Congenital or acquired control of the clotting
mechanism resulting in a widespread thrombotic tendency. Protein C is a
vitamin K-dependent serine protease zymogen that selectively inhibits
factors Va and VIII:C in human plasma, and thus has an important
anticoagulant role. It is associated with an increased tendency to
thrombosis. It is either inherited or acquired: bacterial sepsis (especially
of meningococcal origin), hepatic disease, disseminated intravascular
coagulation, l-asparaginase therapy, nephrotic syndrome, conditioning
therapy in bone marrow transplantation, warfarin-induced skin lesions.
Congenital Thrombotic Protein C Deficiency; Hereditary
Thrombophilia; PC Deficiency; ProC Deficiency.
The addition of Protein C deficiency in the list of
thrombotic diseases was suggested by J.H. Griffin in 1981.
Inherited forms: 1:200 to 1:300 for heterozygotes;
1:200,000 for homozygotes.
Autosomal dominant trait with variable
expressivity. Gene map locus: 2q13-q14.
Inherited thrombophilia has been associated with
abnormalities of antithrombin III, fibrinogen, and plasminogen. Protein C is
a vitamin K-dependent serine protease anticoagulant factor. It has several
roles: (a) it is converted on site and on demand during the coagulation
activation into activated protein C; its anticoagulant activity is related
to inactivation of factors Va and VIIIa; the presence of protein S as a
nonenzymatic cofactor is necessary for those reactions; (b) it promotes
fibrinolysis by binding plasminogen activator inhibitor I; (c) it prevents
the proinflammatory consequences of local thrombin formation, for example,
release of vasoactive proinflammatory factors (tumor necrosis factor
(TNF)-α, interleukin (IL)-1β, etc.), and an increase of
endothelial permeability. Consequently, a deficiency in protein C results in
defective control of the clotting mechanism with a widespread thrombotic
tendency. Heterozygotes show an increased thrombotic tendency, whereas
homozygotes present with severe thrombotic sequelae in the neonatal period.
Most cases of protein C deficiency have had a quantitative defect in the
protein C molecule. Protein C deficiency with a mutation that causes
diminished synthesis of protein has been referred to as type I and that with
synthesis of a dysfunctional molecule as type II.
Positive family history and a significant history of
thrombosis or gangrene (skin, retinal, etc.). Severe symptoms typically
develop when the serum protein C level is below 20 to 25% of normal (4
μg/mL). Specific laboratory tests and assays are needed to exclude
other causes of disseminated intravascular coagulation.
Heterozygotes for Protein C Deficiency (serum concentrations 40 to 60% of normal) usually presents in
adolescence with recurrent thrombophlebitis, deep venous thrombosis, and
pulmonary thromboembolism. There is also an increased risk of thrombotic
renal and cerebral disease and an increased risk of myocardial infarction.
Homozygotes manifest fatal thromboses in the neonatal period—massive subcutaneous thrombosis (neonatal
purpura fulminans) with cutaneous necrosis, gangrene, and widespread venous thrombosis, which usually starts
in the first 24 hours of life. Severe bilateral vitreous hemorrhages,
gangrene, and widespread venous thrombosis have been reported. Bilateral
adrenal hemorrhage may lead to abdominal pain, hypotension, and
hyponatremia. Hypertension and ...