Guidelines for Transfusion and Patient Blood Management, and Discuss Relevant Transfusion Related Topics

Home , Blood plasma, Cryosupernatant, Iatrogenic anemia

Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

Community Transfusion Committee CHAIR: Aina Silenieks, M.D., [email protected]

MEMBERS: A.Owusu-Ansah, M.D. S. Dunder, M.D. M. Furasek, M.D. D. Lester, M.D. D. Voigt, M.D. B. J. Wilson, M.D.

COMMUNITY Juliana Cordero, Blood Bank Coordinator, CHI Health Nebraska Heart REPRESENTATIVES: Becky Croner, Laboratory Services Manager, CHI Health St. Elizabeth Mackenzie Gasper, Trauma Performance Improvement, Bryan Medical Center Kelly Gillaspie, Account Executive, Nebraska Community Blood Bank Mel Hanlon, Laboratory Specialist - Transfusion Medicine, Bryan Medical Center Kyle Kapple, Laboratory Quality Manager, Bryan Medical Center Lauren Kroeker, Nurse Manager, Bryan Medical Center Christina Nickel, Clinical Laboratory Director, Bryan Medical Center Rachael Saniuk, Anesthesia and Perfusion Manager, Bryan Medical Center Julie Smith, Perioperative & Anesthesia Services Director, Bryan Medical Center Elaine Thiel, Clinical Quality Improvement/Trans. Safety Officer, Bryan Med Center Kelley Thiemann, Blood Bank Lead Technologist, CHI Health St. Elizabeth Cheryl Warholoski, Director, Nebraska Operations, Nebraska Community Blood Bank Jackie Wright, Trauma Program Manager, Bryan Medical Center

CONSULTANTS: Jed Gorlin, M.D., Innovative Blood Resources [email protected]

Michael Kafka, M.D., LifeServe Blood Center [email protected]

Alex Smith, D.O., LifeServe Blood Center [email protected]

Nancy Van Buren, M.D., Innovative Blood Resources [email protected]

SUBJECT MATTER Judy Miller, Laboratory Specialist - Hematology, Bryan Medical Center EXPERTS: Scott Persson, Pharmacy Clinical Manager, Bryan Medical Center

Revised January 2021 Page 2 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

Community Transfusion Committee The Community Transfusion Committee is a multidisciplinary group that meets to monitor blood utilization practices, establish guidelines for transfusion and patient blood management, and discuss relevant transfusion related topics. It is comprised of physicians from local hospitals, invited guests, and community representatives from the hospitals’ transfusion services, nursing services, perfusion services, health information management, and blood providers. Transfusion reactions are reviewed and summarized by each of the hospitals’ Transfusion Services and reported back to the committee. This also includes: • Any patient death related to transfusion • Hemolytic or anaphylactic transfusion reactions • Any patient with reported diagnosis of hepatitis or abnormal liver function within 6 months following transfusion • Any other serious adverse reaction or unexpected outcome associated with a transfusion These Guidelines for Transfusion and Patient Blood Management are reviewed and revised biannu- ally by the Community Transfusion Committee to ensure that the industry’s most current practices are promoted. The Guidelines are the standard by which utilization practices are evaluated. They are also designed to provide helpful information to assist physicians and all healthcare providers in providing safe and appropriate blood component therapy to patients. Appendices have been added for informational purposes and are not to be used as guidance for clinical decision making.

Revised January 2021 Page 3 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

Table of Contents

SABM Choosing Wisely 5

AABB Choosing Wisely 8

Patient Blood Management 10

Red Cell Transfusion 12

Platelet Transfusion 17

Thawed Fresh Frozen Plasma/Thawed Plasma for Transfusion 21

Convalescent Plasma 25

Cryoprecipitate Transfusion 29

Special Needs 31

Treatment of the Jehovah’s Witness Patient 35

Appendix A – How to Properly Obtain a Blood Sample 38 for Transfusion Medicine

Appendix B – Blood Component Transfusions in Nonemergency Settings 39

Appendix C – Transfusion Reactions 40

Appendix D – The Coagulation Cascade/Lab Tests/Drugs 43

Appendix E – Anticoagulant Medications 44

Appendix F – Antiplatelet Medications 47

Appendix G – Glossary 49

Revised January 2021 Page 4 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

Society for the Advancement of Blood Management Choosing

Wisely® Five Things Physicians and Patients Should Question An initiative of the ABIM Foundation

Don’t proceed with elective surgery in patients with properly diagnosed and correctable anemia until the anemia has been appropriately treated. Anemia is common, presenting in approximately one-third of patients undergoing elective surgery. There is often the misconception that 1 anemia is harmless, when, in fact, it is independently associated with significant morbidity and mortality that can be as high as 30-40% in certain patient populations. Treatment of anemia improves patient readiness for surgery, aids in management of comorbid conditions, decreases length of stay and readmission rates, and reduces transfusion risks. Treatment modalities may include nutritional supplementations, such as iron, B12 and folate, changes in medication, management of chronic inflammatory conditions or previously undiagnosed malignancy, or other interventions based on the etiology.

Don’t perform laboratory blood testing unless clinically indicated or necessary for diagnosis or management in order to avoid iatrogenic anemia. Up to 90% of patients become anemic by day 3 in the intensive care unit. Although laboratory testing can aid in diagnosis, prognosis and 2 treatment of disease, a significant number of tests are inappropriate or unnecessary. Anemia secondary to iatrogenic blood loss causes an increased length of stay and mortality. Increased phlebotomy for laboratory testing also increases the odds for transfusion and its associated risks. Unnecessary laboratory testing adds to the cost of care through laboratory test charges and also by increasing downstream costs due to unnecessary interventions, prescriptions, etc. Thus judicious use of laboratory testing is recommended, and testing should not be performed in the absence of clinical indications.

Don’t transfuse plasma in the absence of active bleeding or significant laboratory evidence of coagulopathy. 3 Recent studies demonstrate that plasma is often transfused inappropriately. In the absence of active bleeding or clear evidence of coagulopathy, current literature shows no reduction in blood loss or transfusion requirements with the use of plasma, but shows increased risk of transfusion-associated adverse events such as transfusion-related acute lung injury, transfusion-associated circulatory overload and allergic reactions. These transfusion-associated adverse events lead to poorer outcomes and increased cost of care.

Avoid transfusion when antifibrinolytic drugs are available to minimize surgical bleeding. 4 Antifibrinolytic pharmacologic therapy has been shown to reduce blood loss and transfusion requirements in orthopedic and cardiovascular surger- ies. Early administration of tranexamic acid, specifically within three hours, in trauma and obstetric hemorrhage significantly reduces mortality and bleeding.

Avoid transfusion, outside of emergencies, when alternative strategies are available as part of informed consent; make discussion of alternatives part of the informed consent process. 5 Informed choice/consent regarding transfusion and other effective methods should be standardized and consistently delivered. Throughout the world, there is wide variation among medical practitioners and hospitals with regard to medical knowledge about the true risks of transfusion, alternatives to transfusion, and the delivery of this information to patients. Outside of the truly emergent clinical situation, transfusion should be avoided or limited when other interventions are available. Alternative strategies include, but are not limited to pharmacologic agents, cell salvage, normovolemic hemodilution and minimally-invasive surgical techniques.

These items are provided solely for informational purposes and are not intended as a substitute for consultation with a medical professional. Patients with any specific questions about the items on this list or their individual situation should consult their physician.

Revised January 2021 Page 5 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

How This List Was Created The Executive Committee and Board of Directors (BOD) of the Society for the Advancement of Blood Management (SABM) had a strong desire to participate in the Choosing Wisely campaign. Participation allows SABM to align with the national Choosing Wisely® team and other specialty societies to further the mission of collaborative physician-patient health care delivery and responsible use of resources. A Task Force was appointed from within the BOD to draft the initial set of recommendations. Evidence-based recommendations were based on our society’s foundational pillars and structured around published SABM Standards. A critical feature was the review of relevant literature for supporting evidence applicable to each statement. Ultimately, the draft recommendations were submitted to the membership for input via an email survey. This resulted in the final five statements for which evidentiary materials and pertinent references were written. The BOD approved the materials prior to submission. Working with this initiative, our selected recommendations and integrated materials were further honed based on subsequent campaign review. The list and supporting evidence will form the basis of a manuscript for publication in a peer-reviewed journal. SABM will also develop monitors to assess the impact of the initiative for our members and hospital affiliates. We foresee this as a vehicle for outreach to other professional societies, health care providers and patients.

Sources

Mursallana KM, Tamim HM, Richards T et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. Lancet 2011; 378 (9800): 1396-4007. Koch C, Li L, Sun Z et al. Hospital-acquired anemia: prevalence, outcomes, and healthcare implications. J Hosp Med 2013; 8(9): 506-512. 1 Beattie WS, Karkouti K, Wijeysundera DN, Tait G et al. Risk associated with preoperative anemia in non-cardiac surgery; a single-center cohort study. Anesthesiology 2009; 110 (3): 574-581. Munoz M, Acheson AG, Aurbach M et al. International consensus on peri-operative anemia and iron deficiency. Anaesthesia 2017; 72: 233-247. Patient Blood Management Gombotz, Zacharowski & Spahn (eds.), Thieme Publishers, 2016.

Gattinoni L and Chiumello P. Anemia in the intensive care unit: how big is the problem? Transfus Altern Transfus Med 2002; 4 (4): 118-120. Thavendranathan P, Bagai A, Ebidia A et al. Do blood tests cause anemia in hospitalized patients? The effect of diagnostic phlebotomy on hemoglobin and 2 hematocrit levels. J Gen Int Med 2005; 20(6): 520-524. Chant C, Wilson G, Friedrich JO et al. Anemia, transfusion, and phlebotomy practices in critically ill patients with prolonged intensive care unit length of stay: a cohort study. Crit Care 2006; 10 (5): R140.

Stanworth SJ, Brunskill SJ, Hyde CJ et al. Is fresh-frozen plasma clinically effective? A systematic review of randomized controlled trials. Brit J Haematol 2004; 126(11): 139-152. Holland LL, Foster TM, Marlar RA, Brooks JP et al. Fresh frozen plasma is ineffective for correcting minimally elevated international normalized ratios. Transfusion 2005; 45(7): 1234-1235. Segal J and Dzik W. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion 2005; 45(9): 1412-1425. Stanworth S, Grant-Casey J, Lowe D et al. The use of fresh-frozen plasma in England: high levels of inappropriate use in adults and children. Transfusion 3 2011; 51(1): 62-70. Yang L, Stanworth S, Hopewell S et al. Is fresh-frozen plasma clinically effective? An update of a systematic review of randomized controlled trials. Trans- fusion 2012; 52(8): 1673-1686. Muller M, Arbous MS, Spoelstra-de Man AM et al. Transfusion of fresh-frozen plasma in critically ill patients with coagulopathy before invasive procedures: a randomized controlled trial. Transfusion 2015; 55(1): 26-35. Green L, Bolton-Maggs P, Beattie C et al. British Society of Haematology guidelines on the spectrum of fresh frozen plasma and cryoprecipitate products: their handling and use in various patient groups in the absence of major bleeding. Brit J Haematol 2018; 181(1): 54-67.

Henry DA, Carless PA, Moxey AJ et al. Anti-fibrinolytic drugs for reducing blood loss and the need for red blood cell transfusion during and after surgery. Cochrane Database Syst Rev 2011; (3): CD001886. CRASH-2 Trial Collaborators Effects of tranexamic acid on death, vasoocclusive events, and blood transfusion in trauma patients with significant haemor- 4 rhage (CRASH-2): a randomised, placebo-controlled trial. Lancet 2010; 376(9734): 23-32. WOMAN Trial Collaborators Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomized, double-blind, placebo-controlled trial. Lancet 2017; 389(10084): 2105-2116.

Friedman M, Arja W, Bata R et al. Informed consent for blood transfusion: What do medical residents tell? What do patients understand? Am J Clin Pathol. 2012 Oct;138(4):559-65. Davis R, Vincent C, and Murphy M. Blood transfusion safety: the potential role of the patient. Transfus Med Rev 2011; 25(1) 12-23. Booth C, Grant-Casey J, Court EL et al. National comparative audit of blood transfusion: report on the 2014 audit of patient information and consent. 5 Transfus Med 2017: 21(3): 183-189. Vossoughi S, Macauley R, Sazama K, and Fung M. Attitudes, practices, and training on informed consent for transfusions and procedures. Amer J Clin Path 2015; 144: 315-321. Howell CA and Forsythe JLR. Patient consent for blood transfusion- recommendations from the SaBTO. Transfus Med 2011. 21: 359-362. Court EL. Robinson JA, and Hocken DB Informed consent and patient understanding of blood transfusion. Transfus Med 2011; 21: 183-189.

Revised January 2021 Page 6 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

About the ABIM Foundation About the Society for the Advancement of Blood Management The mission of the ABIM Foundation is to advance The Society for the Advancement medical professionalism to improve the health care sys- of Blood Management (SABM) was tem. We achieve this by collaborating with physicians founded in 2001 by health care and physician leaders, medical trainees, health care de- providers, nurses and physicians livery systems, payers, policymakers, consumer organi- who saw the need for a new way zations and patients to foster a shared understanding of thinking about transfusion as a of professionalism and how they can adopt the tenets therapy. SABM included thought leaders who promulgated the concept of professionalism in practice. of patient blood management as the new standard of care. The SABM To learn more about the ABIM Foundation, visit www.abimfoundation.org. mission is broad, its foundation based on appropriate evidence-based transfusion guidelines, the management of anemia, optimization of coagulation and minimization of bleeding, and utilization of interdisciplinary blood conservation strategies. The goal is improved patient outcomes. Today, SABM is recognized as a key educational resource for patient blood management. SABM is grounded in scientific validation and evidence-based practices, and focused on promoting the patients’ best interest through effective and optimal patient blood management. Given our mission and message, SABM is truly honored and proud to partner with the Choosing Wisely® campaign.

For more information or to see other lists of Five Things Physicians and Patients Should Question, visit www.choosingwisely.org.

Revised January 2021 Page 7 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management Choosing Five Things Physicians ® Wisely and Patients Should Question An initiative of the ABIM Foundation

Don’t transfuse more units of blood than absolutely necessary. Each unit of blood carries risks. A restrictive threshold (7.0-8.0g/dL) should be used for the vast majority of hospitalized, stable patients 1 without evidence of inadequate tissue oxygenation (evidence supports a threshold of 8.0g/dL in patients with pre-existing cardiovascular disease). Transfusion decisions should be influenced by symptoms and hemoglobin concentration. Single unit red cell transfusions should be the standard for non-bleeding, hospitalized patients. Additional units should only be prescribed after re-assessment of the patient and their hemoglobin value.

Don’t transfuse red blood cells for iron deficiency without hemodynamic instability. 2 Blood transfusion has become a routine medical response despite cheaper and safer alternatives in some settings. Pre-operative patients with iron deficiency and patients with chronic iron deficiency without hemodynamic instability (even with low hemoglobin levels) should be given oral and/or intravenous iron.

Don’t routinely use blood products to reverse warfarin. 3 Patients requiring reversal of warfarin can often be reversed with vitamin K alone. Prothrombin complex concentrates or plasma should only be used for patients with serious bleeding or requiring emergency surgery.

Don’t perform serial blood counts on clinically stable patients. 4 Transfusion of red blood cells or platelets should be based on the first laboratory value of the day unless the patient is bleeding or otherwise unstable. Multiple blood draws to recheck whether a patient’s parameter has fallen below the transfusion threshold (or unnecessary blood draws for other laboratory tests) can lead to excessive phlebotomy and unnecessary transfusions.

Don’t transfuse O negative blood except to O negative patients and in emergencies for women of child bearing potential with unknown blood group. 5 O negative blood units are in chronic short supply due in part to overutilization for patients who are not O negative. O negative red blood cells should be restricted to: (1) O negative patients; or (2) women of childbearing potential with unknown blood group who require emergency transfusion before blood group testing can be performed.

Revised January 2021 Page 8 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

How This List Was Created Recommendations were drafted by a work group led by AABB Director Jeannie Callum, MD. Ten draft statements were edited by the AABB Clinical Transfusion Medicine Committee, chaired by Aaron Tobian, MD. In order to identify the top five statements, a random sampling of AABB physician members working in the field of transfusion medicine in hospitals, as well as all members of AABB’s Clinical Transfusion Medicine Committee, were asked to rate the 10 draft statements. On a Likert scale, participants were asked to “indicate the importance of including each of the following transfusion-related statements in the Choosing Wisely campaign promoting the appropriate use of health care resources.” The final top five statements were approved by the AABB Board of Directors.

AABB’s disclosure and conflict of interest policy can be found at www.aabb.org.

Sources

Carson JL, Grossman BJ, Kleinman S, Tinmouth AT, Marques MB, Fung MK, Holcomb JB, Illoh O, Kaplan LJ, Katz LM, Rao SV, Roback JD, Shander A, 1 Tobian AA, Weinstein R, Swinton McLaughlin LG, Djulbegovic B; Clinical Transfusion Medicine Committee of the AABB. Red blood cell transfusion: a clinical practice guideline from the AABB. Ann Intern Med. 2012 Jul 3;157(1):49–58.

AABB. Guidelines for patient blood management and blood utilization. Bethesda (MD): AABB; 2011. 52 p. Lin DM, Lin ES, Tran MH. Efficacy and safety of erythropoietin and intravenous iron in perioperative blood management: a systematic review. Transfus 2 Med Rev. 2013 Oct;27(4):221–34. Friedman AJ, Chen Z, Ford P, Johnson CA, Lopez AM, Shander A, Waters JH, van Wyck D. Iron deficiency anemia in women across the life span. J Wom- ens Health (Larchmt). 2012 Dec;21(12):1282–9.

Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, Svensson PJ, Veenstra DL, Crowther M, Guyatt GH; American College of Chest Physi- 3 cians. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2Suppl): e152S–84S.

Napolitano LM, Kurek S, Luchette FA, Corwin HL, Barie PS, Tisherman SA, Hebert PC, Anderson GL, Bard MR, Bromberg W, Chiu WC, Cipolle MD, Clancy KD, Diebel L, Hoff WS, Hughes KM, Munshi I, Nayduch D, Sandhu R, Yelon JA; American College of Critical Care Medicine of the Society of Critical Care 4 Medicine; Eastern Association for the Surgery of Trauma Practice Management Workgroup. Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. Crit Care Med. 2009 Dec;37(12):3124–57.

The Chief Medical Officer’s National Blood Transfusion Committee (UK). The appropriate use of group O RhD negative red cells. Manchester (UK): Na- 5 tional Health Service; 2008. 4 p.

About the ABIM Foundation About the AABB The mission of the ABIM Foundation is to advance AABB is a not-for-profit association representing in- medical professionalism to improve the health care dividuals and institutions involved in the field of system. We achieve this by collaborating with phy- transfusion medicine and cellular therapies. The as- sicians and physician leaders, medical trainees, sociation is committed to improving health by deliv- health care delivery systems, payers, policymakers, ering standards, accreditation and professional edu- consumer organizations and patients to foster a cational programs that focus on optimizing patient shared understanding of professionalism and how and donor care and safety. AABB membership con- they can adopt the tenets of professionalism in sists of approximately 1,800 institutions and 8,000 practice. professional individuals, including roughly 1,600 To learn more about the ABIM Foundation, visit www.abimfoundation.org. physicians. To learn more about the AABB, visit www.aabb.org.

For more information or to see other lists of Five Things Physicians and Patients Should Question, visit www.choosingwisely.org.

Revised January 2021 Page 9 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

PATIENT BLOOD MANAGEMENT Patient Blood Management (PBM) is a comprehensive multispecialty approach to the use of blood and blood products in patient care. PBM uses evidence-based data to provide guidance in the optimal management of a patient who may be a candidate for blood transfusion. Physicians, nurses, laboratory staff, perfusion specialists and other health care providers are all part of the team that evaluates and observes the patient to determine if the patient’s disease process and symptoms are best treated by a transfusion or if other medical and supportive care would be more appropriate. Education of all health care providers caring for the patient is a key component of PBM. Other parameters include identification and management of anemia and bleeding disorders prior to therapeutic interventions, use of intraoperative blood salvage, postoperative and intensive care unit (ICU) patient management strategies that decrease the likelihood of a need for blood transfusion as well as ongoing blood utilization review with communication of the information to ordering providers. The Community Transfusion Committee endorses and supports the elements of a Patient Blood Management program in all of its participating institutions. Key Points of Patient Blood Management • The primary goal of PBM is to improve patient outcomes (and not just reduce the use of transfusions). • PBM is multi-disciplinary, evidence-based, and patient-centered. • Key approaches include correcting anemia, maintaining an appropriate hemoglobin level, optimizing hemostasis, and minimizing blood loss. • PBM emphasizes proactive, rather than reactive, strategies.

Manage Anemia Optimize Hemostasis • Monitor for anemia (early-on & throughout course of • Perform risk assessment (e.g., patient history) care) • Perform appropriate coagulation assessment • Establish & manage anemia causes • Correct abnormalities with goal-directed therapy • Enhance physiologic adaptations to anemia (e.g., • Assess coagulopathy causes increase O2 supply & decrease its demand) • Adjust anticoagulants before procedures • Support hematopoiesis (e.g., iron, ESAs) • Use systematic & topical hemostatic agents, if indicated • Order judicious, evidence-based transfusions • Apply evidence-based use of plasma & pro-coagulants when indicated Patient-Centered Decision Making Interdisciplinary Management • Document & communicate patient's preferences • Measure & assess hemoglobin loss (amount & rate) • Inform patients of risks, benefits & alternatives for • Be vigilant for blood loss & act fast to arrest it treatments & procedures • Consider autologous transfusion techniques (cell saver, • Provide patients with all available PBM options acute, normovolemic hemodilution) • Incorporate patient values & choices in management • Minimize diagnostic (i.e., iatrogenic) blood loss process • Use less-invasive, more meticulous surgical technique, planning, & rehearsal In summary, PBM is a concept of care that places great emphasis on proactive planning, preventive measures, and the sensible use of available interventions to improve quality of care and patient outcomes. The “Choosing Wisely” campaign, an initiative of the American Board of Internal Medicine (ABIM) has also addressed the issue of appropriate blood product usage and patient blood management through partnerships with AABB (see page 8), and the SABM (Society for the Advancement of

Revised January 2021 Page 10 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

Blood Management) (see page 5). The College of American Pathologists (CAP) has also contrib- uted the following recommendation: “Don’t transfuse plasma to correct a laboratory value; treat the clinical status of the patient.” This issue is discussed further in the section of the Guidelines dealing with transfusion of plasma (pages 21-22).

REFERENCES and SUGGESTED READING 1. AABB Patient Blood Management iOS iPhone App. Available from http://appshopper.com/medical/aabb-patient-blood- management. Accessed 7 Oct 2014. 2. Callum JL, Waters JH, Shaz BH, Sloan SR, Murphy MF. The AABB recommendations for the Choosing Wisely campaign of the American Board of Internal Medicine. Transfusion 2014;54:2344-2352. 3. Experts: hospitals can improve care, save health care dollars by cracking down on unnecessary blood transfusions. ED Manag 2013;25:8-11. 4. Goodnough LT, Shander A. Update on erythropoiesis-stimulating agents. Best Pract Res Clin Anaesthesiol 2013;27:121- 129. 5. Hocevar R. Better blood management helps Johns Hopkins reduce length of stay, save nearly $3 million. https://www.hfma.org/Leadership/E-Bulletins/2018/August/Better_Blood_Management_Helps_Johns_Hopkins_Re- duce_Length_of_Stay,_Save_Nearly_$3_Million. 6. Koch CG, et al. Hospital-acquired anemia: Prevalence, outcomes, and healthcare implications. J Hosp Med 2013;8(9):506- 512. 7. LaPar DJ, et al. Blood product conservation is associated with improved outcomes and reduced costs after cardiac surgery. J Thorac Cardiovasc Surg 2013;145(3):796-803. 8. Salisbury AC, et al. Diagnostic blood loss from phlebotomy and hospital-acquired anemia during acute myocardial infarction. Arch Intern Med 2011;171:1646-1653. 9. Sarode R, et al. Prospective monitoring of plasma and platelet transfusions in a large teaching hospital results in significant cost reduction. Transfusion 2010;50:487-492. 10. Shander A, et al. Appropriateness of allogeneic red blood cell transfusion: the international consensus conference on transfusion outcomes. Transfus Med Rev 2011;25:232-246. 11. Shander A, et al. Iron deficiency anemia-bridging the knowledge and practice gap. Transfus Med Rev 2014;28:156-166. 12. Shander A, Gross I, Hill S, Javidroozi M, Sledge S. A new perspective on best transfusion practices. Blood Transfus 2013;11:193-202. 13. Shander A, Hofmann A, Isbister J, Van AH. Patient blood management - the new frontier. Best Pract Res Clin Anaesthesiol 2013;27:5-10. 14. Shander A, Javidroozi M. Patient Blood Management: Beyond sensible use of blood for better outcomes. Americas Blood Centers Blood Bulletin Oct 2014. 15. Shander A, Javidroozi M, Ozawa S, Hare GM. What is really dangerous: anaemia or transfusion? Br J Anaesth 2011;107 Suppl 1:i41-i59. 16. Shander A, Moskowitz DM, Javidroozi M. Blood conservation in practice: an overview. Br J Hosp Med (Lond) 2009;70:16- 21. 17. Shander A, Ozawa S, Gross I, Henry D. Erythropoiesis-stimulating agents: friends or foes? Transfusion 2013;53:1867-1872. 18. Waters J. Promoting Safety, Quality, and Value Through Patient Blood Management. Anesthesiology 11 2017;127:738-740. 19. Waters J. Using Blood Wisely. www.choosingwisely.org/resources/updates-from-the-field/using-blood-wisely.

Revised January 2021 Page 11 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

RED CELL TRANSFUSION

ADULT RED CELL TRANSFUSION

Red Blood Cell Compatibility Chart Patient Donor Unit ABO Group ABO antigens on red blood cells Blood Type O None O A A A and O B B B and O AB A and B AB, A, B and O

All red cell products supplied by Nebraska Community Blood Bank and LifeServe Blood Center are leukocyte reduced. A. Indications 1. One of the following: a. Clinical signs and symptoms including, but not limited to: hypovolemia, hypoxia, syncope, dyspnea, postural hypotension, tachycardia, tachypnea, angina, transient ischemic attack or other symptoms secondary to hemorrhage, trauma, surgery, hemolysis or other conditions, OR b. Evidence of acute loss of 15% of total blood volume or >750 mL blood loss, OR c. Hemoglobin of 7 g/dl or less for hospitalized hemodynamically stable adult patients, including critical care patients or hemoglobin of 8 g/dl or less for patients undergoing orthopedic surgery or cardiac surgery, and those with existing cardiovascular disease. d. Other specific indications (e.g., chronic transfusion therapy program for Sickle Cell Dis- ease to maintain HbS below a specific threshold). 2. Blood should be transfused on a unit-by-unit basis, according to patient symptoms. ONE UNIT OF BLOOD MAY BE SUFFICIENT. POST-TRANSFUSION HEMOGLOBIN OR HEMATOCRIT MAY BE MEASURED AS SOON AS 15 MINUTES AFTER THE COMPLETION OF THE TRANSFUSION. The patient should be evaluated after the transfusion in order to assess if clinical signs and symptoms have improved. That information should be documented and used to assist in determining if additional transfusion is necessary or not. B. The Community Transfusion Committee supports the AABB clinical practice guidelines for red cell transfusion found on the next page.

Revised January 2021 Page 12 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

Clinical Practice Guidelines for Red Blood Cell Transfusion

Recommendation (for hospitalized, Hemoglobin Comments hemodynamically (g/dL) stable patients) Red cell transfu- The AABB recommends a restrictive transfusion strategy (7 g/dL) in 7 sion likely to be hospitalized adult, hemodynamically stable patients including those appropriate who are critically ill.

Red cell transfu- The AABB recommends a restrictive transfusion strategy (8 g/dL) for 8 sion likely to be patients undergoing orthopedic or cardiovascular surgery and those appropriate with pre-existing cardiovascular disease.

The above recommendations do not apply to patients with: acute coronary syndrome; chronic transfusion-dependent anemia; and hematology-oncology patients with severe thrombocytopenia.

The AABB recommends that patients, including neonates, should receive RBC units selected at any point within their licensing dating pe- Age of RBC Units riod (standard issue) rather than limiting transfusion to only fresh (storage length < 10 days) units.

This information is derived from clinical practice guidelines developed by a task force representing the AABB, American Society of Anesthesiologists, American College of Cardiology, American Society of Hematology, Amer- ican Association for the Surgery of Trauma, and Society for Critical Medicine. Clinical practice guidelines and recommendations are not considered to be standards or absolute requirements. They do not apply to all individual transfusion decisions. Each patient’s clinical status must be considered.

PEDIATRIC RED CELL TRANSFUSION A. Indications - Infants less than 4 months of age 1. HCT <20% with low reticulocyte count and symptomatic anemia (tachycardia, tachypnea, poor feeding). 2. HCT <30% and any of the following: a. On <0.35 FiO2 by hood b. On supplemental oxygen by nasal cannula c. On CPAP or mechanical ventilation with mean airway pressure <6 cm H2O d. With significant tachycardia (>180 beats per minute) or tachypnea (>80 breaths per minute), for greater than 24 hours, thought to be related to anemia 3. HCT <35% and either of the following: a. On >0.35 FiO2 by hood b. On CPAP or mechanical ventilation with mean airway pressure ≥6-8 cm H2O 4. HCT <45% and either of the following: a. On ECMO b. With cyanotic congenital heart disease

Revised January 2021 Page 13 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

5. For preterm infants of <1300 grams there is some evidence that a more restrictive transfusion protocol versus a more liberal protocol is associated with fewer infants requiring transfusions, and fewer transfusions needed overall. Data are conflicting as to whether a more restrictive or liberal protocol is associated with better childhood neurodevelopmental outcomes. A more liberal transfusion trigger of 8 g/dL may be indicated for premature infants at risk for necrotizing enterocolitis (NEC). 6. The Neonatal Resuscitation Program (NRP 7th Edition) now recommends cord clamping be delayed for at least 30-60 seconds for most vigorous term and preterm newborns. Potential benefits include increased red blood cell volume, more stable transitional circulation, decreased need for RBC transfusion and reduction in intraventricular hemorrhage. 7. Evidence does not support routine RBC replacement in this population for a given amount of iatrogenic blood loss. 8. Double Volume Exchange Transfusion for hyperbilirubinemia

B. Indications - Patients older than 4 months of age 1. Surgical/Trauma a. Preoperative anemia when other corrective therapy is not available b. Acute/Intraoperative blood loss of >15% total blood volume c. HCT <24% and in perioperative period, with signs and symptoms of anemia d. Emergency surgical procedure in patient with significant postoperative anemia 2. Patients receiving chemotherapy/radiotherapy for malignancies will have transfusion triggers that vary based on their malignancy and clinical situation. Consultation with hematologist/oncologist is recommended. 3. In cases of chronic, congenital or acquired symptomatic anemia transfuse at Hgb of 6 to 8 g/dL a. Acute blood loss with hypovolemia not responsive to other therapy b. HCT <40% and: i. Severe pulmonary disease ii. On ECMO c. Sickle Cell Disease (Recommend Consultation with Pediatric Hematologist): i. CVA ii. Acute chest syndrome iii. Splenic sequestration iv. Aplastic crisis v. Recurrent priapism vi. Preoperatively when general anesthesia planned (target Hgb 10 g/dL) d. Chronic Transfusion Programs for disorders of RBC production (β Thalassemia major and Diamond Blackfan syndrome unresponsive to therapy) e. For stable, critically ill children requiring Pediatric Intensive Care a hemoglobin transfusion threshold of 7 g/dL is not inferior to a threshold of 9.5 g/dL. REMEMBER! Transfusion-Associated Circulatory Overload (TACO) is a leading cause of morbidity and mortality in patients receiving a transfusion! TACO accounted for 22% of transfusion-related fatalities reported to the FDA from 2010 – 2014. Over 20% of TACO reactions are life-threatening and are associated with increased time in the ICU and increased length of hospital stay. TACO can occur after transfusion of any blood product – RBCs, plasma or platelets. Risk factors associated

Revised January 2021 Page 14 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management with TACO include: age >60 years or <3 years, chronic renal failure, congestive heart failure, critically ill status (ICU patients), and the number of products transfused as well as rapid transfusion rate.

REFERENCES and SUGGESTED READING 1. Andersson O, et al. Effect of delayed cord clamping on neurodevelopment at 4 years of age: A randomized clinical trial. JAMA Pediatr 2015;169(7):631-638. 2. Becker J, Shaz B. Guidelines for Patient Blood Management and Blood Utilization. Bethesda, MD: AABB Press, 2011. 3. Bell EF, Strauss RG, Widness JA. Red blood cell transfusion in neonates. Pediatrics 2005;115:1685-1691. 4. Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic transfusion. Cochrane Database Syst Rev 2012;4:CD002042. 5. Carson JL, Carless PA, Hebert PC. Outcomes using lower vs higher hemoglobin thresholds for red blood cell transfusion. JAMA 2013;309:83-84. 6. Carson JL, et al. Clinical practice guidelines from the AABB: Red blood cell transfusion thresholds and storage. JAMA 2016;316(19):2025-2035. 7. Carson JL, et al. Clinical trials evaluating red blood cell transfusion thresholds: An updated systematic review and with additional focus on patients with cardiovascular disease. AHJ 2018;200:96-101. 8. Carson JL, et al. Effect of anaemia and cardiovascular disease on surgical mortality and morbidity. Lancet 1996;348:1055- 1060. 9. Carson JL, et al. Liberal or restrictive transfusion in high-risk patients after hip surgery. N Engl J Med 2011;365:2453-2462. 10. Carson JL, et al. Red blood cell transfusion: A clinical practice guideline from the AABB. Ann Intern Med 2012;157:49-58. 11. Carson JL, Triulzi DJ, Ness PM. Indications for and adverse effects of red-cell transfusion. N Engl J Med 2017;377:1261- 1272. 12. Connell NT. Transfusion Medicine. Prim Care 2016 Dec;43(4):651-659. 13. Cooper DJ, et al. Age of red cells for transfusion and outcomes in critically ill patients. N Engl J Med 2017; 377:1858-1867. 14. Fridey J, et al. A Compendium of Transfusion Practice Guidelines, 3rd Ed., American Red Cross, 2017. 15. Fung MK, Eder AF, Spitalnik SL, Westhoff CM, eds. AABB Technical Manual 19th Ed., 2017. 16. Gammon R. Clinical Practice Guidelines from the AABB: Red Blood Cell Transfusion Thresholds and Storage. Americas Blood Centers Blood Bulletin Dec 2017. 17. Goel R, Josephson C. Strategic initiatives in pediatric transfusion research. AABB News 2018;20(2):6-9. 18. Hebert PC, Carson JL. Transfusion threshold of 7 g per deciliter - the new normal. N Engl J Med 2014;371:1459-1461. 19. Hebert PC, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med 1999;340:409-417. 20. Heddle NM, et al. Effect of short-term vs. long-term blood storage on mortality after transfusion. N Engl J Med 2016; 375:1937-1945. 21. Hendrickson JE, Josephson CD. Neonatal and pediatric transfusion medicine. In: Hillyer CD, Shaz BH, Zimring JC, Abshire TC, eds. Transfusion medicine and hemostasis: Clinical and laboratory aspects. London: Elsevier, 2009:42. 22. Kirpilani H, et al. The Premature Infants in Need of Transfusion (PINT) study: a randomized, controlled trial of a restrictive (low) versus liberal (high) transfusion threshold for extremely low birth weight infants. J Pediatr 2006;149:301-307. 23. Kuehn BM. Guideline tightens transfusion criteria. JAMA 2012;307(17):1788-1789. 24. LaCroix J, et al. Transfusion strategies for patients in pediatric intensive care units. N Engl J Med 2007;356:1609-1619. 25. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004;114:297-316. 26. Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: A systematic review of the literature. Crit Care Med 2008;36:2667-2674. 27. Mazer CD, et al. Restrictive or liberal red-cell transfusion for cardiac surgery. N Engl J Med 2017:377:2133-2144. 28. Muller M, Geisen C, Zacharowski K, Tonn T, Seifried E. Transfusion of packed red cells: indications, triggers and adverse events. Dtsch Arztebl Int 2015;112(29-30):507-517. 29. Patel RM, et al. Association of red blood cell transfusion, anemia, and necrotizing enterocolitis in very low-birth-weight infants. JAMA 2016;315(9):889-897. 30. Rao SV, Harrington RA, Calif RM, Stamler JS. Blood transfusion in patients with acute coronary syndromes. JAMA 2005:293:673-674. 31. Rao SV, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555-1562. 32. Regan DM, Markowitz MA. AABB Association Bulletin #15-02, Transfusion associated circulatory overload (TACO) 12/28/15. 33. Steiner ME, et al. Effects of red-cell storage duration on patients undergoing cardiac surgery. N Engl J Med 2015;372:1419-1429. 34. Tobian AA, Ness PM. Red cells - aging gracefully in the blood bank. N Engl J Med 2016;375:1995-1997.

Revised January 2021 Page 15 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

35. Transfusion Safety Committee/Transfusion Trigger Workgroup America’s Blood Centers. Transfusion Trigger Job Aid – Recommended indications for red cell infusion. ABC 7/31/15. 36. Vallet B, Robin E, Lebuffe G. Venous oxygen saturation as a physiologic transfusion trigger. Crit Care 2010;14:213. 37. Villanueva C, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl Med 2013;368:11-21. 38. Wang JK, Klein HG. Red blood cell transfusion in the treatment and management of anaemia: The search for the elusive transfusion trigger. Vox Sang 2010;98:2-11. 39. Wu WC, Rathmore SS, Wang Y, Radford MJ, Krumholz HM. Blood transfusion in elderly patients with myocardial infarction. N Engl J Med 2001;345:1230-1236. 40. Tay J, et al. Liberal Versus Restrictive Red Blood Cell Transfusion Thresholds in Hematopoietic Cell Transplantation: A Ran- domized, Open Label, Phase III, Noninferiority Trial. Journal of Clinical Oncology 38, no. 13 (May 01, 2020) 1463-1473. 41. Franz A, et al. Effects of Liberal vs Restrictive Transfusion Thresholds on Survival and Neurocognitive Outcomes in Ex- tremely Low-Birth-Weight Infants. JAMA. 2020;324(6):560-570.

Revised January 2021 Page 16 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

PLATELET TRANSFUSION

ADULT PLATELET TRANSFUSION The purpose in establishing guidelines for platelet transfusion is to reduce the risk of disease transmission and allosensitization. It is also important to ensure that the use of a product that is in limited supply is clinically indicated. Assessment of need for platelet transfusion should include evaluation of current or potential risk of bleeding. Pre-transfusion and post-transfusion platelet counts should be used to monitor indications for and response to platelet therapy as well as the need for additional platelet transfusion. It is difficult to establish a uniform dose of platelets for transfusions. However, the basic adult dose of one unit of pheresed platelets should increase the platelet count approximately 25,000 to 50,000/mm3 in a stable adult. Decreased platelet increments can be caused by rapid utilization or destruction of platelets and may be an indication of allosensitization and a refractory state. Certain antibiotics may stimulate the formation of drug-dependent antibodies that may be responsible for shortened platelet survival. All platelet products supplied by Nebraska Community Blood Bank and LifeServe Blood Center are leukocyte reduced. A. Indications 1. Actively bleeding patient a. To keep platelet counts above 50,000/mm3 in most bleeding situations, and above 100,000/mm3 if there is DIC, or central nervous system bleeding b. For bleeding (regardless of platelet count) due to a platelet dysfunction when there is an abnormal platelet function test or documentation of a clinical history indicative of platelet dysfunction (e.g., inherited qualitative disorder; following ingestion of aspirin or platelet inhibitors such as Plavix®; or chronic uremia) TXA administration should be considered with bleeding in the setting of platelet inhibitors. c. Patients having cardiopulmonary bypass (CPB) who exhibit perioperative bleeding with thrombocytopenia and/or evidence of platelet dysfunction 2. Preparation for an invasive procedure. (Most of the data used to determine bleeding risk come from retrospective studies of patients who are afebrile and have thrombocytopenia and no coagulopathy.) a. Elective central venous catheter placement with a platelet count less than 20,000/mm3 b. Elective diagnostic lumbar puncture with a platelet count less than 50,000/mm3 c. Neurosurgery or ocular surgery with a platelet count less than 100,000/mm3 d. Most other major surgery with a platelet count less than 50,000/mm3 e. Neuraxial anesthesia, including the removal of epidural catheters with a platelet count of less than 80,000/mm3 f. Percutaneous Liver Biopsy with platelet count of less than 50,000/mm3 3. Prevention of bleeding a. Bone marrow suppression resulting in a platelet count of 10,000/mm3 or less. Higher thresholds are appropriate for those that are febrile, septic, or have certain diagnoses, such as acute promyelocytic leukemia (APL).

Revised January 2021 Page 17 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

b. After rapid (within 6-12 hours) transfusion of large amounts of blood or per massive transfusion protocol. Massive transfusion protocols may call for 1 platelet dose for a specific number of red cells and/or plasma. B. Contraindications: 1. When bleeding is the result of a coagulation factor deficiency, or inhibitor, anticoagulants, or von Willebrand's factor deficiency 2. When there is no evidence of platelet dysfunction and the platelet range is adequate for hemostasis C. Management of the Allosensitized (Alloimmunized) Patient: 1. Alloimmunization is a potential cause of refractoriness to platelet transfusion, especially in those with a history of repeated transfusions. More common causes of refractoriness are non-immune related and should be excluded (i.e., fever, sepsis, bleeding, splenomegaly, medications, DIC, extensive surgery, and concurrent amphotericin B therapy). 2. There is no evidence to suggest that the transfusion “trigger” should be any different than that of a non-refractory patient. 3. Use of Crossmatch-Compatible Platelets is recommended as the first line approach to platelet refractoriness. 4. When available, HLA-Matched Platelets may overcome alloimmunization-induced refractoriness. These products must be irradiated. 5. Given the transient nature of antibody production, those diagnosed with refractoriness due to alloimmunization need to be reassessed periodically to determine if refractoriness has diminished. One hour post transfusion platelet counts should be ordered to help determine platelet refractoriness. The corrected count increment is calculated as the difference between the platelet count within an hour after transfusion and the platelet count before transfusion, multiplied by the body-surface area (in square meters) and divided by the number of platelets transfused times 1011. The formula for the determination of the Corrected Count Increment is as follows: Corrected Count Increment (CCI) = [BSA (m2)] x (Post Platelet Count – Pre Platelet Count) # of apheresis platelet units x (3 x 1011) 6. The TRAP Study Group defined platelet refractoriness as a corrected count increment of less than 5000 after two consecutive transfusions of ABO compatible platelets.

PEDIATRIC PLATELET TRANSFUSION A. Indications - Infants less than 4 months of age 1. Platelet Count of <100,000/mm3 a. Sick, preterm neonate with active bleeding b. Sick, preterm neonate with disseminated intravascular coagulation (DIC) and undergoing invasive procedure 2. Platelet count of <50,000/mm3 a. Term neonate with clinically significant bleeding OR undergoing invasive procedure b. Stable, preterm neonate with clinically significant bleeding OR undergoing invasive procedure c. Extremely low birthweight (<1000 grams) neonate d. Clinically unstable preterm neonate

Revised January 2021 Page 18 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

3. Platelet Count <30,000/mm3 a. Stable preterm neonate b. Clinically unstable term neonate 4. Platelet Count <20,000/mm3 in stable, term neonates

A randomized European Multicenter study published in 2019 in the NEJM (PlaNeT2 MATTISE Trial) of preterm infants <34 weeks gestation, randomized the participants to a low platelet transfusion of 25K versus a high transfusion threshold of 50K, showed a higher incidence of death or major bleeding in the high transfusion threshold of 50K compared to the low transfusion threshold of 25K (26% vs 19% respectively, OR 1.57, 95% CI 1.06-2.32).

While not recommending a change in transfusion indications for babies <34 weeks based on this study alone, it’s important for practitioners to be aware of this study’s findings.

B. Indications – Patients older than 4 months of age 1. Platelet Count of <100,000/mm3 a. ECMO hemorrhagic risk b. Active hemorrhage c. Acute liver failure d. Severe coagulopathy, DIC 2. Platelet count of <80,000/mm3 for ECMO standard risk 3. Platelet count of <50,000/mm3 for post-operative neurosurgery or intracranial pressure monitoring 5. Platelet Count of <20,000/mm3 for pre-procedure such as lumbar puncture 6. Platelet Count of <10,000/mm3 for platelet production failure 7. Without thrombocytopenia in a patient with a qualitative platelet defect and active bleeding REMEMBER! Transfusion-Associated Circulatory Overload (TACO) is a leading cause of morbidity and mortality in patients receiving a transfusion! TACO accounted for 22% of transfusion-related fatalities reported to the FDA from 2010 – 2014. Over 20% of TACO reactions are life-threatening and are associated with increased time in the ICU and increased length of hospital stay. TACO can occur after transfusion of any blood product – RBCs, plasma or platelets. Risk factors associated with TACO include: age >60 years or <3 years, chronic renal failure, congestive heart failure, critically ill status (ICU patients), and the number of products transfused as well as rapid transfusion rate.

REFERENCES and SUGGESTED READING 1. Andrew M, et al. A randomized, controlled trial of platelet transfusions in thrombocytopenic premature infants. J Pediatr 1993;123(2):285-291. 2. Anna C, et al. Randomized Trial of Platelet-Transfusion Thresholds in Neonates. NEJM 2019;380:242-51 3. Bennett-Guerrero E, et al. Variation in use of blood transfusion in coronary artery bypass graft surgery. JAMA 2010; 304(14):1568-1575. 4. Christie DJ, Van Buren N, Lennon SS, Putnam JL. Vancomycin dependent antibodies associated with thrombocytopenia and refractoriness to platelet transfusion in leukemia patients. Blood 1990;75(2):518-523. 5. Connell NT. Transfusion Medicine. Prim Care 2016 Dec;43(4):651-659.

Revised January 2021 Page 19 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

6. Delaflor-Weiss E, Mintz PD. The evaluation and management of platelet refractoriness and alloimmunization. Transfus Med Rev 2000;14:180-196. 7. Frazer K, Kirley K, Stevermer J. Consider this strategy for upper GI bleeds. J Fam Pract 2013;62(9):E6-E8. 8. Fridey J, et al. A Compendium of Transfusion Practice Guidelines, 3rd Ed., American Red Cross, 2017. 9. Fung MK, Eder AF, Spitalnik SL, Westhoff CM, eds. AABB Technical Manual 19th Edition, 2017. 10. Guideline of Care: Blood Product Transfusion. Seattle Children’s 2016. 11. Juskewitch J, et al. How do I … manage the platelet transfusion – refractory patient? Transfusion 2017;57;2828-2835. 12. Kaufman RM, et al. Platelet transfusion: A clinical practice guideline from the AABB. Ann Intern Med 2015;162(3):205- 213. 13. Kumar A, et al. Platelet transfusion: a systematic review of the clinical evidence. Transfusion 2015; 55:1116. 14. McFarland J, et al. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med 1997;337:1861-1869. 15. Regan D, Markowitz M. AABB Association Bulletin #15-02, Transfusion associated circulatory overload (TACO) 12/28/15. 16. Schiffer CA, et al. Platelet transfusion for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2018;36(3):283-299. 17. Slichter SJ, et al. Dose of prophylactic platelet transfusions and prevention of hemorrhage. N Engl J Med 2010;362(7):600- 613. 18. Transfusion Safety Committee/Transfusion Trigger Workgroup America’s Blood Centers. Transfusion Trigger Job Aid – Recommended indications for platelet transfusion. ABC 7/31/15. 19. Van de Weerdt E, et al. Central venous catheter placement in coagulopathic patients: risk factors and incidence of bleeding complications. Transfusion 2017;57:2512-2525. 20. Van Veen JJ, Nokes TJ, Makris M. The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals. Br J Haematol 2010; 148:15. 21. Wong E, et al. Pediatric Transfusion: A Physician’s Handbook, 4th Ed., AABB, 2015. 22. Zeller MP, Al-Habsi KS, Heddle NM. Prophylactic platelet transfusions: should they be a treatment of the past? Curr Opin Hematol 2014;21:521-527.

Revised January 2021 Page 20 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

THAWED FRESH FROZEN PLASMA AND/OR THAWED PLASMA FOR TRANSFUSION

ADULT THAWED FRESH FROZEN PLASMA AND/OR THAWED PLASMA FOR TRANSFUSION

Plasma Compatibility Chart Patient Donor Unit ABO Group Serum antibodies Blood Type O A and B O, A, B and AB A B A and AB B A B and AB AB None AB

Thawed Plasma is the same as Thawed Fresh Frozen Plasma except that it should not be used to treat coagulation factor deficiencies of factor V and factor VIII. Dose guidelines: 10-15 mL per kg. One unit of FFP is ~ 300 mLs. Fresh Frozen Plasma transfusions are primarily indicated for the treatment of bleeding in patients with congenital and acquired coagulation defects, but is FREQUENTLY (30-90% of cases, Gorlinger K and Saner) transfused without clear clinical indications for its use. Per ASCP Choosing Wisely Recommendations, plasma transfusion to a patient with an INR of <1.6 has minimal effect, and transfusion for INR values between 1.6 and 2 should be carefully considered. Since a mildly elevated INR is usually not associated with spontaneous hemorrhage and doesn’t increase the risk of bleeding during routine invasive procedures, excessive transfusion of plasma is unnecessary and increases the risk of transfusion-associated circulatory overload (TACO), which is a leading cause of transfusion associated morbidity and mortality. Plasma transfusion is also associated with a high risk of adverse events other than transfusion-associated circulatory overload (TACO), including transfusion-related acute lung injury (TRALI), as well as allergic and anaphylactic reactions. Those patients that experience fluid overload/TACO have a 29% increase in length of hospital stay with an increase in hospital costs. A. Indications 1. Preparation for major bleeding or an urgent invasive procedure when there is insufficient time for reversal of warfarin with vitamin K and the INR is substantially elevated (> 2.0) and prothrombin complex concentrate is not available or indicated 2. Treatment of multiple coagulation factor deficiencies, e.g. liver disease, DIC 3. Specific coagulation factor deficiency AND factor concentrates are not available 4. Massive transfusion protocol (Group A thawed plasma may generally used safely in patients before blood type is available in emergent settings) 5. Plasma infusion or exchange for thrombotic thrombocytopenic purpura, other thrombotic microangiopathies, catastrophic antiphopholipid syndrome, and for managing clotting factor depletion. 6. C1 Esterase Deficiency B. Contraindications: 1. Prophylactic correction of INR <2 in a non-bleeding stable patient 2. Warfarin reversal without first trying Vitamin K or prothrombin complex concentrates

Revised January 2021 Page 21 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

3. Reversal of anticoagulation induced by heparin, direct thrombin inhibitors or direct factor Xa inhibitors 4. Volume expansion or colloid replacement 5. Protein source 6. Prophylaxis in multiply transfused patients who do not have a documented coagulation defect Hemostatic factor content of factor V and VIII in a typical fresh frozen plasma unit are shown in the following table: Factor Level when freshly Level at 24 hours Level at 5 days thawed V 80 IU/mL 75 IU/mL 66 IU/mL VIII 92 IU/mL 51 IU/mL 41 IU/mL

PEDIATRIC THAWED FRESH FROZEN PLASMA AND/OR THAWED PLASMA FOR TRANSFUSION NOTE: Be aware of the patient’s volume status to avoid transfusion-associated volume overload. A. Indications 1. Preparation for an urgent invasive procedure when there is insufficient time for reversal of warfarin with vitamin K 2. Management of major bleeding associated with warfarin anticoagulation and/or vitamin K deficiency 3. Treatment of multiple coagulation factor deficiencies, e.g. liver disease, DIC 4. Specific coagulation factor deficiency AND factor concentrates are not available 5. Massive transfusion protocol 6. Plasma exchange for thrombotic thrombocytopenic purpura REMEMBER! Transfusion-Associated Circulatory Overload (TACO) is a leading cause of morbidity and mortality in patients receiving a transfusion! TACO accounted for 22% of transfusion-related fatalities reported to the FDA from 2010 – 2014. Over 20% of TACO reactions are life-threatening and are associated with increased time in the ICU and increased length of hospital stay. TACO can occur after transfusion of any blood product – RBCs, plasma or platelets. Risk factors associated with TACO include: age >60 years or <3 years, chronic renal failure, congestive heart failure, critically ill status (ICU patients), and the number of products transfused as well as rapid transfusion rate.

REFERENCES and SUGGESTED READING 1. Adcock D, Gosselin R. The danger of relying on the APTT and PT in patients on DOAC therapy, a potential patient safety issue. Int J Lab Hem 2017;39(Suppl. 1):37-40. 2. Abdel-Wahab OI, Healy B, Dzik WH. Effect of fresh-frozen plasma transfusion on prothrombin time and bleeding in patients with mild coagulation abnormalities. Transfusion 2006;46:1279-1285. 3. Alcorn K, Ramsey G, Souers R, Lehman CM. Appropriateness of plasma transfusion: a College of American Pathologists Q- probes study of guidelines, waste, and serious adverse events. Arch Pathol Lab Med 2017;141:396-401. 4. Amendments and corrections to the ‘Transfusion Guidelines for neonates and older children’ (BCSH, 2004a); and to the ‘Guidelines for the use of fresh frozen plasma, cryoprecipitate and cryosupernatant’ (BCSH, 2004b). Br J Haematol 2007;136:514–516.

Revised January 2021 Page 22 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

5. Banerjee D, Hussain R, Mazer J, Carino G. A prophylactic fresh frozen plasma transfusion leads to a possible case of transfusion-related acute lung injury. BMJ Case Rep 2014:published online 21 July 2014. 6. Biu E, Beraj S, VyshKa G, Nunci L, Cina T. Transfusion of fresh frozen plasma in critically ill patients: effective or useless? Maced J Med Sci 2018;6(5):820-823. 7. Bryan AW Jr, et al. Plasma transfusion demystified: A review of the key factors influencing the response to plasma transfusion. Lab Med 2017:48(2):108-112. 8. Callum JL, Waters JH, Shaz BH, Sloan SR, Murphy MF. The AABB recommendations for the Choosing Wisely campaign of the American Board of Internal Medicine. Transfusion 2014;54:2344-2352. 9. Cheng C, Sadek I. Fresh-frozen plasma transfusion in patients with mild coagulation abnormalities at a large Canadian transfusion center. Transfusion 2007;47:748. 10. Chowdary P, Saayman AG, Paulus U, Findlay G, Collins P. Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients. Br J Haematol 2004;125(1):69-73. 11. Desborough M, Stanworth S. Plasma transfusion for bedside, radiologically guided, and operating room invasive procedures. Transfusion 2012;52 Suppl 1:20S-29S. 12. Don’t transfuse plasma to correct a laboratory value; treat the clinical status of the patient. American Society for Clinical Pathology and Choosing Wisely. Added on September 25, 2018. 13. Fridey J, et al. A Compendium of Transfusion Practice Guidelines, 3rd Ed., American Red Cross, 2017. 14. Fung MK, Eder AF, Spitalnik SL, Westhoff CM, eds. AABB Technical Manual 19th Edition, 2017. 15. Garcia DA and Crowther MA. Reversal of warfarin: case-based practice recommendations. Circulation 2012;125:2944- 2967. 16. Gorlin J, Kinney S, Fung MK, et al. Prothrombin complex concentrate for emergent reversal of warfarin: an international survey of hospital protocols. Vox Sanguinis 2017;112(6):595-597. 17. Gorlinger K, Saner F. Prophylactic plasma and platelet transfusion in the critically Ill patient: just useless and expensive or even harmful? BMC Anesthesiol 2015;15:86-91. 18. Haas T, et al. Usefulness of standard plasma coagulation tests in the management of perioperative coagulopathic bleeding: is there any evidence? Br J Anaesth 2015;114(2):217-224. 19. Holland L, Brooks J. Toward rational fresh frozen plasma transfusion. Am J Clin Pathol 2006;126:133-139. 20. Holland L, Foster T, Marlar R, Brooks J. Fresh frozen plasma is ineffective for correcting minimally elevated international normalized ratios. Transfusion 2005;45:1234-1235. 21. Holland L, Sarode R. Should plasma be transfused prophylactically before invasive procedures? Curr Opin Hematol 2006;13:447-451. 22. Hshieh TT, Kaung A, Hussain S, Curry MP, Sundaram V. The international normalized ratio does not reflect bleeding risk in esophageal variceal hemorrhage. Saudi J Gastroenterol 2015; 21(4):254-258. 23. Jia Q, et al. Prophylactic plasma transfusion for surgical patients with abnormal preoperative coagulations tests: a single- institution propensity-adjusted cohort study. Lancet Hematol 2016 Mar;3(3):e139-48. 24. Kennedy S, Milovanovic L, Midia M. Major bleeding after percutaneous image-guided biopsies: frequency, predictors, and periprocedural management. Semin Intervent Radiol 2015;32:26-33. 25. Magee G, Zbrozek A. Fluid overload is associated with increases in length of stay and hospital costs: pooled analysis of data from more than 600 US hospitals. ClinicoEcon Outcomes Res 2013;5:289-296. 26. McCully S, et al. The international normalized ratio overestimates coagulopathy in stable trauma and surgical patients. J Trauma Acute Care Surg 2013;75(6):947-953. 27. Muller M, et al. Transfusion of fresh‐frozen plasma in critically ill patients with a coagulopathy before invasive procedures: a randomized clinical trial (CME). Transfusion 2015;55:26–35. 28. Muller MC, et al. FFP transfusion fails to influence the hemostatic balance in critically ill patients with a coagulopathy. J Thromb Haemost. 2015;13(6):989-997. 29. Nixon C, Tavares M, Sweeney J. How do we reduce plasma transfusion in Rhode Island? Transfusion 2017;57:1863-1872. 30. Puchalski JT, Argento AC, Murphy TE, Araujo KL, Pisani MA. The safety of thoracentesis in patients with uncorrected bleeding risk. Ann Am Thorac Soc 2013;10(4):336-341. 31. Raval JS, Waters JH, Triulzi DJ, Yazer MH. Complications following an unnecessary peri-operative plasma transfusion and literature review. Asian J Transfus Sci 2014;8(2):139-141. 32. Raturi M, Shastry S, Balinga P. Adding up the evidence: Trigger for prophylactic plasma transfusion (Letter to the editor). Asian J Transfus Sci 2017;11(2):214-215. 33. Raturi M, Shastry S, Murugesan M, Balinga P, Chakravarthy K. Effect of plasma component transfusion on conventional coagulation screening tests. Asian J Transfus Sci 2018;12(1):57-61. 34. Regan DM, Markowitz MA. AABB Association Bulletin #15-02, Transfusion associated circulatory overload (TACO) 12/28/15. 35. Roubinian NH, et al. Contemporary risk factors and outcomes of transfusion-associated circulatory overload. Crit Care Med 2018 Apr;46(4);577-585.

Revised January 2021 Page 23 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

36. Roback JD, Caldwell S, Carson J, et. al. Evidence-based practice guidelines for plasma transfusion. Transfusion 2010;50:1227-1239. 37. Shah N, Baker SA, Spain D, et.al. Real-time clinical decision support decreases inappropriate plasma transfusion. Am J Clin Pathol 2017;148(2):154-160. 38. Segal J, Dzik W. Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review. Transfusion 2005;45:1413-1425. 39. Shih A, Arnold D. Plasma transfusion trials and tribulations. Transfusion 2015;55:14-16. 40. Shih A, Crowther M. Reversal of direct oral anticoagulants: a practical approach. Hematology 2016;1:612-619. 41. Soundar E, Besandre R, Hartman S, Teruya J, Hui S. Plasma is ineffective in correcting mildly elevated PT-INR in critically ill children: a retrospective observational study. J Intens Care 2014;2:64. 42. Stanworth S. The evidence based use of FFP and cryoprecipitate for abnormalities of coagulation tests and clinical coagulopathy. Hematology (Am Soc Hematol Educ Program) 2007;2007(1):179-186. 43. Stanworth S, Brunskill S, Hyde C, McClelland D, Murphy M. Is fresh frozen plasma clinically effective? A systematic review of randomized controlled trials. Br J Haematol 2004;126:139-152. 44. Stanworth S, et al. A national study of plasma use in critical care: clinical indications, dose and effect on prothrombin time. Crit Care 2011;15(2):R108. 45. Stevens W, et al. Incompatible type A plasma transfusion in patients requiring massive transfusion protocol: Outcomes of an Eastern Association for the Surgery of Trauma multicenter study. J Trauma Acute Care Surg 2017;83(1):25-29. 46. Subramaniam K, et al. Red blood cell transfusion is associated with further bleeding and fresh‐frozen plasma with mortality in nonvariceal upper gastrointestinal bleeding. Transfusion 2016;56(4):816-826. 47. Tomaselli, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagu- lants. J Am Coll Cardiol. 2017;70(24):3042–3067. 48. Transfusion Safety Committee/Transfusion Trigger Workgroup America’s Blood Centers. Transfusion Trigger Job Aid – Recommended indications for plasma infusion. ABC 9/14/15. 49. Triulzi D, et al. A multicenter study of plasma use in the United States. Transfusion 2015;55(6):1313-1319. 50. Triulzi D. The art of plasma transfusion therapy. Transfusion 2006;46:1268-1270. 51. Van de Weerdt E, et al. Central venous catheter placement in coagulopathic patients: risk factors and incidence of bleeding complications. Transfusion 2017;57:2512-2525. 52. Venkatesh V, Khan R, Curley A, New H, Stanworth S. How we decide when a neonate needs a transfusion. Br J Haematol 2013;160:421-433. 53. Wallis JP, Dzik S. Is fresh frozen plasma overtransfused in the United States? Transfusion 2004 Nov;44(11):1674-1675. 54. Warner M, et al. Prophylactic plasma transfusion before interventional radiology procedures is not associated with reduced bleeding complications. Mayo Clin Proc 2016 Aug;91(8):1045–1055. 55. Warner MA, Chandran A, Jenkins G, Kor DJ. Prophylactic plasma transfusion is not associated with decreased red blood cell requirements in critically ill patients. Anesth Analg 2017 May;124(5):1636-1643. 56. West K, Adamson C, Hoffman M. Prophylactic correction of the international normalized ratio in neurosurgery: a brief review of a brief literature. J Neurosurg 2011 Jan;114(1):9-18. 57. Yang L, Stanworth S, Hopewell S, Doree C, Murphy M. Is fresh frozen plasma clinically effective? An update of a systematic review of randomized controlled trials. Transfusion 2012;52:1673-1686. 58. Zhang LM, Li R, Zhao XC, Zhang Q, Luo XL. Increased transfusion of FFP is associated with mortality or worse functional outcomes after severe traumatic brain injury: A retrospective study. World Neurosurg 2017;104:381-389.

Revised January 2021 Page 24 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

CONVALESCENT PLASMA

DEFINITION: Convalescent plasma refers to blood plasma that is collected from individuals who have recovered from an infectious illness that is then transfused to other patients who are ill with the same disease. Convalescent plasma contains antibodies to the infectious agent and potentially may help patients with serious or life-threatening disease. This type of passive antibody therapy has been used in the past to treat new infectious diseases for which vaccines, monoclonal antibody therapy or specific drug therapy has not yet been developed or identified. In 2020, this therapeutic modality has been used for patients ill with the novel coronavirus, SARS-CoV-2/COVID-19.

HISTORICAL BACKGROUND: The initial use of whole blood or serum from recovered patients was in the 1890s, when this treatment was used for patients with diphtheria. The first Nobel Prize in Physiology or Medi- cine, awarded in 1901, was given to Emil Adolf von Behring “for his work on serum therapy, especially its application against diphtheria, by which he has opened a new road in the domain of medical science and thereby placed in the hands of the physician a victorious weapon against illness and deaths.” There is also documentation in the literature of convalescent plasma therapy used to protect Italian children exposed to measles in 1907, by Francesco Cenci. During the Spanish influ- enza pandemic of 1918-1920, multiple studies were done that suggested that convalescent blood or plasma could be helpful in the treatment of these patients. Subsequently, convalescent blood products were used for patients with scarlet fever, pertussis, Argentine hemorrhagic fever, influ- enza, chicken pox, Cytomegalovirus, and parvovirus B19. More recently, this treatment has been

Revised January 2021 Page 25 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management used in the management of patients with SARS (2003), MERS (2012) and Ebola (2014-2016) infec- tions. The results have been variable, but mostly favorable, and significant complications have been rare. Most of the studies of the use of convalescent plasma in these diseases have had the same major limitations: 1) small sample size/patient numbers, 2) few randomized clinical trials, 3) diffi- culty in determining what neutralizing or other type of antibody titer is necessary to provide pro- tective effect and 4) determining which patients would benefit most from this type of treatment. Since convalescent plasma therapy provides passive immunity, it has typically been used as an early phase treatment or as a prophylactic measure.

COVID-19: The year 2020 brought the new novel SARS-CoV-2 virus and the COVID-19 pandemic. The disease was first identified in Wuhan, China in December of 2019, but in 2020 quickly spread across the world. In March of 2020, the first of several small uncontrolled reports were published on the potential use of convalescent plasma in COVID-19 patients. Shen et al described a series of 5 critically ill patients in which administration of COVID-19 Convalescent Plasma (CCP) was followed by improvement in clinical status. Duan et al described a series of 10 patients given CCP that had significant improvement in clinical symptoms. On March 24, 2020, the United States Food and Drug Administration (FDA) published its first recommendations on the use of CCP in patients ill with COVID-19. This established three sep- arate mechanisms by which patients could receive CCP: 1) An emergency use investigational new drug (eIND) application for compassionate use in an individual patient, 2) Application for an IND to support research, or 3) A government-led expanded access program (EAP) IND for participating institutions. Mayo Clinic became the lead institution in the EAP IND for hospitalized patients with severe or life-threatening COVID-19 infection. A total of 2,730 sites participated in the Mayo study which involved 12,983 physicians and 105,740 patients, of whom 85,766 were administered CCP. On August 12, 2020, initial results of three months of experience with the use of CCP were published by the Mayo Clinic study group. The transfusion of COVID-19 convalescent plasma that had higher antibody levels to hospitalized patients significantly reduced mortality when compared to transfusion of plasma with low antibody levels. In addition, transfusions within three days of COVID-19 diagnosis resulted in greater reductions in mortality. Based on a review of the historical evidence using convalescent plasma in prior outbreaks of respiratory viruses, available preclinical evidence, the results of small clinical trials of CCP con- ducted during the current outbreak and the data from the National Convalescent Plasma Ex- panded Access Protocol (EAP) sponsored by the Mayo Clinic, on August 23, 2020, the FDA issued an Emergency Use Authorization (EUA) for the emergency use of COVID-19 convalescent plasma for the treatment of hospitalized patients with COVID-19. The EUA further defined that COVID-19 CP is human plasma collected from individuals whose plasma contains anti-SARS-CoV-2 antibodies tested by the Ortho VITROS SARS-CoV-2 IgG test with a signal-to-cutoff value of 12 or higher, and that the donors must meet all donor eligibility requirements. The CCP transfusion was to be administered according to standard hospital procedures and practices with each patient receiving one or two units of plasma based on clinical judgement and patient response. The FDA noted that “adequate and well-controlled randomized trials remain necessary for a definitive demonstration of COVID-19 convalescent plasma efficacy and to determine the optimal product attributes and appropriate patient populations for its use”.

Revised January 2021 Page 26 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

COVID-19 convalescent plasma is now in widespread use in the treatment of hospitalized patients with the disease. A plethora of studies and trials are in progress, and numerous articles on its use are appearing with increasing frequency.

MECHANISM OF ACTION: Convalescent plasma is a method of passive immunization. The goal is the neutralization of the pathogen and its elimination. The plasma is collected by apheresis and contains neutralizing antibodies, as well as anti-inflammatory cytokines, clotting factors, other natural antibodies, de- fensins (host defense peptides that have either direct antimicrobial activity, immune signaling ac- tivities or both and are active against bacteria, fungi and many viruses), pentraxins (a family of proteins with a pentraxin protein domain that are involved in acute immunological responses, exam- ples include C-reactive protein and serum amyloid P component) as well as other undefined proteins from the donor. Rojas et al reviewed possible mechanisms by which convalescent plasma may act to miti- gate the consequences of COVID-19 infection. These include antiviral mechanisms such as direct neutralization of the virus, interference with viral replication, binding of IgG and IgM to the virus (which could possibly contribute to prophylaxis or symptomatic improvement), control of an over- active immune system and immunomodulation of a hypercoagulable state.

CLINICAL TRIALS: As of October 26, 2020, there are 3,721 clinical trials listed at www.clinicaltrials.gov , 3,790 clinical trials on the WHO International Clinical Trial Registry Platform (www.who.int/docs/default- source/coronaviruse/covid-19-trials) and 2,388 clinical trials listed on the Cytel Global Coronavirus Clinical Trial Tracker (www.covid-trials.org), all studying various aspects of COVID-19 patient treatment. In the United States, there is a specific platform for facilitating clinical trials of convalescent plasma (https://ccpp19.org/). The International Society of Blood Transfusion has created a resource library for convalescent plasma (http://isbtweb.org/covid-19resources/covid-19-convalescent-plasma-document-library ) for additional information.

PRELIMINARY RESULTS: Early small studies, case reports, and now larger trials across the world have shown, for the most part, reduced mortality, clinical improvement, radiologic improvement, viral clearance, re- covery from mechanical ventilation, lower ICU admission rates, absence of an increase in supplemental oxygen requirements, and other indications of improvement in patient status. Complica- tions have been rare (less than 1%) and include those typically associated with plasma transfusion (Transfusion-Related Acute Lung Injury/TRALI, Transfusion-Associated Circulatory Overload/TACO, and severe allergic transfusion reactions). Other, more theoretical risks include antibody-dependent enhancement of infection, antibody-mediated proinflammatory effects and exacerbation of coagulation derangements associated with advanced COVID-19 infection.

CONCLUSION: Preliminarily, case reports and clinical trials have shown that treatment of selected patients with COVID-19 disease is a possible therapeutic option that is relatively safe and may reduce disease mortality. Refinement of criteria and protocols, and the collation of the results of the myriad studies in progress will be necessary before definitive conclusions may be drawn.

Revised January 2021 Page 27 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

REFERENCES: 1. Duan K, Liu B, Li C et al. Effectiveness of convalescent plasma therapy in severe COVID-19 patients. PNAS 2020 117(17):9490-9496 doi/10.1073/pnas.2004168117 2. Focosi D, Anderson AO, Tang JW and Tuccori M. Convalescent Plasma Therapy for COVID- 19: State of the Art. Clin Microbiol Rev 2020 Aug 12;33(4):e00072-20 doi:10.1128/CMR.00072-20 3. Joyner MJ, Wright RS, Fairweather D et al. Early safety indicators of COVID-19 convalescent plasma in 5000 patients. J Clin Invest. 2020;130(9):4791-4797 doi:10.1172/JCI140200 4. Joyner MJ, Senefeld JW, Klassen SA et al. Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience. medRxiv. 2020 Aug 12:2020.08.12.20169359. doi:10.1101/2020.08.12.20169359. 5. Joyner MJ, Bruno KA, Klassen SA et al. Safety Update: COVID-19-Convalescent Plasma in 20,000 Hospitalized Patients. Mayo ClinProc. 2020 Sep;95(9):1888-1897. doi: 10.1016/j.mayocp.2020.06.028. 6. Klassen SA, Senefeld JW, Johnson PW et al. Evidence favoring the efficacy of convalescent plasma for COVID-19 therapy. medRxiv.2020 Oct 29:2020.07.29.20162917. doi: 10:1101/2020/07.29.20162917. 7. Marano G, Vaglio S, Pupella S et al. Convalescent plasma: new evidence for an old therapeutic tool? Blood Transfus 2016 14:152-7 doi 10.2450/2015.0131-15 8. Marson P, Cozza A, De Silvestro G. The true historical origin of convalescent plasma therapy. Transfus Apher Sci. 2020 Jun 12: 102847.doi: 10.1016/j.transci.2020.102847 9. Rojas M, Rodriquez Y, Monsalve DM et al. Convalescent plasma in Cvid-19: Possible mechanisms of action. Autoimmun Rev 2020 Jul;19(7):102554 doi: 10.1016/j.au- trev.2020.102554 10. Shen C, Wang Z, Zhao F et al. Treatment of 5 Critically Ill Patients With COVID-19 With Con- valescent Plasma. JAMA 2020;323(16):1582-1589 doi:10.1001/jama.2020.4783 11. VanBuren N, Fredrich N, Gammon R. COVID-10 Convalescent Plasma – a Potentially Effec- tive Therapeutic Modality. America’s Blood Centers Blood Bulletin May 2020 12. www.NobelPrize.org

Revised January 2021 Page 28 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

CRYOPRECIPITATE TRANSFUSION Cryoprecipitate is the insoluble protein precipitate that forms when fresh frozen plasma is thawed at 1-6°C. Each unit comes from a single donor. Typically, five cryoprecipitate units are pooled to- gether into a single bag. Therefore, the risk of transfusion transmitted disease such as hepatitis increases concomitantly with each unit administered in the pool. Cryoprecipitate is an excellent source of Factor VIII:C (the Factor VIII procoagulant portion), Factor VIII:vWF (von Willebrand’s factor), fibrinogen, and Factor XIII. More recently, human fibrinogen concentrates have been recognized as an alternative source for fibrinogen replacement, and are derived from pooled plasma. Single units of cryoprecipitate are reserved for neonatal and pediatric use. Cryoprecipitate should not be used to treat von Willebrand disease or factor XIII deficiency as it once was, since more pu- rified and virally inactivated products containing VWF and factor XIII, respectively, are available. Currently, cryoprecipitate is used primarily for fibrinogen replacement and in the manufacturing of fibrin sealants and glue. Dosing (for any age) • One individual unit of cryoprecipitate per 7 kg patient weight to increase fibrinogen by 100 mg/dL • In an average 70 kg patient, 5 units ( one pool) will increase fibrinogen by about 50 mg/dL Composition: Single units 1. Factor VIII: At least 80 IU/cryo unit 2. Fibrinogen: At least 150 mg/cryo unit, average is ~250mg/cryo unit 3. vWF ristocetin cofactor activity: ~170 units/bag 4. Factor XIII: ~60 units/bag 5. Fibronectin Pools 1. Factor VIII: At least 400 IU/cryo pool 2. Fibrinogen: At least 750 mg/cryo pool, average is ~1250mg/cryo pool 3. vWF ristocetin cofactor activity: ~850 units/pool 4. Factor XIII: ~300 units/pool 5. Fibronectin A. Indications – one of the following: 1. Plasma Fibrinogen level below 100 mg/dL or dysfunctional fibrinogen and bleeding or expected bleeding (or between 150-200 mg/dl in obstetric, neurosurgery or trauma patients) 2. Dysfunctional platelets – DDAVP (desmopressin) recommended initially a. Congenital (e.g., platelet storage pool disease) b. Acquired (e.g., uremia) 3. Factor XIII deficiency and bleeding or expected bleeding and recombinant product or factor concentrate not available 4. Hemophilia A (Factor VIII: C deficiency) and bleeding or expected bleeding and recombinant product or factor concentrate not available in the following: a. Prophylaxis prior to surgery/dental extraction DDAVP is preferred in mild form (6-30% VIII:C levels)

Revised January 2021 Page 29 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

b. Traumatic hemorrhage i. If mild ii. Following minor trauma, may use DDAVP initially c. CNS hemorrhage d. Bleeding episodes in small children with Hemophilia A (when recombinant and plasma- derived Factor VIII products are not available) 5. von Willebrand’s disease (Factor VIII:vWF deficiency) and bleeding or expected bleeding and DDAVP is not effective and recombinant VWF or VWF concentrate is not available a. Congenital i. Prophylaxis prior to surgery/dental extraction; DDAVP is recommended in Type 1 ii. Spontaneous hemorrhage; DDAVP recommended initially only for Type 1 but contra- indicated for Type 2B b. Acquired i. Collagen Vascular Disease a) SLE b) Scleroderma ii. Lymphoproliferative disorders a) Non-Hodgkin’s lymphoma b) CLL B. Contraindications: 1. Coagulation deficiencies of factors not present in cryoprecipitate 2. Thrombocytopenic bleeding 3. Reversal of warfarin or other Vitamin K antagonists

REFERENCES and SUGGESTED READING 1. AABB, the American Red Cross, America’s Blood Centers, and the Armed Services Blood Program. Circular of information for the use of human blood and blood components. Bethesda, MD: AABB, Oct 2017.Bandarenko N, King K eds. Blood Transfusion Therapy: A Physician’s Handbook, AABB, 12th ed., 2017. 2. Bolliger, D., Gorlinger, K., & Tanaka, K. Pathophysiology and treatment of coagulopathy in massive hemorrhage and hemodilution. Anesthesiology, 2010; 113: 1205–1219. 3. Hedges, S. J., Dehoney, S. B., Hooper, J. S., Amanzadeh, J., & Busti, A. J. Evidence-based treatment recommendations for uremic bleeding. Nat Clin Pract Nephrol 2007; 3:138–153. 4. Fung MK, Eder AF, Spitalnik SL, Westhoff CM, eds. AABB Technical Manual 19th ed., 2017. 5. Levy, J. H., Sziam, F., Tanaka, K. A., & Sniecienski, R. M. Fibrinogen and hemostasis: A primary hemostatic target for the management of acquired bleeding. Anesth Analg 2012; 11:261-274. 6. McCallum J, Farkouh ME, Scales DC, et al. Effect of fibrinogen concentrate vs cryoprecipitate on blood component transfusion after cardiac surgery: The FIBRES randomized clinical trial. JAMA 2019; doiL10.1001/jama.2019.17312. 7. Silvergleid AJ. 2018. Clinical use of cryoprecipitate. In JS Tirnauer (Ed.), UpToDate. Retrieved 2 Jul 2018 from http://www.uptodate.com/contents/ clinical-use-of-cryoprecipitate. 8. Standards for Blood Banks and Transfusion Services. 30th ed. Bethesda, MD: AABB; current.

Revised January 2021 Page 30 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

SPECIAL NEEDS SPECIAL NEEDS • Irradiation • Washed • Volume-Reduced • CMV-Negative • Sickle Cell-Negative • Anti-CD38, Anti-CD47

IRRADIATION • To prevent transfusion-associated graft-vs-host disease (TA-GVHD) • TA-GVHD occurs when T-cells in a transfused blood products engraft and proliferate in the transfusion recipient. These T-cells see the recipient’s own cells as foreign which results in their attack on the recipient’s human leukocyte antigen (HLA)-expressing cells, especially the skin, bone marrow, and gastrointestinal tract. • Recognition is often delayed because the signs and symptoms (ssx) are nonspecific, the ssx typically begin around 8 to 10 days after the transfusion (although they can begin between 3 and 30 days) and are attributed to the patient’s underlying condition, and TA-GVHD is not considered • Mortality rate is greater than 90%. There are no effective treatments so the focus is on prevention by irradiation of blood components. • Irradiation of blood products for at-risk patients is commonplace therefore TA-GVHD is extremely rare and the true incidence is unknown • Patients most at risk of GVHD are those who are severely immunocompromised or cannot recognize the transfused T-cells as foreign • Indications o For at‐risk patients, all red cell and platelet components should be irradiated o Transfusions from first‐ or second‐degree relatives o HLA‐matched platelets o Granulocytes o Intrauterine transfusion o Neonatal transfusion o Neonatal exchange transfusion o Congenital cell-mediated immunodeficiencies o Patients taking purine analogs o Patients taking antithymocyte globulin or alemtuzumab o Hodgkin lymphoma o Hematopoietic stem cell donors during the week prior to hematopoietic cell har- vesting o Hematopoietic stem cell transplantation recipient from initiation of conditioning chemotherapy until GVHD prophylaxis ends

Revised January 2021 Page 31 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

WASHED • To remove plasma in the unit for patients with specific complications • Red blood cells (RBCs) and platelets may be washed o RBCs must be transfused within 24 hours o Platelets must be transfused within 4 hours • Indications o Severe or recurrent allergic reactions o History of anaphylactic transfusion reaction o IgA deficiency o Individuals at risk for hyperkalemia

VOLUME-REDUCED • Red blood cells (RBCs) and platelets may be volume-reduced o RBCs must be transfused within 24 hours o Platelets must be transfused within 4 hours • Indication o Patients at risk of circulatory overload, e.g. congestive heart failure, renal failure

CMV-NEGATIVE • Cytomegalovirus (CMV) o Herpesvirus o Can cause lifelong infection with potential for reactivation o Infection is mild in immunocompetent individuals o Can be fatal in immunocompromised patients o Can be transmitted through infected white blood cells in blood products • Virtually all blood products are leukoreduced, i.e. have most of the white blood cells re- moved, and are considered equivalent to blood products tested negative for CMV • There is still a hypothetical risk of CMV transmission from blood products collected before seroconversion or following early antibody production, so certain individuals may theoreti- cally benefit from units tested negative for CMV, including the following: o Solid organ transplant recipients o Hematopoietic stem cell transplant recipients o Fetuses o Low birth weight neonates o HIV-positive individuals o Pregnant women • Testing is only needed for red blood cells and platelets

SICKLE-CELL NEGATIVE • Hemoglobin S is an abnormal hemoglobin that causes red blood cell sickling during reduced oxygen concentration

Revised January 2021 Page 32 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

• The sickling can obstruct smaller blood vessels thus resulting in reduced oxygenation and subsequent damage to surrounding tissues • Some individuals with an undiagnosed condition that results in higher levels of hemoglobin S, e.g. sickle cell trait, may qualify to donate blood. Most of the time these donors’ blood products do not cause complications. • Blood products may be tested for hemoglobin S or lack thereof • Indications o Intrauterine transfusion o Neonate o Patient with sickle cell disease

ANTI-CD38, ANTI-CD47 • CD38 o Antigen overexpressed on neoplastic plasma cells, e.g. multiple myeloma o Also expressed on red blood cells (RBCs) o Daratumumab and other anti-CD38 agents are used in the treatment of certain leu- kemias o The binding of anti-CD38 to RBCs causes aberrant RBC testing results • CD47 o Antigen overexpressed in hematologic malignancies and some solid tumors o Also expressed on RBCs and platelets o Hu5F9-G4 and other anti-CD47 agents are currently in clinical trials o The binding of anti-CD47 to RBCs causes aberrant RBC testing results • Recommendations for patients anticipated to receive these medications o A preliminary type-and-screen and serologic phenotype should be obtained before the patient receives the first dose o A genotype is also strongly recommended

REFERENCES • Cohn, C., Delaney, M., Johnson, S. and Katz, L., 2020. Technical Manual. 20th ed. Bethesda: AABB. • Goldfinger, D. and Lu, Q., 2020. Granulocyte Transfusions. [online] UpToDate. Available at: [Accessed 8 September 2020]. • Kleinman, S., 2020. Practical Aspects Of Red Blood Cell Transfusion In Adults: Storage, Pro- cessing, Modifications, And Infusion. [online] UpToDate. Available at: [Accessed 8 September 2020]. • Shoushtari, A. and Hellmann, M., 2020. Principles of Cancer Immunotherapy. [online] Up- ToDate. Available at: [Accessed 8 September 2020].

Revised January 2021 Page 33 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

• Silvergleid, A., 2020. Leukoreduction to Prevent Complications of Blood Transfusion. [online] UpToDate. Available at: [Accessed 8 September 2020]. • Silvergleid, A., 2020. Transfusion-Associated Graft-Versus-Host Disease. [online] UpToDate. Available at: [Accessed 8 September 2020]. • Treleaven, J., Gennery, A., Marsh, J., Norfolk, D., Page, L., Parker, A., Saran, F., Thurston, J. and Webb, D., 2010. Guidelines on the use of irradiated blood components prepared by the British Committee for Standards in Haematology blood transfusion task force. British Journal of Haematology, 152(1), pp.35-51. • Yuan, S. and Goldfinger, D., 2020. Clinical and Laboratory Aspects of Platelet Transfusion Therapy. [online] UpToDate. Available at: [Accessed 8 September 2020].

Revised January 2021 Page 34 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

TREATMENT OF THE JEHOVAH’S WITNESS PATIENT Patients who practice the Jehovah’s Witness faith believe that blood transfusions are prohibited by the Bible. These patients present a challenge to physicians because they need alternative treatment options. Adult Jehovah’s Witnesses carry a card, called a No Blood Document, which is considered a legal document and specifies blood beliefs. The use of fractionated products, such as albumin, immuno- globulins, and clotting factors are a matter of conscience and may be acceptable. Typically products from allogeneic whole blood are not. In treating the emergency Jehovah’s Witness patient, simultaneously assess, control hemorrhage, and administer fluid resuscitation. The priority is to arrest internal and external bleeding. Mobilize appropriate resources early – surgeons, surgery, specialists. For questions and concerns, contact the local Jehovah’s Witness hospital liaison or Jehovah’s Witnesses Hospital Information Services at (718) 560-4300. Hospital Information Services for the Jehovah’s Witnesses has distributed a document, “Clinical Strategies for Avoiding and Controlling Hemorrhage and Anemia without Blood Transfusion in Sur- gical Patients*” to provide guidance to physicians in treating Jehovah’s Witness patients. Some general principles from this document are included here. The General Nonblood Management Principles are: 1. Formulate a detailed and individualized clinical management plan to minimize blood loss and treat anemia. Comprehensive prospective planning should make optimal use of a combination of modalities to prevent or respond to hemorrhage or anemia. A blood conservation program cannot depend on a single modality. 2. Obtain informed consent for anticipated or potential procedures. Discuss the risks and benefits (both short- and long-term) of proposed interventions with the patient/family. 3. Consider the risk of transfusion and available blood management options, refer patient to another institution if better resources are available elsewhere. 4. Employ a multidisciplinary approach. Collaborate with other disciplines to develop the most appropriate blood management strategy. Communicate management plan to all team members, assigning clear roles and responsibilities. Maintain ongoing communication regarding patient management, especially where there are multiple conditions treated by multiple physicians. 5. Maintain surveillance for blood loss or physiological deterioration. Early recognition and in- volvement of appropriate senior staff and prompt action to prevent/control abnormal bleeding are essential. The threshold for intervention should be lower than for patients who will accept allogeneic blood transfusion. 6. Prompt action to secure hemostasis in the actively bleeding patient who refuses blood transfusion is lifesaving. Use diagnostic tests that will provide rapid results, minimize delays, and thus reduce blood loss. In general, avoid a “watch and wait” approach to the bleeding patient. 7. Exercising clinical judgement, be prepared to modify routine practice when conditions change.

Revised January 2021 Page 35 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

8. Consult promptly with senior specialists with experience in managing patients without allogeneic transfusion at an early stage if complications arise. 9. Transfer a stabilized patient, if necessary, to a major center before the patient’s condition deteriorates.

The General Therapeutic Principles are: 1. Adopt a proactive approach including anticipation, preparation, and management steps to prevent uncontrolled blood loss, utilizing a combination of interventions. 2. Perform a thorough pre-operative work-up. Methodical history taking, physical examina- tion, and judicious diagnostic tests should be part of an integrated assessment approach to facilitate perioperative planning. Identify abnormalities of coagulation and previous treatments that may increase the risk of blood loss. 3. Identify appropriate management strategies to optimize the patient’s condition before surgery. Interventions applied prospectively to create a favorable physiological environment are more likely to result in a favorable outcome than those applied retroactively as treatment. 4. Restrict diagnostic phlebotomy. Perform essential tests only and use less blood for analysis. 5. Combine surgical and anesthetic blood conservation techniques: meticulous surgical hemostasis and minimization of blood loss, and rigorous intraoperative blood management using appropriate autologous blood procurement strategies. 6. Optimize oxygen delivery and consider measures to minimize oxygen consumption. 7. In trauma or postoperative patients with active bleeding, perform immediate concomitant investigation and diagnosis and early intervention aimed at rapidly controlling hemorrhage. Consider moderate fluid underresuscitation in the presence of uncontrolled hemorrhage.

* The Clinical Strategies document is an informational resource and reference for medical practitioners only. It provides neither medical advice nor treatment recommendations and does not substitute for an appropriately qualiﬁed health-care professional. The editor does not recommend or endorse any test, physician, product, or procedure, and has endeavored to include accurate, timely information. However, not all listed strategies are appropriate or acceptable to all patients. It is the responsibility of each provider to maintain awareness of new information, discuss options for care, and assist patients in making choices in accord with their wishes, values, and beliefs. Patients should always seek the advice of a qualiﬁed health-care professional regarding a medical condition or treatment.

REFERENCES and SUGGESTED READING 1. Blood and Blood Components: Addendum F – Treating Jehovah’s Witness Patients. Bryan Health 2018. 2. Clinical Strategies for Avoiding and Controlling Hemorrhage and Anemia without Blood Transfusion in Surgical Patients. Dist by Hospital Information Services for Jehovah’s Witnesses. http://www.jw.org/en/medical-library. 3. Remmers PA, Speer AJ. Clinical strategies in the medical care of Jehovah’s Witnesses. AJM 2006;119(12):1013–1018.

Revised January 2021 Page 36 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

APPENDICES

Appendix A – How to Properly Obtain a Blood Sample for Transfusion Medicine

Appendix B – Blood Component Transfusions in Nonemergency Settings

Appendix C – Transfusion Reactions

Appendix D – The Coagulation Cascade/Lab Tests/Drugs

Appendix E – Anticoagulant Medications

Appendix F – Antiplatelet Medications

Appendix G – Glossary

Revised January 2021 Page 37 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

APPENDIX A

How to Properly Obtain a Blood Sample for Transfusion Medicine.

Patient samples for blood bank testing are typically a 10ml EDTA tube or clot tube (some institutions require both). Samples are identified with an affixed label along the length of the tube, not overlapping the lid. The label contains information for unique identification of the patient and specimen. This includes: • Patient first and last name • Date of birth • A unique identification number • Date and time of collection • Collector’s identification. The collector should enter the patient’s room, introduce themselves and explain that a blood sample will be collected. The patient will be asked to state their name and date of birth while collector compares the information to the patient’s armband. The patient must have an armband with identifying information on their wrist or ankle. The armband cannot be taped to the bed. The specimen must be labeled at the patient’s bedside, before leaving the room. The transfusion service will accept only those samples that are complete with required information, accurate and legible. Any discrepancy will require the specimen be re-collected.

The transfusion service will verify that the requisition for testing matches the specimen label. Any discrepancy will require the specimen be re-collected. The transfusion service will have a policy in place to reduce the risk of misidentification of the patient’s pre-transfusion sample. This is generally accomplished by performing a history check. If no previous history for the patient exists, a second specimen collected at a different time will be required to confirm the ABO Rh Type before receiving a transfusion.

Specimens should be stored at refrigerated temperatures (1-10C0) for a minimum of 7 days after transfusion. There should be a policy defining the maximum time during which a sample may be used before obtaining a new sample, typically 72 hours.

Revised January 2021 Page 38 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

APPENDIX B Blood Component Transfusions in Nonemergency Settings1

Suggested Adult Flow Rate Component First 15 After 15 Pediatric Special ABO Filter minutes minutes Dosage/Rates2 Considerations Compatibility Red Blood 1-2 mL/min As rapidly as 10 mL/kg, not to Generally administered over 1-2 Whole blood: ABO In-line (170-260 Cells (RBCs) (60-120 tolerated: exceed 15 mL/kg at hours for hemodynamically stable re- identical micron)

mL/hr) approx 4 mL 2-5 mL/kg/hr cipients; infusion should not exceed RBCs: ABO compatible with Leukocyte reduc- /min or 240 4 hrs recipient’s plasma tion, if indicated mL/hr For patients at risk of fluid overload, Crossmatch required may adjust flow rate to 1 mL/kg/hr Platelets 2-5 mL/min 300 mL/hr or 5-10 mL/kg of body Usually given over 1-2 hrs Crossmatch not required In-line (170-260 (120-300 as tolerated weight For patients at risk of fluid overload, ABO/Rh compatibility pref- micron) mL/ hr) Run over 30 min to use slower flow rate (see under erable but not required Leukocyte reduc- a max of 4 hr RBCs) May be HLA matched tion, if indicated Fresh Frozen 2-5 mL/min As rapidly as Acute hemorrhage: Thaw time needed before issue Crossmatch not required In-line (170-260 Plasma (120-300 tolerated: 15-30 mL/kg as in- Expiration – 24 hrs after thaw time ABO compatibility with micron) mL/hr) approx300 dicated Do not hang longer than 4 hrs recipient red cells mL/hr Clotting deficiency: 10-15 mL/kg at 1-2 For patients at risk of fluid overload, mL/min use slower flow ratesee under RBCs Granulo- 1-2 mL/min 120 - 150 Over approx 2 hrs Crossmatch required In-line (170-260 cytes (60-120 mL/hr or as Infuse ASAP after collection /release ABO/Rh compatibility micron) mL/hr) tolerated of product required No LR filter or Irradiate May be HLA matched depth-type mi- croaggregate filters Cryoprecip- As rapidly as As rapidly as 1-2 U/10 kg, not Infuse ASAP after thawing; pooling is Crossmatch and ABO com- In-line (170-260 itated AHF tolerated tolerated; ap- faster than 1 preferred patibility not required micron) prox 5-10 mL/kg/min Maximum benefit if used within 2 hrs ml/min 1Fung MK, Eder AF, Spitalnik SL, Westhoff CM, eds. AABB Technical Manual 19th Edition, 2017. 2Weinstein SM. Plumer’s Principles & Practice of Infusion Therapy. Philadelphia, PA.: Lippincott Williams & Wilkins, 9th ed., 2014. 3Legacy Laboratory Services. Adult and Pediatric Transfusion Guidelines, 2017.

Revised January 2021 Page 39 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management APPENDIX C Transfusion Reactions

INTRODUCTION While innumerable measures are taken to assure that transfusion of blood and blood products is done in such a manner as to minimize risk, transfusion reactions do occur. It is imperative that these reactions are promptly recognized, reported to the laboratory and properly treated. Every hospital and clinical laboratory has a system in place to respond to this occurrence. Transfusion reaction protocols are to be immediately initiated and followed to completion in the event of a transfusion reaction. Transfusion reactions are reported to and reviewed by the Community Transfusion Committee. A variety of regulatory agencies may also be involved in the reporting process, depending upon the type of reaction. Review of individual transfusion reaction cases, as well as aggregate data, is helpful in identifying trends, patterns or systemic problems that may then be addressed to minimize the occurrence of reactions in the future. The recognition of a transfusion reaction by patient care staff should always be followed by the following steps: 1. STOP the transfusion. 2. Notify the Blood Bank/laboratory (this initiates the transfusion reaction evaluation process). 3. Notify the patient’s physician or other health care provider that a transfusion reaction has occurred, that the workup has been initiated and ask if any other patient care actions are needed. 4. Initiate additional treatment as directed by physician or other health care provider. It is a regulatory and accrediting agency REQUIREMENT that the laboratory perform a transfusion reaction evaluation when the patient develops signs and symptoms of a transfusion reaction. The laboratory evaluation may NOT be cancelled by the clinician. The ONLY transfusion reaction which does NOT require reporting and testing is an URTICARIAL REACTION. This type of reaction is routinely managed by the administration of antihistamines. The administration of the product may be resumed when the reaction subsides. The following pages include basic information on the most common types of transfusion reactions. This is not a comprehensive list of all possible transfusion reactions, which is beyond the scope of this document. ANY type of adverse reaction or change in a patient’s condition occur- ring during the transfusion of blood or blood products should be quickly recognized and reported according to existing transfusion reaction protocols. REFERENCES and SUGGESTED READING 1. Cohen R, et al. Feeling the burn: the significant burden of febrile nonhemolytic transfusion reactions. Transfusion 2017;57(7):1674-1683. 2. College of American Pathologists Laboratory Accreditation Program Inspection Checklist, 2014. 3. Connell NT. Transfusion Medicine. Prim Care 2016 Dec;43(4):651-659. 4. Fung MK, Eder AF, Spitalnik SL, Westhoff CM, eds. AABB Technical Manual 19th Ed., 2017. 5. Roubinian, NH, et al. Contemporary risk factors and outcomes of transfusion-associated circulatory overload. Crit Care Med 2018;46:577-585. 6. Standards for Blood Banks and Transfusion Services. 30th ed. Bethesda, MD: AABB; 2015. 7. The Joint Commission Laboratory Accreditation Standards, 2014. 8. Wood E, Cox L. Hot and bothered: management and outcomes for patients with febrile nonhemolytic transfusion reactions. Transfusion 2017;57(7):1639-1641.

Revised January 2021 Page 40 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management APPENDIX C Transfusion Reactions (cont) Type Frequency Onset Symptoms Etiology Treatment Differential Diagnosis Transfusion- 1-8% of Within 6 Respiratory distress (dyspnea Fluid overload Diuretics, use slow TRALI, anaphylactic reaction Associated transfusions hours of in 77%, orthopnea, cough), infusion rate in at- Circulatory transfusion increased BNP, increased risk population (very Overload CVP, evidence of left heart old and very young) (TACO) failure, radiographic evidence of pulmonary edema Transfusion- 1:1300- Within 6 Acute hypoxemia, noncardio- Leukocyte anti- Aggressive support- Anaphylactic reaction, circulatory Related Acute 1:190,000 hours of genic pulmonary edema, bi- bodies in donor ive care, intubation, overload, bacterial contamination, Lung Injury approxi- transfusion lateral pulmonary infiltrates etc. coincidental clinical event/underly- (TRALI) mately 20% on CXR ing disease process are fatal Acute 1:77,000 Usually Fever, chills, pain (esp. back Incompatible Based on clinical Sepsis, immune hemolysis (AIHA, Hemolytic with immediate or flank), nausea, vomiting, component status of patient, CHD, PNH, RhIG administration), Transfusion 1:630,000 dyspnea, hypotension/shock, (usually ABO) fluid resuscitation, nonimmune hemolysis (incompati- Reaction fatal tachycardia, blood in urine, with resultant pressor support ble fluids, improper storage, mal- (AHTR) feeling of impending doom, intravascular functioning blood warmer), hemo- renal failure, DIC hemolysis lytic anemias (G6PD def., congenital spherocytic anemia), hemoglobi- nopathies (sickle cell), drug-induced hemolysis, microangiopathic hemolytic anemias (TTP, HUS, HELLP) Febrile Less than 1% Variable, Fever (increase of 2°F or Leukocyte Antipyretics Bacterial contamination of unit, Nonhemolytic of leukocyte most occur >1°C), chills, rigors, cold, dis- antibodies, TRALI, acute hemolysis, underlying (FNHTR) reduced RBC within first comfort, nausea, vomiting cytokines clinical condition associated with transfusions 90 min. of fever, drug reaction transfusion Bacterial Con- 1:5,000 with Usually Typically severe, fever, chills, Bacterial con- As for sepsis: fluids, Immune hemolytic reaction, tamination/ 1:70,000 immediate pain, rigors, hypotension, tamination of antibiotics, pressors, non-immune hemolytic reaction, Septic fatal, usually /during shock, nausea, vomiting product etc. allergic/anaphylactic reaction with plate- transfusion lets

Revised January 2021 Page 41 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management APPENDIX C Transfusion Reactions (cont) Type Frequency Onset Symptoms Etiology Treatment Differential Diagnosis Urticarial 1.1% During Localized or diffuse hives/ IgE-mediated Antihistamines Anaphylaxis, allergic reaction to (allergic) transfusion redness hypersensitivity drug or other substance May restart transfu- reaction to sion if pt responds to transfused antihistamines proteins Anaphylactic 1:20,000- Rapid, often Severe hypotension, laryngeal Recipient IgA Epinephrine, Acute hemolytic reaction, septic 1:47,000 immediate edema, circulatory collapse, deficiency with pressure support shock, TRALI, circulatory overload; units shortness of breath, crushing production of coincidental clinical events (cardio- substernal pain, cyanosis, ur- anti-IgA anti- genic shock, PE), underlying disease ticarial, nausea, vomiting bodies (most common); IgE- mediated reaction to transfused allergen Hypotensive Very rare, Immediate Drop in BP of >30 mmHg, Pt on ACE Stop transfusion, Hemolytic reaction, septic reaction, approxi- facial flushing, resolves inhibitor with stop ACE inhibitor, anaphylactic reaction, hemorrhage, mately quickly when transfusion altered brady- avoid bedside filtra- PE, MI 0.015% of stopped kinin metabo- tion, avoid albumin transfusions lism, pt with ge- volume replacement netic polymor- for plasmapheresis phism Delayed 1:2,500- 7-14 days Fever, anemia, jaundice, Anamnestic Supportive, depend- Hemolysis from other causes Hemolytic 11,000 trans- after transfu- increased bilirubin, new posi- response to ing on severity, Transfusion fusions sion tive DAT or antibody screen re-exposure to identify antibody Reaction a red cell anti- (DHTR) gen to which patient has an antibody

Revised January 2021 Page 42 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management APPENDIX D THE COAGULATION CASCADE/LAB TESTS/DRUGS

INTRINSIC PATHWAY EXTRINSIC PATHWAY PTT (argatroban, heparin) PT (warfarin) surface activation III/tissue factor + prekallikrein + HMW kininogen ! XII XIIa

XI XIa

IX IXa VII

VIII to VIIIa VIIa

COMMON PATHWAY

X Xa

ANTI-Xa ASSAY (Monitoring: heparin, LMW heparin, fondaparinux) ANTI-Xa ASSAY (Not Quantifiable: apixaban, betrixaban, edoxaban, rivaroxaban – used to determine presence or absence of drug)

V Va + Calcium/Phospholipid

II (prothrombin) IIa (thrombin)

I (fibrinogen) fibrin

THROMBIN TIME (not quantifiable: dabigatran – used to determine presence or absence of drug)

XIIa XIII cross-linked fibrin clot

Revised January 2021 Page 43 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

NOTE: The information in this appendix is intended for educational purposes only. It should not be used to direct specific patient therapy. Current literature and prescribing information should be consulted for the purpose of clinical decision-making and patient care. APPENDIX E Overview of Anticoagulant Medications Anticoagulant Mechanism Usual Elimina- Routine Monitoring Effect on Other Lab Tests Reversal Medication tion Half-Life# Apixaban Factor Xa 12 hours No FDA approved test for PT/INR no effect or may be Andexanet alpha (Eliquis®) inhibitor monitoring. Heparin Anti- ; aPTT no effect or may (Andexxa®); 4-factor PCC* Xa for heparin testing may be ; Thrombin Time no may be helpful; activated be used as a screening effect; Anti-Xa  charcoal if within 2-4 hours test to exclude the pres- Mixing studies: Looks like of ingestion; minimally dia- ence of anti-Xa DOACs. inhibitor lyzable (~14% reduction plasma concentrations) Argatroban Direct throm- 39-51 minutes aPTT aPTT ; PT/INR  No reversal agent or anti- bin inhibitor Mixing Studies: Looks like dote inhibitor Bivalirudin Direct throm- 25 minutes ACT PT/INR ; aPTT ; No reversal agent or anti- (Angiomax®) bin inhibitor Mixing Studies: Looks like dote inhibitor Dabigatran Direct throm- 12-17 hours; No FDA approved test for Thrombin time    (in- Idarucizumab (Praxbind®); (Pradaxa®) bin inhibitor, 15-34 hours monitoring. Thrombin dicates residual drug ef- 4-factor PCC* prevents acti- with renal im- time may be used as a fect); PT/INR no effect or may be helpful; activated vation of Fac- pairment screening test to exclude may be ; aPTT  or ; charcoal if within 2-4 hours tors V, VIII, XI & the presence of drug. Anti-Xa no effect of ingestion; hemodialysis XIII Mixing Studies: Looks like reduces plasma concentra- inhibitor tions 59-68%

Revised January 2021 Page 44 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

APPENDIX E (cont) Overview of Anticoagulant Medications Anticoagulant Mechanism Usual Elimina- Routine Monitoring Effect on Other Lab Tests Reversal Medication tion Half-Life# Edoxaban Direct Factor 10 hours No FDA approved test for PT/INR no effect or may be No FDA approved reversal (Savaysa®) Xa inhibitor monitoring. Heparin Anti- ; aPTT no effect or may agent or antidote; 4-factor without need Xa for heparin testing may be ; Thrombin Time no PCC* may be helpful; acti- of a co-factor be used as a screening effect; Anti-Xa  vated charcoal if within 2-4 for activity test to exclude the pres- Mixing studies: Looks like hours of ingestion; hemodi- ence of anti-Xa DOACs. inhibitor alysis reduces plasma concentrations minimally Fondaparinux Factor Xa inhib- 17-21 hours Anti-factor Xa for PT/INR minimal change; No reversal agent or anti- (Arixtra®) itor Arixtra, if needed aPTT minimal change dote; 4-factor PCC* may be (referred test) Mixing Studies: Looks like helpful; hemodialysis in- inhibitor creases clearance ~20% Heparin Binds to anti- 30-90 Minutes Heparin Level; Anti Xa PT/INR no effect or SL ; Protamine; not dialyzable thrombin to ac- (dose depend- (unfractionated or UFH); aPTT  tivate it which ent) aPTT Mixing Studies: looks like then inacti- inhibitor vates thrombin (Factor II) & Xa. Inhibits coag cascade at multiple sites (basi- cally all factors except III) Low Molecular Inhibits Factor Enoxaparin 4.5- Heparin Level; Anti-Xa PT/INR no effect; aPTT no Protamine partially reverses Weight Heparins: Xa and Factor 7 hours LMWH - Enoxaparin (Love- effect or SL  the anticoagulant effect Enoxaparin (Love- IIa Dalteparin 3-5 nox) Mixing Studies: Looks like (60%); 4-factor PCC*, nox®), Dalteparin hours inhibitor FFP* (Fragmin®) Not dialyzable

Revised January 2021 Page 45 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

*This modality may have been used by others, but experience is limited and without consensus. # Half-life may not reflect clinical effect, which may depend on medication pharmacodynamics and/or multiple patient-specific factors.

Prescribing information for listed medications can be found at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. General resources utilized in the preparation of this educational appendix included: 1. UW Medical Center Anticoagulation Services. UW Medicine Pharmacy Services: UW Medical Center Anticoagulation Clinic. N.p., n.d. Web. 9 Jan. 2013. . 2. Annen, K. Overview of Factor Xa Inhibitors: Evaluation, Bleeding Management, and What’s Coming Next. Americas Blood Centers Blood Bulletin June 2014. 3. Neale, Todd. Andexanet alpha, the first reversal agent for factor Xa inhibitors, finally gains FDA approval. TCTMD 09/26/18. 4. Tomaselli GF, et al. 2017 ACC Expert Consensus Decision Pathway on Management of Bleeding in Patients on Oral Anticoagulants: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(24):3042-3067.

Revised January 2021 Page 46 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

NOTE: The information in this appendix is intended for educational purposes only. It should not be used to direct specific patient therapy. Current literature and prescribing information should be consulted for the purpose of clinical decision-making and patient care. APPENDIX F Overview of Antiplatelet Medications Antiplatelet Mechanism Usual Elimination Routine Monitoring Effect on Other Lab Tests Reversal Medications Half-Life# Anagrelide Decreased 1.5 hours Platelet count No specific reversal agent (Agrylin®) megakaryocyte or antidote hypermaturation; disrupts postmitotic phase maturation; results in reduced platelet production Aspirin Inhibits platelet 20 min (plasma) Platelet Function As- Platelet transfusion if plate- cyclooxygenase-1 5-10 days say (PFA) lets <100K; consider and 2 enzymes, (platelet-bound) DDAVP, if severe bleeding inhibits platelet aggregation Aspirin and Di- Prevents CMAP 14 hours Variable effect on PFA No specific reversal agent pyridamole degradation; or antidote; platelet trans- (Aggrenox®) inhibits platelet fusion if platelets <100K cyclooxygenase Cangrelor P2Y12 platelet 3-6 minutes No specific reversal agent (Kengreal®) receptor inhibitor or antidote Cilostazol Phosphodiester- 11-13 hours Variable effect on PFA No specific reversal agent (Pletal®) ase III inhibitor, in- or antidote; platelet trans- hibition of platelet fusion unproven aggregation

Revised January 2021 Page 47 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

APPENDIX F (cont) Overview of Antiplatelet Medications Antiplatelet Mechanism Usual Elimination Routine Monitoring Effect on Other Lab Tests Reversal Medications Half-Life# Clopidogrel P2Y12 platelet 6-8 hours Variable effect on PFA No specific reversal agent (Plavix®) receptor inhibitor or antidote; ± DDAVP; platelet transfusion if platelets <100K Dipyridamole Inhibits platelet 10-12 hours Variable effect on PFA ± DDAVP; platelet transfu- (Persantine®) aggregation by sion unproven inhibiting adeno- sine uptake Eptifibatide GPIIb/IIIa Inhibitor 2.5 hours ACT No specific reversal agent (Integrilin®) aPTT or antidote Prasugrel P2Y12 platelet 7 hours Variable effect on PFA No specific reversal agent (Effient®) receptor inhibitor or antidote; ± DDAVP; platelet transfusion if platelets <100K

Ticagrelor P2Y12 platelet 7 hours Variable effect on PFA No specific reversal agent (Brilinta®) receptor inhibitor or antidote; platelet transfusion unproven Tirofiban GPIIb/IIIa Inhibitor 2 hours ACT No specific reversal agent (Aggrastat®) aPTT or antidote

Vorapaxar PAR-1 receptor 5-13 days No specific reversal agent (Zontivity®) antagonist or antidote # Half-life may not reflect clinical effect, which may depend on medication pharmacodynamics and/or multiple patient-specific factors. ‡ Check with laboratory for availability of test.

Prescribing information for listed medications can be found at http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm. General resources utilized in the preparation of this educational appendix included: 1. Konkle, B. Oral Platelet Inhibitory Drugs and Bleeding Complications: Implications for Transfusion. Americas Blood Centers Blood Bulletin October 2016.

Revised January 2021 Page 48 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

APPENDIX G Glossary of Abbreviations AABB Formerly American Association of Blood Banks ABIM American Board of Internal Medicine ACE Angiotensis – Converting Enzyme ACT Activated clotting time AHTR Acute Hemolytic Transfusion Reaction AIHA Autoimmune hemolytic anemia APL Acute promyelocytic leukemia aPTT Activated Partial Thromboplastin Time ASAP As soon as possible BSA Body Surface Area CAP College of American Pathologists CCI Corrected Count Increment CHD Coronary heart disease CLL Chronic lymphocytic leukemia CMV Cytomegalovirus CNS Central nervous system CPAP Continuous positive airway pressure CPB Cardiopulmonary bypass Cryo Cryoprecipitated Antihemophilic Factor CVA Cerebrovascular accident CXR Chest x-ray DAT Direct antiglobulin test DDAVP Desmopressin DHTR Delayed Hemolytic Transfusion Reaction DIC Disseminated intravascular coagulation ECMO Extracorporeal membrane oxygenation FDA Food and Drug Administration FiO2 Fraction of Inspired Oxygen FFP Fresh frozen plasma FNHTR Febrile Non-Hemolytic Transfusion reaction GVHD Graft versus host disease HCT Hematocrit HELLP Syndrome with Hemolysis, Elevated Liver enzymes, Low Platelet count Hgb Hemoglobin HLA Human leukocyte antigen HMW High Molecular Weight HTLV Human T-cell lymphotropic virus HUS Hemolytic uremic syndrome ICU Intensive Care Unit INR International normalized ratio IU International Unit MI Myocardial Infarction LMWH Low molecular weight heparin NEC Necrotizing enterocolitis PBM Patient Blood Management PCC Prothrombin complex concentrate PE Pulmonary Embolism PFA Platelet Function Assay PNH Paroxysmal nocturnal hemoglobinuria

Revised January 2021 Page 49 Guidelines for Transfusion and Community Transfusion Committee Patient Blood Management

PT Prothrombin time PTT Partial thromboplastin time RBC Red blood cell SABM Society for the Advancement of Blood Management SLE Systemic lupus erythematosus TACO Transfusion Associated Circulatory Overload TA-GVHD Transfusion associated - graft versus host disease TRALI Transfusion-Related Acute Lung Injury TRAP Trial to Reduce Alloimmunization to Platelets TRIM Transfusion-related immunomodulation TTP Thrombotic thrombocytopenic purpura vWF Von Willebrand Factor WBC White blood cell

Revised January 2021 Page 50