Mark K. Fung1 & Nancy M. Heddle2
1Department of Pathology, University of Vermont and Fletcher Allen Health Care, Burlington, Vermont, USA
2Department of Medicine, McMaster University and Canadian Blood Services, Hamilton, Canada
Febrile and allergic reactions are the most common acute adverse events that occur during or following the transfusion of blood components. Signs and symptoms typical of these reactions can also be associated with other types of transfusion reactions and/or caused by treatments and medications that the patient may be receiving as well as comorbidities; hence, to establish causation and an appropriate management strategy can be challenging. In this chapter, febrile nonhaemolytic transfusion reactions (FNHTRs) and both mild and severe forms of allergic reactions will be discussed.
Febrile nonhaemolytic transfusion reactions
Clinical presentation
The classical definition of an FNHTR includes fever (usually defined as ≥1°C rise in temperature) during or within 2 hours of completing the transfusion, along with other symptoms that can include a cold feeling, chills and a generalized feeling of discomfort. Less frequently headache, nausea and vomiting may also occur and in severe reactions rigors can be present. Although this is the classical definition, in practice only 15% of patients develop a fever, with chills, cold and discomfort being the primary findings [1].
Differential diagnosis
Unfortunately, these symptoms are not specific for an FNHTR. The challenge for the transfusing physician is to consider the other possibilities as part of the differential diagnosis and to develop a systematic approach for establishing a definitive diagnosis. When a patient presents with fever, the differential diagnosis should include:
· FNHTR;
· acute haemolytic reactions;
· delayed haemolytic reactions;
· bacterial contamination;
· transfusion-related acute lung injury (TRALI);
· acute pain reactions;
· comorbid conditions; and
· medications.
Although all of these reactions can be associated with fever, it is especially important to rule out acute haemolysis, bacterial contamination and TRALI, as these conditions can frequently be associated with morbidity and mortality unless rapidly recognized and treated. Bacterial contamination and TRALI also have implications for donor management and handling of other components prepared from the implicated donation, emphasizing the importance of considering these types of reactions in the differential diagnosis (see Chapters 9 and 14). In contrast, FNHTRs cause discomfort and distress, although not long-term morbidity, for the patient and consume additional healthcare resources for their treatment and investigation. Preliminary data were recently published suggesting that patients who experience FNHTR may be more likely to develop red cell alloimmunization. The hypothesis to explain this observation is that cytokines involved in causing FNHTR may alter the immune system towards a Th2 response to foreign red cell antigens, resulting in an increased risk of alloimmunizations [2]. Although this hypothesis needs to be confirmed, it illustrates the potential for secondary sequelae to be associated with FNHTR, emphasizing the importance of preventing this adverse event.
To further complicate the investigative process in patient populations where transfusion-associated fever occurs frequently, e.g. in haematology/oncology patients, clinical judgement should be incorporated into the decision-making process.
Frequency
The frequency of FNHTRs varies with the:
· patient population;
· type of blood components being transfused;
· age of the blood component.
Reactions to platelets occur more frequently than reactions to red cells. However, precise estimates of FNHTR associated with platelet transfusions are difficult as milder reactions are likely to be underreported. In a general hospital population, FNHTRs to red cells occur with 0.04–0.44% of transfusions, while the frequency of reactions to platelets is higher, ranging from 0.06 to 2.2%. In specific patient populations such as adult haematology/oncology patients, reactions to platelets are even more common, occurring in up to 37% of transfusions if non-leucocyte-reduced platelets are used [1]. When pre-storage leucocyte-reduced platelets are transfused, the frequency of acute reactions decreases dramatically (<2% of transfusions) [3]. In paediatric ICU patients 1.6% of blood components transfused (40/2509) were associated with acute reactions, with FNHTR accounting for 60% (24/40) of these events [4]. FNHTRs to blood components other than red cells and platelets are rare and there are limited data to estimate their frequency.
Pathogenesis
The pathogenesis of FNHTRs is multifactorial and varies for red cells and platelets. Our current understanding of the mechanisms causing these reactions with red cells and platelets are summarized below.
· Antibody mechanism. Patients' plasma contains a leucocyte antibody that reacts with leucocytes present in the blood component. An antigen–antibody reaction occurs, resulting in the release of endogenous pyrogens/cytokines by the donor leucocytes. These biological response modifiers act on the hypothalamus to cause fever. This antigen–antibody hypothesis is believed to be the primary mechanism causing FNHTRs to red cells, but probably accounts for less than 10% of FNHTRs to platelets [1].
· Leucocyte/platelet-derived biological response modifiers. During storage of the blood component, proinflammatory cytokines (interleukin 1 (IL-1), interleukin 6 (IL-6) and tumour necrosis factor α (TNFα)) are released from leucocytes present in the blood component. This typically happens when the component is stored at room temperature. Cytokines accumulate to high levels by the end of the product storage period and, when infused, cause fever by stimulation of the hypothalamus. This is the primary mechanism responsible for FNHTRs to platelets. Platelets are stored at room temperature for a maximum of 5 days and have high cytokine concentrations at the end of the storage period if contaminating leucocytes are present [5]. Platelet-derived cytokines such as CD40 ligand (sCD40L) and RANTES also accumulate in stored platelets and may play a role in some reactions. When the receptor for CD40L is engaged, proinflammatory cytokines are synthesized (IL-6, IL-8, monocyte chemotactic protein-1 (MCP-1)). One study suggested an incremental effect where reactions were more frequent when high levels of multiple biological response mediators were present [6]. There are over 15 different cytokines that have been shown to accumulate in platelet products during storage.
· Other biological response modifiers (BRMs). Other BRMs such as complement and neutrophil priming lipids have been detected in some stored blood components and it is hypothetically possible that they may cause or contribute to FNHTRs in some patients. However, there are no clinical data linking these substances to an increased risk of an adverse event [1].
Patient susceptibility
Patient factors may also play a role in susceptibility to FNHTRs. Reactions caused by leucocyte antibodies may be more common in females due to leucocyte antibody formation during pregnancy. Patients whose disease or treatments result in an inflammatory response may also be more likely to have reactions as the additive effect of transfusion-related cytokines may be sufficient to cause the symptoms and signs of FNHTRs. Recent data also suggests that certain gene polymorphisms may result in an increase in inflammatory cytokine gene expression, resulting in an increased susceptibility to FNHTR. One genotype that has been shown to increase susceptibility for FNHTRs is IL1RN*2.2 [7].
Management of FNHTRs
The management of FNHTRs includes the exclusion of other causes of fever. However, the management strategy requires clinical judgement and must balance the benefits and risks of their investigation and treatment. The following questions should be considered.
· Is the blood component leucocyte reduced? The risk of an FNHTR in a setting where all red cell and platelet components are universally pre-storage leucocyte reduced is low (see above). In this latter situation, stopping the transfusion and investigating every reaction not only consumes significant healthcare resources but may put patients at risk as they may not receive the required components in a timely manner.
· Does the patient have a history of FNHTRs? Some patients are susceptible to repeated FNHTRs when blood components are transfused, e.g. because of the presence of leucocyte antibodies; hence the patient's history of reaction should be considered.
· If a temperature increase occurred, was it greater than or equal to 2°C? It is very uncommon for the temperature to rise more than 2°C with an FNHTR. In this situation, bacterial contamination should be suspected, the transfusion should be stopped immediately and appropriate investigations initiated.
· Would you describe the patient's signs and symptoms as mild, moderate or severe? If the symptoms are mild, a less aggressive management approach may be initiated but careful observation of the patient is essential. If the symptoms are severe, the transfusion should be stopped immediately and supportive care given to the patient. Investigations to rule out other possible causes of the reaction should be initiated. If the clinical findings are categorized as moderate, the questions above need to be considered and clinical judgement is required as to how patient management should proceed.
Finally, the management strategy for FNHTRs associated with red cell transfusions should include an approach to rule out an acute haemolytic transfusion reaction. Haemolysis following platelet transfusion is rare but can occur when the plasma of the platelet product contains a high titre ABO antibody that reacts with the patient's red cells.
The management approach should also aim to alleviate the signs and symptoms associated with an FNHTR. This may involve temporary discontinuation of the transfusion while antipyretic medication is administered to the patient. Medications should never be injected into the blood component. In most cases, the transfusion can be resumed once the signs and symptoms subside. There is some evidence that pethidine (or meperidine in North America) is effective treatment for alleviating rigors associated with transfusions.
A conservative strategy for minimizing the risk to patients while investigating reactions would include the following steps:
· Temporarily stop the transfusion but keep the line open with saline.
· Perform a bedside clerical check between the blood and the patient to ensure that the right blood has been transfused.
· Observe the blood component to determine if there is discoloration or particulate matter present.
· Notify the blood transfusion laboratory and send appropriate samples if laboratory investigations are deemed necessary to rule out other causes of acute reactions with fever.
Prevention of FNHTRs
As the pathogenesis of FNHTRs is different for red cells and platelet transfusions, the strategy for their prevention also depends on the blood component being transfused.
Red cells
Since most reactions are caused by the leucocyte antigen–antibody mechanism, the primary way to prevent these reactions is to reduce the number of leucocytes in the red cell component. Prevention can be accomplished for most patients by removing approximately one log of leucocytes to a level of less than or equal to 108 leucocytes/unit of red cells. This can be achieved by post-storage filtration, centrifugation with buffy coat removal (either during the manufacturing process or post-storage) or pre-storage filtration during the component preparation phase. Filtration (pre- or post-storage) using current leucocyte reduction filters results in red cell products with less than 106leucocytes, which is well below the threshold needed to prevent most FNHTRs. If a patient still reacts to a leucocyte-reduced red cell product, other options for preventing future reactions include washing and/or selecting fresher blood for transfusion [1].
Platelets
Most platelet reactions (90%) are caused by leucocyte-derived cytokine accumulation during storage. Hence, post-storage leucocyte reduction is not an effective strategy for preventing these reactions. FNHTRs to platelets can be prevented by pre-storage leucocyte reduction by either filtration or centrifugation (buffy coat method of platelet preparation). If pre-storage leucocyte-reduced platelets are not available, the plasma supernatant on the stored platelets can be removed and replaced with a suitable platelet additive solution washing to remove the cytokine-rich plasma, or fresher platelets (≤3 days of storage) can be transfused [1].
Premedication
Premedication of the patient with an antipyretic drug, paracetamol in the UK and acetominophen in North America, has become standard practice to prevent FNHTRs. Aspirin should not be used as a premedication in any patient requiring platelet transfusions as it affects platelet function. In some centres, it is routine practice to premedicate all patients prior to transfusion. However, there are no clinical data to justify this universal approach and when using leucocyte-reduced blood components such a practice is not warranted. However, patients with recurrent FNHTRs can be treated with an antipyretic approximately 30 minutes prior to starting the transfusion, which should help to alleviate or prevent symptoms [8,9].
Allergic transfusion reactions
Clinical presentation
Allergic transfusion reactions can be either nonsystemic/localized or systemic/generalized and are classified as mild, moderate or severe.
· Nonsystemic reactions are usually mild, consisting of urticaria and occasionally focal angioedema. These are benign and self-limiting though still cause symptoms that are distressing to the patient. However, such mild reactions may progress to more severe and systemic reactions with repeated transfusions.
· Systemic reactions range from moderate (generalized urticaria) to severe and life-threatening. Although urticaria is considered a pathognomonic finding for an allergic reaction, cutaneous signs or symptoms may not always be present in severe allergic reactions. Severe reactions usually present with a combination of skin, respiratory or circulatory changes, and less commonly with gastrointestinal symptoms. However, approximately 14% of severe reactions present only with respiratory symptoms or only with hypotension [10].
· Anaphylactic and anaphylactoid reactions behave identically clinically and are managed in the same way. These reactions should be considered a medical emergency as failure to initiate prompt treatment can have fatal consequences. Anaphylaxis usually begins 1–45 minutes after starting the transfusion and, in addition to an urticarial rash, presents with hypotension/shock, upper or lower airway obstruction (hoarseness, wheezing, chest pain, stridor, dyspnoea, anxiety, feeling of impending doom), gastrointestinal symptoms and rarely death.
Differential diagnosis
To ensure that appropriate treatment is administered in a timely fashion, patients presenting with systemic symptoms should also be promptly evaluated for:
· other causes of respiratory distress including circulatory overload, TRALI or any other comorbid condition such as pulmonary embolism and exacerbations of chronic lung disease;
· other causes of shock such as acute haemolytic transfusion reactions, sepsis and other comorbid clinical conditions that can be associated with shock;
· hypotension with or without cutaneous flushing due to bradykinin (BK) or des-Arg9-BK generation with the use of negatively charged bedside leucocyte reduction filters, or its transient accumulation in platelets during storage. Such hypotensive reactions may occur in a subset of patients being treated with an angiotensin-converting enzyme (ACE) inhibitor or who have inherited decreased ability to metabolize BK or des-Arg9-BK [11].
Incidence (frequency)
It is estimated that about 1% of transfusions are adversely affected by allergic reactions and that allergic reactions comprise 13–33% of all transfusion reactions. Rates of allergic transfusion reactions vary widely between the studies depending on product type and preparation. In a review of the studies done between 1990 and 2005 [8]:
· allergic reactions associated with packed red cell transfusions were reported to range from 0.03 to 0.61% with a median of 0.15% (1 reaction per 667 transfusions);
· allergic reactions associated with platelet transfusions occurred at a higher rate, ranging from 0.09 to 21% with a median of 3.7% (1 reaction per 27 transfusions); and
· the frequency of allergic reactions associated with the transfusion of plasma was lower than platelets but more common than reactions to red cells.
True anaphylaxis is a systemic reaction caused by antigen-specific crosslinking of IgE molecules on the surface of tissue mast cells and peripheral blood basophils, with immediate release of potent mediators. In contrast, immediate systemic reactions that mimic anaphylaxis but are not caused by an IgE-mediated immune response are termed anaphylactoid reactions. Both anaphylactic or anaphylactoid reactions are severe and life-threatening, but fortunately they are rare and comprise only about 1.3% of all transfusion reactions, affecting 1/20 000–1/47 000 transfusions.
Pathogenesis
Generally, an allergic transfusion reaction is defined as a type I hypersensitivity response mediated by IgE antibodies binding to a soluble allergen and resulting in the activation of mast cells. In these reactions, the allergen is often not known and the actual mechanism continues to remain largely speculative. In contrast, severe reactions that involve anaphylaxis which are not mediated by IgE antibodies but involve IgG anti-IgA are classified as type III reactions. These reactions result in complement activation with subsequent amplified release of anaphylotoxins C3a and C5a leading to anaphylaxis. When the aetiology of an allergic reaction is identified, it usually falls into one of the following categories:
· recipient pre-existing antibodies to plasma proteins in the blood component;
· recipient antibodies against a substance in the blood component that either is lacking or has a distinctly different allelic expression in the patient (i.e. IgA, haptoglobulin, C4); and
· extraneous substances in the component (i.e. passively transmitted donor IgE antibodies, drugs, other allergens).
For the vast majority of patients, the underly aetiology is believed to be a recipient pre-existing antibody to plasma proteins in the blood component that cannot be specifically identified (i.e. deficiencies in IgA, haptogloblin and C4 are not commonly encountered and represent a very small minority of allergic reactions). In some instances, an allergic reaction can be traced back to donor-specific factors, but with only a 5% chance of causing an allergic reaction in another recipient; therefore patient-specific factors are a predominant cause of allergic reactions [12].
Management
When there is a suspicion for any transfusion reaction, a general principle of treatment is to discontinue the transfusion immediately and until the patient is clinically assessed.
· Mild nonsystemic allergic transfusion reactions are usually treated with an antihistamine, commonly diphenhydramine 25–50 mg IM or IV in North America and chlorphenamine (Piriton) 10–20 mg IM or IV in the UK. The transfusion can often be restarted at a slower rate once symptoms have settled.
· Moderate reactions can additionally be treated with a dose of corticosteroids and the transfusion is usually discontinued indefinitely.
· In severe reactions, the transfusion is never restarted. Anaphylaxis is treated as with any other anaphylactic reaction.
· In addition to discontinuation of the current transfusion, other blood components collected simultaneously from the same donor should be identified and avoided for this patient, particularly apheresis platelets, where two or three doses may have been created from a single collection. However, the likelihood of donor-specific factors triggering an allergic reaction in a different recipient is low relative to patient-specific factors; therefore it would be considered safe to use other associated blood components from this donor for other patients [12].
The management strategy for anaphylaxis differs for adults and paediatric patients. For adults/adolescents, immediate administration of adrenaline (epinephrine in the USA) 500 μg (0.5 mL of 1:1000 solution) IM is key. Aggressive volume expansion with IV normal saline, oxygen supplementation and antihistamines are also required. If the hypotension is intractable, adrenaline 500 μg (5 mL 1:10 000 solution) IV can be given every 5–10 minutes and preparations should be made to transfer the patient to an intensive care unit where an IV drip of inotropic therapy can be maintained. Intubation may be necessary if the airway becomes compromised.
For paediatric patients, the treatment of anaphylaxis should include: adrenaline 10 μg/kg 1:1000 concentration IM (e.g. under 6 months: 50 μg or 0.05 mL of adrenaline 1 in 1000; 6 months to 6 years: 120 μg or 0.12 mL; 6–12 years, 250 μg or 0.25 mL) that can be repeated every 5 minutes (maximum dose 300 μg). A μg/kg dose should be used rather than an mL/kg dose as there are different concentrations of adrenaline. Administration of chlorphenamine (250 μg/kg IV for children 1 month to less than 1 year of age; 2.5–5 mg for 1–5 years; 5–10 mg for 6–12 years; 10 mg for over 12 years) or diphenhydramine 1 mg/kg IV/IM in the USA and ranitidine 1 mg/kg IV (maximum dose 50 mg) are also effective for supportive management.
While the above drugs are being prepared, the focus should be on resuscitation, including oxygen therapy, suctioning and positioning of the patient to open the airway, maintenance of the circulation, oxygen saturation monitoring, establishing an IV if possible and administering a fluid bolus with 20 mL/kg sodium chloride 0.9% if venous access is established. If signs and symptoms persist despite a single-dose IM of adrenaline then a paediatric intensive care specialist should be consulted to provide airway and further haemodynamic support.
Prevention
Premedication with antipyretics and/or antihistamines
It has been reported that 50–80% of transfusions in Canada and the USA are premedicated. A recent systematic review of the literature assessing the efficacy of premedication in FNHTRs including the results of three small prospective randomized controlled trials found no evidence that premedication prevented NHTRs including allergic or febrile reactions [13]. A retrospective review of 7900 transfusions in 385 paediatric oncology patients also found no statistically significant difference in allergic transfusion reactions between those who received premedication and those who did not [14]. This study also found that there was no difference in allergic reactions with or without premedication, even in those with a previous history of two or more allergic reactions. In addition, allergic reactions were not more common in those with a history of two or more allergic transfusion reactions. Although premedication does not appear to affect the incidence of allergic reactions, there have been no studies to date that have evaluated whether premedication has an effect on the severity of such reactions.
Leucocyte reduction
Unlike FNHTRs, there is no significant reduction in allergic transfusion reactions with the use of leucocyte-reduced blood components.
Washed components/plasma-reduced components
Red cells have minimal volumes of residual plasma and would require washing to further reduce the amount of plasma proteins transfused. Washing was associated with a decrease in allergic reaction rates of 2.7% to 0.3% for red cells [15]. For apheresis platelets, plasma reduction was associated with a lowering of allergic reactions from 5.5% to 1.7%, and was further reduced with washing to 0.5% [15]. Platelet recovery was better with plasma reduction (80.7%) than with washing (70.5%), which was not considered a significant difference. Platelet activation was significantly higher with washing (24.2% increase) versus with plasma reduction (10.3% increase). In contrast, plasma reduction only removed 51.1% of plasma proteins versus 96% with washing [16]. With the exclusion of severe or life-threatening allergic reactions, which would benefit from washing of cellular products, the use of plasma reduction was sufficient to decrease the number of allergic reactions in 67.4% of patients with clinically significant or multiple urticarial reactions.
IgA-deficient blood components
IgA deficiency is the most common primary immunodeficiency in the Western world, affecting up to 1 in 20 people. Severe IgA deficiency, defined as IgA <0.05 mg/L, can be associated with anaphylactic reactions to blood components that almost always contain IgA [17]. Patients with anaphylactic transfusion reactions should have further testing using a pretransfusion patient serum sample to quantify their serum IgA level as well as anti-IgA antibody titres. However, in actual experience, the vast majority of patients with anaphylactic transfusion reactions are not IgA deficient. Only a small proportion of those individuals who are IgA deficient have anti-IgA antibodies, and only a small subset of individuals with antibodies have been documented to have anaphylactic reactions with non-IgA deficient products [17]. Given the near ubiquitous presence of IgA in blood components, a patient with a recent transfusion within the past 24 hours with no reaction has essentially passed an antigen (IgA) stimulus test and therefore is unlikely to have IgA deficiency as their underlying cause of anaphylaxis. If serum IgA is detectable in the patient, anaphylaxis due to IgA deficiency is very unlikely, though not entirely excluded, with 0.7% of patients with low or normal IgA levels having detectable anti-IgA [17]. Due to the limited sensitivity of the IgA assay in most hospital laboratories (0.20–50 mg/dL with nephelometry or turbidometry), additional testing is usually required to identify patients with severe IgA deficiency (less than 0.05 mg/dL) and to test for anti-IgA antibodies. Such testing is performed in a limited number of reference laboratories. Due to the additional time necessary to perform these confirmatory assays, it is possible that requests for additional transfusions are made prior to availability of results. In such circumstances, IgA-deficient or washed blood components should be used whenever possible until severe IgA deficiency and anti-IgA antibodies are confirmed or excluded with the additional laboratory tests. In the event that IgA-deficient or washed blood components (such as IgA-deficient plasma) are not immediately available for a patient in a life-threatening situation, and where confirmatory testing is not yet completed, withholding transfusions may cause greater harm than a slow transfusion with careful monitoring [18]. If allergic transfusion reactions secondary to IgA antibodies due to IgA deficiency is confirmed, IgA-deficient products should be given in any future transfusions. Even in such circumstances, when faced with a life-threatening need for transfusion prior to the availability of IgA-deficient products, a slow transfusion with intense monitoring and immediate access to supportive care in the event of a severe reaction may outweigh the risk of anaphylaxis as a recurrence of anaphylaxis due to IgA is not a given certainty [19]. Since anaphylactic transfusion reactions are rare and often not due to IgA deficiency, while transfusions are common and often urgent, it is both impractical and not cost effective to widely screen for IgA deficiency in the pretransfused population.
Key points
1. Allergic and FNHTRs are the most common transfusion reactions. Anaphylaxis is rare.
2. Mild allergic reactions usually only require antihistamine treatment and the transfusion can be continued unless systemic symptoms develop.
3. Mild FNHTRs usually respond to the administration of an antipyretic.
4. If a moderate to severe transfusion reaction is suspected, the transfusion must be stopped until the patient is assessed and possible causes of the reaction are investigated.
5. Systemic symptoms warrant prompt clinical assessment as treatment can vary widely between diagnoses and, in particular, failure to administer adrenaline (epinephrine) in anaphylactic reactions can be fatal.
References
1. Heddle NM. Febrile non hemolytic transfusion reactions. In: MA Popovsky (ed.), Transfusion Reactions, 3rd edn. Bethesda, MD: AABB Press; 2007, pp. 57–103.
2. Yazer MH, Triulzi DJ, Shaz B, Kraus T & Zimring JC. Does a febrile reaction to platelets predispose recipients to red blood cell alloimmunization? Transfusion 2009; 49: 1070–1075.
3. Paglino JC, Pomper GJ, Fisch GS, Champion MH & Snyder EL. Reduction of febrile but not allergic reactions to RBCs and platelets after conversion to universal prestorage leukoreduction. Transfusion 2004; 44: 16–24.
4. Gauvin F, Lacroix J, Robillard P, Lapointe H & Hume H. Acute transfusion reactions in the pediatric intensive care unit. Transfusion 2006; 46: 1899–1908.
5. Heddle NM, Klama L, Singer J et al. The role of the plasma from platelet concentrates in transfusion reactions. N Engl J Med 1994; 331: 625–628.
6. Blumberg N, Gettings KF, Turner C, Heal JM & Phipps RP. An association of soluble CD40 ligand (CD154) with adverse reactions to platelet transfusions. Transfusion 2006; 46: 1813–1821.
7. Addas-Carvalho M, Salles TS & Saad ST. The association of cytokine gene polymorphisms with febrile non-hemolytic transfusion reaction in multitransfused patients. Transfus Med 2006; 16: 184–191.
8. Geiger TL & Howard SC. Acetaminophen and diphenhydramine premedication for allergic and febrile nonhemolytic transfusion reactions: good prophylaxis or bad practice? Transfus Med Rev 2007; 21: 1–12.
9. Tobian AA, King KE & Ness PM. Transfusion premedications: a growing practice not based on evidence. Transfusion 2007; 47: 1089–1096.
10. Domen RE & Hoeltge GA. Allergic transfusion reactions. An evaluation of 273 consecutive patients. Arch Pathol Lab Med 2003; 127: 316–320.
11. Eastlund T. Vasoactive mediators and hypotensive transfusion reactions. Transfusion 2007; 47: 369–372.
12. Savage WJ, Tobian AA, Fuller AK, Wood RA, King KE & Ness PM. Allergic transfusion reactions to platelets are associated more with recipient and donor factors than with product attributes. Transfusion 2011; 51: 1716–1722.
13. Martí-Carvajal AJ, Solà I, González LE et al. Pharmacological interventions for the prevention of allergic and febrile non-haemolytic transfusion reactions. Cochrane Database Syst Rev 2010; (6): CD007539.
14. Sanders RP, Maddirala SD, Geiger TL, Pounds S, Sandlund JT, Ribeiro RC, Pui CH & Howard SC. Premedication with acetaminophen or diphenhydramine for transfusion with leucoreduced blood products in children. Br J Haematol 2005; 130: 781–787.
15. Tobian AA, Savage WJ, Tisch DJ, Thoman S, King KE & Ness PM. Prevention of allergic transfusion reactions to platelets and red blood cells through plasma reduction. Transfusion 2011; 51: 1676–1683.
16. Veeraputhiran M, Ware J, Dent J, Bornhorst J, Post G, Cottler-Fox M, Pesek G, Theus J & Nakagawa M. A comparison of washed and volume-reduced platelets with respect to platelet activation, aggregation, and plasma protein removal. Transfusion 2011; 51: 1030–1036.
17. Vassallo RR. Review: IgA anaphylactic transfusion reactions. Part I. Laboratory diagnosis, incidence, and supply of IgA-deficient products. Immunohematology 2004; 20: 226–233.
18. Sandler SG & Zantek ND. Review: IgA anaphylactic transfusion reactions. Part II. Clinical diagnosis and bedside management. Immunohematology 2004; 20: 234–239.
19. Sandler SG. How I manage patients suspected of having had an IgA anaphylactic transfusion reaction. Transfusion 2006; 46: 10–13.
Further reading
Heddle NM, Klama L, Meyer R et al. A randomized controlled trial comparing plasma removal with white cell reduction to prevent reactions to platelets. Transfusion 1999; 39: 231–238.
Heddle NM, Blajchman MA, Meyer RM et al. A randomized controlled trial comparing the frequency of acute reactions to plasma-removed platelets and prestorage WBC-reduced platelets. Transfusion 2002; 42: 556–566.