Protein C and S deficiency – causes, symptoms, diagnosis, treatment, pathology

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