Protein S deficiency

The clinical phenotype centres on a markedly increased risk of venous thromboembolism. While family-based studies report a 5- to 10-fold increased risk, population-based cohorts suggest a more modest relative risk (no more than 2.5) for unselected carriers. Most affected individuals present in adolescence or adulthood with deep vein thrombosis or pulmonary embolism; thrombosis at less common sites (including cerebral, mesenteric and hepatic veins) also occurs. Recurrent episodes are common, and a positive family history of unprovoked thrombosis is a frequent clinical clue. The elevated thrombotic risk reflects impaired down-regulation of thrombin generation, with broad inter- and intra-familial variability in clinical expressivity even among individuals sharing the same pathogenic variant. A rare severe form manifests in the neonatal period with purpura fulminans, a life-threatening microvascular thrombotic emergency featuring widespread cutaneous necrosis and disseminated intravascular coagulation. Estrogen exposure, pregnancy and the puerperium are recognised provoking factors that may precipitate a first thrombotic event in otherwise asymptomatic individuals.

The prevalence of protein S deficiency (plasma protein S <60%) in the general population is estimated at 0.2%.

Protein S deficiency is caused by germline pathogenic variants in PROS1, which encodes protein S, a vitamin K-dependent plasma glycoprotein that functions as a non-enzymatic cofactor for activated protein C (APC) and for tissue factor pathway inhibitor (TFPI). Loss-of-function variants reduce circulating free protein S antigen and/or its anticoagulant activity, attenuating APC- and TFPI-dependent down-regulation of thrombin generation. Rare biallelic loss of function produces a severe early-onset phenotype.

Protein S deficiency follows an autosomal dominant inheritance pattern; rarely, an autosomal recessive form has been described. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

Diagnosis is established biochemically by demonstrating persistently reduced plasma free protein S antigen and/or protein S anticoagulant activity (cofactor function for activated protein C). The free antigen assay is more accurate and reproducible than the activity assay. Confirmation requires repeat testing, as transient decreases occur with pregnancy, estrogen therapy, vitamin K antagonists, acute thrombosis, hepatic disease and intercurrent illness.

• Establishing a molecular diagnosis can confirm the underlying genetic cause and end the diagnostic odyssey, particularly where clinical or biochemical findings alone are insufficient.
• A confirmed molecular diagnosis is a prerequisite for individualized clinical management; management decisions rest with the treating physicians in consultation with the affected individual.
• Identification of the pathogenic variant in a proband enables predictive testing of at-risk relatives, supporting earlier identification of variant carriers and individualized counselling.

• Vrtel P, Slavik L, Vodicka R, Stellmachova J, Prochazka M, Prochazkova J, et al. Detection of unknown and rare pathogenic variants in antithrombin, protein C and protein S deficiency using high-throughput targeted sequencing. Diagnostics (Basel). 2022;12(5):1060. doi:10.3390/diagnostics12051060. PMID:; PMCID:PMC9139221.
• Chaudhry SA, Haj AK, Ryu J, Jurgens SJ, Rodriguez Espada A, Wang X, et al. Population-scale studies of protein S abnormalities and thrombosis. JAMA. 2025;333(16):1423-32. doi:10.1001/jama.2025.0155. PMID:; PMCID:PMC11877412.
• Middeldorp S, Nieuwlaat R, Baumann Kreuziger L, Coppens M, Houghton D, James AH, et al. American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing. Blood Adv. 2023;7(22):7101-38. doi:10.1182/bloodadvances.2023010177. PMID:; PMCID:PMC10709681.
• Manderstedt E, Lind-Halldén C, Halldén C, Elf J, Svensson PJ, Dahlbäck B, et al. Classic thrombophilias and thrombotic risk among middle-aged and older adults: a population-based cohort study. J Am Heart Assoc. 2022;11(4):e023018. doi:10.1161/JAHA.121.023018. PMID:; PMCID:PMC9245807.
• Khider L, Gendron N, Mauge L. Inherited thrombophilia in the era of direct oral anticoagulants. Int J Mol Sci. 2022;23(3):1821. doi:10.3390/ijms23031821. PMID:; PMCID:PMC8837096.