Disorders of Complement

• Functions of Complement

  Host defense

  Clearance of immune complexes

  Disposal of apoptotic debris

  Regulation of immune response
• 3 Main Complement Pathways: 1) Alternative 2) Classical 3) Lectin
• Deficiencies of the early classical pathway result in immune complex disease (SLE)
• Deficiencies of the alternative pathway components result in pyogenic infections
• Deficiencies of the terminal pathway components (C5, C6, C7, C8, C9) - MAC components, results in increased susceptibility to Neisserial infections
• CH50 lab test tests all complement components: C1-C9
• Routine lab tests can provide a direct measurement of C3 and C4
• Complement attack requires multiple steps under tight control by plasma proteins
• Complement attack of bystander host cells is prevented by inhibitory membrane-bound proteins on host cells
• Complement Regulatory Proteins in Plasma

  C1 inhibitor (C1 INH)

  Factor I

  Factor H
• Membrane-Bound Complement Regulatory Proteins

  Decay Acceleration Factor (DAF, CD55)

  CD59

  Membrane Cofactor Protein (CD46)
• Deficiency of C1 inhibitor manifests as hereditary angioedema
• Deficiency of CD55 or CD59 inhibitors manifests as Paroxysmal Noctural Hemoglobinuria (PNH)
• Deficiency of Factor H or Factor I manifests as complement-medicated aHUS
• Deficiency of MCP (CD46) manifests as age-related macular degeneration
• Hereditary angioedema presents as recurrent episodes of angioedema with no hives or itching. Onset is associated with mild trauma or allergen.
• In hereditary angioedema, C1 inhibitor deficiency leads to overproduction of bradykinin which is a potent vasodilator
• Hereditary angioedema can be diagnosed with recurrent episodes of angioedema, family history, decreased serum C4 and measurement of C1 inhibitor protein and function
• Hereditary Angioedema can be treated with fresh frozen plasma, C1 inhibitor concentrate or recombinant C1 inhibitor
• Thrombotic microangiopathies are a group of disorders that cause thrombotic microangiopathy. They are mediated by endothelial cell injury and platelet activation. Clinical findings include microangiopathic hemolytic anemia, decreased platelets and acute renal failure.
• Primary Causes of Thrombotic Microangiopathies

  Shiga-toxin mediated HUS

  Atypical HUS (complement-mediated)

  Thrombotic thrombocytopenic purpura

  Drug-mediated TMAs
• Secondary Causes of Thrombotic Microangiopathies

  Scleroderma

  SLE/antiphospholipid antibody

  Malignant HTN

  Pregnancy

  Transplant rejection
• Complement Medicated HUS (aHUS) is caused by acquired or hereditary abnormalities of factors that reduce activation of complement by the alternative pathway
• Complement-Mediated TMA is caused by uncontrolled activation of the alternative pathway due to decreased activity of regulatory protein (factor H, factor I, CD46) or increased activity of C3 or factor B
• Complement-mediated HUS can be treated with eculizumab which prevents cleavage of C5
• Paroxysmal Nocturnal Hemoglobinuria is caused by mutations in the phosphatidylinositol glycan complementation group a gene (PIGA)
• CD55 (DAF) and CD59 (inhibitor of MAC) use PIGA to attach to the RBC surface
• 5-10% of cases of PNH can develop myelodysplastic syndrome or acute myelogenous leukemia
• PNH treatment includes anticoagulation and complement inhibition with eculizumab
• Age-related macular degeneration can be classified as dry or wet
• Age-related macular degeneration is caused by aging (10%), smoking, mutation ATP synthase gene, and mutations in Factor H gene
• Age-related macular degeneration results in increased inflammation and reactive oxygen species
• Age-related macular degeneration can be treated with nutritional supplements and potentially complement inhibition
• Before treating a patient with eculizumab, give the meningococcal vaccine
• In patients with PNH, thrombosis is the leading cause of disease related death. Particularly portal and hepatic vein thrombosis.