Complement testing in angioedema and hemolytic anemia

In unexplained angioedema it is important to consider C1-inhibitor (C1-INH) deficiency. Deficiency of C1-INH deficiency can be genetically determined that is hereditary or acquired.

Hereditary angioedema (HAE) is caused by a mutation in the serping1 gene coding for C1-INH. The mutation affects one of the C1-INH genes implying that HAE is a heterozygous disease with dominant inheritance (homozygous cases are very rare, reported in two families).Two forms of HAE are distinguished; type I (about 85% of cases) there the mutated gene give rise to no protein and type II there the mutation results in production of a dysfunctional protein. A large number of different mutations have been reported. In both types there is one normal gene which results in synthesis of C1-INH (ref 1). A new form of HAE with normal C1INH was first described in 2000 and is sometimes referred to as HAE type III (ref 2).

Acquired angioedema (AAE) due to C1-INH deficiency occur typically in patients with lymphoproliferative disease. In some cases antibodies against C1-INH are found.

In both HAE and AAE an increased activation of mainly the classical pathway is seen which generally results in a low C4 level. Analysis of complement including functional assays gives the diagnose C1-INH-deficiency. Results should be confirmed in a second sample.

Examples of typical test results in patients

Analysis HAE type I HAE type II AAE
Classical pathway function Low Low    Low
Alternative pathway function Normal Normal Normal
C1-INH Low* Normal Low**
C1-INH function Low Low Low – Normal**
C1q Normal Normal Low
C4 Low Low Low – Normal**
C3 Normal Normal Normal
Anti-C1-INH antibodies Not measured Not measured Positive/Negative

*Usually <30% of the normal (immunochemical method).  

**The reduction from normal varies. 


Genetic analysis in HAE is of value mostly in small children from affected families and in unclear cases to distinguish between HAE and AAE. There is no clear relation between the clinical symptoms and the type of mutation.

In immune hemolytic anemia analysis of complement in serum may reveal increased activation of the classical pathway. This may be seen as reduced functional activity and the increased consumption may give rise to a reduced C4 level.

In cases with hemolytic anemia when paroxysmal nocturnal hemoglobulinuria (PNH) is suspected the blood cells are analysed (ref 3). Presences of various lipid-anchored proteins including complement regulatory proteins decay accelerating factor (DAF, CD55) and protectin (CD59) are now analysed by flow cytometry, which have replaced earlier tests based on the fragility of the red blood cell membranes. Since PNH is a clonal disorder a fraction of the cells lack these proteins on their surface.


Page References

1. Bowen T, Cicardi M, Farkas H et al. 2010 International consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010 6:24. doi: 10.1186/1710-1492-6-24.

2.  Zuraw BL, Bork K, Binkley KE et al. Hereditary angioedema with normal C1 inhibitor function: consensus of an international expert panel. Allergy Asthma Proc. 2012 Nov-Dec;33 Suppl 1:S145-56. doi: 10.2500/aap.2012.33.3627.

3.  Madkaikar M, Gupta M, Jijina F, Ghosh K. Paroxysmal nocturnal haemoglobinuria: diagnostic tests, advantages, & limitations. Eur J Haematol. 2009 83:503-11, 2009.


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