Clinical Information

Thrombotic microangiopathy (TMA) is a pathologic condition characterized by abnormalities in the walls of small blood vessels (arterioles and capillaries) that result in microvascular thrombosis. Typically, they feature microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, but these features may not be apparent in kidney-limited disease. Laboratory findings may include anemia, thrombocytopenia, presence of schistocytes on peripheral smear, elevated lactate dehydrogenase, and elevated serum creatinine.(1,2) The main categories of TMA include complement-mediated thrombotic microangiopathy (CM-TMA; also known as atypical hemolytic syndrome [aHUS]), thrombotic thrombocytopenic purpura (TTP), Shiga toxin-mediated hemolytic uremic syndrome, and drug-induced TMA. Due to the overlapping clinical features, laboratory testing is useful in differentiated these disorders.(3)

CM-TMA (aHUS) is a well-recognized disease entity characterized by complement activation in the microvasculature. Abnormalities of the alternate pathway of complement, which may be inherited (genetic) or acquired, underlie both the sporadic and familial forms of the disease and are identified in approximately 60% of patients.(3,4) Unlike many other monogenic disorders of the immune system, multiple hits may be required for disease manifestation, which may include a trigger event (transplantation, pregnancy, malignant hypertension, autoimmune disorders, sepsis, malignancy, etc) and one or more contributing genetic variants or risk haplotypes in the alternate pathway complement genes.(3) Individuals with genetic CM-TMA (aHUS) may experience relapse even after complete recovery following the presenting episode.

TTP is a rare clinical entity but is important to diagnose properly since it is associated with very high mortality (90%) if untreated. Mortality can be reduced by early plasma exchange. Congenital TTP is due to genetic defects in the ADAMTS13 gene, while acquired TTP is related to autoantibodies against ADAMTS13, which reduces function. While TTP was initially characterized by thrombocytopenia, MAHA, fluctuating neurological signs, kidney failure and fever, not all of these features may be present in the manifestation of the disease.(1,2)

The hereditary form of CM-TMA is characterized by the presence of disease-causing variants in one or more of the genes known to be associated with aHUS, irrespective of familial history, or when two or more members of the same family are affected by the disease at least 6 months apart and exposure to a common triggering infectious agent has been excluded.(3) A patient may have both genetic variants in the alternative complement pathway and autoantibodies. While genetic testing may be used during the diagnostic work-up, the presence of disease-causing variants may also alter recurrence risk and impact decisions related to continuation of anti-complement therapy after resolution of symptoms.

Complement 3 glomerulopathies (C3G) include dense deposit disease and C3 glomerulonephritis and are characterized by C3 deposition within the glomeruli. In these disorders, the activity of the C3 convertase is increased by C3 nephritic factors, which are antibodies that stabilize the convertase, or loss of complement regulator activity, which may be due to genetic variants, autoantibodies, or other immunoglobulins. C3G may be preceded by an upper respiratory tract infection in some cases. Patients typically have proteinuria or hematuria and may present with variable kidney impairment. In addition to medical therapy, patients may be treated with kidney transplantation; however, disease recurrence and graft loss may occur.

It is important to note that while TMA and C3G are associated with complement dysregulation, disease-causing variants in these genes may also result in complement deficiency, which is associated with recurrent infections with encapsulated pathogens or connective tissue diseases with no evidence of aHUS/TMA.(5)

Two risk alleles associated with increased susceptibility to aHUS/TMA and variants in C5 associated with poor response to anticomplement therapy are also included on this panel to aid in risk assessment:

-CFH-H3 Risk Haplotype: The variants that comprise this risk haplotype are common in the general population, but in the context of additional pathogenic genetic and environmental factors, the presence of this risk haplotype is associated with an increased risk for development or progression of atypical hemolytic uremic syndrome. (6)

-MCP/CD46 Risk Haplotype: The variants that comprise this risk haplotype are common in the general population, but in the context of additional pathogenic genetic and environmental factors, the presence of this risk haplotype is associated with an increased risk for development or progression of atypical hemolytic uremic syndrome.6)

-C5 Genotype: Two variants, p.Arg885His and p.Arg885Cys, have been associated with poor response to eculizumab.(7)