Workup for Protein S Deficiency
Measure free protein S levels using functional assays, as free protein S is the most reliable diagnostic marker with 97.7% sensitivity and 100% specificity for identifying PROS1 gene defects. 1
Diagnostic Testing Algorithm
Initial Laboratory Assessment
- Measure free protein S levels as the primary diagnostic test, since free protein S (not bound to C4b-binding protein) is the functionally active form and provides the most accurate diagnosis 2, 1
- Measure total protein S levels to assess the overall protein S distribution 2, 3
- Perform functional protein S assays, as conventional immunologic methods may show normal or only mildly reduced levels despite markedly reduced functional activity 2
- Use crossed immunoelectrophoresis or ELISA methods to distinguish between free and C4b-binding protein-bound forms 2, 3
Classification of Protein S Deficiency Types
- Type I deficiency: All or most protein S is complexed to C4b-binding protein with little or no free protein, resulting in correspondingly low functional activity 2
- Type II deficiency: Little or no protein S present in either bound or free forms 2
Timing Considerations - Critical Pitfalls
- Avoid testing during acute thrombosis, as protein S levels will be artificially low and non-diagnostic 4
- Defer testing until at least 6 weeks postpartum in pregnant women, since pregnancy significantly lowers protein S levels 4
- Do not test patients on warfarin, as vitamin K antagonists reduce protein S levels 5
- Ensure normal prothrombin levels or obtain positive family history to establish inherited deficiency rather than acquired causes 4
Comprehensive Thrombophilia Panel
When protein S deficiency is suspected based on venous thromboembolism, simultaneously evaluate other hereditary thrombophilic factors:
- Prothrombin 20210A mutation (DNA testing) 5
- Factor V Leiden mutation (DNA testing) 5
- Antithrombin III levels (functional coagulation assay) 5
- Protein C levels (functional coagulation assay) 5
- Plasma homocysteine levels (biochemical measurement) 5
- Lupus anticoagulant and anticardiolipin antibodies to exclude acquired thrombophilia 5
Rationale for Panel Testing
- Venous thrombosis is multifactorial, and multiple genetic risk factors commonly coexist 5
- Compound heterozygosity (e.g., protein S deficiency plus prothrombin mutation) carries substantially higher recurrence risk 6
- Risk stratification through panel testing targets anticoagulation therapy to highest-risk patients 5
Confirmatory Testing Strategy
- For symptomatic patients with thrombosis: A single abnormal test showing low free protein S with clinical correlation is sufficient to guide treatment decisions 4
- For asymptomatic family members identified through screening: Repeat testing is necessary to exclude laboratory error or transient causes before confirming hereditary deficiency 4
- Once hereditary deficiency is confirmed: Routine repeat testing provides no clinical benefit and wastes resources 4
Genetic Testing Considerations
- Genetic analysis of the PROS1 gene can definitively confirm protein S deficiency when phenotypic testing is inconclusive 1
- Relatives with splice-site or major structural PROS1 gene defects have significantly lower total and free protein S levels and higher thrombotic risk compared to those with missense mutations 1
- Genetic confirmation is particularly valuable for family screening and counseling 1
Clinical Context Assessment
Document the following to guide management decisions:
- Thrombotic history: First episode versus recurrent events, provoked versus unprovoked thrombosis 5
- Family history: Positive family history increases postpartum thrombotic risk to 1.76% 7
- Precipitating factors: Surgery, immobility/trauma, pregnancy/puerperium, oral contraceptives 1
- Age at first thrombotic event: First events typically occur in young adults 4
- Type of thrombosis: Deep vein thrombosis, pulmonary embolism, cerebral venous thrombosis, or unusual site thrombosis 4