mean age 39 years vs 62 years in the general population), 27 which emphasizes that thrombophilic defects are risk factors for venous thrombosis at young age. 22 It also explains why first episodes of venous thrombosis associated with malignancy were scarce in our study. Although numbers were small, it is tempting to speculate that subjects with venous thrombosis and free protein S levels in the lower 5th percentile could benefit from prolonged anticoagulant treatment, given the high rate of recurrence.…”

Section: Discussionmentioning

confidence: 64%

“…Hazard ratios were calculated using a multivariable Cox regression model. As our study cohort consisted of subjects from thrombophilic families and were therefore prone to have multiple thrombophilic defects, 5,22 we first adjusted for these defects with stepwise Cox regression, including antithrombin or protein C deficiency, factor V Leiden, prothrombin G20210A, and high factor VIII levels. To account for the nonrandomness of the relatives analyzed, outcome rates were also adjusted for clustering of events within families with Cox regression analysis and the robust sandwich method (in SAS 9.1).…”

Section: Discussionmentioning

confidence: 99%

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

Lijfering

Mulder

Kate

et al. 2009

Blood

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Conflicting 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 singlecenter 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 , IntroductionProtein S is a vitamin K-dependent plasma glycoprotein that functions as a nonenzymatic cofactor of activated protein C in the inactivation of the procoagulant factors Va and VIIIa, and plays an important role in regulating thrombin generation. 1 Approximately 60% of total protein S is bound to complement component C4b-binding protein. 2 Until recently, it was believed that only free protein S has activated protein C cofactor activity. However, new evidence suggests that both bound and free protein S are cofactors for activated protein C. 3 Three subtypes of protein S deficiency are recognized: type I, with decreased levels of both total and free protein S antigen (ie, a quantitative defect); type II, with total and free protein S antigen levels within their normal ranges, but decreased protein S activity (ie, a qualitative defect); and type III, with decreased free protein S and normal total protein S antigen levels. 4 Whereas type I deficiency is an established risk factor for venous thrombosis, 5,6 conflicting data have been reported on the risk of thrombosis associated with type III deficiency. [6][7][8][9][10][11][12][13][14] A difference in risk between subjects with type I and type III deficiency, together with variation in the studied populations may explain this discrepancy. Another explanation could be that the cutoff level for protein S deficiency type III (ie, the lower limit of the normal range; in our laboratory Ͻ 65 IU/dL) is too high to identify subjects at risk for venous thrombosis. 11 Moreover, studies that did not show an increased risk of venous thrombosis in association with free protein S deficiency may have been confounded by the inclusion of subjects with mild decrements in free protein S levels. The diagnostic criteria for type III protein S deficiency therefore likely need to be reconsidered.We performed a retrospective study in a large series of families to assess the absolute risk of first venous thrombosis and its recurrence for different free protein S levels, to define an optimal cutoff level of free protein S to identify subjects at risk for venous thrombo...

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