A Therapeutic Platelet Transfusion Strategy Is Safe and Feasible in Patients After Autologous Peripheral Blood Stem Cell Transplantation

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ORIGINAL ARTICLE A therapeutic platelet transfusion strategy is safe and feasible in patients after autologous peripheral blood stem cell transplantation

H Wandt, K Schaefer-Eckart, M Frank, J Birkmann and M Wilhelm

BMT-Unit, Hematology/Oncology, Klinikum Nu¨rnberg Nord, Nu¨rnberg, Germany

Prophylactic platelet transfusions are considered as transmission of bacterial and viral infections, circulatory standard in most hematology centers, but there is a congestion, transfusion-related acute lung injury and long-standing controversy as to whether standard pro- alloimmunization. phylactic platelet transfusions are necessary or whether During the last 10 years, it has been clearly shown by this strategy could be replaced by a therapeutic transfu- several studies that severe thrombocytopenia after intensive sion strategy. In 106 consecutive cases of patients chemotherapy for acute myeloid leukemia can be safely receiving 140 autologous peripheral blood stem cell managed with a threshold of 10 Â 109/l or even lower for transplantations, we used a therapeutic platelet trans- routine prophylactic platelet transfusion.1–4 On the basis fusion protocol when patients were in a clinically of these results, three clinical studies were performed with stable condition. Platelet transfusions were only used a10Â 109/l trigger in recipients of high-dose chemo- when relevant bleeding occurred (more than petechial). therapy7total body irradiation (TBI), followed by hemato- Median duration of thrombocytopenia o20 Â 109/l and poietic stem cell support.5–7 All three studies proved the o10 Â 109/l was 6 and 3 days, which resulted in a total of safety of the 10 Â 109/l trigger for prophylactic platelet 989 and 508 days, respectively. In only 26 out of 140 transfusion after autologous bone marrow or peripheral transplants (19%), we observed clinically relevant bleed- blood stem cell transplantation (PBSCT). ing of minor or moderate severity. No severe or life- A recent survey of transfusion practices at 18 transplant threatening bleeding was registered. The median and mean centers in the US and Canada reported that ﬁve centers number of single donor platelet transfusions was one per used a threshold for prophylactic platelet transfusion of transplant (range 0–18). One-third of all transplants, and o10–15 Â 109/l. Most severe bleeding events occurred at 47% after high-dose melphalan could be performed platelet counts of greater than 20 Â 109/l and therefore without any platelet transfusion. Compared with a histo- would not have been prevented even using this level as a rical control group, we could reduce the number of platelet transfusion trigger.8 transfusions by one half. This therapeutic platelet trans- Virtually the same data were reported from an analysis of fusion strategy can be performed safely resulting in a 1402 bone marrow transplants at Johns Hopkins Hospital.9 considerable reduction in prophylactic platelet transfusions. Therefore, the American Society of Clinical Oncology Bone Marrow Transplantation (2006) 37, 387–392. recently published clinical practice guidelines with a doi:10.1038/sj.bmt.1705246; published online 9 January prophylactic platelet transfusion trigger of 10 Â 109/l for 2006 acute leukemia and hematopoietic cell transplantation.10 Keywords: platelet transfusion; autologous transplant- The use of peripheral blood stem cells instead of ation; bleeding complication bone marrow in autologous transplants has substantially shortened the duration of severe thrombocytopenia. It is still not known whether a prophylactic platelet transfusion strategy is necessary, or whether a therapeutic transfusion Introduction strategy is as safe and more cost effective. Therefore, we started a prospective study with a new therapeutic platelet There is an increasing demand for single donor platelet transfusion protocol for all consecutive patients after transfusions due to intensive chemotherapy and blood stem autologous PBSCT beginning in the year 2001. cell or bone marrow transplantation. Platelet transfusions The main objective of the study was the safety and however are expensive and associated with a number of side feasibility of a therapeutic transfusion strategy. The effects including febrile or allergic transfusion reactions, study was approved by the institutional review board of the Hematology/Oncology Department at the Klinikum Nuremberg, Germany.

Correspondence: Dr H Wandt, BMT-Unit, Hematology/Oncology, Patients and methods Klinikum Nu¨ rnberg Nord, Nu¨ rnberg D-90419, Germany. E-mail: [email protected] Received 18 July 2005; revised 7November 2005; accepted 8 November Since 2001, a therapeutic platelet transfusion strategy 2005; published online 9 January 2006 has been offered to all consecutive patients receiving Therapeutic platelet transfusion strategy H Wandt et al 388 myeloablative high-dose chemotherapy7TBI, followed Bleeding and toxicity by autologous PBSCT. Patients with a diagnosis of During each therapy course, bleeding complications AL-amyloidosis, documented aspergillus infection, cerebral according to WHO criteria (0, none; I, petechial; II, mild lesions or life-threatening bleeding complications during blood loss; III, gross blood loss; IV, debilitating blood loss) prior chemotherapy courses were excluded. All patients were recorded as well as the number of platelet transfusions gave their informed consent for stem cell transplantation administered. Clinically relevant bleeding was defined as and our transfusion strategy. melena, hematemesis, macrohematuria, hemoptysis, vaginal bleeding, epistaxis with gross blood loss, retinal bleeding with impairment of vision or soft tissue bleeding Transfusion strategy requiring blood transfusions. The bleeding complications Therapeutic platelet transfusions were defined as transfu- were recorded by the responsible physician. The examina- sions to treat a patient with documented clinically relevant tion for bleeding was performed twice daily. Bleeding bleeding during thrombocytopenia. complications were reviewed by one senior physician (HW, Petechias, retinal bleeding without impairment of visus KS). Maximal bleeding per transplant was counted. Only and minimal self-limiting nasal bleeding were not consid- fevers greater than 38.51C were documented, as well as the ered as clinically relevant. origin of fever and the underlying organisms in case of In clinically stable patients, no prophylactic platelet septicemia. Mucositis was documented according to the transfusions were performed irrespective of the morning Bearman toxicity score.12 platelet count. These patients received only therapeutic platelet transfusions when clinically relevant bleeding was documented. In cases of significant bleeding (according Statistics to the World Health Organisation (WHO) grade II or Numbers of transplants without any platelet transfusion in greater), platelets were transfused within 3–4 h. different groups were compared using the w2 test and All platelet transfusions were random single donor frequencies of transfusion between multiple myeloma apheresis platelets, ABO compatible, with platelet concen- patients and other diagnoses or between the TBI and non- trations according to German guidelines of the ‘Deutsche TBI group were calculated using the Mann–Whitney U-test Gesellschaft fu¨ r Transfusionsmedizin und Immunha¨ mato- running on a computer-based program (STATISTICA for logie’ with 2–5 Â 1011 platelets/unit. All transfusions were Windows, 2001, Statsoft Inc., Tulsa, OK, USA). leukocyte-reduced (o106 leukocytes). Platelet transfusions were available 24 h a day. In clinically unstable patients, platelet transfusions were Results given prophylactically when the morning platelet count was o10 Â 109/l. The study included 106 consecutive patients with a total The definition of a clinically unstable patient was fever number of 140 transplantation procedures. Patients’ 438.51C and/or local infectious infiltrations suspicious for characteristics are listed in Table 1. The median age of invasive aspergillosis, sepsis syndrome or clinically relevant the patients was 54 years, with a range of 18–70 years. The plasmatic coagulation disorders. In case of surgery and male to female ratio was about 2:1. The diagnoses were biopsies (except bone marrow), the platelet count should be multiple myeloma in 43%, malignant lymphoma in 32% 420 Â 109/l. and acute leukemia in 16% of the cases. Only 8% of the Daily morning platelet count was performed until the patients were transplanted because of a solid tumor. platelet count was self-supporting and greater than Seventy-six patients received one transplant. In 26 and 20 Â 109/l for 2–3 days. Blood counts were performed four patients, respectively, a double or triple transplant- on EDTA-anticoagulated blood using a hemocytometer ation program was performed. The conditioning regimens (Sysmex SF-3000, Sysmex Corp., Kobe, Japan). The included chemotherapy and TBI in 19 patients, whereas the patients were examined twice daily for evidence of other patients received high-dose chemotherapy-based hemorrhage. Fundoscopy was performed only in case of regimens alone. All of these regimens were established impairment of vision. myeloablative combination treatments (see Table 1). Hemoglobulin levels were maintained at greater than 80 g/l by packed red cell transfusions. Bleeding complications The median number of days with platelets below 20 Â 109/l Infection prophylaxis and treatment was 6 (range 0–92) and the median number of days with Prophylactic oral antimycotics and antibiotics, as well as platelets below 10 Â 109/l was 3 (range 0–62). We observed the initiation of intravenous antibiotics for fever greater a total of 989 days with platelets below 20 Â 109/l and 508 than 38.51C, and the start of intravenous antimycotics were days with platelets below 10 Â 109/l. applied according to the German guidelines.11 Granulocyte In 114 out of 140 transplants (81%), no clinically colony-stimulating factor was given to all patients on relevant bleeding was observed. In 26 transplants (19%), day þ 6 after transplantation until the leukocyte count patients experienced maximal bleeding of WHO grade II. was above 1 Â 109/l for 3 days. Aspirin and nonsteroidal WHO grade I (clinically not relevant) was registered in 28 anti-inflammatory drugs were avoided. Paracetamol and transplants (20%). We observed no bleeding WHO grade metamizol were used as antipyretics. All patients were III and IV. Bleeding complications of WHO grad II were hospitalized during the study period. caused by epistaxis in 12 out of 26 transplants (46%), and

Bone Marrow Transplantation Therapeutic platelet transfusion strategy H Wandt et al 389 Table 1 Patients characteristics, diagnoses, conditioning regimen Table 3 Number of transfusions related to diagnoses and conditioning regimen Patients PBSCTs Transplants Transfusions Number of Po0.05 Number 106 140 (no.) (no.) platelet transfusions Age (year) median (range) Median (range) 54 (18–70) Female/male 38/68 Multiple myeloma 68 871 (0–18) Sign Other diagnosis 72 148 1 (0–13) Diagnoses Multiple myeloma 46 68 TBI 19 69 3 (0–7) Sign Lymphoma 34 35 Non-TBI 121 166 1 (0–18) Acute leukemia 1717 conditioning NSGCT 5 9 Ovarian cancer 4 11

Conditioning regimens Melphalan (140/200 mg/m2)4668 TBI/Cy 19 19 median and mean number of therapeutic platelet transfu- BEAM/CEAM/CEIAP/ICE 18 21 sions per tranplantation was 0 (0–18) and of prophylactic BuCy/BuCyVP16/Bu mono 15 15 platelet transfusions was 1 (0–13), respectively. Carbo/Treo/Tax/Mel 4 11 Forty-eight out of 140 transplants (34%) could be CarboPEC 4 6 performed without any platelet transfusion. In patients NSGCT nonseminomatous germ cell tumor; TBI total body irradia- with normal marrow recovery (o14 days of duration of ¼ ¼ 9 tion; BEAM ¼ busulfan, etoposide, cytarabine, melphalan; CEAM ¼ platelet recovery to 420 Â 10 /l), even 42% of all cyclophosphamide, etoposide, cytarabine, melphalan; CEIAP ¼ cyclophos- transplants could be performed without any platelet phamide, etoposide, ifosfamide, cytarabine, cisplatinum; ICE ¼ ifosfamide, transfusion. cyclophosphamide, etoposide; BuCy ¼ busulfan, cyclophosphamide; BuCy There was a statistically significant difference in the VP16 ¼ busulfan, cyclophosphamide, etoposide; Crabo/Treo/Tax/Mel ¼ carboplatin in combination with treosulfan, paclitaxel and melphalan; number of platelet transfusions according to diagnosis of CarboPEC ¼ carboplatin, etoposide, cyclophosphamide. the patients, and whether they received a TBI or non-TBI conditioning regimen (Table 3). The percentage of transplants without any platelet transfusion between patients with multiple myeloma and other diagnoses was 47versus Table 2 Indications for prophylactic and therapeutic platelet 22%, and between patients with non-TBI and TBI regimens transfusion 37and 0%, respectively. No. of No. of During the study period, a total number of 154 transplantations (%) transfusions (%) prophylactic and 81 therapeutic platelet units were transfused (see Table 2). The main indications for Prophylactic 64 (100) 154 (100) prophylactic platelet transfusions were fever of unknown FUO 23 (36) 43 (28) FUO and mucositis 9 (14) 27(18) origin (FUO) in 46% and septicemia with or without Septicemia 12 (19) 20 (13) mucositis in 20%. Forty-two out of 106 patients were Septicemia and mucositis 5 (8) 11 (7) clinically unstable according to our definition and therefore Pneumonia 3 (5) 11 (7) received platelet transfusions prophylactically. Forty-two out of a total number of 235 transfusions Without indication 4 (4) 10 (6) Mucositis only 8 (12) 32 (21) (27%) were given without a clear indication according to the study protocol. This occurred during 16% of all transplant procedures. Mucositis without relevant bleeding Therapeutic was the indication in most (76%) of these transfusions (see Bleeding WHO II 26 (100) 81 (100) Epistaxis 12 (46) 14 (17) Table 2). Forty-two out of 106 patients were clinically Mucositis 8 (30) 23 (28) unstable according to our definition and therefore received Hematemesis 2 (8) 4 (5) platelet transfusions prophylactically. Pulmonary bleeding 2 (8) 23 (28) Major indications for therapeutic platelet transfusions Hematochezia 1 (4) 3 (4) were epistaxis or mucositis with bleeding (76%) for which, Vaginal bleeding 1 (4) 14 (17) however, only 45% of all therapeutic transfusions were needed (see Table 2). There was no difference in the number of platelet units transfused in patients below or above the median age of 54 by mucosal bleeding due to mucositis in eight transplants years (data not shown). (30%) (Table 2).

Retrospective analysis Transfusions In a retrospective matched pair analysis, we compared the The median and mean number of single donor platelet ﬁrst 60 transplant procedures in this prospective study with transfusions was one per transplantation (range 0–18). The 60 historical peripheral blood stem cell transplants that

Bone Marrow Transplantation Therapeutic platelet transfusion strategy H Wandt et al 390 Table 4 Retrospective analysis platelet transfusion strategy.5,6,8,9 In the study of Bernstein et al.,8 in patients after autologous PBSCT, only major, Prospective study Retrospective (50 pat, 60 analysis (54 pat, severe and life-threatening bleeding was counted (corre- PBSCTs) 60 PBSCTs) sponding to bleeding WHO grade III and IV). They reported an incidence of 9%. In the analysis performed Age/years) with a prophylactic transfusion strategy at Johns Hopkins Median 55 49 Range 18–6717–61 Hospital, 18.5% moderate and severe bleeding was reported for autologous transplants.9 This higher incidence Female/male 21/29 25/29 of severe bleeding events might be explained by the fact that Multiple myeloma/lymphoma 41 41 these transplants were performed with bone marrow Acute leukemia 10 10 Solid tumor 9 9 leading to a longer duration of leukocytopenia and Germ cell cancer thrombocytopenia. The low incidence and severity of clinically relevant TBI conditioning 5 5 bleeding (19% WHO grade II) in our study is the reason why only a minority (34%) of all platelet transfusions was Platelet transfusions Median 1 3 performed for therapeutic purposes. Bleeding events were Mean 1.9 4 mainly caused by epistaxis and mucositis (in 76%). Range 0–18 0–27 In patients treated with TBI-containing regimens, we observed a more severe mucositis which lead to significantly Total no of platelet transfusions 111 237 more transfusions compared with patients after chemotherapy-based regimens alone. Our experience is in accordance with published data of patients with multiple myeloma who were randomized to a TBI and non-TBI regimen. were performed during the year before we started our new Patients with TBI 8 Gy and melphalan 140 mg/m2 needed strategy. Our former strategy required platelet transfusions twice the platelet transfusions compared with melphalan routinely at a morning platelet count o10 Â 109/l. Patients 200 mg/m2.13 were matched for gender, diagnosis and TBI conditioning. In 46% of all prophylactic transfusions, fever of The total number of transfused platelet units could be unknown origin was the main trigger for transfusion. We reduced from 237to 111, the median number of single did not see an increased bleeding risk in those clinically donor apheresis platelet transfusions per transplant was stable patients with fever. Therefore, we believe that fever decreased from 3 to 1 (Table 4). per se need not be a trigger for prophylactic platelet Bleeding complications of WHO grade II and III were transfusion in future transfusion protocols. registered in 20 and 1%, respectively, which was very In 16% of all transplant procedures, platelet transfusions comparable to the incidence in our study patients. The were not performed in complete accordance with our median number of red blood cell transfusions needed was 2 protocol. Seventy-six percent of these transfusions were (range 0–6). This was exactly the same number and range given prophylactically for mucositis without bleeding. This we needed in our study cohort. experience shows the difficulty for the medical staff to reduce prophylactic platelet transfusions even within a protocol. For further multicenter studies, it is important to Discussion educate physicians and nurses to follow strictly the guidelines of the therapeutic transfusion strategy, which was To our knowledge, this is the first clinical study that proven to be safe in our study. replaced standard prophylactic platelet transfusion by a Despite 27% of all transfusions being given in violation therapeutic transfusion strategy in clinically stable patients to the protocol guidelines, we could reduce the number of after autologous PBSCT regardless of the morning platelet apheresis platelet transfusions substantially (about one count. half) by our new transfusion strategy compared to a With this prospective study, we could show in 106 matched historical control group. Thirty-four percent of all patients that our therapeutic platelet transfusion strategy is procedures and about half of the transplants for multiple safe and more cost effective than the standard prophylactic myeloma could be performed without a single platelet transfusion strategy with the 10 Â 109/l trigger. No severe transfusion. bleeding (grade III and IV according to the WHO A survey in 1991 conducted of institutional members classification) occurred during 140 transplants after high- of the American Association of Blood Banks (hospitals) dose chemotherapy7TBI and 508 days of severe thrombo- in hematology/oncology patients has shown that about cytopenia (o10 Â 109/l). By the use of peripheral blood 20% of the hospitals did not administer prophylactic stem cells, the median duration of severe thrombocytopenia transfusions, but rather used therapeutic platelet trans- below 10 Â 109/l or 20 Â 109/l was a very short period of fusions only in response to active bleeding.14 In 1987, there 3 and 6 days, respectively. The incidence of minor and were only a minority of 5% of leukemia and bone marrow moderate bleeding (maximal WHO grade II) was only transplant services which did not transfuse platelets 19%. This bleeding incidence compares favorably with prophylactially.15 However, the hospitals using platelets moderate and severe bleeding events reported in the prophylactically administered twice as many platelet literature for autologous transplants with a prophylactic transfusions.

Bone Marrow Transplantation Therapeutic platelet transfusion strategy H Wandt et al 391 Previous studies comparing bleeding risks in patients 3 Heckman KD, Weiner GJ, Davis CS, Strauss RG, Jones MP, with leukemia who received therapeutic rather than Burns P. Randomized study of prophylactic platelet trans- prophylactic transfusions indicated that bleeding was fusion threshold during induction therapy for adult acute corrected in all patients. Thus, a therapeutic platelet leukemia: 10 000/ml versus 20 000/ml. J Clin Oncol 1997; 15: transfusion policy is a promising approach, but its actual 1143–1149. 4 Wandt H, Frank M, Ehninger G, Schneider C, Brack N, efficacy was unproven because of the small numbers of 9 16–18 Daoud A et al. Safety and cost effectivenes of a 10 Â 10 /l patients included in these prior studies. trigger for prophylactic platelet transfusions compared with There is a long-standing controversy in the scientific the traditional 20 Â 109/l trigger: a prospective comparative community of hematologists and oncologists as to whether trial in 105 patients with acute myeloid leukemia. Blood 1998; standard prophylactic platelet transfusions are necessary or 91: 3601–3606. whether this strategy should better be replaced by a 5 Gil-Ferna´ ndez JJ, Alegre A, Ferna´ ndez-Villalta MJ, Pinilla I, therapeutic transfusion strategy.10,17,19–22 Go´ mez Garcı´ a V, Martinez C et al. Clinical results of a During the last 20 years, the recommendations of the stringent policy on prophylactic platelet transfusion: non- American Society of Clinical Oncology reduced the trigger randomized comparative analysis in 190 bone marrow for prophylactic platelet transfusion from 20 Â 109/l down transplant patients from a single institution. Bone Marrow Transplant 1996; 18: 931–935. to 10 Â 109/l for thrombocytopenia following intensive 6 Wandt H, Frank M, Gro¨ schel W, Birkmann J, Gallmeier WM. chemotherapy or after hematopoietic stem cell transplant- Safety of the 10/nl trigger for prophylactic platelet transfusion 10 ation. The decision to administer platelet transfusions in ASCT [abstract]. Bone Marrow Transplant 1995; 15 (Suppl should incorporate individual clinical characteristics of the 2): 541a. patient and not simply be a reflex to the morning platelet 7Zumberg MS, del Rosario MLU, Nejame CF, Pollock BH, count. Platelet transfusions are expensive and associated Garzarella L, Kao KJ et al. A prospective randomized trial with a number of side effects. Recently Ballen et al.23 of prophylactic platelet transfusion and bleeding incidence reported autologous stem cell transplantations without the in hematopoietic stem cell transplant recipients: 10 000/ml use of blood product support in Jehovah’s Witnesses, a versus 20 000/ml trigger. Biol Blood Marrow Transplant 2002; 8: religious group that refuses transfusion of any major blood 569–576. product. Of 26 patients, there was only one lethal cerebral 8 Bernstein SH, Nademanee AP, Vose JM, Tricot G, Fay JW, Negrin RS et al. A multicenter study of platelet recovery bleeding in a patient with a still active brain medulloblas- and utilization in patients after myeloablative therapy toma. Another patient had life-threatening gastrointestinal and hematopoietic stem cell transplantation. Blood 1998; 91: bleeding but the patient recovered after regeneration of 3509–3517. platelets. Three other patients had moderate bleeding with 9 Nevo S, Swan V, Enger C, Wojno KJ, Bitton R, Shabooti M epistaxis and/or hematuria. This report supports our et al. Acute bleeding after bone marrow transplantation therapeutic platelet transfusion strategy since timely plate- (BMT) – incidence and effect on survival. A quantitative let transfusion could have corrected all major bleeding analysis in 1402 patients. Blood 1998; 91: 1469–1477. events except in the case of the medullablastoma patient. 10 Schiffer CA, Anderson KC, Bennett CL, Bernstein S, Elting Patients with cerebral infiltrations, however, were excluded LS, Goldsmith M et al. Platelet transfusion for patients with from our therapeutic transfusion strategy. cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001; 19: 1519–1538. A large prospective randomized trial is needed compar- 11 Link H, Bo¨ hme A, Cornely OA, Hoffken K, Kellner O, Kern ing the new therapeutic platelet transfusion strategy with WV et al. Antimicrobial therapy of unexplained fever in the standard prophylactic platelet transfusion strategy neutropenic patients – Guidelines of the Infectious Disease using a morning trigger of 10 Â 109/l for transfusion. Working Party (AGIO) of the German Society of Hematology Therefore, we have now started such a multicenter trial in and Oncology (DGHO). Ann Hematol 2003; 82 (Suppl 2): Germany. 105–117. 12 Bearman SI, Appelbaum FR, Buckner CD, Petersen FB, Fisher LD, Clift RA et al. Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1998; Acknowledgements 6: 1562–1568. 13 Moreau Ph, Facon Th, Attal M, Hulin C, Michallett M, We thank Rex Nichols for preparing the manuscript and the Maloisel F et al. Comparison of 200 mg/m2 melphalan and staff of the bone marrow transplant unit at the Nuremberg 8 Gy total body irradiation plus 140 mg/m2 melphalan as hospital for the continuous support during the study. conditioning regimens for peripheral blood stem cell transplantation in patients with newly diagnosed multiple myeloma: final analysis of the Intergroupe Francophone du Mye´ lome 9502 randomized trial. Blood 2002; 99: 731–735. References 14 Pisciotto PT, Benson K, Hume H, Glassman AB, Oberman H, Popovsky M et al. Prophylactic versus therapeutic platelet 1 Gmu¨ r J, Burger J, Schanz U, Fehr J, Schaffner A. Safety of transfusion practices in hematology and/or oncology patients. stringent prophylactic platelet transfusion policy for patients Transfusion 1995; 35: 498–502. with acute leukemia. Lancet 1991; 338: 1223–1226. 15 Patten E, Toy P. Prophylactic platelet transfusion policies 2 Rebulla P, Finazzi G, Marangoni F, Avvisati G, Gugliotta L, [abstract]. Blood 1998; 72 (Suppl 1): 283a. Rognoni G et al. For the Gruppo Italiano Malattie Emato- 16 Murphy S, Litwin S, Herring LM, Koch P, Remischovsky J, logiche Maligne Dell’Adulto. The threshold for prophylactic Donaldson MH et al. Indications for platelet transfusion platelet transfusin in adults with acute myeloid leukemia. in children with acute leukemia. Am J Hematol 1982; 12: N Engl J Med 1997; 337: 1870–1875. 347–356.

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