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

Abstract

The online version of this article has a Supplementary Appendix. BackgroundProtein S, which circulates in plasma in both free and bound forms, is an anticoagulant protein that stimulates activated protein C and tissue factor pathway inhibitor. Hereditary type I protein S deficiency (low total and low free protein S) is a well-established risk factor for venous thrombosis, whereas the thrombosis risk associated with type III deficiency (normal total and low free protein S) has been questioned. Design and MethodsKaplan-Meier analysis was performed on 242 individuals from 30 families with protein S deficiency. Subjects were classified as normal, or having type I or type III deficiency according to their total and free protein S levels. Genetic and functional studies were performed in 23 families (132 individuals). ResultsThrombosis-free survival was not different between type I and type III protein S-deficient individuals. Type III deficient individuals were older and had higher protein S, tissue factor pathway inhibitor and prothrombin levels than type I deficient individuals. Thrombin generation assays sensitive to the activated protein C-and tissue factor pathway inhibitor-cofactor activities of protein S revealed similar hypercoagulable states in type I and type III protein S-deficient plasma. Twelve PROS1 mutations and two large deletions were identified in the genetically characterized families. ConclusionsNot only type I, but also type III protein S deficiency is associated with a hypercoagulable state and increased risk of thrombosis. These findings may, however, be restricted to type III deficient individuals from families with mixed type I/III protein S deficiency, as these represented 80% of type III deficient individuals in our cohort.

Biology of tissue factor pathway inhibitor

“…system has accumulated through a series of clinical studies demonstrating that the plasma TFPIa concentration and anticoagulant activity are decreased in PS-deficient plasma, suggesting that PS and TFPIa circulate as a complex in plasma. [111][112][113] Functional studies of the TFPIa-PS interaction have revealed that it requires K3 residues Arg199 8 and Glu226 114 and the presence of a membrane surface. 6 Thus, it appears that PS enhances FXa inhibition primarily by localizing TFPIa to the membrane surface, a notion supported by experiments demonstrating that PS has cofactor activity toward the soluble TFPI variant protein K1K2K3 8,115 but has no cofactor activity toward the same variant protein when it is attached to the cell surface with a GPI anchor.…”

Protein S levels and the risk of venous thrombosis: results from the MEGA case-control study

“…3,4 Hereditary protein S deficiency is a haploinsufficiency disorder associated with an increased risk of venous thrombosis. 5 Protein S deficiency can be classified as type I (decreased levels of both total and free protein S antigen), type II (decreased activated protein C-cofactor activity but total and free protein S antigen levels within their normal ranges), and type III (decreased levels of free protein S antigen levels only). 6 The genetic basis of protein S deficiency is heterogeneous.…”

“…8 We, along with others, have shown that gross deletions and insertions of PROS1 are present in approximately 30% of the point mutation-negative families. 5,10,11 Most of the insights regarding the association between protein S deficiency and venous thrombosis have been derived from studies of thrombophilic families. This has led to the notion that the risk of venous thrombosis in protein S deficient subjects is 5 to 10 times higher than in nonprotein S deficient relatives.…”

Integrated laboratory coagulation tests in hypercoagulation diagnosis and thrombosis risk assessment. Part II. The sensitivity of integral tests to hypercoagulable states

“…ЭТП повышен практически при любых видах тромбофилии, включая полиморфизм G20210A [32], дефицит антитромбина [33], V Leiden [34] (с добавле-нием aPC), дефицит протеина S [35] (с добавлением aPC), а также при приеме оральных контрацептивов (с добавлением aPC) [36] и онкологических заболева-ниях [37]. В работах [38,39] ЭТП был повышен при бе-ременности, но в [40] ЭТП возрастал в I триместре относительно нормы и далее держался постоянным в течение всего срока беременности, в то время как маркеры активации свертывания D-димеры, F1 + 2 и TAT возрастали.…”