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Case Reports
DHTR), hemoglobinuria in 11 patients, and positive DAT results or antibody formation in 12 patients (anti-MNS3, anti-KEL6, anti-RH10 + anti-RH20, anti-MNS5, anti-FY5 in one patient each, one patient developed multiple anti- bodies including anti-MNS3, anti-RH20 and auto-anti- bodies, two patients developed auto-antibodies and two patients delevopde allo-antibodies for which the speci- ficity could not be determined and two patients had pos- itive DAT but no new antibody was subsequently identi- fied). A 19th patient received anti-C5 antibody for hyper- hemolysis but it was impossible to determine whether this patient had DHTR due to hemolysis under extracor- poreal membrane oxygenation,14 so this patient was excluded from the analysis.
The main characteristics of the patients are presented in Table 1. Sixteen patients (89%) had risk factors for DHTR: a history of previous DHTR (n=2), a history of RBC antibodies (n=11), or the administration of fewer than 12 pRBC units before the episode leading to DHTR (n=11).15 Three patients had a history of ineffective pRBC transfusions, possibly due to previous undetected episodes of DHTR. None of the patients were enrolled in chronic transfusion programs. Five patients underwent repeat transfusions before the diagnosis of DHTR, which may have worsened their clinical presentation at diagno- sis.
The findings at diagnosis and during follow-up, com- pared with those of a historical cohort1 are presented in Table 1 (see Online Supplementary Data for individual timelines). At diagnosis, the patients had particularly severe DHTR, with parameters highly indicative of hemolysis (low Hb, high LDH concentrations), and the failure of at least one organ in 50% of cases (n=9): kidney failure (n=7), liver failure (n=4, including two with indi- cations for liver transplantation), respiratory failure (n=5). Five patients had hemodynamic failure requiring treat- ment with vasoactive agents.
One to three anti-C5 doses were administered at 1- week intervals (one dose n=6, two doses n=9 and three doses n=1), in association with other treatments (Table 1). Unfortunately, complement activation measurements were not performed for most patients. The number of pRBC units transfused was restricted as much as possi- ble, to limit exacerbations of hyperhemolysis.
Remarkably, a worsening of clinical conditions during follow-up occurred only in the hours immediately fol- lowing anti-C5 infusion (i.e., due to the progression of pre-existing organ damage due to DHTR; n=2), or as a result of sepsis due to additional infectious complications (n=2). One patient suffered hemodynamic failure within a few hours of anti-C5 infusion. One patient (16P) with kidney failure, hemodynamic failure and a severe hepatic alteration before anti-C5 infusion rapidly progressed to hepatic failure a few hours after the first infusion.
The outcome was favorable in 15 patients (83%), with a complete recovery of all failing organs. Three patients died (17%). All three had acute liver failure requiring emergency transplantation (already present at DHTR diagnosis in two of these patients). Two patients improved after one and two anti-C5 infusions and were able to undergo transplantation. However, both died from infectious complications due to encapsulated bacte- ria unrelated to anti-C5 treatment but promoted by the immunosuppressive regimen: ventilator-associated pneu- monia 11 days after transplantation in patient 8H, and digestive and urinary infection 47 days after transplanta- tion in patient 16P. No compatible organ could be found for patient 3C, who died one day after anti-C5 antibody infusion.
Despite the heterogeneity of the data, linear mixed- effect model analysis with adjustment to produce the best model (P<0.05) highlighted an influence of the anti- C5 antibody treatment on total Hb and LDH levels (Figure 1). The inversion of the slope for total Hb and LDH levels before and after anti-C5 treatment indicated that hyperhemolysis was stopped, or at least greatly decreased, by treatment. The gradual increase in Hb lev- els may also be due to the other treatments received by the patients, especially erythropoietin (EPO) (Table 1). The stimulation of erythropoiesis improves the reticulo- cyte count, and proportionally increases hemoglobin S (HbS). In several patients who received secondary RBC transfusion, HbA concentration was maintained post transfusion (e.g., patients 2B, 15O, 16P, 17Q).
In conclusion, this is the largest series to date of cases of severe DHTR with hyperhemolysis in SCD patients, treated with anti-C5 antibody. It demonstrates the effect of anti-C5 therapy against hyperhemolysis in DHTR, with remarkable beneficial effects on pre-existing organ failure and additional organ failure once the effects of the treatment are established. These findings consolidate the recommendation in the ASH guidelines to use anti-C5 antibody in patients with SCD and ongoing hyperhemol- ysis.12 Other anti-complement drugs may also be useful for treatment in this context. A prospective clinical trial would be required to determine whether all DHTR patients would benefit from anti-C5 therapy or whether such treatment is beneficial only for the most severe clin- ical presentations.
Aline Floch,1 Alexandre Morel,2 Fabian Zanchetta-Balint,2 Catherine Cordonnier-Jourdin,3 Slimane Allali,4
Maximilien Grall,5 Ghislaine Ithier,6 Benjamin Carpentier,7 Sadaf Pakdaman,1 Jean-Claude Merle,8 Radjiv Goulabchand,9
10 11 12 Tackwa Khalifeh, Ana Berceanu, Ceć ile Helmer,
Christelle Chantalat-Auger,13 Véronique Frémeaux-Bacchi,14 Marc Michel,15 Mariane de Montalembert,4 Armand Mekontso-Dessap,16 France Pirenne,1 Anoosha Habibi2
and Pablo Bartolucci2
1Etablissement francais du sang Ile de France, INSERM Unit 955, Laboratory of Excellence GR-Ex, Mondor Institute of Biomedical Research, Paris-Est Creteil University, Creteil; 2French Sickle Cell Referral Center, Henri Mondor Teaching Hospital, Assistance Publique-Hopitaux de Paris, Laboratory of Excellence GR-Ex, INSERM Unit 955, Mondor Institute of Biomedical Research, Paris- Est Creteil University, Creteil; 3Department of Pharmacy, Henri Mondor Teaching Hospital, Assistance Publique-Hopitaux de Paris; 4Department of Pediatrics, Necker Hospital for Sick Children, Assistance Publique-Hopitaux de Paris, Laboratory of Excellence GR- Ex, Paris Descartes University, Paris; 5Department of Internal Medicine, Rouen Teaching Hospital, Rouen; 6Hematology Unit, Reference Center of Sickle Cell Disease, Robert Debré Hospital, Assistance Publique-Hopitaux de Paris, Paris; 7Department of Hematology, Saint Vincent de Paul Hospital, Lille Catholic University, Lille; 8Department of Anesthesia and Surgical Intensive Care, Liver Intensive Care Unit, Henri Mondor Teaching Hospital, Assistance Publique-Hopitaux de Paris, Creteil; 9Department of Internal Medicine-Multiorganic Diseases, Local Referral Center for Autoimmune Diseases, Saint-Eloi Hospital, Montpellier University, Montpellier; 10Pediatric Medical-Surgical Department, Poitiers Teaching Hospital, Poitiers, France; 11Intensive Care Hematology Unit, Besancon Teaching Hospital, Besancon; 12Etablissement francais du sang Auvergne-Rhône Alpes, Grenoble; 13Department of Internal Medicine, Bicetre Teaching Hospital, Assistance Publique-Hopitaux de Paris, Universite Paris 11, Le Kremlin-Bicetre, Paris; 14Laboratory of Immunology, European Georges Pompidou Hospital, Assistance Publique-Hopitaux de Paris, Mixed Health Research Unit INSERM
haematologica | 2020; 105(11)