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).
This review does not focus on the absolute need for platelet transfusions in this patient population but will instead focus on whether a prophylactic platelet transfusion policy is required. The standard practice in most haematology units across the developed world is to use prophylactic transfusions, in line with guidelines (Board 2009; BCSH 2003; BCSH 2004; NBA 2012; Schiffer 2001; Slichter 2007; Tinmouth 2007). The experimental intervention will be to give platelet transfusions only when bleeding occurs (therapeutic-only strategy).
How the intervention might work
Prophylactic platelets versus therapeutic-only platelet transfusions
A retrospective review of almost 3000 thrombocytopenic adult patients over a 10-year period showed no relationship between the first morning platelet count, or the lowest platelet count of the day, and the risk of severe or life-threatening bleeding (World Health Organization (WHO) grade 3 to 4 bleeding) (Friedmann 2002). This raised the question as to whether a threshold-defined prophylactic platelet transfusion approach is appropriate. Further large studies have confirmed this finding and also shown no relationship between the morning platelet count and the risk of clinically-significant bleeding (WHO grade 2 bleeding) the following day except at very low platelet counts (≤ 5 x 109/L) (Slichter 2010; Wandt 2012). Further support for the absence of a relationship between the severity of thrombocytopenia and bleeding came from a review of case reports of severe intracranial haemorrhage. No clear evidence was found for an association between the occurrence of major intracranial bleeding and absolute platelet count just prior to the onset of severe bleeding (Stanworth 2005). Thus, the overall benefit of a prophylactic platelet transfusion policy over a policy to use platelets only therapeutically, using a platelet count threshold, has not been established. A recent trial suggested a therapeutic-only platelet transfusion policy might become the new standard of care in selected patients, however the primary endpoint for this study was a reduction in the number of platelet transfusions, rather than a clinical outcome such as bleeding (Wandt 2012). Another large RCT (TOPPS trial) has just been completed and may answer this question (Stanworth 2010; Stanworth 2012).
Assessment of bleeding
A bleeding assessment is a more clinically-relevant measure of the effect of platelet transfusions than surrogate markers such as platelet count 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 are 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 2012; 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.
Why it is important to do this review
Considerable advances have been made in platelet transfusion therapy in the last 40 years, however three 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-only 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). Although the original review was recently updated (Estcourt 2012a), it is now out-dated because two new large studies have recently been completed (Stanworth 2012; Wandt 2012). There is now sufficient additional information regarding these different questions. For clarity and simplicity the review has now been split to answer each question separately.
This review will focus solely on the third question: are prophylactic platelet transfusions superior to therapeutic-only platelet transfusions for the prevention and/or control of life-threatening thrombocytopenic bleeding?
The other two questions will be assessed by two separate reviews, with an additional third review assessing the use of alternative agents instead of prophylactic platelet transfusions.
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).
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. These topics have been covered by recent systematic reviews (Butler 2013; Heddle 2008; Pavenski 2013; Shehata 2009).