Splenectomy versus medical treatment for idiopathic thrombocytopenic purpura

The American Journal of Surgery 184 (2002) 606 – 610

Scientific paper

Splenectomy versus medical treatment for idiopathic thrombocytopenic purpura Michael Gadensta¨tter, M.D.a,*, Bernd Lamprecht, M.D.b, Anton Klingler, Ph.D.a, Gerold J. Wetscher, M.D.a, Richard Greil, M.D.b, Thomas Schmid, M.D.a a

Department of Surgery, University of Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria b Department of Hematology and Oncology, University of Innsbruck, Innsbruck, Austria Manuscript received July 31, 2002; revised manuscript August 18, 2002

Presented at the 54th Annual Meeting of the Southwestern Surgical Congress, Coronado, California, April 7–10, 2002.

Abstract Background: Treatment strategies for idiopathic thrombocytopenic purpura (ITP) are still uncertain and its management is primarily empirical. The aim of this study was to investigate the role of splenectomy in the therapy of ITP and to evaluate whether medical or surgical treatment is superior. Methods: Ninety-two patients with ITP were included in the study. All of these patients had medical therapy and 38 of them underwent splenectomy subsequently. Follow-up was completed in 91 patients after a median of 64 months. Results: Side effects of medical therapy were noticed in 32 patients (35%), whereas after surgery only 2 patients (5%) had minor complications. A complete or partial remission was achieved in 35 patients (92%) after splenectomy, whereas this was achieved in only 27 patients (30%) after medical therapy. On multivariate analysis splenectomy and age were the only significant independent factors for complete and partial remission. Conclusions: Splenectomy is highly effective and safe in the treatment of ITP and is superior over medical therapy. These results should stimulate the discussion about splenectomy for ITP, possibly establishing evidence-based guidelines for surgical treatment in hematology. © 2002 Excerpta Medica Inc. All rights reserved. Keywords: Idiopathic thrombocytopenic purpura; Splenectomy; Medical treatment

Idiopathic thrombocytopenic purpura (ITP; also known as autoimmune thrombocytopenic purpura) is an autoimmune hematologic disease characterized by platelet destruction caused by antiplatelet autoantibodies [1]. This results in platelet phagocytosis via the reticuloendothelial system and consecutively in a variable degree of persistent thrombocytopenia. ITP is a potentially life-threatening condition, the risk for fatal bleeding events in adults ranges between 0.4% and 13% per year depending on patient age [2]. The spleen is not only the major site of antiplatelet antibody production, but also of subsequent platelet destruction. The main goal of treatment is to achieve normal platelet counts in order to prevent serious hemorrhage. However,

* Corresponding author. Tel.: ⫹43-512-504-2911; fax: ⫹43-512-5042577. E-mail address: [email protected]

appropriate treatment strategies for ITP are still a matter of debate and its management is primarily empirical. Conventional management of this disease includes glucocorticoid therapy (first-line) and surgical treatment by splenectomy (second-line) [3]. Additional treatment modalities are intravenous immunoglobulin, pulsed high-dose dexamethasone, azathioprine, INF-alpha, vinblastine and some more therapies [4]. Splenectomy offers a more definitive approach to the therapy of ITP and should be considered in patients who fail to respond to medical therapy or acquire adverse reactions, or present with severe bleeding. So far there is no clear evidence about the ideal time for surgical treatment and only some authors report about related prognostic factors in the therapy and long-term outcome of ITP [5–7]. Therefore the aim of this study was to investigate the role of splenectomy in the therapy of ITP, to evaluate whether medical or surgical treatment is superior, and to identify predictors of response.

0002-9610/02/$ – see front matter © 2002 Excerpta Medica Inc. All rights reserved. PII: S 0 0 0 2 - 9 6 1 0 ( 0 2 ) 0 1 0 9 1 - 7

M. Gadensta¨tter et al. / The American Journal of Surgery 184 (2002) 606 – 610

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Table 1 Demographic data of patients with idiopathic thrombocytopenic purpura treated by splenectomy or medical therapy alone

Splenectomy Medical treatment alone All patients

M:F ratio

Age (years)

Platelet count (g/L)

APA positive

ANA positive

13:25 20:34 33:59

36 (24–55)* 52 (32–67) 49 (30–63)

25 (12–31) 20 (7–40) 20 (9–35)

6 (12%) 11 (21%) 17 (33%)

7 (18%) 5 (13%) 12 (31%)

Values expressed as medians (interquartile range). * P ⬍ 0.05 versus medical treatment. APA ⫽ antiplatelet antibodies (determined in 52 patients); ANA ⫽ antinuclear antibodies (determined in 38 patients).

Patients and methods

Statistical analysis

The study population consisted of 92 patients with ITP, who presented to our Department of Hematology and Oncology within a 10-year period (1991 to 2000). There were 33 male and 59 female patients with a median age of 49 years (range 15 to 93). ITP was defined as an isolated thrombocytopenia (platelet count below 140 g/L) without clinically apparent associated conditions or other causes of thrombocytopenia. Patients usually presented with hemorrhagic symptoms (57 patients, 62%), 56 of them had skin or mucosal bleeding including epistaxis, hemoptysis and hypermenorrhea, and in 1 patient the diagnosis of ITP was revealed following a spontaneous intracerebral bleeding. In 35 patients (38%) who had no specific symptoms ITP was diagnosed incidentally. In the first-line all patients underwent medical therapy. Seventy-eight patients (85%) had glucocorticoid therapy alone, 9 (10%) a combination of glucocorticoid and immunoglobulin treatment and the remaining 5 patients (5%) had pulsed high dose dexamethasone, immunoglobulin, or vinblastine therapy alone. Thirtyeight patients (41%) underwent splenectomy after a median interval of 7 months (2 to 13) from the first diagnosis. Surgical treatment was indicated when patients did not respond to medical therapy or acquired adverse reactions, or presented with severe bleeding. Splenectomy was performed in all 38 patients via a midline laparatomy. A laparoscopic approach, which has become the routine procedure at our department, was applied in the following patients. However, these patients have not been included in the study owing to too short of a follow-up period. Demographic data of patients are shown in Table 1. Follow-up was completed in 91 patients (99%) after a median of 64 months (46 to 117). Complete remission (CR) was achieved when patients had normal platelet counts and required no further therapy, partial remission was achieved when patients had nearly normal platelet counts (but below the normal range of 140 to 400 g/L) and required no therapy. Failure of treatment included lack of initial response, a continuous decline in platelet count below 140 g/L during the follow-up and the need for further (medical) therapy.

Data are expressed as medians, in addition the interquartile range (IQR) is quoted. Continuous variables (eg, age, platelet count) were compared using the Wilcoxon test for unpaired observations, a chi-square test was used for nominal variables (eg, gender, response). A logistic regression analysis was applied for the evaluation of prognostic factors on complete or partial response. A P value below 0.05 was considered to be statistically significant.

Results All patients underwent medical therapy, side effects were noticed in 32 (35%) of them (Fig. 1). Of the 38 patients, who underwent splenectomy, 19 (50%) had adverse reactions to medical therapy. Splenomegaly, defined as organ size greater than 11 ⫻ 7 ⫻ 4 cm, was observed in 23 patients (25%); 10 of these patients (11%) underwent splenectomy. Postoperative complications were seen in only 2 patients (5%). One patient had a seroma in the left upper abdominal

Fig. 1. Side effects of medical therapy were noticed in 32 of the 92 patients (35%) treated for idiopathic thrombocytopenic purpura. Some patients presented with more than one adverse reaction.

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M. Gadensta¨ tter et al. / The American Journal of Surgery 184 (2002) 606 – 610

Table 2 Outcome of patients with ITP treated by splenectomy or medical therapy

Splenectomy Medical treatment

CR

PR

Failure

Lowest PC after therapy

Highest PC after therapy

33 (87%)* 15 (17%)

2 (5%)* 12 (13%)

3 (8%)* 64 (70%)

180 (150–200)* 80 (50–140)

340 (270–425)* 170 (100–230)

The lowest and highest platelet count observed during the follow-up period is shown. Values expressed as medians (interquartile range). * P ⬍ 0.05 versus medical treatment. CR ⫽ complete response; PR ⫽ partial response; PC ⫽ platelet count (g/L).

quadrant which was treated conservatively, the second patient acquired a thrombosis with consecutive renal infarction. There were no postoperative deaths. Duration of medical therapy prior to splenectomy had no influence on the development of postoperative complications. A complete or partial remission was achieved in 35 patients (92%) after splenectomy whereas only 27 patients (30%) responded to medical therapy (P ⬍ 0.05). Three patients failed to respond to splenectomy. One of the 3 splenectomy failures was APA positive and none was ANA positive. All 3 required postoperative glucocorticoid maintenance therapy, subsequently 2 of them had normal platelet counts while the third patient still had a permanent platelet count below 140 g/L. In none of these 3 patients an accessory spleen was detected by computertomography or scintigraphy. In total 4 (11%) of the 38 splenectomy patients had accessory spleens. Detailed outcome data are shown in Table 2. A stepwise logistic multivariate analysis was performed to analyze correlations between several factors and outcome of ITP treatment. The following factors were included in this analysis: age, sex, presence of symptoms, initial platelet count, antinuclear antibodies, antiplatelet antibodies, splenomegaly, megakaryocytosis, different medical therapies, and splenectomy. Age of the patients (odds ratio 1.028) and splenectomy (odds ratio 9.13) were shown to be the only significant independent predictors of complete or partial remission.

Comments Idiopathic thrombocytopenic purpura is one of the most common and well-studied hematologic diseases in which medical as well as surgical treatment strategies have been proposed. Current treatment algorithms advocate steroid administration as first-line therapy in most patients [8]. Splenectomy has been accepted as a treatment option in hematological diseases including ITP since the beginning of the 20th century [9]. In the case of ITP splenectomy is usually indicated as second-line therapy [3,8]. Although the role of the spleen in ITP has not clearly been identified the benefits of splenectomy in these patients may be considered as a combined effect of eliminating the major source of antiplatelet antibody production as well as platelet destruc-

tion [1,10]. The major goals of any treatment modality are to achieve normal platelet counts and to prevent the patient from further bleeding episodes with minimal side effects of therapy. Patients with persistent low platelet counts have a poor prognosis due to a high risk of fatal bleeding episodes [2]. Medical treatment of ITP mainly includes glucocorticoid therapy but also further treatment modalities as intravenous immunoglobulin, pulsed high-dose dexamethasone, azathioprine, INF-alpha, and vinblastine therapy [4]. The efficacy of glucocorticoid therapy usually does not exceed a complete remission rate of 60%, in case of drug discontinuation the remission rate may decrease to 30% [8,11]. Medically treated patients are likely to develop potential adverse effects of glucocorticoid therapy with all signs and symptoms of hypercortisolism. This may indicate splenectomy. Splenectomy offers a more definitive approach to the therapy of ITP and should be considered in patients who fail to respond to medical therapy or acquire adverse reactions, or present with severe bleeding. Response rates up to 90% following splenectomy are reported [5,12,13]. Our study does not only confirm these data, it furthermore demonstrates that early indication for splenectomy may be the appropriate alternative in the case of patients refractory to medical therapy. Although there is no definitive documentation about the ideal time for surgical treatment it may be suggested that splenectomy at the present time should be considered earlier to avoid severe side effects of medical therapy [14]. With the advances in surgical technology the minimally invasive approach is now applied routinely for splenectomy, and it has been shown to be as safe as the open technique with the same results regarding the outcome of ITP treatment [15–18]. The size of the spleen seems to be the only factor influencing the outcome of laparoscopic splenectomy [19]. However, usually the spleen is rather small in ITP patients. There are also concerns about residual splenic function due to accessory spleens not detected during laparoscopic surgery. The incidence of accessory spleens varies between 15% to 20% and may influence the clinical outcome of splenectomy for ITP [4,20]. If accessory spleens are left behind they can result in relapse of ITP [8,21]. However, if this circumstance occurs an accessory spleen can be removed successfully by a second minimal invasive approach [22]. In our series of patients none of the 3 nonresponders to

M. Gadensta¨ tter et al. / The American Journal of Surgery 184 (2002) 606 – 610

splenectomy had an accessory spleen left behind. This may be due to the fact that splenectomy was performed via laparatomy in all patients with a consequent stepwise search for accessory spleens comparable with staging laparatomies for other oncological diseases. There is still a lack of prognostic factors for splenectomy in ITP. In our series of patients, only patient age and splenectomy were shown to be significant independent predictors of outcome. Younger patients had a higher probability for a better outcome than older patients did. Several authors confirm that age is a predictive factor of long-term response to splenectomy [6,7,23]. Contrary to our results, some authors describe an influence of sex, positivity of ANA, and prior response or nonresponse to medical therapy as predictors of outcome following splenectomy [5,23–25]. Summarizing these data it may be suggested that especially younger ITP patients (younger than 40 years) should earlier be referred to the surgeon and that a proper selection of patients for splenectomy may further improve the outcome. According to our experience we suggest that patients should be referred to splenectomy if medical therapy of 3 to 6 months fails. We conclude that splenectomy is highly effective and safe in the treatment of ITP and superior over various medical therapies. Concurrently with the well-known advantages of minimal invasive surgery these results should stimulate the discussion about splenectomy for ITP, perhaps establishing evidence-based guidelines for surgical treatment in hematology.

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Discussion John Potts (Houston, TX): This is a very nice series of 38 patients who underwent splenectomy for ITP out of a total of 92 patients seen in their unit over about a 10-year period. They’ve done so with a very admirably low complication rate and also with a full five years of follow-up which allows them to support their conclusions. Hypothesis is that splenectomy is superior to medical therapy for ITP. Indeed in their experience it appears to be so in that 87% of their patients who underwent splenectomy had a complete response and another 5% had a partial response compared to a 49% failure rate with medical therapy. I do have some questions for Dr. Gadenstatter. First, you state that your indications for operation include the failure of medical therapy yet 26 patients out of the 92 failed medical therapy and