Free Protein S — Trimester-Specific Reference Ranges

Free Protein S, the active cofactor for activated Protein C, decreases significantly in pregnancy due to increased C4b-binding protein and the physiologic hypercoagulable state.

* Lower limits of normal: 2nd trimester: 29% • 3rd trimester: 23%

Physiologic changes in pregnancy

• ↑ C4b-binding protein decreases the free (active) Protein S fraction.
• Pregnancy is a hypercoagulable state with ↓ Protein S and ↓ Protein C activity.
• Free Protein S may fall to 40–50% of baseline by mid-pregnancy.
• Low values are expected and should not be used alone to diagnose hereditary deficiency during pregnancy.

Causes of low free Protein S

• Physiologic pregnancy-related decrease
• Hereditary Protein S deficiency (Types I, II, III)
• Liver disease
• Vitamin K deficiency
• DIC / consumptive coagulopathy
• Acute thrombosis (consumption)
• Nephrotic syndrome
• Estrogen therapy
• Systemic inflammation (↑ C4bBP)
• HIV infection
• Varicella infection

Causes of high free Protein S

• Rare compensatory increase following thrombosis
• Occasional idiopathic elevations
• Generally not clinically significant

References

1. Abbassi-Ghanavati M, Greer LG, Cunningham FG. Pregnancy and laboratory studies: a reference table. Obstet Gynecol. 2009;114:1326–31. PMID: 19935037
2. Khor B, Van Cott EM. Laboratory evaluation of hypercoagulability. Clin Lab Med. 2009;29:339–66.
3. Paidas MJ et al. Protein S levels and pregnancy complications. J Thromb Haemost. 2005;3:497–501.
4. Williams Obstetrics, 26th ed. Hematologic physiology.