Blood Transfusion Complications[1]

8/8/2019 Blood Transfusion Complications[1]

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In 2004, 3.4 million blood components were issuedin the UK and 539 events were voluntarily reported tothe Serious Hazards of Transfusion Scheme (SHOT).This represents an increase of 19% over 2003. Datacollected as reporting became compulsory are notyet available (www.transfusionguidelines.org.uk). 1

Serious complications of blood transfusion are

outlined in Table 1. Although immunologicallymediated reactions to transfusion products arepotentially serious, anaesthetists are most likely toencounter those relating to massive blood transfusionand transfusion related acute lung injury (TRALI).These adverse events are of most relevance to ourprofession and will be discussed rst.

Massive transfusion

A massive blood transfusion is de ned as thereplacement of a patients total blood volume in


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HypothermiaRBCs are stored at 4 oC. Rapid transfusion atthis temperature will quickly lower the recipientscore temperature and further impair haemostasis.Hypothermia reduces the metabolism of citrateand lactate and increases the likelihood ofhypocalcaemia, metabolic acidosis and cardiacarrhythmias. A decrease in core temperature shiftsthe oxyhaemoglobin dissociation curve to the left,reducing tissue oxygen delivery at a time when itshould be optimized. This reduction in temperaturecan be minimized by warming all IV uids and by the

use of forced air convection warming blankets toreduce radiant heat loss. 2

Transfusion-related acute lung injury TRALI is the most common cause of major morbidityand death after transfusion. It presents as an acuterespiratory distress syndrome (ARDS) either during orwithin 6 hours of transfusion. 3

Clinical features

Hypoxaemia, dyspnoea, cyanosis, fever, tachycardiaand hypotension result from non-cardiogenicpulmonary oedema. Radiographic appearance isof bilateral pulmonary in ltration, characteristic ofpulmonary oedema. It is important to differentiateTRALI from other causes of pulmonary oedemasuch as circulatory overload or myocardial disease,and other causes of ARDS, such as sepsis. Invasivemonitoring in TRALI demonstrates normal intracardiacpressures. 3

PathogenesisTwo different mechanisms for the pathogenesisof TRALI have been identi ed: immune (antibodymediated) and non-immune. Immune TRALI resultsfrom the presence of leucocyte antibodies in theplasma of donor blood, directed against humanleucocyte antigens (HLA) and human neutrophilalloantigens (HNA) in the recipient. Antibodiespresent in the recipient only rarely cause TRALI. In upto 40% of patients, leucocyte antibodies cannot be

studies, appearing out of proportion to the volume ofblood transfused.

Aggressive, expectant replacement of clotting

factors with fresh frozen plasma (FFP), platelets andcryoprecipitate transfusions are required to preventthis coagulopathy becoming severe enough to makehaemorrhage worse. 2

Biochemistry HypocalcaemiaRBCs in additive solution contain only traces ofcitrate, however, FFP and platelets contain much

higher concentrations. Citrate binds calcium, thuslowering the ionized plasma calcium concentration.This is usually prevented by rapid hepatic metabolismunless the patient is hypothermic. 2 Calcium is animportant co-factor in coagulation, and has a keyrole in mediating the contractility of myocardial,skeletal and smooth muscles. Hypocalcaemia resultsin hypotension, reduced pulse pressure, at ST-segments and prolonged QT intervals on the ECG.

If there is clinical, biochemical or ECG evidence ofhypocalcaemia, it should be treated with slow IVinjection of calcium gluconate 10% (5ml).

HyperkalaemiaThe potassium concentration of blood increasesduring storage, by as much as 510mmol 1. Aftertransfusion, the RBC membrane Na +K+ ATPasepumping mechanism is re-established and cellular

potassium reuptake occurs rapidly. Hyperkalaemiararely occurs during massive transfusions unless thepatient is also hypothermic and acidotic. 2

Acidbase abnormalitiesEach unit of RBCs contains 12mmol of acid. Thisis generated from the citric acid of the anticoagulantand from the lactic acid produced during storage;metabolism of this acid is usually very rapid. Citrate

undergoes hepatic metabolism to bicarbonate andduring a massive transfusion a metabolic alkalosismay occur. A patients acidbase status is alsodependent on tissue perfusion and acidosis often


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TRALI is lower, and the syndrome is encounteredpredominantly in critically ill patients. 3

Incidence

The exact incidence is unknown. Immune TRALI isreported to occur with an overall frequency of 1 in5000 transfused units and non-immune TRALI witha frequency of 1 in 1100. 3 The 2004 SHOT reportdescribes 13 reactions as follows: 6 to FFP, 4 toplatelets, 2 to packed cells and 1 to whole blood. Thepreponderance of reactions with FFP and platelets isthought to result from their high plasma component,in comparison with packed cells and cryoprecipitate,which have a low plasma component. There is a10-fold plasma difference between the two types oftransfusion product; 300ml compared with 30ml. 1 Measures taken to reduce the risk of TRALI includesourcing plasma for FFP and platelet suspension solelyfrom male donors; HLA antibodies are more commonin multiparous women as a result of transplacentalpassage during pregnancy. The incidence of immune

TRALI has also been signi cantly reduced by theleucodepletion of transfused blood (www.bloodco.uk).

Haemolytic transfusion reactionsThe most serious complications of blood transfusionresult from interactions between antibodies in therecipients plasma and surface antigens on donorRBCs. Although more than 250 RBC group antigenshave been described, they differ in their potentialfor causing immunization. The ABO and Rhesus Dgroups account for the majority of reactions of clinicalsigni cance.

Blood group antibodies are either naturally-occurringor immune in origin. Naturally-occurring antibodiesare present in the plasma of individuals who lackthe corresponding antigens. The most important areanti-A and anti-B, and they are usually of the IgMclass. Immune antibodies develop after a subjectsexposure to RBCs expressing antigens which theylack. This results from previous blood transfusions or

and ank pain, fever, chills, ushing, rigors, nauseaand vomiting, urticaria, dyspnoea and hypotension.In anaesthetized patients, these features may bemasked and the rst signs may be hypotension andthe features of increased blood destruction; namely,haemoglobinuria and disseminated intravascularcoagulation. 4 5

These reactions constitute medical emergencies.Consequently, management of the reaction precedesinvestigation into its cause. The transfusion should bestopped immediately, and attention directed towardscardiac and respiratory support and the maintenanceof adequate renal perfusion. Microvascular thrombosisand deposition of haemoglobin in the distal renaltubule can result in acute renal failure. The extentof precipitation is inversely related to urine ow. IV

uids, vasopressors and diuretics should be given tomaintain renal perfusion pressure, and to produce adiuresis. If acute renal failure develops, haemo ltrationshould be considered where available. 4 5

Haemolytic transfusion reactions should beinvestigated as a matter of urgency. The transfusionproducts administered should be meticulouslydocumented and returned to the laboratory, togetherwith a post-transfusion blood sample. Repeat bloodgroup analysis and compatibility testing will beperformed. In cases of true haemolytic transfusionreaction, the direct antiglobulin test (Coombstest) will be positive, because donor RBCs arecoated with recipient antibody. Haemoglobinaemia,haemoglobinuria and an increase in both serumunconjugated bilirubin and lactate dehydrogenaseconcentrations are useful in con rming thediagnosis. 45

Delayed reactionsThe donor RBC antigenplasma antibody interactionsresponsible for this subset of transfusion reactionmore commonly result from incompatibility withminor blood groups such as Rhesus and Kidd. Onpre-transfusion antibody screening, these patients


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the same as for anaphylaxis from other causes, withIV uid resuscitation, epinephrine administration(to reestablish vasomotor tone and reversebronchospasm), antihistamines, corticosteroidsand respiratory support. If subsequent transfusionsare required in such patients, washed RBCs shouldbe used (residual plasma and therefore IgA isremoved). 5

Transfusion-related infectionsBacterial Bacterial contamination of blood components is aninfrequent complication of transfusion. However, ifit does occur, the potential for fulminant sepsis inthe recipient is associated with high mortality. It canresult from contamination during venepuncture or ifan asymptomatic donor is bacteraemic at the timeof donation. Symptoms occur during or shortly aftertransfusion of the contaminated unit and include highfever, rigors, erythema and cardiovascular collapse. 6

RBCs are stored at 4 oC, making contamination withGram-negative bacteria such as Yersinia enterocolitica and Pseudomonas species more likely, as theyproliferate rapidly at this temperature. Gram-positivebacteria such as Staphylococcus epidermidis ,Staphylococcus aureus and Bacillus speciesproliferate more readily at room temperature and soare more commonly seen as platelet contaminants.There are no screening tests currently available fordetection of bacterial contamination; therefore, visual

inspection of the bag before transfusion is important.Contaminated bags may seem unusually dark incolour or contain gas bubbles. Diagnosis rests withculture of the same organism from both the patientand the implicated blood component. 6

Viral The incidence of transfusion-related viral infectionhas greatly reduced since the mid-1980s, when

pre-donation questionnaires to identify groups withhigh-risk behaviour were implemented. There havealso been improvements in pre-transfusion testingof donated blood Currently in the UK donor blood

Delayed transfusion reactions are dif cult to preventas very low titres of antibody in recipients plasma arenot easily detected. Subsequent antibody productionmay complicate later transfusions.

Non-haemolytic febrile reactionsThese reactions are very common and are usuallynot life-threatening. Reactions result from donorleucocyte antigens reacting to antibodies present inthe recipients plasma. These antibodies react withthe leucocytes to form a leucocyte antigenantibodycomplex that binds complement and results inthe release of endogenous pyrogensIL-1, IL-6and TNF a . Non-haemolytic febrile reactions canalso occur after platelet transfusions and are notcaused by antibodies, but by cytokines derived fromcontaminating leucocytes, that have accumulatedin the bag during storage. 4 Since the introductionof universal leucodepletion in the UK in 1999, anoticeable reduction in febrile reactions to both RBCsand platelets has been observed.

Symptoms of non-haemolytic febrile reactionsinclude fever, chills, headache, myalgia and generalmalaise. Rarely, they may progress to hypotension,vomiting and respiratory distress. Onset is during,or several hours after, transfusion and the severityof the reaction is dependent upon leucocyte loadand the rate of transfusion. Fever is a feature of bothnon-haemolytic febrile and haemolytic transfusionreactions. Distinction may be drawn between thesetwo diagnoses by performing a direct antiglobulintest. This will be negative with febrile reactions asthere will be no attachment of plasma antibody todonor RBCs. 4 5

Controversy exists in the current literature on whetherthe transfusion should be discontinued; however,there is consensus that the rate of transfusion shouldbe reduced. Anti-pyretics such as acetaminophen

should be administered. Allergic reactionsAllergic reactions are common and usually mild The


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Transfusion-associated graft-vs-host diseaseTransfusion-associated graft-vs-host disease (GvHD)

is a very rare complication of blood transfusion; thereare no identi able cases in the most recent SHOTreport. This reduction in incidence has resulted fromthe implementation of universal leucodepletion. GvHDcan complicate allogenic bone marrow transplants,but in those who are immunocompromised, it canoccur after simple blood transfusion. Ninety percent of cases are fatal. Donor derived immunecells, particularly T-lymphocytes, mount an immune

response against host tissue. Clinical features includea maculopapular rash (typically affecting the face,palms and soles), abdominal pain, diarrhoea andabnormal liver function tests. Destruction of bonemarrow stem cells by donor T-lymphocytes causespancytopenia. Prevention is by irradiation of bloodproducts, which inactivates any donor lymphocytes. 4

Immunomodulation

The potential to modulate the immune systemof transfusion recipients remains an exciting butcontroversial area of transfusion medicine. Theprolonged survival of renal allografts in patients whohave received pre-transplantation blood transfusionsis evidence for this effect. Transfusion-relatedimmune suppression is manifest as an increasedrisk of postoperative infections, increased tumourrecurrence after surgical resection, activation of latent

viral infection, improvement in immune in ammatorydisease and prevention of recurrent miscarriage.

These effects are thought to be initiated by donorleucocytes and are related to the Class I and Class IIHLA antigens which they express. It is possible thatthe aetiology of immunomodulation is multifactorial aslaboratory studies have shown a reduction in naturalkiller cell activity, IL-2 production, CD4/CD8 ratiosand macrophage function. 7

References1. Serious Hazards of Transfusion Annual Report 2004.ISBN 0 9532 789 7 2. Available from www.shot-uk.org2. Donaldson MDJ, Seaman MJ, Park GR. Massive bloodtransfusion. Br J Anaesth 1992; 69: 621303. Bux J. Transfusion-related acute lung injury (TRALI): aserious adverse event of blood transfusion. Vox Sang 2005;89: 1104. Perrotta PL, Snyder EL. Blood transfusion. In: WarrellDA, Cox TM, Firth JD, Benz EJ. eds. Oxford Textbook ofMedicine. Oxford: Oxford University Press, 2003; 7918005. Miller RD. Transfusion therapy. In: Miller RD. ed.

Anaesthesia. Philadelphia, PA: Churchill Livingstone, 2000;1613446. Kopko PM, Holland PV. Mechanisms of severe transfusionreactions. Transfus Clin Biol 2001; 8: 278817. Kirkley SA. Proposed mechanisms of transfusion-induced immunomodulation. Clin Diagn Lab Immnuol 1999;6: 65257

Table 2: Current risk of transfusion-related infection after a unit of screened blood in the UK

Infection Estimated risk per unit of transfused blood

Hepatitis A NegligibleHepatitis B 1 in 100 000

Hepatitis C

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Blood Transfusion Complications[1]