Transfusion Reactions

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Guideline on the investigation and management of acute transfusion reactions Prepared by the BCSH Blood Transfusion Task Force

TRANSFUSION REACTIONS

  1. STOP TRANSFUSION IMMEDIATELY
  2. Alert Blood Bank of suspected transfusion reaction
  3. Keep IV line open
  4. Assess clinical status of patient and treat based upon severity and type of reaction
  5. Complete transfusion reaction report, send remaining product bag and blood sample tube to lab
  6. For urticarial reactions ONLY, treat with antihistamine and continue transfusion after symptoms resolve


TRANSFUSION REACTION TYPES

  • Acute Hemolytic Transfusion Reaction (AHTR)
    • Potentially catastrophic reaction to transfusion
      • Mortality estimated as 1:100,000 to 600,000 transfusions
    • Most often result of clerical errors leading to mistaken identity of recipient
    • Can result from ABO mismatched transfusion as well as from non-ABO antigen-antibody reactions (e.g.: Kidd, Kell, Rh antigen families)
    • Symptoms: Fever and chills (most common); nausea/vomiting; flank or back pain; pain at blood product infusion site; dyspnea, hypotension, “sense of impending doom”, bleeding at IV sites, red/dark urine
    • Severe manifestations can include renal failure, shock, DIC
    • Labs: Hemoglobinemia, hemoglobinuria (from intravascular hemolysis), decreased haptoglobin, elevated LDH. Direct Antibody Test (DAT, aka “Coombs” test) positive for complement +/- IgG
    • Evaluation of suspected AHTR: STOP TRANSFUSION IMMEDIATELY.  Contact Blood Bank.  Do not dispose of implicated unit.  Send blood/urine sample to Blood Bank if requested.
    • Treatment: Hypotension – IVFs +/- vasopressor support; maintain renal perfusion, monitor UOP closely; treat DIC if life-threatening hemorrhage present.

 

  • Febrile Non-Hemolytic Transfusion Reaction (FNHTR)
    • Common reaction following transfusion of RBCs and platelets: estimated in up to 0.4% of RBC transfusions, up to 2% of platelet transfusions; higher incidence in non-leukoreduced units
    • Symptoms: Fever (rise of ≥1°C from pre-transfusion), rigors/chills (even in absence of frank fever) typically at end of transfusion, but can occur up to 1-2 hours post-transfusion; typically resolves without any sequelae. May be associated with headache, nausea, vomiting.
    • Cause: Recipient anti-HLA antibodies versus donor WBCs; infusion of storage-generated cytokines
    • Treatment: Stop transfusion immediately, rule out hemolytic reaction or infection; return unused portion of blood product to blood bank; give anti-pyretics; use leukocyte reduced products in future (slowing infusion rates may also decrease severity of, or prevent, future FNHTRs).
    • Routine premedication with acetaminophen and/or diphenhydramine has not been shown to be effective. (Though acetaminophen can be considered if recurrent FNHTRs occur.)

 

  • Transfusion Related Acute Lung Injury (TRALI)
    • Occurs during or within 6 hours following transfusion – any blood product containing plasma can be implicated (plasma and platelets most common)
    • Estimated incidence of 1:5,000 transfusions
    • Mortality rate ~10%; #1 cause of transfusion attributed mortality in US
    • Symptoms: acute onset of hypoxemia, can develop into ARDS; hypotension and fever also common
    • Definition: 1) Acute Onset; 2) Hypoxemia (PaO2/FiO2 ≤ 300); 3) Bilateral opacities on CXR; 4) No evidence of circulatory overload
    • Cause: anti-HLA antibodies (most common) or anti-neutrophil antibodies in donor plasma (though other etiologies are possible)
    • Treatment: ICU-level supportive care, treat as per other etiologies of ARDS.
      • Often resolves after 2-3 days of supportive care

 

  • Transfusion Associated Circulatory Overload (TACO)
    • Due to hydrostatic edema following transfusion
    • Major cause of transfusion-associated morbidity/mortality – globally under-reported
    • Pathophysiology: increased pulmonary blood volume leads to increased pulmonary venous and LA pressures; resulting increased in pulmonary capillary pressure leads to transudation of edema fluid into pulmonary interstitium.
    • Symptoms: Dyspnea (77%), orthopnea, edema usually within 1-2 hours of transfusion (can occur during transfusion); also common: hypertension (44%) and hypoxemia (36%).
    • Labs/tests: BNP/Pro-BNP elevated; imaging consistent with hydrostatic pulmonary edema.
    • Risk factors: Female gender (smaller blood volumes), Hx of CHF or ESRD, positive net fluid balance, recent surgery, recent/active vasopressor/inotrope requirements, mechanical ventilation; age > 60 years old (~80% of cases)
    • DDx: TRALI, anaphylaxis.
    • Treatment: STOP transfusion, support oxygenation requirements, diuretics (response to diuretics can help differentiate TACO from TRALI)
    • Prevention: Minimize transfusion of blood products given to at risk patients (single unit RBC transfusions instead of two unit transfusions – an official SCCM guideline), administer all blood products slowly, consider diuretics during transfusion or between transfused units.

 

  • Allergic Transfusion Reactions
    • Most common transfusion reaction; occurs in 1-3% of plasma/platelet transfusions.
    • Presents on a spectrum from mild allergic reactions to anaphylactoid/anaphylaxis.
    • Mild allergic reactions (by far the most common) present with urticaria, erythema, pruritus with minimal systemic symptoms and the absence of fever.
    • Treatment of mild allergic reactions: pause transfusion, use H1-blocking anti-histamine (e.g.: 25-50mg IV diphenhydramine). IF urticaria resolves after anti-histamine, transfusion can be resumed.  THIS IS THE ONLY TRANSFUSION REACTION WHERE THE TRANSFUSION OF THE IMPLICATED UNIT CAN BE COMPLETED.
    • Routine premedication with anti-histamines has not been proven to be effective, and is generally not recommended as the vast majority of allergic reactions are idiosyncratic. However, if repeated allergic reactions occur in a specific patient, premedication may be considered for them.
    • If allergic reactions occur uniformly with transfusion, or are of increasing severity, washed blood products may be considered, though this should be decided in consultation with the Blood Bank physician.
    • Severe allergic reactions are rare – 1:20,000-50,000 transfusions.
    • Symptoms: Severe systemic symptoms involving multiple organ systems.
      • Cutaneous: pruritus, urticarial, erythema, flushing, angioedema
      • Pulmonary: laryngeal edema and bronchospasm with stridor, wheezing, coughing, respiratory distress
      • Cardiovascular: hypotension, tachycardia, cardiac arrhythmias
      • Gastrointestinal: nausea, vomiting, abdominal cramps, diarrhea
      • Fever is typically absent
    • DDx includes Transfusion Associated Hypotension (TAH) – seen in transfused patients receiving ACE inhibitors (transfusion results in bradykinin synthesis, clearance of which is blocked by the ACEI)
    • Treatment of severe allergic/anaphylactic reactions:
      • STOP transfusion
      • Treat hypotension
        • Epinephrine 1:1000 (1 mg/mL) 0.3-0.5mL SC/IM q15 minutes
        • Epinephrine 1:10,000 (0.1 mg/mL) 1mL in 10mL NS IV for severe symptoms
        • IV fluids
      • Bronchospasm
        • Albuterol nebulized/MDI
        • Supplemental O2
      • Prevention:
        • If recipient has history of anaphylactic transfusion reaction(s) in the past, can consider washing RBCs or platelets prior to transfusion to reduce plasma volume. (Though washing does markedly reduce function and survival of both RBCs and platelets.)
          • Can also consider premedication regimen with glucocorticoids (prednisone or hydrocortisone) and H1/H2-blockade.
        • If recipient is known to have absolute IgA deficiency with anti-IgA antibodies, can request Blood Bank obtain IgA-deficient blood products.

 

  • Transfusion Transmitted Infection
    • Many potential pathogens implicated, from bacteria to viruses to prions
    • Symptoms can manifest from immediately to years post-transfusion
    • Most acute and dangerous are “Septic Transfusion Reactions,” almost always resulting from transfusion-transmitted bacterial infection from contaminated units
      • 3rd most common cause of transfusion-related fatalities reported to FDA
      • Most commonly implicated blood products are platelets; RBCs far less frequently implicated
        • Estimated rates of symptomatic bacteremia from platelet transfusion range from 1:15,000-100,000 transfusions; RBC rates from 1:200,000-5,000,000.
        • Sepsis from contaminated platelets under-recognized and under-reported
      • Both GPCs and GNRs implicated in contaminated platelet units – common organisms include Staph aureus, Staph epidermidis, Strep , Klebisella spp., Serratia spp., Salmonella spp.
      • RBCs typically contaminated with cold-resistant organisms – Yersinia enterocolitica, Pseudomonas
      • If septic transfusion reaction suspected:
        • STOP THE TRANSFUSION IMMEDIATELY
        • Retain implicated product(s), inform Blood Bank of potential contamination, and return products to Blood Bank promptly
        • Treat for sepsis/septic shock as per standard practice (early empiric Abx to cover possible pathogens listed above)
      • Always think about bacterial contamination when evaluating febrile transfusion reactions, especially if platelets were transfused
  • Delayed Hemolytic Transfusion Reaction (DHTR)
    • Usually clinically mild hemolytic reaction
    • Incidence as high as 1:2,339-11,652 units transfused
    • Results from an anamnestic response to transfused RBCs in a previously allo-immunized patient (i.e.: prior anti-RBC antigen antibodies)
      • Can occur in the presence of a negative antibody screen – blood group antibodies can drop below detectable levels but re-exposure can rapidly boost allo-antibody production leading to hemolysis
    • Clinical presentation:
      • Most common – anemia symptoms within 1-2 weeks of transfusion
      • Less common – fever, leukocytosis, mild jaundice
      • Rare – hemoglobinuria, renal failure
    • Lab Findings:
      • Spherocytes on peripheral smear
      • Decreased hemoglobin, elevated bilirubin, decreased haptoglobin
      • Positive DAT (“Direct Coombs”) +/- positive antibody screen (usually within 7 days of transfusion)
    • Treatment:
      • No specific treatment, though monitoring renal function reasonable
      • Future transfusions should use RBCs lacking antigens implicated in anamnestic response
    • Can be particularly problematic in patients with sickle cell disease
      • Transfusion may trigger sickle crises, which can evolve into hyperhemolysis syndrome
        • Hyperhemolysis is a life-threatening condition where RBC transfusion triggers hemolysis of both allogenic and autologous blood.
        • Suspect if Hgb levels drop rapidly post-transfusion, especially if post-transfusion Hgb is lower pre-transfusion level
        • If suspected, hold/stop all RBC transfusions, and contact Blood Bank IMMEDIATELY

 

  • Delayed Serological Transfusion Reaction (DSTR)
    • Anamnestic response to transfusion but without evidence of hemolysis
    • More common than DHTR
    • Clinically benign

 

  • Post-Transfusion Purpura (PTP)
    • An uncommon complication of transfusion, analogous to hyperhemolysis syndrome but involving platelets rather than RBCs
    • Clinical presentation:
      • Abrupt onset of severe, self-limited thrombocytopenia (<10,000/µL), ~9 days after transfusion
      • Purpura, epistaxis, hematuria, GI bleeding common
      • Mortality can occur from intracranial hemorrhage in severe cases
    • Demographics:
      • Most patients have previously been pregnant or previously transfused
      • Classically seen in multiparous women
      • Male:Female ratio of 1:5
    • Risk factors:
      • Most commonly follows transfusion of RBCs, but has been reported following transfusion of platelets or plasma.
    • Pathophysiology:
      • Anamnestic reponse to platelet antigens, most commonly against antigens on the GPIIb/IIIa complex, the majority being allo-antibodies against HPA-1a
      • No definitive explanation for why an anamnestic alloimmune response leads to destruction of autologous platelets
    • Treatment:
      • High-dose IVIG for 3-5 days is first line therapy
      • Steroids considered adjunctive treatment only
      • Platelet transfusions may be considered as temporizing measure only in the setting of major hemorrhage

 

  • Transfusion Associated Graft-Versus-Host Disease (TA-GVHD)
    • Very rare, usually fatal complication of transfusion
    • Results from attack of host (transfusion recipient) tissues, including bone marrow by viable donor (blood product) lymphocytes
    • Acute, severe bone marrow aplasia and resulting sepsis is the primary cause of death
    • RBCs, platelets and fresh plasma have been implicated in TA-GVHD, FFP and cryoprecipitate have not
    • Clinical manifestations:
      • Symptoms develop 4-30 days after transfusion
      • Symptoms include fever, erythematous maculopapular rash, nausea/vomiting, watery or bloody diarrhea, hepatitis, lymphadenopathy and pancytopenia
    • Pathogenesis:
      • Immunocompetent patients receiving “partially HLA-matched” blood products
        • In brief, donor lymphocytes recognize host tissues as foreign, but the host immune system sees the donor lymphocytes as self. Tissue destruction results from attack of donor lymphocytes on host.
      • In immunodeficient individuals, tissue injury results from HLA-disparate donor lymphocytes not destroyed by recipient’s immune syste
    • Risk Factors:
      • Bone marrow and stem cell transplant recipients
      • Congenital T-cell immunodeficiency syndromes
      • Fetal or neonatal transfusion recipients
      • Receipt of transfusion from blood relatives
      • Hematologic malignancy
      • Receipt of fludarabine or alemtuzumab (Campath, a potent anti-CD52 monoclonal antibody)
      • Not risk factors: HIV/AIDS, non-hematologic malignancy, solid organ transplant
    • Prevention/Treatment:
      • Irradiation of RBCs and platelets for at-risk patients
      • No good treatment options — >90% mortality
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