New Approaches to Preventing Transfusion Reactions

1. New Approaches to Preventing Transfusion Reactions Aaron Tobian, MD, PhD Transfusion Medicine Division Johns Hopkins Hospital

2. Transfusions in United States Centrifuged blood… 16 million units of whole blood donated annually • Plasma • Cryoprecipitate • Platelets • Red blood cells From: http://www.nsbri.org/HumanPhysSpace/focus3/fig2.jpg

3. Adverse Reactions Have Always Accompanied Transfusions • Ramirez (1919): Patient developed asthma to horse dandruff within two weeks of receiving a blood transfusion. Ramirez suggested transfer of “anaphylactic bodies.” • Polaye and Lederer (1932): Evaluated 2500 reactions; etiology due to ABO incompatibility, transmission of diseases, and “allergic phenomena” in the recipients • Wiener (1940): Described febrile transfusion reactions that were not due to ABO incompatibility or lack of aseptic techniques; hypothesized that the reactions are due to “extraneous factors”

4. National Hemovigilance Program The CDC and AABB in 2010 launched the Hemovigilance Module of the National Healthcare Safety Network. Gives all U.S. hospitals the opportunity to contribute data on adverse events associated with blood transfusions. Goal: improve patient safety by analyzing transfusion reaction data and identifying effective interventions. http://www.cdc.gov/nhsn/about.html

5. Incidence of Transfusion Reactions Karafin AABB 2010 FIGURE.Percent of transfusions (N=73,766) resulting in an adverse reaction by blood product type.

6. How bad is it?(selected comments from an anonymous survey) “Allergic transfusion reactions are usually a huge waste of my time.” “There’s nothing like getting called for 1 hive at 3AM.” “I believe my negative attitude largely stems from…” A common frustration is that there is nothing that can be done for common transfusion reactions. Savage 2011

7. On the other hand…. People getting transfusions are already sick, and additional morbidity is a burden Result in wasted blood products Transfusion reaction evaluations are expensive Overutilization and expense of pre-medications to prevent transfusion reactions Some physicians care…

8. Objectives Be able to accurately diagnose transfusion reactions. Be able to advise clinicians on how to appropriately treat and prevent transfusion reactions. Understand how your laboratory can manipulate blood products to reduce transfusion reactions. Recognize new additive solutions and products that are being introduced to reduce transfusion reactions.

9. Transfusion Reaction • 60 y.o. female with a history of MDS and follicular lymphoma s/p autologous transplant • Three mild allergic transfusion reactions over the past three years • Admitted for neutropenic fever, but afebrile at the time of transfusion of 2 units of apheresis platelets • Pt received 650 mg Tylenol and 25 mg Benadryl prior to transfusion • 15 minutes into the second platelet unit pt notes chills • Temperature increased from 37.4 oC to 38.6 oC

10. Suspected Reaction Workup • Assume all reactions are hemolytic • STOP the transfusion! • Required parts of work-up • Paperwork and bag check for clerical error • Check for hemoglobinemia and hemoglobinuria • DAT • Repeat ABO testing for RBC transfusions

11. Differential Diagnosis of Febrile Reaction • Acute hemolytic transfusion reaction • Febrile nonhemolytic transfusion reaction • Bacterial contamination • TRALI

12. Acute Hemolytic Reaction Immunologic destruction of transfused RBCs due to preformed ABO antibodies in recipient against donor red cell antigens. Most often caused by a clerical error (e.g., incorrectly labeled sample). The symptoms result from intravascular hemolysis due to complement activation after the preformed antibodies bind to the donor red cells.

13. Acute Hemolytic Reaction http://commons.wikimedia.org/wiki/File:Main_symptoms_of_acute_hemolytic_reaction.svg

14. Acute Hemolytic Reaction • Lab Findings • Increased LDH • Elevated indirect bilirubin • Decreased haptoglobin • RBC abnormalities • Schistocytes • Spherocytes • Positive DAT • Positive eluate with alloantibody on transfused RBCs • Hemoglobinemia • Hemoglobinuria Tobian Transfusion 2010

15. Acute Hemolytic Reaction • Treatment • Stop transfusion • Support volume and pressure to maintain urine output • Watch for DIC • Report event • Sentinel event and requires reporting to JCAHO. • Suspicion of death, FDA requires notification within 24 hours by phone and a written report within 7 days.

16. Febrile Non-hemolytic Reaction (FNHTR) • One of the most common reactions reported • Up to 1% of transfusions of RBCs and 5% of apheresis platelets. • Temperature elevation > 1 ºC • Must be distinguished from hemolytic and septic reactions • Only 15% of pts with one febrile reaction develop fever with subsequent transfusions

17. Mechanism of FNHTR(Biological Response Modifiers – secreted prior to transfusion) Donor’s Platelets With leukocytes ( ) IL-1B IL-6 TNF Donor leukocytes produce cytokines BRMs increase during storage Plasma interacts with plastic bag Increased C3a and C4a Lipids prime and activate PMNs FNHTR

18. Mechanism of FNHTR(HLA, platelet, or granulocyte antibodies in recipients plasma interact with transfused antigens, e.g., donor WBCs) Donor’s Leukocytes ( ) Patient’s Antibody Complement activation FEVER C3 IL-1B IL-6 TNF Stimulates patient’s macrophage

19. Febrile Non-hemolytic Reaction (FNHTR) • Signs and Symptoms • Fever ≥38oC and ≥1oC increase from pre-transfusion • Chills and Rigors • Headache, nausea, vomiting • Less frequently dyspnea • Negative culture of components and patient’s blood sample • Patient does not have other conditions to explain fever

20. Leukocyte Reduction Reduces FNHTRs Between 1994 and 2001, all transfusion reactions associated with RBC transfusion were retrospectively analyzed. King Transfusion 2004

21. Transfusion Reaction • 65 y.o. female with AML s/p allogeneic stem cell transplant now with relapse • No previous history of transfusion reactions • Afebrile at the time of transfusion of 2 units of apheresis platelets • During second unit of platelets, patient became hypoxic and temperature increased from 36.8 oC to 38.2 oC. • Patient is subsequently intubated and requires supportive care.

22. Differential Diagnosis of Hypoxia During Transfusion • Allergic/Anaphylactic reaction • TACO (transfusion associated circulatory overload) • TRALI (transfusion related acute lung injury)

23. Transfusion Associated Circulatory Overload (TACO) • Occurs when excess blood volume overwhelms cardiovascular system and produces pulmonary edema. • Relatively common complication of transfusion with a reported incidence ranging from 1% to up to 8% of patients. • Patients at risk • Elderly • Small patients including kids • Patients with impaired cardiac, renal, pulmonary function • Oncology patients

24. Individuals with TACO Have Positive Fluid Balance Prior to Transfusion Tobian Transfusion 2008

25. Signs and Symptoms Acute respiratory distress (dyspnea, tachypnea) Elevated systolic blood pressure Jugular venous distension Tachycardia Bilateral pulmonary edema on CXR Symptoms responsive to diuretics Transfusion Associated Circulatory Overload (TACO) http://en.wikipedia.org/wiki/File:Pulmonary_oedema.jpg

26. Treatment Volume reduction with diuresis Supportive care Prevention Transfuse slowly Plasma reduced products Transfusion Associated Circulatory Overload (TACO)

27. Transfusion Related Acute Lung Injury (TRALI) • Leading etiology of transfusion-related fatality in the United States. • Frequency: 1:1000 to 1:4500 transfusions • Symptoms within 6 hours of transfusion. • Respiratory distress (tachypnea, dyspnea) • Fever • Hypotension • Exclusion of other etiologies of acute lung injury or circulatory overload.

28. TRALI Pathophysiology (Two Mechanisms) • Donor antibody hypothesis • Reaction of donor’s human leukocyte antigens (HLA) or granulocyte specific antibodies against recipient’s leukocytes that then aggregate in lungs • Two-event hypothesis • First, something stimulates recipient’s neutrophils to aggregate in lungs. • Second, transfusion of stored blood products accumulate lipids that activate neutrophils. • Either hypothesis leads to complement activation, capillary damage and subsequent pulmonary edema.

29. Transfusion Related Acute Lung Injury (TRALI) Bilateral white-out Baseline and 48 hours post transfusion http://en.wikipedia.org/wiki/Transfusion_related_acute_lung_injury

30. TRALI Management • Treatment: aggressive respiratory support • Immediately report suspected transfusion reactions to the blood collection facility • Quarantine other components associated with donor • Evaluate donor for HLA antibodies • Confirmed donor HLA antibodies do not alter management of this reaction

31. TRALI and HLA Antibodies • Antibodies to human leukocyte antigens (HLA) due to sensitization (e.g., transfusion, transplantation, pregnancy). • HLA antibody prevalence among blood donors: • Men: 1.7% • Women: 17.3% • Women with at least four pregnancies: 32.2% • In 2006, AABB advised blood centers to reduce plasma components from individuals with potential HLA antibodies. • The Red Cross began distributing male plasma and diverting female plasma for pharmaceutical manufacturing Triulzi Transfusion 2009 and Eder Transfusion 2010

32. Eder Transfusion 2010

33. Transfusion Reaction • 38 y.o. female with leiomyoma s/p myomectomy x 2 and hypothyroidism • Patient had TAH-BSO and small bowel resection and transfused one unit of apheresis platelets • No previous transfusion reactions, but patient received 25 mg Benadryl and 650 mg Tylenol prior to the transfusion. • One hour into transfusion, patient developed hives on neck and trunk. • No changes in temperature, blood pressure or difficulty breathing.

34. Allergic Transfusion Reactions (ATRs) • A spectrum of hypersensitivity reactions to transfused blood (particularly plasma component) • Typically manifest <2 hours of Tx • Urticaria, pruritus, flushing • Angioedema, laryngeal edema, bronchospasm • Anaphylaxis • Most common transfusion reaction, particularly with products containing plasma • 1-3% of all transfusions • 3% of transfusion-related mortalities

35. Classic Hypersensitivity Reaction Allergen IgE Mast cell/ Basophil Histamines Leukotrienes Cytokines Chemokines

36. Signs and Symptoms Itching Hives, urticaria Flushing Tachycardia Laryngeal stridor Dyspnea Treatment Antihistamines Steroids Epinephrine Washed RBC (anti-IgA) Acute Allergic Reactions

37. Can pre-medication with diphenhydramine prevent allergic transfusion reactions?

38. No Effect of Diphenhydramine Premedication to Reduce ATRs Tobian Transfusion 2007

39. What additional methods could prevent allergic transfusion reactions?

40. Removing Plasma Reduces Allergic Reactions (5.5%) (1.7%) (0.7%) (0.7%) (0.4%) Tobian Transfusion, In Press

41. Washing Platelets Reduces CCI • 40 patients at JHH were evaluated after being placed on a washed protocol. • CCIs were averaged for a two day period pre- and post- transfusion Tanz ASH 2001

42. Washed platelets • Patients receiving washed platelets subsequently received increased platelet equivalent units (8.1 vs. 10.5, p<0.0005) • Increased frequency of platelet transfusions were required. • No. of days between transfusions: • 1.47 days vs. 0.89 days (p<0.005) • However, there was still an overall decrease in bleeding score indicating no change in in vivo efficacy of washed platelets Tanz ASH 2001

43. Workload Implications • Greater than 20,000 platelet transfusion annually at Johns Hopkins • 70% for oncology and hematologic malignancies • 1600 (7.95%) require concentration and/or resuspension • 400 (1.99%) require platelet washing • Platelet manipulations are costly, reduce shelf life, and reduce in vivo effectiveness

44. Transfusion Reactions Associated with Plasma • Allergic Hypersensitivity • Febrile Non Hemolytic • TRALI • Transfusion Transmitted Infections • ABO Mismatched Hemolysis Additional methods to reduce transfusion reactions are needed.

45. Plasma Additive Solution (PAS) AABB Bulletin #10-06 • RBC crystalloid additive solution has extended shelf life and viability of RBCs. • PAS replaces ~65% of the plasma used when storing platelets. • Long history of use in Europe to increase plasma supplies for transfusion and fractionation. • There are numerous different compositions of platelet additive solutions (variable glucose, acetate, MgCl2, NaCl) • FDA approved the first platelet additive solution on July 30, 2010 • (PAS-C; InterSol, Fenwal/Baxter, Lake Zurich, IL).

46. Transfusion Reactions Reduced with PAS Platelets • Multicenter, randomized trial of 84 patients in each arm who received ABO matched products • Azuma et al., showed a 42% reduction in allergic TR and FNHTRs among patients who received PAS platelets (Transfusion 2009) • Wildt-Eggen showed a 66% reduction in transfusion reactions (Transfusion 2000) Kerkhoffs Blood 2006

47. Comparison of PAS Platelets vs. Platelets Stored in Plasma • Prospective, open-label, randomized • Hematology/oncology patients • Buffy coat (pools of 5); ABO-matched • Three arms • Control (platelets in plasma) • PAS III (65/35) • PAS III plus PR (Intercept) Kerkhoffs Br J Hematol 2010

48. Bleeding after Receiving PAS Platelets Kerkhoffs Br J Hematol 2010

49. CCI and PAS Platelets * Off-protocol platelets were suspended in T-Sol Kerkhoffs Br J Hematol 2010

50. Transfusion Service Questions • PAS platelets have medical advantages for oncology users but potential disadvantages for surgical patients. Usage of FFP may increase. • Will neonatologists accept PAS in platelets? • Will ABO matching requirements for plasma in platelets be reduced? • What is the in vivo survival of PAS platelets? • Will platelet costs go up, and if so, will they be balanced by workload reductions at the transfusion service? • How will PAS platelets be implemented into the blood supply chain? Ness 2011