How I approach hereditary hemolytic anemia and splenectomy.

Hereditary hemolytic anemias (HHA) are a heterogeneous group of anemias associated with decreased red cell survival. While there can be clinical benefit of splenectomy in many cases, splenectomy is not appropriate for all types of HHA. Additionally, there are significant risks during and following splenectomy including surgical risks, postsplenectomy sepsis, and thrombotic complications. This review discusses the diagnostic approach to HHA as well as the role of splenectomy in the management. Surgical approaches and outcomes for total and partial splenectomy are discussed.

Clinical and biological features in PIEZO1-hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients.

We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a 'Gardos channelopathy'. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.

Recommendations regarding splenectomy in hereditary hemolytic anemias.

Hereditary hemolytic anemias are a group of disorders with a variety of causes, including red cell membrane defects, red blood cell enzyme disorders, congenital dyserythropoietic anemias, thalassemia syndromes and hemoglobinopathies. As damaged red blood cells passing through the red pulp of the spleen are removed by splenic macrophages, splenectomy is one possible therapeutic approach to the management of severely affected patients. However, except for hereditary spherocytosis for which the effectiveness of splenectomy has been well documented, the efficacy of splenectomy in other anemias within this group has yet to be determined and there are concerns regarding short- and long-term infectious and thrombotic complications. In light of the priorities identified by the European Hematology Association Roadmap we generated specific recommendations for each disorder, except thalassemia syndromes for which there are other, recent guidelines. Our recommendations are intended to enable clinicians to achieve better informed decisions on disease management by splenectomy, on the type of splenectomy and the possible consequences. As no randomized clinical trials, case control or cohort studies regarding splenectomy in these disorders were found in the literature, recommendations for each disease were based on expert opinion and were subsequently critically revised and modified by the Splenectomy in Rare Anemias Study Group, which includes hematologists caring for both adults and children.

Novel Gardos channel mutations linked to dehydrated hereditary stomatocytosis (xerocytosis).

Dehydrated hereditary stomatocytosis (DHSt) is an autosomal dominant congenital hemolytic anemia with moderate splenomegaly and often compensated hemolysis. Affected red cells are characterized by a nonspecific cation leak of the red cell membrane, reflected in elevated sodium content, decreased potassium content, elevated MCHC and MCV, and decreased osmotic fragility. The majority of symptomatic DHSt cases reported to date have been associated with gain-of-function mutations in the mechanosensitive cation channel gene, PIEZO1. A recent study has identified two families with DHSt associated with a single mutation in the KCNN4 gene encoding the Gardos channel (KCa3.1), the erythroid Ca(2+) -sensitive K(+) channel of intermediate conductance, also expressed in many other cell types. We present here, in the second report of DHSt associated with KCNN4 mutations, two previously undiagnosed DHSt families. Family NA exhibited the same de novo missense mutation as that recently described, suggesting a hot spot codon for DHSt mutations. Family WO carried a novel, inherited missense mutation in the ion transport domain of the channel. The patients' mild hemolytic anemia did not improve post-splenectomy, but splenectomy led to no serious thromboembolic events. We further characterized the expression of KCNN4 in the mutated patients and during erythroid differentiation of CD34+ cells and K562 cells. We also analyzed KCNN4 expression during mouse embryonic development.

Clinical outcomes of splenectomy in children: report of the splenectomy in congenital hemolytic anemia registry.

The outcomes of children with congenital hemolytic anemia (CHA) undergoing total splenectomy (TS) or partial splenectomy (PS) remain unclear. In this study, we collected data from 100 children with CHA who underwent TS or PS from 2005 to 2013 at 16 sites in the Splenectomy in Congenital Hemolytic Anemia (SICHA) consortium using a patient registry. We analyzed demographics and baseline clinical status, operative details, and outcomes at 4, 24, and 52 weeks after surgery. Results were summarized as hematologic outcomes, short-term adverse events (AEs) (≤30 days after surgery), and long-term AEs (31-365 days after surgery). For children with hereditary spherocytosis, after surgery there was an increase in hemoglobin (baseline 10.1 ± 1.8 g/dl, 52 week 12.8 ± 1.6 g/dl; mean ± SD), decrease in reticulocyte and bilirubin as well as control of symptoms. Children with sickle cell disease had control of clinical symptoms after surgery, but had no change in hematologic parameters. There was an 11% rate of short-term AEs and 11% rate of long-term AEs. As we accumulate more subjects and longer follow-up, use of a patient registry should enhance our capacity for clinical trials and engage all stakeholders in the decision-making process.

Comparative effectiveness of different types of splenectomy for children with congenital hemolytic anemias.

OBJECTIVE: To compare the effectiveness of different types of splenectomy in children with congenital hemolytic anemias. STUDY DESIGN: We constructed key questions that addressed outcomes relevant to clinicians and families on effects of partial or total splenectomy, including hematologic effect, splenic function, and the risk of adverse events. We identified from Pubmed and Embase 703 studies that evaluated different types of splenectomy and accepted 93 studies that satisfied entry criteria. We graded the quality of each report and summarized the overall strength of research evidence for each key question. RESULTS: We did not identify any randomized clinical trials. All types of splenectomy have favorable clinical outcomes in most diseases. We did not identify any hematologic advantage of laparoscopy compared with laparotomy. Adverse events are uncommon in most studies and are minimized with use of laparoscopy. CONCLUSIONS: There is a need for randomized clinical trials and improved data collection of different types of splenectomy in congenital hemolytic anemias. Outcomes studied should address the concerns of families and clinicians to assess the risks and benefits of various treatments.

[Splenectomy in hereditary hemolytic anemia: 82 Tunisian cases]. / La splenectomie dans les anemies hemolytiques constitutionnelles: a propos de 82 cas tunisiens.

BACKGROUND: Splenectomy is frequently advised in hereditary hemolytic anemia. Severe complications could occur after splenectomy. AIM: To provide the indication and benefit of splenectomy METHODS: clinical and biological patterns were performed in a retrospective study of 82 patients: 17 homozygous beta thalassemia, 17 thalassemia intermedia, 33 heterozygote Hb/S beta thalassemia and 15 hereditary spherocytosis. RESULTS: Splenectomy was performed for: Hypertransfusion in homozygous thalassemia, hereditary spherocytosis; hypersplenism in Thalassemia intermedia and splenic sequestration in heterozygote HbS/beta thalassemia. The benefit of splenectomy was proved in hereditary spherocytosis (100%), heterozygote HbS/beta thalassemia (90%) and thalassemia intermedia (75%); nevertheless in homozygous beta thalassemia. Post splenectomical complication are often thrombocytosis, thrombosis and infections. CONCLUSION: Splenectomy should be performed in hereditary hemolytic anemia to reduce and avoid transfusion.

Hemostatic alterations in splenectomized and non-splenectomized patients with beta-thalassemia/hemoglobin E disease.

Beta-thalassemia/hemoglobin (Hb) E is a hereditary hemolytic anemia with varying degrees of severity. Severely affected patients are treated with blood transfusion and/or splenectomy in order to maintain an optimum level of hemoglobin for normal growth and physical activities. As thrombosis has been observed among splenectomized patients, we have investigated alterations in coagulation and fibrinolysis in beta-thalassemia/Hb E patients. Plasma levels of prothrombin, fibrinogen, factors V, VII, VIII, IX and XI, protein C, protein S, thrombin activatable fibrinolysis inhibitor (TAFI) and prothrombin fragment 1+2 were determined in 61 patients (21 non-severe non-splenectomized, 18 severe non-splenectomized, 22 severe splenectomized) and 28 healthy individuals. Serum levels of D-dimer, ferritin, aspartate transaminase and alanine transaminase were also measured. All severe patients received regular blood transfusion. Prothrombin fragment 1+2 and D-dimer were significantly elevated in splenectomized patients compared to the healthy control subjects, whereas levels of proteins C, protein S, TAFI, fibrinogen, and factors V and VIII in the splenectomized groups were statistically lower than those in control group. There are no statistical differences for the other parameters measured between patients and controls. Coagulation tests showed only significantly reduction in TAFI and factor V and VIII levels in severe splenectomized group in comparison with severe non-splenectomized patients. These results demonstrate the existence of a low grade consumptive coagulopathy among blood-transfused splenectomized patients with severe clinical manifestations, indicating that these patients may have a higher risk for thrombosis than comparable patients with intact spleen.

[Recurrence of thromboembolic disease after splenectomy for hereditary xerocytosis]. / Maladie thromboembolique récidivante après splénectomie pour stomatocytose héréditaire.

CASE REPORT: The diagnosis of hereditary xerocytosis is made in a 57 year old woman splenectomized 30 years ago for a chronic hemolytic anemia. In following, she developed many thrombophlebitis of lower limbs and portal vein. DISCUSSION: The methods of diagnosis of this rare hereditary stomatocytosis are recalled, and the mechanisms of thrombotic tendency after splenectomy are discussed. This case underlines the fact that splenectomy is banned in the treatment of hereditary stomatocytosis, and that the serious consequences of iron overload, which is very frequent in this disease, must be prevented.

[Red cell membrane defects]. / Erythrozytäre Membrankrankheiten.

Genetic defects of red cell membrane proteins constitute in Europe the most common cause of congenital hemolytic anemias. During the past decennium the defects and the pathogenetic mechanisms have been eludicated. Relatively simple hematologic tests allow for differentiation into groups with different severity of the disease. This allows prognostic assessment and careful risk-benefit evaluation for splenectomy.

Triple heterozygosity of a hemoglobin variant: hemoglobin Pyrgos with other hemoglobinopathies.

This article is the first report of hemoglobin (Hb) Pyrgos along with other Hbs forming triple-heterozvgous patterns. Of 2 cases, the first occurred in a Thai girl with thalassemic facies, marked anemia, and hepatosplenomegaly, who had Hb Pyrgos in association with Hb H disease with Hb Constant Spring (CS). This case represents a triple heterozygosity comprising Hb Pyrgos, alpha-thalassemia 1, and Hb CS. Hb electrophoresis revealed an abnormal Hb in addition to Hbs CS, A2, A, Bart's, and H. This abnormal Hb moved slightly faster than Hb A but more slowly than Hb Bart's. Polymerase chain reaction revealed that the abnormal Hb was caused by a missense mutation within codon 83 of the beta-globin gene (GGC to GAC) resulting in a glycine-to-aspartic acid substitution, which corresponds to Hb Pyrgos. The patient required blood transfusions by the age of 3 years. A splenectomy was performed when she was 5 years old, after which her hematocrit level remained above 32%. The second case was the patient's older sister who was also triple heterozygous (Hb Pyrgos, E, and CS) but was healthy.

[Contribution of the spleen to the lipid metabolism in plasma and red cells. On hereditary spherocytosis and hereditary high red cell membrane phosphatidylcholine hemolytic anemia].

Clinical and experimental studies on hereditary spherocytosis (HS) and high red cell membrane phosphatidylcholine hemolytic anemia (HPCHA) were performed in relation to lipid metabolism in plasma and in red cells of these patients. In HS, red cell (RBC) membrane lipids (free cholesterol (FC) and phospholipids (PL) such as phosphatidylethanolamine, phosphatidylcholine (PC), sphingomyelin (SM) and lysophosphatidylcholine (LPC] were markedly decreased in unsplenectomized HS. Plasma lipids (total cholesterol, FC, HDL-cholesterol, PL) were also decreased in these patients. After splenectomy, substantial normalization of plasma and RBC lipids were observed. Concerning lipid kinetics, the extents of 14C-PC synthesis in RBC from 14C-LPC in medium and of 14C-PC exchange between RBC and the medium were almost identical to those in normal control in the in vitro incubation conditions. These observations indicate that the decreased RBC lipids may be induced by the shortage of lipid materials in plasma in the presence of the spleen. In unsplenectomized HPCHA, plasma lipids were also decreased same as in HS. In contrast, membrane lipids (FC and PC) were markedly increased. Even after splenectomy, increased PC contents were rather enhanced in their membranes concomitant to developing of hemolytic anemia, although plasma lipids were almost normalized. Thus RBC membrane lipids in HPCHA appeared not to be affected by plasma lipids. In experimental studies on HPCHA, 14C-PC synthesis from 14C-LPC and 14C-PC uptake in these RBC were increased, in spite that large amounts of PC were already accumulated in these RBC.(ABSTRACT TRUNCATED AT 250 WORDS)

[Acute lymphoblastic leukemia in a patient with congenital hemolytic anemia: case report]. / Congenitalis haemolyticus anaemia és akut lymphoblastos leukaemia társulása: esetismertetés.

The authors present a case of a 13-year-old girl with a history of congenital hemolytic anemia (spherocytosis) who developed acute lymphoblastic leukaemia. She received treatment according to the ALL-BFM 91 protocol standard risk group. During maintenance therapy an aplastic crisis caused by Parvovirus B 19 infection had developed. Chemotherapy was stopped in September 1999, and the patient remained in complete remission. In January, 2000 the patient presented with jaundice, caused by a stone in the ductus choledochus. Cholecystectomy and splenectomy were performed, and the the girl became symptomfree. The authors review the most frequent complications of congenital hemolytic anemias (aplastic crisis, haemolytic crisis and cholelithiasis). The occurrence of acute lymphoblastic leukaemia in a patient with congenital hemolytic anemia has not been previously reported.

[Laparoscopic splenectomy in congenital hemolytic anemia in children]. / Laparoskopicheskaia splenéktomiia pri vrozhdennoi gemoliticheskoi anemii u detei.

Experience of 48 laparoscopic splenectomies in children aged from 3 to 14 years with congenital hemolytic anemia is analyzed. The main stages of laparoscopic splenectomy were the following: isolation of the inferior pole of the spleen, transection of the gastro-splenic ligament, transection of the splenic vascular trunk (with endostapler or intracorporeal ligature), dissection of the splenic ligaments, removal of the organ (with endoscopic sac or morcellator). One-stage cholecystectomy for cholelithiasis was performed in 11 patients. Time of surgery was 110-115 minutes, on the average. One-stage cholecystectomy prolonged surgery by 30-40 minutes. There were no intraoperative and postoperative complications. Conversion to open surgery was necessary in 2 cases because of endostapler failure. Patients were discharged on the 5-8th day after surgery. Physical activity restored completely 10-14 days after surgery. There were no lethal outcomes. Excellent cosmetic results were achieved in all the patients. Laparoscopic splenectomy in congenital hemolytic anemia is safe, sparing and effective endoscopic surgery in childhood.

Abnormalities of the erythrocyte membrane.

Primary abnormalities of the erythrocyte membrane are characterized by clinical, laboratory, and genetic heterogeneity. Among this group, hereditary spherocytosis patients are more likely to experience symptomatic anemia. Treatment of hereditary spherocytosis with splenectomy is curative in most patients. Growing recognition of the long-term risks of splenectomy has led to re-evaluation of the role of splenectomy. Management guidelines acknowledge these considerations and recommend discussion between health care providers, patient, and family. The hereditary elliptocytosis syndromes are the most common primary disorders of erythrocyte membrane proteins. However, most elliptocytosis patients are asymptomatic and do not require therapy.

Esplenectomía parcial en niños con anemias hemolíticas congénitas en el Hospital Pediátrico Docente de Matanzas Eliseo Noel Caamaño / Partial splenectomy in children with congenital hemolytic anemia in the Pediatric Hospital Eliseo Noel Caamaño of Matanzas

Introducción: las anemias hemolíticas se caracterizan por una destrucción precoz de los hematíes, con un acortamiento de su vida media. Estos pacientes pueden requerir para el control de la enfermedad o por el desarrollo de complicaciones esplénicas, la necesidad de ser sometidos a una esplenectomía. Por la morbilidad y posibles complicaciones letales como la sepsis post-esplenectomía de la esplenectomía total en niños, se ha empleado la esplenectomía parcial como opción de tratamiento quirúrgico. Objetivo: evaluar los resultados de la esplenectomía parcial en los pacientes con anemias hemolíticas congénitas. Materiales y Métodos: se realizó un estudio prospectivo, descriptivo longitudinal, del universo de los 15 pacientes con anemias hemolíticas congénitas a los que se les realizó esplenectomía parcial. Resultados: se encontró que la drepanocitosis y la esferocitosis hereditaria fueron los diagnósticos más frecuentes dentro de los casos operados. Las principales indicaciones de la esplenectomía parcial fueron la crisis de secuestro esplénico y la necesidad de transfusiones de sangre respectivamente. Las variables hematológicas analizadas en el período postoperatorio mostraron una respuesta favorable al tratamiento quirúrgico. Conclusiones: la esplenectomía parcial llevó a un mejoramiento clínico y hematológico en los pacientes con anemias hemolíticas congénitas, tributarios de tratamiento quirúrgico, sin complicaciones significativas en un período de seguimiento de 5 años (AU).

Introduction: congenital hemolytic anemia are characterized by an early destruction of red blood cells, with a shortening of their average life. For the control of the disease or due to the development of splenic complications, these patients may require to undergo splenectomy. Due to the morbidity and possible lethal complications such as post-splenectomy sepsis of total splenectomy in children, partial splenectomy has been used as a surgical treatment option. Objective: to evaluate the results of partial splenectomy in patients with congenital hemolytic anemia. Materials and Methods: a longitudinal prospective, descriptive study was performed in 15 patients with congenital hemolytic anemia who underwent partial splenectomy. Results: sickle cell disease and hereditary spherocytosis were the most frequent diagnoses in the group of operated cases. The main indications of partial splenectomy were splenic sequester crises and the necessity of blood transfusions respectively. The hematologic variables analyzed in the post-surgery period showed a favorable answer to surgical treatment. Conclusions: partial splenectomy led to a hematologic and clinical improvement in patients with congenital hemolytic anemia, tributary of surgical treatment, without significant complications in a 5-year follow-up period (AU).