Accessory splenectomy for refractory immune thrombocytopenic purpura
Authors: Gita Thanarajasingam, Rakhee Vaidya, Andrew Erie, Alexandra P. Wolanskyj
Journal: American Journal of Hematology (2011)

Patients with immune thrombocytopenic purpura (ITP) will frequently relapse following splenectomy. The removal of residual spleens remains a therapeutic option in these patients though the effectiveness of this procedure remains unclear. We present a single institution study of outcomes in patients who underwent an accessory splenectomy (AS) for refractory ITP. The study cohort represents a consecutive group of splenectomized patients with ITP who underwent AS for refractory disease. Fourteen patients were identified: 10 adult and 4 pediatric patients. Response was assessed at 4 weeks using standard criteria for complete response (CR), partial response (PR), or no response (NR). Eight adult patients underwent open AS, and two underwent uneventful laparoscopic AS. Overall, 50% (5/10) of adult patients responded (CR or PR) to AS at 1 month. Fifty percent (2/4) of pediatric patients achieved response. Clinical determinants suggestive of a response to AS in adults were female gender, favorable response to prednisone at first exposure and absence of Howell-Jolly Bodies prior to AS. These data suggest that laparoscopic AS remains a viable treatment option for patients with refractory ITP following splenectomy. However, given the role for novel medical therapies for refractory ITP, the potential morbidity of this surgical procedure must be weighed against its effectiveness. Primary immune thrombocytopenic purpura (ITP), previously termed idiopathic thrombocytopenic purpura [ 1], is an autoimmune disorder causing thrombocytopenia from antibody-mediated destruction of platelets. The incidence in adults is 1–2 cases per 100,000 persons per year [2, 3]. Clinical features of the disease include a marked propensity to mucocutaneous bleeding. ITP is clinically distinct in pediatric and adult populations. In children, the illness affects males and females equally, typically presents acutely with the sudden onset of thrombocytopenia often after viral illness, and in over 70% of cases, the disease spontaneously resolves over several weeks to months. The adult-onset form of the disease, on the other hand, disproportionately affects women (2:1), follows a more chronic course with slower onset, and is frequently refractory to treatment [2]. Although the disease itself is rarely fatal, there is often significant morbidity from bleeding as well as from the debilitating effects of immunosuppressive therapy and/or postoperative complications from splenectomy [4]. Corticosteroids are first line therapy for ITP, with response rates ranging from 50% to 75%. However, relapse will occur in the vast majority of patients, requiring protracted steroids or second line therapy including splenectomy [ 5-7]. There are conflicting data on the efficacy of splenectomy over time, with long term success rates reported in 60–75% of patients [4, 8-10]. The search for and removal of an accessory spleen may be an important treatment modality for refractory ITP that may lead to remission and avoids the potential hazards of continued immunosuppression [ 11]. Previously published outcome studies of accessory splenectomy (AS) in ITP have had several limitations. These include inconsistent definitions of ITP and of response criteria to therapy, small number of patients, lack of follow-up, and the combining of pediatric and adult patients into the same series [12-21]. To address these limitations, we present a single institution study of the outcomes in pediatric and adult patients who underwent AS for refractory ITP and clinical correlates of response using both standard criteria for diagnosis and response in adults. A total of 14 patients were identified who underwent AS for refractory ITP: 4 pediatric patients (age at diagnosis of ITP ≤ than 18 years) with a median age at diagnosis of 11 years (range 7–14) and 10 adult patients with a median age at diagnosis of ITP of 41 years (range 20–63). In all cases, the accessory spleen was detected by radionuclide imaging. Medical therapies used prior to AS in the cohort included corticosteroids, cyclosporine, azathioprine, vincristine, Danazol, rituximab, and IVIG. Characteristics at diagnosis for adult and pediatric patients are summarized in Tables I and II (Supporting Information). Eight of ten adult patients underwent open laparotomy, three of whom experienced significant post-operative complications, one resulting in death. The other two patients had laparoscopic AS. A median number of 1 [ 1-4] splenules was removed. In those in whom data was available, Howell-Jolly Bodies (HJB) were present in 66% (6/9) patients prior to AS and 100% (7/7) patients post-operatively. Overall, 50% (5/10) of adult patients responded to AS at the initial evaluation period of 4 weeks (CR or PR). Two patients achieved a CR, three patients had a PR and five patients had NR. The median follow-up after accessory splenectomy was 11 months (range 1–265), during which time three patients remained in remission and two patients relapsed at 2 and 45 months, respectively and required additional therapy. Additional characteristics of adult patients at the time of AS are presented in Table III (Supporting Information). All four pediatric patients had open laparotomy with one postoperative complication (formation of a pancreatic fistula). Fifty percent (2/4) achieved CR, and two did not respond at 1 month after AS. With a median follow-up time of 64 months (16–137) from the time of AS, one responder relapsed at 6 months and the other remained relapse-free and in continued CR at last follow-up 137 months after AS. Additional characteristics of pediatric patients at the time of AS are presented in Table IV (Supporting Information). Female gender. ○ A total of 80% (4/5) of females responded to AS, versus 20% (1/5) of males (Chi-squared P-value 0.06, Fisher's exact P-value not significant). Favorable response to prednisone at first exposure. ○ A total of 71% (5/7) of those who responded to initial prednisone therapy also responded to AS, versus 0% (0/3) of those who failed initial prednisone therapy (Chi-squared P-value 0.04, Fisher's Exact P-value not significant). Absence of HJB prior to AS. ○ 100% (3/3) of those who lacked HJB prior to AS responded to the procedure, versus only 33% (2/6) of those with HJB prior to AS responded (Chi-squared P-value 0.06, Fisher's exact P-value not significant). Notably, there was no evidence of correlation between response to AS and age at diagnosis of ITP, prior response to splenectomy, number of prior therapies, or volume of accessory spleens. The literature on the effectiveness of accessory splenectomy is limited by small numbers of patients, as most published reports are single cases. The omission of important data such as postoperative platelet count and the use of concomitant therapies limit the interpretation of results in most series. Additionally, the lack of a consensus on standardized definitions, outcomes criteria and terminology among the various reports is a significant obstacle to producing a precise meta-analysis of existing reports. Nevertheless, to summarize the published literature in the context of our study, we have synthesized previously reported data on the outcomes of AS in adults with refractory ITP from reports where ≥3 cases were included and also presented reinterpretation of the initial reports by using our standardized criteria (Table V, Supporting Information). This report presents the largest single institution study of AS in relapsed ITP. Approximately one-half of both the pediatric and adult patients demonstrated a response to AS at 4 weeks of follow-up which belies the therapeutic validity of this procedure. These results are slightly more encouraging than those obtained in the original case series by Verheyden et al. [ 12] where only 4 of 15 patients (six patients from the original case series and nine from a literature review) significantly improved after splenectomy, one requiring less medication to control the thrombocytopenia. Pawelski et al. in 1981 [18] reported 12 patients who underwent AS for refractory ITP, all of whom had a complete remission after the procedure. However, this study is limited by the fact that there are no platelet counts reported at the time of diagnosis or removal of the accessory spleen. Also, the criteria for diagnosis of ITP are ambiguous, which may have lead to the inclusion of patients having thrombocytopenia that is not truly primary immune thrombocytopenia. Akwari et al. [14] contributed 9 case reports to the literature of whom 6 had a complete response to AS (66%). Their extensive review of literature involving 56 patients found an excellent response in 41 patients (73%) and a moderate response in others (27%). However, the summarization of results in this study is imprecise, as the definition of CR, PR, and NR after AS was different for each individual case series in the reports reviewed. In our experience, a 50% response rate in both adults and children makes AS a viable treatment option in patients who have a relapse of ITP after primary splenectomy. These results are encouraging, as they present AS as a potential third line therapy which can be considered in the previously reported 25–40% of patients who fail corticosteroids and splenectomy [ 4, 8-10]. Laparoscopic accessory splenectomy may represent an important treatment option for select patients with refractory ITP following splenectomy based on the present study. It would be clinically useful to gain insight into factors that predict a favorable response to AS so as to identify the patients that would most benefit from the procedure. Previous studies have listed prior response to prednisone therapy and a younger patient age as positive prognostic factors for response to primary splenectomy [ 26, 27], although these data were refuted in a larger meta-analysis. It is difficult to draw statistically significant conclusions about predictors of response to accessory splenectomy in our study owing to small cohort size. However, our series has identified three possible predictors of response to AS in adults. The female patients with refractory ITP who underwent accessory splenectomy demonstrated more favorable outcomes than male patients. The reason for this difference is unclear. As with primary splenectomy, responsiveness to initial prednisone therapy also correlated with a more favorable response to accessory splenectomy as did the absence of Howell-Jolly bodies prior to AS. This last correlate makes intuitive sense as it would be anticipated that patients lacking evidence of a functionally splenectomized state would improve after removal of residual functional splenic tissue. An important correlate to this is that an accessory spleen in a relapsed ITP patient who demonstrates abundant HJB on peripheral blood smear is likely a nonfunctional splenuncule, the removal of which would not impact the patient's disease and may instead subject them to an unnecessary surgical procedure. There have been speculations in previous case reports about possible correlation between the size of the accessory spleen and response to AS. Whereas such an association was supported by Verheyden et al. [ 12], it was refuted in the observations made by Pawelski et al. [18]. Our study failed to show any association between the size of the accessory spleen and response to AS. This is an interesting observation, as it implies that even small splenuncules may be capable of sequestering a large amount of platelets. Facon et al. indicated that platelet kinetic studies may be of value in determining predominant liver versus splenic sequestration of platelets, further adding that patients with predominant liver sequestration may not respond favorably to AS [20]. Gibson et al. looked at length of remission following primary splenectomy as a predictor of response to AS, and found no such correlation [19]. This is consistent with the findings from our series. In conclusion, laparoscopic AS remains a viable and effective treatment option for patients with refractory ITP, potentially more so in those with favorable predictors including female sex, prior brisk response to corticosteroids, and absence of HJBs on peripheral smear. It must be recognized that although minimal, there is still a measurable degree of risk involved from this invasive surgical procedure. Given the role for novel medical therapies for ITP, including rituximab [ 28] and thrombopoietin agonists [29, 30], the potential morbidity of accessory splenectomy must be weighed against its effectiveness. This study was conducted within the guidelines and approval of the institutional review board. The study cohort represents a consecutive group of patients with ITP that fulfilled the American Society of Hematology (ASH) diagnostic criteria [ 7, 22] (specifically, platelet count of ≤30,000 per microliter with or without bleeding or platelet count of <50,000 per microliter with bleeding) and underwent accessory splenectomy (84 patients). Patients were seen at the Mayo Clinic (Rochester, MN) from 1935 to 2008. Careful attention was paid to omit patients in whom the ITP may have been secondary to another condition including: patients with chronic lymphocytic leukemia, HIV, B-cell lymphoma, systemic lupus erythematosus, drug-induced thrombocytopenia, congenital, or hereditary thrombocytopenia and pancytopenia (41 patients). The study population was drawn from the remaining cohort and comprises the 14 patients who underwent therapeutic open or laparoscopic AS for refractory ITP. Four cases that have been reported previously [12, 23] are included with additional follow-up. Four pediatric patients (age at diagnosis of ITP ≤ 18 years) were analyzed separately from 10 adult patients. Patient characteristics and subsequent clinical outcomes were collected retrospectively, by chart review, and prospectively, by means of a questionnaire mailed to patients. Date and cause of death were confirmed by probing the social security death index. Response to medical and surgical interventions (splenectomy and AS) were adapted from previously defined criteria [1, 24]. Definition of major bleeding was also adapted from previously defined methods [25] as listed below. A complete response (CR) was defined as a mean platelet count of >150 × 109 per liter without concomitant therapy at 4 weeks of follow-up other than tapering steroids. A partial response (PR) was defined as a mean platelet count of >30 × 109 per liter but <150 × 109 per liter without concomitant therapy at 4 weeks of follow-up other than tapering steroids. A nonresponse (NR) was defined as a mean platelet count of <30 × 109 per liter or a mean platelet count of ≥30 × 109 per liter but requiring concomitant therapy at 4 weeks of follow-up other than tapering steroids. Major bleeding included symptomatic hemorrhage affecting the retina, the central nervous system or the retroperitoneum; any bleeding that resulted in hemodynamic instability; the need for transfusion of 2 units or more of red blood cells; or a decrease in hemoglobin level by at least 2 g/dL from baseline. Minor bleeding included all other bleeding including the presence of petechiae or purpura. Adult patients were analyzed for predictors of initial response to AS which was determined at less than or equal to 4 weeks following the procedure, as previously described [ 24]. Pediatric data was excluded from analysis given the small size of the patient cohort. The effect of demographics, clinical, and laboratory factors at diagnosis on outcome of accessory splenectomy was evaluated using Chi-squared and Fisher-Exact test statistics for comparison between categorical variables, and Mann-Whitney U for comparisons between categorical and continuous variables. Variables were identified using stepwise selection and backward elimination. Patient factors that potentially influenced the outcome of AS were analyzed using Chi-square tests. All statistical tests were two-sided; P-values less than 0.05 were considered significant. Analyses were carried out using StatView version 5.0.1 (SAS Institute, Cary, NC). Continuous variables are summarized as median (range) and discrete, categorical variables are summarized as count (percentage) unless otherwise indicated. Additional Supporting Information may be found in the online version of this article. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Gita Thanarajasingam*, Rakhee Vaidya , Andrew Erie , Alexandra P. Wolanskyj§, * Brigham and Women's Hospital, Department of Medicine, Boston, Massachusetts, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, Mayo Medical School, Mayo Clinic, Rochester, Minnesota;, § Division of Hematology, Mayo Clinic, Rochester, Minnesota.