Some risk factors for deep vein thrombosis or pulmonary embolism in patients with protein S deficiency include pregnancy, older age, hormonal therapy, consumption of birth control pills, recent surgery, trauma, and physical inactivity.

The cytogenetic location of the gene in question is chromosome 3, specifically 3q11.1[6][7] Protein S deficiency can also be acquired due to vitamin K deficiency, treatment with warfarin, liver disease, kidney disease, chemotherapy, infection, surgery, birth control pills, pregnancy,[4] and acute thrombosis (antiphospholipid antibodies may also be a cause as well)[1] In regards to the mechanism of protein S deficiency, Protein S is made in liver cells and the Endothelium.

[2][10] Mutations in this condition change amino acids, which in turn disrupts blood clotting.

[6] The diagnosis for deficiency of protein S can be done as part of a thrombophilia investigation, along with reviewing family history of thrombotic disease.

Protein S activity assays may be useful in patients with a normal free protein S antigen in occasional situations: 1) if no abnormality is identified during a thrombophilia workup, but clinical suspicion persists; or 2) in specific populations in which type II deficiencies are more common.