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Protein C and Protein S Deficiency Paolo Aquino 18 February 2003 Hemostasis The hematologic system is in a balanced flux between pro-coagulant and anticoagulant factors Imbalance in either direction produces dire consequences: – Pro-coagulation: obstruction, stasis ischemia – Anti-coagulation: bleeding, blood loss Protein C 62-kD vitamin K-dependent glycoprotein Synthesized in the liver as a singlechain zymogen Clipped into a serine-protease-like enzyme on phospholipid cell surfaces by thrombin Protein C Activated protein C (APC) then binds protein S for further activity Protein C also has pro-fibrinolytic, antiinflammatory and anti-ischemic properties Protein S Single chain, vitamin K-dependent glycoprotein Bound state with C4BbP (60%) Only free state is capable of binding APC (40%) Protein S 2 identified genes on chromosome 3 PROS-a is the active gene PROS-b is an evolutionarily duplicated non-functional gene Protein C/Protein S complex Require negatively charged phospholipids and Ca2+ for normal anti-coagulant activity Complex acts by proteolyzing Factor VIII and Factor V, which in turn prevents activation of factor X and prothrombin Deficiency of Protein C and S Genetic – Autosomal dominant disorders – Homozygous and heterozygous forms – Homozygous form presents in infancy as neonatal purpura fulminans – Heterozygotes generally are not symptomatic until the 3rd and 4th decades Deficiency of Protein C and S Acquired – Liver disease – DIC – Vitamin K deficiency – Antagonism with anti-coagulant treatment – Septic shock – Chemotherapy Symptoms Deep vein thrombosis is the most common symptomatic manifestation Pulmonary embolism Post-phlebitic syndrome Fetal loss Lab studies INR, PT, aPTT Protein activity level Protein antigen- total and free Classification – Type I: decrease in total protein antigen – Type II: decrease in protein activity – Type III: decrease in free protein level Confounders Active clotting causes consumption of procoagulant and anti-coagulant proteins Coumadin therapy causes decreased protein activity Check vitamin K levels Repeat test on separate specimen Differential Anti-thrombin deficiency DVT Dysfibrogenemia Subclavian vein thrombosis Superficial thrombophlebitis Anti-phosopholipid syndrome Treatment Heparin therapy for a minimum of 5 days with standard protocol Start Coumadin administration on day 1 or 2 of heparin therapy Once therapeutic on Coumadin based on INR, can halt heparin therapy 6-9 months of initial treatment recommended Controversy regarding lifelong Coumadin therapy