Protein S deficiency is a condition in which there is a quantitative or qualitative defect in vitamin K-dependent coagulation cofactor protein S that impairs the normal fibrinolysis mechanism and results in increased risk of thromboembolism. The prevalence of protein S deficiency is unknown; however, within patients with history of venous thromboembolism (VTE), the prevalence is less than 1%.

Protein S deficiency has autosomal dominant inheritance and results from mutations in the PROS1 gene on chromosome 3. Most patients are heterozygous for the PROS1 mutation; however, homozygous or compound heterozygous patients have been described. Protein S deficiency is further categorized on how the mutation affects total protein S levels, free protein S levels, or protein S function. Type 1 refers to decreased total protein S, free protein S, and reduced function. Type 2 is when total and free protein S levels are normal but function is reduced. Type 3 is isolated free protein S deficiency with normal total protein S and normal function.

The primary presentation of protein S deficiency is the development of VTE, with deep vein thrombosis and pulmonary embolism being the most common presentations.