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Differentiating congenital Type I protein C deficiency from Type II deficiency
Evaluating the significance of decreased functional protein C, especially when decreased protein C activity might be congenital rather than acquired (eg, due to oral anticoagulant effect, vitamin K deficiency, liver disease, or intravascular coagulation and fibrinolysis/disseminated intravascular coagulation)
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.
The 2 types of hereditary heterozygous protein C deficiencies that are recognized are:
-Type I (concordantly decreased protein C function and antigen)
-Type II (decreased protein C function with normal antigen)
Acquired deficiency 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)
Normal, full-term newborn infants or healthy premature infants may have decreased levels of protein C antigen (15%-50%), which may not reach adult levels until later in childhood or early adolescence.*
*See Pediatric Hemostasis References in Coagulations Studies in Special Instructions.
Values <70% to 75% may represent a congenital deficiency state, if acquired deficiencies can be excluded.
Protein C antigen and activities generally are undetectable in individuals with severe, homozygous protein C deficiency.
Acquired protein C deficiency is of uncertain clinical hemostatic significance.
Clinical significance of increased protein C is unknown.
Assay of protein C functional activity (CFX / Protein C Activity, Plasma) is recommended for initial laboratory evaluation of patients suspected of having congenital protein C deficiency (personal or family history of thrombotic diathesis).
Not useful for predicting a thrombotic event.
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 Haemeostasis. J Pediatr 1989;114:528-534
4. Miletrich 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