Guidelines for the diagnosis and management of aplastic anaemia
2009; Wiley; Volume: 147; Issue: 1 Linguagem: Inglês
10.1111/j.1365-2141.2009.07842.x
ISSN1365-2141
AutoresJudith Marsh, Sarah E. Ball, Jamie Cavenagh, Phil Darbyshire, Inderjeet Dokal, E. C. Gordon‐Smith, Jane Keidan, Andrew D. Laurie, Anna Martín, Jane Mercieca, Sally Killick, R. H. M. Stewart, John A. Liu Yin,
Tópico(s)Hematological disorders and diagnostics
ResumoThe guideline group was selected to be representative of UK-based medical experts, experienced district general hospital haematologists and a patient representative. MEDLINE and EMBASE were searched systematically for publications in English from 2004 to 2008 using key word aplastic anaemia. The writing group produced the draft guideline which was subsequently revised by consensus by members of the General Haematology Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by 59 practising UK haematologists, the BCSH (British Committee for Standards in Haematology) and the British Society for Haematology Committee and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as outlined in appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com/process1.asp#App3) and given at the end of this Guideline as Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with acquired aplastic anaemia. The guidance may not be appropriate to patients with inherited aplastic anaemia and in all cases individual patient circumstances may dictate an alternative approach. Because aplastic anaemia is a rare disease, many of the statements and comments are based on review of the literature and expert or consensus opinion rather than on clinical studies or trials. A previous guideline on the diagnosis and management of aplastic anaemia was published in this journal (Marsh et al, 2003). This guideline is an update of the 2003 guideline and is to replace the 2003 guideline (Marsh et al, 2003). Aplastic anaemia (AA) is a rare but heterogeneous disorder. The majority (70–80%) of these cases are categorised as idiopathic because their primary aetiology is unknown. In a subset of cases, a drug or infection can be identified that precipitates the bone marrow failure/aplastic anaemia, although it is not clear why only some individuals are susceptible. In approximately 15–20% of patients the disease is constitutional/inherited, where the disease is familial and/or presents with one or more other somatic abnormalities. Careful history and clinical examination is important to help exclude rarer inherited forms. A detailed drug and occupational exposure history should always be taken. Any putative drug should be discontinued and should not be given again to the patient. Any possible association of aplastic anaemia with drug exposure should be reported to the Medicines and Healthcare products Regulatory Agency (MHRA) using the Yellow card Scheme. All patients presenting with aplastic anaemia should be carefully assessed to: confirm the diagnosis and exclude other possible causes of pancytopenia with hypocellular bone marrow. classify the disease severity using standard blood and bone marrow criteria. document the presence of associated paroxysmal nocturnal haemoglobinuria (PNH) and cytogenetic clones. Small PNH clones, in the absence of haemolysis, occur in up to 50% of patients with aplastic anaemia and abnormal cytogenetic clones occur in up to 12% of patients with aplastic anaemia in the absence of myelodysplatic syndrome (MDS). exclude a possible late onset inherited bone marrow failure disorder. A multidisciplinary team (MDT) approach to the assessment and management of newly presenting patients is recommended. A specialist centre with expertise in aplastic anaemia should be contacted soon after presentation to discuss a management plan for the patient. Best supportive care Prophylactic platelet transfusions should be given when the platelet count is <10 × 109/l (or <20 × 109/l in the presence of fever). There is no evidence to support the practice of giving irradiated blood components except for patients who are undergoing bone marrow transplantation (BMT). We would recommend empirically that this practice is extended to patients receiving immunosuppressive therapy. Transfusion of irradiated granulocyte transfusions may be considered in patients with life-threatening neutropenic sepsis. The routine use of recombinant human erythropoietin (rHuEpo) in aplastic anaemia is not recommended. A short course of granulocyte colony-stimulating factor (G-CSF) may be considered for severe systemic infection that is not responding to intravenous antibiotics and anti-fungal drugs, but should be discontinued after 1 week if there is no increase in the neutrophil count. Prophylactic antibiotic and antifungal drugs should be given to patients with neutrophil count 1000 μg/l. Definitive treatment Infection or uncontrolled bleeding should be treated first before giving immunosuppressive therapy. This also applies to patients scheduled for BMT, although it may sometimes be necessary to proceed straight to BMT in the presence of severe infection as a BMT may offer the best chance of early neutrophil recovery. Haemopoietic growth factors such as rHuEpo or G-CSF should not be used on their own in newly diagnosed patients in an attempt to ‘treat’ the aplastic anaemia. Prednisolone should not be used to treat patients with aplastic anaemia because it is ineffective and encourages bacterial and fungal infection. Allogeneic BMT from a human leucocyte antigen (HLA)-identical sibling donor is the initial treatment of choice for newly diagnosed patients if they have severe or very severe aplastic anaemia, are 40 years old and (iii) younger patients with severe or very severe disease who do not have an HLA-identical sibling donor. The standard immunosuppressive regimen is a combination of antithymocyte globulin (ATG) and ciclosporin. ATG must only be given as an in-patient. Ciclosporin should be continued for at least 12 months after achieving maximal haematological response, followed by a very slow tapering, to reduce the risk of relapse. The routine use of long term G-CSF, or other haemopoietic growth factors, after ATG and ciclosporin, is not recommended outside the setting of prospective clinical trials. Matched unrelated donor (MUD) BMT may be considered when a patient has severe aplastic anaemia, has no matched sibling donor but a matched unrelated donor, is 20 × 109/l, if possible. It is safe to use ciclosporin in pregnancy. Aplastic anaemia is defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate and with no increase in reticulin. For a comprehensive update on the pathophysiology, the reader is directed to a recent review (Young et al, 2006). These guidelines will focus specifically on idiosyncratic acquired aplastic anaemia, and will not refer to the inevitable and predictable aplasia that occurs after chemotherapy and/or radiotherapy. The incidence of acquired aplastic anaemia in Europe and North America is around 2 per million population per year (Issaragrisil et al, 2006; Montanéet al, 2008). The incidence is 2–3 times higher in East Asia. There is a biphasic age distribution with peaks from 10 to 25 years and >60 years. There is no significant difference in incidence between males and females (Heimpel, 2000). Congenital aplastic anaemia is very rare, the commonest type being Fanconi anaemia, which is inherited as an autosomal recessive disorder in most cases. Patients with aplastic anaemia most commonly present with symptoms of anaemia and skin or mucosal haemorrhage or visual disturbance due to retinal haemorrhage. Infection is a less common presentation. There is no lymphadenopathy or hepatosplenomegaly (in the absence of infection) and these findings strongly suggest another diagnosis (Gordon-Smith, 1991). In children and young adults, the findings of short stature, café au lait spots and skeletal anomalies should alert the clinician to the possibility of a congenital form of aplastic anaemia, Fanconi anaemia, although Fanconi anaemia can sometimes present in the absence of overt clinical signs. Patients with Fanconi anaemia most commonly present between the ages of 3 and 14 years but can occasionally present later in their 30s [up to 32 years in males and 48 years in females reported by Young & Alter, (1994)]. The findings of leucoplakia, nail dystrophy and pigmentation of the skin are characteristic of another inherited form of aplastic anaemia, dyskeratosis congenita, with a median age at presentation of 7 years (range 6 months to 26 years) (Dokal, 2000; Walne & Dokal, 2009). Some affected patients may have none of these clinical features and the diagnosis is made later after failure to respond to immunosuppressive therapy (Vulliamy & Dokal, 2006). A preceding history of jaundice, usually 2–3 months before, may indicate a post-hepatitic aplastic anaemia (Gordon-Smith, 1991; Young & Alter, 1994). Many drugs and chemicals have been implicated in the aetiology of aplastic anaemia, but for only very few is there reasonable evidence for an association from case control studies, and even then it is usually impossible to prove causality (Baumelou et al, 1993; Young & Alter, 1994; Heimpel, 1996; Kauffmann et al, 1996; Issaragrissil et al, 1997), (see Table I). A careful drug history should be obtained, detailing all drug exposures for a period beginning 6 months and ending 1 month prior to presentation (Heimpel, 1996; Kauffmann et al, 1996). If at presentation the patient is taking several drugs which may have been implicated in aplastic anaemia, even if the evidence is based on case report(s) alone, then all the putative drugs should be discontinued and the patient should not be re-challenged with the drugs at a later stage after recovery of the blood counts. The MHRA should be informed using the Yellow Card Scheme on every occasion that a patient presents with aplastic anaemia where there is a possible drug association (website: http://www.yellowcard.gov.uk). Similarly, a careful occupational history of the patient may reveal exposure to chemicals or pesticides that have been associated with aplastic anaemia, as summarised in Table II. Aplastic anaemia is a rare disorder. Most cases are idiopathic, but careful history and clinical examination is important to identify rarer inherited forms. Although most cases of aplastic anaemia are idiopathic, a careful drug and occupational exposure history should be taken. Any putative drug should be discontinued and should not be given again to the patient. Any possible association of aplastic anaemia with drug exposure should be reported to the MHRA using the Yellow card Scheme. The following investigations are required to (i) confirm the diagnosis (ii) exclude other possible causes of pancytopenia with a hypocellular bone marrow (iii) exclude inherited aplastic anaemia (iv) screen for an underlying cause of aplastic anaemia and (v) document or exclude a co-existing abnormal cytogenetic clone or a PNH clone. See Table III for a summary of investigations required for the diagnosis of aplastic anaemia. The full blood count (FBC) typically shows pancytopenia although usually the lymphocyte count is preserved. In most cases the haemoglobin level, neutrophil and platelet counts are all uniformly depressed, but in the early stages isolated cytopenia, particularly thrombocytopenia, may occur. Anaemia is accompanied by reticulocytopenia, and macrocytosis is commonly noted. Careful examination of the blood film is essential to exclude the presence of dysplastic neutrophils and abnormal platelets, blasts and other abnormal cells, such as hairy cells (as seen in hairy cell leukaemia). The monocyte count may be depressed but the absence of monocytes should alert the clinician to a possible diagnosis of hairy cell leukaemia. In aplastic anaemia, anisopoikilocytosis is common and neutrophils may show toxic granulation. Platelets are reduced in number and mostly of small size. Fetal haemoglobin (HbF) should be measured pre-transfusion in children as this is an important prognostic factor in paediatric myelodysplastic syndrome (MDS) which may feature in the differential diagnosis of pancytopenia in children. Both a bone marrow aspirate and trephine biopsy are required. Bone marrow aspiration and biopsy may be performed in patients with severe thrombocytopenia without platelet support, providing that adequate surface pressure is applied (Kelsey et al, 2003). Fragments are usually readily obtained from the aspirate. Difficulty obtaining fragments should raise the suspicion of a diagnosis other than aplastic anaemia. The fragments and trails are hypocellular with prominent fat spaces and variable amounts of residual haemopoietic cells. Erythropoiesis is reduced or absent, dyserythropoiesis is very common and often marked, so this alone should not be used to make a diagnosis of MDS. Megakaryocytes and granulocytic cells are reduced or absent; dysplastic megakaryocytes and granulocytic cells are not seen in aplastic anaemia. Lymphocytes, macrophages, plasma cells and mast cells appear prominent. In the early stages of the disease, one may also see prominent haemophagocytosis by macrophages, as well as background eosinophilic staining representing interstitial oedema. A trephine is crucial to assess overall cellularity, to assess the morphology of residual haemopoietic cells and to exclude an abnormal infiltrate. In most cases the trephine is hypocellular throughout but sometimes it is patchy, with hypocellular and cellular areas. Thus, a good quality trephine of at least 2 cm is essential. A ‘hot spot’ in a patchy area may explain why sometimes the aspirate is normocellular. Care should be taken to avoid tangential biopsies as subcortical marrow is normally ‘hypocellular’. Focal hyperplasia of erythroid or granulocytic cells at a similar stage of maturation may be observed. Sometimes lymphoid aggregates occur, particularly in the acute phase of the disease or when the aplastic anaemia is associated with systemic autoimmune disease, such as rheumatoid arthritis or systemic lupus erythematosus. The reticulin is not increased and no abnormal cells are seen. Increased blasts are not seen in aplastic anaemia, and their presence either indicates a hypocellular MDS or evolution to leukaemia (Marin, 2000; Tichelli et al, 1992; Bennett & Orazi, 2009). To define aplastic anaemia there must be at least two of the following (i) haemoglobin <100 g/l (ii) platelet count <50 × 109/l (iii) neutrophil count <1·5 × 109/l (International Agranulocytosis and Aplastic Anaemia Study Group, 1987). The severity of the disease is graded according to the blood count parameters and bone marrow findings as summarised in Table IV (Camitta et al, 1975; Bacigalupo et al, 1988). However, because of routine and more accurate automated reticulocyte counting, this will over-estimate the level of reticulocyte count used in the historical Camitta criteria (Camitta et al, 1975) for defining disease severity. The assessment of disease severity is important in treatment decisions but has less prognostic significance today in terms of correlation with response to ATG treatment (Scheinberg et al, 2009). Patients with bi-or tri-lineage cytopenias that are less severe than this are not classified as aplastic anaemia. However, they should have their blood counts monitored to determine whether they will develop aplastic anaemia with time. Liver function tests should be performed to detect antecedent hepatitis, but in post-hepatitic aplastic anaemia the serology is most often negative for all the known hepatitis viruses. The onset of aplastic anaemia occurs 2–3 months after an acute episode of hepatitis and is more common in young males (Brown et al, 1997). Blood should be tested for hepatitis A antibody, hepatitis B surface antigen, hepatitis C antibody and Epstein–Barr virus (EBV). Cytomegalovirus (CMV) and other viral serology should be assessed if BMT is being considered. Parvovirus causes red cell aplasia but not aplastic anaemia. Human immunodeficiency virus (HIV) is not a recognised cause of aplastic anaemia, but it can cause isolated cytopenias. We would recommend that prior to a diagnosis of aplastic anaemia, appropriate investigations to exclude alternative aetiologies of cytopenias (B12, red cell folate and HIV) should be performed. Vitamin B12 and folate levels should be measured to exclude megaloblastic anaemia which, when severe, can present with pancytopenia. If a deficiency of B12 or folate is documented, this should be corrected before a final diagnosis of aplastic anaemia is confirmed. Bone marrow aplasia due to vitamin deficiency is exceedingly rare. The occurrence of pancytopenia in systemic lupus erythematosus may (i) be autoimmune in nature occurring with a cellular bone marrow or (ii) be associated with myelofibrosis or rarely (iii) occur with a hypocellular bone marrow. Blood should be tested for anti-nuclear antibody and anti-DNA antibody in all patients presenting with aplastic anaemia. Paroxysmal nocturnal haemoglobinuria should be excluded by performing flow cytometry (Dacie & Lewis, 2001; Parker et al, 2005). The Ham test and sucrose lysis test have been abandoned by most centres as diagnostic tests for PNH. Analysis of glycosylphosphatidylinositol (GPI)-anchored proteins, such as CD55 and CD59 by flow cytometry, is a sensitive and quantitative test for PNH enabling the detection of small PNH clones which occur in up to 50% of patients with aplastic anaemia, the proportion depending on the sensitivity of the flow cytometric analysis used (Dunn et al, 1999; Socie et al, 2000; Sugimori et al, 2005). Such small clones are most easily identified in the neutrophil and monocyte lineages in aplastic anaemia and will be detected by flow cytometry and not by the Ham test. If the patient has had a recent blood transfusion, the Ham test may be negative whereas a population of GPI-deficient red cells may still be detected by flow cytometry. However, the clinical significance of a small PNH clone in aplastic anaemia as detected by flow cytometry remains uncertain. Such clones can remain stable, diminish in size, disappear or increase. What is clinically important is the presence of a significant PNH clone with clinical or laboratory evidence of haemolysis. Urine should be examined for haemosiderin to exclude intravascular haemolysis which is a constant feature of haemolytic PNH. Evidence of haemolysis associated with PNH should be quantified with the reticulocyte count, serum bilirubin, serum transaminases and lactate dehydrogenase (LDH). Cytogenetic analysis of the bone marrow should be attempted although this may be difficult in a very hypocellular bone marrow and often insufficient metaphases are obtained. In this situation, one should consider fluorescence in situ hybridization (FISH) analysis for chromosomes 5 and 7 in particular. It was previously assumed that the presence of an abnormal cytogenetic clone indicated a diagnosis of MDS and not aplastic anaemia, but it is now evident that abnormal cytogenetic clones may be present in up to 12% of patients with otherwise typical aplastic anaemia at diagnosis (Appelbaum et al, 1989; Tichelli et al, 1996; Gupta et al, 2006). The presence of abnormal cytogenetics at presentation in children, especially monosomy 7, should alert to the likelihood of MDS. Abnormal cytogenetic clones may also arise during the course of the disease (Socie et al, 2000). The management of a patient with aplastic anaemia who has an abnormal cytogenetic clone is discussed in Section 9. Peripheral blood lymphocytes should be tested for spontaneous and diepoxybutane (DEB) or mitomycin C (MMC)-induced chromosomal breakage to identify or exclude Fanconi anaemia. This should be performed in all patients who are BMT candidates. Siblings of Fanconi anaemia patients should also be screened. For all other patients, it is difficult to set an upper age limit for Fanconi anaemia screening because the age at diagnosis may sometimes occur in the fourth decade, and rarely in the fifth decade, of life (Alter, 2007). Dyskeratosis congenita may be excluded by identifying a known mutation but there are probably many mutations yet to be identified (Vulliamy et al, 2005; Walne & Dokal, 2009). Along with measuring telomere lengths, this is not currently available as a routine clinical service. A chest X-ray is useful at presentation to exclude infection and for comparison with subsequent films. Routine X-rays of the radii are no longer indicated as all young patients should have peripheral blood chromosomes analysed to exclude a diagnosis of Fanconi anaemia. Abdominal ultrasound: the findings of an enlarged spleen and/or enlarged lymph nodes raise the possibility of a malignant haematological disorder as the cause of the pancytopenia. In younger patients, abnormal or anatomically displaced kidneys are features of Fanconi anaemia. The above investigations should exclude causes of a hypocellular bone marrow with pancytopenia other than aplastic anaemia. These include: Hypocellular MDS/acute myeloid leukaemia (AML) can sometimes be difficult to distinguish from aplastic anaemia. The following features of MDS are not found in aplastic anaemia: dysplastic cells of the granulocytic and megakaryocytic lineages, blasts in the blood or marrow (Tuzuner et al, 1995; Jaffe et al, 2001; Bennett & Orazi, 2009). In trephine specimens, increases in reticulin associated with residual areas of haemopoiesis suggest hypocellular MDS rather than aplastic anaemia. The presence of abnormal localisation of immature precursors (ALIPs) is difficult to interpret in this context because small collections of immature granulocytic cells may be seen in the bone marrow in aplastic anaemia when regeneration occurs. As discussed previously, dyserythropoiesis is very common in aplastic anaemia. Hypocellular acute lymphoblastic leukaemia (ALL) occurs in 1–2% of cases of childhood ALL. Overt ALL usually develops within 3–9 months of the apparent bone marrow failure. In contrast to aplastic anaemia, the neutropenia is usually more pronounced than the thrombocytopenia and sometimes there is an increase in reticulin within the hypocellular bone marrow (Chessells, 2001). Immunophenotyping may help confirm the diagnosis. Treatment should not be deferred in severe aplastic anaemia in children just in case they turn out to have ALL. For all new paediatric cases of aplastic anaemia, a national central morphology review is planned under the aegis of the Medical Research Council Childhood Leukaemia Working Party Subgroup for rare haematological diseases. Hairy cell leukaemia classically presents with pancytopenia but the accompanying monocytopenia is a constant feature of this disorder. It is usually difficult or impossible to aspirate on bone marrow fragments. In addition to the typical interstitial infiltrate of hairy cells with their characteristic ‘fried egg’ appearance in the bone marrow trephine, there is always increased reticulin. Immunophenotyping reveals CD20+, CD11c+, CD25+, FMC7+, CD103+ tumour cells that are typically CD5−, CD10− and CD23−. Although splenomegaly is a common finding in hairy cell leukaemia, it may be absent in 30–40% of cases. Lymphomas, either Hodgkin lymphoma or non-Hodgkin lymphoma and myelofibrosis may sometimes present with pancytopenia and a hypocellular bone marrow. The bone marrow biopsy should be examined very carefully for foci of lymphoma cells or fibrosis which may be seen in only a small part of the trephine. Since lymphocytes are often prominent in aplastic anaemia, immunophenotyping should be performed. Myelofibrosis is usually accompanied by splenomegaly and the absence of an enlarged spleen in the presence of marrow fibrosis should alert one to secondary malignancy. Marker studies and gene rearrangement studies will help to confirm the diagnosis of lymphoma. Mycobacterial infections can sometimes present with pancytopenia and a hypocellular bone marrow, this is seen more commonly with atypical mycobacteria. Other bone marrow abnormalities include granulomas, fibrosis, marrow necrosis and haemophagocytosis. Demonstrable acid alcohol fast bacilli (AAFB) and granulomas are often absent in Mycobacterium tuberculosis infection. AAFB are more frequently demonstrated in atypical mycobacterial infections where they are often phagocytosed by foamy macrophages. The bone marrow aspirate should be sent for AAFB culture if tuberculosis is suspected (Bain et al, 2001). Anorexia nervosa or prolonged starvation may be associated with pancytopenia. The bone marrow may show hypocellularity and gelatinous transformation (serous degeneration/atrophy) with loss of fat cells as well as haemopoietic cells, and increased ground substance which stains a pale pink on haematoxylin/eosin stain (Bain et al, 2001). The pink ground substance may also be seen as on an May–Grünwald–Giemsa stained aspirate. Some degree of fat change may also be seen in aplastic anaemia, especially early in its evolution. Occasionally aplastic anaemia can present with an isolated thrombocytopenia, and pancytopenia develops later. Such patients can initially be misdiagnosed as autoimmune immune thrombocytopenia (ITP) but bone marrow examination in aplastic anaemia shows hypocellularity with reduced or absent megakaryocytes, which is not seen in ITP. A recent comprehensive review on aplastic anaemia in children discusses in more detail conditions that may present with pancytopenia and a hypocellular bone marrow in children (Davies & Guinan, 2007). A MDT meeting approach is recommended to collate relevant results and develop a treatment plan. Consideration should also be given to review of blood and bone marrow slides by a specialist centre, especially if there are unusual morphological features or where there is any doubt about the diagnosis. All new patients presenting with aplastic anaemia should be carefully assessed to: confirm the diagnosis and exclude other possible causes of pancytopenia with hypocellular bone marrow classify the disease severity using standard blood and bone marrow criteria document the presence of associated PNH and cytogenetic clones exclude a possible late onset inherited bone marrow failure disorder A MDT approach to the above assessment is recommended and also to formulate an appropriate management plan for the patient. If there is doubt about the diagnosis and/or management plan, referral of the case for specialist advice and/or review of the blood and bone marrow morphology slides at a specialist centre, is encouraged. Support with red cell and platelet transfusions is essential for patients with aplastic anaemia to maintain a safe blood count. It is recommended to give prophylactic platelet transfusions when the platelet count is <10 × 109/l (or <20 × 109/l in the presence of fever) (Grade C recommendation; level IV evidence), rather than giving platelets only in response to bleeding manifestations (Kelsey et al, 2003). Prediction of bleeding is difficult in an individual patient. Fatal haemorrhage, usually cerebral, is more common in patients who have <10 × 109/l platelets, extensive retinal haemorrhages, buccal haemorrhages or rapidly spreading purpura. However, cerebral haemorrhage may be the first major bleed in patients who have none of these other bleeding manifestations (Gordon-Smith, 1991). For invasive and surgical procedures, platelet transfusion(s) must be given to achieve appropriate levels as recommended by BCSH guidelines, and a pre-procedure platelet count checked to ensure that level has been achieved. A common problem in multi-transfused patients with aplastic anaemia, compared with leukaemia patients, is that they may develop alloimmunisation to leucocytes present in red cell and platelet transfusions by generating HLA or non-HLA (minor histocompatibility) antibodies. This can result in platelet refractoriness, as well as an increased risk of graft rejection after allogeneic BMT (Kaminsky et al, 1990). Routine pre-storage leucocyte depletion of all units of red cells and platelets in the UK is likely to reduce the risk of alloimmunisation (Killick et al, 1997; Ljungman, 2000). In a retrospective, single centre study, the incidence of HLA alloimmunisation was reported to be 50% in patients with aplastic anaemia who had received blood products prior to the introduction of pre-storage leucocyte depletion in the UK compared with only 12% for patients who received only leucocyte depleted blood products (Killick et al, 1997). Patients who become refractory to platelet transfusions should be screened for HLA antibodies. However, other causes of platelet refractoriness, such as infection and drugs, should be excluded. If a patient does become sensitised to random donor platelets resulting in platelet refractoriness, HLA-matched platelets should be
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