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Transfusion Reactions: What? How? What now? Margo Rollins, MD Assistant Professor of Pathology Emory University SOM Assistant Medical Director for Tissue, Transfusion & Apheresis Children s Healthcare of Atlanta Immucor Webinar Series January 26, 2018

Disclosures None

Objectives Define and categorize transfusion reactions Describe clinical manifestations of specific transfusion reactions Discuss patient evaluation and management when transfusion reaction is suspected

Background Blood transfusions are one of the most common procedures for hospitalized pts Transfusion reactions are the most frequent adverse event associated with the administration of blood products A transfusion reaction can lead to severe discomfort for the patient and extra cost burden to the healthcare system Although rare, reactions can be fatal 1: 200,000 420,000 units associated with death Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836.

Background https://patientsafety.aabb.org/ NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Transfusion Reactions and Prevalence Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836.

Transfusion Risks Over Time Hillyer, Shaz, Zimring, Abshire. Transfusion Medicine and Hemostasis, 2009

Technical Definition of Transfusion Reactions Each CDC defined transfusion associated adverse reaction must be classified according to: Reaction specific case definition Severity Imputability Surveillance definitions are distinctly different from clinical definitions Designed to capture data consistently and reliably in order to identify trends and inform quality improvement practices Not intended as clinical diagnostic criteria or to provide treatment guidance https://patientsafety.aabb.org/ NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Technical Definition of Transfusion Reactions https://patientsafety.aabb.org/content/public-docs/linkedcontent/aabb-center-for-patient-safety-double-sided-flyer.pdf

General Management Rules Transfusion reactions are usually reported to the physician by the nurse administering the blood product and often cause a change in vital signs or a new symptom Depending on the severity, the main treatment strategy for all reaction types is: STOP the transfusion and keep the intravenous line open with normal isotonic saline Start supportive care to address the patient s cardiac, respiratory, and renal functions as necessary Provide symptomatic therapy The blood product labelling and patient identification should be rechecked to confirm that the patient received their intended product and the reaction should be reported to the blood transfusion laboratory for additional testing Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836.

Allergic Transfusion Reaction (Mild) Definition Occurs within 4hrs of cessation of transfusion Mild urticaria Frequently associated with platelet transfusions (302/100,000 platelet units). Hives, angioedema, pruritis, erythema, flushing NOT ASSOCIATED WITH VITAL SIGN CHANGES IgE response to soluble proteins in donor plasma, release histamine, leukotrienes, prostaglandins Management Cutaneous symptoms only) H₁ antihistamine Transfusion can be restarted with the same unit at a slower rate if symptoms resolve Discontinue transfusion if : Symptoms recur Additional symptoms appear beyond local cutaneous manifestations Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Anaphylactic Transfusion Reaction (Severe) Definition Occurs within 4hrs of cessation of transfusion Incidence 8/100,000 units Usually occurs during / shortly after cessation of transfusion Mucocutaneous symptoms in addition to respiratory and/or cardiovascular systems: Hypotension, hypotonia, syncope Laryngeal (tightness in the throat, dysphagia, dysphonia, hoarseness, stridor) or pulmonary (dyspnea, cough, wheezing, bronchospasm, hypoxemia) symptoms Management PROMPT IM administration of epinephrine Supportive measures as clinically indicated Second line drugs: H₁ antihistamine Bronchodilators (β₂ adrenergic agonist) Glucocorticoids (IV) H₂ antihistamine R/o serum protein deficiency (immunoglobulin A and haptoglobin) Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Allergic Transfusion Reaction: Pre-medications Previous mild allergic transfusion reaction: No evidence to support routine prophylaxis with antihistamines or glucocorticoids Previous moderate to severe allergic transfusion reaction: Counselled about their diagnosis and needs for future transfusion Premedication with antihistamines Plasma reduction: Centrifugation Washing Platelets stored in additive solutions Reduces incidence or decreases severity of future reactions Use of corticosteroids as premedication has not been studied but is used widely clinically Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Acute Hemolytic Transfusion Reaction (AHTR) Definition During or within 24 hours of cessation of transfusion with new onset of the following: Back/flank pain, renal failure Chills/rigors, fever DIC, oozing at IV site Hematuria (gross) Hypotension fibrinogen OR haptoglobin bilirubin OR LDH Hemoglobin emia/uria Spherocytes on blood film +DAT (anti IgG or anti C3) +Elution (Allo Abs present on the transfused RBCs) Management STOP THE TRANSFUSION IMMEDIATELY Post transfusion labs (CBCD, CMP, DAT, Urinalysis, Coags) Management is supportive No evidence exists for the use of any specific intervention after an ABO incompatible RBC transfusion (case reports suggest use of RBCx or PLEX, IVIG, and complement inhibiting drugs) Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Acute Hemolytic Transfusion Reaction (AHTR) Two forms of AHTR: Immune mediated Clinical findings and demonstration of serological incompatibility Result from infusion of RBCs that are incompatible with the pt s anti A, anti B, or other RBC antibodies (Abs) Usually caused by failure of Pt identification at specimen collection or transfusion, and less commonly by infusion of incompatible plasma, usually from an apheresis platelet transfusion Non Immune mediated Occur when RBCs are hemolyzed by factors other than Abs: Co administration of RBCs with incompatible crystalloid solution Incorrect storage of blood Use of malfunctioning or non validated administration systems Commonly responsible Abs: Rh, Kell, Duffy, Kidd, MNS, Diego Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Delayed Hemolytic Transfusion Reaction (DHTR) Definition +DAT for Abs 24hrs 28 days after cessation of transfusion + Elution with alloantibody present on the transfused RBC Newly identified RBC allo Abs in recipient serum Inadequate rise of posttransfusion Hgb or rapid fall in Hgb back to pre transfusion levels Dark urine Jaundice (45 50%) Fever, chills Pain (chest, abdominal or back) Dyspnea Management Post transfusion labs (CBCD, CMP, DAT, Urinalysis, Coags) Management is supportive Most patients do not require treatment Additional transfusions to maintain desired hemoglobin RBCx to remove incompatible red cells Anti CD20 + steroids have been proposed for management in severe cases Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Delayed Hemolytic Transfusion Reaction (DHTR) Anamnestic immune response Commonly responsible Abs: Rh, Kell, Duffy, Kidd, MNS, Diego The recipient is unknowingly EXPOSED to RBCs that express foreign antigens Foreign antigen causes a rise in RBC Ab titers 24 h to 28 days after transfusion accompanied by clinical manifestations Incidence: 1/2500 transfusions Rises to 11% in pts with sickle cell disease (SCD) Pts at risk: history of RBC Abs (pregnancy or transfusion exposure) Ab titer subsequently to levels undetectable by rou ne Ab detec on tes ng Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Special Note: Hyper-hemolysis in SCD RARE Mainly caused by destruction of both donor AND recipient RBCs Exact mechanism is still not well understood Autologous RBC destruction is bystander hemolysis = sickled RBCs are destroyed by Abs without expressing the specific antigen against which this Ab is directed RBC destruction is associated with activation of Mφ peripheral destruction Characterized by: Severe anemia (Hgb lower than pre transfusion levels) Pain, Fever Signs of hemolysis (jaundice, LDH, ibili, and hemoglobinuria) Reticulocytopenia Reticulocytosis Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836.

Special Note: Hyper-hemolysis in SCD Classified into acute or delayed Acute: Symptoms appear within seven days of receiving RBCs DAT generally negative Delayed: Usually appears seven days after a transfusion DAT results are usually positive New allo Abs can be detected in the pt's serum DO NOT TRANSFUSE unless life threatening exacerbation of hyper hemolysis Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836.

Febrile Non Hemolytic Transfusion Reaction (FNHTR) Definition Occurs during or within 4 hours of cessation of transfusion Fever > 38 C/100.4 F oral and a change of at least 1 C/1.8 F) from pretransfusion value Chills/rigors Transient HTN Management Antipyretics Lab testing: DAT Visual check for grossly hemolyzed plasma Blood cultures from the patient and RBC unit if available Supportive management Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Febrile Non Hemolytic Transfusion Reaction (FNHTR) Diagnosis of exclusion Common occurring 1% of transfusion episodes (1 3% per unit transfused) Caused by pro inflammatory cytokines or recipient Abs encountering donor antigen in the blood product Pre storage leukocyte reduction can prevent Premedication with antipyretics does not decrease rate of reactions in most pts and should be discouraged Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836.

Hypotensive Transfusion Reaction Definition HypoTN during or within 1 hr after cessation of transfusion Adults ( 18 yo): SBP 30 mmhg AND SBP 80 mmhg Children, adolescents (1 yo < 18yo): > 25% in SBP from baseline Neonates and small infants (< 1 yo OR any age and <12 kg): 25% in baseline measurement being recorded (MAP, BP) Management STOP transfusion immediately Supportive therapy No specific treatment is indicated HypoTN typically resolves once transfusion is discontinued The same unit should not be restarted No routine preventative measures have been identified other than not using bedside leucocyte reduction filters Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Hypotensive Transfusion Reaction Uncommon Thought to occur with activation of the intrinsic contact activation pathway of the coagulation cascade and generation of bradykinin and its active metabolite More likely to occur in patients who: Have hypertension Are taking angiotensin converting enzyme (ACE) inhibitors Are being transfused through a negatively charged bedside leukocyte reduction filter Undergoing apheresis Receiving platelets Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Septic Transfusion Reaction Definition During or within 4 hrs of cessation of transfusion Laboratory evidence of a pathogen in the transfusion recipient found in the transfused product Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn Management STOP transfusion immediately Cultures on the pt and gram stain and culture of all units transfused (if possible) Supportive therapy Therapy directed antibiotics, anti parasitics or antiviral agents Inform the supplier IMMEDIATELY

Septic Transfusion Reaction 58,000 75,000 transfusions/yr Bacterial contamination platelets > RBCs Platelet 1/ 3000 5000 units Can be presumed in a culture negative patient with clinical sepsis if bacteria are isolated from the transfused unit Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825-2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Septic Transfusion Reactions: Transfusion Transmitted Pathogens Updated from AuBuchon, Birkmeyer, Busch. Ann Intern Med 1997;127:904-9.

Current Estimated Residual Risk of Some Transfusion-Transmittable Agents HIV I/II HCV HBV 1:2,135,000 (ID-NAT) 1:1,930,000 (ID-NAT) 1:277,000 (ID-NAT) HTLV-II 1:2,993,000 WNV 1:350,000 Malaria < 1:1,000,000-5,000,000 Bihl, Florian et al. Transfusion-Transmitted Infections. Journal of Translational Medicine 5 (2007): 25. PMC.

Clinically Significant Pathogens in Transfusion NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn

Honorable Mention Transfusion Associated Circulatory Overload (TACO) Post Transfusion Purpura (PTP) Transfusion Associated Graft vs Host Disease (TA GvHD)

Resources Delaney, M., et al. (2016). "Transfusion reactions: prevention, diagnosis, and treatment." The Lancet 388(10061): 2825 2836. NHSN Biovigilance Component Hemovigilance Module Surveillance Protocol v2.4 www.cdc.gov/nhsn http://www.aabb.org/research/hemovigilance

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