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Protein S deficiency: Clinical manifestations and diagnosis

INTRODUCTION

Inherited thrombophilia is a genetic tendency to venous thromboembolism. The factor V Leiden and prothrombin gene mutations are the most common causes of the syndrome, accounting for more than 50 percent of cases. Deficiencies in protein S, protein C, and antithrombin account for most of the remaining cases, while rare causes include the dysfibrinogenemias [1,2]. The total incidence of an inherited thrombophilia in individuals with a deep vein thrombosis ranges from 24 to 37 percent overall compared with approximately 10 percent in controls. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia'.)

This topic review will discuss the genetics, prevalence, clinical presentation, and diagnosis of protein S (PS) deficiency. Issues related to screening for and the management of the inherited thrombophilias are discussed separately. (See "Evaluation of the patient with established venous thrombosis" and "Screening for inherited thrombophilia in asymptomatic individuals" and "Management of inherited thrombophilia" and "Diagnosis and treatment of venous thrombosis and thromboembolism in infants and children".)

PHYSIOLOGY OF PROTEIN S

Protein S (PS), a vitamin K-dependent glycoprotein, is a cofactor of the protein C system. It was originally discovered and purified in Seattle, leading to the designation protein S. It is synthesized by hepatocytes, endothelial cells, and megakaryocytes. It circulates in two forms: 40 to 50 percent as the free form, and the remainder bound to the complement component, C4b-binding protein (C4b-BP); only the free form has activated protein C cofactor activity [3,4].

In the presence of PS, activated protein C inactivates factor Va and factor VIIIa at an increased rate, resulting in reduced thrombin generation [5]. PS also serves as a cofactor for protein C enhancement of fibrinolysis, and can directly inhibit prothrombin activation via interactions with other coagulation factors [6-10].

The average plasma concentration of total PS antigen in normal adults is 23 mcg/mL, which by definition is assigned a value of 100 percent, or 1 unit/mL (100 units/dL) [11]. Levels increase with advancing age and are significantly lower and more variable in females than males [12,13]. The increase with age is seen with total PS but not free PS; the latter finding is explained by an association between beta-chain containing C4b-binding protein antigen levels and age [12].

                  

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Literature review current through: Mar 2014. | This topic last updated: Jan 15, 2014.
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