Sandbox:Roukoz

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Roukoz A. Karam, M.D.[2]

Overview

Protein S deficiency is an autosomal dominant thrombophilia, which leads to an increased risk of thromboembolic events. Protein S is a vitamin K-dependent glycoprotein and plays a role in anticoagulation. It is mainly a cofactor to the activated protein C (APC), which inactivates coagulation factors Va and VIIa and thereby controlling the coagulation cascade.

Historical Perspective

Protein S was first discovered and purified in Seattle, Washington in 1979, and it was arbitrarily named protein S after the city it was discovered in. The function of this protein was still unknown; however, it was hypothesized that protein S plays a role in activating protein C. Protein S deficiency was first discovered in 1984 when two related individuals with recurrent thromboembolic events and normal coagulation tests were studied. At the time, protein C deficiency was usually associated with recurrent familial thrombosis. These individuals were found to have diminished anticoagulation activity with normal coagulation tests (including a normal protein C level), and when purified human protein S was added to their plasma, effective anticoagulation was restored. (1)

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In [year], [scientist] was the first to discover the association between [risk factor] and the development of [disease name].

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Classification

Protein S deficiency can be subdivided into three types depending on whether the abnormality affects total protein S level, free protein S level, and/or protein S function:

• Type I: Reduced total protein S, free protein S, and protein S function

It is the classic type of inherited protein S deficiency. Typical findings include total protein S of approximately 50 percent of normal and free protein S as low as 15 percent of normal [15,19]. Most of the mutations responsible for type I deficiency are missense or nonsense mutations [31]. Microinsertions, microdeletions, and splice site mutations have also been reported.

●Type II – Type II deficiency (normal total and free protein S; reduced protein S function) is rare (case reports only). This is also referred to as a qualitative defect. Five mutations described in the original reports were missense mutations located in the aminoterminal end of the protein, which includes the domains that interact with activated protein C [32-35]. These mutations may alter the conformation of protein S or interfere with carboxylation of the gamma-carboxyglutamic acid domain of the protein [33]. In a series of 118 French patients with thromboembolism associated with protein S deficiency, 26 had a serine to proline substitution at amino acid 460 (the Heerlen polymorphism), which affects protein S metabolism [36,37]. The low free plasma protein S may result from increased binding of the abnormal protein S to C4b-binding protein [38,39]. The thrombophilic risk with this polymorphism has been questioned [37].

●Type III – Type III deficiency (selectively reduced free protein S and protein S function; normal total protein S) is another type of quantitative defect.