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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Département de Pédiatrie,
Laboratoire d'Hématologie, Service de médecine
nucléaire, Service d'épidémiologie et de
statistique, INSERM U 292, Hôpital Bicétre, Le Kremlin
Bicétre, France; Assistance Publique des Hôpitaux de Paris,
Faculté de Médécine Paris XI, Paris, France; and
Lawrence Berkeley National Laboratory, University of California,
Berkeley, CA.
Clinical manifestations of hereditary spherocytosis (HS) can be
abrogated by splenectomy. However, concerns exist regarding exposure of
patients to a lifelong risk for overwhelming infections and, to a
lesser extent, to vascular complications after total splenectomy. In
the search for alternative treatment modalities, we assessed, in a
previous pilot study, the potential usefulness of subtotal splenectomy
in a small population of patients. During a mean follow-up period of
3.5 years, subtotal splenectomy was shown to be effective in decreasing
the hemolytic rate, while maintaining the phagocytic function of the
spleen. In the current study, we evaluated the clinical and biologic
features of 40 patients with HS who underwent subtotal splenectomy and
were monitored for periods ranging from 1 to 14 years. The beneficial
effect of subtotal splenectomy included a sustained decrease in
hemolytic rate and a continued maintenance of phagocytic function of
the splenic remnant. However, mild-to-moderate hemolysis was persistent and accounted for secondary gallstone formation and aplastic crisis in
a small subset of patients. Surprisingly, regrowth of the remnant spleen did not seem to have a major impact on the beneficial outcomes of these individuals. Our results suggest that subtotal splenectomy appears to be a reasonable treatment option for management of patients
with HS, especially young children.
(Blood. 2001;97:399-403) Hereditary spherocytosis (HS) is a relatively
common inherited hemolytic anemia, with an estimated incidence in
Northern Europe of 1 to 2 in 5000 individuals. Spherocytic red cells,
precociously trapped in the spleen, are phagocytosed by splenic
macrophages, resulting in chronic hemolysis and an increased propensity
for gallstone formation. The clinical expression is heterogeneous, varying from benign chronic hemolysis to severe transfusion-dependent anemia.1 Removal of the spleen results in increased red
cell life span, decreased transfusion requirement, and decreased
incidence of gallstones. Splenectomy is thus the treatment of choice
for moderate-to-severe forms of the disease.2,3 Increased
awareness that splenectomized patients face a lifelong risk of
overwhelming life-threatening infections has dampened enthusiasm for
the routine use of total splenectomy for the management of
HS.4-7 The phagocytic activity of splenic macrophages and
the synthesis of antipolysaccharide antibodies by splenic B-lymphocytes
both are necessary to mount an optimal defense against infections.
Infectious complications due to circulating encapsulated bacteria can
occur irrespective of age and of the time interval after the surgical
procedure.8,9 The risk is particularly high during the
first years of life. Although vaccinations and systematic oral
penicillin prophylaxis have decreased the overall risk,10
concerns still exist about serotypes that are not represented in
vaccines, penicillin-resistant pneumococcal strains, and lifelong
compliance.9 Recent studies have also raised additional
concerns regarding long-term complications after splenectomy, such as
atherosclerotic events and pulmonary hypertension,11-13
reinforcing the need for alternative treatment strategies. In a
previous study, we assessed the potential usefulness of subtotal
splenectomy in managing a small population of patients with
HS.14 During a mean follow-up period of 3.5 years,
subtotal splenectomy was shown to be effective in decreasing the
hemolytic rate, while maintaining the phagocytic function of the
spleen. Although these findings were encouraging, a number of issues
remained unanswered, including whether the clinical benefit can be
sustained over a long period and what are the clinical implications of
the regrowth of the remnant spleen. This study attempts to address these issues. We evaluated the clinical and biologic features of 40 patients with HS who underwent subtotal splenectomy and were monitored
for periods ranging from 1 to 14 years. The beneficial effect of
subtotal splenectomy included a sustained decrease in the hemolytic
rate that transformed a moderately severe-to-severe hemolytic anemia to
mild chronic hemolytic anemia and the continued phagocytic function of
the splenic remnant. It did not, however, abolish the risk of aplastic
crisis or the formation of gallstones. Interestingly, the regrowth of
the remnant spleen did not have a major impact on the beneficial
outcome. Subtotal splenectomy thus seems to be a reasonable option for
the management of patients with HS, especially young children.
Subjects
Splenic necrosis was documented in one child after subtotal
splenectomy. Five other children were lost to follow-up during the
first year after surgery. For the remaining 34 patients, total duration
of follow-up after subtotal splenectomy was 203 patient-years. The mean
duration of follow-up for individual patients was 6 ± 3.7 years
(range of 1 to 14 years). Seventeen of these subjects were followed for
a minimum of 5 years.
Surgical procedure
Assessment of hemolytic rate and of erythropoietic compensation
Assessment of the phagocytic function of the spleen The phagocytic function of the splenic remnant was assessed by sequential evaluation of the number of circulating pitted red cells by interference contrast phase microscopy with Nomarski optics,16 and by the study of the splenic uptake of technetium99-labeled heat-damaged erythrocytes with radionuclide scanning.17Growth of the splenic remnant Postoperative growth of the splenic remnant was quantitated over time in a subset of subjects by repeated isotopic splenic scans. Before 1996, multiple planar views of the spleen were acquired by using a parallel collimator, and splenic volume was calculated by using a spheroid geometric model. Since 1996, abdominal single photon emission computed tomography (SPECT) acquisition was performed, and splenic volume was calculated by using a threshold algorithm previously validated on a phantom study. A very good correlation between splenic volume determined with planar or SPECT technique was noted (r = 0.97). Calculated values for the splenic volume were compared with the expected normal splenic volume value by using the algorithm: splenic volume (mL) = 6.516 × body weight (kg) (0.797).18Postsurgical growth pattern and quality of life Height growth was assessed by using standard growth curves. The quality of life was evaluated by interviewing both the parents and the affected child regarding the child's sleep patterns, the ability to perform schoolwork, and participation in athletics.Statistical analysis Mean values of hemoglobin and reticulocyte count at 1 year, 3 to 4 years, 5 to 6, 7 to 9, and 10 years or more were compared with mean values before subtotal splenectomy. Mean values at 7 to 9 years and 10 years or more were also compared with mean value at 1 year after surgery. Equality of means were compared by Wilcoxon matched-pairs signed-ranks test. A Bonferroni correction was applied to take into account multiple comparison tests (multiplication by 7 applied to the P-values). Correlation between the isotopic splenic volume and the hemoglobin value or reticulocyte count was analyzed with the Spearman coefficient. The threshold significance was set at 0.05.
Surgical procedure Subtotal splenectomy was feasible in all 40 patients. The lower part of the spleen was preserved in 39 of the 40 cases, whereas in one case, the upper part of the spleen had to be preserved because of an unusual anatomic presentation. The mean duration of surgery was 1 hour 30 minutes ± 30 minutes for subtotal splenectomy, and 1 hour 45 minutes ± 20 minutes for subtotal splenectomy in conjunction with cholecystectomy. During the surgical procedure, 85% ± 6% of the splenic tissue was removed from all patients. In one case, an incidental contact of the thermocauter with the vascular pedicle perfusing the remnant resulted in an arterial wound, leading to remnant necrosis.Intraoperative bleeding was mild in all but one of the patients who had to be transfused postoperatively and reoperated on to achieve local hemostasis. Cholecystectomy was performed on 22 patients because of either symptomatic (7 cases) or asymptomatic cholelithiasis (8 cases), or at the request of parents to prevent the future occurrence of gallstones (7 cases). In 2 of the patients, stones had to be removed from the main bile duct. During the postoperative course, 20 of the 40 patients experienced transient episodes of fever, but all the children were discharged 4 to 7 days after surgery. Variations in mean hemoglobin values and mean reticulocyte counts over time Hemoglobin values and reticulocyte counts after subtotal splenectomy are shown in Figure 2. In the children with at least 10 years of follow-up, no significant differences were noted between the one-year and the 10-year postoperative hemoglobin values and reticulocyte counts. After 8 years, hemoglobin values were above 12 g/dL in 6 of the 8 patients. We observed relapse of a well-tolerated, chronic anemia in only one patient at 5 years after surgery. Red cell life-span determination in 10 patients showed that after subtotal splenectomy red cell half-life (T50) increased on the average by 6.5 days (range: 5 to 14.5 days).14 The mean bilirubin values decreased from 50 mM before surgery to 20 mM after surgery.
Platelet counts During the first month after surgery, the mean platelet count in the 40 patients with HS was 610 × 109/L (range: 367 to 850). Thrombocythemia, defined as platelet count greater than 500 × 109/L, was noted in 30 of the 40 patients after surgery. However, platelet counts returned to values of less than 420 × 109/L in all patients within 2 years.Transfusion requirements The overall need for blood transfusions in our HS population decreased dramatically after subtotal splenectomy. Patients with HS received, on the average, 0.32 units of blood per year of life before surgery but only 0.02 units of blood per year of life after surgery. During the follow-up period, only 5 patients required blood transfusions. Parvovirus B19 infection in 3 patients and Epstein-Barr virus infection in one patient led to transient acute aregenerative anemia requiring a single transfusion. A fifth patient was transfused twice during a 4-year period to manage recurrence of acute anemia in conjunction with transient increases in the size of the splenic remnant.Phagocytic function of the spleen All patients had been vaccinated against Haemophilus influenzae either before splenectomy or since 1993 during infancy. Strepococcus pneumoniae immunization was performed before surgery, and booster vaccinations were given every 5 years. Oral penicillin prophylaxis was prescribed to all individuals for 1 year after surgery and was only discontinued after documentation of the persistence of the filtering ability of the spleen. In very young children, it was prescribed up to 5 years of age.No overwhelming infection was documented in any of the patients with a splenic remnant during the follow-up period. Howell-Jolly bodies appeared transiently after surgery in 19 of 40 patients. In 16 of these patients, they were noted only during the first week after surgery, but in 3 others, they persisted up to 3.5, 12, and 33 months. The percentage of pitted erythrocytes was in the normal range (less than 2%) in 26 patients during a follow-up period that ranged from 1 to 14 years. In 2 patients, the percentage of pitted erythrocytes transiently increased at 3 and 6 years after surgery but was found to be normal at a subsequent evaluation performed 6 months later. Radionuclide scanning was performed on 31 children at periods ranging from 1 to 14 years after subtotal splenectomy. In 30 of the children, normal uptake of heat-damaged red cells in the splenic remnant could be consistently shown. In contrast, in the one patient who had experienced perioperative splenic necrosis, no uptake of heat-damaged red cells could be demonstrated. In this patient, the absence of splenic function was confirmed by the finding of increased circulating pitted red cells and Howell-Jolly bodies. Growth of the splenic remnant The mean splenic volume before surgery was estimated to be 4 to 5 times larger than that of a normal spleen in age-matched controls. Growth of the splenic remnant over time after surgery was assessed by performing 39 radionuclide splenic scans on 31 children. Significant regrowth of the splenic remnant was noted during the first year after surgery. Surprisingly, after this initial spurt, the rate of growth was much reduced and appeared to reach either a plateau value or show a modest increase over the years (Figure 3). The remnant regrowth did not correlate with the measured hemoglobin values (P = .09) or reticulocyte counts (P = .2). It should be noted, however, that a marked increase in the splenic remnant volume was found in 2 children assessed at 8 years after surgery.
Postsurgical growth pattern and quality of life In the 5 prepubertal children who we were able to study, we could document a growth spurt after surgery. The increase was equivalent to 2 standard deviations in normal height growth curves. Improvement in the quality of life was noted in 92% of the cases 1 year after surgery and was sustained. It must be stressed that in some cases such improvement was indeed marked. For example, many patients after surgery were able to effectively sustain physical activities such as cycling or hiking with their unaffected siblings.Clinical complications and secondary total splenectomies Three patients experienced complications that led to a secondary total splenectomy. A male patient, who underwent surgery at the age of 26 months, had an acute episode of anemia (hemoglobin value of 7.5 g/dL) 11 months after surgery and an abrupt increase in the remnant spleen size. He was treated with a single red blood cell transfusion. During the following 5 months, the splenic remnant returned to its precrisis size and the hemoglobin value was stable at 10 to 11 g/dL. However, a similar acute episode recurred 2 years later requiring another transfusion and the patient underwent a total splenectomy. Neither the surgical exploration nor the macroscopic and histologic examination of the remnant spleen offered any clues to the cause of these 2 acute episodes. As splenic sequestration crises are observed in sickle cell disease, we looked for but could not document abnormal hemoglobin in this child. Neither could we document clinical or biologic signs of viral-induced splenic enlargement. In 2 other patients, total splenectomy was performed 4 and 6 years after subtotal splenectomy because of the recurrence of icterus, chronic fatigue, and mild anemia. Secondary surgery was uneventful in all 3 cases. Newly formed gallstones, a consequence of the persistent mild hemolysis, were detected by systematic ultrasound echography in 4 of the 18 noncholecystectomized patients 7 to 56 months after surgery.
Classical manifestations of HS include anemia, chronic icterus, and cholelithiasis. Total splenectomy, which abrogates hemolysis, is the most attractive treatment option. Yet, it is likely to expose the patient to a lifelong risk for potentially lethal infections.8,9 Chronic hypercoagulable states leading to thrombosis have also been reported in some human heritable hemolytic disorders and in murine HS.19 Secondary atherosclerotic events can occur in human subjects after splenectomy for trauma11 or HS.12 Splenectomized individuals, including patients with HS, are overrepresented in a population with pulmonary hypertension.13 We previously suggested that subtotal splenectomy could potentially be an effective alternative to total splenectomy in HS-affected individuals.14 However, this preliminary study left many questions unanswered. The current study provides data on a larger population of patients, with a substantially longer period of follow-up. For all 40 patients with HS, the surgery was easily feasible with no perioperative morbidity. In only one case did the splenic remnant necrose, and this occurred after thermal trauma to the pedicle. This highlights the fact that during the surgical procedure the minute vascular pedicle needs to be handled with greatest caution. Sectioning of the parenchyma is better performed with a knife rather than with a thermocautery, so as to prevent electric burns of the single persistent narrow pedicle. In one other case, the abrupt onset of a severe anemia and increase in the size of the remnant spleen led to the surgical removal of the splenic remnant. This complication has previously been reported in individuals with HS who have coexistent hemoglobinopathies20,21 and after partial splenectomy in Gaucher's disease.22 Subtotal splenectomy leads to a decrease in hemolysis, as evidenced by an increase in 51Cr-labeled red blood cell life span, an increase in hemoglobin values, and a decrease in reticulocyte counts. We show here that beneficial clinical effects are sustained over a long period. However, the hematologic improvement after subtotal splenectomy is less spectacular than that observed after total splenectomy.23 A mild hemolytic state is still persistent. The occurrence of severe anemia in 4 patients with virus-related acute red cell aplasia illustrates the fact that the decrease in hemolysis after subtotal splenectomy is not of sufficient magnitude to compensate for a transient arrest in erythropoiesis. Patients and families should be aware of such a possibility when subtotal splenectomy is being considered, especially in the absence of antiparvovirus B19-specific IgG. Similarly, gallstone formation occurred after subtotal splenectomy in the patients in whom cholecystectomy had not been performed, as a result of persistent mild hemolysis. Various approaches to evaluate the phagocytic function of the remnant spleen shed insight into the postsurgical preservation of this function. During a total observation period of 203 patient- years of life with a splenic remnant, we did not encounter a single case of severe infection. This finding, however, does not allow us to make any definite conclusion because the mortality rate after splenectomy has been estimated to be 0.73 per 1000 years8 and has probably decreased, as a result of the widespread use of prophylactic treatment strategies.10 In contrast, the assessment of pitted red cells and uptake of heat-damaged red cells by the splenic remnant provide strong indirect evidence that the filtering function of the spleen is being sustained. However, it has to be stressed that the ability of such patients to produce antipolysaccharide antibodies that are involved in humoral defense against encapsulated bacteria and are synthesized by a splenic B-lymphocyte subpopulation has still to be evaluated.24,25 Obvious clinical benefits could be documented in patients with HS after subtotal splenectomy. In our experience, chronic discomfort that does not correlate with the intensity of anemia is a frequent finding in untreated patients with HS. Cytokines produced by activated splenic macrophages, the numbers of which are markedly increased in HS,26 could be responsible for chronic discomfort. We suggest that, by decreasing the macrophage mass, subtotal splenectomy may reduce cytokine production and thereby reduce chronic discomfort. The increase in height growth score after surgery provides an additional objective validation of the clinical benefit of subtotal splenectomy. Several factors are relevant in assessing the potential thrombotic risk after either total or subtotal splenectomy in patients with HS. In the case of total splenectomy, thrombocythemia is often persistent, hemoglobin values are significantly higher than that of normal controls,15 and it is likely that the percentage of circulating abnormal red cells that can potentially activate platelets is increased. In contrast, after subtotal splenectomy, platelet counts returned to normal values, hemoglobin values were found to be in the low normal range, and severely abnormal red cells are still being cleared from circulation. On the basis of these findings, we suggest that subtotal splenectomy is likely to carry a lower risk of thrombotic events than total splenectomy. If subtotal splenectomy is being contemplated for HS, evaluating the adequate amount of splenic tissue to be removed is an important issue. In a rat model of incremental partial splenic resection, animals could survive intravenous injection of S pneumoniae as long as 25% to 50% of the normal splenic tissue was preserved.27,28 In humans, optimal protection is likely to depend on the residual splenic mass29-31 and on the preservation of adequate blood flow.32 To obtain a splenic remnant accounting for 25% of the volume of a normal spleen required that approximately 90% of the volume of an enlarged spleen be removed. This is achieved by preserving the splenic tissue supplied by a single pedicle. The size of the remnant spleen increased in all cases. Although growth velocity was high during the first postsurgical year, it subsequently slowed, and during subsequent years, the volume of the splenic remnant stabilized. Moreover, we did not find any obvious correlation between the growth velocity of the splenic remnant and the degree of resurgent hemolysis. Should severe hemolysis re-emerge in a subset of patients who underwent subtotal splenectomy during the coming decades, total splenectomy will be considered, and families should be made aware of such a possibility. In our experience, performing a secondary total splenectomy several years after a subtotal splenectomy did not pose any significant surgical difficulties. Subtotal splenectomy has proven, in our hands, to provide a persistent decrease in the hemolytic rate, while preserving the integrity of splenic phagocytic function. On the basis of our own experience, we favor subtotal splenectomy as the first line of treatment in HS cases in which splenectomy is being considered for transfusion-dependent infants. It should be stated, however, that subtotal splenectomy has to be accompanied by taking all necessary precautions regarding potential sepsis risk in case of secondary necrosis of the remnant. Antipneumococcal and anti-Haemophilus vaccinations must be performed before surgery. Oral penicillin prophylaxis can be discontinued only if normal phagocytic function of the splenic remnant is documented. Hopefully, this alternative management strategy for HS will partly solve the distressing dilemma between the risk of long-term severe infectious complications and the prompt necessity to decrease anemia and provide a better quality of life.
Submitted June 5, 2000; accepted September 22, 2000.
Supported in part by la Direction de la Recherche Clinique Assistance Publique-Hôpitaux de Paris (CRC 96082) and by a National Institutes of Health Grant DK26263.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Narla Mohandas, Life Sciences Division, Berkeley National Laboratory, Mailstop 74-157, 1, Cyclotron Rd, Berkeley, CA 94720; e-mail: mnarla{at}lbl.gov.
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© 2001 by The American Society of Hematology.
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  C. M. Cavett Partial Splenectomy for Children with Congenital Hemolytic Anemia AAP Grand Rounds, June 1, 2008; 19(6): 67 - 67. [Full Text] [PDF]
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 B. Zhang, J. Groffen, and N. Heisterkamp Resistance to farnesyltransferase inhibitors in Bcr/Abl-positive lymphoblastic leukemia by increased expression of a novel ABC transporter homolog ATP11a Blood, August 15, 2005; 106(4): 1355 - 1361. [Abstract] [Full Text] [PDF]
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 P. G. Gallagher Red Cell Membrane Disorders Hematology, January 1, 2005; 2005(1): 13 - 18. [Abstract] [Full Text] [PDF]
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 P H B Bolton-Maggs Hereditary spherocytosis; new guidelines Arch. Dis. Child., September 1, 2004; 89(9): 809 - 812. [Full Text] [PDF]
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 S. Shah and R. Vega Hereditary Spherocytosis Pediatr. Rev., May 1, 2004; 25(5): 168 - 172. [Full Text] [PDF]
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Abstract
Introduction
