What is being tested?Proteins C and S help adjust the rate of blood clot formation. 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 (VTE - venous thromboembolism) and, more 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 2 forms, free and bound, but only the free Protein S is available to combine with Protein C. There are 3 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 Protein S.
Decreased Protein C and Protein S quantity 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 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 that cannot bind properly to its cofactor (C or S)
- an abnormal protein which when combined, does not degrade 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). A heterozygous change raises the risk of developing a 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.
