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Complications of Transfusion

By Ravindra Sarode, MD, The University of Texas Southwestern Medical Center at Dallas

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The most common complications of transfusion are

  • Febrile nonhemolytic reactions

  • Chill-rigor reactions

The most serious complications, which have very high mortality rates, are

  • Transfusion-associated circulatory overload

  • Transfusion-related acute lung injury

  • Acute hemolytic reaction due to ABO incompatibility

Early recognition of symptoms suggestive of a transfusion reaction and prompt reporting to the blood bank are essential. The most common symptoms are chills, rigor, fever, dyspnea, light-headedness, urticaria, itching, and flank pain. If any of these symptoms (other than localized urticaria and itching) occur, the transfusion should be stopped immediately and the IV line kept open with normal saline. The remainder of the blood product and clotted and anticoagulated samples of the patient’s blood should be sent to the blood bank for investigation. Note: The unit in question should not be restarted, and transfusion of any previously issued unit should not be initiated.Further transfusion should be delayed until the cause of the reaction is known, unless the need is urgent, in which case type O Rh-negative RBCs should be used.

Hemolysis of donor or recipient RBCs (usually the former) during or after transfusion can result from ABO/Rh incompatibility, plasma antibodies, or hemolyzed or fragile RBCs (eg, by overwarming stored blood or contact with hypotonic IV solutions). Hemolysis is most common and most severe when incompatible donor RBCs are hemolyzed by antibodies in the recipient’s plasma. Hemolytic reactions may be acute (within 24 h) or delayed (from 1 to 14 days).

Acute hemolytic transfusion reaction

About 20 people die yearly in the US as a result of acute hemolytic transfusion reaction (AHTR). AHTR usually results from recipient plasma antibodies to donor RBC antigens. ABO incompatibility is the most common cause of AHTR. Antibodies against blood group antigens other than ABO can also cause AHTR. Mislabeling the recipient’s pretransfusion sample at collection and failing to match the intended recipient with the blood product immediately before transfusion are the usual causes.

Hemolysis is intravascular, causing hemoglobinuria with varying degrees of acute renal failure and possibly disseminated intravascular coagulation (DIC). The severity of AHTR depends on the degree of incompatibility, the amount of blood given, the rate of administration, and the integrity of the kidneys, liver, and heart. An acute phase usually develops within 1 h of initiation of transfusion, but it may occur late during the transfusion or immediately afterward. Onset is usually abrupt. The patient may complain of discomfort and anxiety. Dyspnea, fever, chills, facial flushing, and severe pain may occur, especially in the lumbar area. Shock may develop, causing a rapid, feeble pulse; cold, clammy skin; low blood pressure; and nausea and vomiting. Jaundice may follow acute hemolysis.

If AHTR occurs while the patient is under general anesthesia, the only symptom may be hypotension, uncontrollable bleeding from incision sites and mucous membranes caused by an associated DIC, or dark urine that reflects hemoglobinuria.

If AHTR is suspected, one of the first steps is to recheck the sample and patient identifications. Diagnosis is confirmed by a positive direct antiglobulin test, measuring urinary Hb, serum LDH, bilirubin, and haptoglobin. Intravascular hemolysis produces free Hb in the plasma and urine; haptoglobin levels are very low. Hyperbilirubinemia may follow.

After the acute phase, the degree of acute kidney injury determines the prognosis. Diuresis and a decreasing BUN usually portend recovery. Permanent renal insufficiency is unusual. Prolonged oliguria and shock are poor prognostic signs.

If AHTR is suspected, the transfusion should be stopped and supportive treatment begun. The goal of initial therapy is to achieve and maintain adequate blood pressure and renal blood flow with IV 0.9% saline and furosemide. IV saline is given to maintain urine output of 100 mL/h for 24 h. The initial furosemide dose is 40 to 80 mg (1 to 2 mg/kg in children), with later doses adjusted to maintain urinary flow > 100 mL/h during the first day.

Drug treatment of hypotension must be done cautiously. Pressor drugs that decrease renal blood flow (eg, epinephrine, norepinephrine, high-dose dopamine) are contraindicated. If a pressor drug is necessary, dopamine 2 to 5 mcg/kg/min is usually used.

A nephrologist should be consulted as early as possible, particularly if no diuretic response occurs within about 2 to 3 h after initiating therapy, which may indicate acute tubular necrosis. Further fluid and diuretic therapy may be contraindicated, and early dialysis may be helpful.

Delayed hemolytic transfusion reaction

Occasionally, a patient who has been sensitized to an RBC antigen has very low antibody levels and negative pretransfusion tests. After transfusion with RBCs bearing this antigen, a primary or anamnestic response may result (usually in 1 to 4 wk) and cause a delayed hemolytic transfusion reaction. A delayed hemolytic transfusion reaction usually does not manifest as dramatically as acute hemolytic transfusion reaction. Patients may be asymptomatic or have a slight fever. Rarely, severe symptoms occur. Usually, only destruction of the transfused RBCs (with the antigen) occurs, resulting in a falling Hct and a slight rise in lactate dehydrogenase and bilirubin and a positive direct antiglobulin test. Because delayed hemolytic transfusion reaction is usually mild and self-limited, it is often unidentified, and the clinical clue may be an unexplained drop in Hb to the pretransfusion level occurring 1 to 2 wk posttransfusion. Severe reactions are treated similarly to acute reactions.

Febrile nonhemolytic transfusion reaction

Febrile reactions may occur without hemolysis. Antibodies directed against WBC HLA in otherwise compatible donor blood are one possible cause. This cause is most common in multitransfused or multiparous patients. Cytokines released from WBCs during storage, particularly in platelet concentrates, are another possible cause.

Clinically, febrile reactions consist of a temperature increase of 1° C, chills, and sometimes headache and back pain. Simultaneous symptoms of allergic reaction are common. Because fever and chills also herald a severe hemolytic transfusion reaction, all febrile reactions must be investigated as for acute hemolytic transfusion reaction, as with any transfusion reaction.

Most febrile reactions are treated successfully with acetaminophen and, if necessary, diphenhydramine. Patients should also be treated (eg, with acetaminophen) before future transfusions. If a recipient has experienced more than one febrile reaction, special leukoreduction filters are used during future transfusions; most hospitals use prestorage, leukoreduced blood components.

Allergic reactions

Allergic reactions to an unknown component in donor blood are common, usually due to allergens in donor plasma or, less often, to antibodies from an allergic donor. These reactions are usually mild and include urticaria, edema, occasional dizziness, and headache during or immediately after the transfusion. Simultaneous fever is common. Less frequently, dyspnea, wheezing, and incontinence may occur, indicating a generalized spasm of smooth muscle. Rarely, anaphylaxis occurs, particularly in IgA-deficient recipients.

In a patient with a history of allergies or an allergic transfusion reaction, an antihistamine may be given prophylactically just before or at the beginning of the transfusion (eg, diphenhydramine 50 mg po or IV). Note: Drugs must never be mixed with the blood. If an allergic reaction occurs, the transfusion is stopped. An antihistamine (eg, diphenhydramine 50 mg IV) usually controls mild urticaria and itching, and transfusion may be resumed. However, a moderate allergic reaction (generalized urticaria or mild bronchospasm) requires hydrocortisone (100 to 200 mg IV), and a severe anaphylactic reaction requires additional treatment with epinephrine 0.5 mL of 1:1000 solution sc and 0.9% saline IV (see Anaphylaxis : Treatment) along with investigation by the blood bank. Further transfusion should not occur until the investigation is completed. Patients with severe IgA deficiency require transfusion of washed RBCs, washed platelets, and plasma from an IgA-deficient donor.

Volume overload

Although volume overload is underrecognized and underreported, recently it has been recognized as the second most common cause of transfusion-related deaths (20%) reported to the FDA. The high osmotic load of blood products draws volume into the intravascular space over the course of hours, which can cause volume overload in susceptible patients (eg, those with cardiac or renal insufficiency). RBCs should be infused slowly. The patient should be observed and, if signs of heart failure (eg, dyspnea, crackles) occur, the transfusion should be stopped and treatment for heart failure begun.

Typical treatment is with a diuretic such as furosemide 20 to 40 mg IV. Occasionally, patients requiring a higher volume of plasma infusion to reverse a warfarin overdose may be given a low dose of furosemide simultaneously; however, prothrombin complex concentrate (PCC) is the first choice for such patients. Patients at high risk of volume overload (eg, those with heart failure or severe renal insufficiency) are treated prophylactically with a diuretic (eg, furosemide 20 to 40 mg IV).

Acute lung injury

Transfusion-related acute lung injury is an infrequent complication caused by anti-HLA and/or antigranulocyte antibodies in donor plasma that agglutinate and degranulate recipient granulocytes within the lung. Acute respiratory symptoms develop, and chest x-ray has a characteristic pattern of noncardiogenic pulmonary edema. This complication is the most common cause of transfusion-related death (45% of deaths reported to the FDA). Incidence is 1 in 5,000 to one in 10,000, but many cases are mild. Mild to moderate transfusion-related acute lung injury probably is commonly missed. General supportive therapy typically leads to recovery without long-lasting sequelae. Diuretics should be avoided. Using blood donated by men reduces the risk of this reaction. Cases should be reported to the hospital transfusion medicine service or blood bank.

Altered oxygen affinity

Blood stored for > 7 days has decreased RBC 2,3-diphosphoglycerate (DPG), and the 2,3-DPG is absent after >10 days. This absence results in an increased affinity for oxygen and slower release of oxygen to the tissues. There is little evidence that 2,3-DPG deficiency is clinically significant except in exchange transfusions in infants, in sickle cell patients with acute chest syndrome and stroke, and in some patients with severe heart failure. After transfusion of RBCs, 2,3-DPG regenerates within 12 to 24 h.

Graft-vs-host disease

Transfusion-associated graft-vs-host disease (GVHD—see also Other complications) is usually caused by transfusion of products containing immunocompetent lymphocytes to an immunocompromised host. The donor lymphocytes attack host tissues. GVHD can occur occasionally in immunocompetent patients if they receive blood from a donor (usually a close relative) who is homozygous for an HLA haplotype for which they are heterozygous. Symptoms and signs include fever, rash (centrifugally spreading rash becoming erythroderma with bullae), vomiting, watery and bloody diarrhea, lymphadenopathy, and pancytopenia due to bone marrow aplasia. Jaundice and elevated liver enzyme levels are also common. GVHD occurs 4 to 30 days after transfusion and is diagnosed based on clinical suspicion and skin and bone marrow biopsies. GVHD has > 90% mortality because no specific treatment is available.

Prevention of GVHD is with irradiation (to damage DNA of the donor lymphocytes) of all transfused blood products. It is done

  • If the recipient is immunocompromised (eg, patients with congenital immune deficiency syndromes, hematologic cancers, or hematopoietic stem cell transplants; neonates)

  • If donor blood is obtained from a 1st-degree relative

  • When HLA-matched components, excluding stem cells, are transfused

Treatment with corticosteroids and other immunosuppressants, including those used for solid organ transplantation, is not an indication for blood irradiation.

Complications of massive transfusion

Massive transfusion is transfusion of a volume of blood greater than or equal to one blood volume in 24 h (eg, 10 units in a 70-kg adult). When a patient receives standard resuscitation fluids of packed RBCs (colloid) plus crystalloid (Ringer's lactate or normal saline) in such large volume, the plasma clotting factors and platelets are diluted, causing a coagulopathy (dilutional coagulopathy). This coagulopathy worsens the consumptive coagulopathy due to major trauma itself (ie, as a result of extensive activation of the clotting cascade) and leads to a lethal triad of acidosis, hypothermia, and bleeding. Recently, protocols for massive transfusions have been developed in which fresh frozen plasma and platelets are given earlier in resuscitation before coagulopathy develops, rather than trying to "catch up." Such protocols have been shown to decrease mortality, although the ideal ratios of RBCs, plasma, and platelets are still being developed. A recent trial showed no significant mortality difference between giving one unit of plasma and one platelet concentrate for each 2 units of RBCs (1:1:2) versus giving one unit of plasma and one platelet concentrate for every 1 unit of RBCs (1:1:1 [1]).

Hypothermia due to rapid transfusion of large amounts of cold blood can cause arrhythmias or cardiac arrest. Hypothermia is avoided by using an IV set with a heat-exchange device that gently warms blood. Other means of warming blood (eg, microwave ovens) are contraindicated because of potential RBC damage and hemolysis.

Citrate and potassium toxicities generally are not of concern even in massive transfusion; however, toxicities of both may be amplified in the presence of hypothermia. Patients with liver failure may have difficulty metabolizing citrate. Hypocalcemia can result but rarely necessitates treatment (which is 10 mL of a 10% solution of calcium gluconate IV diluted in 100 mL D5W, given over 10 min). Patients with kidney failure may have elevated potassium if transfused with blood stored for > 1 wk (potassium accumulation is usually insignificant in blood stored for < 1 wk). Mechanical hemolysis during transfusion may increase potassium. Hypokalemia may occur about 24 h after transfusion of older RBCs (> 3 wk), which take up potassium.

Post-transfusion purpura

Post-transfusion purpura is a very rare complication in which the platelet count falls rapidly 4 to 14 days after an RBC transfusion, causing moderate to severe thrombocytopenia. Almost all patients are multiparous women who typically received RBC transfusion during a surgical procedure. The exact etiology is unclear. However, the most accepted hypothesis is that a patient who is negative for human platelet antigen 1a (HPA1a) develops alloantibodies due to exposure to HPA1a antigen from the fetus during pregnancy. Because stored RBCs contain platelet microparticles and because most (99%) donors are HPA1a positive, platelet microparticles from the donor blood may trigger an antibody response in previously sensitized patients (anamnestic response). Because these platelet microparticles attach to the recipient's platelets (and thus coat them with HPA1a antigen), the alloantibodies destroy the recipient's platelets, causing thrombocytopenia. The disorder resolves spontaneously as the antigen-coated platelets are destroyed.

Patients develop purpura along with moderate to severe bleeding—usually from the surgical site. Platelet and red cell transfusions make the condition worse.

The differential diagnosis usually includes heparin-induced thrombocytopenia (HIT), although HIT is not associated with bleeding. Diagnosis is made by documenting HPA1a antibodies in the patient's plasma and absence of corresponding antigen on the patient's platelets.

Treatment is high-dose IV immunoglobulins (1 to 2 g/kg) and avoidance of further transfusion of platelets or RBCs. Plasma exchange may be considered in severe cases and, for patients with severe bleeding, platelets donated by HPA1a-negative donors could be transfused if available.

Infectious complications

Bacterial contamination of packed RBCs occurs rarely, possibly due to inadequate aseptic technique during collection or to transient asymptomatic donor bacteremia. Refrigeration of RBCs usually limits bacterial growth except for cryophilic organisms such as Yersinia sp, which may produce dangerous levels of endotoxin. All RBC units are inspected before dispensing for bacterial growth, which is indicated by a color change. Because platelet concentrates are stored at room temperature, they have greater potential for bacterial growth and endotoxin production if contaminated. To minimize growth, storage is limited to 5 days. The risk of bacterial contamination of platelets is 1:2500. Therefore, platelets are routinely tested for bacteria.

Rarely, syphilis is transmitted in fresh blood or platelets. Storing blood for 96 h at 4 to 10° C kills the spirochete. Although federal regulations require a serologic test for syphilis on donor blood, infective donors are seronegative early in the disease. Recipients of infected units may develop the characteristic secondary rash.

Hepatitis may occur after transfusion of any blood product. The risk has been reduced by viral inactivation through heat treatment of serum albumin and plasma proteins and by the use of recombinant factor concentrates. Tests for hepatitis are required for all donor blood (see Table: Infectious Disease Transmission Testing). The estimated risk of hepatitis B is 1:500,000; of hepatitis C, 1:2.6 million. Because its transient viremic phase and concomitant clinical illness likely preclude blood donation, hepatitis A (infectious hepatitis) is not a significant cause of transfusion-associated hepatitis.

HIV infection in the US is almost entirely HIV-1, although HIV-2 is also of concern. Testing for antibodies to both strains is required. Nucleic acid testing for HIV-1 antigen and HIV-1 p24 antigen testing are also required. Additionally, blood donors are asked about behaviors that may put them at high risk of HIV infection. HIV-0 has not been identified among blood donors. The estimated risk of HIV transmission due to transfusion is 1:2.6 million.

Cytomegalovirus (CMV) can be transmitted by WBCs in transfused blood. It is not transmitted through fresh frozen plasma. Because CMV does not cause disease in immunocompetent recipients, routine antibody testing of donor blood is not required. However, CMV may cause serious or fatal disease in immunocompromised patients, who should receive CMV-negative blood products that have been provided by CMV antibody-negative donors or by blood depleted of WBCs by filtration.

Human T-cell lymphotropic virus 1 (HTLV-1), which can cause adult T-cell lymphoma/leukemia and HTLV-1–associated myelopathy/tropical spastic paraparesis, causes posttransfusion seroconversion in some recipients. All donor blood is tested for HTLV-1 and HTLV-2 antibodies. The estimated risk of false-negative results on testing of donor blood is 1:641,000.

Creutzfeldt-Jakob disease has never been reported to be transmitted by transfusion, but current practice precludes donation from a person who has received human-derived growth hormone or a dura mater transplant or who has a family member with Creutzfeldt-Jakob disease. New variant Creutzfeldt-Jakob disease (vCJD, or mad cow disease) has not been transmitted by blood transfusion. However, donors who have spent significant time in the United Kingdom and some other parts of Europe may be permanently deferred from donation (see Table: Some Reasons for Blood Donation Deferral or Denial).

Malaria is transmitted easily through infected RBCs. Many donors are unaware that they have malaria, which may be latent and transmissible for 10 to 15 yr. Storage does not render blood safe. Prospective donors must be asked about malaria or whether they have been in a region where it is prevalent. Donors who have had a diagnosis of malaria or who are immigrants, refugees, or citizens from countries in which malaria is considered endemic are deferred for 3 yr; travelers to endemic countries are deferred for 1 yr.

Babesiosis, Chagas disease, and West Nile virus have rarely been transmitted by transfusion.

Zika virus infection has been reported to be transmitted via blood products in Brazil. Therefore, the FDA has mandated testing for Zika virus in the US and its territories. In lieu of Zika testing, pathogen reduction technologies approved for platelets and plasma could also be used; however, their use is currently very limited, and this technology is still unavailable for red cells.

General reference

  • 1. Holcomb JB, Tilley BC, Baraniuk S, et al: Transfusion of plasma, platelets, and red blood cells in a 1:1:1 vs a 1:1:2 ratio and mortality in patients with severe trauma: the PROPPR randomized clinical trial. JAMA 313(5):471–482, 2015. doi:10.1001/jama.2015.12

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