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Protein C and Protein S
Paolo Aquino
18 February 2003
The hematologic system is in a balanced
flux between pro-coagulant and anticoagulant factors
 Imbalance in either direction produces dire
– Pro-coagulation: obstruction, stasis
– 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
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
Bound state with C4BbP (60%)
Only free state is capable of binding APC
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
– 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
– Liver disease
– Vitamin K deficiency
– Antagonism with anti-coagulant treatment
– Septic shock
– Chemotherapy
Deep vein thrombosis is the most common
symptomatic manifestation
 Pulmonary embolism
 Post-phlebitic syndrome
 Fetal loss
Lab studies
 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
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
Anti-thrombin deficiency
 Dysfibrogenemia
 Subclavian vein thrombosis
 Superficial thrombophlebitis
 Anti-phosopholipid syndrome
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