Protein S

Alternative Names

  • PROS1
  • Protein S, Alpha
  • PSA
  • Protein S Pseudogene
  • PROSP
  • Protein S, Beta
  • PROS2
  • PSB
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WHO-ICD-10 version:2010

Diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism

Coagulation defects, purpura and other haemorrhagic conditions

OMIM Number

176880

Mode of Inheritance

Autosomal dominant

Gene Map Locus

3q11.1

Description

Protein S deficiency is an autosomal dominant disorder characterized by decreased levels of plasma protein S antigen or activity. Protein S is a vitamin K-dependent plasma protein that inhibits blood clotting by serving as a cofactor for activated protein C (also a vitamin K-dependent protein), and exists in 2 forms in plasma: the free, functionally active form and the inactive form complexed with C4b-binding protein. Three types of protein S deficiency have been described according to the levels of total and free protein S antigen, as well as APC cofactor activity, in plasma. In type I or quantitative protein S deficiency, total and free protein S antigen values are decreased together with reduced anticoagulant activity. In type III or free PROS1 deficiency, free PROS1 antigen and PROS1 activity levels are reduced, whereas total PROS1 antigen levels are normal. In the rare type II or qualitative protein S deficiency, only the APC cofactor activity is reduced. The disorder is associated with recurrent venous thrombosis and pulmonary embolism. In some rare cases, thrombosis can be found at unusual sites, like the axillary, mesenteric, and cerebral veins. Protein S deficiency is found in 2-3% of patients with thromboembolism and has an incidence of 1 in 5,000.

Protein S deficiency is caused by mutations in the protein S gene (PROS1), mapping to 3p11.1.

Molecular Genetics

Protein S deficiency is caused by mutations in the protein S gene (PROS1), mapping to 3p11.1-q11.2. Protein S is a plasma glycoprotein that plays an important role in the protein C anticoagulant pathway by acting as a cofactor to activated protein C (APC) in the specific proteolytic inactivation of factors Va and VIIIa. Mature protein S has a modular structure and consists of a vitamin K-dependent Gla domain that includes an aromatic stack region, a region sensitive to cleavage by thrombin, 4 domains homologous to epidermal growth factor, and a region homologous to sex hormone binding globulin.

Epidemiology in the Arab World

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Other Reports

Egypt

[See also: Kuwait > Mohanty et al., 1996].

Iraq

[See also: Kuwait > Mohanty et al., 1996].

Jordan

Awidi et al. (1993) conducted a four-year prospective study on patients admitted or referred with thromboembolic disease to Jordan University Hospital or to the Thrombosis/Haemostasis Laboratory at the University of Jordan. There were a total of 217 patients (102 males and 115 females) with confirmed thromboembolic disease. A total of 49 patients (26 males and 23 females) fulfilled the criteria of hereditary thrombophilia. There were 17 cases of protein C deficiency (PC), 15 protein S deficiency (PS), 10 antithrombin III deficiency (ATIII), 3 dyfibrinogenemia, 2 heparin cofactor II deficiency, and 2 plasminogen defects. Twenty-seven additional relatives with deficiency were identified upon family studies.

Eid (2002) studied 602 (265 female, 337 male) patients with suspected thrombosis, arterial or venous. The prevalence of hereditary deficiencies of antithrombin (AT), protein S (PS), and protein C (PC) were studied over a seven-year period (1993-2000). A diagnosis was established in 22.4% (n = 135) of the subjects (20.3% venous, 2.1% arterial). Protein C deficiency was found in 3.8%, protein S deficiency in 2.3% and antithrombin deficiency in 1.4% of the sample group.

[See also: Kuwait > Mohanty et al., 1996].

Kuwait

Mohanty et al. (1996) conducted a 4-year (1986-1990) retrospective study on 130 unrelated patients with recurrent deep venous thrombosis in order to determine the possible etiology. The study group consisted of only ethnic Arab patients from Kuwait, Palestine, Jordan, Egypt, Sudan, Iraq, and Syria. Fifteen patients were found to have hereditary protein C deficiency (11.52%). Family studies revealed autosomal recessive inheritance in one patient and a dominant pattern in the remaining 14 patients. Protein S deficiency was found in eight cases (6.1%), AT-III deficiency was established in five cases (3.8%) and a fibrinolytic defect in 33 cases (25.4%). Thrombosis of visceral and cerebral vessels and a positive family history were more frequently found among patients who had hereditary deficiency of one or the other antithrombotic factor. Thrombophlebitis of superficial veins was found to be very common in patients with protein C and protein S deficiency and virtually absent in AT-III deficiency.

Oman

Pathare et al. (2006) studied the prothrombotic risk factors in Omani patients who presented with their first thrombophilic event. All Omani patients (39 patients: 24 females and 15 males), who were admitted between 2001 and 2003 with a first episode of deep venous thrombosis (DVT) with or without pulmonary embolism (PE) or with thrombosis in an unusual site, were included in the study. Only two patients (5.12%) were found to have low levels of protein S. Pathare et al. (2006) had suggested conduction of a larger study to relate the hereditary markers for thrombophilia to the actual event.

Palestine

Inbal et al. (1997) described two children from two unrelated Arab families with purpura fulminans who were double heterozygotes for factor V Leiden inherited from their fathers and protein S deficiency inherited from their mothers. No previous thrombotic events have occurred in either patient or their respective family members. In one patient sepsis accompanied by disseminated intravascular coagulation appeared to be the trigger of purpura fulminans. In the other patient varicella infection preceded purpura fulminans and was also associated with disseminated intravascular coagulation.

[See also: Kuwait > Mohanty et al., 1996].

Saudi Arabia

Al-Jaouni (2003) conducted a retrospective analysis in 179 consecutive Saudi patients (74 males, 105 females) that were screened between October 1997 and January 2002 at the King Abdul-Aziz University Hospital (KAUH) and King Fahd Armed Forces Hospital (KFAFH), Jeddah, Kingdom of Saudi Arabia. All patients had at least one of the following features: history of recurrent venous thromboembolism (VTE), first episode of unprovoked VTE, thrombosis in unusual site or thrombosis at young age with or without positive family history. Thrombotic workup included protein C, protein S, antithrombin (AT), APCR, prothrombin mutation, lupus anticoagulant (LA), and anticardiolipin (ACL). Functional assays were carried out in 179 patients. Protein S deficiency was the most common, identified in 26/179 (14.5%) followed by protein C in 15/179 (8.4%), while AT was not deficient in all 179 tested patients. Activated protein C resistance was present in only 4 patients (2.2%).

Sudan

[See also: Kuwait > Mohanty et al., 1996].

Syria

[See also: Kuwait > Mohanty et al., 1996].

United Arab Emirates

Al Talabani et al. (1998) studied the pattern of major congenital malformations in 24,233 consecutive live and stillbirth in Corniche hospital, which is the only maternity hospital in Abu Dhabi, between January 1992 to January 1995. A total of 401 babies (16.6/1,000), including 289 Arabs, were seen with major malformation. Single gene disorders accounted for 24% of the cases, 21% were due to autosomal dominant disorders. In their study, Al Talabani et al. (1998) observed one case of protein S deficiency causing cerebral venous sinus thrombosis in a family from the United Arab Emirates. Recurrence was reported in the family. Al Talabani et al. (1998) concluded that this study is very close to representing the true incidence of congenital abnormalities in the whole United Arab Emirates, as this study included over 98% of deliveries in Abu Dhabi, the capital of United Arab Emirates.

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