Subtotal and total splenectomy for hereditary pyropoikilocytosis: Benefits and outcomes
Authors: Thomas Pincez, Corinne Guitton, Judith Landman‐Parker, Valentine Brousse, Frédéric Gauthier, Lydie Da Costa, Kaldoun Ghazal, Denis Dufillot, Gil Tchernia, Véronique Picard, Loïc Garçon
Journal: American Journal of Hematology (2018)

To the Editor: Hereditary pyropoikilocytosis (HPP) is a rare expressive type of hereditary elliptocytosis (HE) characterized by a severe hemolytic anemia secondary to weakness in the horizontal interactions inside the red cell membrane skeleton.1 The marked hemolysis usually begins during neonatal period, persists over time and can lead to transfusion-dependent anemia. Total splenectomy (TS) may be performed to reduce the intensity of hemolysis. Subtotal splenectomy (STS) has been proposed in hereditary spherocytosis (HS) in order to preserve a functional spleen tissue.2, 3 We published 10 years ago a preliminary report on STS results in three HPP patients.4 However, data on long-term outcome of both techniques are lacking. We propose here a retrospective multicentric survey of TS and STS in a series of nine HPP patients, including an update on the outcome of the three initial ones. The study included nine patients from six families referred between 1988 and 2016 for HPP in three French centers (Necker, Trousseau and Bicêtre hospitals). Six patients underwent initial STS and three patients initial TS (Supporting Information Table S1). Diagnosis of HPP was based on familial HE history, red blood cell morphology and osmotic gradient ektacytometry.5 All patients had a severe neonatal expression, with a profound anemia (median pretransfusion Hb 71 ± 3.5 g/L) requiring iterative transfusions (median number of transfusions per patient and per year: 11 ± 5) leading to iron overload in patients 5 and 7. Decision of splenectomy was taken after parents' information and consent. The choice of initial TS versus STS was based on the hematological severity and discussion with the parents. No patient had concomitant cholecystectomy. All patients were vaccinated against encapsulated germs following recommendations for asplenic patients and received oral-penicillin prevention. Concerning the six patients who underwent STS, the median preoperative hemoglobin level was 70 ± 3.2 g/L with a median number of transfusions of 14 ± 1.9 per year per patient. STS was performed at a median age of 1.2 ± 0.94 years and consisted in open resection of 80-90% of the initial spleen volume as described previously.6 No surgical complications occurred. The phagocytic function of the spleen remnant was conserved (assessed by absence of Howell-Jolly bodies on blood smear and a normal fixation on splenic scintigraphy) allowing antibiotic prevention to be stopped. No severe infection was documented during the follow-up period. For patients 4 and 5, no significant hematological improvement after STS was noticed with an unchanged transfusion rate (Figure 1A). The four others experienced a reduction in the transfusion requirement (−12 ± 1.1 transfusion per year per patient, P < .0001 [two-sided Student's t test]) and an elevation in the hemoglobin level (+29 ± 10 g/L, P < .05) but only patient 2 reached a normal hemoglobin level. Hemolysis was not abrogated, as confirmed by the elevated reticulocyte count and bilirubin level (median level at 1 year, respectively: 486 ± 228 G/L and 42 ± 11 μmol/L, Figure 1B). Three patients developed gallstones requiring subsequent cholecystectomy 1 to 1.3 year after STS. The median postoperative spleen remnant volume was 109 ± 35% of a normal spleen volume for the age (Figure 1C).6 As reported in HS,2 regrowth of the remnant was systematic but heterogeneous and was not correlated to the hematological response. Finally, all the six patients underwent secondary TS 1-12.9 years after STS, either because of STS primary failure (patients 4 and 5) or because of a secondary worsening in the hemoglobin level and transfusion requirement (patients 1, 2, 3 and 6). Secondary TS was performed by laparotomy without major surgical difficulty. TS were performed in all patients (median age 4.2 ± 3.5 years), three as “primary” TS and six after STS. Focusing on the three “primary” TS, the age at surgery was significantly older than STS (median 3.7 ± 0.4 years, P < .005). The median preoperative hemoglobin level was 75 ± 1.7 g/L with a median number of 2.2 ± 4.3 transfusions per year per patient. Considering the whole cohort, TS led to an increase in the hemoglobin level for all patients (median increase 41 ± 7.9 g/L [P < .0001, Figure 1D]). At last follow-up (median 9.5 ± 5.2 years), the hemoglobin level remained stable (median 119 ± 21 g/L) and no patient required regular transfusions. However, TS decreased but never abrogated hemolysis (Figure 1E). Median reticulocyte count remained elevated (216 ± 201 G/L) and all patients presented persistent hemolysis with decreased haptoglobin (n = 9), elevated LDH (813 ± 126 U/L, n = 8) and/or elevated total bilirubin levels (34 ± 21 μmol/L, n = 8). Thrombocytosis was constant and persistent for all patients (median platelets at last endpoint 695 ± 531 G/L on optic-based analyzers). Patients 4, 5 and 7 received long-term aspirin for a platelet number above 1000 G/L and no thrombotic event was noticed at last follow-up. Hyperferritinemia of patients 5 and 7 progressively decreased after TS and iron chelation could be stopped 2 years after TS for both. For patient 4, ferritin level increased gradually despite the absence of transfusion and required oral chelation using deferasirox from the age of 18 years. If the scarcity of HPP limits the number of patients, our study helps to precise the benefits that can be expected from STS and TS in this rare membrane disorder. STS appeared to be safe in this population. However, its efficiency was inconstant (only two-third of patients experienced a significant hematological improvement) and always transient with a 100% rate of remnant removal. Its main benefit in responders was to alleviate the transfusion rate and delay TS to an age where it is safer in terms of infectious risk. In contrast, TS led to a significant and persistent hematological improvement with transfusion independence in all cases. However, contrary to HS,2 this hematological response was partial, with persistent hemolytic features. In HPP, the weakness in the horizontal interactions inside the red cell skeleton, either by defect in the spectrin tetramerization site or at the junctional complex level, leads to a red cell fragmentation in the blood flow similar to the one observed in severe burning after destruction of the cytoskeleton interactions by heat.1 Our data highlight the fact that the clearance of the red cell fragments occurs mainly, although not exclusively, in the spleen.2 Indeed, TS could improve significantly the hematological phenotype in all cases and should therefore be the best therapeutic option in patients with transfusion-dependent HPP. GT initiated the study. TP, CG, GT and LG designed the study, collected data and wrote the paper. TP, CG, JLP, VB, LG and DD were in charge of the patients. FG was the referent surgeon. VP and LDC performed ektacytometry and molecular biology. KG performed erythrocyte membrane electrophoresis. All authors revised and approved the manuscript. The authors have no conflicts of interest to disclose. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.