Protein S Activity

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Measures the functional activity of Protein S in the blood

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Protein S Activity Test - Comprehensive Guide

Why is it done?
- Test Purpose: Measures the functional activity of Protein S, a natural anticoagulant that acts as a cofactor for Protein C to inhibit blood clotting factors V and VIII.
- Primary Indications: Investigation of thrombophilia (tendency toward blood clot formation), unexplained venous thromboembolism (DVT/PE), recurrent pregnancy loss, family history of thrombosis, or evaluation of abnormal coagulation screening tests.
- Clinical Scenarios: Performed when evaluating patients with unexplained thrombosis before age 50, thrombosis at unusual sites, recurrent thrombotic events, women with adverse pregnancy outcomes, patients on anticoagulation therapy requiring baseline assessment, or as part of comprehensive thrombophilia workup.
- Timing: Ideally performed at least 2 weeks after discontinuing anticoagulation therapy (warfarin or heparin) and during periods of clinical stability, not during acute thrombotic events.
Normal Range
- Reference Range: 70-140% (or 0.70-1.40 international units/mL depending on laboratory assay methodology).
- Units of Measurement: Percentage (%) of normal activity or International Units per milliliter (IU/mL); results typically reported as activity levels rather than antigen levels.
- Normal Interpretation: Results within the reference range indicate adequate Protein S activity and normal anticoagulant function; associated with normal anticoagulation capacity.
- Low Results: Values below 70% suggest Protein S deficiency and indicate increased thrombotic risk; may be hereditary (Type I, II, or III deficiency) or acquired.
- High Results: Values above 140% are uncommon and generally not clinically significant; may represent measurement variation or laboratory-specific variation.
- Borderline Results: Values between 60-70% may warrant repeat testing and further evaluation to determine clinical significance and patient risk stratification.
Interpretation
- Detailed Result Analysis: Low Protein S activity (<70%) indicates deficiency of this natural anticoagulant, creating a hypercoagulable state and significantly increasing risk for venous thromboembolism, particularly in lower extremities and pulmonary circulation.
- Type I Deficiency: Both Protein S activity and antigen levels are reduced (approximately 50% of normal); most common hereditary form (accounts for ~70% of deficiency cases).
- Type II Deficiency: Protein S antigen is normal but activity is reduced (qualitative defect); dysfunctional Protein S protein is produced; accounts for ~20% of hereditary cases.
- Type III Deficiency: Free Protein S is reduced while total Protein S may be normal; results from increased binding of Protein S to C4b-binding protein; rare hereditary form.
- Factors Affecting Results: Warfarin therapy, acute thrombosis, malignancy, liver disease, kidney disease, autoimmune antibodies (lupus anticoagulant), vitamin K deficiency, disseminated intravascular coagulation, L-asparaginase therapy, estrogen therapy, pregnancy, and oral contraceptive use can all decrease Protein S activity.
- Clinical Significance of Patterns: Hereditary deficiency presents with early-onset thrombosis (before age 50), family history of thrombosis, and often multiple thrombotic episodes. Acquired deficiency may develop acutely and resolve with treatment of underlying condition. Combined defects (e.g., Protein S + Protein C deficiency, Factor V Leiden) confer substantially increased thrombotic risk.
- Heterozygous vs. Homozygous: Heterozygous deficiency (one abnormal gene) typically presents with thrombosis in adulthood; homozygous or compound heterozygous deficiency can cause severe neonatal thrombosis, including purpura fulminans.
Associated Organs
- Primary Organ Systems: Hematologic system (blood and blood-forming tissues); vascular endothelium; liver (site of Protein S synthesis); kidneys (involved in clearance and can affect coagulation factors).
- Associated Medical Conditions: Venous thromboembolism (deep vein thrombosis, pulmonary embolism), arterial thrombosis, thrombophilia, recurrent miscarriage/pregnancy loss, neonatal thrombosis/purpura fulminans, myocardial infarction (in young patients), ischemic stroke, mesenteric thrombosis.
- Disease Associations with Abnormal Results: Cirrhosis and chronic liver disease, nephrotic syndrome, disseminated intravascular coagulation, acute leukemia, malignancy, vitamin K deficiency, autoimmune conditions (particularly lupus anticoagulant syndrome), HIV infection.
- Diagnostic Value: Test helps diagnose hereditary thrombophilia, identify acquired deficiency states, evaluate unexplained thrombotic events, assess pregnancy-related complications, and guide therapeutic anticoagulation decisions.
- Potential Complications: Patients with Protein S deficiency face increased risk of recurrent thrombosis, complications during pregnancy (thrombosis, placental insufficiency, fetal loss), complications with surgery or immobilization, and potential warfarin-induced skin necrosis (particularly at deficiency onset of anticoagulation).
Follow-up Tests
- Complementary Testing: Protein S antigen level (to differentiate Type I vs. Type II deficiency); free Protein S (to identify Type III deficiency); Protein C activity and antigen; Factor V Leiden mutation; prothrombin G20210A mutation; anticardiolipin and anti-beta-2 glycoprotein antibodies.
- Initial Thrombophilia Workup: Prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), platelet count, fibrinogen level, FVIII activity, and assessment for lupus anticoagulant.
- Genetic Testing: DNA sequencing of PROS1 gene to confirm hereditary deficiency, identify specific mutations, and enable family screening and genetic counseling.
- Vascular Imaging: Compression ultrasound of lower extremities, CT pulmonary angiography (CTPA), or venography to confirm or exclude thrombotic events; may be indicated based on clinical presentation.
- Baseline Assessment Tests: Liver function tests (AST, ALT, bilirubin, albumin); renal function tests (creatinine, BUN); CBC to assess for bone marrow disease or malignancy.
- Repeat Testing: For borderline low results, repeat testing is recommended at least 2-3 weeks after initial test during anticoagulant-free period; consider repeat testing if acquired deficiency suspected (after resolution of acute illness).
- Monitoring Frequency: For diagnosed deficiency: baseline testing completed; periodic reassessment if clinical status changes; in pregnancy, consider testing in third trimester; during anticoagulation therapy, monitor with INR/aPTT rather than Protein S activity.
- Family Screening: If hereditary Protein S deficiency confirmed, recommend testing first-degree relatives (parents, siblings, children) to identify carriers and assess their thrombotic risk.
Fasting Required?
- Fasting Status: NO - Fasting is NOT required for Protein S activity testing.
- Sample Collection Requirements: Blood sample collected via standard venipuncture into appropriate tube (typically 3.2% sodium citrate tube); proper tube filling and mixing is critical for accurate results.
- Medication Considerations: MUST discontinue warfarin for at least 2 weeks before testing; unfractionated heparin or low-molecular-weight heparin should also be discontinued (though testing may be performed on heparin if acute evaluation needed); continue other routine medications unless specifically instructed otherwise by healthcare provider.
- Timing and Clinical State: Test should be performed during clinically stable periods, avoiding acute thrombotic events, acute illness, recent surgery, or trauma; if possible, schedule testing in morning hours.
- General Preparation Instructions: Wear loose-fitting clothing with easily accessible upper arm; arrive well-hydrated; inform phlebotomist of any recent bruising or bleeding episodes; remain seated for 5 minutes after blood draw to prevent syncope.
- Special Patient Populations: Pregnant women: Protein S levels naturally decrease during pregnancy (can be 30-40% lower); testing ideally performed before conception or deferred until postpartum period for diagnostic purposes; if urgent assessment needed, interpret results with pregnancy-related baseline adjustment.

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