World J. Surg. 16, 1001-1005, 1992
World Journal of Surgery O 1992 by the Soci61~ lntemationale de Chirmgie
S
• urglcal Treatment of Immune Thrombocytopenic Purpura
H e r o Chirletti, M . D . , Maurizio Cardi, M . D . , Paolo Barillari, M . D . , A l e s s a n d r a Vitale, M . D . , Paolo S a m m a r t i n o , M . D . , Antonio Bolognese, M . D . , Rossella Caiazzo, M . D . , M a r c o Ricci, M . D . , Irnerio A. Muttillo, M . D . , and Vincenzo Stipa, M.D. Cattedra di Patologia Chirurgica IX and Cattedra di Ematologia, Universit~ degli Studi di Roma "La Sapienza", Rome, Italy The role of surgery in the treatment of immune thrombocytopenic PUrpura (ITP) is still discussed. The aim of this study was to verify our criteria of patient selection for splenectomy, to analyze the results of a Protocol for the evaluation of the hemorragic risk, and to discuss long-term results of 70 patients with ITP who underwent surgical treatment from 1984 to 1990. All patients received steroid therapy. Sixty.two patients were given high doses of lgG (600 mg/kg/iv bolus) pre-operatively in order to obviate the need for Intra-operative platelet transfusions. Forty-three patients showed a significant increase in the platelet count, 8 a moderate increase, while 11 patients did not respond. No operative mortality was observed, however postoperative minor COmplications occurred in 14 (20%) patients. Accessory spleens were found in 11 (15.7%) patients. Mean follow-up was 21 months. Response to Splenectomy was considered as complete (platelets > 150,000 mm a with no need for medical treatment) in 63 (90%) patients. No response was observed in 7 patients. In 2 of the non-responders postoperative indium111 scan revealed accessory spleens and ITP remitted after accessory splenectomy. All non-responders were in the group of patients who did not respond to the pre-operative infusion of high dose lgG. It can be COncluded that splenectomy is a safe and effective treatment for ITP and that response to pre-operative infusion of IgG may be considered as predictive for the outcome after splenectomy.
Immune thrombocytopenic purpura (ITP) is a disease characterized by marked reduction of circulating platelets. The hyPothesis of an autoimmune etiology was proposed and confirmed by many authors [1--4] who demonstrated that thrombocytopenia was due to the production of an anti-platelet antibody (IgG) able to react with host platelets yielding an ~mmunocomplex sequestrated and destroyed by the reticuloendothelial system of the spleen. Harrington [1] showed a reduction in the platelet count in normal volunteers transfused with Plasma from patients with ITP, and this thrombocytopenic effect was diminished if normal subjects were sptenectomized. The role of the spleen in the pathophysiology of ITP has then been shown to be not only the major site of platelet destruction but also the site of antibody production [3]. Based on this Presented at the Soci6t6 Internationale de Chirurgie in Stockholm, SWeden, August, 1991• • Reprint requests: Prof, Piero Chirletti, Canedra di Patologia Chirurgtca IX, I Istituto di Clinica Chirurgica, Viale del Policlinico, 00161 Roma, Italy.
premise, splenectomy represents a valid alternative to medical treatment which gives responses in 50% to 70% of patients [5]. The aim of our study is to report the results of splenectomy for ITP in our practice and to verify our criteria of patient selection for surgery. Material and M e t h o d s
Patients
From 1984 to 1990, 70 patients affected by ITP were referred and underwent surgery in our institution. Twenty-six were male and 44 were female with a mean age of 23.9 years (range 6 to 56 years). Fifteen patients were in the pediatric age group ( 1,000 mcg IgG/107 platelets). Antibody titers returned within normal range in all responders (mean antibody titer 150 mcg IgG/107 ptatelets). In the non-responders, antibody titer remained unchanged or were even higher than pre-operatively.
Response to Pre-Operative Corticosteroids All patients selected for splenectomy showed a failure of pre-operative corticotherapy. An initial transient complete response and partial response was observed, respectively, in 33 (47.1%) and 27 (38.5%) patients. Those patients underwent splenectomy either for recurrence of thrombocytopenia or for the impossibility to taper high doses of steroids necessary to maintain platelet count over bleeding levels. No correlation was found in the non-responders after splenectomy as regards to the pre-operative response to corticosteroids. Of the 5 non-responders, 2 patients were in the group who showed a complete response and 2 were in the group who showed a partial response,
World J. Surg. Vol. 16, No. 5, Sept./Oct. 1992
Response to Intravenous lmmunoglobulins Forty-three (69.3%) patients had a complete response to i.v. infusion of IgG requiring no further therapy before operation. Eight patients had a partial response while 11 patients were considered non-responders.
Accessory Spleen Accessory spleens were demonstrated in 5 patients by preoperative sonography and in 11 (15.7%) patients at operation. Six accessory spleens were found at the splenic hilum, 3 in the gastrocolic ligament, and 1 each at the mesenteric root, at the superior border of the pancreas, and at the left paracolic gutter. One patient had 2 accessory spleens.
Surgical Results Mean weight of the spleen was 193 g. No operative mortality was observed. Mean postoperative stay in the hospital was 7.6 days. Fourteen (20%) minor complications were observed, 10 patients with pleural effusions, 3 with wound infections, and 1 with pneumonia.
Response to Splenectomy Follow-up data were available from the Department of Hematology for all patients and ranged from 6 months to 6 years. Complete response was observed in 63 (90%) patients. The remaining 7 patients were classified as non-responders and required continuous immunosuppressive therapy to maintain platelet count above bleeding level. All the non-responders were in the group of patients who showed no response to pre-operative i.v. infusion of IgG. Those patients were further studied by radionuclide imaging scans using indium-111 labeled platelets revealing accessory spleens in the gastrocolic omenturn of 2 patients, 3 and 5 months after primary splenectomy. ITP remitted completely after accessory splenectomy, and antibody titers dropped to normal values. The patients showed no recurrence at 37 and 63 months from the second operation. Discussion
Glucocorticoids were the first medical therapy demonstrated to be effective in the treatment of ITP [6]. Later, other immunosuppressive agents such as cyclophosphamide, azathioprine, and vinka alkaloids have been used. Steroids are the initial treatment of choice in pediatric and most adult patients with ITP. Complete remission has been observed in 30--60% of patients but in most of the patients, particularly in adults, response is only transient [5]. Splenectomy is still the most effective therapeutic measure for long-term remission [5, 7-12] (Table 1). In this study, 90% of the patients achieved at discharge a platelet count of > 150,000/ mm 3 and needed no further medical treatment during follow-up. No mortality was observed in our series and incidence of postoperative complications is low. Overwhelming sepsis has not occurred in any of the asplenic patients. Pneumococcal vaccination should be used routinely in all patients, particularly in the pediatric age group. Thromboembolic complications were
P. Chirletti et al.: Surgery for Immune Thrombocytopenic Purpura
1003
Table 1. Splenectomy for immune thrombocytopenic purpura: results of collected series in literature.
Series (yr) Schwartz (1980) Mintz (1981) Musser (1983) Coon (1987) Akwari (1987) Current report
No. of pts. 120 71 65 216 I00 70
Response (%) Complete 88 77 77 72 71 90
not observed and did not correlate with postoperative thrombocytosis, as reported by others [13]. Postoperative anticoagulants were never administered. Among the 7 non-responders, 3 Patients had an initial transient response after sptenectomy but thrombocytopenia recurred at 3, 8, and 14 months after operation, and were treated by gtucocorticoids and more powerful immunosuppressive agents (2 patients). Four patients never showed any elevation in the platelet count after operation. This group of patients was studied by indium-Ill labeled platelet scan and in 2 of them the presence of accessory spleens not seen at the primary splenectomy was discovered. Both underWent accessory splenectomy with resolution of ITP. Incidence of accessory spleens in our study was 15.7%, similar to other reports [8, 12]. A thorough search for accessory spleens in common anatomical locations is the most efficient Way to prevent this failure, and non-responders should be investigated for this possibility. For the other patients, no explanation could be found for persistance of ITP. Although the spleen is the major site of Platelets destruction, other reticoloendothelial organs, such as the liver, could sequestrate the platelet-antiplatelet antibody Complexes with subsequent thrombocytopenia [14]. Selection of patients with ITP for splenectomy has long been recognized and is of great importance. Splenectomy must be avoided in the acute form of the disease, particularly in pediatric patients [15]. ITP almost always remits within 6 months and Operation is indicated only in those patients in whom the disease has become chronic, with failure to remit or inability to taper high dosage of steroids. Demonstration of anti-platelet serum antibodies is an important criteria of selection for surgery, as secondary thrombocytopenia is frequent. Connective tissue disease [16] and hematologic malignancies [17, 18] are frequent cause of thromboeytopenia, as well as drugs such as quinidine [19]. Only 1 of Our patients among the non-responders developed a connective tissue disease (cutaneous systemic lupus erythematosus (S.L.E.) in the follow-up period. Few factors have been found helpful in predicting a favorable response to splenectomy in ITP. Some authors found a correlation with age and duration of the symptoms [5] stating that Pediatric patients respond better than adults. No such correlation has been found in the present series. Four of the 7 non-responders were under 12 years of age. Others [20, 21] found that good response to splenectomy is correlated with pre-operative platelet elevation induced by corticosteroids. On the contrary, Schwartz and coworkers [9], in agreement with Our findings, found that failure to respondto steroids did not influence response to sptenectomy.
Partial 5 16 15 28 -
Failure (%) 7 7 8 29 10
Mortality (%) 4 1 2 2 -
Our study suggests a clinical correlation between the response to pre-operative infusion of high doses of IgG and the response to splenectomy. All the 7 failures after operation were in the group of 1t patients who did not respond with platelet elevation following i.v. infusion of IgG and no failure was observed in the group of patients who showed a complete or partial response to this pre-operative treatment. The mechanism of action seems to be a competitive blockage of the receptor site for the Fc fragment of the antibody, and also perhaps a diminished synthesis of anti-platelet antibodies [22]. This finding could be related to the observations of Akwary and associates [12] and Schreiber and colleagues [23] that in the spleen, the number of receptors in responders could be significantly higher or better expressed than those of non-responders. The lack of receptors would then produce no increase in the platelet count after IgG infusion in this group of patients and splenectomy would have little impact. Further studies are needed to clarify the exact mechanism of action and to confirm the pre-operative IgG infusion as predictive of outcome after sptenectomy. R6sum~
Le r61e de la chirurgie dans le traitement du purpura thrombocytop6nique d'origine immune (PTI) reste discut6e. Le but de cette 6tude a 6t6 de v6rifier les crit~res de s61ection pour proposer une spl6nectomie, d'analyser les r6sultats d'un protocole d'6valuation du risque h6morragique et, enfin, de discuter les r6sultats ~ long-terme chez 70 patients ayant un PTI trait6s chirurgicalement entre 1984 et 1990. Tous les patients ont re~u une corticoth6rapie. Soixante-deux patients ont re,u, en pr~op6ratoire par injection intraveineuse unique de fortes doses d'IgG (600 mg/kg) dans le but de r6duire le besoin en transfusions de plaquettes. Quarante-trois patients ont eu une augmentation significative de leur hombre de plaquettes, huit, une augmentation mod6r6e, alors qu'onze n'ont eu aucune r6ponse. Aucun patient n'est d6c6d6 en p6riode p6riop6ratoire, mais on a enregistr6 14 complications (20%) postop6ratoires mineures. Des rates accessoires ont 6t6 retrouv6es dans 11 cas (15.7%). Le suivi moyen a 6t6 de 21 mois. La r6ponse h la spl6nectomie a 6t6 consid6r6e comme compl6te (plaquettes sup6rieures b. 150000/ram3 sans besoin de traitement compl6mentaire) chez 63 patients (90%) alors qu'aucune r6ponse n'a 6t6 obtenue dans sept cas. Chez deux des patientes n'ayant pas r6pondu h la spl6nectomie, une scintigraphie ~ l'In-111 a montr6 l'existence de rates accesoires: le PTI a regress6 apr6s ablation de ces rates accesoires. Tous les patients qui n'ont pas r6pondu ~ la spl6nectomie 6talent parmi les patients qui n'avaient pas r6pondu
1004
World J. Surg. Vol. 16, No. 5, Sept./Oct. 1992
la perfusion prroprratoire de fortes doses d'IgG. On conclue que la splrnectomie est stare et efficace dans le traitement du PTI et que la rrponse/~ une perfusion prroprratoire d'IgG est corrrlre ~ la rrponse A ia splrnectomie.
4.
Resumen
6.
E1 papel de la cirugia en el tratamiento de la Ptirpura Trombocitop6nica Inmune (PTI) es todavfa motivo de discusi6n. El prrposito del presente estudio fue verificar los criterios de selecci6n del paciente para esplenectomia, analizar los resultados de un protocolo para la evaluacirn de los riesgos de hemorragia y discutir los resultados a largo plazao en 70 pacientes con PTI sometidos a tratamiento quirtirgico entre 1984 y 1990. La totalidad de los pacientes recibi6 terapia esteroidea. A 62 pacientes se les administraron altas dosis de IgG (600 mg/kg en bolo IV) preoperatoiramente con el fin de obviar la necesidad de transfusirn intraoperatoria de plaquetas. Cuarenta y tres pacientes exhibieron un incremento significativo en el recuento de plaquetas y 8 un incremento moderado, en tato que no hubo respuesta en 11 pacientes. No se registr6 mortalidad operatoria, pero hubo compticaciones menores en 14 casos (20%). Se hallaron bazos accesorios en 11 casos (15.7%). E1 seguimiento promedio fue de 21 meses. Se considerfi que hubo respuestra completa a la esplenectomfa (plaquetas sobre 15.000 mm 3 sin necesidad de terapia) en 63 pacientes (90%); no hubo respuesta en 7 casos. En 2 de los pacientes que no respondieron la escanograffa con In-I 11 revel6 bazos accesorios y se logr6 remisi6n de la PTI con la rescessi6n de 6stos. La totalidad de los casos que no respondieron se hall6 en el grupo de pacientes que no exhibieron respuesta a la infusirn preoperatoria de altas dosis de IgG. Se llega a la conclusi6n de que la esplenectom[a es una modalidad de tratamiento seguro y eficaz para la PTI y que la respuesta a la infusi6n preoperatoria de IgG puede ser considerada como un factor de prediccirn del resultado de la esplenectomfa.
7.
References
i. Harrington, W.J., Minnich, V., Hollingsworth, J.W.: Demonstration of a thrombocytopenic factor in the blood of patients with thrombocytopenic purpura. J. Lab. Clin. Med. 38:1, 1951 2. Harrington, W.J., Sprague, C.C., Minnich V.: Immunologic mechanism in idiopathic and neonatal thrombocytopenic purpura. Ann, Intern. Med. 38:433, 1953 3. Karpatkin, S.: Detection of splenic anti-platelets antibodies synthe-
Invited Commentary S e y m o u r I. S c h w a r t z , M . D . Department of Surgery, University of Rochester, Rochester, New York, U.S.A.
The authors review of their experience of surgical treatment of immune thrombocytopenic purpura (ITP) incorporates almost all of the salient features that should be considered in the
5.
8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.
19. 20.
21. 22.
23.
sis in idiopathic autoimmune thrombocytopenic purpura. Br. J. Hematol. 23:167, 1972 McMillan, R.: Chronic idiopathic thrombocytopenic purpura. N. Engl, J. Med. 304:1135, 1981 Ahn, Y.S., Harrington, W.J.: The treatment of idiopathic thrombocytopenic purpura. Ann. Rev. Med. 28:299, 1977 Robson, N.H., Duthic, J.J.R.: Capillary resistence and adrenocortical activity. Br. Med. J. 2:971, 1950 Carpenter, A.F., Wintrobe, M.M., Fuller, E.A., Haut, A., Cartwright, G.E.: Treatment of idiopathic thrombocytopenic purpura. J.A,M.A. 171:1911, 1959 Mintz~ S.J., Petersen J.R., Cheson, B., Cordell, L.J., Richards, R.C.: Spleneetomy for immune thrombocytopenic purpura. Arch. Surg. 116:645, 1981 Schwartz, S.I., Hoepp, L.M., Sachs, S.: Splenectomy for thrombocytopenia. Surgery 88:497, 1980 Coon, W.W.: Splenectomy for idiopathic thrombocytopenic purpura. Surg. Gynecol. Obstet. 164:255, 1987 Musser, G., Lazar G., Hocking, W., Busuttil, R.W.: Splenectomy for hematologic disease: The U.C.L.A. experience with 306 patients. Ann. Surg. 201:40, 1983 Akwari, O.E., Itani, K.M.F., Coleman, R.E., Rosse, W.F.: Splenectomy for primary and recurrent immune thrombocytopenic purpura (tTP). Ann. Surg. 206:529, 1987 Boxer, M.A., Braun, J., Ellman, L.: Thromboembolic risk of postsplenectomy thrombocytosis. Arch. Surg. 113:808, 1978 Aster, R.B., Keebe, W.R.: Sites of platelets destruction in idiopathic thrombocytopenic purpura. Br. J. Hematol. 16:61, 1969 Deweese, M.S., Coller, F.A.: Splenectomy for hematologic disorders. West J. Surg. 67:129, 1959 Dameshek, W.: Systemic lupus erithematosus: Complex autoimmune disorder? Ann. Int. Med. 48:707, 1958 Fink, K., AI-Mondhiry, H.: Idiopathic thrombocytopenic purpura in lymphoma. Cancer 37:1999, 1976 Wang, G., Ahn, Y.S., Whitromb, C.C., Harrington, W.J.: Development of polycythemia vera and chronic lymphocytic leukemia during the course of refractory idiopathic thrombocytopenic purpura. Cancer 53:1770, 1984 Rosse, W.F.: Treatment of chronic immune thrombocytopenia. Clin. Hematol. •2:267, 1983 Brennan, M.F., Rappaport, J.M., Moloney, W.C., Wilson, R.E.: Correlation between response to corticosteroids and splenectomy for adult idiopathic thrombocytopenic purpura. Am. J. Surg. 129: 490, 1975 Ikkala, E., Kivilaakso E., Kohlainen, M.: Treatment of idiopathic thrombocytopenic purpura in adults. Ann. Clin. Res. 10:83, 1978 Bussel, J.B., Schulman, I., Hilgartner, M.W., Barandun, S.: The use and mechanism of action of intravenous immunoglobulin with treatment of immune hematologic disease. Br. J. Hematol. 56:1, 1984 Schreiber, A.D., Chien, P,, Tomaski, A., Sines, D.B.: Effect of danazol in immune thrombocytopenic purpura. N. Engl. J. Med. 3•6:503, 1987
management of these patients. It is now generally agreed that splenectomy is not only a valid alternative to medical treatment, but is associated with a significantly higher rate of permanent remission. The permanent remission rate associated with corticosteroid therapy in series we have reviewed was well under 25%, whereas, most surgical series report a permanent remission of well over 80%. The incidence of pediatric cases subjected to splenectomy in the authors' series is significantly higher than general experience. Most children can be managed medically and a longer course of nonsurgical management is applied to the pediatric population. The routine use of pre-
World Journal of Surgery O 1992 by the Soci61~ lntemationale de Chirmgie
S
• urglcal Treatment of Immune Thrombocytopenic Purpura
H e r o Chirletti, M . D . , Maurizio Cardi, M . D . , Paolo Barillari, M . D . , A l e s s a n d r a Vitale, M . D . , Paolo S a m m a r t i n o , M . D . , Antonio Bolognese, M . D . , Rossella Caiazzo, M . D . , M a r c o Ricci, M . D . , Irnerio A. Muttillo, M . D . , and Vincenzo Stipa, M.D. Cattedra di Patologia Chirurgica IX and Cattedra di Ematologia, Universit~ degli Studi di Roma "La Sapienza", Rome, Italy The role of surgery in the treatment of immune thrombocytopenic PUrpura (ITP) is still discussed. The aim of this study was to verify our criteria of patient selection for splenectomy, to analyze the results of a Protocol for the evaluation of the hemorragic risk, and to discuss long-term results of 70 patients with ITP who underwent surgical treatment from 1984 to 1990. All patients received steroid therapy. Sixty.two patients were given high doses of lgG (600 mg/kg/iv bolus) pre-operatively in order to obviate the need for Intra-operative platelet transfusions. Forty-three patients showed a significant increase in the platelet count, 8 a moderate increase, while 11 patients did not respond. No operative mortality was observed, however postoperative minor COmplications occurred in 14 (20%) patients. Accessory spleens were found in 11 (15.7%) patients. Mean follow-up was 21 months. Response to Splenectomy was considered as complete (platelets > 150,000 mm a with no need for medical treatment) in 63 (90%) patients. No response was observed in 7 patients. In 2 of the non-responders postoperative indium111 scan revealed accessory spleens and ITP remitted after accessory splenectomy. All non-responders were in the group of patients who did not respond to the pre-operative infusion of high dose lgG. It can be COncluded that splenectomy is a safe and effective treatment for ITP and that response to pre-operative infusion of IgG may be considered as predictive for the outcome after splenectomy.
Immune thrombocytopenic purpura (ITP) is a disease characterized by marked reduction of circulating platelets. The hyPothesis of an autoimmune etiology was proposed and confirmed by many authors [1--4] who demonstrated that thrombocytopenia was due to the production of an anti-platelet antibody (IgG) able to react with host platelets yielding an ~mmunocomplex sequestrated and destroyed by the reticuloendothelial system of the spleen. Harrington [1] showed a reduction in the platelet count in normal volunteers transfused with Plasma from patients with ITP, and this thrombocytopenic effect was diminished if normal subjects were sptenectomized. The role of the spleen in the pathophysiology of ITP has then been shown to be not only the major site of platelet destruction but also the site of antibody production [3]. Based on this Presented at the Soci6t6 Internationale de Chirurgie in Stockholm, SWeden, August, 1991• • Reprint requests: Prof, Piero Chirletti, Canedra di Patologia Chirurgtca IX, I Istituto di Clinica Chirurgica, Viale del Policlinico, 00161 Roma, Italy.
premise, splenectomy represents a valid alternative to medical treatment which gives responses in 50% to 70% of patients [5]. The aim of our study is to report the results of splenectomy for ITP in our practice and to verify our criteria of patient selection for surgery. Material and M e t h o d s
Patients
From 1984 to 1990, 70 patients affected by ITP were referred and underwent surgery in our institution. Twenty-six were male and 44 were female with a mean age of 23.9 years (range 6 to 56 years). Fifteen patients were in the pediatric age group ( 1,000 mcg IgG/107 platelets). Antibody titers returned within normal range in all responders (mean antibody titer 150 mcg IgG/107 ptatelets). In the non-responders, antibody titer remained unchanged or were even higher than pre-operatively.
Response to Pre-Operative Corticosteroids All patients selected for splenectomy showed a failure of pre-operative corticotherapy. An initial transient complete response and partial response was observed, respectively, in 33 (47.1%) and 27 (38.5%) patients. Those patients underwent splenectomy either for recurrence of thrombocytopenia or for the impossibility to taper high doses of steroids necessary to maintain platelet count over bleeding levels. No correlation was found in the non-responders after splenectomy as regards to the pre-operative response to corticosteroids. Of the 5 non-responders, 2 patients were in the group who showed a complete response and 2 were in the group who showed a partial response,
World J. Surg. Vol. 16, No. 5, Sept./Oct. 1992
Response to Intravenous lmmunoglobulins Forty-three (69.3%) patients had a complete response to i.v. infusion of IgG requiring no further therapy before operation. Eight patients had a partial response while 11 patients were considered non-responders.
Accessory Spleen Accessory spleens were demonstrated in 5 patients by preoperative sonography and in 11 (15.7%) patients at operation. Six accessory spleens were found at the splenic hilum, 3 in the gastrocolic ligament, and 1 each at the mesenteric root, at the superior border of the pancreas, and at the left paracolic gutter. One patient had 2 accessory spleens.
Surgical Results Mean weight of the spleen was 193 g. No operative mortality was observed. Mean postoperative stay in the hospital was 7.6 days. Fourteen (20%) minor complications were observed, 10 patients with pleural effusions, 3 with wound infections, and 1 with pneumonia.
Response to Splenectomy Follow-up data were available from the Department of Hematology for all patients and ranged from 6 months to 6 years. Complete response was observed in 63 (90%) patients. The remaining 7 patients were classified as non-responders and required continuous immunosuppressive therapy to maintain platelet count above bleeding level. All the non-responders were in the group of patients who showed no response to pre-operative i.v. infusion of IgG. Those patients were further studied by radionuclide imaging scans using indium-111 labeled platelets revealing accessory spleens in the gastrocolic omenturn of 2 patients, 3 and 5 months after primary splenectomy. ITP remitted completely after accessory splenectomy, and antibody titers dropped to normal values. The patients showed no recurrence at 37 and 63 months from the second operation. Discussion
Glucocorticoids were the first medical therapy demonstrated to be effective in the treatment of ITP [6]. Later, other immunosuppressive agents such as cyclophosphamide, azathioprine, and vinka alkaloids have been used. Steroids are the initial treatment of choice in pediatric and most adult patients with ITP. Complete remission has been observed in 30--60% of patients but in most of the patients, particularly in adults, response is only transient [5]. Splenectomy is still the most effective therapeutic measure for long-term remission [5, 7-12] (Table 1). In this study, 90% of the patients achieved at discharge a platelet count of > 150,000/ mm 3 and needed no further medical treatment during follow-up. No mortality was observed in our series and incidence of postoperative complications is low. Overwhelming sepsis has not occurred in any of the asplenic patients. Pneumococcal vaccination should be used routinely in all patients, particularly in the pediatric age group. Thromboembolic complications were
P. Chirletti et al.: Surgery for Immune Thrombocytopenic Purpura
1003
Table 1. Splenectomy for immune thrombocytopenic purpura: results of collected series in literature.
Series (yr) Schwartz (1980) Mintz (1981) Musser (1983) Coon (1987) Akwari (1987) Current report
No. of pts. 120 71 65 216 I00 70
Response (%) Complete 88 77 77 72 71 90
not observed and did not correlate with postoperative thrombocytosis, as reported by others [13]. Postoperative anticoagulants were never administered. Among the 7 non-responders, 3 Patients had an initial transient response after sptenectomy but thrombocytopenia recurred at 3, 8, and 14 months after operation, and were treated by gtucocorticoids and more powerful immunosuppressive agents (2 patients). Four patients never showed any elevation in the platelet count after operation. This group of patients was studied by indium-Ill labeled platelet scan and in 2 of them the presence of accessory spleens not seen at the primary splenectomy was discovered. Both underWent accessory splenectomy with resolution of ITP. Incidence of accessory spleens in our study was 15.7%, similar to other reports [8, 12]. A thorough search for accessory spleens in common anatomical locations is the most efficient Way to prevent this failure, and non-responders should be investigated for this possibility. For the other patients, no explanation could be found for persistance of ITP. Although the spleen is the major site of Platelets destruction, other reticoloendothelial organs, such as the liver, could sequestrate the platelet-antiplatelet antibody Complexes with subsequent thrombocytopenia [14]. Selection of patients with ITP for splenectomy has long been recognized and is of great importance. Splenectomy must be avoided in the acute form of the disease, particularly in pediatric patients [15]. ITP almost always remits within 6 months and Operation is indicated only in those patients in whom the disease has become chronic, with failure to remit or inability to taper high dosage of steroids. Demonstration of anti-platelet serum antibodies is an important criteria of selection for surgery, as secondary thrombocytopenia is frequent. Connective tissue disease [16] and hematologic malignancies [17, 18] are frequent cause of thromboeytopenia, as well as drugs such as quinidine [19]. Only 1 of Our patients among the non-responders developed a connective tissue disease (cutaneous systemic lupus erythematosus (S.L.E.) in the follow-up period. Few factors have been found helpful in predicting a favorable response to splenectomy in ITP. Some authors found a correlation with age and duration of the symptoms [5] stating that Pediatric patients respond better than adults. No such correlation has been found in the present series. Four of the 7 non-responders were under 12 years of age. Others [20, 21] found that good response to splenectomy is correlated with pre-operative platelet elevation induced by corticosteroids. On the contrary, Schwartz and coworkers [9], in agreement with Our findings, found that failure to respondto steroids did not influence response to sptenectomy.
Partial 5 16 15 28 -
Failure (%) 7 7 8 29 10
Mortality (%) 4 1 2 2 -
Our study suggests a clinical correlation between the response to pre-operative infusion of high doses of IgG and the response to splenectomy. All the 7 failures after operation were in the group of 1t patients who did not respond with platelet elevation following i.v. infusion of IgG and no failure was observed in the group of patients who showed a complete or partial response to this pre-operative treatment. The mechanism of action seems to be a competitive blockage of the receptor site for the Fc fragment of the antibody, and also perhaps a diminished synthesis of anti-platelet antibodies [22]. This finding could be related to the observations of Akwary and associates [12] and Schreiber and colleagues [23] that in the spleen, the number of receptors in responders could be significantly higher or better expressed than those of non-responders. The lack of receptors would then produce no increase in the platelet count after IgG infusion in this group of patients and splenectomy would have little impact. Further studies are needed to clarify the exact mechanism of action and to confirm the pre-operative IgG infusion as predictive of outcome after sptenectomy. R6sum~
Le r61e de la chirurgie dans le traitement du purpura thrombocytop6nique d'origine immune (PTI) reste discut6e. Le but de cette 6tude a 6t6 de v6rifier les crit~res de s61ection pour proposer une spl6nectomie, d'analyser les r6sultats d'un protocole d'6valuation du risque h6morragique et, enfin, de discuter les r6sultats ~ long-terme chez 70 patients ayant un PTI trait6s chirurgicalement entre 1984 et 1990. Tous les patients ont re~u une corticoth6rapie. Soixante-deux patients ont re,u, en pr~op6ratoire par injection intraveineuse unique de fortes doses d'IgG (600 mg/kg) dans le but de r6duire le besoin en transfusions de plaquettes. Quarante-trois patients ont eu une augmentation significative de leur hombre de plaquettes, huit, une augmentation mod6r6e, alors qu'onze n'ont eu aucune r6ponse. Aucun patient n'est d6c6d6 en p6riode p6riop6ratoire, mais on a enregistr6 14 complications (20%) postop6ratoires mineures. Des rates accessoires ont 6t6 retrouv6es dans 11 cas (15.7%). Le suivi moyen a 6t6 de 21 mois. La r6ponse h la spl6nectomie a 6t6 consid6r6e comme compl6te (plaquettes sup6rieures b. 150000/ram3 sans besoin de traitement compl6mentaire) chez 63 patients (90%) alors qu'aucune r6ponse n'a 6t6 obtenue dans sept cas. Chez deux des patientes n'ayant pas r6pondu h la spl6nectomie, une scintigraphie ~ l'In-111 a montr6 l'existence de rates accesoires: le PTI a regress6 apr6s ablation de ces rates accesoires. Tous les patients qui n'ont pas r6pondu ~ la spl6nectomie 6talent parmi les patients qui n'avaient pas r6pondu
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la perfusion prroprratoire de fortes doses d'IgG. On conclue que la splrnectomie est stare et efficace dans le traitement du PTI et que la rrponse/~ une perfusion prroprratoire d'IgG est corrrlre ~ la rrponse A ia splrnectomie.
4.
Resumen
6.
E1 papel de la cirugia en el tratamiento de la Ptirpura Trombocitop6nica Inmune (PTI) es todavfa motivo de discusi6n. El prrposito del presente estudio fue verificar los criterios de selecci6n del paciente para esplenectomia, analizar los resultados de un protocolo para la evaluacirn de los riesgos de hemorragia y discutir los resultados a largo plazao en 70 pacientes con PTI sometidos a tratamiento quirtirgico entre 1984 y 1990. La totalidad de los pacientes recibi6 terapia esteroidea. A 62 pacientes se les administraron altas dosis de IgG (600 mg/kg en bolo IV) preoperatoiramente con el fin de obviar la necesidad de transfusirn intraoperatoria de plaquetas. Cuarenta y tres pacientes exhibieron un incremento significativo en el recuento de plaquetas y 8 un incremento moderado, en tato que no hubo respuesta en 11 pacientes. No se registr6 mortalidad operatoria, pero hubo compticaciones menores en 14 casos (20%). Se hallaron bazos accesorios en 11 casos (15.7%). E1 seguimiento promedio fue de 21 meses. Se considerfi que hubo respuestra completa a la esplenectomfa (plaquetas sobre 15.000 mm 3 sin necesidad de terapia) en 63 pacientes (90%); no hubo respuesta en 7 casos. En 2 de los pacientes que no respondieron la escanograffa con In-I 11 revel6 bazos accesorios y se logr6 remisi6n de la PTI con la rescessi6n de 6stos. La totalidad de los casos que no respondieron se hall6 en el grupo de pacientes que no exhibieron respuesta a la infusirn preoperatoria de altas dosis de IgG. Se llega a la conclusi6n de que la esplenectom[a es una modalidad de tratamiento seguro y eficaz para la PTI y que la respuesta a la infusi6n preoperatoria de IgG puede ser considerada como un factor de prediccirn del resultado de la esplenectomfa.
7.
References
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Invited Commentary S e y m o u r I. S c h w a r t z , M . D . Department of Surgery, University of Rochester, Rochester, New York, U.S.A.
The authors review of their experience of surgical treatment of immune thrombocytopenic purpura (ITP) incorporates almost all of the salient features that should be considered in the
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management of these patients. It is now generally agreed that splenectomy is not only a valid alternative to medical treatment, but is associated with a significantly higher rate of permanent remission. The permanent remission rate associated with corticosteroid therapy in series we have reviewed was well under 25%, whereas, most surgical series report a permanent remission of well over 80%. The incidence of pediatric cases subjected to splenectomy in the authors' series is significantly higher than general experience. Most children can be managed medically and a longer course of nonsurgical management is applied to the pediatric population. The routine use of pre-
