Canine immune-mediated thrombocytopenia (IMT)

Transcription

1 J Vet Intern Med 2007;21: Treatment of Severe Immune-Mediated Thrombocytopenia with Human IV Immunoglobulin in 5 Dogs Domenico Bianco, P. Jane Armstrong, and Robert J. Washabau Background: Glucocorticoids with or without other immunotherapy are the initial treatment of choice for dogs with severe immune-mediated thrombocytopenia (IMT). The majority of treated dogs will have improvements in platelet counts within 5 to 7 days of starting therapy, but complications from hemorrhage often occur before a response is seen. Human IV immunoglobulin (hivig) blocks Fc receptors on mononuclear phagocytic cells in dogs; it is used in people with idiopathic thrombocytopenic purpura. Hypothesis: The purpose of this study was to describe adverse effects and benefit of hivig in addition to conventional immunosuppressive therapy in dogs with severe IMT. Animals: Five client-owned dogs with severe primary IMT. Methods: Case series. The hospital database was searched for dogs with primary IMT treated with hivig. Results: No adverse effects were noted during or after hivig infusion in any treated dog. Over a 6-month follow-up, all dogs were clinically normal when using conventional immunosuppressive therapy. Human IVIG was administered 3 days after initiation of immunosuppressive therapy in 4 dogs, and, after 2 days, in 1 dog. In all dogs, the mean platelet counts preand 24 hours post-hivig infusion ( g/kg) were 2,500/mL and 50,600/mL (62,750/mL for the 4 responders), respectively. One dog failed to respond as promptly to hivig (0.34 g/kg), and the platelet count increased to 66,000/mL after 9 days of immunosuppressive therapy. The mean duration of hospitalization post-hivig in all 5 dogs was 1.8 days (12 hours for responders), and the mean total length of hospitalization was 4.6 days (3.5 days for responders). Active hemorrhage resolved and no packed red blood cell transfusions were required after hivig infusion for responders. Conclusions and Clinical Importance: Human IVIG was well tolerated and appeared to be associated with rapid platelet count recovery and amelioration of clinical signs in most dogs with IMT. Key words: Canine; Idiopathic thrombocytopenic purpura; Platelet; Prednisone; Vincristine. Canine immune-mediated thrombocytopenia (IMT) is a serious and relatively common hematologic disorder in veterinary medicine in which platelet-bound antibodies initiate premature destruction by cells of the mononuclear phagocytic system. 1 It may be a primary condition in which there is no apparent inciting cause for the production of antiplatelet antibodies, or it may occur secondary to a known antigenic stimulus, such as neoplasia, 2 infectious diseases, 3 or drug exposure. 4 Because antiplatelet antibody assays have variable specificity and sensitivity and are not widely available, their use has limited clinical utility, and a diagnosis of primary IMT is made on the basis of exclusion of other identifiable causes of thrombocytopenia and response to treatment. 3,5 8 Primary canine IMT has a mortality rate of up to 30% during initial episodes or relapses, usually because of uncontrollable hemorrhage, owner financial constraints, or severe adverse effects associated with longterm immunosuppressive therapy. 1 Standard therapy for canine IMT has been the administration of immunosuppressive dosages of glucocorticoids. 1,9 11 Most dogs with severe primary IMT have resolution of severe thrombocytopenia within 5 to 7 days of starting glucocorticoid therapy, with or without vincristine, From the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN. Reprint requests: Domenico Bianco, Veterinary Clinical Sciences Department, College of Veterinary Medicine, University of Minnesota, 1352 Boyd Avenue, St. Paul, MN 55108; bianc037@ umn.edu. Submitted October 11, 2006; Revised December 4, 2006; Accepted January 11, Copyright E 2007 by the American College of Veterinary Internal Medicine /07/ /$3.00/0 respectively. 12 Use of additional therapies, such as azathioprine, cyclosporine, danazol, cyclophosphamide, and leflunomide also have been reported. 1,13,14 Patient outcomes may be improved and cost of care reduced, if early adjunctive therapy were possible with a product that could rapidly and reliably increase the platelet count, even if temporarily. Human IV immunoglobulin (hivig) is used for this purpose in human patients with idiopathic thrombocytopenic purpura (ITP). Human IVIG is a sterile and highly purified immunoglobulin (Ig) preparation that contains IgG and trace amounts of IgM and IgA from the healthy human donor population. It was approved by the Food and Drug Administration for use in 6 human conditions: ITP, primary and secondary immunodeficiency, pediatric immunodeficiency virus infection, Kawasaki disease, prevention of graft-versus-host disease, and infection in bone marrow transplant recipients. Only 1 dog with IMT not responding to glucocorticoid therapy and successfully treated with hivig has been reported in the veterinary literature, 15 but hivig also has been safely and successfully used in other diseases of dogs, such as immune-mediated hemolytic anemia (IMHA), 16,17 myelofibrosis, 18 drug-induced Stevens-Johnson syndrome, 19 other adverse cutaneous drug reactions, 20 and in erythema multiforme in a cat. 21 Blockade of Fc receptors on mononuclear phagocytic cells has been proposed as the most likely mechanism for the observed response to hivig infusion in dogs. 22 The purpose of this report is to describe the safety and effects of hivig in addition to glucocorticoids in 5 dogs with severe IMT and uncontrollable hemorrhage that required multiple blood product transfusions. Material and Methods All dogs were referred to the Veterinary Medical Center (VMC) at the University of Minnesota between October 2005 and March

2 Human IVIG and Thrombocytopenia for intensive care and investigation of severe thrombocytopenia (platelet count,20,000/ml). The dogs underwent physical examination; CBC, including platelet count, serum biochemistry profile, coagulation profile (including fibrinogen, prothrombin time, activated partial thromboplastin time, and fibrin degradation products); serologic testing for vector-borne diseases; thoracic radiography; abdominal radiography or ultrasonography or both; and, in 3 dogs, bone marrow cytology and histopathology. Platelet counts were determined in EDTA-anticoagulated blood by use of automated cell counters. Platelet counts,40,000/ml were confirmed by manual counting of platelets with a hemocytometer, a and blood smears were evaluated for additional confirmation of thrombocytopenia or evidence of platelet clumping. All dogs were treated with doxycycline b 5 mg/kg q12h (pending vector-borne disease serologic testing), immunosuppressive therapy (prednisone c 1.1 mg/kg PO q12h), and gastroprotectant agents, (famotidine d 0.5 mg/kg PO q24h and sucralfate e g/dog PO q8h). Two dogs (dogs 1 and 5) were treated with an additional immunosuppressive drug (azathioprine f 2 mg/kg PO q24h initially, starting on days 5 and 4, respectively), and 1 dog (dog 4) also was treated with vincristine g (0.02 mg/kg IV) once, on day 4. Crossmatched packed red blood cell (prbc) transfusions (10 ml/kg IV) were administered as needed. Because of active hemorrhage necessitating transfusion therapy and declining clinical condition of all 5 dogs, use of hivig was offered to owners who gave their informed consent. Human IVIG h was administered once IV as a constant rate infusion at g/kg in a 5% sterile saline solution over 6 hours. Before the infusion, all dogs were treated with diphenhydramine (0.5 mg/kg IV), and rectal temperature, heart rate, and respiratory rate were monitored every 10 minutes for the first 40 minutes of infusion. Response to therapy was monitored by performing a platelet count immediately after hivig infusion and then every 24 hours until the platelet count exceeded 40,000/mL. Platelet counts were repeated at weeks 2, 6, 10, 14, 18, 22, and 26; prednisone dosages was decreased by 25% at 2- or 4-week intervals accordingly and discontinued after 6 months of therapy. Results Dog 1 An 8-year-old spayed female mixed-breed dog, weighing 31.1 kg, was evaluated for a 3-week history of epistaxis and hematochezia. The dog did not have any exposure to drugs or toxins, and had no travel history outside of Minnesota. She was vaccinated 8 months before presentation for canine distemper virus, adenovirus (type II), parainfluenza, parvovirus, rabies, and Borrelia burgdorferi. Tick exposure was reported by the pet owner, even though the dog was treated with heartworm and with flea and tick preventative medications during the 6 warmer months of the year. Petechiation of the oral mucosa and hematochezia were detected on physical examination. An interpretation of the CBC results revealed 1,000 platelets/ml (reference range, 160, ,000/mL); serum alkaline phosphatase activity was 855 U/L (reference range, U/L), and there was 1+ occult blood on voided urinalysis. There was no bacterial growth on urine culture. Results of coagulation profile, thoracic radiography, abdominal radiography, and ultrasonography were normal. Serologic testing was negative for Ehrlichia canis, Babesia canis, Rickettsia rickettsii, and Anaplasma phagocytophilum. Cytologic evaluation of a bone marrow aspirate and histologic evaluation of core bone marrow biopsy specimens indicated moderate megakaryocytic hyperplasia. A presumptive diagnosis of IMT was made and immunosuppressive therapy with glucocorticoids began on day 2. On the next 3 days, daily platelet counts were,1,000 platelets/ml, epistaxis and melena continued intermittently, and the dog developed large ecchymoses on the ventral abdomen. A normocytic normochromic anemia with hematocrit of 16% (reference range, 38 57%) developed, and 2 prbc transfusions were administered on 2 consecutive days. On day 4, an IV infusion of hivig was administered at a dosage of 0.32 g/kg over 6 hours. No adverse reactions were noted during or after the infusion. A platelet count immediately after the infusion was 12,000/ ml and 24 hours later was 75,000/mL. Epistaxis and hematochezia resolved, azathioprine was added to the treatment protocol, and the dog was discharged from the hospital on day 5. Platelet count was within reference range (160, ,000 platelets/ml), and the patient had no evidence of bleeding from week 2 until week 26, and immunosuppressive drugs were discontinued after 6 months of therapy. Dog 2 A 7-year-old neutered male Shetland sheepdog, weighing 13.2 kg, was referred with a 2-day history of melena and hematochezia. The owner denied any travel history, drug, or toxin exposure. The dog was vaccinated 6 months before presentation for canine distemper virus, adenovirus (type II), parainfluenza, parvovirus, and rabies. Physical examination disclosed pale mucous membranes, petechiae on oral mucosa and ventral abdomen, grade III/VI holosystolic murmur at the left heart base, and melena. An inflammatory leukogram with regenerative left shift, normocytic normochromic regenerative (248,730 reticulocytes/ml) anemia (hematocrit, 10%), and severe thrombocytopenia (2,000 platelets/ml) were present. Evaluation of RBC morphology revealed no evidence of spherocytosis or autoagglutination, and a direct Coombs test was negative. Serum biochemistry profile disclosed an increased serum urea nitrogen (BUN) and panhypoproteinemia. Results of coagulation profile, thoracic radiography, and abdominal ultrasonography were normal. Serologic testing for antibodies to Rickettsia rickettsii and Anaplasma phagocytophilum was negative. A presumptive diagnosis of IMT with secondary anemia attributable to gastrointestinal blood loss was made, and immunosuppressive glucocorticoid therapy was started. Over the next 3 days, 3 transfusions of prbcs were administered, and daily platelet counts ranged between 2,000 and 6,000/mL. On day 3, an IV infusion of hivig was administered at 0.76 g/kg over a 6-hour infusion. No adverse reactions were noted during or after the infusion. A platelet count immediately after the infusion was 58,000/ ml. At that time, melena and hematochezia had resolved, and the patient was discharged from the

3 696 Bianco, Armstrong, and Washabau hospital with a hematocrit of 27%. Platelet count was within reference range, and the patient was asymptomatic from week 2 until week 26, and prednisone was discontinued after 6 months of treatment. Dog 3 A 7-year-old spayed female Labrador Retriever, weighing 35.7 kg, was referred to the VMC with a 4- day history of lethargy and hematemesis. The owner reported no toxin or drug exposure in the previous 3 months and no recent travel history. The dog was vaccinated 11 months before presentation for canine distemper virus, adenovirus (type II), parainfluenza, parvovirus, and rabies. On physical examination, numerous petechiae on the oral mucosa and large ecchymotic lesions on the ventral abdomen were noted. The platelet count was,1,000/ml. A direct Coombs test was negative. Results of serum biochemistry, coagulation profile, thoracic radiography, and abdominal ultrasonography were normal. Serologic testing was negative for Ehrlichia canis, Rickettsia rickettsii, and Anaplasma phagocytophilum. Cytologic evaluation of a bone marrow aspirate and histologic evaluation of core bone marrow biopsy specimens indicated marked megakaryocytic hyperplasia, and mild granulocytic and erythroid hyperplasia. A presumptive diagnosis of IMT was made, and glucorticoid immunosuppressive therapy was started. Over the next 3 days, daily platelet counts were between 0 and 3,000/mL, 2 prbc transfusions were administered, and the patient had 3 episodes of hematemesis. On day 3, an IV infusion of hivig was administered at 0.28 g/kg as a 6-hour infusion. No adverse reactions were noted during or after the infusion. A platelet count immediately after the infusion was 68,000/mL. At that time, hematemesis had resolved, and the patient was discharged from the hospital. The platelet count was within reference range, and the patient was asymptomatic from week 2 until week 26; glucocorticoid therapy was discontinued after 6 months of treatment. Dog 4 An 11-year-old neutered male American Eskimo, weighing 14.6 kg, was referred because of a 2-day history of profuse melena. The dog had no history of drug or toxin exposure, no travel history, and had not been vaccinated in the previous 4 years. On physical examination, the dog was obese and lethargic, with pale mucous membranes and large ecchymoses in the inguinal region. Hematologic abnormalities included severe thrombocytopenia (,1,000 platelets/ml); neutrophilia (14,300 neutrophils/ml; reference range, 2,100 to 11,200/mL), with a left shift (570 band neutrophils/ml; reference range, 0 to 130/mL); and normocytic normochromic regenerative (125,180 reticulocytes/ml) anemia (hematocrit, 16%). An evaluation of RBC morphology revealed no spherocytosis or autoagglutination, and a direct Coombs test was negative. Serum biochemical abnormalities included increased BUN and panhypoproteinemia, compatible with gastrointestinal bleeding. Results of a coagulation profile, thoracic radiography, and abdominal ultrasonography were normal. Serologic testing was negative for Ehrlichia canis, Rickettsia rickettsii, and Anaplasma phagocytophilum. Cytologic evaluation of a bone marrow aspirate and histologic evaluation of core bone marrow biopsy specimens indicated moderate-to-marked erythroid and megakaryocytic hyperplasia. A presumptive diagnosis of IMT was made, and immunosuppressive glucocorticoid therapy was started. Two prbc transfusions were administered on 2 consecutive days. On day 3, an IV infusion of hivig was administered at 0.34 g/kg as a 6-hour infusion. No adverse reactions were noted during or after the infusion. A platelet count 24 hours after completion of the infusion was still 2,000/ ml, and vincristine was administered. In the next 5 days, the platelet count remained the same, another 3 prbc transfusions were administered, and severe melena continued. On day 9, the platelet count had increased to 66,000/mL, and the patient was discharged from the hospital. The platelet count was within the reference range, and the dog had no melena from week 2 until week 26, and prednisone was discontinued after 6 months of therapy. Dog 5 A 5-year-old spayed female Lhasa Apso, weighing 8.8 kg, was presented with a 2-week history of lethargy, inappetence, and pale mucous membranes. The dog had been treated with cephalexin (20 mg/kg PO q12 h) for 1 week, 5 weeks before presentation, and had been vaccinated for canine distemper virus, adenovirus (type II), parainfluenza, parvovirus, and rabies 3 months before the onset of clinical signs. On physical examination, the dog was obese, with pale mucous membranes and melena. A grade II/VI holosystolic murmur was heard at the left heart base. An evaluation of CBC results indicated severe thrombocytopenia (3,000 platelets/ml); neutrophilia (24,530 neutrophils/ml), with a left shift (2,620 band neutrophils/ ml); and severe normocytic normochromic nonregenerative (54,000 reticulocytes/ml) anemia (hematocrit 16%). An evaluation of peripheral blood smears indicated no evidence of spherocytosis, and a direct Coombs test was negative. The results of a coagulation profile and of thoracic and abdominal radiographies were normal. Serologic testing for Ehrlichia canis also was negative. A presumptive diagnosis of IMT was made, immunosuppressive therapy with glucocorticoids began on day 2, and 2 prbc transfusions were administered. On day 3, the platelet count was,1,000 platelets/ml, and hivig was administered at 0.51 g/kg as a 6-hour IV infusion. No adverse reactions were noted during or after the infusion. A platelet count immediately after the infusion was 6,000/mL and 24 hours later was 50,000/mL. On day 4, melena had resolved, azathioprine was added to the treatment protocol, and the patient was discharged from the hospital. The platelet count was within

4 Human IVIG and Thrombocytopenia 697 the reference range, and the patient was asymptomatic from week 2 until week 26, and immunosuppressive drugs were discontinued after 6 months of therapy. Summary Human IVIG was administered after 3 days of initiation of immunosuppressive therapy in 4 dogs, and after 2 days in 1 dog (dog 5). In all the dogs, the mean platelet counts pre- and 24 hours post-hivig infusion were 2,500/mL and 50,600/mL (62,750/mL for the 4 responders, and 2,000/mL for the nonresponder), respectively. Overall, the mean dosage of hivig was 0.44 g/kg (0.46 g/kg for the responders, and 0.34 g/kg for the nonresponder). Median number of transfusions received by all dogs was 2 (2 for the responders, and 5 for the nonresponder), and no prbc transfusions were required after hivig infusion for responders. The mean duration of hospitalization post-hivig in all 5 dogs was 1.8 days (12 hours for the responders and 6 days for the nonresponder), and mean total length of hospitalization was 4.6 days (3.5 days for the responders and 9 days for the nonresponder). Discussion Glucocorticoids were the first medication used to successfully increase platelet counts in canine patients with IMT and, consequently, became the standard therapy of this disorder. 1,9 11 The general good response of acute canine IMT to glucocorticoid therapy and the lack of prospective, randomized, controlled clinical trials that evaluate the efficacy of other therapeutic strategies made management of acute IMT a matter of the clinician s preference. In a prospective, nonrandomized, unmasked study, early administration of vincristine was associated with faster increases in platelet counts and slightly shorter hospitalization time compared with prednisone alone. 12 Adjunctive therapy to corticosteroids for the acute phase of IMT would be helpful in managing dogs with severe, uncontrolled, or life-threatening hemorrhage before the platelet count increases in response to corticosteroid therapy. The ideal therapy for severe acute IMT should rapidly and reliably increase platelet counts, result in the release of fully functional platelets, and have minimal adverse effects. All 5 dogs in this case series were suspected of having had severe thrombocytopenia attributable to an underlying immune-mediated mechanism on the basis of the following criteria: all dogs had marked thrombocytopenia on presentation, and 3 of 3 dogs had increased numbers of megakaryocytes demonstrable in bone marrow aspirates and core biopsy specimens. Other causes of thrombocytopenia, such as neoplasia, disseminated intravascular coagulation, and common vectorborne diseases in our geographic area were excluded. Finally, all dogs responded to therapy with immunosuppressive doses of glucocorticoids; 4 dogs also showed some benefit from treatment with hivig, which is a known immunomodulatory agent in humans. With 3 of the dogs, additional immunotherapy was used: 2 dogs (dogs 1 and 5) were treated with azathioprine after good response to hivig, with the purpose of long-term steroid-sparing immunosuppressive therapy. Another dog (dog 4) also was treated with vincristine after no apparent response to hivig. In 2 dogs (dogs 2 and 5), bone marrow examination was not performed, but a 6- month follow-up helped to rule out possible underlying neoplastic disease. All 5 patients in this report were treated with a single infusion of hivig because of persistent severe thrombocytopenia, active hemorrhage that required multiple blood transfusions, and to prevent potential severe complications, such as systemic infection secondary to bacterial translocation from the gastrointestinal tract. In this case series of 5 dogs, no associated systemic or local adverse effects attributable to hivig infusion were observed, but careful monitoring was given to patient vital signs during and after hivig administration. Adverse reactions during hivig treatment in humans are uncommon, occurring in less than 5% of patients, and, in the veterinary literature, only 1 dog was reported to vomit once during hivig infusion. 15 Because of the relatively high oncotic pressure of hivig, its use in patients with cardiac disease should be carefully monitored, and concomitant administration of other colloids should be avoided. Evidence of thromboembolic disease and transient thrombocytopenia was detected in 50% and 60% of dogs with IMHA after treatment with hivig, respectively, 17 but these complications are commonly encountered in IMHA, and they were not observed in other dogs treated with hivig for IMHA in another report 16 and for other conditions In our case series, no evidence of thromboembolic disease was detected in any of the treated dogs. When hivig is used, a single dose is given because of concern that a second administration of a foreign protein may incite a severe allergic reaction or immune complex formation. Whether long-term adverse effects of hivig administration will occur in dogs currently is unknown. The safety of hivig needs to be more clearly established before this treatment is routinely recommended. Recommended dosages for hivig in dogs range from 0.5 to 1.5 g/kg. Although most studies used a dosage of 1 g/kg, no difference in efficacy was noted when using a dosage of 0.5 g/kg Because of financial constraints, in 3 dogs of this case series, hivig was used at a dose of,0.5 g/kg (range, g/kg), and 1 of these dogs did not respond to hivig infusion. In children with acute ITP, a single dose of 0.8 g/kg hivig was found to reliably increase the platelet count in the majority of patients, and additional hivig is administered to the one third of children who continue to have platelet counts of #20,000/ ml, hours after the start of treatment. 23,24 Recently, a more rapid increase in platelet count and fewer nonresponders were observed in children with primary acute ITP treated with high-dose immunoglobulin (2 g/ kg) compared with low dose (0.6 g/kg), indicating a possible dose-response relation of the hivig effect. 25 The effect of hivig on platelet function in dogs with IMT has not been studied, but, after an increase in platelet counts to.40,000/ml, no dogs treated with hivig in this case series had any evidence of active hemorrhage.

5 698 Bianco, Armstrong, and Washabau Furthermore, the 4 responders had a stable hematocrit after hivig infusion, and, over a 6-month follow-up, no long-term clinical signs attributable to decreased platelet function were detected in any of the 5 dogs. Although availability and cost were not addressed in this case series, the cost of hivig ($500.00/10-kg dog i ) compared with corticosteroids is considerably higher but may be offset by a shorter duration of hospitalization and potential decrease in transfusion requirements. Dogs with severe IMT usually are hospitalized until overt bleeding ceases, hematocrit is stable, and platelet count exceeds 30,000/mL. When using these guidelines, the mean duration of hospitalization after hivig in the 5 dogs of this case series was 1.8 days (12 hours for the 4 responders), and total length of hospitalization was 4.6 days (3.5 days for the responders). This compares with a mean duration of hospitalization of 5.4 days for 12 dogs with IMT treated with vincristine and prednisone in a recent study. 12 Furthermore, responders had mean platelet counts pre- and 24 hours post-hivig infusion of 2,500/mL and 62,750/mL, respectively, and none of them required any blood transfusion after hivig treatment. The median number of transfusions received by all dogs was 2 (2 for the responders and 5 for the nonresponder). Decreased use of blood products also may contribute to less medical care expense for patients rapidly responding to hivig therapy. The apparent response of 4 of 5 dogs (80%) and the safety of hivig administration in this case series suggest potential therapeutic benefit for hivig therapy and may support judicious use of this product in dogs with severe IMT before serious morbidity and mortality develop. One criticism of this case series is that the apparent platelet count recovery after hivig infusion could have been coincidental or related to glucorticoid therapy. Therefore, larger prospective, randomized, controlled studies that compare the early use of hivig and glucocorticoids versus glucocorticoids alone will be necessary to determine the efficacy and the safety of hivig therapy for canine IMT. Footnotes a Cell-Dyne System, Diagnostics Division, Abbott Laboratories, Santa Clara, CA b Doxycycline, doxycycline tablets, IVAX Pharmaceuticals Miami, FL c Prednisone, prednisone tablets, Watson Labs Corona, CA d Famotidine, Pepcid AC tablets, distributed by Goldline labs, manufactured by IVAX Pharmaceuticals Inc, Miami, FL e Sucralfate, sucralfate tablets, Major Pharmaceuticals Livonia, MI f Azathioprine, Roxane Labs, Columbus, OH g Vincristine, vincristine injectable, manufactured for Mayne Pharma Inc, Paramus, NJ, by Mayne Pharma Pty Ltd, Mulgrove VIC 3170 Australia h Human Globulin Intravenous, Polygam S/D, Baxter Healthcare Corporation, Westlake Village, CA i University of Minnesota, Veterinary Medical Center Pharmacy, St Paul, MN References 1. Lewis DC, Meyers KM. Canine idiopathic thrombocytopenic purpura. J Vet Intern Med 1996;10: Helfland SC, Couto CG, Madewell BR. Immune-mediated thrombocytopenia associated with solid tumors in dogs. 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