Resistance to Activated Protein C in Nine Thrombophilic Families: Interference in a Protein S Functional Assay

Abstract

SummaryNine thrombophilic patients who had had previous diagnoses of functional protein S deficiency were reinvestigated. The functional protein S assays gave dose-response curves that were not parallel to those of the reference plasma. The same pattern was true for approximately half of the first-degree relatives of the propositi. When protein S was extracted from the plasma of the patients by immunoabsorption, it had a normal ratio of functional activity to immunologic concentration. Restriction fragment length polymorphism analysis, informative in one family, showed no linkage between the protein S gene marker and the abnormal behavior of the protein S functional assay. All the propositi and 23/36 first-degree relatives were resistant to the prolongation of activated partial thromboplastin time induced by activated protein C. Furthermore, there was striking concordance in all patients and relatives between the abnormal pattern of the protein S functional assay and resistance to activated protein C. We conclude that a plasma-based functional protein S assay is sensitive to activated protein C resistance and this may lead to spuriously low results in the assay. In agreement with the results of others, this study indicates that resistance to activated protein C is a frequent hemostatic defect in selected thrombophilic populations.

Venous thrombosis: the history of knowledge

“…Despite these discoveries on the genetic basis of hypercoagulability and of the associated risk of thrombosis, the great majority of cases of venous thrombosis, particularly those occurring in the absence of circumstantial risk factors, remained unexplained. In 1993 Dahlback [26] and his colleagues in Malmo (Sweden) demonstrated in patients with a history of venous thrombosis a relation between the inherited resistance of plasma to the anticoagulant action of activated protein C and the development of venous thrombosis, a finding confirmed in the same year by Griffin et al [27], Koster et al [28], and Faioni et al [29]. On the next year Rogier Bertina [30] and his team in Leiden discovVenous thrombosis: the history of knowledge Pathophysiol Haemost Thromb, Vol.…”

Normal Functional Protein S Activity Does Not Exclude Protein S Deficiency

“…Resistance to APC has been previously shown to interfere with prothrombin-time-based functional assay of PS [15] . This interference leads to artifi cially low levels of PS activity and to misclassifi cation of thrombophilic patients.…”

Infrequency of Stroke Caused by Specific Coagulation Disorders

“…The significance of this disorder for arterial thromboem bolism is less clear. In a study of 30 patients with juvenile or recurrent arterial stroke of unknown cause, resistance of protein C was measured in 20% [30], Notably, acti vated protein C resistance may be misdiagnosed as func tional protein S deficiency [31,32], and studies that used a functional protein S clotting assay have to be re-evaluated. The technique for measuring activated protein C resistance was not available in our laboratory at the lime the samples were analyzed.…”