Transfusion complications case file

Transfusion complications case file

Eugene C. Toy, MD, Barry C. Simon, MD, Terrence H. Liu, MD, MHP, Katrin Y. Takenaka, MD, Adam J. Rosh, MD, MS

Case 47

A 10-year-old boy with sickle cell disease presents to the emergency department (ED) in the midst of presumed sickle cell crisis manifested as severe abdominal pain, pleuritic chest pain, dyspnea, and fever. His initial hemoglobin is 9 g/dL, white blood cell count (WBC) is 15,500 cells per mm³, and chest x-ray reveals a nonspecific infiltrate in the left lung field with a small left pleural effusion. The electrocardiogram reveals sinus tachycardia. Following treatment with intravenous fluid, supplemental oxygen by nasal canula, parenteral analgesics, and empiric broad-spectrum antibiotics therapy, the patient complained of worsening dyspnea and chest pain, requiring increased oxygen supplementation by face-mask and eventual endotracheal intubation. At this juncture, exchange transfusion therapy is contemplated.

⯈ What are the complications associated with blood transfusions in this setting?

⯈ What are the ways to reduce the incidence of transfusion-related complications?

ANSWER TO CASE 47:

Transfusion Complications

Summary: A 10-year-old boy with sickle cell crisis associated with severe respiratory symptoms (acute chest syndrome). The patient continues to have significant respiratory symptoms despite supportive care, and therefore exchange transfusion therapy is considered.

• Transfusion complications: Transfusion reactions and transfusion-related infections.
• Ways to reduce transfusion complications: Strict adherence to patient identification, specimen handling, and blood product storage protocols, and thorough review of transfusion history. Transfuse blood products based on need rather than arbitrary transfusion triggers.

ANALYSIS

Objectives

1. Develop an understanding of the epidemiology and basic pathophysiology of transfusion reactions.

2. Learn the evaluation and treatment of acute, life-threatening transfusion complications.

3. Learn the indications for blood product transfusion.

Considerations

Because sickle cell disease predisposes the patient to chronic anemia, it is more than likely that this particular patient has had an extensive history of transfusions; therefore, a thorough review of the transfusion history is vital. If the patient or the medical records indicate prior occurrence of minor transfusion reactions, then premedication with antihistamines and/or antipyretics may be useful. As a group, patients who are homozygous for sickle hemoglobin are at markedly increased risk of suffering complications from transfusion therapy, including transfusion-related infections (approximately 10% are infected with hepatitis C virus), and noninfectious etiologies related to alloimmunization (affecting up to 50% of sickle cell patients). The increased risks of alloimmunization are primarily related to recurrent antigen exposure and phenotypic dissimilarities between blood cells in the predominately white-donated blood supply and African American sickle cell patients.

To reduce the risk of transfusion-related complications, blood banks have intensified the cross-matching process for transfusions in sickle cell patients, with a demonstrable decrease in rates of alloimmunization. Leukocyte-reduced packed red blood cells (PRBC) are recommended for patients with sickle cell disease and other patients requiring recurrent transfusions. Additional benefits include a reduced rate of human leukocyte antigen (HLA) alloimmunization, and possible decreased rates of febrile nonhemolytic transfusion reactions (FNHTRs).

Approach To:

Transfusion Complications

CLINICAL APPROACH

Conceptually, transfusion complications are best categorized into acute immunemediated reactions, delayed immune-mediated reactions, nonimmunologic complications, and infectious complications.

ACUTE IMMUNE-MEDIATED REACTIONS

Acute Hemolytic Transfusion Reactions

Acute hemolytic transfusion reactions occur in 1:25,000 transfusions and cause death in 1:470,000 transfusions. The majority of acute hemolytic transfusion reactions are due to errors made during the processing of the blood, either at the patient bedside or in the blood bank. The majority of these reactions may be avoided with meticulous specimen processing, patient identification, and transfusion guidelines. Onset of reaction is immediate, presenting with a combination of hypotension, tachypnea (often with the sensation of chest constriction), tachycardia, fever, chills, nausea, hemoglobinuria, and body pain (joints, lower back, legs). Hemolysis can be either intravascular (more severe) or extravascular and is directed toward donor red blood cells (RBCs), usually mediated by preformed antibodies (anti-A, anti-B) within the recipient’s serum. Because the causative antibodies to ABO group antigens are preexisting in susceptible individuals, no prior alloantigen exposure is necessary for acute hemolysis to occur. However, recent sensitization to other alloantigens (such as an Rh-negative patient being exposed to Rh-positive blood) can result in similar pathology if a subsequent blood transfusion contains the same alloantigen(s). Given the potential for new alloantibody formation, a blood sample from the recipient should only be used for cross-matching assays within 48 hours from the time of collection.

Immediate management of suspected cases includes stopping the transfusion and changing the IV tubing or using alternative access sites to initiate aggressive crystalloid infusions, aiming to maintain urine output above 1 to 1.5 mL/kg/h for 24 hours. The remainder of the transfusion and a sample of the patient’s blood should be sent to the blood bank for testing. The sequelae of acute hemolysis include acute tubular necrosis (ATN), disseminated intravascular coagulation (DIC), and myocardial ischemia (as a consequence of hemodynamic instability). DIC may be confirmed by the presence of hemoglobinuria and plasma-free hemoglobin. The definitive diagnosis of acute hemolytic transfusion reactions is made with direct antiglobulin test (DAT, also known as the direct Coombs assay), which detects antibody or complement bound to the surface of donor RBCs in a sample of the recipient’s blood.

Febrile Nonhemolytic Transfusion Reactions

These reactions occur with approximately 0.5% to 1% RBC units, 2% apheresis platelet unit, and 5% to 30% donor-pooled platelets. Febrile nonhemolytic transfusion reactions (FNHTR) constitute the most common and least-worrisome complications of blood product transfusion. Patients may present with fever, chills, rigors, headache, malaise, and tachycardia, but without hemodynamic instability and respiratory compromise. Because prior history of transfusion is required for this reaction, fever in a first-time transfusion recipient should be treated as an acute hemolytic reaction until proven otherwise. Conversely, prior episodes of FNHTR indicate an increased risk of recurrence.

Management may include stopping the transfusion, administration of an antipyretic, and patient reassurance. Patients with a history of febrile reactions can be premedicated with antipyretics. Antipyretic premedication is a matter of preference, but should be generally avoided in first-time transfusion recipients, because fever is more likely to represent serious sequelae in these patients. Because FNHTR is a diagnosis of exclusion, samples of patient’s blood and the transfusate should be sent to rule out a hemolytic reaction or bacterial contamination.

Allergic Transfusion Reactions

The incidence of these allergic reactions is 1% to 3% of transfusions, and the reactions

are caused by recipient antibodies (immunoglobulin [Ig] E) against donor

serum proteins; symptoms may range from urticaria to frank anaphylaxis. Urticaria

can be managed symptomatically with antihistamines and by briefly stopping the

transfusion until symptoms resolve. Mild allergic reactions do not necessitate discontinuing

the transfusion, as symptoms are not strictly dose related. Patients prone

to develop these reactions can be premedicated with antihistamines to prevent the

development of mild allergic reactions.

Frankly, anaphylactic reactions to blood products are rare (1:20,000 to 1:170,000) and can occur within seconds of transfusion initiation. Anaphylactic reactions are IgE-mediated and occur, in most cases, as the result of genetic deficiency of IgA in the recipient, resulting in the production of anti-IgA, -IgE. Other less-common causes of anaphylaxis include reactions caused by IgE against allergens in the transfused blood, and the passive transfer of reactive IgE from donor to the recipient. Patients with known IgA deficiency should be given RBCs and platelets that have been thoroughly washed free of plasma proteins. Plasma component transfusions in IgA-deficient patients should be obtained from IgA-deficient donors.

Anaphylaxis should be managed by immediately addressing the ABCs (airway, breathing, circulation), accompanied by the administration of epinephrine, antihistamines, and corticosteroids, along with the immediate discontinuation of the transfusion. Patients taking angiotensin-converting enzyme (ACE) inhibitors will have more severe anaphylactic reactions (ie, severe angioedema) because of their inability to degrade bradykinin.

Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury (TRALI), with an estimated incidence of 1:4500 transfusions, is an under-recognized life-threatening complication of transfusion. TRALI is thought to be mediated by anti-leukocyte antibodies, resulting in systemic inflammation and neutrophil-mediated lung injury. The onset is generally within 6 hours of exposure to plasma-containing transfusion products, with most cases occurring within 1 to 2 hours. Random donor platelet transfusions (pooled platelets) are responsible for the majority of cases. Patients with hematological malignancies and cardiac disease are at increased risk of developing TRALI. Fever, tachycardia, and dyspnea are the most common presenting symptoms. The hallmark of this complication is respiratory distress with the presence of diffuse, bilateral alveolar and interstitial infiltrates on radiographic imaging. TRALI may be easily confused with acute pulmonary edema secondary to volume overload. Because TRALI patients have normal to low left-heart pressures, echocardiography may be useful to differentiate between TRALI and pulmonary edema. The management of this condition consists of stopping the transfusion and immediate attention to the “ABCs,” which may include intubation and mechanical ventilation. Respiratory compromise is usually self-limiting within 48 to 72 hours. The mortality rate associated with TRALI is about 10%.

DELAYED IMMUNE-MEDIATED REACTIONS

Delayed Hemolytic Transfusion Reactions

Delayed hemolytic transfusion reactions (DHTRs) are notably less severe than their acute hemolytic counterparts. The incidence is about 1:1000 transfusions. The mechanisms of DHTR are related to recipients having developed antibodies against RBC alloantigens from prior foreign RBC exposures, most often through transfusions or pregnancies.

Unlike acute hemolytic reactions, which require high circulating levels of reactive antibodies, the alloantibodies responsible for DHTR are present only at low levels prior to transfusion. Following exposure to these alloantigens, antibody generation is slowly increased over the following days, resulting in hemolysis of the donor RBCs. Symptoms associated with DHTR are mild to nonexistent. Patients typically present with a mild fever and recurrent anemia. No specific therapy is warranted aside from repeat transfusion.

Graft-Versus-Host Disease

Transfusion-related graft-versus-host disease (GVHD) is a rare disorder where donor lymphocytes engraft and proliferate in the recipient’s bone marrow, which over time may lead to a severe graft-mediated reaction against the recipient’s tissues, including the bone marrow. It is fatal in more than 90% of cases. Symptoms of GVHD develop on average 1 to 2 weeks following transfusion and include fevers, maculopapular rashes, hepatitis, diarrhea, nausea, vomiting, weight loss, and pancytopenia leading to sepsis and death. Immunocompromised recipients are especially at risk for GVHD; therefore, blood products administered to these patients should be subjected to gamma irradiation to render remaining leukocytes incapable of proliferation. Blood products donated by first-degree relatives or between patients with partially matched HLA haplotypes have an increased risk of donor lymphocyte engraftment because of homology between donor and recipient HLA genes; therefore, blood product donated by first-degree relatives should be irradiated prior to transfusions. The highest incidence of GVHD has been from regions where the population is racially homogeneous with highly likelihood of shared HLA haplotype (eg, Japan). GVHD is most problematic when patients receive fresh blood that is processed within 7 days from time of collection. In the United States, blood products that are older than 7 days generally do not contain viable lymphocytes.

Post-transfusion Purpura

Post-transfusion purpura is a rare complication, characterized by sudden thrombocytopenia occurring 5 to 10 days following transfusion of any blood product. The pathophysiology involves native platelet destruction, mediated by antibodies to the platelet antigen (PLA)1. Anti-PLA1 antibodies develop in patients previously exposed to foreign platelets through transfusion or pregnancy. Patients usually present with spontaneous bleeding (mucous membranes, epistaxis, hematochezia, hematuria). Nine percent of patients may develop intracranial hemorrhage. Treatment involves administration of intravenous immunoglobulin, corticosteroids, plasma exchange therapy, and transfusion with PLA1-negative platelets. If left untreated, the thrombocytopenia usually resolves spontaneously within 2 weeks of onset.

Alloimmunization

Alloimmunization refers to the formation of new antibodies against antigens on donated cells. The formation of alloantibodies against HLA surface molecules may render patients refractory to platelet transfusions, thus supporting the administration of leukoreduced blood for patients who will likely need exogenous platelets in the future. The presence of alloantibodies is primarily responsible for the increased rates of transfusion complications seen in repeat transfusion recipients.

Infectious Complications

The most frequent and concerning infectious complication of transfusion therapy is bacterial contamination, which can be detected in up to 2% of blood products. The most commonly isolated organism in refrigerated products (ie, RBCs) is Yersinia enterocolitica, which can grow at temperatures as low as 1°C (33.8°F). Other cryophilic organisms include Pseudomonas, Enterobacter and Flavobacterium. Platelets, which are stored at room temperature (22°C-24°C [71.6°F-75.2°F]), are more likely to develop gross contamination than are refrigerated products. Staphylococcus and Salmonella are often reported in fatal cases of platelet transfusion-mediated sepsis. Signs and symptoms may include fevers, rigors, chills, rash, hypotension, and even shock accompanied by sepsis. Symptoms may develop immediately or over several hours. Suspected cases of contamination should be managed with respiratory and circulatory support, immediate discontinuation of the transfusion, and broadspectrum antibiotic therapy. Because it is difficult to distinguish some of the immunemediated transfusion reactions from bacterial transmission, any transfusion that causes hypotension in the setting of fever warrants immediate testing of the donor blood with Gram stain and culture, in addition to standard workup for hemolytic reactions.

Indications for Blood Products

Given the potential complications from blood product transfusion, it is imperative that physicians understand and follow the indications for blood transfusion. The transfusion of blood products is indicated in patients with acute blood loss associated with hemodynamic instability and those with large amount of ongoing blood loss in hemodynamically stable individuals. The use of transfusion triggers had been a common practice in the past; however, based on the findings of a randomized controlled clinical trial (TRICC trial), hospitalized patients maintained at a hemoglobin values of 7 to 9 g/dL had lower in-hospital mortality than those maintained at hemoglobin values of 10 to 12 g/dL. The findings of the TRICC trial demonstrated that critically ill patients (with the exception of patients with acute coronary syndrome) can tolerate much lower hemoglobin levels, and the transfusion of packed RBC should be determined based on patients’ needs rather than an arbitrary laboratory value. Platelet transfusion is generally indicated in patients with platelet count of less than 10,000 μL, 10,000 to 20,000 with bleeding, less than 50,000 with a severe trauma, and those with bleeding time greater than 15 minutes. Fresh-frozen plasma transfusion is considered appropriate in bleeding patients with prothrombin time more than 17 seconds and following massive transfusion where replacement of 1 unit of fresh-frozen plasma and one single donor platelet unit for each unit of PRBC transfused is recommended as a strategy to improve clotting and hemostasis (hemostatic resuscitation).

COMPREHENSION QUESTIONS

47.1 A hemodynamically stable 40-year-old man with gastrointestinal (GI) bleeding and hemoglobin of 6 g/dL is receiving packed RBC transfusion. Soon after the initiation of blood transfusion, the patient becomes confused, develops urticaria, and subsequently unresponsive with a systolic blood pressure of 60 mm Hg. Which of the following agents may have worsened this patient’s condition?

A. Lisinopril (an ACE inhibitor)

B. Atenolol

C. Lactated Ringer solution

D. Morphine sulfate

E. Salicylate

47.2 A 60-year-old woman with chronic anemia caused by a myelofibrosis presents to the emergency room from her oncologist’s office with a hemoglobin of 6 g/dL. She notes feeling very lethargic over the past week, and had some mild chest discomfort while climbing stairs in her house last night. A type- and cross-match is performed for 2 units of packed erythrocytes, which are given without incident and marked improvement in her symptoms is seen. While going over discharge instructions with the emergency physician, the patient notes that she feels feverish and slightly short of breath. Over the next several minutes her dyspnea worsens markedly. Vital sign measurement reveals an oxygen saturation of 93%, a heart rate of 120 beats per minute, and a blood pressure of 95/55 mm Hg. The patient continues to deteriorate from a respiratory standpoint despite supplemental oxygen, requiring endotracheal intubation.

A portable chest radiograph shows evidence of diffuse bilateral infi ltrates. Which of the following statements is most accurate regarding this patient’s condition?

A. This patient’s left ventricular end-diastolic pressure is likely to be elevated.

B. This condition has a mortality rate of up to 90%.

C. Diuretic therapy is unlikely to be effective.

D. Radiographic abnormalities develop several days after the onset of clinical manifestations.

E. Mechanical ventilatory support is generally not helpful.

ANSWERS

47.1 A. Patients taking ACE inhibitors may experience a more severe anaphylactic reaction than other patients because of their inability to degrade bradykinin; however, these agents do not confer an increased risk of anaphylaxis. Patient misidentification is the leading preventable cause of transfusion reactions.

47.2 C. Patients with TRALI are not volume overloaded, but rather suffer from increased capillary permeability at the level of the pulmonary vasculature. As such, they have normal to low left-side heart pressures, and will only be harmed by diuretic therapy because of the potential to cause organ hypoperfusion. Mortality rates are around 10%. Radiographic abnormalities are present almost immediately, and persist for several days after the resolution of clinical manifestations. Mechanical ventilatory support is a mainstay of therapy for patients with suspected TRALI, as the process is generally self-limiting.

CLINICAL PEARLS

⯈ TRALI, thought to be mediated by antileukocyte antibodies, presents with fever, tachycardia, and dyspnea as the most common presenting symptoms.

⯈ The hallmark of TRALI is respiratory distress with the presence of diffuse, bilateral alveolar and interstitial infiltrates on radiographic imaging.

References

Herbert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirement in critical care. Transfusion requirements in critical care investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340:409-417. 

Leo A, Pedal I. Diagnostic approaches to acute transfusion reactions. Forensic Sci Med Pathol. 2010;6: 135-145. 

Vamvakas EC, Blajchman MA. Blood still kills: six strategies to further reduce allogeneic blood transfusion-related mortality. Transfus Med Rev. 2010;24:77-124.

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