Clinical utility of complement biomarkers in the diagnosis and treatment of acute thrombotic microangiopathies
Year: 2014
Type: article
Study design: Case Report
Abstract: While the majority of patients clinically diagnosed with atypical haemolytic uraemic syndrome (aHUS) will respond incompletely (no recovery of renal/neurologic function) to plasma exchange (PEX), some will respond completely to a discrete course of PEX therapy (Noris et al, 2010). While the presence of severely deficient ADAMTS13 activity (<10%) confirms the diagnosis of thrombotic thrombocytopenic purpura (TTP), measurable ADAMTS13 activity in an acute thrombotic microangiopathy (TMA) patient is not specific for the diagnosis of aHUS. We propose that complement biomarkers derived from alternative and terminal complement pathway activation may confirm the clinical diagnosis of aHUS and differentiate it from forms of TMA not driven by complement dysregulation. We report three consecutive patients with an acute TMA characterized by non-deficient ADAMTS13 activity and a complete response to a discrete course of PEX therapy (Tables 1 and 2). Patient 1 was a 58-year-old male with a history of hyperlipidemia with two previous acute TMA episodes in 1980 and 2002, the first of which was treated with supportive care alone. He presented with cough, haematuria and abdominal pain, similar to his previous TMA episodes. He received 8 daily, one-plasma volume PEX procedures resulting in a complete response. He has maintained his clinical response for 17 months since his last PEX procedure. Genetic testing later revealed a mutation of CD46 (previously termed membrane cofactor protein, MCP) that was consistent with his previous acute TMA presentations. Patient 2 was a 52-year-old female with a history of hypertension, diabetes mellitus, systemic lupus erythematosus and asthma who initially presented with abdominal pain and bloody diarrhoea. She received antibiotics and was discharged, returning several days later with repeat symptoms and weakness. She was anaemic and thrombocytopenic, with schistocytes on the peripheral blood smear. Stool cultures and assays for the Shiga toxin were negative. She began daily PEX and recovered after only 3 PEX treatments and has maintained her response for 9 months from her last PEX. Genetic testing revealed a mutation of complement factor I (CFI). Patient 3, a 51-year-old female, presented with fever and cough and was diagnosed with a community-acquired pneumonia. During hospitalization she developed a progressive anaemia and thrombocytopenia and was transferred to our institution owing to concern for an acute TMA. She achieved a complete response after 6 daily PEX treatments. Genetic testing was negative for any complement protein mutations. She has maintained her remission for 24 months since her last PEX procedure. While the majority of patients with aHUS will not respond completely to PEX (Noris et al, 2010), the subset of patients that completely respond to PEX may be difficult to accurately classify based only on the response to PEX therapy, given that TTP, aHUS and other forms of TMA might all respond to PEX therapy. We recently reported that the median levels of C5b-9 and C5a (terminal complement activation) were greater than 4× and almost 2× the upper limit of normal, respectively, in 19 patients clinically diagnosed with aHUS (Cataland et al, 2014). In Patient 1, the course of chronic relapses and recovery with both supportive care and PEX would be consistent with the diagnosis of aHUS mediated by a CD46 mutation. The marked activation of biomarkers of the alternative pathway (Bb) and terminal complement activation (C5b-9 and C5a) would also be consistent with our previously reported data in aHUS patients (Cataland et al, 2014). While the presence of a mutation of a complement protein in the appropriate clinical context would confirm a diagnosis of aHUS, as in Patient 1, a documented mutation in a patient with a subacute or atypical presentation would be less useful in confirming the diagnosis, as demonstrated by Patient 2, who clearly had clinical findings consistent with an acute TMA and a CFI mutation, but the relatively mild renal injury and rapid recovery after only 3 d of PEX are not typical for an acute aHUS presentation. Furthermore, the complement biomarker studies showed, in contrast, only minimal elevation of C5b-9 and normal C5a levels at presentation. This would not be consistent with previously reported data in patients with aHUS (Cataland et al, 2014) and are inconsistent with what would be expected in a disorder mediated by complement dysregulation. In these cases, the complement biomarker studies could be viewed as markers of functional activity of the classical/lectin (C4d), alternative (Bb) or terminal complement (C5b-9 and C5a) pathways that may be more useful than mutation studies alone. This is especially true in a disease such as aHUS where the penetrance of the reported genetic mutations is incomplete (Noris et al, 2010; Loirat & Fremeaux-Bacchi, 2011). The non-deficient ADAMTS13 activity and no significant terminal complement activation (C5b-9 and C5a) in Patients 2 and 3 would argue that their presentation is not consistent with a diagnosis of aHUS that is primarily driven by complement dysregulation. We would also hypothesize that, given the essentially normal markers of terminal complement activation, these two patients would be less likely to benefit from terminal complement blocking therapy with eculizumab. While the complement biomarker studies from this acute episode in Patient 2 (with the CFI mutation) are inconsistent with the diagnosis of aHUS, it is certainly possible that she could suffer a future acute TMA episode more consistent with aHUS. Should that occur, these same biomarker studies should be conducted to help in evaluating that acute TMA episode. Measurements of C5b-9 are now increasingly available from reference laboratories and could be ordered at the same time as the ADAMTS13 activity. In patients with acquired TTP and ADAMTS13 activity <10%, increased levels of C5b-9 and C5a would identify patients who may be at greater risk of dying from their acute TMA episode (Wu et al, 2013). In patients with measureable ADAMTS13 activity, marked elevation of biomarkers of terminal complement activation (C5b-9 and C5a) would confirm the clinical diagnosis of aHUS, and a finding of normal C5b-9 and C5a would suggest an alternative aetiology of the patient's TMA. JY performed the research and wrote the manuscript; VMH analysed the data and wrote the paper, SY performed the research and edited the paper, HMW performed the research, analysed the data and wrote the paper, SRC designed the study, analysed the data and wrote the paper.
Source: British Journal of Haematology
DOI: 10.1111/bjh.13025
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2041536638