What is being tested?Proteins C and S are normally present in small quantities in the blood. They work together to inhibit excessive blood clotting. When a blood vessel or tissue is injured, the body initiates the
coagulation cascade, a step-by-step process involving the activation of up to 20 protein factors, which results in the formation of a stable blood clot. This clot prevents additional blood loss and protects the injury until it heals. Once it is no longer needed, other factors break the clot down so that it can be removed.
Thrombin is a clotting factor that can accelerate or decelerate blood clot formation by promoting or inhibiting its own activation. It forms a feedback loop that uses Protein C and Protein S to slow down the coagulation cascade. Thrombin first combines with a protein called thrombomodulin, then activates Protein C. This activated Protein C (APC) then combines with Protein S (a cofactor) and together they work to degrade coagulation factors VIIIa and Va (these activated factors are required to produce thrombin). This has the net effect of slowing down the generation of new thrombin and inhibiting further clotting. If there is not enough Protein C or Protein S, or if either one is not functioning normally, then thrombin generation goes on largely unchecked. This can lead to excessive or inappropriate clotting that may block the flow of blood in the veins and, rarely, in the arteries.
Problems with Protein C and Protein S can be inherited or acquired. There are two types of Protein C deficiencies: type 1 is related to quantity and type 2 to abnormal function. Protein S exists in two forms: free and bound, but only the free Protein S is available to combine with Protein C. There are three types of Protein S deficiencies. Type 1 deficiency is due to an insufficient quantity, type 2 to abnormal function, and type 3 to a shift from free Protein S to bound (or total) Protein S.
Tests for Protein C and Protein S may look at their function (activity) or quantity. Decreased levels of Protein C and Protein S may be related to insufficient production or to increased use. Since both proteins are produced in the liver and are vitamin K dependent, liver disease, a shortage of vitamin K, or anticoagulant therapy that opposes vitamin K, may result in reduced Protein C and/or Protein S levels. Conditions such as disseminated intravascular coagulation (DIC) that cause clotting and bleeding simultaneously throughout the body use up clotting factors, including Protein C and Protein S, at an increased rate, and so, decrease their concentrations in the blood.
Although inherited mutations in the genes that produce Protein C and Protein S are relatively rare, they can result in:
- a decreased level of Protein C or Protein S being produced,
- an abnormal Protein C or S that cannot bind properly to the other to form a functional activated protein C complex,
- an abnormal protein which can bind and form a complex, but the complex is not capable of degrading factors VIIIa and Va normally.
When these mutations occur, they are independent of each other and the mutation is most likely to be in one or the other (Protein C or Protein S). Changes in the gene may be heterozygous (one mutated copy of the C or S gene) or homozygous (two changed copies of C or S genes). A heterozygous change raises the risk of developing a venous thromboembolism (VTE) a moderate amount, but a homozygous change in either gene can cause severe clotting – it may cause life-threatening purpura fulminans or DIC in the newborn, and it requires a lifetime of vigilance against recurrent thrombotic episodes.
