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Thrombotic thrombocytopenic purpura: Indications for and results of splenectomy
Thrombotic Thrombocytopenic Purpura: Indications for and Results of Splenectomy Glenn A. Winslow, MD, Edward W. Nelson, MD, Salt Lake City, Utah
BACKGROUND: Thrombotic thrombocytopenic purpura (ITP) is a rare, life-threatening disorder of unknown pathophysiology. The role of splenectomy in the multimodality therapy of TTP is controversial. . MATERIALS AND METHODS: All charts of patients with TTP at the University of Utah between 1964 and 1994 were reviewed to evaluate various treatment regimens, and specifically, the impact of splenectomy on morbidity and survival. RESULTS: Of the 15 patients identified, 14 underwent initial treatment with plasmapheresis and steroids. Nine patients were treated with medical therapy only, 6 of whom completely recovered, while 3 patients died. Six patients failed plasmapheresis and underwent splenectomy. There were no operative complications or postoperative deaths. All surgical patients had no active disease at last follow-up. CONCLUSION: Plasmapheresis and steroid administration remain the first-line therapy for TTP. This series documents that splenectomy offers excellent results with minimal morbidity and mortality in patients who do not respond to or who relapse after plasmapheresis. Am J Surg.
1995;170:556-563.
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hrombotic thrombocytopenic purpura (TTP) was first described by Moschcowitz in 1924 as an acute, febrile illness with pleochromatic anemia and hyaline thrombosis of the terminal arterioles and capillaries.’ It is characterized clinically by a pentad: microangiopathic hemolytic anemia, consumptive thrombocytopenia, central nervous system abnormalities, renal dysfunction, and fever.* The pathophysiology of TTP is poorly understood, but central to the process is damage to vascular endothelium resulting in platelet aggregation and subsequent microvascuIar occlusion.3 Without treatment, TTP is a rapidly progressive and fatal disease, with 90% of patients surviving ~3 months.2
From the Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah. Requests for reprints should be addressed to Edward W. Nelson, \rlD, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah 84132. Presented at the 47th Annual Meeting of the Southwestern surgical Congress, San Antonio, Texas, April 23-26, 1995.
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Splenectomy was first attempted as therapy for TTP in 1927, but success was not reported until 1951.4-5 In 1957, steroids and splenectomy were combined in the treatment of TTP and remained the primary therapy for the next 20 years with survival rates of 51%.6-7 Although anecdotal reports of improvement in TTP after whole blood transfusion were reported, plasma exchange was not advocated as primary therapy for TTP until 1977.7s Currently, plasmapheresis and steroids represent first-line therapy for TIP, and have resulted in significantly improved response rates.7j9 Largely ignored in the surgical literature is the current role of splenectomy in the multimodality therapy for TTP. While reports of splenectomy combined with medical therapy in the management of refractory TTP document durable remission rates of 87% to 91%, the role of splenectomy remains controversial.“‘” To analyze the role of splenectomy and add to the sparse surgical literature on this topic, we reviewed our experience with splenectomy in the treatment of TTP over the last 10 years.
MATERIALS AND METHODS Charts of all adult patients admitted with ,the diagnosis of TTP to the University of Utah Health Sciences Center from January 1984 through February 1994 were reviewed. Eighteen patients were identified, 3 of which were excluded because of lack of follow-up data. TTP was defined by consumptive thrombocytopenia (platelet count ~100 X l@/mm3), microangiopathic hemolytic anemia (hematocrit ~30%; evidence of schistocytes, burr cells, et cetera, on peripheral blood smear; elevated serum lactate dehydrogenase [LDH]; elevated serum bilirubin), renal dysfunction (serum creatinine >2.0 g/dL, hematuria, or proteinuria), neurologic impairment (abnormality results of neuropsychiatric examination), and fever (temperature >38”C). For each patient, appropriate clinical and laboratory data were recorded. In addition, the treatment sequence and subsequent outcome of each patient were analyzed. No active disease was defined as normalization of laboratory values and resolution of clinical symptoms. RESULTS Of the 15 cases available for review, 11 were women and 4 were men, with a mean patient age of 43 years. Nine patients presented with the acute form of TTP, only 4 patients demonstrated the relapsing variant, and 2 patients presented with TTP thought to be secondary to systemic lupus erythematosus. Clinical characteristics and laboratory values of the patients on admission are summarized in the Table. The sequence of treatment for all patients is outlined in Figure 1. With the exception of 1 patient who refused plasmaDECEMBER
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pheresis because of reliTABLE gious persuasion and s&seClinical Characteristics and Laboratory Values of 15 Patients quently died, all 15 paWith Thrombotlc Thrombocytopsnic Purpura on Admission tients underwent initial Clinical No. of treatment with plasmaCharacteristic Patients (%) Lab Values i SEM Range pheresis (60 to 80 mL/kg of Thrombocytopenia 15 (100) Plt count 23,000 * 5,604/mm3 2,000-78,000/mm3 plasma removed and reAnemia 14 (93) Hct (%) 23 * 1.0 20-30 placed with fresh frozen Renal dysfunction 14 (93) Cr (g/dL) 3.0 r 0.4 (n = 5) 2.2-4.5 hematuria (n = 9) plasma 1.3 times volume of proteinuria (n = 1) plasma removed) comElevated LDH 15 (100) LDH (U/L) 1,538 i 322 467-4,285 bined with steroids (predFever Temp (“C) 38.5 * 0.31 38-40 6 (40) nisone; 60 to 200 mg/d). Neurologic dysfunction 12 (80) Daily plasmapheresis was performed for a mean of 5.2 SEM = standard error of the mean; P/t count = platelet count; Ml= hematocrit; Cr = serum creatinine; LDH = serum lactate dehydrogenase; Temp = temperature. days (range’ 0 to 13). Adjunct therapies were ad- L ministered per physician preference and included the following: acetylsalicylic acid (ASA) (325 mg/d, 3 patients); dipyriPatients (15) damole (50 mgTID, 4 patients); vincristine (0.03 m&g weekly, I 5 patients); dextran (250 to 500 mL BID; 1 patient); and IV immunoglobulin (400 to 1,ooO mg,kg per day, 2 patients). Of Medical Therapy (15)’ the 9 patients treated with medical therapy alone, 3 died, while 6 recovered completely with no active disease (mean followup of 23 months, range 2 to 48). Of the 3 patients who died, 2 had a rapid progressive downhill clinical course despite maxMedical Therapy Medical Therapy + imum medical therapy, and 1 patient deteriorated rapidly durSplenectomy (6) Only (6) ing a relapse of TTP after undergoing an initial successful course of medical therapy. J\ f Six of the 15 patients underwent splenectomy; 4 who iniNAD (6) Death (3) NAD (6) tially responded to medical therapy but suffered a relapse, and 2 who showed no improvement during medical therapy. Flgurs 1. Treatment sequence of all patients with thrombotic The mean interval between admission and splenectomy was thrombocytopenic purpura at the University of Utah Health 8 days (range 2 to 23). Blood requirements, which had avSciences Center over a lo-year period. of the 9 patients treated eraged 8 units (range 2 to 12) during plasmapheresis, were with medical therapy alone, 6 completely recovered while 3 eliminated in all but 2 patients after splenectomy. All padied. Six of the 15 patients failed medical therapy alone and tients treated with splenectomy received steroids after undrwent splenectomy with complete recovery. With the exsurgery. One patient required postoperative plasmapheresis ception of 1 patient who refused plasmapheresis, all 15 patients underwent initial treatment with plasmapheresis and steroids in to resolve refractory anemia and thrombocytopenia. There various combinations of acetylsalicylic acid, dipyrldamole, vinwere no operative complications or postoperative deaths. cristine, dextran, and intravenous immunoglobulin. Numbers of The average length of stay was 7 days (range 5 to 11). All patients are given in parentheses. ‘Plasmapheresis, steroids f surgical patients were discharged with complete recovery and adjunct therapy. NAD = no active disease. maintained remission at a mean follow-up of 21 months (range 6 to 38). A variety of forms of TIP have been described. The acute variant of TTP is a fulminant process usually resulting in COMMENTS death within 3 months if treatment is unsuccessful. The most A review of TTP in 1966 concluded that this disease was common clinical variant of TTP described is the relapsing almost uniformly fatal, with no consistently effective therform.’ After a successful course of therapy, patients may reapy.* Despite recent advances in the treatment of this disease, the mortality rate of TIP is still 10% to 20%.9 The proposed lapse after remaining symptom free for periods of months or years. The chronic form of T’TP is rare. Patients develop pathophysiology of TTP includes endothelial damage secsymptoms insidiously and survive many years with minimal ondary to circulating antibodies, immune complexes, and bacmorbidity. Numerous conditions predisposing the patient to terial endotoxins. Other theories, including deficient prostadeveloping TTP are known (ie, collagen vascular diseases, cyclin bioavailability, presence of abnormally large factor neoplastic disorders, pregnancy). Finally, a rare familial variVIII/van Willebrand factor (FVIII/vWF) multimeric strucant with an autosomal recessive-type of inheritance pattern tures, and a platelet aggregating factor, have all been postuhas been described.T lated as possible causative factors in the pathogenesis of TIP.3 The patients in this series are a typical group of those who Since there are no well-controlled, prospective, randomized develop TTP with a female-to-male ratio of 3:2 and a peak trials comparing the numerous therapeutic modalities used for incidence in the third decade of life.*,’ All patients in this this rare disease, and the pathophysiology remains obscure, series presented with thrombocytopenia and subsequent current therapy for TTP remains largely empiric. THE AMERICAN
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hemorrhagic manifestations. Anemia, renal dysfunction, neurologic impairments, and fever were noted less frequently. Several previous large reviews have also outlined similar presenting symptoms, including thrombocytopenia (83% to 96%), microangiopathic hemolytic anemia (98%), and elevation of LDH (up to 6 times normal).2~12-‘3Renal disease has been noted in 88% of patients and varies in severity from hematuria to acute renal failure. Neurologic symp toms from headache to frank paresis are present in 84% to 92% of patients presenting with TIP, while fever is found in 60% to 98% of cases. The complete pentad is present in 40% of patients presenting with TIP. Plasmapheresis and steroids are established effective therapy for TTP. Since Bukowski et all4 first advocated plasmapheresis for primary therapy of TTP in 1977, considerable data, including several large reviews in support of this modality, have been published, demonstrating remission in 70% to 82% of patients. 7~12A recent, multicenter, prospective trial of medical therapy demonstrated an initial response rate of 47% with plasmapheresis, and a survival rate of 96% at 6-months’ follow-up. l5 Investigators have stated that the benefit of plasma exchange stems from not only replacing a substance deficient in patients with TTP, but also from removing theoretically toxic factors during the exchange process.” The use of steroids alone or as an adjunct to other forms of therapy in the treatment of TTP is based on the proposed immunologic cause of the disease.16 Although the actual benefit of steroids in the treatment of TIP is unclear, it is difficult to disprove, as the majority of patients who have survived TTP have received steroids. A plethora of other agents have been used in conjunction with plasmapheresis and steroids, although no studies have been performed to show clear benefit in the treatment of TTP.9 Dextran was the first platelet inhibitor used, and has been proposed to be of some benefit in combination with splenectomy, steroids, and plasmapheresis.lO-ll The role of ASA and dipyridamole continues to be questioned.’ Vincristine is thought to interfere with the action of the large FVIII/vWF structures present, while IV immunoglobulin is infrequently used to “neutralize” the platelet aggregating factor found in patients with TTP.*7-‘8 Despite considerable controversy in the literature, splenectomy remains an important part of treatment for TIP. This series presents one of the largest reports of splenectomy for TTP, and further documents that this surgery can be performed with excellent results and minimal morbidity and mortality in patients who do not respond to or who relapse after plasmapheresis. Onundarson et all9 advocated splenectomy as a therapeutic modality for patients who demonstrate the relapsing form of TTP based on experience with 7 patients who underwent splenectomy with minimal morbidity and 1 mortality, with a mean follow-up of 42 months. The single surgical death failed preoperative plasmapheresis, and at the time of surgery remained severely thrombocytopenic, comatose, and had declining renal function. Other authors have consigned the role of splenectomy, after using ptasmapheresis, steroids, and dextran, to be “salvage” therapy (ie, nonresponders or relapsing variant).“J3 Thompson et all3 reported 14 patients treated with splenectomy. Seven patients had relapsing disease after an initial successful course 560
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of medical therapy, while the other 7 patients were nonrespenders to medical therapy. Of these 14 patients, 12 responded completely to splenectomy, although no follow-up data were reported. In a smaller series, Schneider et al” demonstrated a durable remission rate of 91% at a mean follow-up of 13 months when splenectomy in conjunction with medical therapy was performed for relapsing TTP. In contrast, other authors have suggested that splenectomy has no role in the management of TTP, and that clinical improvement noted with splenectomy is largely due to transfusion of blood products. 2o Of note is that only 2 patients who underwent splenectomy in our series required blood products. In a recent, retrospective review, Hayward et al9 compared groups treated with splenectomy for refractory disease to those treated with medical therapy only. Patients treated with splenectomy demonstrated an increased time to complete remission and an increased requirement of blood transfusion. These observations may only reflect that patients who fail medical therapy have significantly higher morbidity, regardless of the eventual use of splenectomy. Furthermore, the series by Hayward et al also reported a durable remission rate of 85%. in those undergoing splenectomy, with a duration of follow-up of 1.7 years. Bell et a12’ described splenectomy in 6 patients who did not respond to medical therapy. All 6 of these patients had pronounced deterioration after surgery, with 4 becoming comatose. One patient died in the immediate postoperative period. The remaining 5 patients survived complex prolonged hospital courses requiring plasmapheresis and blood transfusions. Based on this group’s experience, splenectomy has been abandoned since 1984. Despite this controversy, splenectomy remains an important part of the multimodality therapy for TTP. The reason for clinical improvement after splenectomy, however, remains speculative. The spleen is enlarged in approximately 20% of patients with TIP, and pathologic examination demonstrates congestion and arteriolar occlusions by hyaline platelet thrombi. 1o,22Kadri et alz3 noted intrasplenic erythrophagocytosis in a patient with TTP and postulated that splenectomy may remove a major site of cell destruction. Appropriate medical therapy after splenectomy may be required if no clinical improvement is noted.“J3 All patients who undergo splenectomy should receive steroids during and after surgery, with addition of plasmapheresis if no improvement in clinical status is noted. Based on our review and the results of this series, we propose the following approach to the management of patients presenting with TTP (Figure 2). An experienced surgeon should be notified upon admission of any patient with suspected TTP, and should be actively involved in the decision making and care of the patient. Medical therapy consisting of plasmapheresis, steroids,. and adjunctive agents represents the initial therapy for TIP. If a patient has a relapse or is an initial nonresponder to medical therapy, splenectomy should be performed. Using numerous clinical and laboratory data, the clinician can measure the success or failure of therapy both prior to and after splenectomy. Neurologic abnormalities appear to be the most sensitive to therapy, with resolution observed within the first hours to days in those undergoing successful therapy.t3 A significant DECEMBER
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7. Bukowski RM, King JW, Hewlett JS. Plasmapheresis in the treatment of thrombotic thrombocytopenic purpura. Blood. 1977;50:413-417. 8. Rubenstein MA, Kagan BM, MacGillviray MH, et al. Unusual remission in a case of thrombotic thrombocytopenic purpura syndrome following fresh blood exchange transfusions. Ann Intern Med. 1959;51: 1409-1419.
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9. Hayward CPM, Sutton DM, Carter WH. Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Arch Intern Med. 1995;154:982-987. 10. Cuttner J. Thrombotic thrombocytopenic purpura: a ten-year experience. Blood. 1980;56:302-306.
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Splenectomy + Medical Therapy Figure 2. Proposed treatment algorithm for the management of thrombotic thrombocytopenic purpura (TfP). Medical therapy consisting of plasmapheresis, steroids, and adjunctive agents represents the first-line therapy for lTP. An experienced surgeon should be notified upon admission of any patient with suspected UP. If a patient has a relapse of their disease or is an initial nonresponder to medical therapy, splenectomy should be performed. *Notify surgeon of patient’s admission.
decrease in LDH is also a reliable indicator of successful therapy. Platelet counts have been traditionally followed up to assess response, but may lag days behind changes in other clinical variables. Patton et alz4 recently demonstrated that after the third day of medical therapy for TTP, there were highly significant differences in both LDH levels and platelet counts for survivors and nonsurvivors. They have now incorporated LDH levels and platelet counts into their treatment protocol as factors for determining escalation of conventional medical therapy and for early institution of alternative treatments. Finally, renal dysfunction may persist days to weeks after normalization of other clinical symptoms and laboratory data.13 In summary, plasmapheresis, steroid administration, and adjunct medical therapy remain first-line therapy for TTP. In patients who do not respond to or relapse after plasmapheresis, splenectomy and continued medical therapy should be used, offering excellent results with minimal morbidity and mortality.
REFERENCES 1. Moschcowitz E. An acute febrile nleiochromic anemia with hvaline thrombosis of the terminal arterioles and capillaries. Arch In&n Med. 1925;36:89-93. 2. Amorosi EL, Ultman JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine (Baltimore). 1966;45:139-159. 3. Ruggenenti P, Gemuzzi G. Thrombotic thrombocytopenic purpura and related disorders. Hemutol GncoI Chinhbrth Am. 1990;4:2 19-241. 4. Baehr G, Klemperer P, Schifrin A. An acute febrile anemia and thrombocytopenic purpura with diffuse platelet thromboses of capillaries and arterioles. Trans Assoc Am Physicians. 1936;51:42-58. 5. Meacham GC, Orbison L, Heinle RW, et al. Thrombotic thrombocytopenic purpura a disseminated disease of arterioles. B&d. 1951;6:
706-719. 6. Shapiro HD, Doktor D, Churg J. Thrombotic
thrombocytopenic purpura (Moschcowin’s disease): report of a case with remission after splenectomy and steroid therapy. Ann Intern Med. 1957;47:582-585.
11. Schneider PA, Rayner AA, Linker CA, et al. The role of splenectomy in multimodality treatment of thrombotic thrombocytopenic purpura. Ann Surg. 1985;202:318-322. 12. Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature. Medicine (Baltimore), 1981;60:413429. 13. Thompson CE, Damon LE, Ries CA, Linker CA. Thrombotic microangiopathies in the 1980’s: clinical features, response to treatment, and the impact of the human immunodeficiency virus epidemic. Blood. 1992;80:1890-1895. 14. Bukowski RM, Hewlett JS, Reimer RR, et al. Therapy of thrombotic thrombocytopenic purpura: an overview. Semin Thromb Hemost. 1981;7:14. 15. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. NEJM. 1991;325:393-397, 16. Pisciotto P, Rosen D, Silver H, et al. Treatment of thrombotic thrombocytopenic purpura. Evaluation of plasma exchange and review of the literature. VOX Sang. 1983;45:185-196. 17. Remuzzi G. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. In: Glassock RJ, ed. Current Therapy in NephroIoa and Hypertension-2. Toronto: BC Becker; 1987:15+160. 18. Wong P, Itoh K, Yoshida S. Treatment of thrombotic thrombocytopenic purpura with intravenous gamma globulin. NEjM. 1986; 314:385. Letter 19. Gnundarson PI’, Rowe JM, Heal JM, Francis CW. Response to plasma exchange and splenectomy in thrombotic thrombocytopenic purpura. Arch Intern Med. 1992;152:791-795. 20. Bymes JJ, Lian ECY. Recent therapeutic advances in thrombotic thrombocytopenic purpura. Semin Thromb Hemost. 1979;5:199-215. 21. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. NEJM. 1991;325:398-403. 22. Rutkow IM. Thrombotic thrombocytopenic purpura (TTP) and splenectomy: a current appraisal. Ann Surg. 1978;188:701-705. 23. Kadri A, Moinuddin M, De Leeuw NKM. Phagocytosis of blood cells by splenic macrophages in thrombotic thrombocytopenic purpura. Ann Inrem Med. 1975;82:799-802. 24. Patton JF, Manning KR, Case D, Owen J. Serum lactate dehydrogenase and platelet count predict survival in thrombotic thrombocytopenic purpura. Am J Hem&. 1994;47:9+99.
DISCUSSION Arlo Hertnreck, MD (Kansas City, Kansas): Dr. Winslow pointed out that the hallmark of thrombotic tluombocytopenic purpura (TTP) is a pure consumptive thrombccytopenia that appears to be independent of immunologic processes. In contrast to venous thrombosis and disseminated intravascular coagulation, minimal fibrinogen consumption occurs in TTP. Virtually all of the symptoms are secondary to the occlusion of capillaries and precapillary arterioles by platelet thrombi. The mechanisms for this generalized platelet thrombosis are unclear at the present time. The rarity of TTP has hampered efforts to study therapies in a randomized, controlled manner. Despite these limita-
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tions, the prognosis for TTP has improved dramatically over the past 20 years, from a death rate of 80% to 90% to a survival rate of 80% to 90%. The therapy for TIP is working, despite the limitations of not being able to do a randomized, prospective study. In your series of 18 patients, 3 were excluded because of lack of follow-up. Were any of these 3 patients in the splenectomized group, and, if so, what was their status at the time of hospital discharge? Can you amplify on the associated disease’ processes in the 9 medically treated patients versus the 6 splenectomized patients? You mentioned in the manuscript that 2 of your medically treated patients had systemic lupus erythematosus (SLE). We all know that those patients do not respond as well to therapy if they develop TIP. Did any of your patients have a recent bone marrow transplant? In our institution, bone marrow transplantation is becoming a frequent condition associated with TTP. In general, these patients do not do well when they develop TTP. In one recent bone marrow transplant series in the literature, 6.3% of the allogenic transplants developed TTP and 0.7% of the autogenous transplants developed TTP. Dr. Amare, a hematologist at our institution reported on a series of TTP patients in I979 similar to the series you are reporting on today. This was before the era of whole blood exchanges and plasmapheresis. Like your series, all 6 of the patients undergoing splenectomy in our institution survived and they only received prednisone and antiplatelet agents. Despite this, we currently are doing virtually no splenectomies for TX’. The last 2 patients that I have operated on for TTP have been for the insertion of an internal jugular dialysis catheter for the purpose of plasmapheresis. I believe the major contribution of this paper is to demonstrate again that splenectomy can be safely performed in the patient with T’TP if necessary, and leads me to my final question. Since some patients with splenectomy develop TIP, would you elaborate on the mechanisms whereby splenectomy helps the patient with TTP? Barry Fisher, MD (Las Vegas, Nevada): 1 also enjoyed this presentation because I am just as confused as many of us are on the mechanism of why TTP occurs. I only have one question for the authors. How do you account for the dramatic difference in the 40% response to medical therapy reported in the 3 series on the surgical side of the slide as compared to the 80% response coming from those authors who use medical therapy alone? Victor Zannis, h4D (Phoenix, Arizona): I wanted to ask Dr. Winslow and Dr. Nelson if -they have an opinion on whether this group of patients are reasonable candidates for splenectomy by laparoscopy? Ronald Hinder, MD (Omaha, Nebraska): If one is to accept that there is an improved response in the surgical group, what do the authors feel about laparoscopic splenectomy, which may make the splenectomy an easier and safer procedure if carried out by experienced surgeons? Turner Osler, MD (Albuquerque, New Mexico): This is a nonrandomized study. Can you really draw any conclusion about the comparison of medical and surgical efficacy! CLOSING Glenn Winslow, MD: I would like to thank Dr. Hermreck and the other discussants for their comments. To address Dr. 562
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Hermreck’s first question, we had a total of 18 patients admitted with TTP over this time period; however, we felt that follow-up was very important in terms of outcome data, since the relapsing form of TIP is very common in the natural history of the disease. Thus, 3 patients were excluded from the study because of lack of follow-up data. All 3 patients underwent aggressive medical therapy with steroids, plasmapheresis, and adjunctive agents without splenectomy and were discharged with complete recovery. Regarding patients with SLE and TTP, I didn’t discuss in detail the clinical variants of TTP because of time restraints. These include the acute, chronic, and the most common relapsing form. TTP has also been noted in patients secondary to numerous conditions, and Dr. Hermreck mentioned several of these, one being SLE. We presented 2 patients with TTP thought to be secondary to SLE. Both patients underwent aggressive medical therapy and had complete recovery at discharge. With regard to Dr. Hermreck’s comments on bone marrow transplantation, we have had no experience in our institution with patients presenting with TTP thought to be secondary to malignancy and subsequent bone marrow transplantation. This falls into the category of clinical variants of TTP with secondary disease. As mentioned in the presentation, the mechanism behind improvement after splenectomy is currently unknown. There are few references that addressed this issue, one of which was by Kadri et al who noted intrasplenic erythrophagocytosis in a patient with TTP and postulated that splenectomy may remove a major site of cell destruction. Thus, platelets become injured on passing through the spleen, with subsequent aggregation and thrombosis in distant organ sites. In addition, I made references to the unusually large factor VIII/van Willebrand factor multimeric structures present in patients with ‘TTP. For unknown reasons, patients who present with a relapse of their disease do not have these structures present, while those in remission or who have had splenectomy have these structures present, lending credence to perhaps these structures’ playing a role in the microinvasive thrombosis present. I appreciate Dr. Fisher’s comment regarding the larger series reported in the medical literature. Hayward et al present 52 patients, while Bell’s group presents over 100 patients. One reason for this is that both groups include a similar condition of thrombotic microangiopathy termed hemolyticuremic syndrome (HUS) into their category of TTP. The natural history, clinical course, and prognosis of HUS are often indistinguishable from TTP, except for the age of the patients involved and higher rate of renal failure in HUS. Hayward et al did present a larger series of I3 splenectomies, while Bell’s group presented a series of 6 splenectomies. Since 1984, Bell’s group has not performed splenectomy in the multimodality management of TTP, since their experience had been so poor, although in this modem day of intensive care units, perhaps these patients would have a better prognosis. With regard to comments from Dr. Zannis and Dr. Hinder regarding laparoscopic splenectomy, I have had no experience with this and don’t know if Dr. Nelson may have any thoughts. Preliminary data would indicate that laparoscopic splenecDECEMBER
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tomy could decrease the morbidity and mortality of splenectomy in certain situations, but there is no current experience with TTP patients. I completely agree with Dr. Osler’s comment. As Dr. Hermreck mentioned, this is a rare disease, and no controlled, prospective, randomized trials have been performed. Therefore, we are not able to draw any definitive conclusions from this study. We examined our experience retrospectively, reported our results, and feel that splenectomy for patients who fail or relapse after medical therapy offers ex-
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cellent results with minimal morbidity and mortality in the management of refractory TTP. Thank you. Edward Nelson, MD: We have no experience using a laparoscopic technique for this group of patients. I know that there is a paper to be presented at this meeting regarding laparoscopic surgery for patients with idiopathic thromhocytopenic purpura (ITP). My comment regarding TTP patients would be that these are many times very, very, sick patients, and I think the consideration of the selected use of laparoscopic surgery in this group should he much further down the line.
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BACKGROUND: Thrombotic thrombocytopenic purpura (ITP) is a rare, life-threatening disorder of unknown pathophysiology. The role of splenectomy in the multimodality therapy of TTP is controversial. . MATERIALS AND METHODS: All charts of patients with TTP at the University of Utah between 1964 and 1994 were reviewed to evaluate various treatment regimens, and specifically, the impact of splenectomy on morbidity and survival. RESULTS: Of the 15 patients identified, 14 underwent initial treatment with plasmapheresis and steroids. Nine patients were treated with medical therapy only, 6 of whom completely recovered, while 3 patients died. Six patients failed plasmapheresis and underwent splenectomy. There were no operative complications or postoperative deaths. All surgical patients had no active disease at last follow-up. CONCLUSION: Plasmapheresis and steroid administration remain the first-line therapy for TTP. This series documents that splenectomy offers excellent results with minimal morbidity and mortality in patients who do not respond to or who relapse after plasmapheresis. Am J Surg.
1995;170:556-563.
T
hrombotic thrombocytopenic purpura (TTP) was first described by Moschcowitz in 1924 as an acute, febrile illness with pleochromatic anemia and hyaline thrombosis of the terminal arterioles and capillaries.’ It is characterized clinically by a pentad: microangiopathic hemolytic anemia, consumptive thrombocytopenia, central nervous system abnormalities, renal dysfunction, and fever.* The pathophysiology of TTP is poorly understood, but central to the process is damage to vascular endothelium resulting in platelet aggregation and subsequent microvascuIar occlusion.3 Without treatment, TTP is a rapidly progressive and fatal disease, with 90% of patients surviving ~3 months.2
From the Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah. Requests for reprints should be addressed to Edward W. Nelson, \rlD, Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah 84132. Presented at the 47th Annual Meeting of the Southwestern surgical Congress, San Antonio, Texas, April 23-26, 1995.
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Splenectomy was first attempted as therapy for TTP in 1927, but success was not reported until 1951.4-5 In 1957, steroids and splenectomy were combined in the treatment of TTP and remained the primary therapy for the next 20 years with survival rates of 51%.6-7 Although anecdotal reports of improvement in TTP after whole blood transfusion were reported, plasma exchange was not advocated as primary therapy for TTP until 1977.7s Currently, plasmapheresis and steroids represent first-line therapy for TIP, and have resulted in significantly improved response rates.7j9 Largely ignored in the surgical literature is the current role of splenectomy in the multimodality therapy for TTP. While reports of splenectomy combined with medical therapy in the management of refractory TTP document durable remission rates of 87% to 91%, the role of splenectomy remains controversial.“‘” To analyze the role of splenectomy and add to the sparse surgical literature on this topic, we reviewed our experience with splenectomy in the treatment of TTP over the last 10 years.
MATERIALS AND METHODS Charts of all adult patients admitted with ,the diagnosis of TTP to the University of Utah Health Sciences Center from January 1984 through February 1994 were reviewed. Eighteen patients were identified, 3 of which were excluded because of lack of follow-up data. TTP was defined by consumptive thrombocytopenia (platelet count ~100 X l@/mm3), microangiopathic hemolytic anemia (hematocrit ~30%; evidence of schistocytes, burr cells, et cetera, on peripheral blood smear; elevated serum lactate dehydrogenase [LDH]; elevated serum bilirubin), renal dysfunction (serum creatinine >2.0 g/dL, hematuria, or proteinuria), neurologic impairment (abnormality results of neuropsychiatric examination), and fever (temperature >38”C). For each patient, appropriate clinical and laboratory data were recorded. In addition, the treatment sequence and subsequent outcome of each patient were analyzed. No active disease was defined as normalization of laboratory values and resolution of clinical symptoms. RESULTS Of the 15 cases available for review, 11 were women and 4 were men, with a mean patient age of 43 years. Nine patients presented with the acute form of TTP, only 4 patients demonstrated the relapsing variant, and 2 patients presented with TTP thought to be secondary to systemic lupus erythematosus. Clinical characteristics and laboratory values of the patients on admission are summarized in the Table. The sequence of treatment for all patients is outlined in Figure 1. With the exception of 1 patient who refused plasmaDECEMBER
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pheresis because of reliTABLE gious persuasion and s&seClinical Characteristics and Laboratory Values of 15 Patients quently died, all 15 paWith Thrombotlc Thrombocytopsnic Purpura on Admission tients underwent initial Clinical No. of treatment with plasmaCharacteristic Patients (%) Lab Values i SEM Range pheresis (60 to 80 mL/kg of Thrombocytopenia 15 (100) Plt count 23,000 * 5,604/mm3 2,000-78,000/mm3 plasma removed and reAnemia 14 (93) Hct (%) 23 * 1.0 20-30 placed with fresh frozen Renal dysfunction 14 (93) Cr (g/dL) 3.0 r 0.4 (n = 5) 2.2-4.5 hematuria (n = 9) plasma 1.3 times volume of proteinuria (n = 1) plasma removed) comElevated LDH 15 (100) LDH (U/L) 1,538 i 322 467-4,285 bined with steroids (predFever Temp (“C) 38.5 * 0.31 38-40 6 (40) nisone; 60 to 200 mg/d). Neurologic dysfunction 12 (80) Daily plasmapheresis was performed for a mean of 5.2 SEM = standard error of the mean; P/t count = platelet count; Ml= hematocrit; Cr = serum creatinine; LDH = serum lactate dehydrogenase; Temp = temperature. days (range’ 0 to 13). Adjunct therapies were ad- L ministered per physician preference and included the following: acetylsalicylic acid (ASA) (325 mg/d, 3 patients); dipyriPatients (15) damole (50 mgTID, 4 patients); vincristine (0.03 m&g weekly, I 5 patients); dextran (250 to 500 mL BID; 1 patient); and IV immunoglobulin (400 to 1,ooO mg,kg per day, 2 patients). Of Medical Therapy (15)’ the 9 patients treated with medical therapy alone, 3 died, while 6 recovered completely with no active disease (mean followup of 23 months, range 2 to 48). Of the 3 patients who died, 2 had a rapid progressive downhill clinical course despite maxMedical Therapy Medical Therapy + imum medical therapy, and 1 patient deteriorated rapidly durSplenectomy (6) Only (6) ing a relapse of TTP after undergoing an initial successful course of medical therapy. J\ f Six of the 15 patients underwent splenectomy; 4 who iniNAD (6) Death (3) NAD (6) tially responded to medical therapy but suffered a relapse, and 2 who showed no improvement during medical therapy. Flgurs 1. Treatment sequence of all patients with thrombotic The mean interval between admission and splenectomy was thrombocytopenic purpura at the University of Utah Health 8 days (range 2 to 23). Blood requirements, which had avSciences Center over a lo-year period. of the 9 patients treated eraged 8 units (range 2 to 12) during plasmapheresis, were with medical therapy alone, 6 completely recovered while 3 eliminated in all but 2 patients after splenectomy. All padied. Six of the 15 patients failed medical therapy alone and tients treated with splenectomy received steroids after undrwent splenectomy with complete recovery. With the exsurgery. One patient required postoperative plasmapheresis ception of 1 patient who refused plasmapheresis, all 15 patients underwent initial treatment with plasmapheresis and steroids in to resolve refractory anemia and thrombocytopenia. There various combinations of acetylsalicylic acid, dipyrldamole, vinwere no operative complications or postoperative deaths. cristine, dextran, and intravenous immunoglobulin. Numbers of The average length of stay was 7 days (range 5 to 11). All patients are given in parentheses. ‘Plasmapheresis, steroids f surgical patients were discharged with complete recovery and adjunct therapy. NAD = no active disease. maintained remission at a mean follow-up of 21 months (range 6 to 38). A variety of forms of TIP have been described. The acute variant of TTP is a fulminant process usually resulting in COMMENTS death within 3 months if treatment is unsuccessful. The most A review of TTP in 1966 concluded that this disease was common clinical variant of TTP described is the relapsing almost uniformly fatal, with no consistently effective therform.’ After a successful course of therapy, patients may reapy.* Despite recent advances in the treatment of this disease, the mortality rate of TIP is still 10% to 20%.9 The proposed lapse after remaining symptom free for periods of months or years. The chronic form of T’TP is rare. Patients develop pathophysiology of TTP includes endothelial damage secsymptoms insidiously and survive many years with minimal ondary to circulating antibodies, immune complexes, and bacmorbidity. Numerous conditions predisposing the patient to terial endotoxins. Other theories, including deficient prostadeveloping TTP are known (ie, collagen vascular diseases, cyclin bioavailability, presence of abnormally large factor neoplastic disorders, pregnancy). Finally, a rare familial variVIII/van Willebrand factor (FVIII/vWF) multimeric strucant with an autosomal recessive-type of inheritance pattern tures, and a platelet aggregating factor, have all been postuhas been described.T lated as possible causative factors in the pathogenesis of TIP.3 The patients in this series are a typical group of those who Since there are no well-controlled, prospective, randomized develop TTP with a female-to-male ratio of 3:2 and a peak trials comparing the numerous therapeutic modalities used for incidence in the third decade of life.*,’ All patients in this this rare disease, and the pathophysiology remains obscure, series presented with thrombocytopenia and subsequent current therapy for TTP remains largely empiric. THE AMERICAN
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hemorrhagic manifestations. Anemia, renal dysfunction, neurologic impairments, and fever were noted less frequently. Several previous large reviews have also outlined similar presenting symptoms, including thrombocytopenia (83% to 96%), microangiopathic hemolytic anemia (98%), and elevation of LDH (up to 6 times normal).2~12-‘3Renal disease has been noted in 88% of patients and varies in severity from hematuria to acute renal failure. Neurologic symp toms from headache to frank paresis are present in 84% to 92% of patients presenting with TIP, while fever is found in 60% to 98% of cases. The complete pentad is present in 40% of patients presenting with TIP. Plasmapheresis and steroids are established effective therapy for TTP. Since Bukowski et all4 first advocated plasmapheresis for primary therapy of TTP in 1977, considerable data, including several large reviews in support of this modality, have been published, demonstrating remission in 70% to 82% of patients. 7~12A recent, multicenter, prospective trial of medical therapy demonstrated an initial response rate of 47% with plasmapheresis, and a survival rate of 96% at 6-months’ follow-up. l5 Investigators have stated that the benefit of plasma exchange stems from not only replacing a substance deficient in patients with TTP, but also from removing theoretically toxic factors during the exchange process.” The use of steroids alone or as an adjunct to other forms of therapy in the treatment of TTP is based on the proposed immunologic cause of the disease.16 Although the actual benefit of steroids in the treatment of TIP is unclear, it is difficult to disprove, as the majority of patients who have survived TTP have received steroids. A plethora of other agents have been used in conjunction with plasmapheresis and steroids, although no studies have been performed to show clear benefit in the treatment of TTP.9 Dextran was the first platelet inhibitor used, and has been proposed to be of some benefit in combination with splenectomy, steroids, and plasmapheresis.lO-ll The role of ASA and dipyridamole continues to be questioned.’ Vincristine is thought to interfere with the action of the large FVIII/vWF structures present, while IV immunoglobulin is infrequently used to “neutralize” the platelet aggregating factor found in patients with TTP.*7-‘8 Despite considerable controversy in the literature, splenectomy remains an important part of treatment for TIP. This series presents one of the largest reports of splenectomy for TTP, and further documents that this surgery can be performed with excellent results and minimal morbidity and mortality in patients who do not respond to or who relapse after plasmapheresis. Onundarson et all9 advocated splenectomy as a therapeutic modality for patients who demonstrate the relapsing form of TTP based on experience with 7 patients who underwent splenectomy with minimal morbidity and 1 mortality, with a mean follow-up of 42 months. The single surgical death failed preoperative plasmapheresis, and at the time of surgery remained severely thrombocytopenic, comatose, and had declining renal function. Other authors have consigned the role of splenectomy, after using ptasmapheresis, steroids, and dextran, to be “salvage” therapy (ie, nonresponders or relapsing variant).“J3 Thompson et all3 reported 14 patients treated with splenectomy. Seven patients had relapsing disease after an initial successful course 560
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of medical therapy, while the other 7 patients were nonrespenders to medical therapy. Of these 14 patients, 12 responded completely to splenectomy, although no follow-up data were reported. In a smaller series, Schneider et al” demonstrated a durable remission rate of 91% at a mean follow-up of 13 months when splenectomy in conjunction with medical therapy was performed for relapsing TTP. In contrast, other authors have suggested that splenectomy has no role in the management of TTP, and that clinical improvement noted with splenectomy is largely due to transfusion of blood products. 2o Of note is that only 2 patients who underwent splenectomy in our series required blood products. In a recent, retrospective review, Hayward et al9 compared groups treated with splenectomy for refractory disease to those treated with medical therapy only. Patients treated with splenectomy demonstrated an increased time to complete remission and an increased requirement of blood transfusion. These observations may only reflect that patients who fail medical therapy have significantly higher morbidity, regardless of the eventual use of splenectomy. Furthermore, the series by Hayward et al also reported a durable remission rate of 85%. in those undergoing splenectomy, with a duration of follow-up of 1.7 years. Bell et a12’ described splenectomy in 6 patients who did not respond to medical therapy. All 6 of these patients had pronounced deterioration after surgery, with 4 becoming comatose. One patient died in the immediate postoperative period. The remaining 5 patients survived complex prolonged hospital courses requiring plasmapheresis and blood transfusions. Based on this group’s experience, splenectomy has been abandoned since 1984. Despite this controversy, splenectomy remains an important part of the multimodality therapy for TTP. The reason for clinical improvement after splenectomy, however, remains speculative. The spleen is enlarged in approximately 20% of patients with TIP, and pathologic examination demonstrates congestion and arteriolar occlusions by hyaline platelet thrombi. 1o,22Kadri et alz3 noted intrasplenic erythrophagocytosis in a patient with TTP and postulated that splenectomy may remove a major site of cell destruction. Appropriate medical therapy after splenectomy may be required if no clinical improvement is noted.“J3 All patients who undergo splenectomy should receive steroids during and after surgery, with addition of plasmapheresis if no improvement in clinical status is noted. Based on our review and the results of this series, we propose the following approach to the management of patients presenting with TTP (Figure 2). An experienced surgeon should be notified upon admission of any patient with suspected TTP, and should be actively involved in the decision making and care of the patient. Medical therapy consisting of plasmapheresis, steroids,. and adjunctive agents represents the initial therapy for TIP. If a patient has a relapse or is an initial nonresponder to medical therapy, splenectomy should be performed. Using numerous clinical and laboratory data, the clinician can measure the success or failure of therapy both prior to and after splenectomy. Neurologic abnormalities appear to be the most sensitive to therapy, with resolution observed within the first hours to days in those undergoing successful therapy.t3 A significant DECEMBER
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7. Bukowski RM, King JW, Hewlett JS. Plasmapheresis in the treatment of thrombotic thrombocytopenic purpura. Blood. 1977;50:413-417. 8. Rubenstein MA, Kagan BM, MacGillviray MH, et al. Unusual remission in a case of thrombotic thrombocytopenic purpura syndrome following fresh blood exchange transfusions. Ann Intern Med. 1959;51: 1409-1419.
Medical Therapy (plasmapheresis/sterolds)
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9. Hayward CPM, Sutton DM, Carter WH. Treatment outcomes in patients with adult thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Arch Intern Med. 1995;154:982-987. 10. Cuttner J. Thrombotic thrombocytopenic purpura: a ten-year experience. Blood. 1980;56:302-306.
Relapse
Splenectomy + Medical Therapy Figure 2. Proposed treatment algorithm for the management of thrombotic thrombocytopenic purpura (TfP). Medical therapy consisting of plasmapheresis, steroids, and adjunctive agents represents the first-line therapy for lTP. An experienced surgeon should be notified upon admission of any patient with suspected UP. If a patient has a relapse of their disease or is an initial nonresponder to medical therapy, splenectomy should be performed. *Notify surgeon of patient’s admission.
decrease in LDH is also a reliable indicator of successful therapy. Platelet counts have been traditionally followed up to assess response, but may lag days behind changes in other clinical variables. Patton et alz4 recently demonstrated that after the third day of medical therapy for TTP, there were highly significant differences in both LDH levels and platelet counts for survivors and nonsurvivors. They have now incorporated LDH levels and platelet counts into their treatment protocol as factors for determining escalation of conventional medical therapy and for early institution of alternative treatments. Finally, renal dysfunction may persist days to weeks after normalization of other clinical symptoms and laboratory data.13 In summary, plasmapheresis, steroid administration, and adjunct medical therapy remain first-line therapy for TTP. In patients who do not respond to or relapse after plasmapheresis, splenectomy and continued medical therapy should be used, offering excellent results with minimal morbidity and mortality.
REFERENCES 1. Moschcowitz E. An acute febrile nleiochromic anemia with hvaline thrombosis of the terminal arterioles and capillaries. Arch In&n Med. 1925;36:89-93. 2. Amorosi EL, Ultman JE. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine (Baltimore). 1966;45:139-159. 3. Ruggenenti P, Gemuzzi G. Thrombotic thrombocytopenic purpura and related disorders. Hemutol GncoI Chinhbrth Am. 1990;4:2 19-241. 4. Baehr G, Klemperer P, Schifrin A. An acute febrile anemia and thrombocytopenic purpura with diffuse platelet thromboses of capillaries and arterioles. Trans Assoc Am Physicians. 1936;51:42-58. 5. Meacham GC, Orbison L, Heinle RW, et al. Thrombotic thrombocytopenic purpura a disseminated disease of arterioles. B&d. 1951;6:
706-719. 6. Shapiro HD, Doktor D, Churg J. Thrombotic
thrombocytopenic purpura (Moschcowin’s disease): report of a case with remission after splenectomy and steroid therapy. Ann Intern Med. 1957;47:582-585.
11. Schneider PA, Rayner AA, Linker CA, et al. The role of splenectomy in multimodality treatment of thrombotic thrombocytopenic purpura. Ann Surg. 1985;202:318-322. 12. Ridolfi RL, Bell WR. Thrombotic thrombocytopenic purpura. Report of 25 cases and review of the literature. Medicine (Baltimore), 1981;60:413429. 13. Thompson CE, Damon LE, Ries CA, Linker CA. Thrombotic microangiopathies in the 1980’s: clinical features, response to treatment, and the impact of the human immunodeficiency virus epidemic. Blood. 1992;80:1890-1895. 14. Bukowski RM, Hewlett JS, Reimer RR, et al. Therapy of thrombotic thrombocytopenic purpura: an overview. Semin Thromb Hemost. 1981;7:14. 15. Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. NEJM. 1991;325:393-397, 16. Pisciotto P, Rosen D, Silver H, et al. Treatment of thrombotic thrombocytopenic purpura. Evaluation of plasma exchange and review of the literature. VOX Sang. 1983;45:185-196. 17. Remuzzi G. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. In: Glassock RJ, ed. Current Therapy in NephroIoa and Hypertension-2. Toronto: BC Becker; 1987:15+160. 18. Wong P, Itoh K, Yoshida S. Treatment of thrombotic thrombocytopenic purpura with intravenous gamma globulin. NEjM. 1986; 314:385. Letter 19. Gnundarson PI’, Rowe JM, Heal JM, Francis CW. Response to plasma exchange and splenectomy in thrombotic thrombocytopenic purpura. Arch Intern Med. 1992;152:791-795. 20. Bymes JJ, Lian ECY. Recent therapeutic advances in thrombotic thrombocytopenic purpura. Semin Thromb Hemost. 1979;5:199-215. 21. Bell WR, Braine HG, Ness PM, Kickler TS. Improved survival in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Clinical experience in 108 patients. NEJM. 1991;325:398-403. 22. Rutkow IM. Thrombotic thrombocytopenic purpura (TTP) and splenectomy: a current appraisal. Ann Surg. 1978;188:701-705. 23. Kadri A, Moinuddin M, De Leeuw NKM. Phagocytosis of blood cells by splenic macrophages in thrombotic thrombocytopenic purpura. Ann Inrem Med. 1975;82:799-802. 24. Patton JF, Manning KR, Case D, Owen J. Serum lactate dehydrogenase and platelet count predict survival in thrombotic thrombocytopenic purpura. Am J Hem&. 1994;47:9+99.
DISCUSSION Arlo Hertnreck, MD (Kansas City, Kansas): Dr. Winslow pointed out that the hallmark of thrombotic tluombocytopenic purpura (TTP) is a pure consumptive thrombccytopenia that appears to be independent of immunologic processes. In contrast to venous thrombosis and disseminated intravascular coagulation, minimal fibrinogen consumption occurs in TTP. Virtually all of the symptoms are secondary to the occlusion of capillaries and precapillary arterioles by platelet thrombi. The mechanisms for this generalized platelet thrombosis are unclear at the present time. The rarity of TTP has hampered efforts to study therapies in a randomized, controlled manner. Despite these limita-
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tions, the prognosis for TTP has improved dramatically over the past 20 years, from a death rate of 80% to 90% to a survival rate of 80% to 90%. The therapy for TIP is working, despite the limitations of not being able to do a randomized, prospective study. In your series of 18 patients, 3 were excluded because of lack of follow-up. Were any of these 3 patients in the splenectomized group, and, if so, what was their status at the time of hospital discharge? Can you amplify on the associated disease’ processes in the 9 medically treated patients versus the 6 splenectomized patients? You mentioned in the manuscript that 2 of your medically treated patients had systemic lupus erythematosus (SLE). We all know that those patients do not respond as well to therapy if they develop TIP. Did any of your patients have a recent bone marrow transplant? In our institution, bone marrow transplantation is becoming a frequent condition associated with TTP. In general, these patients do not do well when they develop TTP. In one recent bone marrow transplant series in the literature, 6.3% of the allogenic transplants developed TTP and 0.7% of the autogenous transplants developed TTP. Dr. Amare, a hematologist at our institution reported on a series of TTP patients in I979 similar to the series you are reporting on today. This was before the era of whole blood exchanges and plasmapheresis. Like your series, all 6 of the patients undergoing splenectomy in our institution survived and they only received prednisone and antiplatelet agents. Despite this, we currently are doing virtually no splenectomies for TX’. The last 2 patients that I have operated on for TTP have been for the insertion of an internal jugular dialysis catheter for the purpose of plasmapheresis. I believe the major contribution of this paper is to demonstrate again that splenectomy can be safely performed in the patient with T’TP if necessary, and leads me to my final question. Since some patients with splenectomy develop TIP, would you elaborate on the mechanisms whereby splenectomy helps the patient with TTP? Barry Fisher, MD (Las Vegas, Nevada): 1 also enjoyed this presentation because I am just as confused as many of us are on the mechanism of why TTP occurs. I only have one question for the authors. How do you account for the dramatic difference in the 40% response to medical therapy reported in the 3 series on the surgical side of the slide as compared to the 80% response coming from those authors who use medical therapy alone? Victor Zannis, h4D (Phoenix, Arizona): I wanted to ask Dr. Winslow and Dr. Nelson if -they have an opinion on whether this group of patients are reasonable candidates for splenectomy by laparoscopy? Ronald Hinder, MD (Omaha, Nebraska): If one is to accept that there is an improved response in the surgical group, what do the authors feel about laparoscopic splenectomy, which may make the splenectomy an easier and safer procedure if carried out by experienced surgeons? Turner Osler, MD (Albuquerque, New Mexico): This is a nonrandomized study. Can you really draw any conclusion about the comparison of medical and surgical efficacy! CLOSING Glenn Winslow, MD: I would like to thank Dr. Hermreck and the other discussants for their comments. To address Dr. 562
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Hermreck’s first question, we had a total of 18 patients admitted with TTP over this time period; however, we felt that follow-up was very important in terms of outcome data, since the relapsing form of TIP is very common in the natural history of the disease. Thus, 3 patients were excluded from the study because of lack of follow-up data. All 3 patients underwent aggressive medical therapy with steroids, plasmapheresis, and adjunctive agents without splenectomy and were discharged with complete recovery. Regarding patients with SLE and TTP, I didn’t discuss in detail the clinical variants of TTP because of time restraints. These include the acute, chronic, and the most common relapsing form. TTP has also been noted in patients secondary to numerous conditions, and Dr. Hermreck mentioned several of these, one being SLE. We presented 2 patients with TTP thought to be secondary to SLE. Both patients underwent aggressive medical therapy and had complete recovery at discharge. With regard to Dr. Hermreck’s comments on bone marrow transplantation, we have had no experience in our institution with patients presenting with TTP thought to be secondary to malignancy and subsequent bone marrow transplantation. This falls into the category of clinical variants of TTP with secondary disease. As mentioned in the presentation, the mechanism behind improvement after splenectomy is currently unknown. There are few references that addressed this issue, one of which was by Kadri et al who noted intrasplenic erythrophagocytosis in a patient with TTP and postulated that splenectomy may remove a major site of cell destruction. Thus, platelets become injured on passing through the spleen, with subsequent aggregation and thrombosis in distant organ sites. In addition, I made references to the unusually large factor VIII/van Willebrand factor multimeric structures present in patients with ‘TTP. For unknown reasons, patients who present with a relapse of their disease do not have these structures present, while those in remission or who have had splenectomy have these structures present, lending credence to perhaps these structures’ playing a role in the microinvasive thrombosis present. I appreciate Dr. Fisher’s comment regarding the larger series reported in the medical literature. Hayward et al present 52 patients, while Bell’s group presents over 100 patients. One reason for this is that both groups include a similar condition of thrombotic microangiopathy termed hemolyticuremic syndrome (HUS) into their category of TTP. The natural history, clinical course, and prognosis of HUS are often indistinguishable from TTP, except for the age of the patients involved and higher rate of renal failure in HUS. Hayward et al did present a larger series of I3 splenectomies, while Bell’s group presented a series of 6 splenectomies. Since 1984, Bell’s group has not performed splenectomy in the multimodality management of TTP, since their experience had been so poor, although in this modem day of intensive care units, perhaps these patients would have a better prognosis. With regard to comments from Dr. Zannis and Dr. Hinder regarding laparoscopic splenectomy, I have had no experience with this and don’t know if Dr. Nelson may have any thoughts. Preliminary data would indicate that laparoscopic splenecDECEMBER
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tomy could decrease the morbidity and mortality of splenectomy in certain situations, but there is no current experience with TTP patients. I completely agree with Dr. Osler’s comment. As Dr. Hermreck mentioned, this is a rare disease, and no controlled, prospective, randomized trials have been performed. Therefore, we are not able to draw any definitive conclusions from this study. We examined our experience retrospectively, reported our results, and feel that splenectomy for patients who fail or relapse after medical therapy offers ex-
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cellent results with minimal morbidity and mortality in the management of refractory TTP. Thank you. Edward Nelson, MD: We have no experience using a laparoscopic technique for this group of patients. I know that there is a paper to be presented at this meeting regarding laparoscopic surgery for patients with idiopathic thromhocytopenic purpura (ITP). My comment regarding TTP patients would be that these are many times very, very, sick patients, and I think the consideration of the selected use of laparoscopic surgery in this group should he much further down the line.
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