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Intraarterial Platelet Infusion for Patients with Intractable Gastrointestinal Hemorrhage and Severe Refractory Thrombocytopenia
Brief Reports
Intraarterial Platelet Infusion for Patients with Intractable Gastrointestinal Hemorrhage and Severe Refractory Thrombocytopenia David C. Madoff, MD, Michael J. Wallace, MD, Benjamin Lichtiger, MD, PhD, Krishna V. Komanduri, MD, William A. Ross, MD, Aida B. Narvios, MD, and C. Lee Parmley, MD, JD Transarterial therapies used for the treatment of acute nonvariceal gastrointestinal (GI) hemorrhage have traditionally included vasopressin infusion and embolization. However, for patients with diffuse or multifocal hemorrhage and severe refractory thrombocytopenia, these options are suboptimal because platelet counts and coagulation parameters may not be adequate to allow for the formation of a stable clot. Herein two such patients treated with direct intraarterial (IA) infusion of platelets into the vascular territory supplying the hemorrhage are described. In both patients, after IA platelet infusion, blood product requirements were immediately reduced, bleeding from the GI tract resolved by clinical and laboratory criteria, and no significant bowel ischemia was seen. J Vasc Interv Radiol 2004; 15:393–397 Abbreviations: GDA ⫽ gastroduodenal artery, GI ⫽ gastrointestinal, IA ⫽ intraarterial, ICU ⫽ intensive care unit, LDH ⫽ lactate dehydrogenase, PRBC ⫽ packed red blood cell, SMA ⫽ superior mesenteric artery
TRANSARTERIAL therapies used for the treatment of acute nonvariceal gastrointestinal (GI) hemorrhage have traditionally included vasopressin infusion and embolization. Historically, vasopressin was more commonly used for lower GI hemorrhage (1,2) and embolization was reserved for upper GI hemorrhage (2,3). More recently, improvements in microcatheter and microcoil technology and the desire of many interventional radiologists to simplify the process of transarterial therapy have led to a shift from intraarterial (IA) vasopressin to emboli-
From the Division of Diagnostic Imaging, Interventional Radiology Section (D.C.M., M.J.W.), and Departments of Laboratory Medicine (B.L., A.B.N.), Blood and Marrow Transplantation (K.V.K.), Gastrointestinal Medicine and Nutrition (W.A.R.), and Critical Care Medicine (C.L.P.), University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 325, Houston, Texas 77030 – 4009. Received September 15, 2003; revision requested December 5; revision received December 23; accepted December 26. Address correspondence to D.C.M.; E-mail: [email protected] None of the authors have identified a conflict of interest. © SIR, 2004 DOI: 10.1097/01.RVI.0000123318.06419.93
zation. This shift ensued after several clinical studies demonstrated the safety and efficacy of embolization for lower GI applications (2,4). When the sources of hemorrhage remain occult despite angiography, empiric embolization or vasopressin infusion of the arterial supply corresponding to the lesion identified by endoscopy can be performed (1,2,5,6). However, coagulation parameters and platelet counts need to be optimized to allow for the formation of a stable clot during the process of embolization (7). Successful embolization is a significant challenge in patients with severe thrombocytopenia, and the challenge is compounded when such patients are refractory to platelet transfusion. Selective infusion of platelets in the arterial system has previously been attempted after unsuccessful coil and gelatin sponge embolization (8). Herein we present two cases of acute GI hemorrhage in patients refractory to platelet transfusion who were treated solely with IA platelet infusion. The institutional review board at our institution approved our retrospective study, and a waiver was granted for informed consent.
CASE 1 A 33-year-old man with chronic myelogenous leukemia who had undergone peripheral blood stem cell transplantation from a matched unrelated donor 150 days earlier presented with melanotic stools over a 24-hour period. The patient’s posttransplantation course was complicated by severe steroid-refractory graft-versus-host disease. At initial evaluation, the patient developed tachypnea and mental status changes necessitating intubation and admission to the intensive care unit (ICU). Laboratory studies on admission revealed the following values: hemoglobin, 3.4 g/dL; white blood cells, 5.5 ⫻ 109 U/L; platelets, 13 ⫻ 109 U/L; blood urea nitrogen, 103 mg/dL; and creatinine, 2.0 mg/dL. The patient developed hematochezia, and initial sigmoidoscopy was unsuccessful because of excessive colonic blood and inadequate bowel preparation. A nuclear medicine tagged red cell bleeding scan suggested a potential site of bleeding in the upper mid-abdomen. Subsequent esophagogastroduodenoscopy revealed inflammation with diffuse oozing within the second to third portion of the duodenum, consistent
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Figure 1. Hemoglobin levels for the patient in case 1. The hemoglobin level remained stable despite the substantial reduction in PRBC transfusions. The upward-pointing arrow and dotted vertical line show the time of the IA platelet infusion procedure. The downward-pointing arrows demonstrate the daily PRBC transfusion requirements (in units) before and after IA platelet infusion.
with intestinal graft-versus-host disease. The bleeding lesions were not amenable to endoscopic therapy (9), so resuscitation maneuvers were continued. The patient was excluded as a surgical candidate because of his debilitated and severely immunocompromised state. Thirty units of packed red blood cells (PRBCs) and 87 U of randomdonor platelets were transfused during the 14-day period after initial presentation. On day 14, interventional radiology was consulted to perform angiography with potential therapeutic intervention to decrease the patient’s ongoing blood loss. Immediately before angiography, the patient’s hemoglobin level was 7.5 g/dL and platelet count was 28 ⫻ 109 U/L; therefore, 6 U of random-donor platelets were infused intravenously during the procedure. After informed consent was obtained, the patient’s right common femoral artery was accessed with a micropuncture set (Cook, Bloomington, IN), with subsequent placement of a 5-F vascular sheath. The celiac artery, gastroduodenal artery (GDA), and superior mesenteric artery (SMA) were selectively catheterized with use of a 5-F Chuang B catheter (Cook). Angiography failed to identify any focal lesion within the duodenum that was amenable to embolization. After multidisciplinary consultation, the decision was made to proceed with IA
platelet infusion. Four units of random-donor platelets (240 mL total; one 60-mL syringe per unit) were obtained from the blood bank for IA delivery, with the dose equally divided between the SMA and GDA. The 5-F catheter was positioned in the SMA orifice, and a 3-F microcatheter (Mass Transit; Cordis, Miami, FL) was advanced coaxially into the proximal SMA. Two units of random-donor platelets were slowly infused over a period of 10 minutes into the SMA territory, with no change in SMA flow. The GDA was then selected, and through the microcatheter, the remaining units of random-donor platelets were infused. Postinfusion GDA arteriography demonstrated normal antegrade flow. After the intervention, the sheath and catheters were withdrawn, and hemostasis was achieved with the use of a vascular closure device (Perclose; Abbott Vascular, Redwood City, CA) and local pressure. After IA platelet infusion, PRBC transfusion requirements decreased dramatically and the hemoglobin level increased to 9.3 g/dL within 12 hours. The patient received a total of 2 U of PRBCs in the 4 days after IA platelet infusion (total of 7 U in the 15 days after infusion; Fig 1). His platelet count transiently increased to 84 ⫻ 109 U/L, but by day 2, it had decreased to 24 ⫻ 109 U/L, necessitating additional platelet transfusions. The patient developed transient (⬍24 hours) diffuse
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abdominal tenderness (pain score ⬍ 4 of 10) and distension 1 day after IA platelet infusion, with no clinical evidence of peritonitis. Although the patient’s lactate dehydrogenase (LDH) level (significant increase of LDH serum marker may indicate presence of necrotic bowel) increased after the procedure (⬎2,700 U/L), LDH levels were fluctuating dramatically before IA platelet infusion (Fig 2). Repeat esophagogastroduodenoscopy performed 8 days later revealed complete resolution of the diffuse oozing from the second to third portion of the duodenum. Nine days after IA platelet infusion, the patient’s improved clinical status led to his transfer from the ICU to a nonmonitored hospital floor, and by day 21, he was discharged to an inpatient hospice (as a result of refractory graft-versus-host disease and progressive pneumonia). At the time of discharge, the patient began to bleed from his oral mucosa and continued to require intermittent PRBC and platelet transfusions as a result of his underlying poor marrow graft function. However, there was no clinical evidence of recurrent GI bleeding after IA platelet infusion.
CASE 2 A 53-year-old man with acute myelogenous leukemia presented with a 4-day history of nasal bleeding and black stools and a 1-day history of nausea, vomiting, and epigastric pain. On the day of presentation, the patient developed hematemesis and melena. Laboratory studies revealed the following values: hemoglobin, 4.9 g/dL; platelets, 1 ⫻ 109 U/L; white blood cells, 0.8 ⫻ 109 U/L; prothrombin time, 13.5 seconds; and activated partial thromboplastin time, 27.8 seconds. The patient was admitted to the ICU for resuscitation. Frequent transfusion of PRBCs (average of 3 U per day) and platelets (range of 6 –14 U per day) was required, but the patient’s platelet count failed to increase to greater than 6 ⫻ 109 U/L. Upper and lower endoscopy procedures were deferred because of the patient’s profound thrombocytopenia. A nuclear medicine tagged red blood cell scan was performed and suggested a potential source of hemorrhage within the upper mid-abdomen. On the third hospital day, interventional radiology
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and lower-extremity hemorrhage. The patient’s overall status continued to deteriorate, and by day 11, his platelet count was 5 ⫻ 109 U/L. He developed multiple organ failure and died 12 days after IA platelet infusion. At the family’s request, no autopsy was performed.
DISCUSSION
Figure 2. Graph of LDH levels over 60 days for the patient in case 1. Although the patient’s LDH level increased after IA platelet infusion, this level was not a substantial alteration from previous dramatically fluctuating levels. The arrow indicates the time of IA platelet infusion.
was consulted to perform angiography with embolization. Celiac, SMA, and inferior mesenteric arteriography were performed but revealed no bleeding source. Subsequent esophagogastroduodenoscopy revealed multiple petechiae throughout the esophagus, stomach, and duodenum and evidence of recent duodenal bleeding just distal to the ampulla of Vater with active oozing. This lesion was treated with bipolar coagulation, epinephrine injection (12 mL), and topical application of Floseal® Matrix Hemostatic Sealant (Baxter Healthcare Corporation, Fremont, CA). Despite this intervention, the patient experienced persistent hematochezia. Colonoscopy performed on the sixth hospital day demonstrated ulceration with adherent blood within the mid-transverse colon and scattered petechiae that were not actively bleeding, most prominently within the right colon. Cytologic brushings of the ulcer were obtained, but no therapeutic measures were attempted because of the patient’s marked thrombocytopenia (2 ⫻ 109 U/L). Immediately after colonoscopy, repeat visceral angiography was performed and demonstrated multiple small areas of contrast material pooling, particularly within the right colon (Fig 3). Because of the patient’s profound thrombocytopenia, multiple bleeding sites in the right colon, and suspected bleeding from the proximal to mid-transverse colon, IA platelet in-
fusion was performed. Four units of random-donor platelets (240 mL total; one 60-mL syringe per unit) were infused slowly into the proximal SMA over a period of 20 minutes (5 minutes per unit). Angiography was performed after each unit of platelets was administered. The completion SMA angiogram demonstrated a patent SMA with normal flow and no sites of continued extravasation. After IA platelet infusion, GI hemorrhage was no longer clinically evident. The patient’s PRBC transfusion requirements decreased from 15 U over the 5 days before IA platelet infusion to 2 U over the 6 days after IA platelet infusion. The patient’s concomitant pulmonary alveolar hemorrhage required PRBC transfusion administered on day 3 after IA platelet infusion. Unlike the patient in case 1, he did not experience abdominal pain. LDH levels were increased (no change before and after infusion), but this was believed to be a result of causes other than mesenteric ischemia (ie, hepatic failure). The patient’s platelet count had transiently increased to 57 ⫻ 109 U/L by day 6 after IA platelet infusion, and the vascular sheath was removed. However, despite no clinical signs of GI hemorrhage, the patient required transfusion of another 4 U of PRBCs (1 U/d on days 7, 9, 10, and 11 after infusion) and 107 U of intravenously administered platelets (104 U random-donor, 3 U single-donor) over the course of the next 12 days for pulmonary, facial,
Endovascular management of acute GI hemorrhages with IA vasopressin infusion and embolization is well documented (1–7). However, few articles have addressed the safety or efficacy of these procedures in the setting of severe coagulopathy or thrombocytopenia (5,7,8). Factors strongly associated with clinical failure resulting from recurrent bleeding include coagulation disorders and coil embolization when not used in combination with other embolic agents. Specifically, Encarnacion et al (7) reported that 73% of treatment failures (eight of 11) in their cohort (n ⫽ 29) occurred in patients with coagulopathy (defined as prothrombin ratio ⬎ 1.3, partial thromboplastin time ⬎ 40 sec, or platelet count ⬍ 80 ⫻ 109 U/L). Their analysis also revealed that embolization was 2.9 times more likely to be unsuccessful and that death from bleeding after embolization was 9.6 times more likely to occur in patients with coagulopathy than in those without. These data were strongly supported by Aina et al (5), who found that clinical failure after embolization was 19.6 times more likely in the presence of coagulopathy. These studies highlight the importance of correcting underlying coagulation disorders before percutaneous intervention. Despite the increased use of and benefit from blood product transfusions for patients with GI hemorrhage who also have coagulopathy and thrombocytopenia, such transfusions do not always work. Specifically, patients undergoing cytotoxic chemotherapy or bone marrow transplantation frequently become refractory to platelet transfusion. Reasons for refractoriness to platelet transfusion include the presence of alloantibodies directed against platelet antigens, disseminated intravascular coagulation, splenomegaly, infection, use of medications including ganciclovir, drugmediated antibodies, administration
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Figure 3. Early phase (a) and delayed phase (b) of SMA arteriogram shows multiple small foci within the vascular territory of the right colon consistent with hemorrhage. In b, the arrows show the two most conspicuous areas of contrast material pooling.
of platelets that were damaged or inactivated during collection or storage, among others (10 –12). These clinical risk factors may result in profound thrombocytopenia (platelet counts from ⬍ 10 ⫻ 109 U/L to 20 ⫻ 109 U/L) requiring frequent platelet transfusions to reduce the risk of spontaneous hemorrhage in the GI tract, central nervous system, or other sites (13). As discussed earlier, successful endovascular intervention in patients with severe coagulopathy or thrombocytopenia almost always requires correction of the underlying coagulopathy and thrombocytopenia (5,7). In patients with thrombocytopenia who are refractory to platelet transfusion, correction of the underlying coagulopathy will most likely not be possible. Recently, a novel technique was used to treat a patient with recurrent upper GI hemorrhage and refractory thrombocytopenia (8). After apparently successful embolization of the gastroepiploic artery with coils and of the GDA with gelatin sponge pledgets, bleeding recurred within 48 hours, which necessitated additional endovascular management. To aid the clotting mechanism, 3 U of platelets were transfused selectively into the bleeding artery proximal to the coils
over a period of 10 minutes. This resulted in complete occlusion of the bleeding vessel. The GDA and inferior pancreaticoduodenal artery were then embolized with coils. In the two patients described herein, we attempted IA platelet infusion. However, these patients required a different approach from that previously reported because the source of bleeding in these patients was not localized to a single branch vessel, but rather involved vascular territories with diffuse oozing. Vasopressin infusion or coil embolization alone may not cause clotting in this “platelet-deficient” environment (5). Given the exceedingly low platelet counts, especially for the patient in case 2, we did not believe that vasopressin infusion was an option. Even in patients with normal coagulation profiles, the rate of recurrence of lower GI hemorrhage is 36%– 43%, and repeated bleeding episodes often occur within the first few days after IA vasopressin infusion (2,3,14,15). Reasons for recurrent bleeding include protective clot lysing or the clot being dislodged before hemostasis can be achieved (2). Coil embolization alone also was not preferred in these two patients. The patient in case 1 did not have a
bleeding source identifiable by arteriography. Empirical coil embolization of the GDA might have resulted in recurrent bleeding (5,7) and precluded access to the artery should further intervention have been needed. The patient in case 2 also was not an appropriate candidate for coil embolization because the bleeding sites were multiple and in various areas of the SMA territory. To overcome this, platelets were infused directly into the arterial vasculature believed responsible for the bleeding source to create a plateletrich environment with the goal of microthrombus formation at the sites of arterial involvement. Four units of random-donor platelets were administered to both patients arbitrarily for IA infusion. Although our institution’s standard of practice for intravenously administered platelets is based on patient body weight (1 U per 10 kg), this IA technique had never been employed, and patient safety (ie, risk of mesenteric ischemia) was a concern. Four units were believed to be a relatively small dose and, when given intravenously, considered a pediatric dose. Random-donor platelets were chosen instead of single-donor platelets because they were more readily avail-
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able and required smaller infusion volumes because of the lower associated plasma volumes. In both patients, blood product requirements were immediately reduced, and bleeding from the GI tract was resolved by clinical and laboratory confirmation. Although we believe that IA platelet infusion helped in both cases, it is important to note that follow-up esophagogastroduodenoscopy after endoscopic coagulation and sclerotherapy of the duodenal oozing was not performed after IA platelet infusion in the patient in case 2. Therefore, it was difficult to know the precise state of the patient’s GI hemorrhage at the time of IA platelet infusion. Our decision to perform IA platelet infusion was guided by the findings of the tagged red blood cell study, colonoscopy, and angiography and the recent development of hematochezia. Also, we believe IA platelet infusion was contributory to the cessation of GI bleeding in the first patient because first-line therapy for gastrointestinal GVHD (ie, steroids) had already failed and the patient required 30 U of PRBCs and 87 U of platelets over a 14-day period. We concluded that GI hemorrhage would not have abated spontaneously. One issue that must be considered regarding IA platelet infusion is its safety. One patient experienced diffuse abdominal tenderness the day after IA platelet infusion but it resolved within 24 hours. Although the cause of this patient’s pain is uncertain, his clinical picture was consistent with reversible mesenteric ischemia. We can speculate that the local platelet-rich environment may have led to the formation of microthrombi, resulting in
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transient ischemic changes within the bowel. This patient did have a higher platelet count at the outset and was less refractory to platelet transfusions than the patient in case 2. It is also important to note that we do not know what platelet levels are required for safe IA platelet infusion. Currently, this technique should be performed only when no other options are available. Further study of IA platelet infusion is warranted to confirm its efficacy and its safety with regard to bowel ischemia. This procedure may provide an effective alternative for the management of intractable GI hemorrhage in the setting of severe refractory thrombocytopenia, and may be performed even in seriously ill patients. References 1. Zuckerman DA, Bocchini TP, Birnbaum EH. Massive hemorrhage in the lower gastrointestinal tract in adults: diagnostic imaging and intervention. AJR Am J Roentgenol 1993; 161:703–711. 2. Darcy M. Treatment of lower gastrointestinal bleeding: vasopressin infusion versus embolization. J Vasc Interv Radiol 2003; 14:535–543. 3. Gomes AS, Lois JF, McCoy RD. Angiographic treatment of gastrointestinal hemorrhage: comparison of vasopressin infusion and embolization. AJR Am J Roentgenol 1986; 146:1031–1037. 4. Evangelista PT, Hallisey MJ. Transcatheter embolization for acute lower gastrointestinal hemorrhage. J Vasc Interv Radiol 2000; 11:601– 606. 5. Aina R, Oliva VL, Therasse T, et al. Arterial embolotherapy for upper gastrointestinal hemorrhage: outcome assessment. J Vasc Interv Radiol 2001; 12:195–200. 6. Dufreyne L, Vanlangenhove P, De Vos M, et al. Embolization as a first ap-
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proach with endoscopically unmanageable acute nonvariceal gastrointestinal hemorrhage. Radiology 2001; 218: 739 –748. Encarnacion CE, Kadir S, Beam CA, Payne CS. Gastrointestinal bleeding: treatment with gastrointestinal arterial embolization. Radiology 1992; 183:505– 508. Hvizda JL, Wood BJ. Selective transcatheter platelet infusion for gastrointestinal bleeding after failed embolization with resistant thrombocytopenia. J Vasc Interv Radiol 2001; 12:549 –550. Schwartz JM, Wolford JL, Thornquist MD, et al. Severe gastrointestinal bleeding after hematopoietic cell transplantation, 1987–1997: incidence, causes and outcomes. Am J Gastroenterol 2001; 96:385–393. Schiffer CA. Diagnosis and management of refractoriness to platelet transfusion. Blood Rev 2001; 15:175–180. Geiger TL, Woodard P, Tong X, et al. Human leucocyte antigen alloimmunization after bone marrow transplantation: an association with chronic myelogenous leukaemia. Br J Haematol 2002; 117:634 – 641. Sanz C, Freire C, Alcorta I, Ordinas A, Pereira A. Platelet-specific antibodies in HLA-immunized patients receiving chronic platelet support. Transfusion 2001; 41:762–765. Benjamin RJ, Anderson KC. What is the proper threshold for platelet transfusion in patients with chemotherapyinduced thrombocytopenia? Crit Rev Oncol Hematol 2002; 42:163–171. Athanasoulis CA, Baum S, Rosch J, et al. Mesenteric arterial infusions of vasopressin for hemorrhage from colonic diverticulosis. Am J Surg 1975; 129: 212–216. Johnson WC, Widrich WC. Efficacy of selective splanchnic arteriography and vasopressin perfusion in diagnosis and treatment of gastrointestinal hemorrhage. Am J Surg 1976; 131:481– 489.
Intraarterial Platelet Infusion for Patients with Intractable Gastrointestinal Hemorrhage and Severe Refractory Thrombocytopenia David C. Madoff, MD, Michael J. Wallace, MD, Benjamin Lichtiger, MD, PhD, Krishna V. Komanduri, MD, William A. Ross, MD, Aida B. Narvios, MD, and C. Lee Parmley, MD, JD Transarterial therapies used for the treatment of acute nonvariceal gastrointestinal (GI) hemorrhage have traditionally included vasopressin infusion and embolization. However, for patients with diffuse or multifocal hemorrhage and severe refractory thrombocytopenia, these options are suboptimal because platelet counts and coagulation parameters may not be adequate to allow for the formation of a stable clot. Herein two such patients treated with direct intraarterial (IA) infusion of platelets into the vascular territory supplying the hemorrhage are described. In both patients, after IA platelet infusion, blood product requirements were immediately reduced, bleeding from the GI tract resolved by clinical and laboratory criteria, and no significant bowel ischemia was seen. J Vasc Interv Radiol 2004; 15:393–397 Abbreviations: GDA ⫽ gastroduodenal artery, GI ⫽ gastrointestinal, IA ⫽ intraarterial, ICU ⫽ intensive care unit, LDH ⫽ lactate dehydrogenase, PRBC ⫽ packed red blood cell, SMA ⫽ superior mesenteric artery
TRANSARTERIAL therapies used for the treatment of acute nonvariceal gastrointestinal (GI) hemorrhage have traditionally included vasopressin infusion and embolization. Historically, vasopressin was more commonly used for lower GI hemorrhage (1,2) and embolization was reserved for upper GI hemorrhage (2,3). More recently, improvements in microcatheter and microcoil technology and the desire of many interventional radiologists to simplify the process of transarterial therapy have led to a shift from intraarterial (IA) vasopressin to emboli-
From the Division of Diagnostic Imaging, Interventional Radiology Section (D.C.M., M.J.W.), and Departments of Laboratory Medicine (B.L., A.B.N.), Blood and Marrow Transplantation (K.V.K.), Gastrointestinal Medicine and Nutrition (W.A.R.), and Critical Care Medicine (C.L.P.), University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 325, Houston, Texas 77030 – 4009. Received September 15, 2003; revision requested December 5; revision received December 23; accepted December 26. Address correspondence to D.C.M.; E-mail: [email protected] None of the authors have identified a conflict of interest. © SIR, 2004 DOI: 10.1097/01.RVI.0000123318.06419.93
zation. This shift ensued after several clinical studies demonstrated the safety and efficacy of embolization for lower GI applications (2,4). When the sources of hemorrhage remain occult despite angiography, empiric embolization or vasopressin infusion of the arterial supply corresponding to the lesion identified by endoscopy can be performed (1,2,5,6). However, coagulation parameters and platelet counts need to be optimized to allow for the formation of a stable clot during the process of embolization (7). Successful embolization is a significant challenge in patients with severe thrombocytopenia, and the challenge is compounded when such patients are refractory to platelet transfusion. Selective infusion of platelets in the arterial system has previously been attempted after unsuccessful coil and gelatin sponge embolization (8). Herein we present two cases of acute GI hemorrhage in patients refractory to platelet transfusion who were treated solely with IA platelet infusion. The institutional review board at our institution approved our retrospective study, and a waiver was granted for informed consent.
CASE 1 A 33-year-old man with chronic myelogenous leukemia who had undergone peripheral blood stem cell transplantation from a matched unrelated donor 150 days earlier presented with melanotic stools over a 24-hour period. The patient’s posttransplantation course was complicated by severe steroid-refractory graft-versus-host disease. At initial evaluation, the patient developed tachypnea and mental status changes necessitating intubation and admission to the intensive care unit (ICU). Laboratory studies on admission revealed the following values: hemoglobin, 3.4 g/dL; white blood cells, 5.5 ⫻ 109 U/L; platelets, 13 ⫻ 109 U/L; blood urea nitrogen, 103 mg/dL; and creatinine, 2.0 mg/dL. The patient developed hematochezia, and initial sigmoidoscopy was unsuccessful because of excessive colonic blood and inadequate bowel preparation. A nuclear medicine tagged red cell bleeding scan suggested a potential site of bleeding in the upper mid-abdomen. Subsequent esophagogastroduodenoscopy revealed inflammation with diffuse oozing within the second to third portion of the duodenum, consistent
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Figure 1. Hemoglobin levels for the patient in case 1. The hemoglobin level remained stable despite the substantial reduction in PRBC transfusions. The upward-pointing arrow and dotted vertical line show the time of the IA platelet infusion procedure. The downward-pointing arrows demonstrate the daily PRBC transfusion requirements (in units) before and after IA platelet infusion.
with intestinal graft-versus-host disease. The bleeding lesions were not amenable to endoscopic therapy (9), so resuscitation maneuvers were continued. The patient was excluded as a surgical candidate because of his debilitated and severely immunocompromised state. Thirty units of packed red blood cells (PRBCs) and 87 U of randomdonor platelets were transfused during the 14-day period after initial presentation. On day 14, interventional radiology was consulted to perform angiography with potential therapeutic intervention to decrease the patient’s ongoing blood loss. Immediately before angiography, the patient’s hemoglobin level was 7.5 g/dL and platelet count was 28 ⫻ 109 U/L; therefore, 6 U of random-donor platelets were infused intravenously during the procedure. After informed consent was obtained, the patient’s right common femoral artery was accessed with a micropuncture set (Cook, Bloomington, IN), with subsequent placement of a 5-F vascular sheath. The celiac artery, gastroduodenal artery (GDA), and superior mesenteric artery (SMA) were selectively catheterized with use of a 5-F Chuang B catheter (Cook). Angiography failed to identify any focal lesion within the duodenum that was amenable to embolization. After multidisciplinary consultation, the decision was made to proceed with IA
platelet infusion. Four units of random-donor platelets (240 mL total; one 60-mL syringe per unit) were obtained from the blood bank for IA delivery, with the dose equally divided between the SMA and GDA. The 5-F catheter was positioned in the SMA orifice, and a 3-F microcatheter (Mass Transit; Cordis, Miami, FL) was advanced coaxially into the proximal SMA. Two units of random-donor platelets were slowly infused over a period of 10 minutes into the SMA territory, with no change in SMA flow. The GDA was then selected, and through the microcatheter, the remaining units of random-donor platelets were infused. Postinfusion GDA arteriography demonstrated normal antegrade flow. After the intervention, the sheath and catheters were withdrawn, and hemostasis was achieved with the use of a vascular closure device (Perclose; Abbott Vascular, Redwood City, CA) and local pressure. After IA platelet infusion, PRBC transfusion requirements decreased dramatically and the hemoglobin level increased to 9.3 g/dL within 12 hours. The patient received a total of 2 U of PRBCs in the 4 days after IA platelet infusion (total of 7 U in the 15 days after infusion; Fig 1). His platelet count transiently increased to 84 ⫻ 109 U/L, but by day 2, it had decreased to 24 ⫻ 109 U/L, necessitating additional platelet transfusions. The patient developed transient (⬍24 hours) diffuse
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abdominal tenderness (pain score ⬍ 4 of 10) and distension 1 day after IA platelet infusion, with no clinical evidence of peritonitis. Although the patient’s lactate dehydrogenase (LDH) level (significant increase of LDH serum marker may indicate presence of necrotic bowel) increased after the procedure (⬎2,700 U/L), LDH levels were fluctuating dramatically before IA platelet infusion (Fig 2). Repeat esophagogastroduodenoscopy performed 8 days later revealed complete resolution of the diffuse oozing from the second to third portion of the duodenum. Nine days after IA platelet infusion, the patient’s improved clinical status led to his transfer from the ICU to a nonmonitored hospital floor, and by day 21, he was discharged to an inpatient hospice (as a result of refractory graft-versus-host disease and progressive pneumonia). At the time of discharge, the patient began to bleed from his oral mucosa and continued to require intermittent PRBC and platelet transfusions as a result of his underlying poor marrow graft function. However, there was no clinical evidence of recurrent GI bleeding after IA platelet infusion.
CASE 2 A 53-year-old man with acute myelogenous leukemia presented with a 4-day history of nasal bleeding and black stools and a 1-day history of nausea, vomiting, and epigastric pain. On the day of presentation, the patient developed hematemesis and melena. Laboratory studies revealed the following values: hemoglobin, 4.9 g/dL; platelets, 1 ⫻ 109 U/L; white blood cells, 0.8 ⫻ 109 U/L; prothrombin time, 13.5 seconds; and activated partial thromboplastin time, 27.8 seconds. The patient was admitted to the ICU for resuscitation. Frequent transfusion of PRBCs (average of 3 U per day) and platelets (range of 6 –14 U per day) was required, but the patient’s platelet count failed to increase to greater than 6 ⫻ 109 U/L. Upper and lower endoscopy procedures were deferred because of the patient’s profound thrombocytopenia. A nuclear medicine tagged red blood cell scan was performed and suggested a potential source of hemorrhage within the upper mid-abdomen. On the third hospital day, interventional radiology
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and lower-extremity hemorrhage. The patient’s overall status continued to deteriorate, and by day 11, his platelet count was 5 ⫻ 109 U/L. He developed multiple organ failure and died 12 days after IA platelet infusion. At the family’s request, no autopsy was performed.
DISCUSSION
Figure 2. Graph of LDH levels over 60 days for the patient in case 1. Although the patient’s LDH level increased after IA platelet infusion, this level was not a substantial alteration from previous dramatically fluctuating levels. The arrow indicates the time of IA platelet infusion.
was consulted to perform angiography with embolization. Celiac, SMA, and inferior mesenteric arteriography were performed but revealed no bleeding source. Subsequent esophagogastroduodenoscopy revealed multiple petechiae throughout the esophagus, stomach, and duodenum and evidence of recent duodenal bleeding just distal to the ampulla of Vater with active oozing. This lesion was treated with bipolar coagulation, epinephrine injection (12 mL), and topical application of Floseal® Matrix Hemostatic Sealant (Baxter Healthcare Corporation, Fremont, CA). Despite this intervention, the patient experienced persistent hematochezia. Colonoscopy performed on the sixth hospital day demonstrated ulceration with adherent blood within the mid-transverse colon and scattered petechiae that were not actively bleeding, most prominently within the right colon. Cytologic brushings of the ulcer were obtained, but no therapeutic measures were attempted because of the patient’s marked thrombocytopenia (2 ⫻ 109 U/L). Immediately after colonoscopy, repeat visceral angiography was performed and demonstrated multiple small areas of contrast material pooling, particularly within the right colon (Fig 3). Because of the patient’s profound thrombocytopenia, multiple bleeding sites in the right colon, and suspected bleeding from the proximal to mid-transverse colon, IA platelet in-
fusion was performed. Four units of random-donor platelets (240 mL total; one 60-mL syringe per unit) were infused slowly into the proximal SMA over a period of 20 minutes (5 minutes per unit). Angiography was performed after each unit of platelets was administered. The completion SMA angiogram demonstrated a patent SMA with normal flow and no sites of continued extravasation. After IA platelet infusion, GI hemorrhage was no longer clinically evident. The patient’s PRBC transfusion requirements decreased from 15 U over the 5 days before IA platelet infusion to 2 U over the 6 days after IA platelet infusion. The patient’s concomitant pulmonary alveolar hemorrhage required PRBC transfusion administered on day 3 after IA platelet infusion. Unlike the patient in case 1, he did not experience abdominal pain. LDH levels were increased (no change before and after infusion), but this was believed to be a result of causes other than mesenteric ischemia (ie, hepatic failure). The patient’s platelet count had transiently increased to 57 ⫻ 109 U/L by day 6 after IA platelet infusion, and the vascular sheath was removed. However, despite no clinical signs of GI hemorrhage, the patient required transfusion of another 4 U of PRBCs (1 U/d on days 7, 9, 10, and 11 after infusion) and 107 U of intravenously administered platelets (104 U random-donor, 3 U single-donor) over the course of the next 12 days for pulmonary, facial,
Endovascular management of acute GI hemorrhages with IA vasopressin infusion and embolization is well documented (1–7). However, few articles have addressed the safety or efficacy of these procedures in the setting of severe coagulopathy or thrombocytopenia (5,7,8). Factors strongly associated with clinical failure resulting from recurrent bleeding include coagulation disorders and coil embolization when not used in combination with other embolic agents. Specifically, Encarnacion et al (7) reported that 73% of treatment failures (eight of 11) in their cohort (n ⫽ 29) occurred in patients with coagulopathy (defined as prothrombin ratio ⬎ 1.3, partial thromboplastin time ⬎ 40 sec, or platelet count ⬍ 80 ⫻ 109 U/L). Their analysis also revealed that embolization was 2.9 times more likely to be unsuccessful and that death from bleeding after embolization was 9.6 times more likely to occur in patients with coagulopathy than in those without. These data were strongly supported by Aina et al (5), who found that clinical failure after embolization was 19.6 times more likely in the presence of coagulopathy. These studies highlight the importance of correcting underlying coagulation disorders before percutaneous intervention. Despite the increased use of and benefit from blood product transfusions for patients with GI hemorrhage who also have coagulopathy and thrombocytopenia, such transfusions do not always work. Specifically, patients undergoing cytotoxic chemotherapy or bone marrow transplantation frequently become refractory to platelet transfusion. Reasons for refractoriness to platelet transfusion include the presence of alloantibodies directed against platelet antigens, disseminated intravascular coagulation, splenomegaly, infection, use of medications including ganciclovir, drugmediated antibodies, administration
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IA Platelet Infusion for GI Hemorrhage and Thrombocytopenia
April 2004
JVIR
Figure 3. Early phase (a) and delayed phase (b) of SMA arteriogram shows multiple small foci within the vascular territory of the right colon consistent with hemorrhage. In b, the arrows show the two most conspicuous areas of contrast material pooling.
of platelets that were damaged or inactivated during collection or storage, among others (10 –12). These clinical risk factors may result in profound thrombocytopenia (platelet counts from ⬍ 10 ⫻ 109 U/L to 20 ⫻ 109 U/L) requiring frequent platelet transfusions to reduce the risk of spontaneous hemorrhage in the GI tract, central nervous system, or other sites (13). As discussed earlier, successful endovascular intervention in patients with severe coagulopathy or thrombocytopenia almost always requires correction of the underlying coagulopathy and thrombocytopenia (5,7). In patients with thrombocytopenia who are refractory to platelet transfusion, correction of the underlying coagulopathy will most likely not be possible. Recently, a novel technique was used to treat a patient with recurrent upper GI hemorrhage and refractory thrombocytopenia (8). After apparently successful embolization of the gastroepiploic artery with coils and of the GDA with gelatin sponge pledgets, bleeding recurred within 48 hours, which necessitated additional endovascular management. To aid the clotting mechanism, 3 U of platelets were transfused selectively into the bleeding artery proximal to the coils
over a period of 10 minutes. This resulted in complete occlusion of the bleeding vessel. The GDA and inferior pancreaticoduodenal artery were then embolized with coils. In the two patients described herein, we attempted IA platelet infusion. However, these patients required a different approach from that previously reported because the source of bleeding in these patients was not localized to a single branch vessel, but rather involved vascular territories with diffuse oozing. Vasopressin infusion or coil embolization alone may not cause clotting in this “platelet-deficient” environment (5). Given the exceedingly low platelet counts, especially for the patient in case 2, we did not believe that vasopressin infusion was an option. Even in patients with normal coagulation profiles, the rate of recurrence of lower GI hemorrhage is 36%– 43%, and repeated bleeding episodes often occur within the first few days after IA vasopressin infusion (2,3,14,15). Reasons for recurrent bleeding include protective clot lysing or the clot being dislodged before hemostasis can be achieved (2). Coil embolization alone also was not preferred in these two patients. The patient in case 1 did not have a
bleeding source identifiable by arteriography. Empirical coil embolization of the GDA might have resulted in recurrent bleeding (5,7) and precluded access to the artery should further intervention have been needed. The patient in case 2 also was not an appropriate candidate for coil embolization because the bleeding sites were multiple and in various areas of the SMA territory. To overcome this, platelets were infused directly into the arterial vasculature believed responsible for the bleeding source to create a plateletrich environment with the goal of microthrombus formation at the sites of arterial involvement. Four units of random-donor platelets were administered to both patients arbitrarily for IA infusion. Although our institution’s standard of practice for intravenously administered platelets is based on patient body weight (1 U per 10 kg), this IA technique had never been employed, and patient safety (ie, risk of mesenteric ischemia) was a concern. Four units were believed to be a relatively small dose and, when given intravenously, considered a pediatric dose. Random-donor platelets were chosen instead of single-donor platelets because they were more readily avail-
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able and required smaller infusion volumes because of the lower associated plasma volumes. In both patients, blood product requirements were immediately reduced, and bleeding from the GI tract was resolved by clinical and laboratory confirmation. Although we believe that IA platelet infusion helped in both cases, it is important to note that follow-up esophagogastroduodenoscopy after endoscopic coagulation and sclerotherapy of the duodenal oozing was not performed after IA platelet infusion in the patient in case 2. Therefore, it was difficult to know the precise state of the patient’s GI hemorrhage at the time of IA platelet infusion. Our decision to perform IA platelet infusion was guided by the findings of the tagged red blood cell study, colonoscopy, and angiography and the recent development of hematochezia. Also, we believe IA platelet infusion was contributory to the cessation of GI bleeding in the first patient because first-line therapy for gastrointestinal GVHD (ie, steroids) had already failed and the patient required 30 U of PRBCs and 87 U of platelets over a 14-day period. We concluded that GI hemorrhage would not have abated spontaneously. One issue that must be considered regarding IA platelet infusion is its safety. One patient experienced diffuse abdominal tenderness the day after IA platelet infusion but it resolved within 24 hours. Although the cause of this patient’s pain is uncertain, his clinical picture was consistent with reversible mesenteric ischemia. We can speculate that the local platelet-rich environment may have led to the formation of microthrombi, resulting in
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transient ischemic changes within the bowel. This patient did have a higher platelet count at the outset and was less refractory to platelet transfusions than the patient in case 2. It is also important to note that we do not know what platelet levels are required for safe IA platelet infusion. Currently, this technique should be performed only when no other options are available. Further study of IA platelet infusion is warranted to confirm its efficacy and its safety with regard to bowel ischemia. This procedure may provide an effective alternative for the management of intractable GI hemorrhage in the setting of severe refractory thrombocytopenia, and may be performed even in seriously ill patients. References 1. Zuckerman DA, Bocchini TP, Birnbaum EH. Massive hemorrhage in the lower gastrointestinal tract in adults: diagnostic imaging and intervention. AJR Am J Roentgenol 1993; 161:703–711. 2. Darcy M. Treatment of lower gastrointestinal bleeding: vasopressin infusion versus embolization. J Vasc Interv Radiol 2003; 14:535–543. 3. Gomes AS, Lois JF, McCoy RD. Angiographic treatment of gastrointestinal hemorrhage: comparison of vasopressin infusion and embolization. AJR Am J Roentgenol 1986; 146:1031–1037. 4. Evangelista PT, Hallisey MJ. Transcatheter embolization for acute lower gastrointestinal hemorrhage. J Vasc Interv Radiol 2000; 11:601– 606. 5. Aina R, Oliva VL, Therasse T, et al. Arterial embolotherapy for upper gastrointestinal hemorrhage: outcome assessment. J Vasc Interv Radiol 2001; 12:195–200. 6. Dufreyne L, Vanlangenhove P, De Vos M, et al. Embolization as a first ap-
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