Adverse Reactions to Blood Products

1. Adverse Reactions to Blood Products Medical Oncology Training Program Academic Half-Day Friday February 20th 2009, 11:00 am – 12:00 pm Christine Cserti-Gazdewich, MD FRCPC FASCP Assistant Professor, University of Toronto, Faculty of Medicine Transfusion Medicine/Hematology, University Health Network Christine.Cserti@uhn.on.ca UHN TGH BTL 3EC-306 14-6303

2. Reactions to Master…. • hemolytic transfusion reactions • FNHTRs • allergic & anaphylactic reactions • acute pain transfusion reactions • bacterial contamination • TRALI • TAGVHD • hypotensive transfusion reactions • posttransfusion purpura • stem cell reinfusion reactions • circulatory overload • IVIG adverse effects

3. Reporting what how

4. Our reporting obligations • WHAT: • all transfusion reactions (no matter how mild) and transfusion-related errors • TO WHOM: • hospital transfusion service • relays information to: • the Transfusion Transmitted Injuries Surveillance System (TTISS) at Public Health Agency of Canada • CBS or Héma-Québec if related to the quality of the product • DEPENDS UPON: • awareness & competence

5. Transfusion Hazards

7. Deaths Due to Transfusion • # 1 cause of transfusion-attributed death: TRALI • overall risk of transfusion-related death: 1 in 200,000 chance = risk of death from anesthesia in a fit person

8. Transfusion attributable symptoms, what they mean, & how they happen fever dyspnea allergy cytopenias delayed infections

9. Fever HTR BaCon FNHTR

10. when is it a fever? • T > 38ºC AND ↑ by Δ1ºC OR • the fever equivalent of chills or rigors

11. Acute Hemolytic Transfusion Reaction • immune • active (recipient antibodies) • passive (donor antibodies) • non-immune • devices physically destroying RBCs • thermal injury to RBCs (hot/cold storage misadventure) • pressurized infusions • post-expiry infusions

12. active AHTR recipient has, and can keep making, specific antibodies against a transfused cellular product that bears vulnerable antigens  antibody-mediated hemolysis of transfused red cells Acute Hemolytic Transfusion Reaction D transfused allogeneic red blood cells D Y host allo- antibody attacks alloantigen R

13. passive AHTR product carries donor antibodies which are specific for a recipient’s cells  antibody-mediated hemolysis of recipient red cells Acute Hemolytic Transfusion Reaction high plasma-volume containing products (FFP, platelets) Y R

14. Causes of active AHTR • ABO mistake • failure to avoid anticipated ABO antibody • group O patient given non-O RBC * • anti-A and anti-B are naturally occurring antibodies and hemolysis is immediate • missed or hidden non-ABOantibody • failure to findunanticipated non-ABO antibody • use of emergency ‘uncrossmatched’ blood • antibody not detected on antibody screen * : ½ of these mistakes are due to hanging the properly labelled blood on the wrong patient, and many of the remainder are due to the recipient being wrongly characterized because of sampling errors

15. the point of the SCREEN (IAT): preventing “minor” RBC antigen-based HTRs…but sometimes failing • relevant to finding recipient antibodies to non-ABO antigens • utilizes O red cells ABO Kell Y Rh(D) Duffy plasma Kidd Y etc 1 Y 2

16. AHTR: clinical facts • presentation: fever/chills, hemoglobinuria, IV or flank pain, ↓BP, nausea/vomiting, dyspnea, renal failure, DIC • case fatality rate: <10% • non-morbidity rate: >50% • + “dose-response” risk (↑ blood = ↑ risk) • cases are usually ABO-related • non-ABO antigens implicated in 13% of AHTRs

17. AHTR: How to pick it up… • look for evidence of red cell incompatibility • clerical error search • re-type • direct antiglobulin test (DAT), • aka Coomb’s test • assess plasma for hemolysis • 10cc (or only 3% of a unit) • of blood is visible…! • re-screen or re-crossmatch • review labs indicative of hemolysis direct Coomb’s test Y Y patient’s cells

18. Suspected HTR: What to do Stop transfusion & run NS; check labels Notify blood bank, send post-transfusion specimen & remainder of product Stat lab work: acute renal failure work-up: electrolytes (hyperkalemia), creatinine DIC work-up: PT/INR, aPTT, fibrinogen Support BP & maintain good urine output Manage coagulopathy and bleeding

19. Bacterial Contamination (BaCon) INCIDENCE • Risk of septic shock: • 1 in 10,000 PPC • 1 in 100,000 RBC • Risk of death from septic shock: • case fatality rate: 24-60% • 1 in 40,000 PLT pools • 1in 1,000,000 RBC • Key Message – Run transfusion slowly for 1st 15 min

20. BaCon ETIOLOGY • donor bacteremia, skin plug, processing • most commonly: • Yersinia enterocolitica • Serratia marcescens/liquefaciens • Staph aureus/epidermidis PRESENTATION • fever, rigors, hypotension, renal failure, DIC • platelets more commonly implicated • RBC more severe

21. FNHTR: what it is • = Febrile Non-Hemolytic Transfusion Reaction • a diagnosis of exclusion • after ruling out: • hemolytic transfusion reaction • bacterial contamination • underlying illness in patient • common • 1/10 platelet transfusions • 1/300 red cell transfusions

22. recipient “leuko-agglutinins” patient previously sensitized to antigens on leukocytes old transfusions pregnancies host antibodies react with passenger leukocytes in blood product product “pyrogens” residual leukocytes secrete cytokines occurs more often with: non-leukoreduced products products under warm storage products near expiry (STORAGE LESION) FHNTR: why it happens donor leukocyte secretes cytokines in storage Y donor leukocyte with an HLA antigen relevant to host HLA alloantibody D D

23. FNHTR: how to manage • acetaminophen • meperidine (Demerol) for rigors • PREVENTION? • acetaminophen • may not work • may obscure an important febrile cue to stop next transfusion • fresh components • not always available • plasma-reduced or washed products • risks product degradation/loss

24. IVIG & Immune Reactions • immune-replacement / immune-modifying therapy = unique immune-mediated adverse effects, attributed to: • cytokines, vasoactive peptides, complement activation via Ig dimerization • common minor effects: • headache, fever, fatigue, chills, vomiting, nausea, dizziness, diarrhea, flushing, abdominal pain, chest tightness, cough, muscle cramps, pruritis, backpan • rarer, more serious effects: • sucrose-induced nephropathy, aseptic meningitis, hemolysis, anaphylaxis, vascular thrombosis

25. Dyspnea TACO TRALI pulmonary allergic reaction (bronchospasm)

26. what to do? • assess patient (focus on cardiorespiratory vitals & volume status) • stop transfusion, notify blood bank • stat CXR + ABG if hypoxic oximetry • treat patient: • oxygenate if hypoxic • diurese if +evidence of volume overload

27. TACO • Transfusion-Associated Circulatory Overload • incidence: • 1 in 700 patients overall • 1 in 100 elderly recipients of blood • specific clues: • fast infusion rate • compensated chronic anemia (hyperdynamic before transfusion) • known congestive heart failure risk • orthopnea, ↑JVP, cyanosis, ↑HR, ↑BP

28. TRALI: what it is • Transfusion Related Acute Lung Injury = NON-cardiogenic pulmonary edema • definition: • new acute lung injury (PaO2/FiO2 <300) • onset during or within 6h of transfusion • excludes: • TACO • underlying CHF • other pre-transfusion pulmonary morbidities • under-recognized & under-reported • estimates: 1 in 1200 to 1 in 5000

29. donor “leuko-agglutinins” multiparous donor sensitized to WBC antigens passive antibodies venously pumped through lungs & encounter host leukocytes & react explains ≥ 75% of cases product toxins cellular products release biologically active lipids interact with illness-“primed” pulmonary endothelium to produce tissue damage TRALI: why it happens donor cells release biologically active lipids D Y recipient leukocyte with an HLA antigen relevant to donor HLA alloantibody H

30. TRALI: outcomes • symptoms & signs: • dyspnea, cough, hypoxia, fever, BP ↑ or ↓, WBC ↓ • resolves in 24-72 hours • 72% require mechanical ventilation • death in 5-10% • most common cause of transfusion-attributed death now • supportive care is key • diuretic utility in non-cardiogenic edema? • prevention: • defer implicated donors • new mandates may restrict use of female plasma

31. Allergy mucocutaneous vs multisystemic IgA deficiency & other causes

32. The Allergic spectrum • hives < 2/3 of body surface area • mild urticaria, pruritis, erythema, flushing • hives > 2/3 of body surface area • angioedema (subcutaneous rather than cutaneous) • respiratory: • bronchospasm • wheezing, stridor, hoarseness, dyspnea, hypoxia, psychologic sense of asphyxia/doom • gastrointestinal instability: • nausea/vomiting/abdominal cramping/diarrhea • cardiovascular instability: • hypotension, chest pain, tachycardia • anaphylactoid / anaphylactic reaction 90%

33. Recipient-donor allergen-IgE interactions classic allergic IgE antibodies and antigens, with one or the other passively infused and interacting in host drugs, foods, chemicals likely the most common explanation no routine tests or traceback methods to confirm URTICARIA to ANAPHYLAXIS Recipient IgG sensitization to normal donor proteins recipient has a rare polymorphism or deficiency of a certain protein compared to most donors eg: IgA, haptoglobin, complement, albumin, α1anti-trypsin, transferrin exposure to proteins = immunizing event anti-protein IgG =ANAPHYLACTOID REACTION Why allergic reactions happen

34. a few words on IgA deficiency • 1 in 500 are IgA deficient • 1 in 1200 have anti-IgA IgG (ie- proof of sensitization) • mysteries: • why/how IgG raised without known exposure • why ½ don’t react if exposed later • explains why reactions may be observed in a 1st transfusion

35. How often & how severely they happen • within 1-45 min of transfusion, but up to 3 h afterwards • if severe: • as little as 10cc may be anaphylactic • dose-responsive • relapsing • frequencies: • minor: 1/100 • severe allergic: 1 in 10 000 to 40 000 • fatal anaphylaxis: 1 in 1 000 000

36. Management of Allergic Reactions • stop transfusion if >2/3rd BSA involved or non-cutaneous (visceral) allergic symptoms • allergic anti-histamines • diphenhydramine (Benadryl), cetirizine (Reactine) ± H2R blockers • ranitidine (Zantac) • epinephrine, β2 receptor agonist bronchodilators • corticosteriods • ACLS: vasopressors, ventilatory support • future transfusions: • modify the patient: • premedication • modify the product: • ± plasma depletion / washing • obtain from donors deficient in the inciting allergen/antigen

37. Hypotension HTR BaCon Allergy Bradykinin

38. Bradykinin-mediated hypotension • bradykinin surge from contact activation: • for donors or recipients on ACE inhibitors: • reduced bradykinin breakdown from cross-reactive suppression of enzyme from drug • recipients of bradykinin: • flushing, hypotension, dyspnea, hypoxia

39. Cytopenias RBC (HTR) platelets (HLA PTR, PTP) WBC (TRAIN) pancytopenia (TA-GVHD)

40. RBC decreases after transfusion • if immediate & not related to hemorrhage: • investigate for acute hemolytic transfusion reaction • usually related to ABO antibodies (preformed) & suspected from fever/hypotension • if delayed (3-14 days after transfusion): • investigate for delayed hemolytic transfusion reaction (DHTR) • usually non-ABO antibodies that took time to “re-surge” after the offending red cell transfusion • may not have symptoms of hemolysis (fever, hemoglobinuria) • 1 in 6715 transfusions • in future: transfuse blood negative for antigen

41. HLA (human leukocyte antige) sensitization recipient makes HLA antibodies from past exposure to WBCs other transfusions pregnancies transplants platelets express 73% of circulating HLA class I (A & B) antigens recipient can destroy platelets bearing vulnerable HLA antigens the cause of 80-90% of platelet transfusion refractoriness HPA (human platelet alloantigen) sensitization recipient with a polymorphic or missing platelet glycoprotein makes antibody against the common glycoprotein type pregnancies other transfusions recipient can destroy platelets bearing vulnerable HPA antigens leads to PTP (post-transfusion purpura) fatal in 8% fortunately RARE! Platelet decreases after transfusion

42. Platelet-Specific Antigens in PTP Most frequently involved polymorphism (75% of PTP cases) But fortunately only 28% make the antibody if exposed

43. donor anti-granulocyte antibodies although usually implicated in TRALI, may also (or instead) cause neutropenia of host’s neutrophils passive alloimmune reaction Post transfusion neutropenia

44. TA-GVHD • Transfusion-Associated Graft Versus Host Disease • passenger lymphocytes “engraft” in recipient • who: • immune compromised • immune recognition failure • what happens: • bone marrow aplasia (empyting from attack) = pancytopenia (all counts down) • fever, rash • liver dysfunction, diarrhea • death in 90%

45. immune compromised congenital immunodeficiency fetuses, premature neonates hematologic malignancies (eg lymphoma) stem cell transplants high dose chemotherapies with immune-ablation potential nucleoside analogue drugs (eg fludarabine for chronic lymphocytic leukemia) immune “oblivious” host’s HLA type is foreign to transfused lymphocytes, which resemble the host enough to be tolerated eg. donor is HLA “homozygous haploidentical” with respect to recipient related donors 1 in 18 000 – 39 000 of strangers Vulnerable recipients A1 A2 B7 B9 C4 C8 A2 A2 B9 B9 C8 C8 recipient tissue type donor lymphocyte

46. Delayed onset infections Viruses (H A/B/C V, HIV, CMV, HTLV, WNV, PVB19, HHV8) Prions (vCJD) Others (protozoal, helminthic, spirochetal, rickettsial)

47. Viral testing of each donation • all donors: • HIV Ab, HIV NAT • HCV Ab, HCV NAT • HBsAg, HBcAb • Syphilis • HTLV-1/2 Ab • WNV NAT • selected cases/products: • CMV Ab • bacterial culture (pre-pooled/high volume platelets only) • Parvovirus B19 (fractionated products only)

48. Residual risk (window period misses)

49. Malaria Toxoplasmosis Leishmaniasis Filariasis Ehrlichiosis Babesiosis Trypanasoma cruzi (Chagas) Borrelia burgdorferi Rocky mountain spotted fever (rickettsial group) Q fever (Coxiella burnetti) variant CJD Other transfusion transmissible infections at this time, screening by donor history alone is performed in order to prevent the entry of these infections in the donor supply