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Lab Test: Activated Protein C Resistance

    Lab Test
    • Activated Protein C Resistance
    • Protein C is a natural endogenous protein found in the blood that serves as an anticoagulant. 
    • This is part of the evaluation of patients with coagulation disorders and identifies patients who are deficient in protein C and/or S. 
    • A deficiency in activated protein C would result in an increased risk for clot formation since there is decreased or no inhibitory feedback on the coagulation cascade by protein C.
    Reference Range
    • Protein S:  60%-130% of normal activity
    • Protein C:  70%-150% of normal activity
    • Note:  Protein C decreases with age and in females.  Second generation assays for APC resistance is near 100%. (Dahlback 1995; Samama 1996).
    Indications & Uses
    • Plasma coagulation system is tightly regulated between clot formation (i.e., thrombosis) and clot breakdown (i.e., fibrinolysis).  The protein C-protein S system is an important inhibitor of the coagulation cascade and clot formation.  Protein C inhibits the activation of co-factors VIII and V and this influence is enhanced by protein S.  Congenital deficiencies of these vitamin K-dependent clotting factors may cause spontaneous intravascular thrombosis. 
    • Nearly 50% of hypercoagulable states are caused by the presence of a factor V that is resistant to protein C inhibition.
    • Protein S activity should be tested alone with protein C because the decreased activity of protein C may the result of decreased protein S. 
    • Both proteins are vitamin K dependent for their functional activation after being made in the liver.  They are decreased in patients taking warfarin (Coumadin; Jantoven), as well as those with liver diseases or severe malnutrition.  Increased binding of protein S may cause an acquired protein S deficiency and hypercoagulable events may occur. 
    • Measurement of plasma free protein S antigen is performed as the initial testing for protein S deficiency.
    • If the free protein S antigen level is below the age- and sex-adjusted normal range, quantification for total plasma protein S antigen is indicated.
    Clinical Application

    Significance of decreased protein C levels:

    • Inherited deficiency of protein C or protein S:  Protein S or C defect may not be recognized until adulthood.
    • Disseminated intravascular coagulation (DIC), hypercoagulable states, pulmonary emboli, arterial or venous thrombosis:  these diseases, when recurrent, may be the result of a protein C or S deficiency. 
    • Vitamin K deficiency:  If vitamin K is not available because of malnutrition, biliary disease, or malabsorption, Protein C and S will not be functionally activated in adequate levels.  Because several coagulation factors are also vitamin K-dependent, a hypercoagulable event may not occur. 
    • Sickle cell disease:  this condition alone does not produce a thrombophilic state.
    • Autoimmune diseases, inflammation:  these proteins may be "used-up" in the inflammatory process. 
    • Warfarin-induced skin necrosis:  Occurs in feet, buttocks, thighs, breasts, upper extremities, and genitalia.  Begin as maculopapular lesions and progress into bullous hemorrhagic, necrotic lesions.  Patients with protein C deficiency are at high risk for warfarin-induced skin necrosis during the initiation of therapy with warfarin (Coumadin; Jantoven).  Approximately one third of patients with warfarin-induced skin necrosis have protein C deficiency as is the reason patients with clots present are initiated on parenteral anticoagulation at the same time as warfarin.
    Related Tests
    • Activated Partial Thromboplastin Time (aPTT)
    • Antithrombin levels or function
    • Disseminated Intravascular Coagulation (DIC) Screening.
    • Factor V Leiden Mutation
    Drug-Lab Interactions
    • Decreased protein C may occur in the postoperative states.
    • Pregnancy or the use of exogenous sex hormones is associated with decreases in proteins C and S.
    • The concentration of citrate in the collection tube varies and can affect activity results.
    • Active clotting states, such as DVT, can lower levels of protein S and C.
    • Vitamin K inhibitors such as warfarin can decrease levels.
    Test Tube Needed
    • Collect a venous blood sample in a blue-top tube. Fill tube to 90% or near complete capacity.
    • If more than one blood test is to be obtained, draw the blood for proteins C or S second to avoid contamination with tissue thromboplastin that may occur in the first tube.
    • If only blood for protein C or S is being drawn, draw a red top first (and throw it away) and then draw the blood for this study in a blue top tube.
    • Place the tube in an ice bath. 
    • Apply pressure to the venipuncture site after procedure.
    •  If the patient is found to be deficient in either protein, encourage the patient's family to be tested as they too may be similarly affected.
    Storage and Handling
    • Place tube in ice bath after obtaining blood is drawn.
    What To Tell Patient Before & After
    • No preparation needed by the patient.
    • Bertina RM et al.  Mutation in blood coagulation factor V associated with resistance to protein C. Nature  1994;369(6475):64-67.  PMID: 8164741
    • Dahlback B.  Resistance to activate protein C, the Arg506 to Gln mutation in the factor V gene, and venous thrombosis.  Functional tests and DNA-based assays, pros and cons.  Thromb Haemost 1995l73:739-42.  PMID: 7482395
    • Dahlback B et al. Factor V and protein S as cofactors to activated protein C. Haematologica 1997;82(1):91-95.  PMID: 9107093
    • LaGow B et al., eds. PDR Lab Advisor. A Comprehensive Point-of-Care Guide for Over 600 Lab Tests.  First ed. Montvale, NJ: Thomson PDR; 2007.
    • Pagana K, Pagana TJ eds. Mosby's Manual of Diagnostic and Laboratory Tests. 5th Ed.  St. Louis, Missouri. 2014.
    • Samama MM et al.  Diagnosis and clinical characteristics of inherited activated protein C resistance.
    • Haemostatsis 1996;26 suppl 4:315-30. PMID: 8979137
    • Pruller F et al. Activated protein C resistance and factor V Leiden. N Engl J Med 2014;371(7):685-6.  PMID: 25119624

MESH Terms & Keywords

  • Activated Protein C Resistance, Hypercoaguable Lab Tests