Abstract
Drug-induced thrombotic microangiopathy (DITMA) is a life-threatening condition which may be immune or nonimmune mediated. Quinine is the most implicated drug in immune-mediated DITMA. However, the optimal treatment is unclear. Complement inhibition by eculizumab has demonstrated success in many DITMA (e.g., carfilzomib, gemcitabine, and tacrolimus), but there are limited data in DITMA, including quinine-associated cases. A 55-year-old female was diagnosed with quinine-associated thrombotic microangiopathy (TMA), as confirmed by a positive quinine-dependent platelet-associated antibody. This was successfully treated with eculizumab with complete resolution of thrombocytopenia and anemia by 1 and 6 weeks. She required hemodialysis for a month and gained full recovery of renal function. We discuss various challenges with the diagnosis and management of DITMA. We also review published data on the use of eculizumab in various DITMA. Our case demonstrates successful treatment of quinine-induced TMA with eculizumab. We recommend further studies to assess the efficacy of complement inhibition in quinine and other DITMA.
Keywords: quinine, eculizumab, drug-induced thrombotic microangiopathy, complement
Introduction
Thrombotic microangiopathies (TMAs) are life-threatening conditions characterized by microangiopathic hemolysis, thrombocytopenia, and microvascular thrombosis causing organ ischemia. Medications and drugs of abuse are important causes of TMA. Collectively, these are categorized as drug-induced thrombotic microangiopathy (DITMA).
Immune-mediated DITMA results from drug-dependent antibodies that react with different cells, including platelets, endothelial cells, and neutrophils. This leads to microvascular damage, microvascular thrombosis, and thrombocytopenia. Some examples are quinine, vancomycin, and oxaliplatin, for which the respective drug-dependent antibodies have been identified to support a definite association with DITMA. 1 Nonimmune DITMA may develop from drug exposure in a dose- and duration-dependent manner. 2 An example is anti-angiogenic agents (eg, bevacizumab) causing renal TMA by lowering vascular-endothelial growth factor. 3
Quinine is the most implicated drug in immune-mediated DITMA. Despite this, the optimal treatment is unclear. Eculizumab, an anticomplement C5 monoclonal antibody, has demonstrated efficacy in treating various DITMA. However, only 1 case of quinine-induced TMA treated by eculizumab has been reported to the author’s knowledge. The patient had dialysis-dependent renal failure (creatinine 724.9 µmol/L) and thrombocytopenia (24 × 109/L), which both normalized after 32 days of eculizumab treatment. 4
We report a case of successful treatment of quinine-associated TMA with eculizumab. We also review the use of eculizumab in various DITMA.
Case Report
A 55-year-old female presented with 4 days of back pain, dark urine, agitation, and diarrhea within 24 hours of consuming quinine for cramps. She was also taking aspirin and clopidogrel due to ischemic heart disease treated with coronary artery stents.
Blood tests on presentation were notable for abnormal liver function studies and markedly elevated ferritin (Table 1), which is not typical of thrombotic thrombocytopenic purpura or complement-mediated thrombotic microangiopathy (CM-TMA).
Table 1.
Blood Tests on Presentation and 4 Months After Diagnosis.
| Test | At diagnosis | 4 months after diagnosis | Reference ranges |
|---|---|---|---|
| Hemoglobin (g/L) | 145 | 138 | 115-165 |
| White cell count (×109/L) | 22.2 | 5.6 | 3.9-11.1 |
| Platelet (×109/L) | 37 | 395 | 150-400 |
| Blood film | Moderate schistocytes, spherocytes, and nucleated red cells. | ||
| Lactate dehydrogenase (u/L) | 7020 | 119 | 30-110 |
| Creatinine (µmol/L) | 507 | 49 | 45-90 |
| eGFR (mL/min) | Trough 8 | >90 | ≥90 |
| Urea (mmol/L) | 52 | 4.2 | 3.5-8 |
| Total bilirubin (µmol/L) | 267 | 6 | ≤19 |
| Alanine transaminase (u/L) | 187 | 21 | 10-35 |
| Aspartate transaminase (u/L) | 730 | 15 | 10-35 |
| Gamma-glutamyl transpeptidase (u/L) | 678 | 30 | ≤35 |
| Alkaline phosphatase (u/L) | 536 | 119 | 30-110 |
| Ferritin (µg/L) | 157 700 | 1963 (at 3 weeks) | 30-300 |
| ADAMTS13 (%) | 34 | 61-131 |
Abbreviation: eGFR, estimated glomerular filtration rate.
She received 2 sessions of plasmapheresis upon suspicion of TMA; this was ceased upon elucidating the history of quinine exposure. Both quinine and clopidogrel were ceased immediately. She received a dose of methylprednisolone and commenced on eculizumab (off-label) treatment for 6 months. The dosing regimen was 900 mg every week for 4 weeks, followed by 1200 mg every 2 weeks.
Subsequently, her thrombocytopenia and anemia resolved by 1 and 6 weeks, respectively. She required hemodialysis for a month and gained full recovery of renal function. A strongly positive quinine-dependent platelet-associated antibody was subsequently reported. Clopidogrel was recommenced 6 months after admission without any recurrence of TMA.
Discussion
Quinine was a popular treatment for nocturnal cramps, but its main indication currently is treatment of Plasmodium falciparum malaria resistant to chloroquine. It is found in beverages (eg, tonic water); hence, a thorough history is required to elucidate the exposure.
The most common cause of immune-mediated DITMA was quinine, accounting for 34 of 104 cases with definite evidence of causality in a systematic review. 2 In a case series (n = 19), acute kidney injury occurred in all patients, with 17 of 18 surviving patients requiring short-term dialysis. 5 Contrary to our case, chronic kidney disease is a common sequalae. Fourteen patients developed chronic kidney disease, including 3 with end-stage renal failure, among which 2 underwent renal transplant.
In this case series, quinine-dependent antibodies reactive to platelets and/or neutrophils were found in all 18 patients. These antibodies can persist for many years and trigger TMA upon quinine re-exposure, even as late as 10 years later. Hence, it is important for patients to avoid further quinine exposure. 6
Our case illustrates various challenges with managing DITMA. Treatment of DITMA requires immediate discontinuation of the offending agent. This may be challenging as patients are often on multiple medications or unable to recall their medication history completely. The patient was taking quinine and clopidogrel, which both have been implicated in DITMA. 7
Identifying the associated drug requires correlation to the timing of exposure and published literature. While drug-dependent antibodies may confirm the cause in DITMA, the test is not readily available, and the turnaround time can be long. Hence, treatment should not be delayed while waiting for results. In this case, quinine was confirmed as the cause by the presence of a strongly positive quinine-dependent platelet-associated antibody.
The optimal treatment for quinine-induced TMA is unknown. As an immune-mediated process, our patient was given a short course of methylprednisolone then treated with eculizumab.
Eculizumab has proven efficacy in CM-TMA, but less data reported in DITMA. A commonly used regimen is 900 mg weekly for 4 doses, followed by 1200 mg every 2 weeks.8,9
A retrospective review of gemcitabine-induced TMA reported complete hematological remission in 10 out of 12 patients (83%) treated with eculizumab. In comparison to patients not treated with eculizumab, less packed red cells were required after 1 dose, median of 3 (0-10) versus 0 (0-1), P < .001. There was a higher median estimated glomerular filtration rate at the end of follow-up, 45 (0-119) versus 33 (0-66) mL/min/1.73 m2 in controls. Two (17%) and 8 (67%) patients had complete and partial recovery of renal function, respectively. The median follow-up of the study was 13 months. Eculizumab was commenced after a median of 15 (4-44) days following diagnosis of TMA with a median of 4 (2-22) doses given. 8
In a systematic review, 11 of 12 (92%) cases of carfilzomib-induced TMA treated with eculizumab had a recovery of hematological and renal function. 9 One patient died of sepsis and progressive multiple myeloma. A least 7 of 10 patients had a complete recovery of renal function. Eculizumab enabled withdrawal of hemodialysis in 7 out of 9 (89%) patients within a median period of 1 month. In 4 patients, eculizumab was successfully stopped within 3 months of treatment.
In a 2-year-old patient with neuroblastoma who developed TMA following cisplatin and carboplatin treatment, there was a significant recovery in renal function, platelet count, and cessation of hemolysis after eculizumab treatment. 10 After 5 weeks of treatment, eculizumab was ceased. Thrombotic microangiopathy recurred 2 months later, which resolved upon re-initiation of eculizumab. Other cases that have reported the efficacy of eculizumab include DITMA in association with mitomycin-C, tacrolimus, bevacizumab, and in a patient treated with docetaxel, doxorubicin, and cyclophosphamide chemotherapy.11-14
The data on complement blockade in DITMA is limited and mostly retrospective. In line with other researchers, we agree that there is a need for more research into the role of complement in the pathophysiology and the role of complement blockade in its treatment. 15
In conclusion, this case of quinine-induced TMA highlights the various challenges in the diagnosis and management of DITMA. We also contribute to the limited literature on the treatment of quinine-induced TMA with eculizumab. We recommend further studies to assess the efficacy of complement inhibition in quinine and other DITMA.
Footnotes
Author Contributions: JYN drafted the work and revised it critically for important intellectual content. CW conceived of the presented idea and revised it critically for important intellectual content. All authors contributed to the final approval of the version to be published.
Availability of Data and Materials: The data that support the findings of this study are not openly available due to patient privacy. Enquiries about data access should be made to the corresponding author, Dr Jun Yen Ng.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.
Ethics Approval and Consent to Participate: Our institution does not require ethical approval for reporting individual cases or case series.
Consent for Publication: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.
Prior Presentation of Abstract Statement: This abstract was previously presented at Blood conference in Sydney, Australia, as a poster. The meeting dates were September 11 to 14, 2022.
This abstract was previously presented at the International Society of Thrombosis and Haemostasis Hematology Congress in Montreal, Canada, as a poster. The congress dates were June 24 to 28, 2023.
ORCID iD: Jun Yen Ng 
https://orcid.org/0000-0002-7995-4696
References
- 1. Reese JA, Bougie DW, Curtis BR, et al. Drug-induced thrombotic microangiopathy: experience of the Oklahoma registry and the BloodCenter of Wisconsin. Am J Hematol. 2015;90(5): 406-410. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Al-Nouri ZL, Reese JA, Terrell DR, Vesely SK, George JN. Drug-induced thrombotic microangiopathy: a systematic review of published reports. Blood. 2015;125(4):616-618. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Eremina V, Jefferson JA, Kowalewska J, et al. VEGF inhibition and renal thrombotic microangiopathy. N Engl J Med. 2008;358(11):1129-1136. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Merrill SA, Brittingham ZD, Yuan X, et al. Eculizumab cessation in atypical hemolytic uremic syndrome. Blood. 2017; 130(3):368-372. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Page EE, Little DJ, Vesely SK, George JN. Quinine-induced thrombotic microangiopathy: a report of 19 patients. Am J Kidney Dis. 2017;70(5):686-695. [DOI] [PubMed] [Google Scholar]
- 6. George J, Adam C. Drug-induced thrombotic microangiopathy. In: L Leung, ed. UpToDate. UpToDate; 2022. [Google Scholar]
- 7. Bennett CL, Connors JM, Carwile JM, et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med. 2000;342(24):1773-1777. [DOI] [PubMed] [Google Scholar]
- 8. Grall M, Daviet F, Chiche NJ, et al. Eculizumab in gemcitabine-induced thrombotic microangiopathy: experience of the French thrombotic microangiopathies reference centre. BMC Nephrol. 2021;22(1):267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Pallotti F, Queffeulou C, Bellal M, et al. Carfilzomib-induced thrombotic microangiopathy treated with eculizumab: a case report and rapid literature review. Kidney Dial. 2022;2(4):625-637. [Google Scholar]
- 10. Gilbert RD, Stanley LK, Fowler DJ, Angus EM, Hardy SA, Goodship TH. Cisplatin-induced haemolytic uraemic syndrome associated with a novel intronic mutation of CD46 treated with eculizumab. Clin Kidney J. 2013;6(4):421-425. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Hausberg M, Felten H, Pfeffer S. Treatment of chemotherapy-induced thrombotic microangiopathy with eculizumab in a patient with metastatic breast cancer. Case Rep Oncol. 2019;12(1):1-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Gabr JB, Bilal H, Mirchia K, Perl A. The use of eculizumab in tacrolimus-induced thrombotic microangiopathy. J Investig Med High Impact Case Rep. 2020;8:2324709620947266. doi: 10.1177/2324709620947266 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Safa K, Logan MS, Batal I, Gabardi S, Rennke HG, Abdi R. Eculizumab for drug-induced de novo posttransplantation thrombotic microangiopathy: a case report. Clin Nephrol. 2015; 83(2):125-129. [DOI] [PubMed] [Google Scholar]
- 14. İnözü M, Özlü SG, Özyörük D, et al. Eculizumab for bevacizumab induced thrombotic microangiopathy: a case report. Pediatr Hematol Oncol J. 2022;7(4):169-172. [Google Scholar]
- 15. Sabulski A, Jodele S. Peering into the darkness of drug-induced thrombotic microangiopathy: complement, are you in there? J Gastrointest Oncol. 2023;14(1):468-471. [DOI] [PMC free article] [PubMed] [Google Scholar]