Protein S Activity

Protein S is a vitamin K–dependent anticoagulant and a cofactor for activated Protein C (APC). Protein S activity falls progressively through pregnancy due to increased C4b-binding protein and reduced free Protein S.

Units	Nonpregnant Adult	1st Trimester	2nd Trimester	3rd Trimester
% Activity	60 – 140	57 – 95	42 – 68	16 – 42

Pregnancy Physiology

Protein S is a vitamin K–dependent cofactor for activated Protein C.
Free Protein S decreases markedly due to increased C4b-binding protein.
Protein S activity declines progressively throughout gestation.
Low Protein S activity in pregnancy is physiologic and not diagnostic of inherited deficiency.
Testing should be repeated ≥ 6 weeks postpartum when values normalize.

Clinical Notes

Protein S circulates in two forms:
- Free Protein S — biologically active
- Bound Protein S — bound to C4b-binding protein (inactive)
Protein S enhances APC-mediated inactivation of factors Va and VIIIa.
It also augments TFPI-mediated inhibition of factor Xa.
Inherited Protein S deficiency types:
- Type I: Low total and free Protein S
- Type II: Normal antigen with low activity
- Type III: Low free with normal total Protein S
Types I and III account for approximately 95% of inherited cases.
Acquired Protein S deficiency is more common than inherited forms.

Causes of LOW Protein S Activity

Physiologic pregnancy-related decline (most common)
Hereditary Protein S deficiency
Liver disease
Vitamin K deficiency
Warfarin therapy
Disseminated intravascular coagulation (DIC)
Acute thrombosis (consumption)
Nephrotic syndrome
Inflammation with increased C4b-binding protein
Estrogen therapy
HIV or varicella infection

Causes of HIGH Protein S Activity

Rebound elevation after acute thrombosis
Occasional idiopathic increases
Generally not clinically significant

References

Abbassi-Ghanavati M, Greer LG, Cunningham FG. Obstet Gynecol. 2009;114:1326–1331.
Khor B, Van Cott EM. Clin Lab Med. 2009;29:339–366.
Van Cott EM, Laposata M. Laboratory Test Handbook, 5th ed. Lexi-Comp.