Case studies and expert opinion on the management of complement-mediated and secondary thrombotic microangiopathy in Singapore

ABSTRACT

Complement-mediated thrombotic microangiopathy (C-TMA), previously referred to as atypical haemolytic uraemic syndrome, is a rare cause of thrombotic microangiopathy (TMA). Secondary TMAs are heterogeneous conditions associated with established triggers (e.g. drugs, infection, pregnancy), some of which may be driven by complement activation. Differentiating between C-TMA and secondary TMA can be difficult, as there may be considerable overlap between the conditions. The authors describe 3 cases of TMA potentially involving complement activation as examples of a multidisciplinary approach to diagnosis and management in Singapore. Complement component 5 (C5) inhibition is central to the treatment of C-TMA, but lack of access to therapy remains a major challenge in the region, as illustrated by Case 1 (probable C-TMA). Case 2 (gemcitabine-associated TMA) and Case 3 (lupus nephritis-associated TMA) explore the emerging role of C5 inhibitors in secondary TMAs. Short-duration C5 inhibitor treatment is feasible for some patients without pathogenic gene variants but should be undertaken only with appropriate monitoring.

Complement-mediated thrombotic microangiopathy (C-TMA)—also known as atypical haemolytic uraemic syndrome¹—refers to the primary form of the syndrome, which arises from genetic abnormalities that result in uncontrolled complement pathway activation.^2,3 C-TMA is a rare cause of TMA and has a varied clinical presentation. The diagnosis is one of exclusion, made after ruling out other causes of TMA, particularly immune thrombotic thrombocytopenic purpura (iTTP) and Shiga toxin-producing Escherichia coli haemolytic-uraemic syndrome (STEC-HUS).² Secondary TMAs are heterogeneous conditions associated with established and clear triggers (e.g. drugs, infection, pregnancy).¹ Complement activation has been implicated in some cases of secondary TMA, with a multi-hit process resulting in TMA.^4,5

Available guidance regards early recognition and prompt treatment of primary C-TMA with complement component 5 (C5) inhibitors as being vital to limiting adverse outcomes, such as end-stage kidney disease (ESKD).^4,6-10 C5 inhibitor therapy may also benefit cases of secondary TMA that have not responded to conventional therapy and may have an element of complement activation.^4,5

Although international guidelines provide general recommendations for the diagnosis and management of C-TMA,^9-12 no Singapore-specific guidance exists. The challenges in Singapore include the rarity of cases, limited physician experience with the condition, restricted availability of specialised investigations, and the high cost of C5 inhibitors. These factors complicate the management of C-TMA and complement-associated secondary TMA.

This article uses illustrative case studies from Singapore to explore the recognition, diagnosis, and management of patients with probable C-TMA (Case 1), gemcitabine-associated TMA (Case 2), and lupus nephritis (LN)-associated TMA (Case 3). The aim is to equip clinicians with practical insights to support early diagnosis, guide appropriate therapy, and optimise outcomes despite practice limitations in Singapore.

Patient case studies

Case 1: Probable C-TMA

A 53-year-old woman presented with generalised tonic-clonic seizures and oliguric acute kidney injury (AKI), following an acute respiratory tract infection and fever. On admission, she had a normal coagulation screen but elevated lactate dehydrogenase (LDH), thrombocytopenia, schistocytes, and low C3 (Table 1). As her ADAMTS13 activity of 23% (i.e. not <10%) was inconsistent with iTTP,¹³ a diagnosis of TMA precipitated by sepsis, or C-TMA, was considered instead. Kidney biopsy showed chronic TMA. A C-TMA genetic panel was negative for pathogenic variants.

Table 1. Clinical features, investigations, treatments, and outcomes of cases of C-TMA and secondary TMA with presumed complement activation.^a

Because of funding limitations for C5 inhibitors, initial treatment was plasma exchange (PLEX), pulsed methylprednisolone, rituximab, and dialysis. Anti-factor H antibodies were not tested, as PLEX and rituximab had been started (which can interfere with the result). Her initial response to PLEX was good, and she was weaned off dialysis 1 month later. Over the next 8 months, PLEX was tapered to once a week. Two months later, she had a relapse of TMA and AKI requiring reinitiation of dialysis. Despite re-intensification of PLEX, kidney function could not be salvaged.

A cost analysis indicated that 6 months of eculizumab, which would provide a 2-year relapse rate of <5%,¹⁴ would cost less than SGD200,000 compared with annual, lifelong costs of SGD210,000–355,000 for PLEX with fresh frozen plasma (FFP) and haemodialysis for patients who developed ESKD.

Funding for eculizumab was secured, and the patient received treatment for a total of 9 months. Her platelet count normalised within a month, and her haemoglobin stabilised. She had no further recurrence of C-TMA at 3-year follow-up after starting eculizumab.

The final diagnosis was probable C-TMA despite a negative genetic panel. The initial episode was triggered by sepsis, but no clear trigger was identified at the time of relapse. The unprovoked relapse and low C3 were suggestive of underlying complement dysregulation.

Case 2: Gemcitabine-associated TMA

A 54-year-old woman presented with TMA 14 days after receiving 6 cycles of adjuvant chemotherapy (capecitabine and gemcitabine) for pancreatic adenocarcinoma. Laboratory results showed microangiopathic haemolytic anaemia (MAHA), mild thrombocytopenia, and AKI (Table 1). Chemotherapy had been administered on day 15 of cycle 6, as TMA onset was not yet recognised. The cumulative dose of gemcitabine was 12,400 mg/m², with TMA onset 162 days after first exposure. Following haematology consultation, gemcitabine was discontinued and the patient received a 4-week trial of corticosteroids, without significant improvement.

Two months later, she presented with mixed nephritic–nephrotic syndrome and worsening MAHA and thrombocytopenia. ADAMTS13 activity was 86%. There was no evidence of autoimmune disease or recurrence of malignancy. Genetic testing indicated a non-pathogenic heterozygous deletion of CFHR3-CFHR1 (multiplex probe, University of Iowa). As there was a clear drug cause for TMA and this CFHR3-CFHR1 deletion is a common copy number variation seen in the general population,¹⁵ anti-factor H antibodies were not tested.

Gemcitabine-associated TMA was clinically suspected. As short-duration eculizumab can be appropriate in such patients,^16-20 she was treated with 6 doses of eculizumab. TMA resolved, and there was partial recovery from AKI within 4 weeks (Supplementary Fig. S1), suggesting that complement activation was a contributing mechanism to the TMA. A later rise in creatinine, attributed to overdiuresis, gradually improved. Ten months later, she remained in cancer remission with no recurrence of TMA.

Case 3: LN-associated (secondary) TMA

A 16-year-old girl presented at a centre outside Singapore with pallor and generalised oedema, anaemia, thrombocytopenia, and AKI (Table 1). Following investigation, she was diagnosed with systemic lupus erythematosus (SLE) with LN, and received methylprednisolone, mycophenolate mofetil, and cyclophosphamide.

The patient was transferred to Singapore 1 month after initial presentation. Her creatinine level had increased further, and she had progressive thrombocytopenia associated with elevated LDH and MAHA on blood film (Table 1). Her ADAMTS13 activity level was 31%. The diagnosis was LN with rapidly progressive glomerulonephritis (RPGN) and LN-associated TMA.

Treatment for proliferative LN and RPGN continued. PLEX was started for LN-associated TMA but produced no early improvement, and the patient continued to have high transfusion requirements. Based on the literature^21-23 and local experience, the prognosis was considered poor, warranting more aggressive therapy. Given that complement is implicated in the pathogenesis of LN, and eculizumab can be beneficial in some cases of LN-associated TMA,^24-26 eculizumab was initiated.

A gradual response was observed for both LN and TMA (Supplementary Fig. S1). In total, she received 7 cycles of pulse intravenous methylprednisolone, 10 sessions of PLEX with FFP as replacement fluid, 7 doses of eculizumab, and an infusion of FFP (without PLEX) before the fourth eculizumab dose. One month after starting eculizumab, she no longer required transfusions and her condition had improved enough for her to be discharged home, suggesting that complement activation was a contributing mechanism to the TMA. Five months later, SLE was in remission, and RPGN and MAHA had resolved.

DISCUSSION

Prompt management of C-TMA and secondary TMA with presumed complement activation is important to prevent complications.^7,10,11,27 In Singapore, where such cases are rare, physicians need to be aware of the different causes of TMA and their underlying triggers, as early diagnosis and treatment are essential to prevent kidney function deterioration.

Given the heterogeneous clinical manifestations of C-TMA, the possible presence of associated conditions, and the occurrence of complement activation in some cases of secondary TMA, diagnosis and management require a multidisciplinary approach.⁶ Not all tests/assays relevant to C-TMA are available in Singapore. ADAMTS13 activity testing (to rule out iTTP) is performed centrally at a reference laboratory in Singapore using fluorescence resonance energy transfer–VWF73 and enzyme-linked immunosorbent assay methodologies.²⁸ STEC-HUS can be ruled out based on clinical and microbiological findings. However, functional testing of complement activities and screening of pathological complement gene variants are not available in Singapore. Where genetic testing was deemed necessary in the example cases, samples were sent to laboratories in the US (Mayo Clinic in Case 1, Invitae and University of Iowa in Case 2). Heterogeneity exists between centres because of the rarity of cases and absence of a standardised pathway. The time required to obtain genetic test results, or the absence of pathogenic gene variants, should not preclude making a clinical diagnosis of C-TMA and prompt treatment initiation.

C5 inhibitors are the cornerstone of C-TMA treatment.^6-8,29,30 Eculizumab and ravulizumab are both approved for use in Singapore.^31,32 Early initiation of C5 inhibitor treatment can help prevent progression to ESKD.^7,27 In addition, without specific treatment of C-TMA, the risk of TMA recurrence is high (Case 1).⁴ As C5 blockade increases the risk of infections, patients should receive meningococcal vaccination before treatment starts and prophylactic antibiotics during C5 inhibitor treatment.^4,29

Since April 2026, eculizumab has been included in the Medication Assistance Fund in Singapore, allowing MediSave, the national medical savings scheme, to be used for payment.³¹ This further reduces patients’ out-of-pocket payments. Case 1 highlights that, in appropriate patients, eculizumab is cost-saving in the long run compared with a lifetime of dialysis and PLEX.

Case 1 also illustrates the clinical consequences of a funding-related treatment delay. Treatment duration for C5 inhibitors should be considered on a case-by-case basis and guided by genetic testing results if available. Although long-term eculizumab may be required in patients with pathogenic variations, it can be discontinued safely after a short duration of treatment in patients with C-TMA without pathogenic variants (Case 1), although with certain caveats.^14,33 A study assessing eculizumab discontinuation after achieving remission reported an overall relapse rate of 23% (13/55 patients), which was highest (50%) in patients carrying rare complement gene variants and lowest (4%) in those without a variant.¹⁴ Investigators implemented structured monitoring after treatment cessation, and eculizumab was resumed within 7 days of relapse in all but 1 case. If eculizumab discontinuation is considered in a routine practice setting, the patient should be monitored closely, and early restart of treatment must be guaranteed in the event of relapse. Data from France and the US indicate that prompt initiation of eculizumab and a genetics-based discontinuation strategy can reduce overall healthcare costs.^14,34

PLEX may be used in patients with TMA until iTTP has been ruled out, in patients with factor H antibodies, or when C5 inhibitors are not available.^6,9 However, PLEX is not a preferred long-term solution and is associated with eventual renal deterioration, mortality, and other transfusion-related complications.⁴ Case 1 illustrates the limitations of PLEX for achieving a durable response, and the importance of prompt C5 inhibitor therapy for salvaging kidney function.

The primary therapeutic strategy for drug-induced TMA is drug cessation.^9,12 The pathophysiology of gemcitabine-associated TMA appears to relate in part to complement activation.^20,35 Eculizumab may be beneficial in some patients.^18-20 It can be considered particularly for severe cases or cases that do not resolve after drug cessation and supportive measures (Case 2).^10,17,18,29 Short-duration eculizumab may be safe and feasible in such patients after removal of the culprit drug.^14,16,20

Autoimmune diseases, such as SLE, can trigger TMA or occur concurrently.^21,22,25,26 Complement overactivation by both classical and alternative pathways is often found in patients with LN.^21,23 Given the increased incidence and severity of SLE in Asian populations,^36-38 physicians in Singapore should be aware of the possibility of SLE-associated TMA. The Kidney Disease: Improving Global Outcomes (KDIGO) 2024 LN guideline recommends managing LN-associated TMA according to its underlying aetiology and lists eculizumab as a treatment to consider once iTTP and other causes have been excluded.³⁹ Eculizumab can provide a favourable response in such patients, including Asian patients.^24-26 Case 3 illustrates that, in appropriate patients, short-duration eculizumab induction therapy can improve thrombocytopenia and kidney function.

Guidelines on the management of patients with C-TMA, including those with secondary TMA associated with complement activation, are available in several Asian countries, including Taiwan, Korea, and Japan,^4,9,12 as well as from international organisations.¹¹ The authors’ recommended approach for healthcare providers in Singapore involves recognising the signs and symptoms of C-TMA, identifying secondary TMA involving complement activation, and ensuring a timely diagnosis and prompt treatment initiation (Fig. 1). The proposed workflow is based on expert opinion and adapts available consensus guidance^10,40 for applicability in Singapore.

Fig. 1. Workflow for suspected C-TMA.

Uncontrolled case observations cannot establish efficacy or causation and are subject to selection and reporting bias. In Cases 1 and 2, the temporal coincidence of eculizumab with recovery cannot exclude a role for concurrent immunosuppression, removal of the offending drug, or the natural history of a resolving trigger. C5 inhibitor treatment was associated with haematological recovery, but its independent contribution to renal outcomes cannot be determined from uncontrolled observations.

CONCLUSION

Physicians need to be aware of C-TMA and secondary TMA associated with complement activation as potential causes of TMA. Early recognition and treatment of TMA are essential to prevent kidney function deterioration. The authors propose a multidisciplinary diagnostic approach to guide healthcare providers in Singapore, based on expert opinion and adapted from international guidance for applicability in Singapore. C5 inhibition is central to the treatment of C-TMA, but lack of access to therapy remains a major problem in this region. There is an emerging role for C5 inhibitors in secondary TMAs postulated to be driven by complement activation. Short-duration treatment is feasible in some patients without pathogenic gene variants but should be undertaken only with appropriate monitoring.

Supplementary material

Fig. S1. Evolution of secondary TMA (with presumed complement activation) during treatment. (A) Serum creatinine and LDH levels during treatment of gemcitabine-associated TMA (Case 2). (B) Laboratory parameters during treatment of lupus nephritis-associated (secondary) TMA in a paediatric patient (Case 3).

Acknowledgements

Medical writing/editorial assistance was provided by Kathy Croom and David P Figgitt PhD, CMPP, on behalf of Content Ed Net, with funding from AstraZeneca Singapore.

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