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Are We Begging a Question or Begging an Answer?

Shander, Aryeh MD*†; Gernsheimer, Terry MD

doi: 10.1213/ANE.0000000000000397
Editorials: Editorial

From the Departments of *Anesthesiology, Critical Care, and Pain Management, Englewood Hospital and Medical Center, Englewood, New Jersey; Mount Sinai School of Medicine, New York City, New York; and Seattle Cancer Care Alliance, Seattle, Washington.

Accepted for publication July 2, 2014.

Funding: None.

Conflict of Interest: See Disclosures at the end of the article.

Reprints will not be available from the authors.

Address correspondence to Aryeh Shander, MD, Department of Anesthesiology, Critical Care, and Pain Management, Englewood Hospital and Medical Center, 350 Engle Street, Englewood, NJ 07631. Address e-mail to aryeh.shander@ehmc.com.

Timely identification of patients in whom the potential benefits of transfusions outweigh the risks remains hotly debated.1 Despite their ubiquitous clinical use, many red blood cell (RBC) transfusion decisions are still based on arbitrary hemoglobin triggers.2 The case of prophylactic platelet transfusion is even more enigmatic, given that clinicians must consider not only platelet number (count) but also the functional status of platelets, not yet commonly measured in the clinical arena and the state of the endothelium, still an evolving field. Platelets are one of many contributors to the complex hemostatic system, and the platelet count and function needed to control bleeding in any clinical situation remains unclear.

Severe thrombocytopenia predisposes to spontaneous bleeding and possibly an increased size of the bleed (both prominent concerns in the central nervous system [CNS]). Thrombocytopenia may also increase the risk of bleeding and adverse outcomes in adults and pediatric patients undergoing invasive procedures.3 Recommendations for platelet transfusion typically use a threshold platelet count number as a cutoff for transfusion.4,5 Commonly used thresholds include: platelet count <10 × 109/L to reduce the risk of spontaneous bleeding in general patients; platelet count <50 × 109/L in patients who are actively bleeding, those with qualitative platelet defects or scheduled for invasive procedures; and platelet count of 70–100 × 109/L in patients with CNS injury or undergoing invasive CNS procedures including intrathecal and epidural catheter placement.4,5 Platelets have also been used as part of balanced transfusion protocols in resuscitation of trauma patients.6 Adding to the arbitrary nature of these recommendations is the clinical observation that many invasive procedures do not lead to significant bleeding despite the presence of thrombocytopenia.7,8 It thus appears likely that many patients receive platelet transfusions with questionable clinical justification or demonstrable benefit.9 A recent Cochrane review of 18 clinical trials has concluded that while there was no evidence to indicate a change from the practice of using a platelet count threshold of <10 × 109/L for transfusion, there is little evidence that prophylactic platelet transfusion (although somewhat more efficacious than therapeutic transfusion in lower platelet counts) prevented bleeding or that the platelet dose affected the number of patients with significant bleeding.10

The usefulness of platelet transfusion in active bleeding due to platelet dysfunction also remains uncertain.4,5 Despite its perceived importance, platelet function has not been well evaluated in clinical studies. In this issue of the journal, Kander et al.11 provide intriguing in vivo data on the impact of platelet transfusion on various laboratory parameters and functional platelet and clotting assays. In their study, they took blood samples before and 1 and 4 hours after transfusion of 1 unit of platelets in 39 patients with hypoproliferative thrombocytopenia (defined as platelet count <50 × 109/L) undergoing central venous catheter insertion. Conventional coagulation tests, thromboelastometry, multiple electrode aggregometry, and platelet flow cytometry were performed. Platelet transfusion resulted in a proportional rise in the patients’ platelet counts at 1 hour that persisted during the 4-hour period and was associated with improved clotting based on thromboelastometry and multiple electrode aggregometry results. The platelet functional status was not significantly improved following transfusion, suggesting that improved clotting parameters following platelet transfusion were predominantly driven by increased platelet counts and not better function.11

Changes that occur in blood upon removal from the circulation and during processing and storage (the so-called “storage lesion”) are well documented in RBC transfusions at various molecular, subcellular, and cellular levels, with some studies suggesting that these changes adversely affect patient outcomes.12,13 The evidence for platelet transfusions is more limited, but studies suggest some loss of effectiveness after prolonged storage,14 with decreased platelet transfusion increments and in vivo survival as soon as 3 days into storage.5,15 Platelets thus have a far shorter shelf-life (5–7 days) than RBCs (42 days). In the study by Kander et al.,11 the transfused platelet units were relatively old (median age of 6 and interquartile range 4–7 days). Hence, it is not surprising that transfused platelets offered little to improve the patients’ platelet functional status overall. Unlike stored RBCs, the lost functionality is primarily related to reduced platelet viability and is thus not expected to be reversible.

Although the observations of Kander et al. shed some light on real-world changes in laboratory parameters following prophylactic platelet transfusions, they should be viewed in light of their limitations. The population studied had a very low bleeding tendency despite low platelet counts and possibly impaired platelet function. Even lower platelet counts (e.g., 20 × 109/L) have been associated with similar rates and grade of bleeding.16 The power of the study is low and could undermine the reliability of any reported statistically nonsignificant P values. Although several statistically significant changes in laboratory parameters are reported, the clinical significance of those changes is undetermined. Platelet transfusions were associated with near doubling of the platelet counts of the recipients, but even the most significant changes in thromboelastometry parameters at the fourth hour were less than 15% of baseline values. Four grade-1 bleedings were reported, but with the study not powered for clinical outcomes and without a control arm, clinical conclusions are severely limited and the necessity of the transfusions remains unknown. Flow cytometry on blood samples obtained from the patients contained platelets from both the patient and transfused units, further blurring the functional contribution of the transfusion.

In their discussion, Kander et al.11 emphasize the paucity of evidence identifying a threshold and dose of platelets transfused prophylactically for invasive procedures. We could not agree more. We need a better understanding of which patients are at risk of bleeding due to thrombocytopenia when undergoing invasive procedures. Performing controlled randomized studies of prophylactic versus no platelet transfusion prior to invasive procedures is understandably difficult (particularly if patients are not adequately advised of the risks associated with platelet transfusions), and trials have yielded mixed results due to the low frequency of bleeding. The often risk-averse medical community has generally preferred transfusing platelets rather than risking bleeding despite the marginal risk/benefit ratio. It is likely that hundreds of patients every year are transfused to prevent 1 bleed that may or may not be clinically significant (grade 1 bleeding) and may result in adverse transfusion effects, not a clinically justified or cost-effective practice.

In their study, Kander et al. approached this problem from behind rather than head-on, relying on laboratory rather than clinical endpoints, demonstrating some degrees of improvements in certain laboratory measures correlated with increased platelet counts but not with demonstrable clinical improvement. Without clear clinical implications, one must ask, “Are we begging for a question or are we begging for an answer?” The key questions remain: Who is at risk of bleeding in the presence of thrombocytopenia, how can we identify them reliably ahead of time, what dominates that risk (count, function, or both), and how can platelet transfusions help with clinical outcomes? Unfortunately, the clinician is left empty-handed despite this and several other studies, and the clinical determination of the safe platelet count for an invasive procedure remains arbitrary with little or no clear clinical evidence.

The take-home messages of the study by Kander et al. are that given a low baseline platelet count, prophylactic platelet transfusion will improve the clotting profile and that the improvements appear to be dominated by platelet counts and not functional status. However, we cannot be assured whether it changes the incidence of clinically significant bleeding. Correlating the decline in platelet number with clotting (assuming the 2 are interrelated) could shed enormous light on this very dark space. We hope this intriguing study will stimulate others to address this question head-on and where it matters most, at the bedside.

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DISCLOSURES

Name: Aryeh Shander, MD.

Contribution: This author helped prepare the manuscript.

Attestation: Aryeh Shander approved the final manuscript.

Conflicts of Interest: Aryeh Shander has been a consultant or speaker with honorarium for or received research support from Baxter, Luitpold, Masimo, Novo Nordisk, OPK Biotech, Gauss, CSL Behring, and the Medicine Company; he is a founding member of the Society for the Advancement of Blood Management.

Name: Terry Gernsheimer, MD.

Contribution: This author helped prepare the manuscript.

Attestation: Terry Gernsheimer approved the final manuscript.

Conflicts of Interest: In the past year, Terry Gernsheimer has done consulting for or received honoraria from Alexion, Amgen, Laboratorio Raffo, Bristol Myers Squibb, Cangene and Medison.

This manuscript was handled by: Avery Tung, MD.

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