Thrombotic Microangiopathy After Long-Lasting Treatment by Gemcitabine: Description, Evolution and Treatment of a Rare Case.

Thrombotic microangiopathy (TMA) is an uncommon but severe complication that may occur in cancer patients under gemcitabine chemotherapy. Gemcitabine-induced thrombotic microangiopathy (G-TMA) can clinically and biologically present as atypical hemolytic uremic syndrome, with activation of the complement pathway asking the question of the use of eculizumab. We describe here the case of a patient suffering from metastatic cholangiocarcinoma treated by gemcitabine for 4 years leading to the remission of the underlying neoplasia. Despite an impressive response to therapy, she developed thrombopenia, regenerative anemia, and acute kidney injury leading to the suspicion then diagnosis based on the renal biopsy of a very late G-TMA. Spontaneous evolution after treatment interruption was favorable without dialysis requirement. However, in this case where gemcitabine is the only chemotherapy remaining for a mortal underlying condition, we discussed the re-initiation of gemcitabine under eculizumab treatment. This atypical case of TMA illustrates the importance of recognizing, even belatedly, this rare but serious complication of chemotherapy. It asks the question of rechallenging discontinued chemotherapy notably under eculizumab cover, in this population with a high risk of cancer progression.

Case report: Timing of eculizumab treatment in catastrophic antiphospholipid syndrome.

Catastrophic antiphospholipid syndrome (CAPS) is a life-threatening condition of small-vessel thrombosis with acute multiple-organ involvement and visceral damage. In this report, we present a case of a patient with CAPS who is refractory to conventional therapy. For the first time in a patient with CAPS, marked C5b-9 formation was demonstrated on microvascular endothelial cells, suggesting the usefulness of therapeutic complement inhibition in this setting. Eculizumab, a C5-blocking monoclonal antibody, is remarkably effective in the treatment of different forms of thrombotic microangiopathy by controlling complement system hyperactivation. It halted the "thrombotic storm" and promptly achieved full recovery of thrombocytopenia. However, kidney function did not recover, possibly because eculizumab was administered too late. Conceivably, the timing of treatment is crucial to achieving disease remission before irreversible structural damage occurs in target organs, thereby preventing their complete functional recovery.

Deciphering Paroxysmal Nocturnal Hemoglobinuria: An Unusual Paradigm of Hemolytic Anemia.

Paroxysmal nocturnal hemoglobinuria (PNH), a clonal hematopoietic stem cell disorder, arises from the increased sensitivity of red blood cells (RBC) to complement due to an acquired deficiency of certain glycosylphosphatidylinositol (GPI)-linked proteins, resulting in chronic intravascular hemolysis, arterial and venous thrombotic phenomena, multi-organ damage, and failure. We present an intriguing case of hemolytic anemia, initially suspected to be drug-induced, and later found to be associated with PNH, despite being a subclinical clone. A clinician should not hesitate to repeat fluorescent-labeled aerolysin (FLAER) cytometry if the clinical picture strongly favors a diagnosis of PNH. This case marks the importance of testing for PNH clones in autoimmune hemolytic anemia (AIHA) since their prevalence is not negligible and may correspond to a prominent hemolytic pattern, a higher thrombotic risk, and a higher therapeutic indication, such as eculizumab. This underscores the significance of conducting a thorough evaluation for occult causes of treatment-unresponsive hemolytic anemia, paving options for an early and alternative therapeutic approach.

IgG-immunoadsorptions and eculizumab combination in STEC-hemolytic and uremic syndrome pediatric patients with neurological involvement.

BACKGROUND: Neurological complications pose a significant threat in pediatric hemolytic and uremic syndrome (HUS) resulting from infections with Shiga toxin-producing Escherichia coli (STEC), with no established treatment. The involvement of complement activation in the pathogenesis of STEC-HUS is acknowledged, and eculizumab (ECZ), a terminal complement blocker, has been documented in several pediatric series with inconsistent results. Antibody-mediated mechanisms have also been suggested, with IgG-immunoadsorption (IgIA) showing promise in adults with neurological complications. We aimed to assess the benefit of combining IgIA with ECZ in pediatric patients with neurological STEC-HUS compared to patients treated with ECZ alone or supportive care. METHODS: Multicenter retrospective study conducted on pediatric patients (< 18 years) with neurological STEC-HUS treated with IgIA + ECZ or ECZ alone from 2010 to 2020 in France. A historical cohort treated with supportive care served as controls. Primary outcome included survival and neurological evaluation at 1-year follow-up (dichotomized as normal vs. abnormal). RESULTS: A total of 42 children were included: 18 treated with IgIA + ECZ, 24 with ECZ alone, and 27 with supportive care. Although there was no significant difference in survival between groups, three deaths occurred in the control group in the acute phase, while none was reported in both the IgIA + ECZ and ECZ alone groups, despite presenting with more severe neurological symptoms for IgIA + ECZ patients. No significant association was found between treatment group and 1-year neurological evaluation after adjustment for age, sex, and initial neurological presentation. CONCLUSIONS: Systematic association of IgIA + ECZ is not supported for all neurological STEC-HUS pediatric patients; potential rescue therapy for severe cases warrants consideration.

Unusual Presentation of Aggressive Atypical Hemolytic Uremic Syndrome With Brugada Syndrome.

Hemolytic uremic syndrome (HUS) is part of a spectrum of disorders known as thrombotic microangiopathies. These disorders are characterized by giving rise to platelet microthrombi, which subsequently develop hemolytic anemia and thrombocytopenia. In HUS, the kidneys are destroyed, mainly due to damage to the renal blood vessels. HUS can be typical or atypical, depending on the cause, and can lead to significant mortality rates. We herein report an unusual case of atypical HUS in a 15-year-old female who presented with fatigue, abdominal pain with nausea and vomiting, loss of appetite, and urine discoloration. Further tests showed low platelets with significant anemia. She was diagnosed with atypical HUS after discovering that she had no previous bloody diarrhea episode with a negative E. coli strain, O157:H7, alongside valid ADAMTS13 activity. The diagnosis was confirmed by genetic testing, and a variant of uncertain significance was found in the CFH gene. The patient, therefore, was started on eculizumab, and a follow-up was done once or twice a month through blood testing. She showed significant improvement. Due to non-compliance with the eculizumab treatment, the patient showed deterioration numerous times. A kidney biopsy was subsequently done, showing signs of acute to chronic thrombotic microangiopathy with moderate tubular atrophy and interstitial fibrosis. After many hemodialysis and plasma exchange sessions and being put on several treatments, such as prednisolone and rituximab, the patient faced death after one year.

Familial thrombotic microangiopathy in a child with coenzyme Q10 deficiency-associated glomerulopathy.

We report a child with biallelic COQ6 variants presenting with familial thrombotic microangiopathy (TMA). A Chinese boy presented with steroid-resistant nephrotic syndrome at 8 months old and went into kidney failure requiring peritoneal dialysis at 15 months old. He presented with hypertensive encephalopathy with the triad of microangiopathic haemolytic anaemia, thrombocytopenia, and acute on chronic kidney injury at 25 months old following a viral illness. Kidney biopsy showed features of chronic TMA. He was managed with supportive therapy and plasma exchanges and maintained on eculizumab. However, he had another TMA relapse despite complement inhibition a year later. Eculizumab was withdrawn, and supportive therapies, including ubiquinol (50 mg/kg/day) and vitamins, were optimized. He remained relapse-free since then for 4 years. Of note, his elder sister succumbed to multiple organ failure with histological evidence of chronic TMA at the age of 4. Retrospective genetic analysis revealed the same compound heterozygous variants in the COQ6 gene.

Thrombotic microangiopathy (TMA) associated with pregnancy: role of the clinical laboratory in differential diagnosis.

Objectives: Thrombotic microangiopathy (TMA) is characterized by thrombocytopenia, microangiopathic hemolytic anemia and target organ damage. Pregnancy is associated with several forms of TMA, including preeclampsia (PE), HELLP syndrome, thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). When HUS is secondary to a deregulation of the alternative complement pathway, it is known as atypical HUS (aHUS). Differential diagnosis is challenging, as these forms share clinical characteristics. However, early diagnosis is crucial for a specific treatment to be established and improve prognosis. Case presentation: We present the case of a 43 year-old primiparous woman admitted to hospital for an urgent C-section at 33 gestational weeks due to a diagnosis of severe preeclampsia and fetal distress. In the immediate postpartum, the patient developed acute liver failure and anuric renal failure in the context of the HELLP syndrome, anemia, thrombocytopenia, arterial hypertension (HTN) and neurological deficit. TMA study and differential diagnosis confirmed pregnancy-associated aHUS. Treatment with eculizumab was initiated, with good response and progressive improvement of clinical and analytical parameters. Conclusions: aHUS is a rare multifactorial disease that used to be associated with high mortality rates before the advent of eculizumab. Due to challenging diagnosis, the clinical laboratory plays a major role in the differential diagnosis and management of the disease.

Clinical characteristics and management of paroxysmal nocturnal haemoglobinuria in Latin America: a narrative review.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, complement-associated, haematological disorder. The level of knowledge about the disease and its management varies around the world. This narrative review provides an overview of available clinical data on PNH in Latin America (LATAM). A search of the PubMed, EMBASE and LILACS/IBECS databases to February 2023, and addition of author-known articles, yielded 24 relevant published articles, the majority (n = 15) from Brazil. Fourteen articles were full papers; 10 were conference abstracts. The prevalence of PNH in Brazil is estimated at 1:237,000 inhabitants. Among blood samples sent for flow cytometry screening for suspected PNH in Brazil and Colombia, 14 - 30% were positive. There is suggestion that disease subtypes may differ among LATAM populations, with classical PNH more common in Brazilian patients and PNH with aplastic anaemia more common in Mexican patients. Median age at diagnosis of PNH ranged from 24 to 41 years. Common symptoms included fatigue, haemoglobinuria, and abdominal pain, although the symptom profile varied by subtype. Three available studies indicated that eculizumab was effective at reducing haemolysis, improving anaemia, and reducing the risk of thrombosis in patients with PNH with intravascular haemolysis. A consensus document from the Brazilian Association of Hematology, Hemotherapy and Cell Therapy RBC and Iron Committee provides guidance on identifying and managing PNH patients, including appropriate selection of patients for eculizumab. Additional data on the epidemiology, natural history and outcomes of patients with PNH in LATAM countries are needed to better understand the disease and its management throughout the region.

Global aHUS Registry Analysis of Patients Switching to Ravulizumab From Eculizumab.

Introduction: Atypical hemolytic uremic syndrome (aHUS) is a progressive rare disease that, if untreated, can result in severe organ damage and death. Ravulizumab, a next-generation terminal complement inhibitor, provides immediate, complete, and sustained complement C5 inhibition. Real-world data in patients with aHUS who switched to ravulizumab from eculizumab are lacking. Methods: The Global aHUS Registry is a multicenter study (NCT01522183) collecting data on adult or pediatric patients with an aHUS diagnosis, regardless of treatment. Patient characteristics, genetic data, hematological and renal parameters, clinical events (e.g., dialysis and kidney transplantation), and adverse events (AEs) were extracted from patients who switched to ravulizumab from eculizumab up to July 3, 2023. Results: Overall, 60 patients switched to ravulizumab (adult: n = 43; pediatric: n = 17); 11 patients were excluded from effectiveness and genetic analyses (N = 49; adult: n = 40; pediatric: n = 9) because they received <3 months ravulizumab treatment and/or had >1 month between eculizumab discontinuation and ravulizumab initiation. Pathogenic complement variants were identified in 11 of 49 patients (22%); the most common was a complement factor H variant (n = 5/49 [10%]). During ravulizumab treatment, 20 AEs occurred in 13 patients, with no unexpected AEs and only 3 treatment-related AEs (infusion reaction, headaches, and fatigue). No meningococcal infections or deaths were reported. No new events of dialysis, kidney transplantation, or thrombotic microangiopathy were reported. Renal and hematological parameters remained stable after switching to ravulizumab. Conclusion: This is the first real-world cohort analysis of data from patients treated with ravulizumab and reinforces the real-world safety and effectiveness data of ravulizumab in patients with aHUS who switched from eculizumab.

Shiga toxin-producing Escherichia coli infection as a precipitating factor for atypical hemolytic-uremic syndrome.

BACKGROUND: Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy characterized by intravascular hemolysis. It can be classified as either typical, primarily caused by Shiga toxin-producing Escherichia coli (STEC) infection, or as atypical HUS (aHUS), which results from uncontrolled complement activation. METHODS: We report the case of a 9-year-old boy with aHUS due to compound heterozygous complement factor H-related genes (CFHR) 1/3 and CFHR1-CFHR4 deletions, leading to the development of anti-complement factor H (CFH) autoantibodies. The patient presented nephrological and neurological thrombotic microangiopathy with STEC positivity. Additionally, we provide an extensive literature review of aHUS cases initially classified as typical. RESULTS: A total of 11 patients were included, 73% of whom were pediatric. Kidney replacement therapy was required in 73% of patients. The recurrence rate was 55%. All cases were found positive for pathological variants of the complement system genes. The most commonly implicated gene was CFH, while the CFHR genes were involved in 36% of cases, although none exhibited anti-CFH autoantibodies. Anti-complement therapy was administered in 54% of cases, and none of the patients who received it early progressed to kidney failure. CONCLUSIONS: STEC infection does not exclude aHUS diagnosis, and early use of anti-complement therapy might be reasonable in life-threatening conditions. Genetic testing can be helpful in patients with atypical presentations and can confirm the necessity of prolonged anti-complement therapy.

The complement model disease paroxysmal nocturnal hemoglobinuria.

We describe initial, current, and future aspects of complement activation and inhibition in the rare hematological disease paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare but severe hematological disorder characterized by complement-mediated intravascular hemolysis resulting in anemia and severe thrombosis. Insights into the complement-mediated pathophysiology ultimately led to regulatory approval of the first-in-class complement inhibitor, eculizumab, in 2007. This anti-complement C5 therapy resulted in the stabilization of many hematologic parameters and dramatically reduced the often fatal, coagulant-resistant thrombotic events. Despite the remarkable clinical success, a substantial proportion of PNH patients experience suboptimal clinical responses during anti-C5 therapy. We describe the identification and mechanistic dissection of four unexpected processes responsible for such suboptimal clinical responses: (1) pharmacokinetic and (2) pharmacodynamic intravascular breakthrough hemolysis, (3) continuing low-level residual intravascular hemolysis, and (4) extravascular hemolysis. Novel complement therapeutics mainly targeting different complement proteins proximal in the cascade attempt to address these remaining problems. With five approved complement inhibitors in the clinic and many more being evaluated in clinical trials, PNH remains one of the complement diseases with the highest intensity of clinical research. Mechanistically unexpected breakthrough events occur not only with C5 inhibitors but also with proximal pathway inhibitors, which require further mechanistic elaboration.

Protein-losing enteropathy as a new phenotype in atypical hemolytic uremic syndrome caused by CD46 gene mutation.

BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a life-threatening thrombotic microangiopathy. Genetic defects in the alternative complement (AP) pathway have been identified in 60-70% of individuals. Eculizumab is recommended as a first-line therapy. METHODS: We collected the clinical data of a pediatric patient with aHUS accompanied by protein-losing enteropathy (PLE). Genetic testing was performed. Related literature on aHUS combined with PLE was reviewed. RESULTS: A 15-year-old Chinese girl was diagnosed with aHUS at 3.7 years of age and experienced five episodes; her symptoms completely resolved with plasma treatment. Severe gastrointestinal symptoms and hypoalbuminemia presented after the first episode, and PLE was diagnosed. A novel homozygous CD46 variant was identified, and FACS revealed significantly decreased CD46 expression. She presented at a recent relapse with persistent GI symptoms and headache and progressed to chronic kidney failure; peritoneal dialysis was initiated. Eculizumab was given 8 months after the last recurrence. Surprisingly, PLE was cured. Afterward, dialysis was discontinued, and eGFR recovered to 44.8 ml/min/1.73 m2. A review of the literature indicated that PLE with thrombosis was caused by CD55 variants via hyperactivation of the AP system. We report an aHUS patient with PLE caused by CD46 variants. Symptoms of both PLE and aHUS were significantly alleviated in our patient and patients with CD55 variants treated with eculizumab, indicating that PLE was a new symptom of aHUS in our patient with a CD46 variant. CONCLUSIONS: Our case expands the phenotype of aHUS caused by a CD46 mutation and provides evidence of the efficacy of eculizumab after a long phase of chronic kidney failure.

Application of eculizumab, a terminal complement inhibitor, in the management of atypical hemolytic uremic syndrome in a 14-month-old Chinese pediatric patient: a case report.

Eculizumab, a recombined humanized monoclonal antibody which possesses high affinity for the complement protein C5, is a therapeutic agent utilized in the treatment of atypical hemolytic uremic syndrome (aHUS) by inhibiting the terminal complement complex C5b-9. In a pediatric patient with aHUS of 14 months, the administration of eculizumab therapy was accompanied by the inclusion of meningococcal vaccine as part of the national immunization program. Notably, no other antibiotics were administered prior to or during the course of eculizumab treatment. Moreover, there were no occurrences of infusion reactions or meningococcal infections observed throughout the course of treatment. Due to the presence of anti-factor H antibodies and insufficient recovery, glucocorticoids and eculizumab were administered at week 0 and week 1, followed by the initiation of mycophenolate mofetil (MMF) at a dosage of 250 mg (approximately 548 mg/m2) per day starting from Day 10. Due to the recovered of complement antibody after 8 doses of eculizumab, the therapeutic interval was extended from once every 3 weeks to once a month since 9th administration. We experienced and successfully treated a rare case of aHUS with eculizumab in a 14-month-old Chinese pediatric patient.

Annual trends in atypical haemolytic uremic syndrome management in Japan and factors influencing early diagnosis and treatment: a retrospective study.

Atypical haemolytic uremic syndrome (aHUS) is a rare disorder characterised by complement-mediated thrombotic microangiopathy (TMA). Despite clinical guidelines, the diagnosis and treatment of aHUS in its early stages remains challenging. This study examined the annual trends in aHUS clinical practices in Japan and explored factors influencing early diagnosis and treatment. Using data from the 2011-2020 Diagnosis Procedure Combination database, 3096 cases with the HUS disease code were identified, of which 217 were confirmed as aHUS and treated with eculizumab or plasma exchange. Early initiation, defined as starting eculizumab or plasma exchange within 7 days of admission, was the focus of the study. Our study revealed no significant changes over time in the number of aHUS diagnoses, cases treated with eculizumab, or early initiation cases. Early initiation cases underwent haemodialysis earlier and had ADAMTS13 activity measured earlier, shorter hospital stays, and lower hospitalisation costs than late initiation cases. In conclusion, we found no increase in the number of newly diagnosed aHUS cases or early treatment initiation over time. Early recognition of TMA and differentiation of the causative disease are crucial for identifying potential aHUS cases, which may lead to better patient prognoses.

The efficacy and safety of eculizumab in patients and the role of C5 polymorphisms.

Eculizumab is an orphan drug with indications for extremely rare autoimmune disorders. It is primarily prescribed for use in patients with paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome; but is also highly effective in the treatment of myasthenia gravis, among others. By binding to the C5 protein in the complement system, eculizumab effectively inhibits cellular hemolysis and autoimmune reactions. Despite this effective treatment, some patients reported no improvement in symptoms. Genetic sequencing revealed three distinct C5 mutations in the non-responders and these polymorphisms appeared to be most prevalent among Japanese, Korean and African populations. Here, we present an overview of the current and potential future applications of eculizumab, as well as the disadvantages of eculizumab treatment in patients with C5 polymorphisms.

Real-world safety profile of eculizumab: an analysis of FDA adverse event reporting system and systematic review of case reports.

BACKGROUND: Most of the safety data regarding eculizumab came from clinical trials, while its safety information in the real world is still limited. RESEARCH DESIGN AND METHODS: The data of eculizumab in the FDA Adverse Event Reporting System (FAERS) database (from the first quarter of 2007 to the first quarter of 2023) was collected and analyzed. The case reports of adverse drug reactions (ADRs) related to eculizumab in PubMed, Embase and Web of Science before May 2023 were systematically reviewed. RESULTS: A total of 464 ADRs of eculizumab were identified in the FAERS database. The top five ADRs with the highest proportional reporting ratio (PRR) are total complement activity decreased, extravascular hemolysis, hemoglobinuria, total complement activity increased and breakthrough hemolysis. Fifty-one cases of ADR related to eculizumab were identified from 44 publications. The number of reported cases of eculizumab associated Neisseria gonorrhoeae infection in case reports was observed to be comparable to the number of cases of Neisseria meningitidis infection. CONCLUSIONS: Clinicians must pay close attention to the risk of infections in patients receiving eculizumab, including severe N. meningitidis infection and other potentially fatal infections such as N. gonorrhoeae infection. In addition, The possible emergence of new ADRs should be vigilant during clinical medication.

Carfilzomib-induced thrombotic microangiopathy (TMA) refractory to eculizumab: A case report and literature review.

This case report describes the clinical course of a patient with relapsed IgA kappa multiple myeloma with high-risk cytogenetics. Initially treated with daratumumab-bortezomib-lenalidomide-dexamethasone (Dara-VRD) then transitioned to lenalidomide maintenance. However, he experienced a relapse and was treated with carfilzomib-based therapy (CFZ) but developed drug-induced thrombotic microangiopathy (DI-TMA). Despite receiving eculizumab and supportive care, the patient's condition worsened, leading to encephalopathy and refractory gastrointestinal bleeding in the setting of persistent thrombocytopenia. Ultimately, the decision was made to transition to comfort-focused care. DI-TMA has been documented with various proteasome inhibitors such as ixazomib and bortezomib. Additionally, other medications such as cyclosporine, tacrolimus, clopidogrel, ticlopidine, and interferon have been associated with DI-TMA as well (Pisoni et al. (Drug Saf 24:491-501, 2001) [18]). Here we discuss a case of carfilzomib-induced TMA (CFZ-TMA) refractory to eculizumab as well as a review of the published literature.

Catastrophic antiphospholipid syndrome: Lessons from the "CAPS Registry".

The catastrophic antiphospholipid syndrome (CAPS) is a rare life-threatening clinical condition that represents the most severe clinical presentation of the antiphospholipid syndrome (APS). It was first described in 1992 in a group of patients that presented with multiorgan involvement and microangiopathic features of APS. Most of the current knowledge of CAPS comes from the analysis of all cases collected at the "CAPS Registry" that was created in 2000 to perform studies on this condition. Most cases are triggered by a prothrombotic situation that leads to a multiorgan thrombosis and a cytokine storm. The analysis of cases included in the "CAPS Registry" has shown that the triple therapy with anticoagulation, glucocorticoids, and plasma exchange and/or intravenous immunoglobulins is associated to a better prognosis of CAPS. The improvement of the knowledge allowed a decrease from the 50% mortality rate reported in the first series to 25-30% in the most recent publications.