Hypercoagulability, venous stasis, and vessel wall injury predispose to thrombus formation. Thrombophilia can be defined as an imbalance in hemostasis caused by genetic or acquired factors that produce blood clots in otherwise healthy people. Genetic causes of thrombophilia include factor V Leiden mutation, prothrombin G20210A, hyperhomocysteinemia, ABO blood group, and deficiency in protein S (PS), protein C (PC), or antithrombin (AT) (formerly known as ATIII).1-3
Acquired risk factors for thrombosis include antiphospholipid antibody syndrome, hyperhomocysteinemia, advancing age, smoking, obesity, surgery, trauma, immobilization, liver disease, heart disease, disseminated intravascular coagulation, inflammatory bowel disease, oral contraceptive use, viral infection (eg, SARS-CoV-2 and HIV), pregnancy and the postpartum period, malignancy, and personal and family history of prior thrombosis.1-7
Inherited deficiencies of natural anticoagulants are more common in patients of Asian descent than in White populations; however, Asian patients are less likely to have factor V Leiden and prothrombin mutation compared with White patients.8 Among Asian populations, Japanese individuals have a higher incidence of thrombophilia related to a gene mutation called PS Tokushima manifested as a qualitative PS deficiency.9 This article will focus on deficiency in PS and will present several case reports of patients with this blood-clotting disorder.
What is PS Deficiency?
PS is a vitamin K-dependent glycoproteins synthesized in the liver that acts as a natural anticoagulant. PS is found in 2 forms: free and bound to a complement protein.3 Approximately 60% of PS is bound to C4b-binding protein (C4BP).3 The free form comprises 30% to 40% of PS and has a cofactor activity with PC. Therefore, PC deficiency also contributes to PS deficiency.4
PS and PC deficiency are uncommon genetic thrombophilic disorders that can cause both arterial and venous thrombosis.5 PS deficiency is caused by mutations in the PROS1 gene and increases the risk for deep vein thrombosis 2- to 11-fold.6 In a retrospective cohort study, obstetrical outcomes in pregnant women with a variety of genetic thrombophilias treated with anticoagulants were similar among those with single vs double genetic thrombophilias.2
Young women have lower levels of PS than men; this level increases with age in women.4 Protein S levels are also transiently reduced during the third trimester of pregnancy and are lower in women taking oral contraceptives than those not taking these medications.2,4 Vitamin K deficiency and warfarin therapy are also linked to reduced PS levels.4
Venous thromboembolism (VTE), arterial thrombosis, and frequent pregnancy losses are the predominant presentations in PS deficiency-related conditions.10-18
A strong family history of VTE; first VTE event before age 50 years; VTE in an unusual site such as portal, mesenteric, or cerebral vein; and recurrent VTE are possible features of underlying PS and PC deficiency.10,11
Individuals with PS deficiency may have a slightly increased risk of arterial thrombosis. Several case reports have described young patients with arterial thrombosis in the setting of inherited PS deficiency.10 Stent and dialysis access catheter thromboses are also reported in individuals with PS deficiency.12,13
Physiological changes in pregnancy predisposes to thrombosis in the presence of underlying anticoagulant deficiencies. Thrombotic disorders such as venous thromboembolism in pregnant women is also a cause of maternal death.2,14 Frequent pregnancy loss is generally associated with thrombophilia and can be prevented by use of low-molecular-weight heparin (LMWH) or aspirin.15-17 Increasing use of oral contraceptive for noncontraceptive reasons can augment clotting in adolescents.18
Diagnosis of Protein S Deficiency
To diagnose PS/PC quantitative deficiency, free PS antigen levels are measured by latex immunoassays or enzyme-linked immunosorbent assay (ELISA) method, and clot-based assays detect PS activity.19 Free PS antigen level is more useful than total PS antigen level for determining PS deficiency.19 Although routine screening for PS deficiency is not recommended, a workup is needed for patients who have had a clotting episode without any existing risk factors.19
A coagulation panel includes tests for factor V Leiden, prothrombin, homocystenemia, PS, PC, and antithrombin levels. Immediate family members of patients with PS deficiency should be screened for this coagulopathy. For example, a young female in the family of a person with manifested PS deficiency should be screened to avoid any pregnancy-related complications in the future. PS antigen is the test of choice for screening to detect PS deficiency.