Sandbox:Roukoz: Difference between revisions
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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. | 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:''' Normal total and free protein S, reduced protein S function | |||
This type 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:''' Selectively reduced free protein S and protein S function, normal total protein S | |||
It is another type of quantitative defect | |||
==Pathophysiology== | ==Pathophysiology== | ||
Revision as of 19:30, 13 September 2018
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)
[Disease name] was first discovered by [name of scientist], a [nationality + occupation], in [year]/during/following [event].
The association between [important risk factor/cause] and [disease name] was made in/during [year/event].
In [year], [scientist] was the first to discover the association between [risk factor] and the development of [disease name].
In [year], [gene] mutations were first implicated in the pathogenesis of [disease name].
There have been several outbreaks of [disease name], including -----.
In [year], [diagnostic test/therapy] was developed by [scientist] to treat/diagnose [disease name].
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: Normal total and free protein S, reduced protein S function
This type 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: Selectively reduced free protein S and protein S function, normal total protein S
It is another type of quantitative defect