Transfusion Troubles: A review of transfusion reactions and management- A Resident Clinical Pearl

Author: Dr. Victoria Landry (iFMEM R2)
Copyedited by Dr. Mark McGraw CCFP EM

Case: A  70 year old female presents to the emergency department via EMS with chest pain and weakness. Her systolic pressure is in the 90s with a MAP of 68. She is placed in a monitored bed. She recently had a STEMI and was successfully thrombolysed but also found to have an LV thrombus. She was discharged on Plavix and warfarin.

Today her bloodwork shows a hemoglobin of 50 and INR 11.6. In the ED she was given 5mg of IV vitamin K. She was typed and crossmatched for three units of blood which were initiated at 85ml/hr. An hour into transfusion she is noted to have temperature of 38.1°C.

You review the differential of transfusion reactions presenting with fever and their features….

• Acute intravascular hemolytic reaction
  • Cause: recipient antibodies induce hemolysis of donor’s RBCs, usually due to ABO incompatibility (resulting from clerical error) ¹
  • Presentation: fever, chills, hemoglobinuria, pain (transfusion site, low back, headache), hypotension, nausea/vomiting, dyspnea, renal failure, DIC, flushing, tachycardia, pulmonary edema, bleeding, bronchospasm¹
• Febrile nonhemolytic transfusion reaction¹
  • Cause: recipient antibody vs donor WBCs, release of cytokines produced during storage¹
  • Presentation: fever within 4hrs of transfusion, chills, rigors, nausea/vomiting, hypotension, headache, myalgias, dyspnea, tachycardia, chest pain usually mild but can be life threatening if tenuous cardiopulmonary status ¹
  • *Consider using leukocyte reduced blood products in the case of recurrent febrile transfusion reactions ¹
• Delayed extravascular hemolytic reaction (FNHTR) ²
  • Cause: in previously sensitized patient, recipient antibodies have delayed reaction to RBC antigens¹, may occur with transfusion-transmitted malaria and babesiosis²
  • Presentation: 3 days to 2 weeks² after transfusion hemolytic anemia occurs with low grade fever or entirely asymptomatic, rarely causes hemodynamic instability¹
• Bacterial sepsis/contamination²
  • Cause: contamination during storage or processing¹
  • Presentation: variable based on underlying source, occurs more common in platelets due to storage temperature 20-24°C ²

You consider your next steps….

• Stop the transfusion^1,2
• Send remaining donor blood and post-transfusion recipient blood specimen for repeat type and cross-match (blood bank will determine if syndrome was due to transfusion reaction)¹
• Send infectious work up:²
  • Bacterial cultures and gram stain of transfusion unit and attached IV solutions
  • Blood culture on patient taken from different IV site
  • Post transfusion urine culture
• If transfusion-associated sepsis suspected, give broad-spectrum antibiotics immediately¹
• Send hemolytic work up¹
  • Direct and indirect coombs test (DAT)
  • CBC, Cr, PT, aPTT
  • Haptoglobin, bilirubin, LDH, plasma free Hgb, urine hemoglobin
• Treat acute intravascular hemolytic reaction and febrile nonhemolytic transfusion reaction the same as initially can’t distinguish between the two¹
  • Maintain renal blood flow and urine output with IV fluids, mannitol, furosemide
  • Cardiorespiratory support (vasopressors) as needed
  • Manage hemorrhage and DIC
  • Acetaminophen, meperidine 25-50mg IV for severe rigors if no contraindications²

Case continued: You re-assess your patient and find her to be asymptomatic aside from having chills and mild rigors.  You stop the transfusion, notify the blood bank and send the remaining blood back to them, send a hemolytic work up, and draw patient blood cultures as well as send a urine culture. You give her acetaminophen. Since she remains otherwise asymptomatic with unchanged stable vitals and negative hemolytic work up, you determine this was a febrile nonhemolytic reaction. You make a note in her chart so that next time she receives blood products she can be pre-medicated with acetaminophen.

After successfully managing this patient, your review other possible transfusion reactions.

If the patient had urticaria, you would consider….

• Allergic reaction: immune response to transfused plasma proteins¹
  • Presentation: urticaria, +/- mild upper respiratory symptoms (cough, wheeze), nausea vomit, cramps, diarrhea²
  • Treatment: stop transfusion, diphenhydramine/antihistamines, notify blood bank, restart transfusion slowly if symptoms resolve/are very mild¹
• Anaphylaxis: 5% of transfusion related fatalities; reaction within 45min to 1hr after start of transfusion²
  • Presentation: urticaria, dyspnea, bronchospasm, hypotension, tachycardia, shock, stridor, wheeze, chest pain, anxiety, nausea, vomiting¹
  • Treatment: stop transfusion, epinephrine, steroids, diphenhydramine, H2 blockers, bronchodilators, vasopressors PRN, do NOT restart transfusion¹
  • Note: those with IgA deficiency may have severe reactions to IgA in donor products (minimized by washing plasma from RBCs) ¹

If the patient had dyspnea, you would consider….

• TACO (transfusion-associated circulatory overload): most common cause of death from transfusion²
  • Presentation: dyspnea, hypoxia, pulmonary edema, orthopnea, cyanosis, tachycardia, increased venous pressure, hypertension²
  • To mitigate, transfuse slowly (2-4ml/kg/hr) in those at risk (age >70yrs, infants, Hgb <50, renal impairment, fluid overload, cardiac dysfunction) ²
  • Treatment: stop transfusion, diuretics&O2 PRN, can consider restarting transfusion at reduced rate if clinical status allows¹
• TRALI (transfusion-related acute lung injury):
  • Cause not fully understood; donor anti-leukocyte antibodies produce polymorphonuclear leukocyte degranulation in lung¹
  • Definition: acute lung injury (acute onset hypoxemia with bilateral lung infiltrates/pulmonary edema on CXR and no evidence of circulatory overload) within 6hrs of completion of transfusion, and no other risk factors for acute lung injury (ALI) ² (“possible TRALI” if ALI risk factors present)
  • Presentation: dyspnea, hypoxemia, fever, hypotension, may be followed by acute transient leukopenia²
  • More common with plasma, RBCs, platelets¹
  • Treatment: stop transfusion, resolves in 24-72hrs with supportive care¹
    • mechanical ventilation required in 72% of cases, death in 5-10%²
    • distinguish from TACO, as aggressive diuresis in TRALI can cause rapid deterioration; steroids not helpful¹
    • notify blood bank to perform special donor and recipient testing²

*ALI risk factors: aspiration, pneumonia, toxic inhalation, lung contusion, near drowning, severe sepsis, shock, trauma, burn injury, acute pancreatitis, cardiopulmonary bypass, drug overdose²

If the patient develops hypotension (>30mmHg drop in systolic or diastolic BP; pediatric: >25% drop in systolic BP) ², you would consider….

• Acute hemolytic transfusion reaction
• Bacterial sepsis
• Severe febrile non-hemolytic transfusion reaction
• Bradykinin mediated hypotension (ACE breaks down bradykinin, usually pt takes ACEi)
• TRALI
• Anaphylaxis

Complications of massive transfusion (>10u of RBCs in 24hrs) ²

• Independent risk factor for multi-organ failure²
• Dilutional coagulopathy: monitor with q1h bloodwork, transfuse to keep ²
  • platelets >50 x10⁹/L (>100 in head injury)
  • INR <1.8
  • Fibrinogen >2.0 g/L
  • Give 1g IV TXA bolus then 1g IV over 8 hrs
• Hypothermia: higher risk with >5 units blood; mortality inversely related to core temperature²
  • low temperature increases blood loss and causes cardiac arrhythmias, platelet dysfunction, reduced citrate clearance, decreased cardiac output, hypotension, decreased coagulation factor activity²
  • Maintain core temp >36°C²
• Citrate (anticoagulant in blood components) accumulation due to liver metabolism of citrate to bicarbonate being overwhelmed ¹
  • Hypocalcemia: citrate binds calcium²
  • Hypomagnesemia: citrate binds magnesium²
  • Hypokalemia: Excess bicarbonate generated by metabolism of citrate, causing alkalemia and driving potassium into cells¹
• Hyperkalemia: Potassium in blood increases during storage (neonates and those with renal insufficiency at most risk) ¹
• Metabolic acidosis (rare; from acid pH of blood products) ²

Other complications

• Cytopenias After Transfusion²
  • Transfusion-associated graft versus host disease (TA GvHD)
  • Post transfusion purpura (PTP)
  • Transfusion-related alloimmune thrombocytopenia
  • Transfusion-related alloimmune neutropenia
  • (See Bloody Easy 4 for more details https://transfusionontario.org/wp-content/uploads/2020/06/EN_BE4-JULY11_FINAL.pdf )
• Hemolysis not related to RBC alloantibodies²
  • Use of hypotonic IV solutions with RBC transfusions
  • Medical device-related (ex: cell saver or blood warmer malfunction)
  • Overheating of RBCs due to improper storage
  • Freezing of RBCs
  • Transfusion under pressure through small bore needle
  • Outdated RBCs

See – EM Cases – Massive Hemorrhage Protocols

Concluding thoughts….

Transfusion pearls¹

• Complications occur in 20% of all transfusions – most are minor, life-threatening reactions are rare
• Watch for unexpected changes in patient status to identify reactions
• First steps in all transfusion reactions:
  • Stop transfusion immediately
  • Contact blood bank (the transfusion physician is a valuable resource)
  • Draw new specimen to re-type and cross-match to resume transfusion
• Do NOT abandon all transfusion! Typically the reaction is due to interaction between individual patient and individual unit – thus is safe if appropriately matched

References

1. Coil C.J., & Santen S.A. (2020). Transfusion therapy. Tintinalli J.E., & Ma O, & Yealy D.M., & Meckler G.D., & Stapczynski J, & Cline D.M., & Thomas S.H.(Eds.), Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 9e. McGraw Hill. https://accessmedicine-mhmedical-com.ezproxy.library.dal.ca/content.aspx?bookid=2353&sectionid=221179053

2. Callum, J. L., Ontario Regional Blood Coordinating Network Staff, Pinkerton, P. H., Lima, A., Lin, Y., Karbouti, K., Lieberman, L., Pendergrast, J. M., Robitaille, N., & Tinmouth, A. T. (2016). Bloody Easy 4: Blood Transfusions, Blood Alternatives and Transfusion Reactions. Ontario Regional Blood Coordinating Network. https://books.google.ca/books?id=6G1ZDQEACAAJ

3. Helman, A. EM Cases Episode 152: The 7 Ts of Massive Hemorrhage Protocols. February 9, 2021. https://emergencymedicinecases.com/7-ts-massive-hemorrhage-protocols/

Figure 2: Red Blood Cell Pre-Transfusion Checklist (Bloody Easy 4) 2

EM Cases – Massive Hemorrhage Protocols