Description of the condition
Haematological malignancies account for between 8% and 9% of all new cancers reported in the UK and US (CDC 2012; ONS 2012), and their incidence is increasing (11% to 14% increase in new cases of lymphoma and myeloma between 1991 to 2001 and 2008 to 2010) (Cancer Research UK 2013). The prevalence of these disorders is also increasing due to increased survival rates (Coleman 2004; Rachet 2009). These improved survival rates are due to the introduction of intensive chemotherapy treatments and use of stem cell transplantation (Burnett 2011; Fielding 2007; Patel 2009). Over 50,000 haematopoietic stem cell transplants (HSCTs) are carried out annually worldwide (Gratwohl 2010), and are used to treat both malignant and non-malignant haematological disorders. Autologous HSCT is the commonest type of HSCT (57% to 59%) (Gratwohl 2010; Passweg 2012). However, chemotherapy and stem cell transplantation can lead to prolonged periods of severe thrombocytopenia (De la Serna 2008; Heddle 2009a; Rysler 2010; Stanworth 2013; Wandt 2012).
Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in thrombocytopenic patients with bone marrow failure secondary to chemotherapy or stem cell transplantation. The ready availability of platelet concentrates has undoubtedly made a major contribution in allowing the development of intensive treatment regimens for haematological disorders (malignant and non-malignant) and other malignancies. The first demonstration of the effectiveness of platelet transfusions was performed in 1910 (Duke 1910). However, it was not until the 1970s and 1980s that the use of platelet transfusions became standard treatment for thrombocytopenic patients with bone marrow failure (Blajchman 2008). Alongside changes in supportive care, the routine use of platelet transfusions in patients with haematological disorders since that time has led to a marked decrease in the number of haemorrhagic deaths associated with thrombocytopenia (Slichter 1980). This has resulted in a considerable increase in the demand for platelet concentrates. Currently, platelet concentrates are the second most frequently used blood component. Administration of platelet transfusions to patients with haematological disorders now constitute a significant proportion (up to 67%) of all platelets issued (Cameron 2007; Greeno 2007; Pendry 2011), and the majority of these (69%) are given to prevent bleeding (Estcourt 2012b).
Patients can become refractory to platelet transfusions. In an analysis of the TRAP 1997 study data, there was a progressive decrease in the post-transfusion platelet count increments and time interval between transfusions as the number of preceding transfusions increased (Slichter 2005). This effect was seen irrespective of whether or not patients had developed detectable human leukocyte antigen (HLA) antibodies (Slichter 2005).
Platelet transfusions are also associated with adverse events. Mild to moderate reactions to platelet transfusions include rigors, fever, and urticaria (Heddle 2009b). These reactions are not life-threatening but can be extremely distressing for the patient. Rarer, but more serious sequelae include: anaphylaxis; transfusion-transmitted infections; transfusion-related acute lung injury; and immunomodulatory effects (Benson 2009; Blumberg 2009; Bolton-Maggs 2012; Heddle 2009b; Knowles 2011; Pearce 2011; Popovsky 1985; Silliman 2003; Knowles 2010).
Any strategy that can safely decrease the need for prophylactic platelet transfusions in haematology patients will have significant logistical and financial implications as well as decreasing patients’ exposure to the risks of transfusion.
Description of the intervention
Platelet transfusions have an obvious beneficial effect in the management of active bleeding in patients with haematological malignancy and severe thrombocytopenia. However, questions still remain on how this limited resource should be used to prevent severe and life-threatening bleeding (Estcourt 2011). Prophylactic platelet transfusions for patients with chemotherapy-induced thrombocytopenia became standard practice following the publication of several, small, randomised controlled trials (RCTs) in the late 1970s and early 1980s (Higby 1974; Murphy 1982; Solomon 1978).
Dose of prophylactic platelet transfusions
The platelet dose is the number of platelets contained within a standard platelet transfusion. For adults, the usual dose given is a single apheresis unit or a pool of four to six whole blood-derived platelets, with the absolute number of platelets in the range of 300 x 109 to 600 x 109 (Stanworth 2005). The experimental interventions will be low dose or high dose platelet transfusion strategies. Low dose platelet transfusions will be platelet transfusions containing a similar dose to that given in the low dose arm of Slichter 2010 (1.1 x 1011/m2 ± 25%). High dose platelet transfusions will be platelet transfusions containing a similar dose to that given in the high dose arm of Slichter 2010 (4.4 x 1011/m2 ± 25%). If the exact dose is unknown the study's own definition of high or low dose will be used.
How the intervention might work
Optimal dose of prophylactic platelets
The dose of the platelet product transfused was based upon the perceived need to raise the patient's platelet count above a certain safe threshold. Over the years, our understanding of bleeding in thrombocytopenic patients has advanced and there is now evidence to suggest that patients require only approximately 7100 platelets/µL per day to maintain haemostasis (Hanson 1985). Platelets have been shown to provide an endothelial supportive function by plugging gaps in the endothelium of otherwise intact blood vessels. Animal studies have shown that thrombocytopenia is associated with the gradual thinning of the vessel wall endothelium over time, and that, if thrombocytopenia persists, gaps gradually occur between adjacent endothelial cells (Blajchman 1981; Kitchens 1975; Nachman 2008). This thinning and fenestration of the endothelium is accompanied by the ongoing and increased use of circulating platelets to prevent the loss of red blood cells (RBCs) through these gaps.
A mathematical model predicted that smaller, more frequent doses of platelets would be as effective as higher doses of platelets in maintaining patients' platelet counts above an agreed threshold (Hersh 1998). This raised the question of whether thrombocytopenic bleeding could be prevented with a lower platelet dose (Tinmouth 2003). Such a strategy has potential economic and resource advantages, as fewer platelet transfusions might be required and donor exposures might be reduced.
Several studies have tried to address this question. The two largest studies came to different conclusions (Heddle 2009a; Slichter 2010). One trial was stopped early because of an excess of World Health Organization (WHO) grade 4 bleeding (Heddle 2009a), and the other study found no difference in bleeding between treatment arms (Slichter 2010).
Assessment of bleeding
A bleeding assessment has been seen as a more clinically-relevant measure of the effect of platelet transfusions than surrogate markers such as platelet increment.
Any review that uses bleeding as a primary outcome measure needs to assess the way that the trials have recorded bleeding. Unfortunately, the way bleeding has been recorded and assessed has varied markedly between trials (Cook 2004; Estcourt 2013a; Heddle 2003).
Retrospective analysis of bleeding leads to a risk of bias because bleeding events may be missed, and only more severe bleeding is likely to have been documented. Prospective bleeding assessment forms provide more information and are less likely to miss bleeding events. However, different assessors may grade the same bleed differently and it is very difficult to blind the assessor to the intervention.
The majority of trials have used the WHO system, or a modification of it, for grading bleeding (Estcourt 2013a; Koreth 2004; WHO 1979). One limitation of all the scoring systems that have been based on the WHO system is that the categories are relatively broad and subjective. This means that a small change in a patient's bleeding risk may not be detected. Another limitation is that the modified WHO categories are partially defined by whether a bleeding patient requires a blood transfusion. The threshold for intervention may vary between clinicians and institutions and so the same level of bleeding could be graded differently in different institutions.
The definition of what constitutes clinically significant bleeding has varied between studies. Although the majority of more recent platelet transfusion studies (Heddle 2009a; Slichter 2010; Stanworth 2010; Wandt 2012) now classify it as WHO grade 2 or above, there has been greater heterogeneity in the past (Cook 2004; Estcourt 2013a; Koreth 2004). The difficulties with assessing and grading bleeding may limit the ability to compare results between studies and this needs to be kept in mind when reviewing the evidence for the effectiveness of prophylactic platelet transfusions at different doses.
Why it is important to do this review
Although considerable advances have been made in platelet transfusion therapy in the last 40 years, 3 major areas continue to provoke debate.
Firstly, what is the optimal prophylactic platelet dose to prevent thrombocytopenic bleeding?
Secondly, which threshold should be used to trigger the transfusion of prophylactic platelets?
Thirdly, are prophylactic platelet transfusions superior to therapeutic platelet transfusions for the prevention and/or control of life-threatening thrombocytopenic bleeding?
The initial formulation of this Cochrane review attempted to answer these questions, but there was insufficient evidence available at the time for any definitive conclusions to be drawn (Stanworth 2004). This review was updated (Estcourt 2012a). For clarity and simplicity the review has now been split to answer each question separately.
This review will focus solely on the first question; what is the optimal prophylactic platelet dose to prevent thrombocytopenic bleeding?
Avoiding the need for unnecessary prophylactic platelet transfusions in haematology patients will have significant logistical and financial implications for national health services as well as decreasing patients' exposure to the risks of transfusion. This knowledge is perhaps even more important in the development of platelet transfusion strategies in the developing world where access to blood components is much more limited (Verma 2009).
The previous version of this review showed that there was no difference in the number of patients who developed WHO grade 2 or above bleeding between patients who received a low dose, standard dose or high dose platelet transfusion strategy (Estcourt 2012a). However, it was not able to establish whether there was any difference in the number of days on which bleeding occurred or in the number of patients with severe or life-threatening haemorrhage (WHO grade 3 to 4) between the various platelet dose strategies. A new study has been published since the previous review (Lufa 2011).
This review will not assess the evidence for the answers to the second and third questions as these are the focus of separate Cochrane reviews, nor will it assess use of alternative agents instead of prophylactic platelet transfusions because this is the focus of another review.
This review will not assess whether there are any differences in the efficacy of apheresis versus whole-blood derived platelet products, the efficacy of pathogen-reduced platelet components, the efficacy of HLA-matched versus random donor platelets, or differences between ABO identical and ABO non-identical platelet transfusions. This is because these topics have been covered by recent systematic reviews (Butler 2013; Heddle 2008; Pavenski 2013; Shehata 2009).