Protein S Deficiency Profile

Plasma, frozen

1 mL

Blue-top (sodium citrate) tube

Avoid warfarin (Coumadin®) therapy for two weeks and heparin therapy for two days prior to the test. Do not draw from an arm with a heparin lock or heparinized catheter.

This test is used for confirmation and characterization of protein S (PS) congenital deficiency.

The presence of heparin or lupus anticoagulants leads to overestimation of PS. aPC resistance due to factor V Leiden mutation or some other cause can falsely lower measured PS activity levels.⁶

Total PS and free PS antigen: Total PS and free PS antigens are measured by latex immunoassay (IA). PS activity: The patient plasma is added to PS-depleted normal plasma with normal levels of all factors but PS. The mixture is supplemented with excess aPC, and factor V is then added. The extent of prolongation of the time to clot formation after calcium chloride is added is proportional to plasma PS activity.

Protein S (PS) is produced by the liver, megakaryocytes, and endothelial cells.^6-8 PS is synthesized as an inactive precursor that is activated by carboxylation of several glutamic acid residues by a vitamin K-dependent carboxylase. PS serves as an essential cofactor of activated protein C (aPC). In the presence of calcium, PS binds tightly to the phospholipid surfaces of endothelial cells and activated platelets. This serves to concentrate the PS/aPC complex at the site of thrombus formation where it regulates the coagulation process by enzymatically neutralizing activated factors Va and VIIIa. PS greatly potentiates the anticoagulant function of aPC. PS is enzymatically neutralized by thrombin. After thrombin proteolysis, PS retains its affinity for phospholipids, but loses its anticoagulant function as the cofactor for aPC.

A portion of the PS in blood is bound to the protein, which binds the C4b region of complement (ie, the C4b-binding protein [C4b-BP]).⁷ This C4b-BP forms a 1:1 complex with PS. In plasma, a dynamic equilibrium is reached between C4b-BP-bound and free PS. The free PS form represents about 40% of total PS in normal individuals. Only the free form can act as the cofactor for aPC and accelerate its anticoagulant activity. The PS that is bound to C4b-BP does not possess any anticoagulant activity because in cannot interact with aPC.

A deficiency in PS, either congenital or acquired, increases the risk of thromboembolism because of a decrease in the anticoagulant capacity of the blood. Thrombotic episodes can occur when PS activity drops to <50% of normal.⁶

Congenital protein S deficiency: The prevalence of congenital PS deficiency in the general population experiencing their first venous thrombosis is approximately 1%.⁷ In patients with a family history of thrombophilia, the likelihood of congenital PS deficiency being the cause reaches as high as 10%.⁷ This autosomal dominant defect occurs in the general population in approximately 1 in 700 individuals.⁶ Nearly 50% of individuals with congenital PS deficiency will experience a thrombotic event before the age of 45.⁶ Thrombosis can sometimes occur at unusual sites, including mesenteric and axillary veins. Recurrent thrombotic events are common.⁶

Congenital PS deficiency can be further classified based on the measured levels of total and free PS antigen along with functional PS activity.⁷

• Type I PS deficiency is the most common type, representing approximately 90% of cases.⁶ This condition is characterized by a reduction in overall PS antigen levels. Levels of total PS in patients with type I deficiency are typically around 50% of normal while free PS and PS activity are often even lower.

• Type II PS deficiency is characterized by a reduced PS activity but with normal antigen levels of both total and free PS.

• Type III PS deficiency is characterized by a disproportionately reduced PS activity and free antigen levels in individuals with normal total PS levels.

Acquired protein S deficiency: Acquired PS deficiency occurs more frequently than congenital deficiency.^6-8 Acquired deficiency can occur as the result of decreased PS synthesis or increased consumption. PS synthesis can be diminished in a number of conditions including oral anticoagulant therapy, vitamin K deficiency, liver disease, chemotherapy, and L-asparaginase therapy. PS consumption can occur during disseminated intravascular coagulation (DIC), acute thrombosis, polycythemia vera, sickle cell disease, and essential thrombocythemia. Protein S levels are also dependent, in part, on age, sex, and hormonal status, tending to be lower in the young and lower in women than in men. Levels may be further decreased in premenopausal women on oral contraceptive agents. Protein S values decrease with increasing gestational age. Free PS antigen and PS activities are also often diminished in nephrotic syndrome.⁷

Warfarin-induced skin necrosis has been reported in some cases of PS deficiency.⁸ Infants born with homozygous or doubly heterozygous PS deficiency are usually born with purpura fulminans of the newborn, a devastating condition requiring immediate treatment.⁸