Introduction

Thalassaemia represents a heterogeneous group of inherited diseases characterised by the lack, or reduced production, of haemoglobin β chains. One feature of the common pathophysiological bedrock is an increased destruction of red blood cells by the reticuloendothelial system, in particular the spleen and this, together with extramedullary haemopoiesis, results in splenic enlargement (splenomegaly) (Cappellini et al., 2018). Many patients with thalassaemia require splenectomy, although it is more commonly needed in non-transfusion dependent thalassemia (NTDT). The main therapeutic rationale for splenectomy in transfusion-dependent patients with β thalassaemia major (TM) has been to decrease blood consumption and transfusion requirements with the ultimate goal of reducing iron overload (Rachmilewitz & Giardina, 2011). However, current transfusion guidelines setting more adequate pre-transfusional haemoglobin levels (90-105 g/l), usually achieved by more frequent transfusions, have considerably reduced the incidence of splenomegaly and the need for splenectomy in TM patients. The probability of undergoing surgery within the first 10 years of life is 57, 22, 6 and 7%, for patients with thalassaemia born in the 1960s, 1970s, 1980s and 1990s respectively (Piga et al., 2011).

Throughout the care of the patient with thalassaemia, the size of the spleen should be carefully monitored and recorded on physical examination and, as needed, by ultrasonography. Splenomegaly due to periods of under-transfusion may be reversible. Before considering splenectomy in this situation, the patient should be placed on an adequate transfusion programme for several months and then re-evaluated. The spleen may increase in size during pregnancy and these patients require careful follow up.

Steps that can be taken to reduce or delay the onset of splenomegaly include

• Adequate transfusion, maintaining pre-transfusion haemoglobin concentration (Hb) 90 g/l as a minimum. Splenomegaly may be reversible by increasing transfusion, albeit at the cost of increased iron load.
• Transfusion of red cells with a minimum haemoglobin content of 40 g.
• Use of the freshest possible red cells but, at the least, those that have been stored for less than2 weeks.
• In certain cases whereby the pre-transfusion Hb is kept at adequate levels and yet the spleen size is increasing, a short period of a few months of hypertransfusion with the aim of increasing the trough Hb and reducing further the extramedullary erythropoiesis might be needed.

Indications for Splenectomy

All current guidelines agree that physicians should adopt a guarded approach and restrict splenectomy to certain indications in view of the observation of an increased risk of venous thrombosis and pulmonary hypertension, alongside overwhelming infections after splenectomy (Vichinsky et al., 2012; Sayani et al., 2009; Taher, Weatherall & Cappellini, 2018).

Splenectomy should be avoided in children less than 5 years of age because of a considerably greater risk of fulminant post-splenectomy sepsis.

The main indications for splenectomy are highlighted in Table 1.

Table 1

Indications for Splenectomy in Thalassaemia Major.

Splenectomy and Peri-operative Complications

Any surgery on the spleen should include a careful search for accessory spleens. There are currently four approaches to splenectomy; open and laparoscopic total splenectomy, partial splenectomy and reduction of splenic tissue by embolization. The two surgical techniques most commonly employed for total splenectomy are open splenectomy (OS) and laparoscopic splenectomy (LS) approaches. LS is associated with a significant reduction in 30-day postoperative mortality, shorter hospital stay, and significantly fewer pulmonary, wound and infectious complications (Musallam et al., 2013). Although there have been doubts raised regarding the suitability of LS for patients with splenomegaly, recent studies have demonstrated the superiority of LS to OS in patients with massive and even supramassive spleens (Koshenkov, Németh & Carter, 2012; Tsamalaidze et al., 2017), although the hand-assisted approach may be necessary (Kercher et al., 2002; Habermalz et al., 2008).

Partial splenectomy is used to preserve some of the immune function of the spleen while reducing the degree of hypersplenism. Because of a lack of randomised trials, no conclusive findings can be drawn about the comparative effectiveness of partial splenectomy compared with total splenectomy (Rice et al., 2012). The long-term success of this approach is still undergoing evaluation. In particular, the likelihood of splenic re-growth and the volume of splenic tissue required to preserve immune function are two questions outstanding.

Reduction of splenic tissue by embolization is a less invasive approach to hypersplenism than complete or partial surgical splenectomy. The exact splenic volume necessary is still undefined but optimal results can be obtained by 50%-70% reduction (Ahuja, Farsad & Chadha, 2015). Common complications are fever, nausea, significant pain and the possible need for a subsequent total splenectomy. Antibiotics should be given before and after the procedure. More significant complications reported include abscess formation, pleural effusion, portal vein thrombosis and liver failure. It should be noted that most of the serious complications occur when the volume embolised is 70% or greater (Koconis, Singh & Soares, 2007). Splenic embolisation has not gained wide acceptance but is certainly worth exploring it as an option at centres where there is expertise in this procedure. Embolization does not permit a search for accessory spleens.

Concomitant Cholecystectomy

An evaluation for gallstones should be performed prior to splenectomy, especially if the patient has experienced symptoms suggestive of biliary tract disease. In some cases, positive findings will lead to cholecystectomy at the same time as splenectomy. Removal of the appendix at the time of splenectomy may prevent later problems in distinguishing infection with Yersinia enterocolitica from appendicitis. Splenectomy also provides a good opportunity for a liver biopsy to assess the liver histology and iron concentration.

Adverse Events of Splenectomy

Peri-operative complications include bleeding, atelectasis and subphrenic abscess. Major immediate and long term adverse effects of splenectomy are sepsis, thrombosis and pulmonary hypertension.

Immune status of patient

The most frequent pathogens that cause infections in splenectomised patients are Streptococcus pneumoniae, Haemophilus influenzae type B, and Neisseria meningitidis, all of which are associated with a high mortality rate. Other organisms associated with systemic infection in splenectomised patients are Escherichia coli, Pseudomonas aeruginosa, Salmonella spp, and Klebsiella pneumoniae (Castagnola & Fioredda, 2003; Yapp et al., 2009). The introduction of routine anti-pneumococcal immunisation and prophylactic antibiotics can prevent severe pneumococcal infections in the first 2-4 critical post-splenectomy years. Immune prophylaxis in splenectomised patients is summarised in Table 2. Protozoan infections due to Babesia have been implicated in a fulminant haemolytic febrile state in splenectomised patients. Malaria is more severe in asplenic people and carries an increased risk of death (Boone & Watters, 1995).

Table 2

Immune prophylaxis in splenectomised patients (modified from Davies 2011).

Characteristics of overwhelming post-splenectomy sepsis include the sudden onset of fever and chills, vomiting and headache. The illness rapidly progresses to hypotensive shock, and is commonly accompanied by disseminated intravascular coagulation. Post-splenectomy sepsis has many of the features of adrenal haemorrhage (Waterhouse–Friederichsen syndrome). The mortality rate for such infections is approximately 50%, despite intensive supportive measures. Therefore, early intervention on the basis of clinical suspicion, even in the absence of many of the above findings, is critical.

Chemoprophylaxis in splenectomised patients (summarized in Fig 1)

The increased risk of infection after splenectomy remains throughout life, but is highest in the first few years post-operatively.

Figure 1

Chemoprophylaxis in splenectomised patients. *Depends on opinion of treating physician and patient characteristics/comorbidities Alternative antibiotics for patients unable to take penicillin include amoxicillin, trimethoprim-sulfamethoxazole and erythromycin. (more...)

A broad spectrum antibiotic should be given pre- and continued post-operatively. There are currently no RCTs regarding the length of time post-splenectomy penicillin should be continued. The use of life-long prophylactic penicillin against pneumococcal disease has been BCSH policy for more than 20 years (BCSH, 1996). Penicillin prophylaxis is highly effective in children with sickle cell disease and this experience provides the main evidence for continuing prophylaxis in other at risk groups (Riddington & Owusu-Ofori, 2002; Cummins, Heuschkel & Davies, 1991). British Society of Haematology guidelines 2011 recommend that life-long prophylactic antibiotics should be offered to patients considered at continued high risk of pneumococcal infection using oral penicillins or macrolides. This advice should be regularly reviewed in the light of local pneumococcal resistance patterns. The 2011 BCSH guidelines recommend penicillin prophylaxis post-splenectomy up to the age of 16 years and over the age of 50 years. In addition, high-risk patients such as diabetics, should have life-long prophylaxis. Other authors recommend prophylaxis in children for 5 years and adults 2 years post-splenectomy (Habermalz et al., 2008).

Antibiotic prophylaxis should be prescribed when a splenectomised patient undergoes invasive dental procedures and vigilance should be applied for antimicrobial cover pre- or post- any other invasive procedure.

The importance of compliance with prophylactic antibiotics should be stressed repeatedly to patients and parents. However, the limitations of antibiotic prophylaxis must also be emphasised. Patients and parents should recognise that chemoprophylaxis does not prevent all cases of post-splenectomy sepsis: the risk of death from febrile illnesses remains, and rapid evaluation of febrile episode is essential. Patient and parent education can be highly effective in preventing overwhelming post-splenectomy infection.

Physicians should emphasise to the patient and parents the importance of recognising and reporting febrile illnesses and seeking immediate medical attention.

For all febrile episodes, the physician should strongly consider:

• Evaluating the patient, including a complete physical examination, obtaining blood and other cultures as indicated.
• Beginning treatment with antimicrobials effective against Streptococcus pneumoniae, Neisseria meningitidis and Klebsiella pneumoniae while waiting for cultures to be evaluated.
• Liver abscess should always be screened for, particularly in diabetic patients.
• Patients also need to be made aware of the potential for travel-related infections such as babesiosis and malaria, as well as the risk inherent in travel to an area where medical care is not readily accessible. In the latter case, an appropriate antibiotic should be made available for the patient to carry with him/her.
• Patients should be reminded always to alert consulting physicians about their splenectomised status. Patients should be given a card with their splenectomy status and contact number of their primary treatment centre/team.

D. Iron overload

In many patients, the iron load of the spleen approaches that of the liver, highlighting the importance of the spleen as a major organ of iron storage in TM. Splenectomy causes major changes in the ferrokinetic profile of iron overload and toxicity in TM patients. Following splenectomy, the total body iron storage capacity is reduced (Casale et al., 2013). Iron will be redirected and accumulated in the liver, heart and other organs and, unless effective chelation protocols are introduced, the iron concentration in these organs will increase (Aydinok et al., 2011; Kolnagou et al., 2013). In addition, splenectomised patients had a higher incidence of myocardial iron load (48%) and higher myocardial iron compared to non-splenectomised patients (28%) (Aydinok et al., 2011).

Box

Summary and Recommendations with Grade of Evidence.

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