Protein S Deficiency

Protein S deficiency is a disorder associated with increased risk of venous thrombosis. Protein S, a vitamin K-dependent physiological anticoagulant, acts as a nonenzymatic cofactor to activate protein C in the degradation of factor Va and factor VIIIa. Decreased (antigen) levels or impaired function of protein S leads to decreased degradation of factor Va and factor VIIIa and an increased propensity to venous thrombosis. Protein S circulates in human plasma in two forms: approximately 60 percent is bound to complement component C4b β-chain while the remaining 40 percent is free, only free protein S has activated protein C cofactor activity

Signs and symptoms

Among the possible presentation of protein S deficiency are:

Cause

Human Chr 3

In terms of the cause of protein S deficiency it can be in inherited via autosomal dominance. A mutation in the PROS1 gene triggers the condition. The cytogenetic location of the gene in question is chromosome 3, specifically 3q11.1 Protein S deficiency can also be acquired due to vitamin K deficiency, treatment with warfarin, liver disease, and acute thrombosis (antiphospholipid antibodies may also be a cause as well)

Pathophysiology

In regards to the mechanism of protein S deficiency, Protein S is made in liver cells and the Endothelium. Protein S is a cofactor of APC both work to degrade factor V and factor VIII. It has been suggested that Zn2+ might be necessary for Protein S binding to factor Xa.

Mutations in this condition change amino acids, which in turn disrupts blood clotting. Functional protein S is lacking, which normally turns off clotting proteins, this increases risk of blood clots.

Diagnosis

PTT blood tests Vacutainer tube

The diagnosis for deficiency of protein S can be done via reviewing family history of condition and genetic testing, as well as the following:

• Protein S antigen test
• Coagulation test (prothrombin time test)
• Thrombotic disease investigation
• Factor V Leiden test

Differential diagnosis

Among the possibilities for differential diagnosis of protein S deficiency are- Antiphospholipid syndrome, disseminated intravascular coagulation and antithrombin deficiency (though this list is not exhaustive)

Types

There are three types of hereditary protein S deficiency:

• Type I – decreased protein S activity: decreased total protein S levels, as well as decreased free protein S levels
• Type II – decreased in regards to the cofactor activity of the protein
• Type III – decreased protein S activity: decreased free protein S levels (normal total protein S levels)

Treatment

Dabigatran

In terms of treatment for protein S deficiency the following are consistent with the management (and administration of) individuals with this condition (the prognosis for inherited homozygotes is usually in line with a higher incidence of thrombosis for the affected individual):

• Unfractionated heparin (w/ warfarin)
• LMWH/Low molecular weight heparin
• Dabigatran
• Direct Factor Xa Inhibitors
• Graduated compressed stocking
• High degree of prophylaxis