What are the complement studies beyond Complement 3 (C3) and Complement 4 (C4)?

From the Guidelines

Beyond C3 and C4 complement studies, additional assessments include CH50, alternative pathway function (AP50), and specific components like C1q, C2, and C5-C9, which are crucial for diagnosing complement deficiencies or overactivation, as highlighted in the practice parameter for the diagnosis and management of primary immunodeficiency 1. When investigating suspected complement deficiencies, the following tests are valuable:

• CH50 assay (total hemolytic complement activity) to assess the classical pathway
• AH50 assay (alternative pathway hemolytic activity) to assess the alternative pathway
• Lectin pathway function to evaluate the lectin pathway
• Level or function of individual complement components, such as C1q, C2, C5-C9, factor B, and factor D, to identify specific deficiencies
• Genetic tests, including targeted gene sequencing or whole-exome/genome sequencing, to identify complement mutations, particularly in cases of familial complement disorders 1. For suspected hereditary angioedema, measuring C1 inhibitor (C1-INH) levels and function is essential 1. In cases of atypical hemolytic uremic syndrome or C3 glomerulopathy, testing for complement regulatory proteins (Factor H, Factor I) and autoantibodies (C3 nephritic factor) is recommended 1. It is crucial to order these tests in consultation with immunology or rheumatology specialists, as proper specimen handling is vital, with most complement components being heat-sensitive and requiring prompt processing of serum samples kept at 4°C 1. Interpretation of results should consider that complement levels may be affected by acute phase reactions, with some components increasing during inflammation while others decrease due to consumption in active disease processes.

From the FDA Drug Label

The FDA drug label does not answer the question.

From the Research

Complement Studies Beyond C3 and C4

The complement system consists of more than 30 proteins and has three types of activation pathways: classical, lectin, and alternative pathways 2. Beyond Complement 3 (C3) and Complement 4 (C4), other components of the complement system that have been studied include:

• C1q, C1s, C2, factor B, factor D, and properdin, which were determined in a study of 80 patients with a history of bacteremic pneumococcal infections or recurrent pneumonia 3
• CH50, which is a measure of whole complement activity, and was found to be lower in newborn infants than in adults 4
• Factor H, which is a key component of the complement system and plays a crucial role in regulating the alternative pathway 5
• Membrane cofactor protein (MCP) and factor I, which are associated with atypical hemolytic uremic syndrome 2
• C5, which is a target for therapeutic intervention, with anti-C5 monoclonal antibodies such as pexelizumab and eculizumab being used to block the final stage of complement activation 2

Complement Components and Their Roles

Some of the key complement components and their roles include:

• C3b, which is the major opsonin and essential for propagation of the complement cascade 5
• Factor H, which controls C3b molecules and prevents damage to self cells and tissues 5
• C1q, which is involved in the clearance of immune complexes and apoptotic cells, and deficiency of which is associated with autoimmune disease 2
• Properdin, which is involved in the alternative pathway and plays a role in the regulation of complement activation 3

Clinical Significance of Complement Studies

Complement studies are important in the diagnosis and management of various diseases, including:

• Immune-mediated diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis 2, 6
• Renal diseases, such as glomerulonephritis and atypical hemolytic uremic syndrome 6, 5
• Infections, such as pneumococcal infections and recurrent pneumonia 3, 4