Author: Natalie Bertrand, MD

Editor: Naillid Felipe, MD

 

Background:

  • Definition: adverse reaction to blood product administration
  • Incidence: more common in children than adults, except for delayed hemolytic transfusion reactions
    • Allergic (non-anaphylaxis) – Platelets 1-3%; RBCs 0.1-0.3% 
    • Febrile Non-hemolytic (FNHTR) – 1%
    • Transfusion-associated circulatory overload (TACO) – 1%
    • Transfusion-related acute lung injury (TRALI) – <0.01%
    • Anaphylaxis/ABO incompatibility – 1:20,000 – 1:50,000
    • Acute Hemolytic – 1:76,000
    • Sepsis – Platelets 1:50,000; RBCs 1:5,000,000
    • Hypotensive Reaction – <0.01%
  • Mortality – 0.6-2.3 per 1,000,000

 

Pathophysiology and General Management

  • Monitor for any adverse reaction from the onset of transfusion for 24 hours-10 days

    • Most common clinical presentation – fever/chills, pruritus, and urticaria
    • Severe reaction – respiratory distress/hypoxia, hypotension, altered mental status, syncope, hemoglobinuria, flank/back pain, jaundice, abnormal bleeding, oliguria
  • Management immediate actions:
    • Always stop the transfusion
    • Assess the patient
    • Keep an open IV line
    • Re-confirm the correct product/patient
    • Inform the transfusion service/blood bank
  • Main signs and symptoms:
    • Fever and chills
      • Febrile Non-Hemolytic Transfusion Reaction, Acute Hemolytic Transfusion Reaction, Delayed Hemolytic Transfusion Reaction, Sepsis, Transfusion Related Acute Lung Injury
    • Respiratory distress 
      • Transfusion Associated Circulatory Overload, Transfusion Related Acute Lung Injury, Anaphylaxis
    • Hypotension  
      • Hypotensive Transfusion Reaction, Anaphylaxis, Acute Hemolytic Transfusion Reaction, Sepsis, Transfusion Related Acute Lung Injury

 

Transfusion Reactions: Allergic

 

Allergic Reaction (Mild)

  • Clinical Presentation
    • Symptom Onset: 0-4 Hours
    • Pruritus, Urticaria
  • Pathophysiology
    • Antigen-antibody interaction
    • Type I immediate hypersensitivity (IgE mediated)
    • Usually against donor serum proteins
  • Management
    • Antihistamines:
      • Diphenhydramine 25-50 mg
      • Famotidine (20-40 mg)
    • Observe for 30 minutes
    • May continue transfusion once symptoms stabilize or resolve
    • Work-up: No labs needed for isolated pruritus/urticaria

 

Anaphylaxis

  • Clinical Presentation:
    • Symptom Onset: 0-10 minutes
    • Pruritus/Urticaria, Respiratory Distress, Wheezing, Angioedema, Hypotension, Nausea/Vomiting
  • Pathophysiology:
    • IgA-deficient recipient with anti-IgA antibodies to the IgA in the transfused product
  • Management:
    • Epinephrine IM 0.01mg/kg every 5-15min OR Epipen IM 0.3 mg
    • IF requiring IM Epi >3x, switch to IV Epi, 0.05-0.1 mg
    • IVF bolus
    • Diphenhydramine 25-50 mg
    • Famotidine 20-40 mg
    • Inhaled bronchodilators or supplemental O2 > BIPAP > Intubation
    • Work-up: CXR, IgA titers

 

Transfusion Reactions: Febrile

  • Differential Diagnosis: Febrile Non-Hemolytic Transfusion Reaction, Acute Hemolytic Transfusion Reaction, Delayed Hemolytic Transfusion Reaction, Sepsis, Transfusion Related Acute Lung Injury

 

Febrile Non-Hemolytic Transfusion Reaction

  • Clinical Presentation:
    • Symptom Onset: 0-4 hours
    • Fevers/chills
    • Diagnosis of exclusion
  • Pathophysiology:
    • Cytokine release from non-leukoreduced blood product
  • Management:
    • Symptom management with antipyretics: Acetaminophen 325-1000mg
    • Work-up: Recommend ruling out hemolysis and sepsis

 

Acute Hemolytic Transfusion Reaction

  • Clinical Presentation:
    • Symptom Onset: 0-4 hours
    • Fever/chills, flank and back pain, bleeding, oliguria, pink urine/hemoglobinuria, pink serum (rare), negative direct antiglobulin test (DAT)
  • Pathophysiology:
    • Recipient immune cells attack transfusion product leading to intravascular hemolysis
    • Often due to ABO incompatibility due to lab or administration error
  • Management:
    • Dilution – IV hydration – 500ml NS/hr until resolution of hemoglobinuria
    • Diuresis – Furosemide IV to main renal output of 1 mL/kg/hr
    • IF DIC, consider need for additional platelets, plasma, or cryoprecipitate transfusion 
    • Work-up: CBC (smear), CMP, reticulocyte count, coags, LDH, haptoglobin, fibrinogen, dimer, DAT, consider nephrology, heme, and ICU consult

 

Delayed Hemolytic Transfusion Reaction

  • Clinical Presentation:
    • Symptom Onset: > 24 hours
    • Fever/chills, chest pain, dyspnea, light-headedness, jaundice, anemia with low reticulocyte count, hemolysis (elevated d-dimer, bilirubin, LDH), positive direct antiglobulin test (DAT), kidney injury
  • Pathophysiology:
    • More common in sickle cell disease
    • Re-exposure to antigens from prior transfusions leading to intravascular hemolysis
  • Management:
    • Similar to acute hemolytic transfusion reaction

 

Sepsis

  • Clinical Presentation:
    • Symptom Onset: 0-1 hours
    • Fever/chills, hypotension, SIRS
    • Must exclude AHTR and TRALI
  • Pathophysiology:
    • IV administration of microorganism, typically higher volume of organism delivery than peripheral infection or other typical infection sources
    • More common in platelet transfusion due to storage at room temperature
  • Management:
    • IVF resuscitation per sepsis guidelines
    • Broad spectrum antibiotics
    • Hemodynamic support
    • Work-up: Blood cultures on patient and transfusion product, UA, CXR, EKG

 

Transfusion Reactions: Respiratory Distress

  • Differential Diagnosis: Transfusion Associated Circulatory Overload, Transfusion Related Acute Lung Injury, Anaphylaxis

 

Transfusion Associated Circulatory Overload (TACO)

  • Clinical Presentation:
    • Symptom Onset: 4-6 hours
    • Respiratory distress, hypoxia, hypertension, elevated central venous pressure, elevated BNP, evidence of pulmonary edema (CXR or POCUS)
  • Pathophysiology:
    • Pulmonary edema caused by volume overload
    • Most common in elderly, children, patients with underlying heart failure or who receive large volume of blood products
    • Transudative pulmonary edema fluid due to cardiogenic source
  • Management:
    • Diuresis – Furosemide IV, dosing dependent on diuretic naivety
    • Respiratory support – Oxygen > BIPAP > Intubation
    • Work-up: CXR, EKG, BNP, Troponin, ABG, consider cardiology consult

 

Transfusion Related Acute Lung Injury

  • Clinical Presentation:
    • Symptom Onset: 4-6 hours
    • Fever/chills, respiratory distress, hypoxia, hypotension, pink/frothy sputum, bilateral chest x-ray infiltrates
  • Pathophysiology:
    • Transfusion product with anti-HLA/anti-HNA causing recipient immune system to activate in lungs causing local cytotoxic effects
    • Exudative pulmonary edema fluid due to inflammatory source
  • Management:
    • Respiratory support
    • ARDS management: https://coreem.net/podcast/episode-195-ards/

 

Transfusion Reaction: Hypotension

Differential Diagnosis: Hypotensive Transfusion Reaction, Anaphylaxis, Acute Hemolytic Transfusion Reaction, Sepsis, Transfusion Related Acute Lung Injury

Hypotensive Transfusion Reaction

  • Clinical Presentation:
    • Symptom Onset: 0-1 hours
    • Hypotension SBP drop by > 30 mm Hg or SBP < 80 mm Hg
    • Rapid improvement after halting transfusion
    • Must exclude other etiologies of hypotension
  • Pathophysiology:
    • Unclear mechanism, likely bradykinin induced
    • Risk factors: ACE inhibitor use and leukocyte reduced product
    • Most common with platelet transfusion
  • Management:
    • IV Fluids as needed
    • Hold ACE inhibitors prior to transfusion
    • Work-up for alternative etiologies as indicated

 

Transfusion Reaction: Transfusion Associated Graft vs Host

  • Clinical Presentation:
    • Symptom onset: 3-30 days
    • Fever/chills, rash/pruritus, nausea and vomiting, diarrhea, dyspnea
  • Pathophysiology:
    • Donor T-cells attack recipient cells and tissue
    • More common in  patients with hematologic malignancies or stem cell transplants
    • Labs demonstrate pancytopenia
    • Mortality 90%
  • Management:
    • Emergent Hematology/Oncology consult (might need immunosuppression or urgent stem cell transplant)

 

Diagnosis

Assessment

  • Always:
    • Vitals
    • Blood glucose
    • Detailed history of event and PMHx
    • Repeat physical exam
    • Re-confirm the correct product/patient
  • Often:
    • Complete Blood Counts
    • Complete Metabolic Panel (including LFTs)
    • Repeat ABO compatibility
    • Additional antibody screen
    • Repeat crossmatch with pre-and post-transfusion specimens 
  • Symptom Specific
    • VBG/ABG
    • Direct antiglobulin testing (Coombs)
    • Hemolysis labs – haptoglobin, LDH, unconjugated bilirubin, and reticulocyte count
    • Cardiac labs – Trop, BNP
    • DIC labs – PT, PTT, fibrinogen, and D-dimer
    • UA – pink color and analysis for free hemoglobin
    • Serial H/H
    • CXR
    • IgA levels

Information to send with the sample to blood bank for transfusion reaction:

    • Patient label with MRN
    • Reason for the transfusion
    • Vital signs before, during, and current
    • PMHx of transfusion reaction 
    • Pretransfusion medications 
    • Time of transfusion initiation, symptom onset, and transfusion stop
    • Detailed patient symptoms

 

Disposition and Next Steps

  • Restart the transfusion?
    • YES, restart
      • Stable vital signs, symptoms resolved, correct product confirmed
      • AND Minor allergic reaction, TACO, FNHR
      • AND <4 hours from onset of transfusion (regulations may be facility dependent)
    • NO, do NOT restart
      • AHTR, TRALI, anaphylaxis, sepsis
      • OR Unstable vitals signs, persistent symptoms, incorrect product/patient
  • Admit for:
    • Persistently unstable VS
    • Sepsis
    • Hemolysis
    • Respiratory distress
    • Need for further transfusions
  • When to discharge:
    • Stable VS
    • Symptoms resolved
    • Underlying need for transfusion has been addressed
  • Prevention of Transfusion Reactions
    • Correct labeling of T&S in ED level and cross matching at blood bank level
    • Allergic Reactions – use WASHED products for patients with IgA deficiency or prior allergic reactions
    • Delayed HTR – use LEUKOREDUCED products for patients with SCD or prior hemolytic reactions
    • Transfusion Associated GVHD – use IRRADIATED products for patient with hematologic malignancies & stem cell transplants 
    • TACO – transfuse slower or with HD for high risk patients (HF, ESRD etc)
    • No evidence for use of APAP or benadryl prophylactically

 

References:

  1. Benson AB, Moss M, Silliman CC. Transfusion-related acute lung injury (TRALI): a clinical review with emphasis on the critically ill. Br J Haematol. 2009 Nov;147(4):431-43. https://doi.org/10.1111/j.1365-2141.2009.07840
  2. Emery, M. Blood and blood components. In: Marx J, ed. Rosen’s emergency medicine. 8th ed. Philadelphia, PA: Elsevier; 2014:75-80.
  4. Hendey G. Transfusion Reactions and Complications. In: Wolfson A, ed. Harwood-Nuss’ Clinical Practice of Emergency Medicine. 6th ed. Philadelphia, PA: Wolters Kluwer; 2015:979-984.
  5. Hirayama F. Current understanding of allergic transfusion reactions: incidence, pathogenesis, laboratory tests, prevention and treatment. Br J Haematol. 2013 Feb;160(4):434-44. https://doi.org/10.1111/bjh.12150
  6. Kwon, S. S., Kim, S., & Kim, H. O. (2022). Incidence and characteristics of hypotensive transfusion reaction: 10-Year experience in a single center. Transfusion, 62(11), 2245–2253. https://doi.org/10.1111/trf.17099
  7. Metcalf, R. A., Bakhtary, S., Goodnough, L. T., & Andrews, J. (2016). Clinical pattern in hypotensive transfusion reactions. Anesthesia & Analgesia, 123(2), 268–273. https://doi.org/10.1213/ane.0000000000001387
  8. Osterman, J. L., & Arora, S. (2017). Blood product transfusions and reactions. Hematology/Oncology Clinics of North America, 31(6), 1159–1170. https://doi.org/10.1016/j.hoc.2017.08.014
  9. Pollard R, Boraski M, Block JG. Hypotensive Transfusion Reaction Treated With Vasopressin in a Patient Taking an Angiotensin-Converting Enzyme Inhibitor: A Case Report. A A Case Rep. 2017 Jul 1;9(1):4-8. https://doi.org/10.1213/XAA.0000000000000507
  10. Savage, W. J., Tobian, A. A. R., Savage, J. H., Wood, R. A., Schroeder, J. T., & Ness, P. M. (2012). Scratching the surface of allergic transfusion reactions. Transfusion, 53(6), 1361–1371. https://doi.org/10.1111/j.1537-2995.2012.03892.x
  11. Skeate, R. C., & Eastlund, T. (2007). Distinguishing between transfusion related acute lung injury and transfusion associated circulatory overload. Current Opinion in Hematology, 14(6), 682–687. https://doi.org/10.1097/moh.0b013e3282ef195a
  12. Vamvakas, E. C., & Blajchman, M. A. (2009). Transfusion-related mortality: The ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood, 113(15), 3406–3417. https://doi.org/10.1182/blood-2008-10-167643
  13. Vlaar, A. P. J., Toy, P., Fung, M., Looney, M. R., Juffermans, N. P., Bux, J., Bolton‐Maggs, P., Peters, A. L., Silliman, C. C., Kor, D. J., & Kleinman, S. (2019). A consensus redefinition of transfusion‐related acute lung injury. Transfusion, 59(7), 2465–2476. https://doi.org/10.1111/trf.15311