Description of the condition

The bone marrow is the site of the production of red cells, white cells, and platelets from stem cells (termed collectively as haematopoiesis). Bone marrow failure disorders encompass a wide range of diseases that cause quantitative (reduced numbers (cytopenia)) or qualitative (reduced function) defects of red cells, white cells, and platelets.

Clinical symptoms of people with bone marrow failure disorders are related to the underlying cytopenias (anaemia, neutropenia, and thrombocytopenia) that arise from this ineffective haematopoiesis. People can present with fatigue and shortness of breath due to anaemia (low red cell count), recurrent infections due to neutropenia (low neutrophil count, a type of white cell), and bleeding or bruising due to thrombocytopenia (low platelet count). Although anaemia is the most common cytopenia, at least one‐third of people with conditions like myelodysplastic syndromes (MDS) have moderate or severe thrombocytopenia (Hellstrom‐Lindberg 2003). Symptoms due to thrombocytopenia depend not only on the severity of the thrombocytopenia but also any associated comorbidities (coagulation abnormalities or lesions that are more likely to bleed, e.g. peptic ulcer).

Bone marrow failure syndromes can be broadly classified into congenital and acquired disorders.

The most common causes of acquired bone marrow failure are aplastic anaemia and MDS, with MDS being the most commonly diagnosed acquired bone marrow failure in adults (Sekeres 2010).

Myelodysplastic syndromes encompass a diverse group of clonal stem cell disorders that are characterised by dysplasia in one or more cell lines (blood cells have an abnormal shape or size), ineffective haematopoiesis, development of peripheral cytopenias, and an increased risk of developing acute myeloid leukaemia (AML) (Steensma 2006). Overall, the incidence of MDS is estimated at between 2.3 to 4.5 per 100,000 per year (Dinmohamed 2014; Garcia‐Manero 2012; Ma 2007; Ma 2012; Neukirchen 2011). However, the incidence increases markedly with age, with the highest incidence in those aged over 80 years (> 30 per 100,000 per year) (Dinmohamed 2014; Ma 2007; Ma 2012; Neukirchen 2011; Rollison 2008). It is also estimated that the incidence of secondary myelodysplasia is increasing because there are a larger number of long‐term cancer survivors who have been treated with chemotherapy such as anthracyclines and etoposide, which increase the risk of developing myelodysplasia (Le Deley 2007).

Acquired aplastic anaemia is a rare disorder that is characterised by 'empty bone marrow' replaced by fat cells. The incidence in Europe and North America is about two per million population per year (Issaragrisil 2006; Montané 2008), whereas the incidence in Asia is higher, with estimates ranging from 3.9 to 7.4 cases per million per year (Young 2008). In most cases the cause is unknown, but environmental factors (industrial chemicals, agricultural pesticides) (Issaragrisil 2006; Young 2008), drugs (Issaragrisil 2006; Young 2008), and hepatitis viruses have been reported to cause aplastic anaemia (Rauff 2011). Treatment is tailored to the individual needs of the patient, but involves a combination of supportive care for pancytopenia (reduced numbers of all the cellular elements of blood) (red cell and platelet transfusions, prophylactic antimicrobials), immunosuppressive therapy, and haemopoietic stem cell transplantation. Most patients are not deemed suitable for a haemopoietic stem cell transplant owing to advanced age, comorbidities, or lack of a compatible donor. As a result, supportive management remains the mainstay of treatment.

The inherited bone marrow failure syndromes include Fanconi anaemia, dyskeratosis congenita, Shwachman‐Diamond syndrome, Pearson syndrome, congenital amegakaryocytic thrombocytopenia, familial aplastic anaemia (X‐linked and autosomal forms), and Diamond Blackfan anaemia (Shimamura 2009). Fanconi anaemia is the most common inherited bone marrow failure disorder, with a reported incidence of approximately 1 in 360,000 live births and a carrier frequency of 1 in 300 (Giri 2004). Haematopoietic stem cell transplantation is the definitive treatment in many of these disorders, but supportive therapy in terms of red cell and platelet transfusions is often needed for symptomatic relief, either prior to transplant, or for those people not suitable to undergo transplant.

Description of the intervention

Despite increasing knowledge about the biology of the underlying diseases, supportive management remains the mainstay of treatment for most people with chronic bone marrow failure disorders.

Platelet transfusions are used in modern clinical practice to prevent and treat bleeding in people with thrombocytopenia. Platelet transfusions have an obvious beneficial effect in the management of active bleeding in people with severe thrombocytopenia. However, questions still remain on how this limited resource should be used to prevent severe and life‐threatening bleeding. Prophylactic platelet transfusions have been shown to reduce World Health Organization (WHO) Grade 2 or above bleeding in people with haematological malignancies receiving chemotherapy or an allogeneic haematopoietic stem cell transplant (Crighton 2015; Stanworth 2013; Wandt 2012).

The evidence for the use of platelet transfusions to prevent bleeding in people with other conditions is less clear‐cut (Schiffer 2013; Stanworth 2013; Stanworth 2014; Wandt 2012). International guidelines considering people with long‐term thrombocytopenia recommend either a therapeutic‐only strategy (platelet transfusions are given to treat bleeding) (Kaufman 2015; Killick 2014; Liumbruno 2009), or a prophylactic platelet transfusion strategy (platelet transfusions are given when the platelet count falls below a prespecified platelet count threshold) (German Medical Association 2014; Killick 2016; NBA 2012; Zeller 2016). This threshold is most commonly a platelet count of 5 x 10⁹/L, German Medical Association 2014, or 10 x 10⁹/L (Bosly 2007; Killick 2016). This threshold can also vary if a person has additional risk factors for bleeding such as sepsis (Killick 2016).

People can become refractory to platelet transfusions (Stanworth 2015). 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 the patient developed detectable human leukocyte antigen (HLA) antibodies (Slichter 2005). Avoidance of unnecessary prophylactic platelet transfusions is therefore very important in people who are likely to require repeated platelet transfusions over a prolonged period of time because they can become refractory to treatment after repeated transfusions (Hod 2008; Slichter 2005; Stanworth 2015).

Platelet transfusions are associated with adverse events. Mild to moderate reactions to platelet transfusions include rigor, fever, and urticaria (Tinegate 2012). These reactions are not life‐threatening but can be extremely distressing for the recipient. Rarer, but more serious sequelae include anaphylaxis, haemolytic transfusion reactions, transfusion‐transmitted infections, transfusion‐associated circulatory overload (TACO), and transfusion‐related acute lung injury (TRALI) (Blumberg 2010; Kaufman 2015; Raval 2015).

This review does not focus on the absolute need for platelet transfusions in people with chronic bone marrow failure disorders, but instead focuses on whether a prophylactic platelet transfusion policy is required.

How the intervention might work

The morning platelet count is usually used to indicate when a person requires a prophylactic platelet transfusion. In the 1970s 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 based partly on the findings of non‐randomised studies that showed that gross haemorrhage (haematuria (blood in the urine), haematemesis (vomiting of blood), and melaena (dark‐coloured stools)) was present at platelet counts below 5 x 10⁹/L more frequently than when the platelet count was between 5 x 10⁹/L and 100 x 10⁹/L (Gaydos 1962; Slichter 1978). However, these studies did not show any threshold effect at a platelet count of 20 x 10⁹/L, nor was any threshold effect seen (Gaydos 1962; Slichter 1978). A threshold of 10 x 10⁹/L is now considered the standard platelet count threshold in people with haematological malignancies who have reversible bone marrow failure (Estcourt 2015; Kaufman 2015; NICE 2015), after multiple studies confirmed the threshold of 10 x 10⁹/L as "safe enough" for prophylactic platelet transfusion (Gmur 1991; Rebulla 1997; Schiffer 2001; Wandt 1998).

There is much less evidence for the benefit of prophylactic platelet transfusions for people with chronic bone marrow failure. A small retrospective study considered platelet transfusion in outpatients with stable chronic severe aplastic anaemia (Sagmeister 1999). Prophylactic platelets were given if the count was 5 x 10⁹/L or less. In total, 55,239 patient days were reviewed with 18,706 days when the platelet count was 10 x 10⁹/L or less. Three major bleeding episodes occurred while participants were on the treatment protocol. The authors concluded that this restrictive policy, with a median transfusion interval of seven days, was feasible, safe, and economical.

Only 7.1 x 10⁹/L platelets per day are required to maintain vascular integrity, and hence spontaneous bleeding in clinically stable patients is uncommon unless the platelet count is less than 5 x 10⁹/L (Slichter 2004). A further large study also showed no relationship between the morning platelet count and the risk of clinically significant bleeding (WHO Grade 2 bleeding) the following day except when the platelet count was very low (≤ 5 x 10⁹/L) (Slichter 2010).

A large retrospective review of almost 3000 adults with thrombocytopenia showed no relationship between the morning platelet count or the lowest platelet count of the day and the risk of severe or life‐threatening bleeding (WHO Grade 3 to 4 bleeding) (Friedmann 2002). This raised the question as to whether a threshold‐defined prophylactic platelet transfusion approach is appropriate.

Most recent clinical trials of platelet transfusions have used bleeding as an outcome. An assessment of bleeding is a more clinically relevant measure of the effect of platelet transfusions than surrogate markers such as the platelet count increment. The definition of what constitutes clinically significant bleeding has varied between studies. Although the majority of more recent platelet transfusion studies now classify it as WHO Grade 2 or above, there has been greater heterogeneity in the past (Estcourt 2013; 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 difficulties with assessing and grading bleeding may limit the ability to compare results between studies, which should be kept in mind when interpreting the evidence for the effectiveness of prophylactic platelet transfusions in this review.

Why it is important to do this review

Blood products including platelet components are a valuable and finite resource, and their availability depends on the goodwill of voluntary donations. Also, platelet components have a limited shelf life of five to seven days, which makes management of platelet inventories difficult and resource intensive (Fuller 2011; Riley 2012).

As discussed above, the recommended platelet count threshold varies significantly from country to country (German Medical Association 2014; Kaufman 2015; Killick 2014; Killick 2016; Liumbruno 2009). This indicates significant uncertainty among clinicians regarding the correct management of people with chronic bone marrow disorders.

This review aimed to provide evidence of whether a therapeutic‐only platelet transfusion strategy is as effective and safe as a prophylactic platelet transfusion strategy for the prevention of clinically significant or life‐threatening bleeding in people with primary bone marrow failure disorders who are thrombocytopenic.

Overall, avoiding the need for unnecessary prophylactic platelet transfusions in people with bone marrow failure disorders will have significant logistical and financial implications for national health services as well as decreasing patients’ exposure to the risks of transfusion. It will also have implications on the quality of life of patients, as it is challenging for patients and caregivers to visit hospital on a regular basis to receive platelet transfusions. The outcomes of this review are 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).