|Year : 2014 | Volume
| Issue : 4 | Page : 232-236
Splenectomy for patients with β-thalassemia major: long-term outcomes
Samir A Ammar1, Khalid I Elsayh2, Asmaa M Zahran3, Mostafa Embaby2
1 Department of Surgery, Assiut University Hospitals, Assiut, Egypt
2 Department of Pediatric, Assiut University Hospitals, Assiut, Egypt
3 Department of Clinical Pathology, Assiut University Hospitals, Assiut, Egypt
|Date of Submission||07-Aug-2014|
|Date of Acceptance||25-Aug-2014|
|Date of Web Publication||24-Dec-2014|
Samir A Ammar
Department of Surgery, Assiut University Hospitals, El Gamaa Street, 71515 Assiut
Source of Support: None, Conflict of Interest: None
The use of splenectomy for thalassemia major is restricted over concerns of its long-term outcome. The aim of this study was to assess the long-term outcomes of splenectomy for patients with β-thalassemia major.
Patients and methods
This study included 70 patients with β-thalassemia major. Patients were classified into two groups: 35 patients underwent splenectomy (S group) and 35 patients did not undergo splenectomy (NS group). Patients were assessed by review of medical records, assessment of medical history, and a clinical examination. In addition to complete blood count, liver function tests and serum ferritin were performed. Assessment of lymphocyte populations was carried out by flow cytometry. These investigations were performed at least 2 years after splenectomy in the S group.
The mean age of the patients who underwent splenectomy was 6.68 ± 2.54 years and the mean postoperative follow-up period was 6.26 ± 3.03 years. Splenectomy improves anemia, but does not reduce iron burden; more patients were found to be on regular iron chelation after splenectomy. Hematocrit and red blood cell indices were significantly increased after splenectomy. Platelet count increased significantly in the S group (644.700 ± 299.400/mm 3 ). There were no significant differences in T-lymphocyte populations between both groups. IgM memory B lymphocytes were lower in the S group compared with the NS group. No overwhelming postsplenectomy infection was reported in this series. Postsplenectomy portal vein thrombosis was reported in one (2.9%) case.
With long-term follow-up after splenectomy for treatment of thalassemia major, thrombocytosis and the risk of thromboembolic persist. Splenectomy improves anemia, but does not reduce iron burden or the requirement for blood transfusion. Proper preoperative vaccination can reduce the risk of overwhelming postsplenectomy infection.
Keywords: complications, hematologic disorders, immune system, lymphocytes, splenectomized
|How to cite this article:|
Ammar SA, Elsayh KI, Zahran AM, Embaby M. Splenectomy for patients with β-thalassemia major: long-term outcomes
. Egypt J Surg 2014;33:232-6
|How to cite this URL:|
Ammar SA, Elsayh KI, Zahran AM, Embaby M. Splenectomy for patients with β-thalassemia major: long-term outcomes
. Egypt J Surg [serial online] 2014 [cited 2021 Jan 23];33:232-6. Available from: http://www.ejs.eg.net/text.asp?2014/33/4/232/147614
| Introduction|| |
Thalassemia is a group of disorders of the red blood cell (RBC) protein, hemoglobin, which is the primary carrier of oxygen in the blood. β-Thalassemia major is one of the most prevalent disorders in Mediterranean regions, caused by mutations in the gene responsible for producing β-globin chain on the chromosome 11 . Worldwide, β-thalassemia is believed to affect about one in 100 000 live births .
The treatment of thalassemia major has traditionally included transfusion of RBCs, iron chelation, and splenectomy. The need for splenectomy in thalassemia major is more likely where the disease is not suppressed efficiently by transfusion treatment.
Yet, even after decades of experience, important questions on splenectomy for thalassemia major remain unresolved, such as long-term hematological and immunological response. The aim of this study was to evaluate the long-term outcomes of splenectomy for the treatment of β-thalassemia major.
| Patients and methods|| |
This study was carried out at Assiut University Hospitals and included 70 patients with β- thalassemia major. An informed written consent in accordance with Assiut University Ethical Committee guidelines was obtained.
Patients were classified into two groups: 35 patients who had previously undergone splenectomy (S group) and 35 patients with β-thalassemia who had not undergone splenectomy (NS group). Splenectomy was performed from January 2004 to December 2011. The indications for splenectomy were a hugely enlarged spleen with blood transfusion requirement more than 250 ml/kg/year and any clinically significant complications such as pancytopenia. Preoperative vaccination against Streptococcus pneumoniae, Haemophilus influenza type B, and Neisseria More Details meningitides was administered to all patients who underwent splenectomy 2-4 weeks before surgery. There was no regular prophylactic antibiotic administration, parenteral or oral, because of poor patient compliance. Antiplatelet was administered if the platelet count exceeded 1000 000/mm 3 . Patients with known diabetes, cardiac, renal, infectious, inflammatory, or pulmonary diseases, and newly diagnosed β-thalassemia cases yet to receive a blood transfusion were excluded from the study.
All children in the study were assessed by review of medical records, assessment of medical history, and clinical examinations. In addition to complete blood count, liver function tests and serum ferritin were performed. Assessment of lymphocyte populations was carried out by flow cytometry using Cell Quest software (Becton Dickinson Biosciences, San Jose, California, USA). In the S group, these investigations were performed at least 2 years after splenectomy.
Monoclonal antibodies against surface markers were used. In immunofluorescence staining of the antibodies, cells were incubated with antibodies conjugated to a fluorochrome (e.g. fluorescein isothiocyanate). The percentages of CD19 + (total B lymphocytes), CD19 + CD27 - (naive B cells), CD19 + CD27 + (total memory B cells), CD19 + CD27 + IgM + (IgM memory B cells), CD19 + CD27 + IgM - (switched memory B cells), CD3 + (T lymphocytes), CD4 + (T-helper cells), and CD8 + (T-cytotoxic cells) were assessed. The data of flow cytometry were saved on a computer and plotted on a graph called a histogram [Figure 1].
|Figure 1: Representative flow cytometric analysis of lymphocyte subsets in thalassemia patients. (a) Forward and side scatter histogram was used to defi ne the lymphocyte population (R1). (b) The expression of CD4+ and CD8+ in T lymphocytes. (c) CD19+ cells were then gated for further analysis. (d) The expressions of IgM and CD27 in B cells were detected. FITC, fl uorescein isothiocyanate; FSC, forward scatter; perCP, peridin chlorophyll protein; PE, phycoerythrin; SCC, side scatter.|
Click here to view
Statistical analyses were carried out using the statistical package for the social sciences (version 16.0; SPSS Inc., Chicago, Illinois, USA). Data are expressed as mean ± SD for continuous variables and percentages for categorical variables. An independent sample t-test was used to analyze continuous variables, whereas the χ2 -test was used to analyze categorical variables. The P-value was considered statistically significant when less than 0.05.
| Results|| |
The mean age of the patients at splenectomy was 6.68 ± 2.54 years. After a mean postoperative follow-up period of 6.26 ± 3.03 years, the mean white blood cells and platelet counts were 16.490 and 644.700/mm 3 , respectively ([Table 1]). RBC count, mean hemoglobin level, hematocrit, and RBC indices were significantly elevated after splenectomy. Splenectomy did not reduce iron burden; more patients were found to be on regular iron chelation after splenectomy. Total and indirect bilirubin were significantly higher in the NS group compared with the S group ([Table 2]).
|Table 1 Characteristics of splenectomized and nonsplenectomized thalassemia patients|
Click here to view
|Table 2 Some hematological parameters and liver function tests in splenectomized and nonsplenectomized thalassemia|
Click here to view
Splenectomized patients showed a significant increase in total lymphocytes and B lymphocytes. However, IgM memory B lymphocytes were significantly lower in the S group compared with the NS group. There was no significant difference in total T lymphocytes, CD4 helper T lymphocytes, CD8 cytotoxic T lymphocytes, or CD4 + /CD8 + ratio among both groups ([Table 3]).
|Table 3 Lymphocytes subsets in splenectomized and nonsplenectomized thalassemia patients|
Click here to view
There was no history of overwhelming postsplenectomy infection (OPSI) in this series. An 18-year-old man had liver abscess; the abscess was in the left lobe of the liver and developed 8 years after splenectomy. The liver abscess was treated by pigtail percutaneous drainage and antibiotics. The culture and sensitivity of the aspirated pus showed Gram-negative bacilli, Klebsiella spp., which was sensitive to amikacin and ciprofloxacin.
Postsplenectomy portal vein thrombosis was reported in an 8-year-old female patient (2.9%). The preoperative platelet count was 410 000/mm 3 . One year after the operation, she developed severe abdominal pain with fever. Laboratory investigation showed thrombocytosis with a platelet count of 1 000 000/mm 3 . Portal vein thrombosis was diagnosed by abdominal ultrasonography and confirmed by color Doppler ultrasound and computerized tomography scan. Liver function tests, prothrombin time, partial thromboplastin time, bleeding time, and clotting time were within normal limits. The patient was treated by an anticoagulant and antiplatelet agent (low-dose aspirin). During regular follow-up at the outpatient clinic, the dose of warfarin was adjusted to maintain the international normalized ratio between 2 and 3.
| Discussion|| |
Since the first deliberate removal of a diseased spleen by Quittenbaum in 1826, splenectomy has become a well-established surgical procedure . A spleenless existence was considered to be quite safe as the spleen was considered unnecessary for life until 1952, when King and Schumacher  drew attention to the risk of OPSI. Since then, interest in splenectomy has reduced. The spleen clearly serves very important hematological and immunological functions .
Elective splenectomy is indicated in the management of a wide variety of medical disorders [6,7]. In patients with thalassemia, there is an increased rate of RBC removal by the spleen; therefore, RBCs, hemoglobin, hematocrit, and RBC indices are elevated after splenectomy. Transfusion frequency, and its subsequent complication, is expected to be reduced after splenectomy. In this study, despite the significant increase in the hemoglobin level after splenectomy, the reduction in blood transfusion frequency did not reach statistical significance. In splenectomized patients, blood transfusion is needed every 34 days on average.
The primary underlying pathology of red cell dysfunction persists after splenectomy; the risk of damage to different organs because of iron overload still remains significant. Aydinok et al.  reported that splenectomized patients had a higher incidence of myocardial siderosis (48%) compared with those with an intact spleen (28%). In the present study, more patients were found to be on regular chelation after splenectomy because of the significantly higher ferritin level, suggesting that splenectomy does not alleviate the iron burden in patients with thalassemia. After splenectomy, the transaminases were higher and serum albumin was lower compared with nonsplenectomized patients. A recent observational study found that the rates of iron overload-related organ damage in splenectomized patients were comparable with those who had not been splenectomized .
In the present study, a high leukocytic and lymphocytic count was found in splenectomized thalassemic patients, mainly B lymphocytes. The significant increase in lymphocytes after splenectomy may suggest that the spleen could play a role in the control of lymphocyte counts and may act as a reservoir for lymphocytes. Our results are consistent with other studies in which splenectomized thalassemia patients show a large increase in the number of B lymphocytes [10,11].
Splenectomized thalassemia patients had lower IgM memory B cells than nonsplenectomized patients. IgM memory B cells express IgM; it develops in the marginal zone of the spleen, and requires the spleen for survival and/or generation [12-14]. Opsonized bacteria are removed efficiently by macrophages in the spleen and liver. However, poorly opsonized bacteria, such as encapsulated bacteria, are only cleared by the spleen. For removal of these bacteria during the course of initial infection, natural antibodies are needed, which are pentameric IgM that can facilitate phagocytosis either directly or through complement deposition on the capsule [12, 15, 16].
Patients with thalassemia major are predisposed to infection by altered complement activation and immunoglobulin levels, cardiopulmonary disease, and hematochromatosis. Splenectomy further increases the risk of infection . The term OPSI defines fulminating sepsis, meningitis, or pneumonia mainly caused by encapsulated bacteria, such as pneumococci, meningococci, and H. influenza type b. Characterized by evolution in a just a few hours, in association with hypotension, alteration of consciousness, or shock, OPSI is a major concern after splenectomy, with a high mortality risk of ~40-50% . Preventive measures (new protein conjugate vaccines, antibiotic prophylaxis, increased awareness, and patient education) are believed to considerably reduce the risk of OPSI. In the present study, with strict application of preoperative vaccination, there were no reported cases of OPSI.
Thrombosis following splenectomy had been reported in the literature [19-21]. Splenectomy leads to immediate reactive thrombocytosis and an increase in circulating microparticles, with an increased risk of subsequent venous thromboembolism particularly within the splenoportal system [18,22-25]. In the literature, the incidence of postsplenectomy portal vein thrombosis ranges from 0.7 to 8%; patients usually present with fever and abdominal pain [26-28]. With long-term postsplenectomy follow-up (mean 6.26 years) in this study, the thrombocytosis persisted. One (2.9%) patient developed portal vein thrombosis 12 months after splenectomy. A high index of suspicion, early diagnosis, and prompt anticoagulation are keys to a successful outcome .
In thalassemia, splenectomy is reserved for patients with marked symptoms related to the extent of splenomegaly, increased transfusion requirements, and complications such as pancytopenia. Splenectomy should not be undertaken lightly and the risks should be weighed against the potential benefits in each individual case. Most of this risk seems to be because of the underlying splenectomy indication and not splenectomy alone .
This study had some shortcomings. Only patients with severe thalassemia major underwent splenectomy. It cannot, therefore, be excluded that the high serum ferritin level and low serum albumin in the splenectomized group were caused by severe disease before the splenectomy. Moreover, there was a discrepancy between both groups in age, body weight, and height.
| Conclusion|| |
With long-term follow-up after splenectomy for the treatment of thalassemia major, thrombocytosis and the risk of thromboembolic remain. Splenectomy improves anemia, but does not reduce iron burden or blood transfusion requirement. Proper preoperative vaccination can reduce the risk of OPSI. Splenectomized β-thalassemia patients had a significantly high absolute lymphocytic count and significantly low level of IgM memory B cells; the abnormal distribution of lymphocytes does not affect T-cell subgroups.
| Acknowledgements|| |
| References|| |
Cao A, Galanello R Beta-thalassemia. Genet Med 2010; 12:61-76.
Galanello R, Origa R Beta-thalassemia. Orphanet J Rare Dis 2010; 5:11.
Clarke PJ, Morris PJ. Surgery of the spleen. In: Morris PJ, Matt RA, editors. Oxford textbook of surgery. New York, Oxford, Tokyo: Oxford Medical Publications 1994; 2121-2133.
King H, Schummacher HB Splenic studies: susceptibility to infection after splenectomy performed in infancy. Ann Surg 1952; 136:239-242.
Weledji PE Benefits and risks of splenectomy. Int J Surg 2014; 12:113-119.
Neunert C, Lim W, Crowther M, Cohen A, Solberg L Jr, Crowther MA, et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood 2011; 117:4190-4207.
Langley JM, Dodds L, Fell D, Langley GR Pneumococcal and influenza immunization in asplenic persons: a retrospective population-based cohort study 1990-2002. BMC Infect Dis 2010; 10:219.
Aydinok Y, Bayraktaroglu S, Yildiz D, Alper H Myocardial iron loading in patients with thalassemia major in Turkey and the potential role of splenectomy in myocardial siderosis. J Pediatr Hematol Oncol 2011; 33:374-378.
Belhoul KM, Bakir ML, Saned MS, Kadhim AM, Musallam KM, Taher AT Serum ferritin levels and endocrinopathy in medically treated patients with thalassemia major. Ann Hematol 2012; 91:1107-1114.
Ahluwalia J, Datta U, Marwaha RK, Sehgal S Immune functions in splenectomised thalassaemic children. Indian J Pediatr 2000; 67: 871-876.
Pattanapanyasat K, Thepthai C, Lamchiagdhase P, Lerdwana S, Tachavanich K, Thanomsuk P, et al. Lymphocyte subsets and specific T-cell immune response in thalassemia. Cytometry 2000; 42:11-17
Kruetzmann S, Rosado MM, Weber H, Germing U, Tournilhac O, Peter HH, et al. Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J Exp Med 2003; 197:939-945.
Carsetti R, Rosado MM, Wardmann H Peripheral development of B cells in mouse and man. Immunol Rev 2004; 197:179-191.
Liu YJ, Malisan F, de Bouteiller O, Guret C, Lebecque S, Banchereau J, et al. Within germinal centers, isotype switching of immunoglobulins genes occurs after the onset of somatic mutation. Immunity 1996; 4:241-250.
Di Sabatino A, Carsetti R, Corazza GR Post-splenectomy and hyposplenic states. Lancet 2011; 378:86-97.
Weller S, Braun MC, Tan BK, Rosenwald A, Cordier C, Conley ME, et al. Human blood IgM 'memory' B cells are circulating splenic marginal zone B cells harbouring a prediversified immunoglobulin repertoire. Blood 2004; 104:3647-3654.
Bisharat N, Omari H, Lavi I, Raz R Risk of infection and death among post-splenectomy patients. J Infect 2001; 43:182-186.
Rodeghiero F, Ruggeri M Short-and long-term risks of splenectomy for benign haematological disorders: should we revisit the indications? Br J Haematol 2012; 158:16-29.
Mohren M, Markmann I, Dworschak U, Franke A, Maas C, Mewes S, et al. Thromboembolic complications after splenectomy for hematologic diseases. Am J Hematol 2004; 76:143-147.
Boyle S, White RH, Brunson A, Wun T Splenectomy and the incidence of venous thromboembolism and sepsis in patients with immune thrombocytopenia. Blood 2013; 121:4782-4790.
Harris W, Marcaccio M. Incidence of portal vein thrombosis after laparoscopic splenectomy. Can J Surg 2005; 48:352-354.
Ho KM, Yip CB, Duff O Reactive thrombocytosis and risk of subsequent venous thromboembolism: a cohort study. J Thromb Haemost 2012; 10:1768-1774.
Kashuk JL, Moore EE, Johnson JL, Biffl WL, Burlew CC, Barnett C, et al. Progressive postinjury thrombocytosis is associated with thromboembolic complications. Surgery 2010; 148:667-674
Frey MK, Alias S, Winter MP, Redwan B, Stübiger G, Panzenboeck A, et al. Splenectomy is modifying the vascular remodeling of thrombosis. J Am Heart Assoc 2014; 3:e000772.
Wang M, Zhang M, Li J, Zhou J, Wu Z, Peng B Risk factors of portal vein thrombosis in patients with beta thalassemia major after splenectomy: laparoscopy versus open procedure. Hepatogastroenterology 2014; 61:48-54.
Chaffanjon PC, Brichon PY, Ranchoup Y, Gressin R, Sotto JJ Portal vein thrombosis following splenectomy for hematologic disease: prospective study with Doppler color flow imaging. World J Surg 1998; 22:1082-1086.
Van't Riet M, Burger JW, van Muiswinkel JM, Kazemier G, Schipperus MR, Bonjer HJ Diagnosis and treatment of portal vein thrombosis following splenectomy. Br J Surg 2000; 87:1229-1233.
Rattner DW, Ellman L, Warshaw AL Portal vein thrombosis after elective splenectomy. An underappreciated, potentially lethal syndrome. Arch Surg 1993; 128:565-569.
Winslow ER, Brunt LM, Drebin JA, Soper NJ, Klingensmith ME Portal vein thrombosis after splenectomy. Am J Surg 2002; 184:631-635.
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||Clinical and hematological features among ß-thalassemia major patients in Jazan region: A hospital-based study
| ||MohammedMansour Khawaji,AhmadAli Hazzazi,MohssenHassen Ageeli,YahyaHassan Mawkili,AbdulrahmanHussain Darbashi,AnwarMohammed Ali Abo Kathiyah,RehabAbdalrhman Humedi |
| ||Journal of Family Medicine and Primary Care. 2020; 0(0): 0 |
|[Pubmed] | [DOI]|
||Study of Platelet Activation, Hypercoagulable State, and the Association with Pulmonary Hypertension in Children with ß-Thalassemia
| ||Mahmoud Alhosiny Fayed,Hesham El-Sayed Abdel-Hady,Mona Mohammed Hafez,Osama Saad Salama,Youssef Abdelhalim Al-Tonbary |
| ||Hematology/Oncology and Stem Cell Therapy. 2017; |
|[Pubmed] | [DOI]|
||Characterization of circulating CD4+ CD8+ double positive and CD4- CD8- double negative T-lymphocyte in children with ß-thalassemia major
| ||Asmaa M. Zahran,Khaled Saad,Khalid I. Elsayh,Mohamd A. Alblihed |
| ||International Journal of Hematology. 2016; |
|[Pubmed] | [DOI]|
||Evaluation of Tricuspid Regurgitant Jet Velocity in Thalassemia Patients with Splenectomy
| ||Marzieh Nikparvar,Nehzat Akiash,Nader Fayazi,Sepideh Fouladi,Fatemeh Jafary,Mahboubeh Pazoki |
| ||Archives of Cardiovascular Imaging. 2015; inpress(inpress) |
|[Pubmed] | [DOI]|