Protein C and Protein S Deficiency

Paolo Aquino 18 February 2003

Hemostasis

 The hematologic system is in a balanced flux between pro-coagulant and anti coagulant 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 single chain 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, anti inflammatory 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 Ca 2+ 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 3 rd and 4 th 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 pro coagulant 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