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Comparison of a therapeutic-only versus prophylactic platelet transfusion policy for people with congenital or acquired bone marrow failure disorders
Malouf R, Ashraf A, Hadjinicolaou A V, Doree C, Hopewell S, Estcourt L J
The Cochrane Database of Systematic Reviews. 2018;5:CD012342.
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Abstract
BACKGROUND Bone marrow disorders encompass a group of diseases characterised by reduced production of red cells, white cells, and platelets, or defects in their function, or both. The most common bone marrow disorder is myelodysplastic syndrome. Thrombocytopenia, a low platelet count, commonly occurs in people with bone marrow failure. Platetet transfusions are routinely used in people with thrombocytopenia secondary to bone marrow failure disorders to treat or prevent bleeding. Myelodysplastic syndrome is currently the most common reason for receiving a platelet transfusion in some Western countries. OBJECTIVES To determine whether a therapeutic-only platelet transfusion policy (transfusion given when patient is bleeding) is as effective and safe as a prophylactic platelet transfusion policy (transfusion given to prevent bleeding according to a prespecified platelet threshold) in people with congenital or acquired bone marrow failure disorders. SEARCH METHODS We searched for randomised controlled trials (RCTs), non-RCTs, and controlled before-after studies (CBAs) in the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2017, Issue 9), Ovid MEDLINE (from 1946), Ovid Embase (from 1974), PubMed (e-publications only), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 12 October 2017. SELECTION CRITERIA We included RCTs, non-RCTs, and CBAs that involved the transfusion of platelet concentrates (prepared either from individual units of whole blood or by apheresis any dose, frequency, or transfusion trigger) and given to treat or prevent bleeding among people with congenital or acquired bone marrow failure disorders.We excluded uncontrolled studies, cross-sectional studies, and case-control studies. We excluded cluster-RCTs, non-randomised cluster trials, and CBAs with fewer than two intervention sites and two control sites due to the risk of confounding. We included all people with long-term bone marrow failure disorders that require platelet transfusions, including neonates. We excluded studies of alternatives to platelet transfusion, or studies of people receiving intensive chemotherapy or a stem cell transplant. DATA COLLECTION AND ANALYSIS We used the standard methodological procedures outlined by Cochrane. Due to the absence of evidence we were unable to report on any of the review outcomes. MAIN RESULTS We identified one RCT that met the inclusion criteria for this review. The study enrolled only nine adults with MDS over a three-year study duration period. The trial was terminated due to poor recruitment rate (planned recruitment 60 participants over two years). Assessment of the risk of bias was not possible for all domains. The trial was a single-centre, single-blind trial. The clinical and demographic characteristics of the participants were never disclosed. The trial outcomes relevant to this review were bleeding assessments, mortality, quality of life, and length of hospital stay, but no data were available to report on any of these outcomes.We identified no completed non-RCTs or CBAs.We identified no ongoing RCTs, non-RCTs, or CBAs. AUTHORS' CONCLUSIONS We found no evidence to determine the safety and efficacy of therapeutic platelet transfusion compared with prophylactic platelet transfusion for people with long-term bone marrow failure disorders. This review underscores the urgency of prioritising research in this area. People with bone marrow failure depend on long-term platelet transfusion support, but the only trial that assessed a therapeutic strategy was halted. There is a need for good-quality studies comparing a therapeutic platelet transfusion strategy with a prophylactic platelet transfusion strategy; such trials should include outcomes that are important to patients, such as quality of life, length of hospital admission, and risk of bleeding.
Clinical Commentary
Xiangrong He, MD, PhD & Claudia S. Cohn, MD, PhD, both of University of Minnesota, Department of Laboratory Medicine and Pathology.
What is known?
Thrombocytopenia represents a common problem for patients withchronic bone marrow failure disorders, the most common of which are myelodysplastic syndrome (MDS) and anaplastic anemia (AA). In addition to thrombocytopenia, both morphologic and functional platelet abnormalities may be seen in these patients as well. Platelet transfusion support is the primary management option for thrombocytopenia and active bleeding in these patients. Platelets are usually transfused prophylactically at counts less than 10 x 109/L and with higher counts in patients with hemorrhage. As compared with no prophylaxis, prophylactic platelet transfusions have been shown to be superior in reducing moderate to severe bleeding, primarily in people with leukemia. However, the evidence of prophylactic use for platelet transfusions in people with chronic bone marrow failure is lacking. Meanwhile, platelets are a precious resource and platelet transfusion carries many risks. Thus, avoiding unnecessary prophylactic platelet transfusions will have significant financial and safety implications for health services.
What did this paper set out to examine?
The authors set out to to review in thrombocytopenic patients with chronic bone marrow failure, whether prophylactic transfusions are really necessary or whether these patients can be effectively supported with only therapeutic platelet transfusions given with the onset of bleeding. In particular, they wanted to show that a therapeutic-only platelet transfusion strategy is as effective and safe as a prophylactic platelet transfusion strategy for the prevention of clinically significant bleeding in thrombocytopenic patients with primary bone marrow failure disorders.
What did they show?
The review included all patients with MDS, acquired AA, or congenital bone marrow failure disorders that were not being actively treated with a stem cell transplant or intensive chemotherapy. To maximize the number of studies eligible for inclusion, not only randomized controlled trials (RCTs), but good quality non-RCTs, and controlled before-after studies were included. Only one trial met the inclusion criteria for this review. Unfortunately, the trial was incomplete due to an unexpected slow recruiting rate. Therefore, no results were provided by the trial authors. Although the review was unable to make any recommendations on prophylactic platelet transfusion policies for this patient population, it did identify an urgent need for good quality studies in this area.
What are the implications for practice and for future work?
Thrombocytopenia (platelet counts < 10 x 109/L) is one of the most common complications in patients with chronic bone marrow failure. For example, 40% to 65% of MDS patients have thrombocytopenia. Meanwhile, in some Western countries, bone marrow failure is one of the most common underlying reasons for receiving a prophylactic platelet transfusion. However, guidelines on a therapeutic platelet transfusion strategy versus a prophylactic platelet transfusion strategy in this population are still lacking. Due to the absence of relevant data, the current review was not able to reach any conclusions on the safety and efficacy of prophylactic platelet transfusion compared with therapeutic platelet transfusion for patients with chronic bone marrow failure. Nontheless, this review identified a major gap in the literature and underscored the urgency of prioritizing research in this area. In the meantime, platelet transfusions for people with bone marrow disorders should still be managed according to national transfusion guidelines.
2.
Use of platelet transfusions prior to lumbar punctures or epidural anaesthesia for the prevention of complications in people with thrombocytopenia
Estcourt LJ, Ingram C, Doree C, Trivella M, Stanworth SJ
The Cochrane Database of Systematic Reviews. 2016;((5)):CD011980.
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Abstract
BACKGROUND People with a low platelet count (thrombocytopenia) often require lumbar punctures or an epidural anaesthetic. Lumbar punctures can be diagnostic (haematological malignancies, epidural haematoma, meningitis) or therapeutic (spinal anaesthetic, administration of chemotherapy). Epidural catheters are placed for administration of epidural anaesthetic. Current practice in many countries is to correct thrombocytopenia with platelet transfusions prior to lumbar punctures and epidural anaesthesia, in order to mitigate the risk of serious procedure-related bleeding. However, the platelet count threshold recommended prior to these procedures varies significantly from country to country. This indicates significant uncertainty among clinicians of the correct management of these patients. The risk of bleeding appears to be low but if bleeding occurs it can be very serious (spinal haematoma). Therefore, people may be exposed to the risks of a platelet transfusion without any obvious clinical benefit. OBJECTIVES To assess the effects of different platelet transfusion thresholds prior to a lumbar puncture or epidural anaesthesia in people with thrombocytopenia (low platelet count). SEARCH METHODS We searched for randomised controlled trials (RCTs) in CENTRAL (The Cochrane Library 2016, Issue 3), MEDLINE (from 1946), EMBASE (from 1974), the Transfusion Evidence Library (from 1950) and ongoing trial databases to 3 March 2016. SELECTION CRITERIA We included RCTs involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people of any age with thrombocytopenia requiring insertion of a lumbar puncture needle or epidural catheter. We only included RCTs published in English. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We identified no completed or ongoing RCTs in English. We did not exclude any completed or ongoing RCTs because they were published in another language. AUTHORS' CONCLUSIONS There is no evidence from RCTs to determine what is the correct platelet transfusion threshold prior to insertion of a lumbar puncture needle or epidural catheter. There are no ongoing registered RCTs assessing the effects of different platelet transfusion thresholds prior to the insertion of a lumbar puncture or epidural anaesthesia in people with thrombocytopenia. Any future RCT would need to be very large to detect a difference in the risk of bleeding. We would need to design a study with at least 47,030 participants to be able to detect an increase in the number of people who had major procedure-related bleeding from 1 in 1000 to 2 in 1000.
Clinical Commentary
Richard Kaufman MD, Brigham and Women’s Hospital, Boston
What is known?
In rare cases, bleeding complicates lumbar punctures and epidural anesthesia. The clinical consequences of bleeding in this setting range from trivial (traumatic tap detectable by cerebrospinal fluid cell count only) to devastating (spinal hematoma/paralysis). Most cases of spinal hematoma following lumbar puncture have been reported in patients with platelet counts below 50 X 109 cells/Lalthough other risk factors for bleeding were present in nearly all of these cases.1 Platelet transfusions are often administered prophylactically to thrombocytopenic patients having a lumbar puncture or epidural anesthesia. But what constitutes a safe minimum platelet count to perform these procedures is unclear, and clinical practices and published practice guidelines vary widely. This is an important topic because: (1) lumbar punctures and epidural anesthesia are performed commonly; (2) these procedures have rare but serious risks; (3) platelet transfusions carry a range of infectious and noninfectious risks; and (4) platelet units are expensive and limited in availability.
What did this paper set out to examine?
The authors conducted a systematic review of the literature aimed at evaluating the risks and benefits of different platelet transfusion thresholds before a lumbar puncture or epidural anesthesia in thrombocytopenic patients. This was an update of a 2016 Cochrane Review.
What did they show?
The authors found that the published literature on this topic remains extremely limited. They identified no high-quality studies. After rigorously screening 999 published reports, the authors included in their analysis only three retrospective cohort studies describing participants who received or did not receive lumbar puncture. One study was in adults; the other two were in children. No study compared different platelet count thresholds before a procedure. No major bleeding complications occurred in the two studies reporting this outcome (150 participants). There was no difference in minor bleeding (traumatic taps) among pediatric or adult patients who received or did not receive platelet transfusion pre-procedure. The authors concluded that no clinical study evidence exists on which to base a correct platelet transfusion threshold before lumbar puncture or epidural anesthesia.
At this time, it is impossible to make firm recommendations on whether platelet transfusions should be administered before lumbar puncture or epidural anesthesia in thrombocytopenic children or adults. A safe minimum platelet count for performing these procedures cannot be identified based on the existing data. Until stronger data allow us to better understand the risks and benefits of platelet transfusion before lumbar puncture or epidural anesthesia, practices will vary among clinicians and will remain a matter of clinical judgment.
What are the implications for practice and for future work?
What are the implications for future research?Because bleeding complication rates are so low in the setting of lumbar puncture and epidural anesthesia, the authors estimate that performing a randomized trial would require more than 47,000 participants. Utilizing large electronic patient registries/databases thus appears to be the only realistic way that our understanding in this area could be improved moving forward.
Predicting bleeding in the setting of any invasive procedure has proven to be remarkably difficult. Hemostasis is complex; bleeding from most procedures is rare; and the tools that we have to assess bleeding risk are crude. Platelet counts tell us nothing about platelet hemostatic function. Other variables, including medications, coagulation factor activity, tissue integrity, and disease state may predominate in determining a patient’s bleeding risk. Platelet counts are easy to measure, but hopefully in the future we will discover better ways to determine whether a platelet transfusion should be given.
What are the implications for future practice? At this time, it is impossible to make firm recommendations on whether platelet transfusions should be administered before lumbar puncture or epidural anesthesia in thrombocytopenic children or adults. A safe minimum platelet count for performing these procedures cannot be identified based on the existing data. Until stronger data allow us to better understand the risks and benefits of platelet transfusion before lumbar puncture or epidural anesthesia, practices will vary among clinicians and will remain a matter of clinical judgment.
References
1. Van Veen JJ, Nokes TJ, Makris M. The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals. Br J Haematol. 148(1):15-25.