What is the pathophysiology of protein C deficiency?

Updated: Jan 04, 2019
  • Author: Shamudheen Rafiyath, MD; Chief Editor: Perumal Thiagarajan, MD  more...
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Answer

Protein C is a 62-kD, vitamin K–dependent glycoprotein synthesized in the liver. It circulates in the blood as an inactive zymogen at a concentration of 4 μg/mL. Its activation into the serine-protease-like enzyme, activated protein C (aPC), is catalyzed by thrombin when it is bound to the endothelial proteoglycan thrombomodulin. [1, 2, 3] The protein C pathway is illustrated in the image below.

The protein C pathway. APC = activated protein C; The protein C pathway. APC = activated protein C; PC = protein C; S= protein S; T = thrombin; TM = thrombomodulin; Va = factor Va; VIII = factor VIIIa.

aPC exerts its anticoagulant activity primarily through inactivation of coagulation factors Va and VIIIa, which are required for factor X activation and thrombin generation. The catalytic activity of aPC is greatly enhanced by the vitamin K–dependent cofactor protein S. [4]

Aside from its role in coagulation, aPC subserves anti-inflammatory and cytoprotective functions, which are mediated through the endothelial protein C receptor and the protease-activated receptor–1 (PAR-1). [5, 6]

A deficiency of aPC disturbs the delicate balance between procoagulant and anticoagulant proteins and engenders a prothrombotic environment. The role of aPC and other anticoagulant proteins in this balance appears to be especially important in the slow-flowing venous circulation, in which procoagulant proteins and platelet phospholipids have  prolonged exposure to the vessel wall. This may explain, in part, why protein C deficiency appears to be associated primarily with venous thrombosis.


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