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Protein C is a vitamin K-dependent anticoagulant proenzyme. It is synthesized in the liver and circulates in the plasma. The biological half-life of plasma protein C is approximately 6 to 10 hours, similar to the relatively short half-life of coagulation factor VII.
Protein C is activated by thrombin, in the presence of an endothelial cell cofactor (thrombomodulin), to form the active enzyme activated protein C (APC). APC functions as an anticoagulant by proteolytically inactivating the activated forms of coagulation factors V and VIII (factors Va and VIIIa). APC also enhances fibrinolysis by inactivating plasminogen activator inhibitor (PAI-1).
Expression of the anticoagulant activity of APC is enhanced by a cofactor, protein S, another vitamin K-dependent plasma protein.
Congenital homozygous protein C deficiency results in a severe thrombotic diathesis, evident in the neonatal period and resembling purpura fulminans.
Congenital heterozygous protein C deficiency may predispose to thrombotic events, primarily venous thromboembolism; arterial thrombosis (stroke, myocardial infarction, etc.) may occur. Some individuals with hereditary heterozygous protein C deficiency may have no personal or family history of thrombosis and may or may not be at increased risk. Congenital heterozygous protein C may predispose to development of coumarin-associated skin necrosis. Skin necrosis has occurred during the initiation of oral anticoagulant therapy.
Two types of hereditary heterozygous protein C deficiency are recognized:
-Type I (concordantly decreased protein C function and antigen)
-Type II (decreased protein C function with normal antigen level)
Acquired deficiencies of protein C may occur in association with:
-Vitamin K deficiency
-Oral anticoagulation with coumarin compounds
-Intravascular coagulation and fibrinolysis/disseminated intravascular coagulation (ICF/DIC)
The clinical hemostatic significance of acquired protein C deficiency is uncertain.
Assay of protein C functional activity is recommended for the initial laboratory evaluation of patients suspected of having congenital protein C deficiency (personal or family history of thrombotic diathesis), rather than assay of protein C antigen (PCAG / Protein C Antigen, Plasma).
As an initial test for evaluating patients suspected of having congenital protein C deficiency, including those with personal or family histories of thrombotic events
Because coagulation testing and its interpretation is complex, Mayo Medical Laboratories suggests ordering THRMP / Thrombophilia Profile.
Detecting and confirming congenital Type I and Type II protein C deficiencies, detecting and confirming congenital homozygous protein C deficiency, and identifying decreased functional protein C of acquired origin (eg, due to oral anticoagulant effect, vitamin K deficiency, liver disease, intravascular coagulation and fibrinolysis/disseminated intravascular coagulation.)
Values <60% to 70% may represent a congenital deficiency state, if acquired deficiencies can be excluded.
Protein C activity (and antigen) is generally undetectable in individuals with severe, homozygous protein C deficiency.
Oral anticoagulant therapy (warfarin, Coumadin) decreases protein C activity, compromising the ability to distinguish between congenital and acquired protein C deficiency. Concomitant measurement of the activity of coagulation factor VII (or factor X) may aid in differentiating congenital deficiency state from acquired protein C deficiency due to oral anticoagulant effect, but the ratio of the activities of protein C:factor VII (or factor X) has not been demonstrated to provide certainty about this distinction.
The clinical significance of acquired protein C deficiency and of increased protein C is unknown.
Protein C Activity result may be affected by:
-Heparin (Unfractionated) >4 U/mL
-Heparin (low-molecular-weight) >2 U/mL
-Hemoglobin >500 mg/dL
-Bilirubin >21 mg/dL
-Triglycerides >890 mg/dL
Heparin therapy may temporarily decrease plasma protein C activity into the abnormal range.
Lipemia may interfere with functional protein C assay. Blood specimens for protein C functional assay should be drawn in the fasting state, if possible.
Protein C functional assay using a venom activator and a chromogenic peptide substrate has the potential of not detecting certain congenital protein C variants that might be detectable using clot-based assay of protein C function.
Normal, full-term newborn infants or healthy premature infants may have decreased levels of protein C activity (15%-50%), which may not reach adult levels until later in childhood or early adolescence.*
*See Pediatric Hemostasis References in Coagulation Studies in Special Instructions.
1. Mannucci PM, Owen WG: Basic and clinical aspects of proteins C and S. In Haemostasis and Thrombosis. Second edition. Edited by AL Bloom, DP Thomas. Edinburgh, Churchill Livingstone, 1987, pp 452-464
2. Marlar RA, Mastovich S: Hereditary protein C deficiency: a review of the genetics, clinical presentation, diagnosis and treatment. Blood Coagul Fibrinolysis 1990;1:319-330
3. Marlar RA, Montgomery RR, Broekmans AW: Diagnosis and treatment of homozygous protein C deficiency. Report of the Working Party on Homozygous Protein C Deficiency of the Subcommittee on Protein C and Protein S, International Committee on Thrombosis and Haemostasis. J Pediatr 1989;114:528-534
4. Miletich J, Sherman L, Broze G Jr: Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987;317:991-996
5. Pabinger I, Allaart CF, Hermans J, et al: Hereditary protein C-deficiency: laboratory values in transmitters and guidelines for the diagnostic procedure. Report on a study of the SSC Subcommittee on Protein C and Protein S. Protein C Transmitter Study Group. Thromb Haemost 1992;68:470-474