Rationale and design of platelet transfusions in haematopoietic stem cell transplantation: the PATH pilot study

Jason Tay, David Allan, Sara Beattie, Christopher Bredeson, Dean Fergusson, Dawn Maze, Mitchell Sabloff, Kednapa Thavorn, Alan Tinmouth, Jason Tay, David Allan, Sara Beattie, Christopher Bredeson, Dean Fergusson, Dawn Maze, Mitchell Sabloff, Kednapa Thavorn, Alan Tinmouth

Abstract

Introduction: In patients with transient thrombocytopenia being treated with high-dose chemotherapy followed by stem cell rescue-haematopoietic stem cell transplantation (HSCT), prophylactic transfusions are standard therapy to prevent bleeding. However, a recent multicentre trial suggests that prophylactic platelet transfusions in HSCT may not be necessary. Additionally, the potential overuse of platelet products places a burden on a scarce healthcare resource. Moreover, the benefit of prophylactic platelet transfusions to prevent clinically relevant haemorrhage is debatable. Current randomised data compare different thresholds for administering prophylactic platelets or prophylactic versus therapeutic platelet transfusions. An alternative strategy involves prescribing prophylactic antifibrinolytic agents such as tranexamic acid to prevent bleeding.

Methods and analysis: This report describes the design of an open-labelled randomised pilot study comparing the prophylactic use of oral tranexamic acid with platelet transfusions in the setting of autologous HSCT. In 3-5 centres, 100 patients undergoing autologous HSCT will be randomly assigned to either a prophylactic tranexamic acid or prophylactic platelets bleeding prevention strategy-based daily platelet values up to 30 days post-transplant. The study will be stratified by centre and type of transplant. The primary goal is to demonstrate study feasibility while collecting clinical outcomes on (1) WHO and Bleeding Severity Measurement Scale (BSMS), (2) transplant-related mortality, (3) quality of life, (4) length of hospital stay, (5) intensive care unit admission rates, (6) Bearman toxicity scores, (7) incidence of infections, (8) transfusion requirements, (9) adverse reactions and (10) economic analyses.

Ethics and dissemination: This study is funded by a peer-reviewed grant from the Canadian Institutes of Health Research (201 503) and is registered on Clinicaltrials.gov NCT02650791. It has been approved by the Ottawa Health Science Network Research Ethics Board. Study results will presented at national and international conferences. Importantly, the results of this trial will inform the feasibility and conduct of a larger study.

Trial registration number: NCT02650791; Pre-results.

Conflict of interest statement

Conflicts of Interest: None declared.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

References

    1. Estcourt L, Stanworth S, Doree C et al. . Prophylactic platelet transfusion for prevention of bleeding in patients with haematological disorders after chemotherapy and stem cell transplantation. Cochrane Database Syst Rev 2012;(5):CD004269 10.1002/14651858.CD004269.pub3
    1. Kaufman RM, Djulbegovic B, Gernsheimer T et al. . Platelet transfusion: a clinical practice guideline from the AABB. Ann Intern Med 2015;162:205–13. 10.7326/M14-1589
    1. Kumar A, Mhaskar R, Grossman BJ et al. . Platelet transfusion: a systematic review of the clinical evidence. Transfusion 2015;55:1116–27; quiz 15 10.1111/trf.12943
    1. Nahirniak S, Slichter SJ, Tanael S et al. . Guidance on platelet transfusion for patients with hypoproliferative thrombocytopenia. Transfus Med Rev 2015;29:3–13. 10.1016/j.tmrv.2014.11.004
    1. Christou G, Kekre N, Petrcich W et al. . Impact of platelet transfusion on toxicity and mortality after hematopoietic progenitor cell transplantation. Transfusion 2015;55:253–8. 10.1111/trf.12817
    1. Stanworth SJ, Estcourt LJ, Powter G et al. . A no-prophylaxis platelet-transfusion strategy for hematologic cancers. N Engl J Med 2013;368:1771–80. 10.1056/NEJMoa1212772
    1. Wandt H, Schaefer-Eckart K, Frank M et al. . A therapeutic platelet transfusion strategy is safe and feasible in patients after autologous peripheral blood stem cell transplantation. Bone Marrow Transplant 2006;37:387–92. 10.1038/sj.bmt.1705246
    1. Wandt H, Schaefer-Eckart K, Wendelin K et al. . Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study. Lancet 2012;380:1309–16. 10.1016/S0140-6736(12)60689-8
    1. Callum JL, Lin Y, Pinkerton PH et al. . Bloody easy 3: blood transfusions, blood alternatives and transfusion reactions, a guide to transfusion medicine. 3rd edn Orbcon, 2011.
    1. Galel SA. Infectious disease screening AABB technical manual. 18th edn 2014:179–206.
    1. Lin Y, Callum JL, Pinkerton PH. Adverse reactions. 2011 edn Clinical Guide To Transfusion, 2013.
    1. Mazzei CA, Popovsky M, Kopko PM. Noninfectious complications of blood transfusion. In: Fung MK, Grossman BJ, Hillyer C, Westhoff CM, eds Technical Manual, 18th edition, 2014:665–92.
    1. Wardrop D, Estcourt LJ, Brunskill SJ et al. . Antifibrinolytics (lysine analogues) for the prevention of bleeding in patients with haematological disorders. Cochrane Database Syst Rev 2013;(7):CD009733 10.1002/14651858.CD009733.pub2
    1. Avvisati G, ten Cate JW, Büller HR et al. . Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia. Lancet 1989;2:122–4. 10.1016/S0140-6736(89)90181-5
    1. Shpilberg O, Blumenthal R, Sofer O et al. . A controlled trial of tranexamic acid therapy for the reduction of bleeding during treatment of acute myeloid leukemia. Leuk Lymphoma 1995;19:141–4. 10.3109/10428199509059668
    1. Stanworth SJ, Estcourt LJ, Llewelyn CA et al. . Impact of prophylactic platelet transfusions on bleeding events in patients with hematologic malignancies: a subgroup analysis of a randomized trial. Transfusion 2014;54:2385–93. 10.1111/trf.12646
    1. Heddle NM, Cook RJ, Tinmouth A et al. . A randomized controlled trial comparing standard- and low-dose strategies for transfusion of platelets (SToP) to patients with thrombocytopenia. Blood 2009;113:1564–73. 10.1182/blood-2008-09-178236
    1. Slichter SJ, Kaufman RM, Assmann SF et al. . Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med 2010;362:600–13. 10.1056/NEJMoa0904084
    1. Tinmouth A, Tannock IF, Crump M et al. . Low-dose prophylactic platelet transfusions in recipients of an autologous peripheral blood progenitor cell transplant and patients with acute leukemia: a randomized controlled trial with a sequential Bayesian design. Transfusion 2004;44:1711–19. 10.1111/j.0041-1132.2004.04118.x
    1. Sensebé L, Giraudeau B, Bardiaux L et al. . The efficiency of transfusing high doses of platelets in hematologic patients with thrombocytopenia: results of a prospective, randomized, open, blinded end point (PROBE) study. Blood 2005;105:862–4. 10.1182/blood-2004-05-1841
    1. Gaydos LA, Freireich EJ, Mantel N. The quantitative relation between platelet count and hemorrhage in patients with acute leukemia. N Engl J Med 1962;266:905–9. 10.1056/NEJM196205032661802
    1. Friedmann AM, Sengul H, Lehmann H et al. . Do basic laboratory tests or clinical observations predict bleeding in thrombocytopenic oncology patients? A reevaluation of prophylactic platelet transfusions. Transfus Med Rev 2002;16:34–45.
    1. Bernstein SH, Nademanee AP, Vose JM et al. . A multicenter study of platelet recovery and utilization in patients after myeloablative therapy and hematopoietic stem cell transplantation. Blood 1998;91:3509–17.
    1. Stanworth SJ, Hyde C, Brunskill S et al. . Platelet transfusion prophylaxis for patients with haematological malignancies: where to now? Br J Haematol 2005;131:588–95. 10.1111/j.1365-2141.2005.05769.x
    1. Schiffer CA, Anderson KC, Bennett CL et al. . Platelet transfusion for patients with cancer: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19:1519–38.
    1. Higby DJ, Cohen E, Holland JF et al. . The prophylactic treatment of thrombocytopenic leukemic patients with platelets: a double blind study. Transfusion 1974;14:440–6. 10.1111/j.1537-2995.1974.tb04558.x
    1. Murphy S, Litwin S, Herring LM et al. . Indications for platelet transfusion in children with acute leukemia. Am J Hematol 1982;12:347–56. 10.1002/ajh.2830120406
    1. Solomon J, Bofenkamp T, Fahey JL et al. . Platelet prophylaxis in acute non-lymphoblastic leukaemia. Lancet 1978;1:267 10.1016/S0140-6736(78)90505-6
    1. Blumberg N, Heal JM, Liesveld JL et al. . Platelet transfusion and survival in adults with acute leukemia. Leukemia 2008;22:631–5. 10.1038/sj.leu.2404920
    1. Eftekharian H, Vahedi R, Karagah T et al. . Effect of tranexamic acid irrigation on perioperative blood loss during orthognathic surgery: a double-blind, randomized controlled clinical trial. J Oral Maxillofac Surg 2015;73:129–33. 10.1016/j.joms.2014.07.033
    1. Karaaslan F, Karaoğlu S, Mermerkaya MU et al. . Reducing blood loss in simultaneous bilateral total knee arthroplasty: combined intravenous-intra-articular tranexamic acid administration. A prospective randomized controlled trial. Knee 2015;22:131–5. 10.1016/j.knee.2014.12.002
    1. Mirghafourvand M, Mohammad-Alizadeh S, Abbasalizadeh F et al. . The effect of prophylactic intravenous tranexamic acid on blood loss after vaginal delivery in women at low risk of postpartum haemorrhage: a double-blind randomised controlled trial. Aust N Z J Obstet Gynaecol 2015;55:53–8. 10.1111/ajo.12262
    1. Roberts I, Coats T, Edwards P et al. . HALT-IT—tranexamic acid for the treatment of gastrointestinal bleeding: study protocol for a randomised controlled trial. Trials 2014;15:450 10.1186/1745-6215-15-450
    1. Sprigg N, Renton CJ, Dineen RA et al. . Tranexamic acid for spontaneous intracerebral hemorrhage: a randomized controlled pilot trial (ISRCTN50867461). J Stroke Cerebrovasc Dis 2014;23:1312–18. 10.1016/j.jstrokecerebrovasdis.2013.11.007
    1. Zehtabchi S, Abdel Baki SG, Falzon L et al. . Tranexamic acid for traumatic brain injury: a systematic review and meta-analysis. Am J Emerg Med 2014;32:1503–9. 10.1016/j.ajem.2014.09.023
    1. National Heart Lung and Blood Institute. The diagnosis, evaluation, and management of von Willebrand disease. NIH publication no 08-5832 Bethesda, MD: U.S. Dept. of Health and Human Services, National Institutes of Health, National Heart, Lung, and Blood Institute, 2007.
    1. Srivastava A, Brewer AK, Mauser-Bunschoten EP et al. . Guidelines for the management of hemophilia. Haemophilia 2013;19:e1–47. 10.1111/j.1365-2516.2012.02909.x
    1. World Health Organization. WHO handbook for reporting results of cancer treatment. Geneva: World Health Organization, 1979.
    1. Bercovitz RS, O'Brien SH. Measuring bleeding as an outcome in clinical trials of prophylactic platelet transfusions. Hematology Am Soc Hematol Educ Program 2012;2012:157–60. 10.1182/asheducation-2012.1.157
    1. Koreth R, Weinert C, Weisdorf DJ et al. . Measurement of bleeding severity: a critical review. Transfusion 2004;44:605–17. 10.1111/j.1537-2995.2004.03153.x
    1. Estcourt LJ, Heddle N, Kaufman R et al. . The challenges of measuring bleeding outcomes in clinical trials of platelet transfusions. Transfusion 2013;53:1531–43. 10.1111/trf.12058
    1. Webert K, Cook RJ, Sigouin CS et al. . The risk of bleeding in thrombocytopenic patients with acute myeloid leukemia. Haematologica 2006;91:1530–7.
    1. Webert KE, Arnold DM, Lui Y et al. . A new tool to assess bleeding severity in patients with chemotherapy-induced thrombocytopenia. Transfusion 2012;52:2466–74; quiz 65 10.1111/j.1537-2995.2012.03634.x
    1. Estcourt LJ, Pinchon D, Symington E et al. . Does bleeding affect patient-reported outcome measures in patients with myelodysplasia or hematologic malignancies: a systematic review. Transfusion 2014;54:1166–79. 10.1111/trf.12441
    1. Heddle NM, Arnold DM, Webert KE. Time to rethink clinically important outcomes in platelet transfusion trials. Transfusion 2011;51:430–4. 10.1111/j.1537-2995.2010.02982.x
    1. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med 2001;33:337–43. 10.3109/07853890109002087
    1. Cella D, Beaumont JL, Webster KA et al. . Measuring the concerns of cancer patients with low platelet counts: the Functional Assessment of Cancer Therapy—thrombocytopenia (FACT-Th) questionnaire. Support Care Cancer 2006;14:1220–31. 10.1007/s00520-006-0102-1
    1. Patient-Centered Outcomes Research Institute 2015. (accessed 05 Nov 2015).
    1. Bearman SI, Appelbaum FR, Buckner CD et al. . Regimen-related toxicity in patients undergoing bone marrow transplantation. J Clin Oncol 1988;6:1562–8.
    1. McQuellon RP, Russell GB, Cella DF et al. . Quality of life measurement in bone marrow transplantation: development of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale. Bone Marrow Transplant 1997;19:357–68. 10.1038/sj.bmt.1700672
    1. Spitzer RL, Kroenke K, Williams JB et al. . A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med 2006;166:1092–7. 10.1001/archinte.166.10.1092
    1. Cook RJ, Heddle NM, Rebulla P et al. . Methods for the analysis of bleeding outcomes in randomized trials of PLT transfusion triggers. Transfusion 2004;44:1135–42. 10.1111/j.1537-2995.2004.03231.x

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere