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 (HSCT) 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 or 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; Taylor 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).
Prophylactic platelet transfusion threshold
Prophylactic platelet transfusions are typically given when blood platelet counts fall below a given trigger level. Studies compared different platelet count thresholds to trigger the administration of prophylactic platelet transfusions.The current consensus is that patients should receive a platelet transfusion when the platelet count is <10x109/L, unless there are other risk factors for bleeding, such as sepsis, concurrent use of antibiotics or other abnormalities of haemostasis (BCSH 2003; BCSH 2004; Board 2009; NBA 2012; Schiffer 2001; Slichter 2007; Tinmouth 2007). The experimental interventions will be higher or lower platelet transfusion thresholds.
The previous review raised the issue that a platelet count of 10x109/L may not be equivalent to 20x 109/L as previously thought (Estcourt 2012a).
How the intervention might work
Prophylactic platelet threshold
The morning platelet count has traditionally been used to indicate when a patient requires prophylactic platelet transfusions. It became standard practice to transfuse platelets at platelet counts below 20 x 109/L, in an attempt to prevent bleeding (Beutler 1993). This practice was partly based on the findings of non-randomised studies (Gaydos 1962; Slichter 1978) which showed that gross haemorrhage (haematuria, haematemesis and melaena) was present more frequently at platelet counts below 5 x 109/L than when the platelet count was between 5 x 109/L and 100 x 109/L. However, these studies did not clearly support the use of a threshold for prophylactic platelet transfusion of 20 x 109/L, nor was any threshold effect seen (Gaydos 1962; Slichter 1978). A similar pattern of increased bleeding at platelet counts ≤ 5 x 109/l has also been seen in two recent RCTs (Slichter 2010; Wandt 2012).
The routine use of platelet transfusions from the 1970s in patients with haematological malignancies resulted in a decreased mortality rate due to bleeding (less than 1% of patients) (Slichter 1980). Despite the lack of evidence, the widespread use of a threshold platelet count of 20 x 109/L for prophylactic platelet transfusions led to a marked growth in demand for platelet concentrates (Sullivan 2002). This increased demand stimulated research to address whether the threshold could be safely lowered to 10 x 109/L (Rebulla 1997, reviewed in Stanworth 2004). The consensus formulated from these trials was that patients should receive a platelet transfusion when the platelet count is <10 x 109/L, unless there are other risk factors for bleeding, such as sepsis, concurrent use of antibiotics or other abnormalities of haemostasis (Board 2009; BCSH 2003; BCSH 2004; NBA 2012; Schiffer 2001; Slichter 2007; Tinmouth 2007) when the threshold should be raised.
There have been calls for a further reduction in the threshold to 5 x 109/L (BCSH 2003; Gmür 1991) because of the previously-mentioned evidence for an increased rate of bleeding at a platelet count of ≤ 5 x 109/L. However, a major concern in doing this is the reported inaccuracy of current automated counters when the platelet count is very low (Harrison 2001). This was well demonstrated in a large multi-centre study of platelet analyser accuracy when measuring platelet counts < 20 x 109/L (Segal 2005).
Platelet mass has been used as a transfusion trigger for neonatal platelet transfusions (Gerday 2009). Different platelet count thresholds have been the only known trigger used in patients with a haematological disorder.
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 World Health Organization (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.
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 second question: which threshold should be used to trigger the transfusion of prophylactic platelets?
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 blood group 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).