Guideline:Splenectomy in β-thalassemia major

Many patients with thalassaemia major require splenectomy. However, optimal clinical management from the time of diagnosis may delay or even prevent hypersplenism, thereby increasing the efficiency of transfusion therapy and reducing the need for splenectomy. Throughout the care of the patient with thalassaemia, the size of the spleen should be carefully monitored on physical examination and, as needed, by ultrasonography.

Splenectomy should be considered when:

provided that they are on the same transfusion scheme and have no other reasons for increased consumption. Such reasons include new alloantibodies, infection, and changes in the haematocrit of the transfused units. For patients maintaining a pre-transfusion Hb level of about 10 g/dl, this increase in transfusion requirements represents consumption of more than 200-220 ml of red cells (assuming haematocrit of transfused cells is 75%)/kg/year (Modell, 1977; Cohen, 1980). The rate of iron overload should also be taken into consideration. For patients who maintain effective chelation therapy despite increased blood requirements, splenectomy may be unnecessary. For patients with increasing iron stores despite good chelation therapy, reduction in the rate of transfusional iron loading by splenectomy may be an important component of the overall management of iron overload. ñ Splenic enlargement is accompanied by symptoms such as left upper quadrant pain or early satiety. Massive splenomegaly causes concern about possible splenic rupture.
 * Annual blood requirements exceed 1.5 times those of splenectomised patients,

(e.g. recurrent bacterial infection or bleeding).
 * Leucopenia or thrombocytopenia due to hypersplenism causes clinical problems

Splenomegaly due to periods of undertransfusion with blood of inappropriately low haemoglobin 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.

It is generally advisable to delay splenectomy until patients are at least five years old because of the increased risk of overwhelming sepsis below this age (see below).

Surgery
The two surgical techniques most commonly employed for total splenectomy are the open and laparoscopic approaches. The laparoscopic approach requires a longer operative time and may not be practical for patients with very large spleens, but the recovery period is shorter and there is virtually no surgical scar. Many surgeons now have extensive experience with this approach.

In some centres, partial splenectomy is used to preserve some of the immune function of the spleen while reducing the degree of hypersplenism (De Montalembert, 1990). 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. Any surgery on the spleen should include a careful search for accessory spleens.

Reduction of splenic tissue by embolisation is a less invasive approach to hypersplenism than complete or partial surgical splenectomy (Pringle, 1982). However, this approach has not gained wide acceptance and may be complicated by fever, significant pain and the possible need for a subsequent total splenectomy. Embolisation does not permit a search for accessory spleens.

An evaluation for gallstones should be performed prior to surgery, 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.

Appropriate immunisations should be administered at least 2 weeks before splenectomy (see below).

Complications of splenectomy Peri-operative complications include bleeding, atalectasis and subphrenic abscess. Postoperative thrombocytosis is common, with platelet counts often reaching 1,000,000-2,000,000/mm3. Because patients with thalassaemia may have an increased thrombotic tendency, special consideration should be given to the use of low-dose aspirin (80 mg/kg/d) for patients with high platelet counts, or the use of anticoagulation for patients with a history of previous thrombosis or other risk factors.

The major long-term risk after splenectomy is overwhelming sepsis. In older studies, the risk of postsplenectomy sepsis in thalassaemia major is increased more than 30-fold in comparison with the normal population (Singer, 1973). Modern preventative measures (see below) have reduced this risk but the overall impact of these measures is unclear. The pathogens most commonly associated with postsplenectomy sepsis are encapsulated organisms (Pedersen, 1983), particularly:


 * Streptococcus pneumoniae (accounting for more than 75% of documented bacterial infections in asplenic patients)
 * Haemophilus influenzae
 * Neisseria meningitidis

Infections with gram negative, rod-shaped bacteria, notably Escherichia coli, Klebsiella and Pseudomonas aeroginosa, occur with increased frequency in asplenic patients and are often associated with high mortality. Other gram-negative organisms have also been implicated in postsplenectomy sepsis.

Protozoan infections due to Babesia have been implicated in a fulminant haemolytic febrile state in splenectomised patients. Malaria is reportedly more severe in asplenic people (Boone, 1995) and carries an increased risk of death.

Characteristics of overwhelming postsplenectomy 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. Postsplenectomy 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.

The risk of overwhelming postsplenectomy infection varies with:

has been reported in adults as much as 25-40 years after splenectomy.
 * Age—risk is very high in children <2 years of age. However, fulminant bacteraemia
 * Time since splenectomy—the greatest risk appears to be in the period 1-4 years after surgery
 * Immune status of patient

Preventative measures
The three types of protective measures a physician can utilise to prevent postsplenectomy sepsis include:
 * 1) Immunoprophylaxis
 * 2) Chemoprophylaxis
 * 3) Patient education

Immunoprophylaxis
Vaccination against Streptococcus pneumoniae is a critical step in preventing overwhelming infection after splenectomy (Landgren, Bjorkholm et al, 2004). The currently available pneumococcal vaccine is a 23-valent polysaccharide vaccine that can be given subcutaneously or intramuscularly. A conjugate vaccine will be available shortly. The protection rate with the 23-valent vaccine is 70-85%. Pneumococcal vaccine should be given at least 2 weeks in advance of a splenectomy and then in 3-5 years. The immune response to this polysaccharide vaccine is poor in children less than two years of age. Children vaccinated under the age of two should be re-vaccinated at age two. Patients who underwent splenectomy without being given pneumococcal vaccine may still benefit from vaccination postsplenectony.

If not administered as part of routine childhood immunisations, Haemophilus influenzae vaccine should be given to patients before they undergo splenectomy and should also be given to splenectomised patients (Spoulou, Tsoumas et al, 2006).

Meningococcal polysaccharide vaccine should also be administered to patients who are undergoing splenectomy and to nonimmunised, previously splenectomised patients.

These vaccines can be given at the same time in different syringes at different sites. Yearly administration of influenza virus vaccine is recommended to prevent this febrile illness that might otherwise require intensive evaluation and management of a febrile episode in the splenectomised host with thalassaemia (see below).

Chemoprophylaxis
Chemoprophylaxis with oral penicillin, 125 mg b.i.d. for children under two years, and 250 mg b.i.d. for children two years and over is recommended to reduce the risk of postsplenectomy sepsis. Alternative antibiotics for patients unable to take penicillin include amoxicillin, trimethoprim-sulfomethoxazole and erythromycin. All splenectomised children under five years of age should be treated with prophylactic antibiotics. The value of chemoprophylaxis after this age is unproven. Some clinicians continuously treat all splenectomised patients with prophylactic antibiotics, irrespective of age, while others treat patients whose spleens are removed after the age of five years only for the first two years after splenectomy. The use of prophylactic antibiotics will need to be regularly re-evaluated as improved vaccines become available and as new data regarding antibiotic-resistant bacteria are developed.

The importance of compliance with prophylactic antibiotics should be stressed repeatedly to patients and parents. However, the limitations of antibiotics 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 (see below).

Education
Patient and parent education can be highly effective in preventing overwhelming postsplenectomy 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 an antimicrobial regimen effective against Streptococcus pneumoniae and Neisseria meningitidis.

If bacteraemia is suspected, the patient should be treated with parenteral antibiotics and observed in a medical facility until the cultures are evaluated.

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 antibiotics 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.

Other complications which have been recognized in splenectomised patients include:


 * Thrombophilia
 * Pulmonary hypertension

Thrombophilia- this is a complication which occurs more frequently in thalassaemia intermedia (see relevant chapter), but a higher risk is seen in splenectomised patients.

The phenomenon of increased coagulability is related to the fact that damaged red cells 120 normally removed by the spleen, persist in the circulation and trigger mechanisms of Thrombin generation (see Figure 2 Chapter 11: Thalassaemia Intermedia and HbE). In postsplenectomy patients markers of thrombin generation such as thrombin AT III (TAT) complexes, prothrombin fragments(F1,2) fibrinopeptide A (FPA) and D-dimer should be assessed annually, and anticoagulant prophylaxis prescribed where indicated. Pulmonary hypertension – this complication is more frequent in thalassaemia intermedia, but it is also increasingly identified in thalassaemia major, especially in splenectomised patients.