Cofactor to Protein C

Protein S (PS), a vitamin K-dependent protein which is made by the liver and acts as the principal cofactor to protein C. Protein S exists as two forms in the blood: a free form and a bound form. Approximately 35% to 40% of total protein S exists as the free form, which is the form that acts with activated protein C (APC) to promote blood thinning.


Adult levels of protein S levels are reached when a child is approximately six months to one-year-old. Compared to men, women tend to have on average a lower level of free protein S, particularly when pregnant or using oral contraceptives. Newborn infants also have lower free and total protein S levels. Levels in heterozygotes (patients with only one abnormal protein S gene) are approximately 40-70% of the normal level.

Many medical conditions may be associated with abnormal protein S levels, including:

  • Liver disease

  • Disseminated intravascular coagulation

  • Herpes infections

  • Systemic lupus erythematosus

  • Ulcerative colitis

Protein S deficiency is rare in the healthy population, with an estimated frequency of approximately one in 700. When considering a selected group of patients with recurrent blood clots or a family history of clotting, the frequency of protein S deficiency ranges from 3% to 6%. The frequency of homozygous deficiency has been estimated to be one in 160,000 to one in 360,000. Infants and babies within the first year of life who have homozygous protein S deficiency characteristically have purpura fulminans.


There are three subtypes of protein S deficiency:

  • Type I: the decrease in the activity of protein S is proportional to the decrease in the level of protein S

  • Type II: the levels of the free and bound forms of the protein are normal, but they do not function properly because of a gene alteration

  • Type III: there is a normal level of total protein S, but the level of free protein S is abnormally low