Protein C and S are two anticoagulation proteins that inactivate coagulation factors Va and
VIIIa in the coagulation cascade. This means they act like brakes on coagulation, limiting
clot formation and preventing clots from growing too big. So when either of these proteins
is deficient, it leads to a hypercoagulable state, meaning a person is at increased risk
of developing a clot that could block blood flow. The most common places for such clots
to develop are in the deep veins of the legs and in the vessels that carry de-oxygenated
blood through the lungs.
Normally, protein C and protein S are 2 of many proteins or enzymes that regulate the
complex process called hemostasis. This is where a solid clot forms in the flowing, liquid
blood to plug the defect in a damaged blood vessel. It has two steps; Primary hemostasis
involves the formation of a platelet plug at the site of injury, and secondary hemostasis
involves coagulation, where several clotting factors come into play to form a fibrin mesh
over the platelet plug to reinforce it, and form the blood clot. The main role of protein
C and protein S is to prevent excess coagulation, or fibrin formation, during secondary hemostasis.
Protein C and S prevent excess coagulation by interacting with several other proteins
involved in a complex system of checks and balances. So, it starts with a protein called
thrombomodulin, which is on endothelial cells that line our blood vessels, and together
with thrombin, they form a complex that also includes protein C and protein S. When protein
S joins this complex, this activates the proteolytic site of protein C, which cleaves and inactivates
active factor V, a cofactor for factor X in the common pathway, and VIII, a cofactor for
factor IX in the intrinsic pathway. The factor V degradation product also binds to this complex
and further enhances its ability to cleave more active factor V and active factor VIII.
By inhibiting both the intrinsic and common pathway, less fibrin is produced and coagulation
slows down dramatically.
So, in people with protein C and S deficiency, the thrombin-thrombomodulin complex can’t
cleave and inactivate factors V and VIII. This increases circulating factor V and factor
VIII levels, and “tips the scale” toward coagulation, putting them at increased risk
for thrombosis, or developing blood clots. This usually occurs in the deep veins of the
legs or in the pulmonary arteries that carry deoxygenated blood from the heart to the lungs.
There are two types of familial, or congenital, protein C and S deficiency; both are inherited
in an autosomal dominant manner. Type I disease is when there’s not enough protein C or
S, so that’s a quantitative defect. Type II disease, however, is a qualitative defect,
because enough protein C or S are made, but the proteins don’t function properly. There
are also acquired forms of protein C or S deficiency, like impaired production as seen
in patients with liver disease or in patients taking warfarin, also called coumadin. Another
cause is excessive urinary loss of these proteins which can happen in people with nephrotic
syndrome.
Protein C or S deficiency is commonly asymptomatic, but symptoms arise when a venous thromboembolism
develops. That’s when a clot forms, usually in the deep veins of the leg, and then parts
of it can break off and travel to other parts of the body. Symptoms of venous thromboembolism
include pain similar to a muscle cramp, and swelling in the affected leg. If a clot breaks
off and travels to the lungs, there can be signs of respiratory distress like pain with
inhalation, fast heart rate, and a fast respiratory rate. If clots get lodged in the cerebral
vessels, which usually occurs in a vein, it could cause headache; numbness or weakness
in the face, arm or leg; confusion; or slurred speech. Clots can also occur in veins in the
abdomen, potentially causing signs or symptoms associated with injury to the liver, spleen
or intestine. A more serious presentation is neonatal purpura fulminans, which is when
a newborn with protein C or S deficiency suffers massive arterial and venous thromboembolisms
with hemorrhagic skin necrosis. Finally, with protein C or S deficiency, there can be warfarin
induced skin necrosis, which means tiny thrombi can form in the blood vessels of the skin,
causing skin necrosis. This is a risk for people taking warfarin, especially in large
doses, without an overlapping rapid-onet blood thinner such as heparin or low molecular weight
heparin.
Protein C or S deficiency is suspected in people with a strong family history of coagulation
disorders, especially those who suffer from recurrent venous thromboembolisms and experience
their first thrombotic event before age fifty. Protein C or protein S deficiency is also
sometimes suspected when a venous thromboembolism develops in an unusual site like the portal,
mesenteric, or cerebral veins.
Diagnosis is made by identifying low levels of protein C and S in the serum. Since warfarin
can lower the levels of protein C and protein S, it is very important that a patient does
not take warfarin for at least 2-4 weeks prior to being tested for protein C or protein S
deficiency.
All right, as a quick recap, protein C and S deficiency refer to two separate hereditary
hypercoagulable disorders that involve the inability to inactivate factors V and VIII
in the coagulation cascade. Most people present with venous thromboembolism, where a blood
clot of the leg veins or lung circulation is most common. Initial treatment of venous
thromboembolisms is the same as it would be for patients with normal protein C and protein
S levels. However, identifying a low protein C or protein S level may, in some situations,
impact long-term decisions about anticoagulation therapy.