555540
research-article2014
AOPXXX10.1177/1060028014555540Annals of PharmacotherapyChoe and Packer
Case Report
Severe Romiplostim-Induced Rebound Thrombocytopenia After Splenectomy for Refractory ITP
Annals of Pharmacotherapy 1–5 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014555540 aop.sagepub.com
Michael J. Choe1, and Clifford D. Packer, MD1,2
Abstract Objective: To report a case of severe rebound thrombocytopenia after temporary discontinuation of romiplostim during splenectomy in the context of refractory immune (idiopathic) thrombocytopenic purpura (ITP). Case Summary: A 65-year-old man with a history of severe refractory ITP failing multiple treatments was considered for romiplostim therapy. He was initiated on 1 µg/kg and titrated upward to 4 µg/kg to elevate and stabilize his platelet levels prior to splenectomy. On day 74 of his clinical course, his platelets increased to 434 × 109/L, and his scheduled dose of romiplostim was withheld on day 75 for fear of romiplostim-induced postsplenectomy rebound thrombocytosis. On day 78, his platelets dropped precipitously to 9 × 109/L, and he experienced multiple episodes of epistaxis. He was reinitiated at 5 µg/kg and soon recovered. He later missed a scheduled dose of romiplostim, and his platelets fell to 23 × 109/L. After resuming romiplostim at 8 µg/kg, his platelets continued to recover. Discussion: Romiplostim, a thrombopoietin mimetic is directly regulated by megakaryocytes and existing circulating platelets via a negative feedback mechanism. This explains the theoretical risk of rapid clearance of romiplostim caused by an increased platelet pool. Clinically, alternative causes of his severe postoperative thrombocytopenia were considered and deemed unlikely. The rebound effect was observed after romiplostim was withdrawn on 2 occasions, and platelet counts improved after restarting romiplostim. The Naranjo Adverse Drug Reaction Probability Score of 7 suggests a probable adverse drug reaction. Conclusion: Physicians using romiplostim as a bridge to splenectomy should be cautious about withholding a scheduled dose around the time of surgery. Keywords romiplostim, rebound, splenectomy, idiopathic thromobocytic purpura, refractory, thrombocytosis, platelets, TPO, mimetic, megakaryocyte, adverse, drug, reaction, events, eltrombopag
Objective Romiplostim is a thrombopoietin (TPO) mimetic (median half-life = 3.5 days) currently considered a second-line treatment for refractory idiopathic thrombocytopenic purpura (ITP). Clinical trials have demonstrated efficacy in increasing long-term platelet counts.1 In a few case reports, romiplostim has been used as an effective bridge to splenectomy.2 We describe a patient with refractory ITP who developed severe postsplenectomy rebound thrombocytopenia that occurred when a single romiplostim dose was held at the time of surgery.
Case Summary
mg weekly, diphenhydramine 25 mg 3 times daily, furosemide 40 mg daily, glipizide 5 mg twice daily, neutral protamine Hagedorn insulin 12 units twice daily, metoprolol 25 mg daily, oxycodone 5 mg every 4 hours as needed, oxymetazoline 0.05% nasal spray as needed, and simethicone 40 mg every 6 hours as needed. He was hospitalized for severe thrombocytopenia with a platelet count of 10 × 109/L. (See Figure 1 for a detailed timeline of his treatment and platelet counts.) He was initially treated with a 5-day course of prednisone and transfusion of 2 units of platelets. His platelet count rose briefly to 119 × 109/L, then dropped down to 3 × 109/L by day 24. He received 1
The patient was a 65-year-old man with a history of chronic ITP on rituximab, chronic hepatitis C, congestive heart failure, type 2 diabetes mellitus, hypertension, gout, and chronic kidney disease. Medications included allopurinol 100 mg daily, colchicine 0.6 mg as needed, rituximab 675
Case Western Reserve School of Medicine, Cleveland Heights, OH, USA 2 Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA Corresponding Author: Michael J. Choe, Case Western Reserve School of Medicine, 2449 Overlook Rd. Apt#4, Cleveland Heights, OH 44106, USA. Email: [email protected]
Downloaded from aop.sagepub.com at TEXAS SOUTHERN UNIVERSITY on November 23, 2014
2
Annals of Pharmacotherapy
Figure 1. Top graph represents patient’s platelet counts throughout the clinical course. Bottom graph represents the temporal relationship of doses of important pharmacotherapeutic agents. Each bar represents a single dose for a given day. Labels include drugs with the corresponding units of doses. Abbreviations: Pred, prednisone; Dexa, dexamethasone; IVIG, intravenous immunoglobulin; Plat, platelets; Rom, romiplostim; Ritux, rituximab.
a second platelet transfusion followed by dexamethasone 40 mg daily for 5 days and intravenous immunoglobulin (IVIG) at 0.5 mg/kg for 2 days, with a temporary rise in platelet count to 61 × 109/L, followed by a rapid drop to 8 × 109/L. Allopurinol and colchicine were discontinued because of concern for possible drug-induced thrombocytopenia. A second 4-day course of dexamethasone and 4 days of IVIG 0.5 mg/kg was given, along with romiplostim 1 µg/kg on day 43;
platelets rose transiently to 119 × 109/L, then dropped again to 150 × 109/L during the first week after splenectomy) had a 94.2% rate of complete response at 1 year. In a series of 33 patients, Supe et al12 reported that responders to splenectomy had mean platelet counts of 170 × 109/L at 24 to 48 hours postsplenectomy. Srinivasan et al13 found that a platelet count of 300 × 109/L immediately following splenectomy was a highly significant predictor of long-term remission (P = 0.018303). Radaelli et al14 found that 84% of patients with platelet counts >100 × 109/L in the first week after splenectomy (even if transient) achieved complete or partial remission. Our patient’s dramatic initial platelet rise after splenectomy (230 × 109/L at 24 hours and 370 × 109/L at 48 hours) strongly suggests that he was an immediate responder. Furthermore, the gradual rise in platelet counts to levels persistently >50 × 109/L by the fourth month after splenectomy suggests that he has had at least a partial longterm response as well. Our patient’s platelet count declined rapidly to 180 × 109/L by day 82 and to
research-article2014
AOPXXX10.1177/1060028014555540Annals of PharmacotherapyChoe and Packer
Case Report
Severe Romiplostim-Induced Rebound Thrombocytopenia After Splenectomy for Refractory ITP
Annals of Pharmacotherapy 1–5 © The Author(s) 2014 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1060028014555540 aop.sagepub.com
Michael J. Choe1, and Clifford D. Packer, MD1,2
Abstract Objective: To report a case of severe rebound thrombocytopenia after temporary discontinuation of romiplostim during splenectomy in the context of refractory immune (idiopathic) thrombocytopenic purpura (ITP). Case Summary: A 65-year-old man with a history of severe refractory ITP failing multiple treatments was considered for romiplostim therapy. He was initiated on 1 µg/kg and titrated upward to 4 µg/kg to elevate and stabilize his platelet levels prior to splenectomy. On day 74 of his clinical course, his platelets increased to 434 × 109/L, and his scheduled dose of romiplostim was withheld on day 75 for fear of romiplostim-induced postsplenectomy rebound thrombocytosis. On day 78, his platelets dropped precipitously to 9 × 109/L, and he experienced multiple episodes of epistaxis. He was reinitiated at 5 µg/kg and soon recovered. He later missed a scheduled dose of romiplostim, and his platelets fell to 23 × 109/L. After resuming romiplostim at 8 µg/kg, his platelets continued to recover. Discussion: Romiplostim, a thrombopoietin mimetic is directly regulated by megakaryocytes and existing circulating platelets via a negative feedback mechanism. This explains the theoretical risk of rapid clearance of romiplostim caused by an increased platelet pool. Clinically, alternative causes of his severe postoperative thrombocytopenia were considered and deemed unlikely. The rebound effect was observed after romiplostim was withdrawn on 2 occasions, and platelet counts improved after restarting romiplostim. The Naranjo Adverse Drug Reaction Probability Score of 7 suggests a probable adverse drug reaction. Conclusion: Physicians using romiplostim as a bridge to splenectomy should be cautious about withholding a scheduled dose around the time of surgery. Keywords romiplostim, rebound, splenectomy, idiopathic thromobocytic purpura, refractory, thrombocytosis, platelets, TPO, mimetic, megakaryocyte, adverse, drug, reaction, events, eltrombopag
Objective Romiplostim is a thrombopoietin (TPO) mimetic (median half-life = 3.5 days) currently considered a second-line treatment for refractory idiopathic thrombocytopenic purpura (ITP). Clinical trials have demonstrated efficacy in increasing long-term platelet counts.1 In a few case reports, romiplostim has been used as an effective bridge to splenectomy.2 We describe a patient with refractory ITP who developed severe postsplenectomy rebound thrombocytopenia that occurred when a single romiplostim dose was held at the time of surgery.
Case Summary
mg weekly, diphenhydramine 25 mg 3 times daily, furosemide 40 mg daily, glipizide 5 mg twice daily, neutral protamine Hagedorn insulin 12 units twice daily, metoprolol 25 mg daily, oxycodone 5 mg every 4 hours as needed, oxymetazoline 0.05% nasal spray as needed, and simethicone 40 mg every 6 hours as needed. He was hospitalized for severe thrombocytopenia with a platelet count of 10 × 109/L. (See Figure 1 for a detailed timeline of his treatment and platelet counts.) He was initially treated with a 5-day course of prednisone and transfusion of 2 units of platelets. His platelet count rose briefly to 119 × 109/L, then dropped down to 3 × 109/L by day 24. He received 1
The patient was a 65-year-old man with a history of chronic ITP on rituximab, chronic hepatitis C, congestive heart failure, type 2 diabetes mellitus, hypertension, gout, and chronic kidney disease. Medications included allopurinol 100 mg daily, colchicine 0.6 mg as needed, rituximab 675
Case Western Reserve School of Medicine, Cleveland Heights, OH, USA 2 Louis Stokes Cleveland VA Medical Center, Cleveland, OH, USA Corresponding Author: Michael J. Choe, Case Western Reserve School of Medicine, 2449 Overlook Rd. Apt#4, Cleveland Heights, OH 44106, USA. Email: [email protected]
Downloaded from aop.sagepub.com at TEXAS SOUTHERN UNIVERSITY on November 23, 2014
2
Annals of Pharmacotherapy
Figure 1. Top graph represents patient’s platelet counts throughout the clinical course. Bottom graph represents the temporal relationship of doses of important pharmacotherapeutic agents. Each bar represents a single dose for a given day. Labels include drugs with the corresponding units of doses. Abbreviations: Pred, prednisone; Dexa, dexamethasone; IVIG, intravenous immunoglobulin; Plat, platelets; Rom, romiplostim; Ritux, rituximab.
a second platelet transfusion followed by dexamethasone 40 mg daily for 5 days and intravenous immunoglobulin (IVIG) at 0.5 mg/kg for 2 days, with a temporary rise in platelet count to 61 × 109/L, followed by a rapid drop to 8 × 109/L. Allopurinol and colchicine were discontinued because of concern for possible drug-induced thrombocytopenia. A second 4-day course of dexamethasone and 4 days of IVIG 0.5 mg/kg was given, along with romiplostim 1 µg/kg on day 43;
platelets rose transiently to 119 × 109/L, then dropped again to 150 × 109/L during the first week after splenectomy) had a 94.2% rate of complete response at 1 year. In a series of 33 patients, Supe et al12 reported that responders to splenectomy had mean platelet counts of 170 × 109/L at 24 to 48 hours postsplenectomy. Srinivasan et al13 found that a platelet count of 300 × 109/L immediately following splenectomy was a highly significant predictor of long-term remission (P = 0.018303). Radaelli et al14 found that 84% of patients with platelet counts >100 × 109/L in the first week after splenectomy (even if transient) achieved complete or partial remission. Our patient’s dramatic initial platelet rise after splenectomy (230 × 109/L at 24 hours and 370 × 109/L at 48 hours) strongly suggests that he was an immediate responder. Furthermore, the gradual rise in platelet counts to levels persistently >50 × 109/L by the fourth month after splenectomy suggests that he has had at least a partial longterm response as well. Our patient’s platelet count declined rapidly to 180 × 109/L by day 82 and to
