Lab Interpretation: Low protein C in adults

ALGORITHM — 

(algorithm 1)

INITIAL EVALUATION — 

Plasma protein C may be measured as part of an evaluation for inherited thrombophilia in selected patients with venous thromboembolism (VTE) and features such as a strong family history of VTE, known familial protein C deficiency, first VTE before age 50, VTE in an unusual site (eg, portal, mesenteric, or cerebral vein), or recurrent VTE. Individuals who have not had a VTE but have a known family history of protein C deficiency are also candidates for testing. Protein C deficiency should also be suspected in patients with warfarin-induced skin necrosis. (See "Protein C deficiency".)

Protein C deficiency may be inherited or acquired. In hereditary protein C deficiency, the deficient activity is due to reduced protein levels (type I) or, less commonly, to functionally defective protein C (type II). Acquired conditions that can transiently reduce protein C include disseminated intravascular coagulation (DIC), liver disease, vitamin K antagonist (VKA) anticoagulants (warfarin), meningococcal infection, and others (table 1). Acquired causes of low protein C are more common than inherited causes and should be considered prior to inferring that the protein C deficiency is hereditary. (See "Protein C deficiency", section on 'Causes of reduced protein C'.)

A variety of assay methods have been developed to measure plasma protein C activity (functional assay) or protein C antigen levels (immunoassay). The preferred initial test is a functional assay because a functional assay will detect reduced protein levels as well as functionally defective protein C (type I and type II defects).

Most patients will require repeat measurement for evaluation of protein C deficiency. Obtain hematology consultation to assist in interpretation of abnormal test results and to guide further evaluation:

●In an asymptomatic individual with a known family history of protein C deficiency, low protein C in either a functional assay or immunoassay confirms the diagnosis of hereditary protein C deficiency. Repeat testing is generally not necessary. Provide education about avoiding conditions that increase thrombotic risk (eg, estrogen-containing contraceptives, prolonged immobility) and about VTE prophylaxis. Inform other first-degree relatives about diagnosis and need for testing if not yet performed. (See "Contraception: Counseling regarding inherited thrombophilias" and "Protein C deficiency", section on 'Testing of first-degree relatives'.)

●If the patient was anticoagulated with warfarin during initial testing, repeat testing is necessary. However, if the results do not immediately impact management, repeat testing may be deferred until the patient has recovered and anticoagulation is discontinued. Warfarin (or another VKA anticoagulant) reduces functional protein C and, to a lesser extent, protein C antigen levels. (If protein C is retested and found to be normal during warfarin therapy, this effectively excludes protein C deficiency.) Heparin, direct thrombin inhibitors, direct oral factor Xa inhibitors, and fondaparinux may interfere in selected functional protein C assays (ie, those using a clotting endpoint). For patients whose testing cannot be deferred, the consulting hematologist may recommend a specific protein C assay be obtained and/or substitution of an alternative anticoagulant.

●If the patient's presentation is most consistent with acquired protein C deficiency, obtain a protein C functional assay after recovery (table 1). If this is not possible, it may be reasonable to retest the individual and base subsequent decisions on the result and how the diagnosis would impact management. In the majority of patients, normal protein C activity on retesting excludes hereditary protein C deficiency.

REFERENCE RANGE — 

In general, in the absence of conditions that interfere with protein C assays, a normal protein C is >65 to 70 percent of normal. However, heterozygous patients with protein C deficiency (proven by identification of causative mutations) have been identified in families with protein C levels over 65 percent (generally 65 to 75 percent). The absolute threshold for deficiency is unclear. In most cases, levels are <55 percent of normal, whereas levels from 55 to 65 percent are indeterminate. Interpretation of a specific result should be based upon the reference range reported by the laboratory.

CITATIONS — 

The supporting references for this content are accessible in the linked topics.