Abstract

Splenectomy has been a standard treatment for adult patients with idiopathic thrombocytopenic purpura (ITP) for more than 50 years. However, the durability of responses, the ability to predict who will respond, and the frequency of surgical complications with splenectomy all remain uncertain. To better interpret current knowledge we systematically identified and reviewed all 135 case series, 1966 to 2004, that described 15 or more consecutive patients who had splenectomy for ITP and that had data for 1 of these 3 outcomes. Complete response was defined as a normal platelet count following splenectomy and for the duration of follow-up with no additional treatment. Forty-seven case series reported complete response in 1731 (66%) of 2623 adult patients with follow-up for 1 to 153 months; complete response rates did not correlate with duration of follow-up (r = -0.103, P = .49). None of 12 preoperative characteristics that have been reported consistently predicted response to splenectomy. Mortality was 1.0% (48 of 4955 patients) with laparotomy and 0.2% (3 of 1301 patients) with laparoscopy. Complication rates were 12.9% (318 of 2465) with laparotomy and 9.6% (88 of 921 patients) with laparoscopic splenectomy. Although the risk of surgery is an important consideration, splenectomy provides a high frequency of durable responses for adult patients with ITP. (Blood. 2004; 104:2623-2634)

Introduction

Splenectomy was the primary treatment for idiopathic (immune) thrombocytopenic purpura (ITP) prior to the introduction of glucocorticoids more than 50 years ago.1  For the past 50 years, splenectomy has remained a standard treatment for adults with ITP who do not respond to glucocorticoid treatment or who continue to require glucocorticoids to sustain a safe platelet count.2-4  Yet even after decades of experience, important questions concerning splenectomy for ITP remain unresolved.

  1. What is the durability of complete responses achieved with splenectomy? Although many case series describe complete remissions in about two thirds of patients,2-4  some studies have reported a continuing occurrence of relapses with long-term follow-up.5,6  It has even been suggested that relapse of ITP may occur in most patients if follow-up after splenectomy is sufficiently long.7  Therefore, the durability of responses to splenectomy is uncertain.

  2. Can any preoperative characteristic predict the success of splenectomy? Multiple patient and disease characteristics have been reported to predict response to splenectomy, but the findings are inconsistent. Therefore, the clinical value of any preoperative characteristic is unknown.

  3. What are the mortality and morbidity of splenectomy for ITP? Splenectomy has been considered to be a safe procedure,2,4  but, because death caused by bleeding in patients with ITP is uncommon, 2 (1.6%) of 134 patients8  and 1 (0.4%) of 245 patients9  in 2 case series, death caused by splenectomy must be low to be acceptable. Complications of splenectomy may be substantial; one case series reported surgery-related death in 1 (1.3%) and postoperative complications resulting in prolonged hospitalization or readmission in 20 (26%) of 78 patients.8  Therefore, the relative risks and benefits of splenectomy are uncertain.

To understand and interpret the large number of publications on these issues, a systematic review10,11  of all articles describing splenectomy for ITP since 1966 was performed. This review focuses on ITP in adults because spontaneous remissions may occur in many children with persistent thrombocytopenia12 ; therefore, splenectomy is rarely performed.13 

Methods

Literature search

Ovid software was used to search the Medline database from January 1, 1966, to February 29, 2004. Case series published prior to 1966 were not retrieved, because they often included patients treated before 1950, for whom splenectomy was performed as the primary treatment, before glucocorticoids became available.1  Also, some current supportive care measures, such as platelet transfusions and intravenous immunoglobulin, were not available prior to 1966. All terms were keyword searched by using unlimited truncation, retrieving articles identified by “splenec:,” “spleen and remov:,” or “spleen and extract:” that were also identified by “thrombocytopenia,” “thrombocytopenic purpura,” “ITP,” or “AITP.” The search was limited to English-language articles. The bibliographies of all retrieved articles were searched for additional relevant articles.

Article selection criteria

Articles published in pediatric journals and articles describing splenic radiation, ultrasound, or embolization were not retrieved. Retrieved articles were selected for review if they reported 15 or more consecutive patients who had splenectomy for ITP and who were followed for at least 1 month after splenectomy, and if they contained data on 1 or more of the 3 outcomes of interest: (1) platelet count response, (2) predictors of response, or (3) surgical complications. Articles reporting fewer than 15 patients were excluded to avoid reports of exceptional patients; however, the bibliographies of these articles as well as the bibliographies of review articles with no patient data were searched to identify additional articles. Case series were not reviewed if it was clear that patient accrual was not consecutive. When multiple case series reported the same or a cumulative group of patients, only the most inclusive case series was selected. Articles describing only group data were selected only if it was clear that all reported patients had had a splenectomy for ITP. Articles were excluded if the data were insufficient to distinguish patients with ITP from patients with disorders other than ITP. When the original authors described their patients as having ITP, we accepted their diagnosis even though some investigators included patients with evidence for other autoimmune disorders within their definition of ITP.

Articles that reported data on children that could not be distinguished from data on adults were included only if it could be determined that 75% or more of the patients were 14 years old or older, or if the case series focused on adults and the mean or median age reflected the adult population, but the range of ages included children. Adults were defined as being 14 years old or older because this was the predominant age distinction for children and adults in the reviewed articles. To assess platelet count response, case series reporting only adults and case series that included both adults and children were analyzed separately. Case series with up to 25% children were not excluded from this review because they accounted for 38 (45%) of all 85 articles that could be analyzed for platelet count response.

Article assessment

In most articles, selection criteria were apparent. For articles in which criteria were unclear, the decision for selection was made by consensus among all authors. Each selected article was reviewed independently by 2 or more of the authors with the use of a standard form and a priori criteria for outcome assessments. Disagreements were resolved by consensus among all of the authors.

Assessment of platelet count response

The platelet count response of patients who survived splenectomy is described in relation to follow-up duration; therefore, patients were not included unless follow-up duration after splenectomy was reported. The platelet count determining a response was defined as the first count obtained after at least 1 month following surgery, to avoid the influence of perioperative treatment for ITP. (1) Complete response was defined as achievement and maintenance of a normal platelet count (> 150 × 109/L or as defined in the original report and at least 100 × 109/L) for all measurements 30 days or longer after splenectomy, and with no additional treatment for ITP, except for the tapering of perioperative glucocorticoids or other treatments. (2) Partial response was defined as achievement of a platelet count of 50 × 109/L (or 30 × 109/L in recent publications) or more for any measurement of 30 days or longer after splenectomy, with or without other treatment, excluding patients who qualify for complete response. Therefore, patients who relapsed after initially achieving a normal platelet count were considered to have a partial response. Some articles only described complete responses and did not describe partial responses. (3) No response was defined as failure to achieve a platelet count of 50 × 109/L (or 30 × 109/L in recent publications) for any measurement of 30 days or longer after splenectomy. If individual patient platelet counts were not reported, the investigators' description of the group response was accepted if it was clear that the responses were consistent with these criteria. Our definition of a complete response is clear but restrictive; other patients who are defined in this review as having a partial response or no response may have had substantial benefit from splenectomy. Although some patients defined as having a partial response may have had only a transient, trivial increase of their platelet count, others may have had a clinically important increase in their platelet count and required no further treatment. Also some patients defined as having no response may have had a substantially increased platelet count. These distinctions among patients defined as having a partial response or no response were not possible in most articles.

Relapse was defined as the recurrence of thrombocytopenia following initial achievement of a normal platelet count. It was not possible to distinguish patients who had a recurrence of only transient, mild thrombocytopenia from patients who had recurrent severe, symptomatic thrombocytopenia. Thirty-seven articles that could be evaluated for platelet count response could not be evaluated for relapse because only a single platelet count was reported, the time of relapse was not reported, or it was not clear whether the patients had ever achieved a normal platelet count.

Because of the frequency of spontaneous remissions in children with chronic ITP,12  data from case series that included up to 25% children and in which data on children and adults could not be distinguished were analyzed separately from case series reporting only adult patients. Because the technique of splenectomy should not affect the platelet count response, data from case series reporting open laparotomy and laparoscopy were combined for this analysis.

Assessment of predictors of response

Articles were analyzed only if data were presented to support the conclusion that a variable did or did not predict a response to splenectomy. Therefore, articles that did not present a statistical analysis of their data, or did not present data from which we could calculate a P value, were excluded from this analysis. Application of uniform criteria or analysis of pooled data from different articles was not possible because case series assessed different demographic, clinical, and laboratory variables in different ways and used different definitions for a successful outcome. Also the methodology of techniques, such as determination of the site of platelet sequestration, was different among the articles. Variables reported in each article were categorized as predictive, not predictive, or not interpretable. We reported variables as predictive if (1) the observed difference was statistically significant and (2) the correlation was persistent for the duration of patient follow-up. If the original authors had performed a multivariate analysis, only the variables that were determined to independently correlate with response after adjustment for other variables were accepted as predictive. If no statistical comparison was made in the original article, we performed an appropriate statistical test to obtain the P value. If appropriate statistical evaluation of the presented data showed no significant correlation of a variable, but the original authors had reported the variable as predictive, we categorized the variable as not interpretable.

Because the technique of splenectomy should not affect the platelet count response, data from case series reporting open laparotomy and laparoscopy were combined for this analysis. Data from case series of adults only and adults plus children were also combined; although patient age may affect the response to splenectomy, age was analyzed as one of the prediction variables.

Assessment of surgical complications

Complications related to splenectomy were defined as those occurring within 30 days of splenectomy, or later if the complication occurred during the original hospitalization for splenectomy. Complications beyond the postoperative period, such as overwhelming sepsis14  and thrombosis15-17  that may be attributable to the absence of the spleen, were not analyzed. Even if an article did not explicitly address surgical complications, data were included in the analysis of surgical mortality if deaths were reported or if it was clear that no patients had died.

Because the technique of splenectomy may affect the risk for surgical complications, case series describing open laparotomy and laparoscopic procedures are described separately. For articles that accrued patients prior to 1991, the year of the first report of laparoscopic splenectomy for ITP,18  and the surgical technique was not defined, it was assumed that splenectomy was performed by open laparotomy. However, if patient accrual began during or after 1991 and the surgical technique was not defined, the article was not included in this analysis. If the article stated that both open laparotomy and laparoscopy were performed but the data did not distinguish these techniques, the article was not included in this analysis. Data from case series reporting adults only and adults plus children were combined for this analysis.

Statistical methods

All data were entered into a Microsoft Access (Redmond, WA) database. The correlation between duration of follow-up and the complete response rate and between duration of follow-up and the relapse rate were evaluated by the Spearman correlation coefficient; the corresponding graphs were produced with Microsoft Excel (Redmond, WA). When it was necessary to analyze data from the reviewed articles for correlation of prediction variables with response, we used the chi-square test of independence to evaluate differences between rates of platelet count response to splenectomy across categorical variables. Mortality rates with open laparotomy and laparoscopic techniques were compared by using Fisher exact test; morbidity rates were compared by using the chi-square test. A 2-sided P less than .05 was considered statistically significant.

Results

The literature search identified 436 articles (Figure 1); 306 articles did not meet our selection criteria and were not reviewed. We selected 130 articles that reported 15 or more consecutive patients who had splenectomy for ITP and that presented evaluable data on 1 or more of the 3 outcomes of interest: (1) platelet count response, (2) predictors of response, or (3) surgical complications. Patient accrual in these articles spanned 58 years, from 1944 to 2002, and the articles represent the experience of 29 countries (Table 1). These 130 articles contained 135 case series, as 5 articles describing surgical techniques reported separate case series for laparotomy and laparoscopic splenectomy.100,102,103,105,140  In 9 of the case series,9,45,59,88,94,115,130,134,141  patients were enrolled and analyzed prospectively for long-term platelet count responses. Two of the 9 prospective case series were randomized trials in which splenectomy was part of the treatment in both groups.59,141  No case series compared splenectomy with either a nonsurgical form of treatment or observation. In 4 other case series, only collection of perioperative data was performed prospectively91,114,120,139 ; the remaining 122 case series were retrospective analyses. The numbers of case series and patients analyzed for each of the different outcomes are presented in Figure 1.

Figure 1.

Article and patient selection. Articles were retrieved for review if their journal, title, or abstract suggested that they contained evaluable data on eligible patients and indicated that the articles did not report primarily on children. Retrieved articles were selected for review if they reported 15 or more consecutive patients who had splenectomy for ITP and who were followed for at least 1 month after splenectomy, and if they contained data on 1 or more of the 3 outcomes of interest: (1) platelet count response, (2) predictors of response, or (3) surgical complications.

Figure 1.

Article and patient selection. Articles were retrieved for review if their journal, title, or abstract suggested that they contained evaluable data on eligible patients and indicated that the articles did not report primarily on children. Retrieved articles were selected for review if they reported 15 or more consecutive patients who had splenectomy for ITP and who were followed for at least 1 month after splenectomy, and if they contained data on 1 or more of the 3 outcomes of interest: (1) platelet count response, (2) predictors of response, or (3) surgical complications.

Table 1.

Case series reporting 15 or more consecutive patients with splenectomy for ITP that contain data on platelet count response, predictors of response, or surgical death and complications


Publication date and accrual years

Reference

Country

No. patients

No. splx ITP patients

Splx method

Complete response (%)

Evaluated predictors of response

Evaluated deaths and complications
1966         
1952-1965   Kwietniak19  Poland   119   35   OS   —   No   Yes  
1967         
1949-1966   Wilde et al20  United States   43   42   OS   —   Yes   Yes  
1968         
1952-1964   Nordoy and Neset21  Norway   179   43   OS   32/37 (86)   No   Yes  
1970         
1951-1966   Orringer et al22  United States   23   23   OS   14/19 (74)   Yes   Yes  
1959-1967   Horta et al23  United States   34   15   OS   10/15 (67)   No   Yes  
1950-1967   Hodam24  United States   310   34   OS   —   No   Yes  
1972         
1945-1970   Thompson et al25  United States   66   36   OS   24/35 (69)   Yes   Yes  
1973         
1956-1971   JiJi et al26  United States   92   51   OS   34/51 (67)   No   Yes  
1974         
1944-1970   Ogawa et al27  Japan   53   33   OS   —   No   Yes  
1975         
1962-1970   Cowick and Leon28  United States   693   21   OS   —   No   Yes  
1967-1974   Brennan et al29  United States   29   29   OS   —   Yes   Yes  
—   MacPherson and Richmond30  United Kingdom   72   72   OS   54/71 (76)   Yes   Yes  
1977         
—   Ries31  United States   34   28   OS   20/28 (71)   Yes   Yes  
1978         
—   Burger et al32  Hungary   86   40   OS   26/40 (65)   Yes   Yes  
1966-1973   Ikkala et al33  Finland   41   24   OS   13/24 (54)   Yes   Yes  
1979         
1967-1979   Laws et al34  United States   130   26   OS   —   No   Yes  
1980         
1971-1979   DiFino et al35  United States   62   37   OS   18/37 (49)   Yes   Yes  
1966-1978   Butoianu36  Romania   188   110   OS   —   No   Yes  
1959-1969   Picozzi et al37  United States   38   36   OS   21/36 (58)   No   Yes  
1947-1978   Schwartz et al38  United States   478   120   OS   101/115 (88)   No   Yes  
1981         
1965-1979   Mintz et al39  United States   481   71   OS   33/45 (73)   No   No  
1964-1977   Pawelski et al40  Poland   177   177   OS   80/118 (68)   No   Yes  
1974-1980   Rubins and Woll41  United States   28   18   OS   12/17 (71)   No   Yes  
1968-1977   Ly and Albrechtsen42  Norway   221   80   OS   —   No   Yes  
1982         
1953-1977   Gruenberg et al43  United States   98   98   OS   79/98 (81)   Yes   Yes  
1983         
—   Kernoff and Malan44  South Africa   67   49   OS   —   Yes   No  
—   Kayser et al45  Germany   16   16   OS   9/15 (60)   Yes   Yes  
1984         
1973-1983   Rocco and Stein46  United States   42   42   OS   23/40 (58)   Yes   Yes  
—   den Ottolander et al47  Netherlands   168   75   OS   21/44 (48)   Yes   Yes  
1967-1980   Salky et al48  United States   69   69   OS   56/69 (81)   No   Yes  
—   Pizzuto and Ambriz49  South America   934   398   OS   259/398 (65)   Yes   Yes  
1956-1981   Musser et al50  United States   306   65   OS   50/64 (78)   No   Yes  
1985         
1979-1984   Schwartz51  United States   129   29   OS   —   No   Yes  
1986         
—   Yasunaga52  Japan   1669   399   OS   —   Yes   No  
1975-1984   Kochupillai et al53  India   90   27   OS   20/27 (74)   Yes   Yes  
1974-1983   Malmaeus et al54  Sweden   167   52   OS   —   No   Yes  
1971-1981   Jacobs et al55  South Africa   148   102   OS   64/98 (65)   Yes   Yes  
1987         
1975-1985   Akwari et al56  United States   565   100   OS   58/100 (58)   Yes   Yes  
1975-1985   Lee et al57  Taiwan   113   32   OS   20/32 (63)   No   Yes  
1969-1983   Dawson et al58  United Kingdom   185   34   OS   —   No   Yes  
1983-1986   Lang et al59  France   26   26   OS   19/26 (73)   No   Yes  
—   Russo et al60  Italy   119   119   OS   78/119 (66)   Yes   Yes  
1967-1987   Coon61  United States   216   216   OS   156/215 (73)   Yes   Yes  
1988         
1963-1982   Wilhelm et al62  United States   400   72   OS   —   No   Yes  
1979-1986   Grant et al63  United Kingdom   106   30   OS   21/25 (84)   No   Yes  
1962-1985   Wanachiwanawin et al64  Thailand   698   146   OS   —   No   Yes  
1954-1983   Guthrie et al65  United States   40   25   OS   —   No   Yes  
1989         
1981-1988   Siegel et al66  United States   59   19   OS   13/19 (68)   Yes   Yes  
1973-1986   Fenaux et al67  France   181   181   OS   136/181 (75)   Yes   Yes  
1979-1987   Shaw and Clark68  New Zealand   148   48   OS   —   Yes   Yes  
1990         
—   Julia et al69  Spain   138   138   OS   91/138 (66)   Yes   Yes  
1974-1986   Johansson et al70  Sweden   200   20   OS   —   No   Yes  
1979-1987   Centurioni et al71  Italy   137   16   OS   11/16 (69)   No   No  
1983-1985   Nieminen72  Finland   109   38   OS   27/38 (71)   Yes   Yes  
1991         
1985-1990   Najean et al73  France   222   103   OS   64/89 (72)   Yes   Yes  
1970-1989   Hoefer et al74  United States   59   17   OS   —   No   Yes  
1992         
1974-1989   MacRae et al75  Canada   142   69   OS   —   No   Yes  
1981-1991   Ketley et al76  United Kingdom   72   24   OS   —   No   Yes  
1984-1990   Chirletti et al77  Italy   70   70   OS   63/70 (90)   Yes   No  
—   Dan et al78  Japan   247   72   OS   17/60 (28)   No   Yes  
1993         
1979-1990   Naouri et al79  France   72   72   OS   51/71 (72)   Yes   Yes  
1984-1990   Lamy et al80  France   111   51   OS   34/51 (67)   Yes   Yes  
1962-1987   Wanachiwanawin et al81  Thailand   416   142   OS   62/126 (49)   Yes   No  
1970-1989   Schiavotto and Rodeghiero82  Italy   490   178   OS   93/133 (70)   Yes   No  
1994         
1977-1987   Ben-Yehuda et al83  Israel   712   173   OS   105/146 (72)   No   Yes  
1995         
1992-1994   Emmermann et al84  Germany   27   19   LS   —   No   Yes  
1980-1993   Linares et al85  Spain   118   32   OS   —   No   Yes  
1978-1988   Stasi et al86  Italy   208   63   OS   23/63 (37)   Yes   Yes  
1978-1992   Aksnes et al87  Norway   135   45   OS   —   No   Yes  
1992-1994   Gigot et al88  Belgium   50   31   LS   22/29 (76)   No   Yes  
1996         
1968-1993   Hashizume et al89  Japan   41   41   OS   26/41 (63)   No   Yes  
1990-1996   Brunt et al90  United States   26   17   LS   13/17 (76)   No   Yes  
1992-1995   Flowers et al91  United States   43   22   LS   18/21 (86)   No   Yes  
1986-1992   Jameson et al92  United Kingdom   64   28   OS   21/28 (75)   No   Yes  
1976-1996   Shiino et al93  Japan   26   26   OS   15/26 (58)   Yes   Yes  
1984-1991   Winde et al94  Germany   72   72   OS   52/70 (74)   Yes   Yes  
1993-1995   Kitano et al95  Japan   24   20   LS   —   No   Yes  
1993-1996   Zamir et al96  Israel   17   15   LS   15/15 (100)   No   Yes  
1997         
1985-1995   Watson et al97  Australia   47   47   OS   39/47 (83)   No   Yes  
—   Schneider et al98  Germany   158   49   —   —   Yes   No  
1990-1994   Bohner et al99  Germany   56   24   OS   —   No   Yes  
1992-1996   Glasgow et al100  United States   28   16   OS   —   No   Yes  
1992-1996   Glasgow et al100  United States   52   23   LS   —   No   Yes  
1980-1994   Mittelman et al101  Israel   69   18   OS   14/18 (78)   No   Yes  
1991-1996   Friedman et al102  United States   74   19   OS   —   No   Yes  
1991-1996   Friedman et al102  United States   63   30   LS   —   No   Yes  
1998         
1990-1997   Lozano-Salazar et al103  Mexico   27   27   OS   15/25 (60)   No   Yes  
1990-1997   Lozano-Salazar et al103  Mexico   22   22   LS   12/21 (57)   No   Yes  
1988-1997   Lord et al104  Australia   34   20   OS   —   No   Yes  
1993-1997   Yuan et al105  Taiwan   22   17   OS   —   No   Yes  
1993-1997   Yuan et al105  Taiwan   30   26   LS   —   No   Yes  
1999         
1992-1997   Harold et al106  United States   27   27   LS   19/26 (73)   Yes   Yes  
1983-1992   Shimomatsuya and Horiuchi107  Japan   20   20   OS   6/16 (38)   No   Yes  
1994-1997   Brody et al108  United States   27   27   LS   24/25 (96)   No   Yes  
—   Louwes et al109  Netherlands   141   47   —   30/47 (64)   Yes   No  
1979-1999   Mazzucconi et al110  Italy   94   94   —   53/81 (65)   Yes   No  
1994-1999   Chung et al111  Korea   40   40   LS   28/40 (70)   Yes   Yes  
—   Ruivard et al112  France   75   75   —   —   Yes   No  
1992-1997   Stanton113  United States   30   30   LS   —   No   Yes  
1993-1998   Donini et al114  Italy   44   24   LS   —   No   Yes  
1992-1997   Tanoue et al115  Japan   76   35   LS   21/35 (60)   No   Yes  
2000         
1982-1998   Vecchio et al116  Italy   26   26   OS   21/26 (81)   Yes   No  
1978-1998   Radaelli et al117  Italy   65   65   —   44/65 (68)   Yes   No  
1992-1999   Bagdasarian et al118  United States   33   22   LS   14/22 (64)   No   Yes  
1982-1995   Wani and Parray119  India   41   41   OS   —   No   Yes  
1993-2000   Park et al120  United States, Canada   203   129   LS   —   No   Yes  
1994-1999   Gibson et al121  United States   27   27   OS,LS   24/27 (89)   No   No  
1993-1999   Trias et al122  Spain   111   48   LS   37/46 (80)   No   Yes  
2001         
1974-1994   Portielje et al8  Netherlands   152   78   OS   51/60 (85)   No   Yes  
1960-1999   Leung et al123  Hong Kong   220   37   OS   —   Yes   No  
1992-1997   Katkhouda et al124  United States, France   67   67   LS   52/67 (78)   Yes   Yes  
—   Fabris et al5  Italy   61   61   —   31/54 (57)   Yes   No  
1987-1994   Bussel et al125  United States, Canada   61   24   OS   —   Yes   No  
1987-1998   Choi et al126  Korea   107   79   OS,LS   —   Yes   No  
2002         
1984-2000   Pamuk et al127  Turkey   321   76   —   33/57 (58)   No   No  
1995-1998   Chan et al128  Australia   31   20   LS   —   No   Yes  
1991-2000   Gadenstatter et al129  Austria   92   38   OS   33/38 (87)   No   Yes  
—   Szold et al130  Israel   104   104   LS   82/102 (80)   No   Yes  
1985-1998   Kumar et al131  United States   140   140   OS,LS   78/106 (74)   Yes   No  
1997-2001   Torelli et al132  Italy   43   23   LS   15/23 (65)   No   Yes  
1993-1998   Bresler et al133  France   27   27   LS   18/27 (67)   No   Yes  
—   Rossi et al134  Italy   25   25   —   14/25 (56)   Yes   No  
1991-1998   Delaitre et al135  France   209   195   LS   —   No   Yes  
2003         
1993-1999   Neylon et al9  United Kingdom   245   30   —   21/28 (75)   No   No  
1983-1996   Srinivasan et al136  India   364   71   —   30/59 (51)   Yes   No  
1990-2001   Zoghlami-Rintelen et al137  Austria   56   48   OS,LS   31/48 (65)   Yes   Yes  
1985-1994   Bourgeois et al138  France   183   183   OS   159/183 (87)   Yes   Yes  
1992-2000   Pace et al139  Canada   52   52   LS   —   No   Yes  
1988-1993   Schwartz et al6  Israel, United States   56   56   OS   32/56 (57)   Yes   Yes  
1995-2000   Cordera et al140  United States   44   44   OS   —   No   Yes  
1995-2000   Cordera et al140  United States   42   42   LS   —   No   Yes  
1997-2000   George et al141  United States   70   28   —   15/28 (54)   No   No  
1985-1994   Andres et al142  France   139   55   OS,LS   33/55 (60)   Yes   No  
1996-2002   Knauer et al143  United States   101   48   LS   —   No   Yes  
2004         
1995-2001
 
Duperier et al144
 
United States
 
67
 
67
 
LS
 
43/67 (64)
 
Yes
 
Yes
 

Publication date and accrual years

Reference

Country

No. patients

No. splx ITP patients

Splx method

Complete response (%)

Evaluated predictors of response

Evaluated deaths and complications
1966         
1952-1965   Kwietniak19  Poland   119   35   OS   —   No   Yes  
1967         
1949-1966   Wilde et al20  United States   43   42   OS   —   Yes   Yes  
1968         
1952-1964   Nordoy and Neset21  Norway   179   43   OS   32/37 (86)   No   Yes  
1970         
1951-1966   Orringer et al22  United States   23   23   OS   14/19 (74)   Yes   Yes  
1959-1967   Horta et al23  United States   34   15   OS   10/15 (67)   No   Yes  
1950-1967   Hodam24  United States   310   34   OS   —   No   Yes  
1972         
1945-1970   Thompson et al25  United States   66   36   OS   24/35 (69)   Yes   Yes  
1973         
1956-1971   JiJi et al26  United States   92   51   OS   34/51 (67)   No   Yes  
1974         
1944-1970   Ogawa et al27  Japan   53   33   OS   —   No   Yes  
1975         
1962-1970   Cowick and Leon28  United States   693   21   OS   —   No   Yes  
1967-1974   Brennan et al29  United States   29   29   OS   —   Yes   Yes  
—   MacPherson and Richmond30  United Kingdom   72   72   OS   54/71 (76)   Yes   Yes  
1977         
—   Ries31  United States   34   28   OS   20/28 (71)   Yes   Yes  
1978         
—   Burger et al32  Hungary   86   40   OS   26/40 (65)   Yes   Yes  
1966-1973   Ikkala et al33  Finland   41   24   OS   13/24 (54)   Yes   Yes  
1979         
1967-1979   Laws et al34  United States   130   26   OS   —   No   Yes  
1980         
1971-1979   DiFino et al35  United States   62   37   OS   18/37 (49)   Yes   Yes  
1966-1978   Butoianu36  Romania   188   110   OS   —   No   Yes  
1959-1969   Picozzi et al37  United States   38   36   OS   21/36 (58)   No   Yes  
1947-1978   Schwartz et al38  United States   478   120   OS   101/115 (88)   No   Yes  
1981         
1965-1979   Mintz et al39  United States   481   71   OS   33/45 (73)   No   No  
1964-1977   Pawelski et al40  Poland   177   177   OS   80/118 (68)   No   Yes  
1974-1980   Rubins and Woll41  United States   28   18   OS   12/17 (71)   No   Yes  
1968-1977   Ly and Albrechtsen42  Norway   221   80   OS   —   No   Yes  
1982         
1953-1977   Gruenberg et al43  United States   98   98   OS   79/98 (81)   Yes   Yes  
1983         
—   Kernoff and Malan44  South Africa   67   49   OS   —   Yes   No  
—   Kayser et al45  Germany   16   16   OS   9/15 (60)   Yes   Yes  
1984         
1973-1983   Rocco and Stein46  United States   42   42   OS   23/40 (58)   Yes   Yes  
—   den Ottolander et al47  Netherlands   168   75   OS   21/44 (48)   Yes   Yes  
1967-1980   Salky et al48  United States   69   69   OS   56/69 (81)   No   Yes  
—   Pizzuto and Ambriz49  South America   934   398   OS   259/398 (65)   Yes   Yes  
1956-1981   Musser et al50  United States   306   65   OS   50/64 (78)   No   Yes  
1985         
1979-1984   Schwartz51  United States   129   29   OS   —   No   Yes  
1986         
—   Yasunaga52  Japan   1669   399   OS   —   Yes   No  
1975-1984   Kochupillai et al53  India   90   27   OS   20/27 (74)   Yes   Yes  
1974-1983   Malmaeus et al54  Sweden   167   52   OS   —   No   Yes  
1971-1981   Jacobs et al55  South Africa   148   102   OS   64/98 (65)   Yes   Yes  
1987         
1975-1985   Akwari et al56  United States   565   100   OS   58/100 (58)   Yes   Yes  
1975-1985   Lee et al57  Taiwan   113   32   OS   20/32 (63)   No   Yes  
1969-1983   Dawson et al58  United Kingdom   185   34   OS   —   No   Yes  
1983-1986   Lang et al59  France   26   26   OS   19/26 (73)   No   Yes  
—   Russo et al60  Italy   119   119   OS   78/119 (66)   Yes   Yes  
1967-1987   Coon61  United States   216   216   OS   156/215 (73)   Yes   Yes  
1988         
1963-1982   Wilhelm et al62  United States   400   72   OS   —   No   Yes  
1979-1986   Grant et al63  United Kingdom   106   30   OS   21/25 (84)   No   Yes  
1962-1985   Wanachiwanawin et al64  Thailand   698   146   OS   —   No   Yes  
1954-1983   Guthrie et al65  United States   40   25   OS   —   No   Yes  
1989         
1981-1988   Siegel et al66  United States   59   19   OS   13/19 (68)   Yes   Yes  
1973-1986   Fenaux et al67  France   181   181   OS   136/181 (75)   Yes   Yes  
1979-1987   Shaw and Clark68  New Zealand   148   48   OS   —   Yes   Yes  
1990         
—   Julia et al69  Spain   138   138   OS   91/138 (66)   Yes   Yes  
1974-1986   Johansson et al70  Sweden   200   20   OS   —   No   Yes  
1979-1987   Centurioni et al71  Italy   137   16   OS   11/16 (69)   No   No  
1983-1985   Nieminen72  Finland   109   38   OS   27/38 (71)   Yes   Yes  
1991         
1985-1990   Najean et al73  France   222   103   OS   64/89 (72)   Yes   Yes  
1970-1989   Hoefer et al74  United States   59   17   OS   —   No   Yes  
1992         
1974-1989   MacRae et al75  Canada   142   69   OS   —   No   Yes  
1981-1991   Ketley et al76  United Kingdom   72   24   OS   —   No   Yes  
1984-1990   Chirletti et al77  Italy   70   70   OS   63/70 (90)   Yes   No  
—   Dan et al78  Japan   247   72   OS   17/60 (28)   No   Yes  
1993         
1979-1990   Naouri et al79  France   72   72   OS   51/71 (72)   Yes   Yes  
1984-1990   Lamy et al80  France   111   51   OS   34/51 (67)   Yes   Yes  
1962-1987   Wanachiwanawin et al81  Thailand   416   142   OS   62/126 (49)   Yes   No  
1970-1989   Schiavotto and Rodeghiero82  Italy   490   178   OS   93/133 (70)   Yes   No  
1994         
1977-1987   Ben-Yehuda et al83  Israel   712   173   OS   105/146 (72)   No   Yes  
1995         
1992-1994   Emmermann et al84  Germany   27   19   LS   —   No   Yes  
1980-1993   Linares et al85  Spain   118   32   OS   —   No   Yes  
1978-1988   Stasi et al86  Italy   208   63   OS   23/63 (37)   Yes   Yes  
1978-1992   Aksnes et al87  Norway   135   45   OS   —   No   Yes  
1992-1994   Gigot et al88  Belgium   50   31   LS   22/29 (76)   No   Yes  
1996         
1968-1993   Hashizume et al89  Japan   41   41   OS   26/41 (63)   No   Yes  
1990-1996   Brunt et al90  United States   26   17   LS   13/17 (76)   No   Yes  
1992-1995   Flowers et al91  United States   43   22   LS   18/21 (86)   No   Yes  
1986-1992   Jameson et al92  United Kingdom   64   28   OS   21/28 (75)   No   Yes  
1976-1996   Shiino et al93  Japan   26   26   OS   15/26 (58)   Yes   Yes  
1984-1991   Winde et al94  Germany   72   72   OS   52/70 (74)   Yes   Yes  
1993-1995   Kitano et al95  Japan   24   20   LS   —   No   Yes  
1993-1996   Zamir et al96  Israel   17   15   LS   15/15 (100)   No   Yes  
1997         
1985-1995   Watson et al97  Australia   47   47   OS   39/47 (83)   No   Yes  
—   Schneider et al98  Germany   158   49   —   —   Yes   No  
1990-1994   Bohner et al99  Germany   56   24   OS   —   No   Yes  
1992-1996   Glasgow et al100  United States   28   16   OS   —   No   Yes  
1992-1996   Glasgow et al100  United States   52   23   LS   —   No   Yes  
1980-1994   Mittelman et al101  Israel   69   18   OS   14/18 (78)   No   Yes  
1991-1996   Friedman et al102  United States   74   19   OS   —   No   Yes  
1991-1996   Friedman et al102  United States   63   30   LS   —   No   Yes  
1998         
1990-1997   Lozano-Salazar et al103  Mexico   27   27   OS   15/25 (60)   No   Yes  
1990-1997   Lozano-Salazar et al103  Mexico   22   22   LS   12/21 (57)   No   Yes  
1988-1997   Lord et al104  Australia   34   20   OS   —   No   Yes  
1993-1997   Yuan et al105  Taiwan   22   17   OS   —   No   Yes  
1993-1997   Yuan et al105  Taiwan   30   26   LS   —   No   Yes  
1999         
1992-1997   Harold et al106  United States   27   27   LS   19/26 (73)   Yes   Yes  
1983-1992   Shimomatsuya and Horiuchi107  Japan   20   20   OS   6/16 (38)   No   Yes  
1994-1997   Brody et al108  United States   27   27   LS   24/25 (96)   No   Yes  
—   Louwes et al109  Netherlands   141   47   —   30/47 (64)   Yes   No  
1979-1999   Mazzucconi et al110  Italy   94   94   —   53/81 (65)   Yes   No  
1994-1999   Chung et al111  Korea   40   40   LS   28/40 (70)   Yes   Yes  
—   Ruivard et al112  France   75   75   —   —   Yes   No  
1992-1997   Stanton113  United States   30   30   LS   —   No   Yes  
1993-1998   Donini et al114  Italy   44   24   LS   —   No   Yes  
1992-1997   Tanoue et al115  Japan   76   35   LS   21/35 (60)   No   Yes  
2000         
1982-1998   Vecchio et al116  Italy   26   26   OS   21/26 (81)   Yes   No  
1978-1998   Radaelli et al117  Italy   65   65   —   44/65 (68)   Yes   No  
1992-1999   Bagdasarian et al118  United States   33   22   LS   14/22 (64)   No   Yes  
1982-1995   Wani and Parray119  India   41   41   OS   —   No   Yes  
1993-2000   Park et al120  United States, Canada   203   129   LS   —   No   Yes  
1994-1999   Gibson et al121  United States   27   27   OS,LS   24/27 (89)   No   No  
1993-1999   Trias et al122  Spain   111   48   LS   37/46 (80)   No   Yes  
2001         
1974-1994   Portielje et al8  Netherlands   152   78   OS   51/60 (85)   No   Yes  
1960-1999   Leung et al123  Hong Kong   220   37   OS   —   Yes   No  
1992-1997   Katkhouda et al124  United States, France   67   67   LS   52/67 (78)   Yes   Yes  
—   Fabris et al5  Italy   61   61   —   31/54 (57)   Yes   No  
1987-1994   Bussel et al125  United States, Canada   61   24   OS   —   Yes   No  
1987-1998   Choi et al126  Korea   107   79   OS,LS   —   Yes   No  
2002         
1984-2000   Pamuk et al127  Turkey   321   76   —   33/57 (58)   No   No  
1995-1998   Chan et al128  Australia   31   20   LS   —   No   Yes  
1991-2000   Gadenstatter et al129  Austria   92   38   OS   33/38 (87)   No   Yes  
—   Szold et al130  Israel   104   104   LS   82/102 (80)   No   Yes  
1985-1998   Kumar et al131  United States   140   140   OS,LS   78/106 (74)   Yes   No  
1997-2001   Torelli et al132  Italy   43   23   LS   15/23 (65)   No   Yes  
1993-1998   Bresler et al133  France   27   27   LS   18/27 (67)   No   Yes  
—   Rossi et al134  Italy   25   25   —   14/25 (56)   Yes   No  
1991-1998   Delaitre et al135  France   209   195   LS   —   No   Yes  
2003         
1993-1999   Neylon et al9  United Kingdom   245   30   —   21/28 (75)   No   No  
1983-1996   Srinivasan et al136  India   364   71   —   30/59 (51)   Yes   No  
1990-2001   Zoghlami-Rintelen et al137  Austria   56   48   OS,LS   31/48 (65)   Yes   Yes  
1985-1994   Bourgeois et al138  France   183   183   OS   159/183 (87)   Yes   Yes  
1992-2000   Pace et al139  Canada   52   52   LS   —   No   Yes  
1988-1993   Schwartz et al6  Israel, United States   56   56   OS   32/56 (57)   Yes   Yes  
1995-2000   Cordera et al140  United States   44   44   OS   —   No   Yes  
1995-2000   Cordera et al140  United States   42   42   LS   —   No   Yes  
1997-2000   George et al141  United States   70   28   —   15/28 (54)   No   No  
1985-1994   Andres et al142  France   139   55   OS,LS   33/55 (60)   Yes   No  
1996-2002   Knauer et al143  United States   101   48   LS   —   No   Yes  
2004         
1995-2001
 
Duperier et al144
 
United States
 
67
 
67
 
LS
 
43/67 (64)
 
Yes
 
Yes
 

The 135 case series that were reviewed for this analysis are presented in order of their year of publication. Case series for which accrual data were not available are designated (—). The technique for splenectomy (splx) is designated as os, splenectomy by open laparotomy, or ls, laparoscopic splenectomy. For studies with patient accrual beginning after 1991, the year of the first report of laparoscopic splenectomy for ITP,18  that did not define the surgical technique, the surgical technique is not specified (—). For studies that accrued patients prior to 1991, splenectomy was assumed to be performed by open laparotomy if the surgical technique was not defined. Articles selected for review had evaluable data for 1 or more of the outcomes of interest: platelet count response, predictors of response, or death and complications caused by splenectomy. When articles could be evaluated for platelet count response, the number and percentage of patients achieving a complete remission is presented with the total number of evaluable patients. Case series that did not describe complete remission are designated (—). In some articles some patients who had splenectomy for ITP were not evaluated for platelet count response because they were not followed or because they were children.

Platelet count response

In 47 case series reporting only adults, 1731 (66%) of 2623 patients had a complete response with a median follow-up of 29 months (range, 1-153 months) (Table 2); 1853 (88%) of 2116 had a complete or partial response. When the median rate of complete response across the 47 individual case series was calculated, rather than combining all patients, the rate of complete response was 67% (range, 37%-100%). In 38 case series that included up to 25% children, the frequency of complete responses was slightly but significantly greater (Table 2): 1775 (72%) of 2463 adults and children had a complete response with a median follow-up of 23 months (range, 3-130 months), 1449 (88%) of 1640 adults and children had a complete or partial response. The median complete response rate across the 38 individual case series of adults and children was also 72% (range, 28%-96%). Platelet count responses were similar when only case series with a median or mean follow-up of at least 5 years after splenectomy were analyzed (Table 2). In 14 case series reporting only adults, 456 (64%) of 707 patients had a complete response with a median follow-up of 7.25 years (range, 5-12.75 years). In 7 case series reporting adults and children, 323 (71%) of 452 patients had a complete response with a median follow-up of 7 years (range, 5-10.83 years). Data from the 9 prospective case series were not different from the retrospective analyses and were, therefore, not reported separately. The frequency of complete responses was not different across the 58 years of patient accrual. The median rate of complete responses in the first 42 case series, published from 1968 to 1994 with patient accrual from 1945 to 1990, was 69% (range, 28%-88%); the median rate of complete responses in the second 43 case series, published from 1995 to 2004 with patient accrual from 1968 to 2001, was 67% (range, 37%-100%) (Table 1).

Table 2.

Platelet count response following splenectomy for ITP




Case series of adults

Case series of adults and children
All case series*   
No. of case series   47   38  
No. patients with complete response/total no. evaluable patients (%)   1731/2623 (66)   1775/2463 (72)  
Case series with at least 5 y of follow-up   
No. of case series   14   7  
No. patients with complete response/total no. evaluable patients (%)
 
456/707 (64)
 
323/452 (71)
 



Case series of adults

Case series of adults and children
All case series*   
No. of case series   47   38  
No. patients with complete response/total no. evaluable patients (%)   1731/2623 (66)   1775/2463 (72)  
Case series with at least 5 y of follow-up   
No. of case series   14   7  
No. patients with complete response/total no. evaluable patients (%)
 
456/707 (64)
 
323/452 (71)
 

Complete response rates for all case series reporting adults only and articles reporting both adults and children, and for case series with a median or mean patient follow-up of at least 5 years. Data from case series reporting open laparotomy and laparoscopy are combined for this analysis.

*

P < .001, comparing case series of adults to case series of adults and children.

P = .014, comparing case series of adults to case series of adults and children.

The complete response rates in case series of adults only and of adults and children did not correlate with the duration of follow-up (Figure 2). There was also no correlation between the complete response rates and duration of follow-up when all 85 case series, combining case series of adults only with case series of adults plus children, were analyzed together (rs = -0.074; P = .50).

Figure 2.

Relationship of complete response rates with median or mean duration of patient follow-up. (A) Data for the 47 case series reporting adults only with follow-up for 1 to 153 months (median, 29 months). (B) Data for the 38 case series reporting adults and children with follow-up for 3 to 130 months (median, 23 months).

Figure 2.

Relationship of complete response rates with median or mean duration of patient follow-up. (A) Data for the 47 case series reporting adults only with follow-up for 1 to 153 months (median, 29 months). (B) Data for the 38 case series reporting adults and children with follow-up for 3 to 130 months (median, 23 months).

Relapse rates following splenectomy were evaluable in 48 of the 85 case series reporting 3355 patients. When case series reporting only adults were analyzed together with case series reporting adults and children, relapses occurred in a median 15% of patients (range, 0%-51%) with a median follow-up of 33 months (range, 3-153 months). The relapse rate appeared to increase with duration of follow-up, but the correlation did not reach statistical significance (rs = 0.275, P = .059). Relapse rates were also not significantly correlated with duration of follow-up when case series reporting only adults and case series reporting adults and children were evaluated separately.

Predictors of response

Demographic, clinical, and laboratory variables that have been studied for their ability to predict response to splenectomy are distinguished as preoperative and postoperative prediction variables (Table 3).

Table 3.

Prediction of response to splenectomy


Variable

Predictive no. articles (no. patients)

Not predictive no. articles (no. patients)

Not interpretable no. articles (no. patients)
Preoperative variables    
Age   14 (1185)5,35,46,47,56,67,69,73,82,93,124,131,142,144   14 (913)6,45,53,79,81,86,110,112,116,117,126,136-138   3 (287)33,61,68  
Sex   1 (26)116   22 (1830)5,6,35,45-47,53,56,61,67-69,79,81,82,93,117,124,126,131,136,138   —  
Duration of illness   2 (86)20,47   27 (2346)5,6,25,33,43,45,46,49,53,61,67,69,79,81,82,86,93,110,112,116,117,124,126,131,136,137,144   1 (71)30  
Response to steroids   11 (923)29,33,44,46,52,61,79,81,117,123,136   19 (1424)5,35,46,53,55,67,69,82,86,93,94,106,110,112,116,124,126,131,144   1 (35)25  
Response to IVIg   3 (154)77,93,126   7 (333)5,98,112,117,125,134,144   —  
Response to anti-(Rh) D   —   —   1 (24)125  
Preoperative platelet count   4 (264)43,81,93,144   9 (750)5,22,33,69,73,116,131,136,138   —  
Severity of bleeding   1 (138)69   2 (121)5,124   —  
Site of platelet sequestration   6 (566)32,60,73,80,94,138   8 (480)31,47,66,67,79,109,117,134   1 (24)33  
Platelet lifespan/turnover   1 (19)66   9 (670)33,45,47,56,67,80,109,134,138   —  
Platelet associated IgG antiplatelet antibody   —   11 (762)44,45,56,66,67,72,79,93,117,126,131   1 (94)110  
Megakaryocyte hyperplasia   1 (70)94   —   —  
Postoperative variables    
Postoperative platelet count   10 (868)22,67,79,111,117,126,131,136 -138  7 (357)35,43,46,53,86,124,134   6 (706)33,45,47,52,61,69  
Postoperative platelet count recovery rate   1 (98)43   1 (37)35   —  
Spleen weight or size   —   6 (333)22,35,46,93,131,144   —  
Splenic follicle hyperplasia
 
1 (70)94 
 

 

 

Variable

Predictive no. articles (no. patients)

Not predictive no. articles (no. patients)

Not interpretable no. articles (no. patients)
Preoperative variables    
Age   14 (1185)5,35,46,47,56,67,69,73,82,93,124,131,142,144   14 (913)6,45,53,79,81,86,110,112,116,117,126,136-138   3 (287)33,61,68  
Sex   1 (26)116   22 (1830)5,6,35,45-47,53,56,61,67-69,79,81,82,93,117,124,126,131,136,138   —  
Duration of illness   2 (86)20,47   27 (2346)5,6,25,33,43,45,46,49,53,61,67,69,79,81,82,86,93,110,112,116,117,124,126,131,136,137,144   1 (71)30  
Response to steroids   11 (923)29,33,44,46,52,61,79,81,117,123,136   19 (1424)5,35,46,53,55,67,69,82,86,93,94,106,110,112,116,124,126,131,144   1 (35)25  
Response to IVIg   3 (154)77,93,126   7 (333)5,98,112,117,125,134,144   —  
Response to anti-(Rh) D   —   —   1 (24)125  
Preoperative platelet count   4 (264)43,81,93,144   9 (750)5,22,33,69,73,116,131,136,138   —  
Severity of bleeding   1 (138)69   2 (121)5,124   —  
Site of platelet sequestration   6 (566)32,60,73,80,94,138   8 (480)31,47,66,67,79,109,117,134   1 (24)33  
Platelet lifespan/turnover   1 (19)66   9 (670)33,45,47,56,67,80,109,134,138   —  
Platelet associated IgG antiplatelet antibody   —   11 (762)44,45,56,66,67,72,79,93,117,126,131   1 (94)110  
Megakaryocyte hyperplasia   1 (70)94   —   —  
Postoperative variables    
Postoperative platelet count   10 (868)22,67,79,111,117,126,131,136 -138  7 (357)35,43,46,53,86,124,134   6 (706)33,45,47,52,61,69  
Postoperative platelet count recovery rate   1 (98)43   1 (37)35   —  
Spleen weight or size   —   6 (333)22,35,46,93,131,144   —  
Splenic follicle hyperplasia
 
1 (70)94 
 

 

 

Numbers of articles (with the sum of reported patients in parentheses) that included analysis of variables that were predictive, not predictive, or not interpretable for the response to splenectomy. The assignment of articles to these 3 categories is described in “Methods.” If there were no articles for a variable in a given category, this was designated (—). When predictive associations were reported, responses were associated with younger age, male sex, shorter duration of illness, previous response to steroids or intravenous immunoglobulin (IVIg), higher preoperative platelet counts, less severe bleeding, platelet sequestration predominantly localized to the spleen, decreased platelet lifespan with increased platelet turnover, no megakaryocyte hyperplasia, greater and more rapidly increasing postoperative platelet counts, and the presence of splenic follicle hyperplasia. Data from case series reporting open laparotomy and laparoscopy and data from case series of adults only and adults plus children were combined for this analysis.

Among variables that are available prior to splenectomy, age at the time of splenectomy most often correlated with response, with 14 case series reporting that younger age was associated with a better response. In 7 of these 14 case series, the mean or median age of the groups of patients with the better outcome was significantly less than the age of the groups of patients with the worse outcome. In these 7 studies there was no specific age cut point; the mean or median age of the patients with better outcomes was 32 to 51 years, compared with 40 to 73 years in the groups with less good outcomes. In the other 7 case series, responses of patients above and below specific ages—30 to 60 years in the different case series—were compared, and the younger group had a better outcome. In all 7 case series that analyzed multiple variables in a multivariate model,5,67,69,82,124,131,144  age was an independent variable for predicting response. Because of the different methods and different definitions of response used in these articles, no summary statement about the relation of age to response is possible. Data could not be pooled to provide estimates of response according to different age categories. Even though younger patients were demonstrated to have more frequent responses in these 14 studies, most of the older patients also responded to splenectomy. Seventeen other case series reported no correlation of age with response, or the data were not interpretable.

Previous response to glucocorticoids was correlated with response in 11 case series, but in all 7 case series that analyzed multiple variables in a multivariate model,5,67,69,82,124,131,144  previous response to glucocorticoids was not an independent variable for predicting response. Previous response to intravenous immunoglobulin correlated with response in only 3 of 7 case series. An influential report that described response to intravenous immunoglobulin as a sensitive (100%) and specific (82%) marker for response to splenectomy was not included in our review because 9 (30%) of the 30 patients were children.145  Only one article reported data on patients who failed both glucocorticoids and intravenous immunoglobulin: 7 of 75 patients failed both treatments; 6 of these 7 patients responded to splenectomy.112 

The principal site of platelet sequestration, determined by different radioisotope techniques, correlated with response in 6 case series reporting that patients who had predominant splenic sequestration had a better response than patients whose platelet sequestration was predominantly nonsplenic. However, in the one case series that analyzed multiple variables in a multivariate model and included analysis of platelet sequestration,67  it was not an independent variable for predicting response after taking age into consideration. Also, 9 other case series reported no correlation of the site of platelet sequestration with response, or the data were not interpretable. There was no apparent difference between the reports describing a significant predictive value and those describing no predictive value regarding the year of the report, the isotope used (51Cr or 111In), the source of the platelets (autologous or homologous), or the measurement technique. Even among the reports describing a better response to splenectomy in patients with predominant splenic sequestration of labeled platelets, many patients with nonsplenic sequestration also responded.

Among postoperative prediction variables, the magnitude and rate of the platelet count increase within the first 4 weeks after surgery were often, but inconsistently, reported to correlate with the response at 30 days following splenectomy. No summary statement about the relation of postoperative platelet count recovery to response is possible because the studies reporting a predictive value used different criteria for platelet count levels and time after splenectomy.

Surgical complications

Data are presented separately for laparotomy and laparoscopic splenectomies; case series reporting only adults are combined with case series reporting adults and children. For laparotomy, 81 case series had data for surgical mortality and 35 case series had data for surgical complications. For laparoscopic splenectomy, 29 case series had data for surgical mortality and 19 case series had data for surgical complications. The frequency of death and complications was significantly greater for laparotomy than for laparoscopic splenectomy (Table 4). The earliest reported laparoscopic splenectomy was in 1991.18  To determine whether the decreased rate of death and complications may only reflect advances in surgical practice, the data for laparoscopic splenectomy were compared with the 5 case series reporting splenectomy by laparotomy that accrued patients beginning in 1991 or subsequently.100,102,105,129,140  In these 5 case series, 1 (0.75%) of 134 patients died, a rate of death that is not significantly different from laparoscopic splenectomy (P = .325). To determine whether the decreased rate of death and complications may only reflect patient selection, with laparotomy performed on the more critical patients, the 5 case series that reported results of both laparoscopy and open laparotomy100,102,103,105,140  were analyzed for patient characteristics. In 4 of these case series,100,102,105,140  there was no indication that the patient groups were different. However, in one case series,103  the data suggested that the ITP was more severe in the patients who had splenectomy by open laparotomy.

Table 4.

Death and surgical complications caused by splenectomy for ITP




Laparotomy

Laparoscopy
Death*   
Articles, no.   81   29  
Mortality rate, % (no. patients who died/total no. evaluable patients)   1 (48/4955)   0.2 (3/1301)  
Causes of death   
Postoperative bleeding, no.   11   1 (intraabdominal)  
Gastrointestinal, no.   5   —  
Intracranial, no.   5   —  
Not specified, no.   1   —  
Cardiovascular, no.   10   1 (aortic aneurysm)  
Cardiac, no.   7   —  
Stroke, no.   2   —  
Aortic aneurysm, no.   1   —  
Infectious, no.   6   1 (sepsis)  
Pneumonia, no.   2   —  
Sepsis, no.   2   —  
Subdiaphragmatic abscess, no.   1   —  
Viral hepatitis, no.   1   —  
Venous thromboembolism, no.   5   —  
Pancreatitis, no.   3   —  
Miscellaneous, no.   3   —  
Not reported, no.   10   —  
Complications*   
Articles, no.   35   19  
Complication rate, % (no. patients with complications/total no. evaluable patients)
 
12.9 (318/2465)
 
9.6 (88/921)
 



Laparotomy

Laparoscopy
Death*   
Articles, no.   81   29  
Mortality rate, % (no. patients who died/total no. evaluable patients)   1 (48/4955)   0.2 (3/1301)  
Causes of death   
Postoperative bleeding, no.   11   1 (intraabdominal)  
Gastrointestinal, no.   5   —  
Intracranial, no.   5   —  
Not specified, no.   1   —  
Cardiovascular, no.   10   1 (aortic aneurysm)  
Cardiac, no.   7   —  
Stroke, no.   2   —  
Aortic aneurysm, no.   1   —  
Infectious, no.   6   1 (sepsis)  
Pneumonia, no.   2   —  
Sepsis, no.   2   —  
Subdiaphragmatic abscess, no.   1   —  
Viral hepatitis, no.   1   —  
Venous thromboembolism, no.   5   —  
Pancreatitis, no.   3   —  
Miscellaneous, no.   3   —  
Not reported, no.   10   —  
Complications*   
Articles, no.   35   19  
Complication rate, % (no. patients with complications/total no. evaluable patients)
 
12.9 (318/2465)
 
9.6 (88/921)
 

Death and complications from splenectomy. Data are reported separately for open laparotomy and laparoscopic splenectomy. Data from case series of adults only and adults plus children were combined for this analysis. Miscellaneous causes of death included respiratory failure, hepatic or renal failure, and gastric perforation. Not all articles for which mortality could be assessed reported the cause of death or the rate of complications.—indicates that no deaths from this cause were reported.

*

P = .008

For laparotomy, the most common reported cause of death was bleeding, accounting for 11 (29%) of the 38 patients for whom a cause of death was reported (Table 4). Intraabdominal bleeding with stroke was the cause of death of 1 of 3 patients who died with laparoscopic splenectomy. Perioperative platelet counts were reported for 5 of the 12 patients who died from bleeding and all were described as less than 16 × 109/L103  or less than 20 × 109/L.38  The clinical importance of complications, such as prolonged hospitalization, readmission to the hospital, or requirement for additional intervention, could not be assessed in most articles.

Discussion

This systematic review documents that splenectomy is an effective treatment for ITP, with two thirds of patients achieving durable complete responses. These results are consistent across 58 years and the 29 countries contributing case series to this review. Because our definitions of partial response and no response could have included patients who had increased platelet counts and required no further treatment, the data on complete responses may underestimate the benefit of splenectomy.

The durability of the responses is supported by the lack of correlation between the rate of complete responses and the duration of follow-up in 85 case series with follow-up durations of 1 month to more than 12 years (Figure 2). Because relapses of ITP following response to splenectomy do occur, yet the rate of complete responses did not change over time in these case series, the occurrence of relapses may be balanced by the occurrence of late remissions, perhaps related to splenectomy or to other treatments, or perhaps occurring spontaneously. The influence of other treatments could not be assessed in these articles. Two case series suggesting that responses to splenectomy are not durable had follow-up durations of more than 7 years in selected patients,5,6  longer than most case series that we reviewed. Therefore, it is possible that publication of more case series with longer follow-up will demonstrate a decreasing frequency of complete remissions over time. However, at this time, the published patient data, including analysis of 21 case series with follow-up of more than 5 years, suggest that the response to splenectomy is durable. Although a continuing occurrence of relapses was suggested in many of these case series, our data did not clearly demonstrate increasing rate of relapse with longer follow-up. Perhaps this unexpected observation is related to the fact that each case series is a single point in time and may reflect different methods of follow-up and different definitions of relapse used in the different studies.

Among all of the prediction variables tested that are available before splenectomy, younger age was most often found to be associated with response (Table 3). In all 7 studies that analyzed variables in a multivariate model, younger age was an independent variable for predicting response. Younger age is also suggested as a predictor for better response by the greater frequency of complete remissions in case series that included children than in case series reporting only adults (Table 2). An equal number of studies demonstrated no correlation of age with response to splenectomy. Furthermore among the studies that did demonstrate a correlation, there was no consistent age that distinguished responders from nonresponders.

Six studies measuring the site of platelet sequestration reported a correlation of predominant splenic sequestration with response; however, 8 other studies reported no correlation, and one study was not interpretable (Table 3). Because these studies used different techniques, because the investigators may have had different levels of experience, and because patients with different clinical characteristics may have been studied, it may not be appropriate to consider these 15 reports as equivalent. However, because these assessments are often qualitative, rather than quantitative, reproducibility among different institutions, even with the same technique, may be difficult.

Although it is possible that some combination of preoperative characteristics may better predict the response to splenectomy, many patients without positive predictive characteristics also respond. Because most patients have a good response to splenectomy, the ability to predict the response may be more difficult and less important.

The decision for splenectomy must be carefully balanced by consideration of the potential risks, because the rate of complications following splenectomy is relatively great. Mortality rates of 0.2% and 1.0%, with laparoscopy and open laparotomy, respectively, are similar to the mortality due to bleeding estimated from large case series of patients with severe ITP followed for 5 to 10 years: 2 (1.6%) of 124 patients8  and 1 (0.4%) of 245 patients.9  However, this comparison may not be appropriate because patients with ITP sufficiently severe to require splenectomy may have a greater risk of death from bleeding than the overall rates reported in these large series. The mortality rate for laparoscopic splenectomy may be more representative of current surgical practice, because assessment of the 5 case series of laparotomy that accrued patients since 1991, the year of the first report of laparoscopic splenectomy, demonstrated no significant difference in mortality from laparoscopy. Although the complication rates of 9.6% and 12.9%, with laparoscopy and open laparotomy, respectively, may seem high, they are consistent with a case series8  that described serious complications, resulting in prolonged hospitalization or readmission, in 20 (26%) of 78 patients. These relatively high rates of death and complications, despite advances in anesthesia and surgical care, may be due to the increasing recognition of ITP among older persons,9,146  the greater risk of surgical complications in older patients,8  and the willingness of surgeons to perform surgery in older patients. It is possible that complications with open laparotomy are greater because it may be performed more often in more severely affected patients, when direct visualization of operative bleeding is preferred.

The risks of splenectomy may be greater than described in this systematic review, because we did not evaluate long-term risks of sepsis and thrombosis. The risk of fatal infection attributed to the absence of a spleen has been estimated to be 0.73 per 1000 patient-years14 ; in this study of patients with hereditary spherocytosis, 3 of the 4 deaths occurred 18 to 30 years following splenectomy,14  well beyond the follow-up time for most patients who were analyzed in this review. An increased risk of thrombosis has also been reported for patients following splenectomy,15-17  but these complications, similar to severe sepsis, may be rare, may be related to multiple risk factors, and may only become apparent many years after splenectomy.15-17 

Because of the risks of splenectomy, intermittent glucocorticoid treatment is often continued with the hope that a remission will eventually occur, or other therapies are considered as an alternative to splenectomy. But the risks of these therapies may be substantial and their benefit is uncertain. Glucocorticoid treatment of even short duration may increase the risk of opportunistic infections, such as aspergillosis.147  In a large case series,8  deaths from infections related to immunosuppressive treatment were more frequent than death as a result of bleeding. For none of these therapies has efficacy been established by prospective controlled studies with clinical outcome measures and long-term follow-up.11  Therefore, alternatives to splenectomy may have similar risk but less benefit.

This systematic review has several weaknesses. The reviewed articles used diverse criteria to evaluate patient characteristics and to report outcomes; therefore, averaging data across studies may not be appropriate. Even the comparison of the results of individual studies, as in our description of predictors of response, may give an inaccurate impression because of different methodologies. Children may have been included in some of the case series that we described as reporting only adults and could have biased descriptions of predictors of response and the durability of responses. The severity of surgical complications could not be quantitatively described. Follow-up duration was often difficult to estimate because of inability to account for all patients in the reported case series. The duration of follow-up may not have been long enough to provide a valid estimate of the rate of relapse and was certainly not long enough to evaluate the risks of overwhelming sepsis and thrombosis that may occur many years after splenectomy.14-17 

The strength of this review is that the comprehensive and critical analysis of all published reports on splenectomy for ITP over 38 years using a defined and reproducible methodology achieves a balance that is not possible in individual case series and selective reviews. These data provide the best current estimate for the benefits and risks of splenectomy. Although surgical risks are important, splenectomy provides effective long-term benefit for adult patients with ITP who do not achieve durable remissions with initial glucocorticoid treatment.

Prepublished online as Blood First Edition Paper, June 24, 2004; DOI 10.1182/blood-2004-03-1168.

Supported by the Daisy Foundation, Glen Ellen, CA

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