New Diagnostic Algorithm for Rare Blood Disorder Threatening Kidneys and Organs

Complement-mediated thrombotic microangiopathy (C-TMA), formally known as atypical hemolytic uremic syndrome (aHUS), is a rare but severe disease in which dysregulation of the complement immune system causes widespread damage to small blood vessels. This results in the classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and end-organ injury — most critically acute kidney injury. Despite significant advances in understanding its molecular pathophysiology and the availability of highly effective complement inhibitors like eculizumab and ravulizumab, diagnosis remains a major clinical challenge because no single definitive diagnostic test exists.

This 2025 educational review by Michael Arthur Cole from Johns Hopkins University, published in Hematology: the American Society of Hematology Education Program, provides a comprehensive update on the diagnostic landscape for C-TMA. The central framework is a systematic diagnostic algorithm designed to guide clinicians through the stepwise evaluation of suspected TMA cases. The first and most urgent step is rapid exclusion of thrombotic thrombocytopenic purpura (TTP) — using ADAMTS13 activity levels — and Shiga toxin-producing Escherichia coli HUS (STEC-HUS), since both require fundamentally different management and can mimic C-TMA closely. An ADAMTS13 activity below 10% confirms TTP, while positive stool cultures or Shiga toxin testing points to STEC-HUS.

Once TTP and STEC-HUS are excluded, the algorithm directs clinicians to carefully evaluate for secondary causes of TMA, which are far more common than primary C-TMA and can include pregnancy-related TMAs (such as preeclampsia/HELLP syndrome), malignant hypertension, drug-induced TMA, transplant-associated TMA, and systemic infections or autoimmune diseases. These secondary triggers can themselves activate complement, making it essential to determine whether complement dysregulation is primary (genetic or autoimmune) or a downstream consequence of another condition — as this distinction profoundly affects treatment decisions.

A major focus of the review is the emerging role of functional complement assays as adjunctive diagnostic tools. The modified Ham assay tests whether a patient's serum can lyse complement-sensitized red blood cells, providing a functional readout of complement overactivation. The HMEC-1 C5b-9 deposition assay measures terminal complement complex deposition on human microvascular endothelial cells — the very cells targeted in C-TMA — offering a more pathophysiologically relevant functional test. Unlike standard complement biomarkers (C3, C4, CH50) which are often normal in C-TMA, these functional assays can directly demonstrate complement hyperactivity even when genetic testing is unrevealing. The review highlights that up to 30–50% of C-TMA patients have no identifiable pathogenic variant on genetic panel testing, making these functional assays potentially critical for diagnosis in genetically unresolved cases.

The review also discusses the expanding panel of complement genetic testing, which now includes pathogenic variants in CFH, CFI, CD46/MCP, CFB, C3, THBD, and others, as well as anti-CFH autoantibodies. However, the presence of a variant does not confirm active disease, and its absence does not exclude it. The author argues for integrating genetic data with clinical context and functional assay results to reach a probabilistic diagnosis. The practical implication is clear: in a patient with TMA whose other causes have been excluded, combining genetic testing with functional complement assays provides the strongest diagnostic framework, enabling timely initiation of complement inhibitor therapy and potentially preventing irreversible kidney damage or death.