C3 Level (Nephelometry)
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The complement system can be activated via three reaction pathways: the classical pathway, which is triggered primarily by cell-bound immune complexes; the mannan-binding lectin pathway, which is triggered by specific carbohydrate groups on microorganisms; and the alternative pathway, which is activated constitutively on all cell surfaces especially microorganisms. The complement component C3 is a key protein in all three reaction pathways, and complement activation is associated with consumption of C3 and a reduction in serum concentration. Diminished serum concentrations of C3 is observed through activation of the alternative pathway, and may be seen in atypical hemolytic uremic syndrome (aHUS) and forms of membranoproliferative glomerulonephritis (MPGN). Diminished serum concentrations of C3 is also observed through activation of the classical pathway (typically in combination with diminished serum levels of complement component C4) in active systemic lupus erythematosus (SLE), in some forms of membranoproliferative glomerulonephritis and in other immune complex diseases.
C3 Gene Sequencing
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C3a
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Activation of the classical, alternative or lectin complement pathways results in the formation of a C3 convertase multimolecular enzyme capable of cleaving C3 to C3a and C3b. C3a has been shown to increase vascular permeability, to be spasmogenic and chemotactic, and to induce the release of pharmacologically active mediators from a number of cell types.
C4 Level (Nephelometry)
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Diminished serum concentrations of C4 is observed primarily in activation of the classical pathway by immune complexes such as in active systemic lupus erythematosus (SLE), in forms of membranoproliferative glomerulonephritis (MPGN), and in other immune complex diseases (e.g. “shunt nephritis” and serum sickness), and is useful in distinguishing systemic activation of the classical pathway versus activation of the alternative complement pathway as seen in atypical hemolytic uremic syndrome (aHUS) and dense deposit disease/MPGN type II.
C5a
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Activation of the classical, alternative, or lectin complement pathways results in the formation of a C5 convertase multimolecular enzyme capable of cleaving C5 to C5a and C5b. C5a has a host of biologic functions including mast cell degranulation, chemotaxis, leukosequestration, as well as cellular activation via binding to the C5a receptor.
CD46 (MCP) Gene Sequencing
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CD46 / Membrane Cofactor Protein (MCP) Expression
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Atypical hemolytic uremic syndrome (aHUS) is associated with defects in the regulation of the alternative complement pathway and results in microvascular injury. Evaluation of the membrane-bound complement proteins – or Membrane Cofactor Protein (MCP) – can be evaluated by testing the CD46 expression on white blood cells (WBC) using flow cytometry. CD46 is normally expressed on all WBC lineages. Mutations of the MCP gene are associated with aHUS and may lead to decreased CD46 expression on the surface of cells including WBCs.
CFB Gene Sequencing
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CFH Gene Sequencing
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CFHR1 Gene Sequencing
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CFHR3 Gene Sequencing
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CFHR3-CFHR1 Deletion Analysis
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CFHR5 Gene Sequencing
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CFI Gene Sequencing
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CH50 (Hemolytic Method)
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The traditional method for determination of functional complement activity is the total hemolytic (CH50) assay. This assay measures the ability of the test sample to lyse a standardized suspension of sheep erythrocytes coated with anti-sheep antibody. Activation of both the classical and terminal complement pathways are measured in this reaction. A normal CH50 result is dependent on the presence and functionality of both classical pathway (C1q, C4, C2, C3) and terminal (C5, C6, C7, C8, and C9) complement components, and is abnormally low if any component is defective.
More recently, this test has become highly useful to monitor patients with either atypical hemolytic uremic syndrome (aHUS) or other forms of thrombotic microangiopathy (TMA) being treated with eculizumab, a monoclonal antibody directed against C5. Adequate dosage and dosing interval of eculizumab should result in a total blockade of activation of the terminal complement pathway, and a patient’s CH50 should be at or near 0 as a result. If a patient is not being adequately dosed with eculizumab, breakthrough activation of the complement system and subsequently disease reactivation may occur.