This patient s real type is O positive

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1 How Will You React? A Look at Transfusion Reactions D. Joe Chaffin, MD LifeStream Blood Bank, San Bernardino, CA 2017 ASCLS Annual Meeting San Diego, CA No disclosures In the past 12 months, I have not had a significant financial interest or other relationship with the manufacturer(s) of the product(s) or provider(s) of the service(s) that will be discussed in my presentation. So help me God Really Let s Do This! 1. Learn actions to take when clinical or lab findings suggest a transfusion reaction 2. Learn to categorize transfusion reactions starting with a single vital sign 3. Learn details about pathophysiology, presentation, management, and prevention of common reactions A Story 68 year old female with severe epistaxis presented to ED Lightheaded but no chest pain or other sx HGB 6.6 g/dl, PLTs 207; no other issues Dx: Bleeding sinonasal AVM A Story Specimen drawn in ED for T&C: ABO type (ECHO): A Rh type (ECHO): Positive Antibody screen (ECHO): Negative *No discrepancies, flags, or other issues Historical type: Not found Pssst.. This patient s real type is O positive Bed 1 Tubes A pos Bed 2 Tubes A pos The Story The Next Morning Two Days Later Two units LRBCs requested 2 units A+ LRBCs issued at 0330 Per transfusion record, in 1st 15 min: 1.5 o C temperature elevation Sharp decrease in BP Tx was completed; 2nd unit given! Parameter PRE POST HGB 6.6 g/dl 7.0 g/dl PLTs 207 x 10 3 /ul 60 x 10 3 /ul WBCs 11.3 x 10 3 /ul 30.2 x 10 3 /ul BUN 21 g/dl 41 g/dl Creatinine 0.8 mg/dl 3.9 mg/dl Creatinine U A+ 2 U A Base Day 1 Day 2 Day 3

2 Two Days Later Happy Ending! FDA Fatalities ( ) LDH U A+ 2 U A+ 9,284 5,636 5,595 Patient fully recovered No residual kidney or other organ damage THEY GOT LUCKY! Base Day 1 Day 2 Day HTR Microbial Anaphylaxis AABB Standards 30th Ed. Severe allergic Septic (PLTS) Bact. Contam (PLTS) Mild allergic 7.3 Classifying Adverse Events The BB/TS shall use standardized definitions to classify donor and patient adverse events. The medical director shall participate in the development of protocols used by the staff to identify, evaluate, and report adverse events. Image Source: Annals of Internal Medicine Mar:E-429 (red boxes added) 12 Defined Reactions 6 R s of Reaction Workups What to Look For Hemolytic Hemolytic Serologic Recognize a possible reaction Report reaction to blood bank/ts Recheck/Retest in lab and at bedside Render an interpretation Report results Review for quality assurance

3 Rule out Hemolysis What to do First? You Never Know... Tier 1 Tier 2 STOP THE TRANSFUSION!! Perform Clerical Check and Draw Post-TX Sample Hemoglobinemia DAT ABO/Rh Testing If Suspicious, Consider Second-tier Testing: Haptoglobin LDH Crossmatch Bilirubin Urine HGB Eluate Step 1: - STOP THE TRANSFUSION!! - Maintain IV access with saline - Amount of incompatible blood is predictive of outcome Step 2: - Perform clerical check At bedside and transfusion service Step 3: Visible Hemoglobin As little as ml can give visible hemoglobinemia Step 4: Direct Antiglobulin Test Transfusion Rxn Workup Others to consider based on situation: - Bili, LDH, haptoglobin (hemolysis) - Gram stain, culture (bacterial) - Chest X-ray, HLA tests (respiratory) - BNP, fluid status check () - IgA/anti-IgA/hapto (anaphylactic) Rule out NON-TRANSFUSION stuff!! Image credit: Zaradona and Yazer, The role of the Coombs test in evaluating hemolysis in adults, Can Med Assoc Journal 2006, 174(3),305-7 Transfusion 2003; 43: Defined Reactions Hemolytic Hemolytic Serologic 12 Defined Reactions Hemolytic Hemolytic Serologic Presenting WITH Fever Hemolytic Hemolytic Presenting WITHOUT Fever Serologic

4 Hemolytic Rxns Potentially catastrophic destruction of incompatible RBCs Incidence: 1:76,000 (1/1.8 M fatal) Clerical errors (~60% at bedside) Hemolytic RXNs Timing: <24 hrs Signs/symptoms - Fever/chills (80%) - Hypotension - Pain (site, chest, back) - Bleeding/DIC - Red urine - Renal failure Hemolytic RXNs Lab findings - Hemoglobinemia, then -uria (hrs to 1 day) - + DAT (IgG and/or C3); + eluate? - Elevated: Bilirubin, LDH - Decreased: Haptoglobin, fibrinogen - DIC markers (D-dimers, FSPs) Image: Public Domain 10 ml Storm! Storm! C3a/C5a Cytokines Inflammatory - TNF-α, IL-1β, IL-6 strongly pyrogenic (fever-inducing) Coagulation - Activation of both clotting and lysing Circulatory: - Cytokine Nitric Oxide generation - Bradykinin from antigen-antibody - Hypotension/shock NO Bradykinin Storm! Renal: - Vasoconstriction (reflex, from NO:HGB complex) - Microthrombi - tubular necrosis - Oliguric renal failure Hemolytic Rxns Treatment - Support circulation and renal function (fluids and diuresis) - Heparin for early DIC controversial - RBC exchange if stable (unlikely) Hemolytic Rxns Prevention - Details, details, details! Phlebotomy Labeling Issue Administration - Two separate types for confirmation - Technology (RFID, bar codes, etc)

5 AHTR Criteria Definitive (1): - Occurs during, or within 24 hours of cessation of transfusion with new onset of ANY of the following signs/symptoms: Back/flank pain Chills/rigors DIC Epistaxis Fever Hematuria (gross visual) Hypotension Oliguria/anuria AND Pain/oozing at IV site Renal failure (Clinical Stuff) AHTR Criteria Definitive (2): AND: Decreased fibrinogen Hemoglobinemia Decreased haptoglobin Hemoglobinuria Elevated bilirubin Plasma discoloration Elevated LDH Spherocytes on film (Lab Stuff) Febrile non-hemolytic Rxn Most reported reaction Definition: - 1 o C or 2 o F; no other explanation Diagnosis of exclusion Not a definitive threshold!! PLTS Substances generated Recipient Fever! Antibodies? Recipient IL-1β, TNF-α, IL-6, etc. FEVER!! Substances generated RBCS FNHTR Management - Stop transfusion, do workup - Acetaminophen or other antipyretic Prevention: Leukoreduction (premedication does not work) FNHTR Criteria - Occurs within 4 hours of cessation of transfusion AND EITHER: Fever (> 38 o C/100.4 o F) + change of at least 1 o C/1.8 o F OR: Chills/rigors are present Transfusion-related Sepsis Number one infectious risk from transfusion today; by FAR! 1 in 3000 contaminated FAR fewer cause harm - ARC: 1:108,000 Transfusion-related Sepsis Timing: Generally < 4 hours Signs/symptoms (endotoxin effect) - Fever > 39 o C (102.2 o F) or > 2 o C up - Hypotension/shock - Rigors - Abdominal complaints - DIC Transfusion-related Sepsis RBCs - Gram-neg rods: Yersinia enterocolitica E.coli Enterobacter/Pantoea Serratia Pseudomonas - Staph. epidermidis

6 Transfusion-related Sepsis Platelets Transfusion-related Sepsis Lab - Dark RBC unit - Junk in platelets - Negative DAT - Gram stain + only half the time - Culture is conclusive Transfusion-related Sepsis Treatment - IV antibiotics - Pressure support Prevention Verax PGD - Careful history and collection technique - Platelet culture (in DC) - Pathogen reduction! - Pre-release testing (Verax PGD, BacTx) Slide courtesy of Dr. Anne Eder Image courtesy Anne Eder, MD Tx-related Sepsis Criteria - Laboratory evidence of a pathogen in the transfusion recipient Imputability is key Tx-related Sepsis Criteria Imputability (relationship to transfusion) - One or more: Pathogen is in component Pathogen is in donor at time of donation Pathogen is in an additional component Pathogen is in an additional recipient from same donation AND: No other exposures to pathogen AND EITHER: Recipient was not infected before tranfusion OR: Strains are related by molecular or extended phenotype Transfusion-related Lung Injury Source: (FY 2015 Fatalities) Standard Definition - NHLBI, Canadian Consensus Conf. - New ALI <6 hrs after transfusion ALI: Hypoxemia (O2 sat <90%) Bilateral chest x-ray infiltrates - No other risk factors for pulm edema Pretransfusion Post-transfusion Common signs/symptoms: - Dyspnea progressing to respiratory failure - Hypertension, then hypotension - Fever/chills Images courtesy of Dr. Chris Silliman, Denver, CO

7 Two main pathways - Donor antibody Transfused anti-hla/hna - Two-event Patient susceptibility comes first Antibodies +/ Neutrophils ~30% of body PMNs are pulmonary Source: (FY 2015 Fatalities) Image courtesy of Dr. Chris Silliman, Denver, CO 1 2 Flaws: 1. Ab, no 2., no Ab Priming Image courtesy of Dr. Chris Silliman, Denver, CO Image: Vlaar APJ et al. Transfusion-related acute lung injury: a clinical review. Lancet 2013; 382(9896): Image courtesy of Dr. Chris Silliman, Denver, CO Diagnosis Proving diagnosis usually difficult -, ARDS, non-tx stuff Fever, hypotension may help distinguish from - Normal BNP levels may help HLA type for patient Anti-HLA (HNA?) for donors Prevention - Predominantly male plasma (2006-8) - Screen parous female PLT donors All implement by Defer implicated donors with antibodies Criteria No evidence of acute lung injury (ALI) prior to transfusion AND ALI onset during or within 6 hours of cessation of transfusion AND Hypoxemia (PaO2/FiO2 < 300 mm Hg OR O2 sat <90% on RA) AND Radiographic evidence of bilateral infiltrates AND No evidence of left atrial hypertension (circulatory overload)

8 Presenting WITH Fever Hemolytic Hemolytic Presenting WITHOUT Fever Serologic Mild Reactions 1-3% incidence - May not report Urticaria (hives); local - Angioedema Type I hypersensitivity Diphenhydramine treats, may not prevent May restart transfusion Severe RXNs Extreme opposite of urticarial Classic: Anaphylaxis early in TX - hypotension, abdominal distress, systemic crash - Almost always have skin findings! Rxn Criteria 2 or more during or within 4 hours of cessation of transfusion: Conjunctival edema Edema of lips, tongue, and uvula Erythema and edema of periorbital area Generalized flushing Hypotension Localized angioedema Maculopapular rash Pruritis (itching) Respiratory distress (bronchospasm) Urticaria (hives) Severe RXNs Classic: IgA deficiency - Generally in those with severely decreased/absent IgA (<0.05 mg/dl) IgE-type anti-iga is difficult to detect (anti-iga in labs is IgG version) VERY few with RXN have anti-iga Severe RXNs Others: - Haptoglobin or C4 deficiency - Latex - Drugs - Foods eaten by donors - Donors passing on severe allergies? Most RXNs do NOT have explanation! DDX HTR Septic transfusion reaction hypotensive reaction (handout) Coincidental anaphylactic RXN Pulmonary embolus, acute MI, others NOTE: Lack of fever and skin findings may be VERY helpful Diagnosis Upon presentation, consider IgA deficiency (possibly haptoglobin) - Test pretransfusion sample Screen for IgA level, then do anti- IgA test if IgA is very low Understand limitations (not IgE) Rare to pursue other etiologies

9 Treatment Diphenhydramine not enough! Epinephrine RIGHT NOW!! - SQ or IM if not hypotensive, but IV if hypotensive/shock Bronchodilator (e.g., aminophylline) Prevention If IgA deficient with anti-iga - IgA-deficient products IgA-deficient donors of RBCs, PLTs, plasma Washed RBCs, PLTs (2 L NaCl) Autologous options for future If not IgA deficient, combination of washed/autologous options Reaction All other reactions presenting with hypotension are ruled out - AHTR, Septic,, severe allergic Hypotension within 1 hour of end of transfusion Systolic down > 30 mmhg and < 80 mmhg congestive heart failure due to transfusion - No fever, early onset (<6 hrs) - Respiratory distress Dyspnea, orthopnea, rales, hypoxia - CHF findings: Systolic HTN, JVD, headache Image source: James Heilman, MD (via Wikipedia) Chest X-Ray Bibasilar infiltrates, widened cardiac silhouette At-risk: - Those already with CHF - Older patients (85% over 60) - Very young patients - Renal failure patients - Chronic compensated anemias vs vs Hot Vs. Fever No fever Hypotension Hypertension No diuretic effect Dramatic diuretic effect Normal BNP Elevated BNP* Transient leukopenia No leukopenia +/- anti-hla/hna Abs No antibodies Treatment - Stop transfusion, sit patient up, diuretics, oxygen Prevention - Slower infusion rates (1 ml/kg/hr) - Split units/aliquots - Volume reduction

10 Criteria - New onset or worsening of 3 or more during or within 6 hours of cessation of transfusion: respiratory distress (dyspnea, orthopnea, cough) Elevated brain natriuretic peptide (BNP) Elevated central venous pressure (CVP) Evidence of left heart failure Evidence of positive fluid balance Radiographic evidence of pulmonary edema Transf. Assoc. Dyspnea respiratory distress within 24 hrs after cessation of transfusion Ruled out: - reaction - - Presenting WITH Fever Hemolytic Hemolytic Presenting WITHOUT Fever Serologic Hemolytic Rxns Mechanism of DHTR Hemolytic Rxns Hemolysis occurring >24 hrs to <28 days after transfusion Almost always a previously present antibody that reappears after exposure - Kidd, Duffy, Kell most common Jk a + 1% or so Recipient Anti-Jk a Jk a + Extravascular (except with Kidd) Signs/symptoms - Often none - Fever/anemia of unknown origin - Unexplained jaundice, scleral icterus Jk a neg Hemolytic Rxns Lab - Icteric serum - + DAT ( mixed field ) - Anemia - Newly identified antibody - Eluate with antibody - Spherocytes - LDH and bili up; haptoglobin down Self Jk a + Self Self Self Jk a + Image source: Hemolytic Rxns Treatment - Often not required - If severe, treat as AHTR Volume and pressure support HTR Criteria +DAT for antibodies developed 24 hrs - 28 days after transfusion AND EITHER: +Elution with alloantibody on the transfused RBCs OR Newly identified RBC alloantibody in recipient serum AND EITHER: Inadequate rise of post-tx HGB or rapid fall back to pre-tx levels OR Otherwise unexplained appearance of spherocytes

11 Normal Activity Counter-Attack Attack on host HLA antigens on tissues by transfused T-lymphocytes - TA part distinguishes from GVHD from stem cell and organ transplant Rare, but nearly always fatal - 3 fatals reported to FDA since cases in literature CD4, CD8, NK Recipient HLA Antigens CD8, NK Recipient HLA Antigens Attack! But, What If There Is.? Criteria - Clinical, up to 6 wks after transfusion, with: Immunosuppression Lymphopenia Recipient HLA Antigens Rash (red, raised, on body then extremities) Diarrhea Fever Hepatomegaly Liver dysfunction (elev ALT, AST, Alk Phos, bili) Marrow aplasia Pancytopenia 7-10 days: Skin, liver, GI tract Bone marrow AND: Characteristic skin or liver biopsy findings Prevention 2500 cgy targeted to center of bag, 1500 cgy to all parts Indications Immunosuppression - T-cell defects (including drugs) - Stem cell/marrow transplants - Aplastic anemia Intrauterine/preemie transfusions Heme malignancies (esp HD) Granulocytes 1st-degree relatives or HLA-matched One-Way HLA Match DONOR A2B7 A2B7 RECIPIENT A2B7 A11B12 Highest risk: Family members HLA-selected products Genetically non-diverse populations

12 Probably NOT at risk Organ transplant recipients Term neonates AIDS patients Previously frozen products - FFP/CRYO: No irradiation - Frozen/thawed RBCs: Debatable Miscellaneous Not for CMV prevention Not for stem cell infusions (duh!) LR is NOT interchangeable! - We don t know minimum threshold Presenting WITH Fever Hemolytic Hemolytic Presenting WITHOUT Fever Serologic Severe thrombocytopenia (< 10K) about 10 days post-transfusion - Platelet or RBC transfusion Females 5:1 (especially those with pregnancy history) HPA-1a + Pregnancy/Transfusion HPA-1a Neg Female Anti-HPA-1a Future Platelet or RBC transfusion (HPA-1a Pos) Anti-HPA-1a HPA-1a Neg Female AutoAb HPA-1a Pos HPA-1a Neg PTP Criteria - Alloantibodies in the patient directed against HPA or other PLT-specific Ag at or after thrombocytopenia AND: - Thrombocytopenia (<20% of pretransfusion PLT count) Treat with IVIG - Formerly plasma exchange Mortality 10% without treatment, very rare with treatment Avoid platelet transfusion if possible Future PLTs should be Ag-matched