Hemolytic Anemia, Transfusion Triggers, and Managing
Blood Component Recalls and Withdrawals
Kimberly W. Sanford, MD, FASCP, MT(ASCP) Phillip J. DeChristopher, MD, PhD, FASCP Glenn E. Ramsey, MD, FASCP
2010 Annual Meeting San Francisco, CA
AMERICAN SOCIETY FOR CLINICAL PATHOLOGY 33 W. Monroe, Ste. 1600 Chicago, IL 60603
Program Content and Disclosure The primary purpose of this activity is educational and the comments, opinions, and/or recommendations expressed by the faculty or authors are their own and not those of the ASCP. There may be, on occasion, changes in faculty and program content. In order to ensure balance, independence, objectivity, and scientific rigor in all its educational activities, and in accordance with ACCME Standards, the ASCP requires all individuals in positions to influence and/or control the content of ASCP CME activities to disclose whether they do or do not have any relevant financial relationships with proprietary entities producing health care goods or services that are discussed in the CME activities, with the exemption of non-profit or government organizations and non-health care related companies. These relationships are reviewed and any identified conflicts of interest are resolved prior to the activity. Faculty are asked to use generic names in any discussion of therapeutic options, to base patient care recommendations on scientific evidence, and to base information regarding commercial products/services on scientific methods generally accepted by the medical community. All ASCP CME activities are evaluated by participants for the presence of any commercial bias and this input is utilized for subsequent CME planning decisions.
The individuals below have responded that they have no relevant financial relationships with commercial interests to disclose:
Course Faculty: Kimberly W. Sanford, MD, FASCP, Phillip J . DeChristopher, MD, PhD, FASCP and Glenn E. Ramsey, MD, FASCP
Annual Meeting/ Weekend of Pathology & Educational Course Planning Committee/ Commission Members and Staff:
N. Volken Adsay, MD, FASCP Carolyn Burns, MD, FASCP Francois Cady, MD, FASCP Michele L. Best, MT(ASCP), MASCP Nikolaj Lagwinski, MD Sondra Moran, MT(ASCP) Cyril Fisher, MD, DSc, FRCPath, FASCP Steven H. Kroft, MD, FASCP Stacy Kiff, MT(ASCP) Syed A. Hoda, MD, FASCP William E. Schreiber, MD, FASCP Suzanne Ziemnik, M.Ed. Monica I. Ruiz, MD Daniel D. Mais, MD, FASCP Kimberly W. Sanford, MD, FASCP Robert A. Goulart, MD, FASCP Peggy Soung Sullivan, MD, FASCP Karen A. Brown, MS, MLS(ASCP) Neil Crowson, MD, FASCP Lynnette G. Chakkaphak, MS, MT(ASCP Syed Ali, MD, FASCP Amy J . Wendel, SCT(ASCP)
The individuals below have disclosed the following financial relationships with commercial interests:
Course Faculty:
Planning Committee/ Commission Members and Staff: Elizabeth A. Wagar, MD, FASCP Becton Dickinson Honorarium Scientific Advisory Board
David J . Dabbs, MD, FASCP USLabs; Ventana Med Systems; Consultant service fees; Consulting Dako
Dennis P. OMalley, MD, FASCP Clarient Salary, Stock Options Employee
David Grignon, MD, FASCP Integrated Lab. Automation Stock Shareholder Solutions
Eric D. Hsi, MD, FASCP Allos; BD; Eli Lilly; Honorarium; Research Consultant Facet Biotech Support
Charles Lombard, MD, FASCP Broncus Tech; Asthmatx; Stock Consultant Neomend
Michael D. Feldman, MD, PhD, FASCP Aperio Technology, Inc., CRI Stock Options; Advisory Board; Consultant Bioimagene Sponsored Research & License Patents
Peter Banks, MD, FASCP Aperio Technology, Inc. Future Stock Options; Advisory Board; Consultant Cambridge Past Stock Options
Andrew Churg, MD, FASCP Various Law Firms Regarding Consulting Fee Consultant/Expert Witness Asbestos Disease
Copyright 2010 by the American Society For Clinical Pathology All Rights Reserved. Printed in the United States of America. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means - electronic, mechanical, photocopying, recording, or otherwise without the prior written permission of the publisher. 6730 Transfusion PracticesWarm Autoimmune Hemolytic Anemia, Transfusion Triggers, and Managing Blood Component Recalls and Withdrawals
Review the complex serologic findings of warm autoantibodies and recommendations for transfusion and communication with clinicians for these patients. You will learn about current transfusion targets, data that indicate that transfusion triggers may be dangerous, and how to manage blood component recalls and withdrawals to ensure patient safety. You will leave with the ability to: Recognize, evaluate and assess serologic findings of patients with autoantibodies and warm autoimmune hemolytic anemias and discuss transfusion recommendations. Review current transfusion targets and analyze the data of why transfusion triggers may be dangerous. Review management of blood component recalls and withdrawals.
Directors: Kimberly W. Sanford, MD, FASCP, MT(ASCP) Virginia Commonwealth University
Phillip J . DeChristopher, MD, PhD, FASCP Loyola University Medical Center
Glenn E. Ramsey, MD, FASCP Northwestern University Medical School
3.0 CME Credits TM MOC: MK PC PBL
1 Warm autoimmune hemolytic anemia and transfusion American Society for Clinical Pathology S F i San Francisco Course 6730 Kimberly W. Sanford, M.D. Department of Pathology Virginia Commonwealth University Kimberly W. Sanford, M.D. Department of Pathology gy Virginia Commonwealth University CME Disclosure: No relevant financial interests Objectives to Learn Etiologies of autoimmune hemolytic anemia (AIHA) Pathogenesis of warm autoantibodies & drug induced hemolytic anemia drug induced hemolytic anemia Lab tests evaluating warm autoantibodies Complications of pretransfusion testing Communicating transfusion recommendations 2 Autoimmune hemolytic anemia (AIHA) IgG and/or IgM antibodies bind to red blood cell (RBC) antigens and initiate destruction of autologous RBCs Complement (C) system Reticuloendothelial system y Does not require exposure to allogenic blood Alloimmune hemolytic anemia Exposure to allogenic RBC required Pregnancy Transfusion AIHA Incidence 1:80,000 100,000 annually Affects all ages Peak: 4-5 th decade Primary AIHA Idiopathic Idiopathic Secondary AIHA Lymphoproliferative disorders Systemic Lupus Erythematous (SLE) Females higher incidence of primary and secondary AIHA Classification of AIHA by frequency Warm AIHA (WAIHA): 70% primary (idiopathic) secondary Cold AIHA (CAIHA): 15% primary (idiopathic) secondary Drug induced immune hemolytic anemia: 12% Paroxysmal cold hemoglobinuria : 2% *Petz LD, Garratty G. Acquired immune hemolytic anemias. New York: Churchill Livingstone, 1980. 3 Responsible Antibodies 41 % Warm autoantibodies (autoabs) 32% Cold autoabs 18% Drug induced abs 7% Mixed abs 2% PCH/DL abs *Sokol RJ, Hewitt S, Stamps BK. Acta Haematol 1983;69:266-74 Warm Autoimmune Hemolytic Anemia Primary idiopathic Most common Typical testing pattern Panreactivity 60%autoabs detected in saline 60% autoabs detected in saline 90% autoabs detected in PEG, gel or solid phase. 30% also have cold autoabs Normal titers at 4 C No reactivity at 30-37C *Petz LD, Garratty G. Acquired immune hemolytic anemias. New York: Churchill Livingstone, 1980. Warm autoantibodies Antibody detection methods that use PEG, enzymes, columns, or solid-phase red cell adherence generally enhance g y autoantibodies. *Leger RM. The positive direct antiglobulin test and immune-mediated hemolysis. In: Roback J. ed: Technical Manual 16 th edition. 4 WAIHA Pathophysiology Microspheroctye in C C C Intravascular hemolysis Spleen Remain sequestered Microspheroctye in circulation Phagocytosis by macrophage RBC autoab Ab reacts with intrinsic RBC antigens May or may not cause pathological effects in vivo Study performed at UCLA 100 autoabs 29% hemolytic Presence or absence of alloabs and hemolysis was significant different *Blackall DP, Wheeler CA. Transfusion 2007; 47:1332. Presentation of patients with warm autoabs Highly variable Asymptomatic No decreased RBC survival No decreased RBC survival Life threatening anemia Fatigue, dizziness, pallor, palpitations, dyspnea Dependent on marrow response 5 Etiologies of Autoabs Immunoregulation breakdown Loss of T-cell suppressor regulation Overactive B cells Leads to emergence of autoabs . Triggers for autoab formation Infections Increase ability of macrophages to phagocytose coated RBC Inflammatory process/disease a ato y p ocess/d sease Lymphoproliferative disorder Medications Fludarabine * Borthakur G, OBrien S, Wierda WG, et al. Br J Haematol 2007;136:800-5 Transfusion Stimulated Antibodies Transfusion can stimulate allo-abs and autoabs RBC autoimmunization recognized 60 years ago *Dameshek W, Levine P. NEJM 1943;228:641-4. Average incidence of alloimmunization after t f i i 2 10% transfusion is 2-10% *Hewitt, PE, et al. Br J Haematol 1988. 69:541-4. *Schonewille H, et al. Transfusion 2006. 250-6. Chronically transfused patients alloimmunization rate 18-60% *Rosse WF, et al.Blood 1990. 76:1431-7. *Vichinsky EP, et al. NEJM 1990. 322:1617-21 6 Transfusion stimulated Autoabs 8535 patients transfused, 34 cases of +DATs 25% of eluates were panreactive Autoab formation Persisted beyond life span of transfused RBC abs adsorb onto recipients antigen-negative RBC Conclusions: Alloimmunization stimulant for autoab formation Autoab production after transfusion is higher than reported. *Ness PM, et al. Transfusion 1990. 30:688-93 2004 study by Young et al. 2618 patients transfused 121 patients developed autoabs Positive direct antiglobulin test (DAT) and indirect antiglobulin test (IAT) 41 patients developed alloabs and autoabs 12 developed autoabs temporally associated with alloimmunization 80 ti t d l d t b 80 patient developed autoabs Conclusions Autoimmunization complication of transfusion Conservative transfusion practices *Young PP, et al Transfusion 2004. 44:67-72. Antibodies coating RBC Quantity and type of immunoglobulin coating RBC influences hemolysis IgG1 and IgG3 versus IgG2 and IgG4 Macrophage receptors for IgG1 and IgG3 IgG1 major subclass in AIHA Complement on RBC accelerates removal Spleen and liver remove coated RBC *Gehrs BC, Friedberg RC. American Journal of Hematology 2002 7 Lab detection of autoabs Ab screens and panels are panreactive. Negative if high binding constant or low titer. Autocontrol is positive Patient RBC & patient plasma DAT results for warm autoab IgG positive +/- C3b The predictive value of positive DAT 83% in a patient with hemolytic anemia 1.4% in patient without hemolytic anemia *Kaplan HS, et al. Diagnostic Med 1985;8:29-32 DAT: sensitized RBCs + AHG AHG reagent Patient RBC Patient RBC Patient RBC Antibody coating RBC in vivo DATs Healthy adults 50-90 IgG molecules/RBC 5-40 C3d molecules/RBC *Garratty G. Transfus Med Rev 1987;47-57. *Freedman J. Transfus Med Rev 1987; 58-70 DAT detection 100-500 molecules of IgG per RBC 400-1100 molecules of C3d per RBC 1-15% of hospital patients have positive DATs *Petz LD, Garratty G. Immune hemolytic anemias. 2004 8 Causes of positive DATs Positive DATs with/without shortened RBC survivial Autoabs to intrinsic RBC antigens Alloabs bound to transfused donor RBC Passively acquired alloabs Maternal alloabs on fetal RBC Abs against drugs bound to RBC membrane. IgG or complement coating of cells due to medications. Adsorbed proteins/immunoglobulins on RBC Hypergammaglobulinemias IVIg Investigating +DAT AABB Technical Manual 15 th ed Elutions Perform on all samples with IgG positive DAT No need to perform eluate on C3 positive only DAT DAT Eluates can concentrate small amounts of IgG antibody undetectable in plasma. 9 Elutions Ab dissociates from RBC Elution methods: 1. Heat 2. Lui Freeze-thaw 3. Acid elution 4. Digitonin acid Test eluate with panel of cells Alloantibody specificity Delayed serologic transfusion reactions (DSTR) Acute or delayed hemolytic transfusion reactions (DHTR) Hemolytic disease of the fetus or newborn (HDFN) Panreactive eluates Autoantibody Eluate in WAIHA Warm autoabs confirmed by elution upon initial diagnosis during pretransfusion testing during pretransfusion testing Eluate reacts with virtually every cell tested. 10 Autoab specificity Typically panreactive Specificity for simple Rh antigens D C E c e D, C, E, c, e More commonly detected in LISS Other specificities include LW, Kell, Kidd, Duffy and Diego Non reactive eluates Eluate is Anti- A or B abs Test A 1 and B cells with eluate. Ab to low incidence antigen 79 % of hospital patients with + DATs have 79 % of hospital patients with DATs have nonreactive eluates One explanation for this is the non-specific uptake of proteins on RBC especially in patients with increased gamma globulin levels. Medication *Toy PT, Chin CA, Reid ME, Burns MA. Vox San 1985; 49:215-20. 3 Mechanisms of drug induced HA Drug adsorption Drug dependent Drug dependent Autoimmune induction AABB Technical Manual 15th edition 11 Drug Adsorption Mechanism Medication/metabolites bind to RBC Penicillin covalently binds to RBC proteins Anti-medication IgG ab sensitizes cell for immune clearance immune clearance DAT usually positive for IgG, eluate negative Rarely causes hemolysis 7 days before hemolysis starts Extravascular hemolysis Drug adsorption Mechanism AABB Technical Manual 15 th edition Drug-dependent Ab Mechanism Medication/metabolite binds transiently to proteins on RBC surface Creates immunogen Ab production Ab production Binds to drug/metabolites on RBC IgG /IgM can activating C Small amount of drug required in sensitized patients AABB Technical Manual 15th edition 12 Drug dependent mechanism Hemolysis abrupt, severe Hours or days Intravascular hemolysis Massive hemoglobinemia/hemoglobinuria Renal failure, DIC, shock Medications 2 nd and 3 rd generation cephalosporins NSAIDs Autoimmune induction mechanism Medication induces RBC autoab Medications - Methyldopa, levodopa, procainamide 11-36% of patients form +DAT after 3 6 months +DAT after 3-6 months <1% have clinical hemolysis Hemolytic anemia Mild-moderate extravascular hemolysis Gradual anemia Hemolysis may persist weeks-months after drug stopped AABB Technical Manual 15th edition Treatment for Drug induced HA Withdraw the drug Some instances hemolysis may persist but short lived lived Rarely requires treatment 13 Summary of Drug Induced HA Type DAT + due to Serum Antibody Hematologic Manifestations Drug adsorption IgG, C3d Ab reacts with drug coating RBC Moderate hemolysis, extravascular Drug-dependent C3d Ab to drug & RBC membrane Abrupt, severe intravascular hemolysis Autoimmune induction IgG Autoab to RBC membrane Mild-moderate, extravascular hemolysis Adsorption techniques Detect underlying alloabs Pretreatment of autologous cells to remove bound autoab for adsorption of autoabs Treatment: Heat cells at 56C for 3-5 minutes and treatment with proteolytic enzymes ZZAP: mix of papain/ficin and DTT PEG treatment Treated cells incubated with plasma Autoadsorptions Multiple sequential autoadsorptions may be necessary Adsorbed plasma should have no reactivity with Adsorbed plasma should have no reactivity with autologous RBC. Perform full panels using absorbed plasma 14 Alloadsorptions Patients transfused within 3 months Reticulocyte harvest Allogenic adsorptions Use donor cells of different phenotypes to adsorb autoabs autoabs Only look to rule out clinically significant abs Rh antigens, K, Fys, Jks, Ss. R 1 R 1 , R 2 R 2 , rr Abs to high frequency antigens cannot be excluded since donor cells express antigen Alloadsorption Alloadsorption performed several times until nonreactive >3 adsorptions can dilute specimen React adsorbed plasma with panel cells p p Phenotypes of adsorbing cells are known If adsorb with Jk(a-) cell Adsorbed plasma reacts with Jk(a+) panel cell Interpret as underlying anti-Jk a Transfusion Autoantibodies mask underlying alloantibodies that increases the risk of a hemolytic transfusion reaction of a hemolytic transfusion reaction, therefore conservative transfusion should be practiced 15 Selecting blood products Adsorption techniques ruling out alloab before transfusion Underlying alloab, select ag negative blood Autoab with ag specificity Autoab with ag specificity Ag negative if active hemolysis If no hemolysis, ag negative blood debatable Even ag negative blood hemolyzed Consider zygosity Phenotypically matched RBC Patient not chronically transfused Not required Chronically transfused patients Patients with sickle cell anemia C, E, K matched in sickle cell patients Frequency of C, E, K, Fya, Fyb, Jkb and S ags different than donors Anti-C,E, K account for 60-98 % of allo-abs Decreased alloimmunization rate from 3 to 0.5% per unit *Vichinsky, EP et al. Transfusion 2001.1086-92 Crossmatching and Transfusion Selecting blood products Antigen neg for underlying alloabs Perform autocontrol with full crossmatches Least incompatible with autocontrol p Transfusion should be reserved for life-threatening anemia Need to increase oxygen carrying capacity Patients at risk Cardiovascular disease Cerebrovascular ischemia 16 Communication with clinicians Direct contact with clinician Gather patients history to assess risk of alloimmunization Transfusion & pregnancy history Determine need for transfusion Determine need for transfusion Symtomatic anemia, bleeding, cardiovascular disease, other comorbidities Discuss investigation for underlying alloabs Alloabs present or absent Assure blood is ABO compatible Risk of alloimmunization Discuss laboratory investigation Search for compatible blood is futile Possibly phenotype patient Clinician and blood bank physician together should approve transfusion Risk vs. benefit clinical decision Conservative transfusion practice Do not deprive patient of transfusions when anemia is severe Transfuse slowly If hemoglobin decreases consider underlying alloab *Ness PM, Transfusion 2006. 46:1859-62. Transfusing patients with WAIHA Monitor closely & transfuse when medical team present Patients with little in vivo destruction tolerate transfusions Survival of transfused RBC is similar to patient RBC Suppress erythropoiesis Suppress erythropoiesis Possibly intensifies autoantibody titer Debatable Increased risk of hemolysis Hemolyze auto and transfused RBC Increases complexity of serologic testing Weigh risks vs. benefits of transfusion 17 Frequency of testing patient AABB Standards require new sample every 3 days. Some argue this is too frequent, unnecessary and too costly for minimal reward. Average incidence of alloimmunization after transfusion is 2-10% *Hewitt, PE, et al. Br J Haematol 1988. 69:541-4. *Schonewille H, et al. Transfusion 2006. 250-6. Alloimmunization rate in patients with warm autoabs Leger and Garratty demonstrated 40% alloimmunization rate with alloantibodies after transfusion *Leger RM, Garraty G. Transfusion 1999:39:11-6 Branch and Petz reviewed 7 independent studies Branch and Petz reviewed 7 independent studies demonstrated 12-40 % alloimmunization rate *Branch DR, Petz LD. Transfusion 1999:39:6-10 Incidence of autoabs detected in coexistence with newly detected alloab is up to 50% *Wheeler CA, et al. Am J Clin Pathol 2004. 680-5 Summary of studies Exclusion of underlying alloantibodies important in this high risk group I d ti it t l ith Increased reactivity not always seen with some underlying alloantibodies. 18 Medical therapies Glucocorticoids Prednisone 60 mg/day for 10-14 days, then taper 70% demonstrate improvement 10% non-responders, can attempt 80-100 mg/day Inhibits monocyte-RBC interaction in spleen Rituximab Monoclonal CD20 ab used to treat immune cytopenias 375mg/m 2 weekly for 4-6 weeks Smaller maintenance dose in responders Other therapies Immunosuppressants Cyclospoirine, mycophenolate, antithymocyte globulin IVIG Less effective with WAIHA vs. ITP Blocks Fc receptors on macrophages in RES Cytotoxic drugs Cytotoxic drugs Use for patients not responding to steroids Splenectomy is contraindicated Azathioprine, cyclophosphamide, chlorambucil Splenectomy Delay until medical therapy fails 2/3 of patients demonstrate partial or complete response Iron and Folate supplements Conclusions Patients with + autocontrols should have DATs performed. Positive broad spectrum DATs need monospecific IgG and complement DAT performed. Eluates Adsorption techniques Crossmatches Communication with clinicians Transfuse conservatively Medical or surgical therapies Treat underlying disease 19 References Petz LD, Garratty G. Acquired immune hemolytic anemias. New York: Churchill Livingstone, 1980 Sokol RJ, Hewitt S, Stamps BK. Autoimmune haemolysis: Mixed warm and cold antibody type. Acta Haematol 1983;69:266-74 Blackall DP, Wheeler CA. Contemporaneous autoantibodies and alloantibodies. Transfusion 2007;47:1332. Borthakur G, OBrien S, Wierda WG, et al. Immune anaemias in patients with chronic lymphocytic leukaemia treated with fludarabine, cyclophosphamide and rituximab- incidence and predictors. Br J Haematol 2007;136:800-5. Dameshek W. Levine P. Isoimmunization with rh factor in acquired hemolytic anemia. N Engl J Med 1943;228:641-4. g ; Hewitt PE, Macintyre EA, Devenish A, et al. A prospective study of the incidence of delayed haemolytic transfusion reactions following peri-operative blood transfusion. Br J Haematol 1988;69:541-4. Rossee WF, Gallagher D, Kinney TR, et al. Transfusion and alloimmuniztion in sickle cell disease. The cooperative study of sickle cell disease. Blood 1990. 76:1431-7. Vichinsky EP, Earles A, Johnson RA, Hoag MS, Williams A, Lubin B. Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. NEJM 1990. 332:1617-21. Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. American Journal of Hematology 2002; 69: 258-71. Ness ONm Shirey RS, Thoman SK, et al. The differentiation of delayed serologic and delayed hemolytic transfusion reactions: incidence, long-term serologic findings and clinical significance. Transfusion 1990.30:668-93 References Schonewille H, van de Watering LMG, Loomans DSE, et al. Red blood cell alloantibodies after transfusion: factors influencing incidence and specificity. Transfusion 2006; 46:250-6. Kaplan HS, Garratty G. Predictive value of direct antiglobulin test results. Diagnostic Med 1985;8:29-32. Garratty G. The significance of IgG on the red cell surface. Transfus Med Rev 1987;1:47-57. Freedman J. The significance of complement on the red cell surface. Transfus Med Rev 1987;1:58-70. Toy PT, Chin CA, Reid ME, Burns MA. Factors associated with positive direct antiglobulin tests in pretransfusion patients: a case control study. Vox Sang 1985; 49:215-20 Vichinsky EP, Luban NLC, Wright E, et al. Prospective RBC phenotype matching in a stroke-prevention trial in sickle cell anemia: a multicenter transfusion trial. Transfusion 2001;41:1086-92. Leger RM, Garratty G. Evaluation of methods for detecting alloantibodies. Transfusion 1999;39:11-16. Wheeler CA, Calhoun L, Blackall DP. Warm reactive autoantibodies : clinical and serologic correlations. Am J Clin Pathol 2004;122:680-5. Ness PM. How do I encourage clinicians to transfuse mismatched blood to patients with autoimmune hemolytic anemia in urgent situations. Transfusion 2006. 46:1859- 62. Leger RM. The positive direct antiglobulin test and immune mediated hemolysis. In: Roback J. Combs MR, Grossman B, et al. eds. Technical Manual. 16 th edition. Bethesda, MD: AABB Press 2008:489-521. Duffy TP. Autoimmune hemolytic anemia and paryoxysmal nocturnal hemoglobinuria. In: Simon TL, Snyder EL, Stowell CP, et al. eds. Rossis Principles of Transfusion Medicine. 4 th edition. Bethesda, MD: AABB Press 2009:321-43. 9/21/2010 1 Transfusion Practices: Managing Blood Component Recalls and Withdrawals American Society for Clinical Pathology San Francisco 2010 Course 6730 1 Course 6730 Glenn Ramsey, MD Department of Pathology Northwestern University Chicago, Illinois Transfusion Practices: Managing Blood Component Recalls and Withdrawals American Society for Clinical Pathology San Francisco 2010 Course 6730 2 Course 6730 Glenn Ramsey, MD CME Disclosure: No relevant financial interests Transfusion Practices: Managing Blood Component g g p Recalls and Withdrawals Glenn Ramsey, MD Department of Pathology Northwestern University, Chicago, IL LochDunvegan, Isle of Skye, Scotland 9/21/2010 2 Outline Recalls and market withdrawals Biological product deviation reports Estimated 1 in 320 blood components General management 4 Compliance, SOP, training, rapid action Physician notification Tangible risk of infection or adverse effect Selected problems High-risk transfusion? More emerging infections Types Of Notices About Issued Blood Components Lookback--donor now has infection (HIV, HCV, etc) Recallproduct in violation of law, subject to legal action 5 Market Withdrawalless significant violation Quarantineisolate unit, pending above determination But most units have been transfused before notices Platelets 5 days, RBCs 42 days storage HIV & HCV Lookbacks 21 CFR 610.47, revised 2008 New lookbacks for HIV+& HCV+donors found now: Donor services-- Quarantine in-dated products within 3 days If donor confirmed+, trace past units as far back as records permit (unless >12 months before a ti t t) 6 negative test) Transfusion services-- Trace recipients within 12 weeks of receiving notice: Reasonable attempts Incompetent or minor patient: find legal rep or relative Deceased recipient: HCV notice not required HIVnext of kin notified 9/21/2010 3 Lookback Reports from Blood Establishments to FDA Lookback Rule Revised, 2008 300 400 500 600 HCV HIV 7 0 100 200 300 FY05 FY06 FY07 FY08 FY09 FDA Bi ol ogi cal Product Devi ati on Report, FY09 HIV HBV Recalls 21 CFR 7.3, 7.40 et seq. Remove or correct products in violation of FDA law and subject to legal action Consignees should carry out instructions immediately Class I: reasonable probability of serious adverse 8 Class I: reasonable probability of serious adverse consequences or death Class II: temporary or reversible adverse consequences or remote probability of serious adverse conseq. Class III: not likely to cause adverse consequences Published in FDA Enforcement Report weekly Ramsey G, Sherman LA. Transfusion 39:473,1999;40:253,2000 Bozzo T. Transfusion 39:439, 1999 Market Withdrawals Products with minor violations, not subject to legal action May be beyond control of manufacturer E.g., post-donation information about donor Not published by FDA, numbers of withdrawals or units i l d k 9 involved are unknown Biological product deviations often lead to withdrawals 9/21/2010 4 2006 Recalls FDA Enforcement Reports (weekly), 2006 Ramsey G, Transfusion 47(suppl):34A, 2007 1,130 blood component recalls of 13,758 units 10 About 1 in 2,000 available blood components recalled Common Recal l Reasons Wi thin Categori es, 2006 Other, 780 629 362 Temp 321 License Other, 1332 2500 3000 3500 4000 4500 5000 i t s 11 411 Malaria 1062 Donor Suitability 1686 Store Temp 1421 Arm Prep 1264 GMP 121 vCJD 313 Ship Temp 1342 Sterility 926 QC Clots Other, 331 Other, 104 Other, 61 0 500 1000 1500 2000 2500 Preparation Collection Store/Ship Inadeq Donor Hx RiskFactors U n Biological Product Deviation Reporting 21 CFR 606.171, instituted 2001 Key elements of BPD scope: Manufacturing E.g., patient specimen, but not patient care 12 g , p p , p Deviations affecting safety, purity, potency No longer errors and accidents Only if product was distributed If not distributed, not reportable Investigation still required (cGMP) 9/21/2010 5 Biological Product Deviation Reports Licensed Facilities, FY 09 = 25,481 Donor-Related Screening 1914 Collection 929 General QC, Distribution 1662 Component Prep 420 FDAAnnual Summary, BPD Reports, www.fda.gov Collection 929 Viral Testing 39 Deferral 37 Post-Donation Information 18,558 Component Prep 420 Routine Testing 289 Labeling 749 Miscellaneous 884 Biological Product Deviations: Post-Donation Information Travel Malaria vCJ D Post-donation illness History tattoo <12 mo History tissue or organ tpt Hx prior disease/surgery Hx hepatitis or exposure Sex partner: HIV grp O risk Other exposures 14 Male-male sex Medications Antiandrogens Retinoids IV drug use Pre- or post-donation positive viral marker Cancer before or after donationno longer BPD Biological Product Deviations: Post-Donation Information Highlighted by NIH/NHLBI for study by REDS-II* Travel---malaria (tropics), variant CJ D (Europe) Medicaldeferring illnesses or medications High risk behaviors/exposure Sexual (High-risk partner male sex with male) *Retrovirus Epidemiology Donor Study II Sexual (High-risk partner, male sex with male) Nonsexual (IVDU, jail) Blood/disease exposurestattoo, piercing, needlestick Transfusion 49 Suppl 3S:52A (x2), 2009--AABB meeting Fed Reg 75:8080, 2/23/2010, planned donor survey 9/21/2010 6 Post-Donation Information: Donor Analysis Licensed facilities, FDA BPD Annual Report, FY09: 93% of PDI donors knew information before donation Only 7% discovered their PDI after donation PDI discovery: later donation 93%; donor call 5% 16 Donor survey, Transfusion 49 Suppl 3S:52A, 2009 48% made two ineligible donations Trends: male, older, better educated (travel) Common Blood Components Recalls, vs. Biological Product Deviations (Licensed)--Post Donation Information 1261 Other PDI 1159 Cancer 817 Tattoo 618 Male sex 603 Finasteride 421 IVDU 5398 Other 15,000 20,000 25,000 BPDs for PDI (Includes 44 Potential Recalls) PDI: 80% of all BPDs Half involve >1 donation 3 components per BPD? 17 6562 Malaria 5659 vCJD 0 5,000 10,000 Preparation Collection Store/Ship Inadeq Donor Hx Risk Factors PDI BPDs Units in Recalls: Blood Component Notices in US: Estimated Frequency Recalls: 13,758 units in FDA FY06 Enforcement Reports Market withdrawals: Est. from Biological Product Deviations (FDA FY08) Post-donation information, ?3 components/report: 18 500 BPDs x 3 =55 500 units 18 18,500 BPDs x 3 =55,500 units Other BPDs, ?2 components/report: 7,000 BPDs x 2 =14,000 units Estimated 83,000 units recalled or withdrawn 26,568,000 units available in US (AABB/HHS 2006) 0.31%, or 1 in 320 blood components in US Northwestern Memorial Hospital, Chicago: 0.45% 9/21/2010 7 Outline Recalls and market withdrawals Biological product deviation reports Estimated 1 in 320 blood components General management 19 Compliance, SOP, training, rapid action Physician notification Tangible risk of infection or adverse effect Selected problems High-risk transfusion? More emerging infections CAP Lab Accreditation Checklist, 2010 Transfusion Medicine TRM.42120, Phase II: Identify/quarantine units from donors now reactive in screening test TRM.42135, Phase I: 20 Have SOP for managing quarantines, recalls, withdrawals TRM.42170, Phase II: Follow FDA and CMS regulations/guidelines for recipients given potentially infectious transfusion HIV/HCV lookbacks & other guidelines AABB Standards, 25th ed., 2008 7.0. Deviations, Nonconformances, and Complications 7.1 Nonconformances 7.1.4 Released Nonconforming Blood, Components Evaluated to determine effect on quality When quality may have been affected, report to customer(other department or facility) 21 customer (other department or facility) Maintain records of nature and action Keep five years 7.4.6. Look-Back. Per FDA rules and recommendations [FDA: Keep lookback records 10 years from notice] 9/21/2010 8 General Considerations I Have a procedure for managing notifications Training Promptly follow instructions from blood supplier 24/7 access to fax or secure e-mail for large 22 notices Quarantine units physically and electronically Medical evaluation as needed Get more info from blood supplier if needed Donor (was/will be) tested later? Ramsey, Transfusion Med Rev 18:36, 2004 General Considerations II Document actions If phone, then paper; track resolution Database by unit? By recipient? Keep records as required (5 yrs or lookbacks 10 yrs) 23 Keep records as required (5 yrs, or lookbacks 10 yrs) Was Source Plasma or Recovered Plasma made and sent elsewhere? Oversight Options Transfusion committee Approve policies Review significant notices Improve awareness of potential for post-transfusion bl 24 problems Risk management/legal Serious problems or large recalls Patient/public relations assistance 9/21/2010 9 25 LochSnizort, Isle of Skye, Scotland Outline Recalls and market withdrawals Biological product deviation reports Estimated 1 in 320 blood components General management 26 Compliance, SOP, training, rapid action Physician notification Tangible risk of infection or adverse effect Selected problems High-risk transfusion? More emerging infections Inform Transfusing Physician? Our general approaches: As required or recommended by FDA-yes HIV, HCV lookback If tangible potential for disease transmissionyes 27 If potential for transfusion reaction (sterility, storage): check for reaction report 9/21/2010 10 Notify Physician? Yes or Suggested Yes: FDA rule: HIV lookback (patient or next of kin) HCV lookback (patient alive) Other donor/unit infection, confirmed: HBV sAg or NAT*, Chagas, West Nile NAT Bacteria in component or co-component 28 Bacteria in component or co component Tangible potential infection risk: HIV or hepatitis risk factor* Malaria travelhigh-risk region and cellular unit Improper donor screening or testing* *Unless later donor testing rules out window period Viral Marker Windows Seroconversion periods important Timing of donor exposure before donation 29 Timing of donor exposure before donation Timing of subsequent testing (interim donations) May rule out recipient exposure in some cases When to test patients after transfusion Window Periods (days) Anti-HIV mean 22 range 6-38 HIV MP-NAT 9 7-12 Anti-HCV 70 54-192 HCV MP NAT 7 NA 30 HCV MP-NAT 7 NA HBsAg 38-43 (06) 37-87 (05) HBV MP-NAT 32-38 (06) NA MP-NAT=Mini-pool nucleic acid test NA=not available Busch, Transfusion 45:254, 2005 Kleinman, J Clin Virol 36(S1):S23, 2006 9/21/2010 11 Notify Physician? It Depends-I If transfusion reaction occurred: Donor or unit bacterial infection risk Antibiotics, arm preparation, other sterility concern Component content problem Clots, hemolysis St bl 31 Storage problem Temperature, incorrectly extended expiration Incorrect CMV status or leukoreduction If recipient was at risk for CMV Teratogenic medication (antiandrogen, retinoid) If recipient was pregnant Notify Physician? It Depends-II Labeling problem: Compatibility: blood type, crossmatch, antigen typing If reaction or potential for delayed reaction 32 Collection bag or apheresis device problem Evaluate details Notify Physician? Suggested No: Post-donation information: vCJ D residence risk Malaria travelMexico, Central America Donor history of: 33 Cancer, post-donation illness Viral screen, unconfirmed: HBcAb; EIA+other markers not confirmed Donor record/ID/unit number No, but fix recipients unit-number record if needed Unit quality control or volume 9/21/2010 12 Recalled Units: Physician Notification? (Withdrawals Not Included) Arm Prep or Sterility Storage Temp RBCAg Leukored? Other Other Malaria, 411 44%: Txn Rxn? 5% More Info 34 Other YES, 181 QC Donor History Adeq? Other GMP Testing, 204 46% No 6% Yes Canadian Policy Recommendations Heddle NM et al, Transfusion 48:2585, 2008 McMaster University survey; recommendations Recipient notification issues include: Develop national or provincial guidelines 35 Notices to hospitals should include recommendations Hospital SOPs should address decision-making Health care personnel should be given adequate information for recipient notification if needed Educate hospital CEOs and risk management personnel Outline Recalls and market withdrawals Biological product deviation reports Estimated 1 in 320 blood components General management 36 Compliance, SOP, training, rapid action Physician notification Tangible risk of infection or adverse effect Selected problems High-risk transfusion? More emerging infections 9/21/2010 13 High Concern for Viral Exposure? Donor with recent confirmed viral exposure or new confirmed infection? HBV, HCV, HIV? Consult infectious disease service for advice about recipient: immediate counseling and treatment? 37 Post-exposure prophylaxis information: National PEPLine (24 hr) 1-888-HIV-4911 (448-4911) General HIV therapy consultation: National HIV Warmline (8am-8pm ET M-F) 1-800-933-3413 Post-Exposure Prophylaxis CDC post-exposure prophylaxis (PEP) guidelines see MMWR Recommendations & Reports 50(RR-11), 2001: Occupational HBV/HCV/HIV 54(RR-02), 2005: Non-occupational HIV 54(RR-09) 2005: Occupational HIV 38 54(RR-09), 2005: Occupational HIV 57(RR-6), 2008: Mass-casualty HBV/HCV/HIV exposure NY State Dept Health: www.ceitraining.org Current NY guidelines Adult or pediatric, occupational or not Post-Exposure Prophylaxis Timing HIV and HBVrapid therapy if possible HIV: antiretroviral medications CDC: ASAP, within hours rather than days (05) NY--ideally <2 hr, and generally not after 36 hr But max time cannot be stated with certainty 39 y HBV: If exposee not immune: HBV Immune Globulin and vaccine Ideally <24 hr, but not after 14 days HCV: No effective PEP, not recommended 9/21/2010 14 Chagas+ Donor Lookback AABB Bulletin #06-08, 12/13/06, recommendations: Withdraw prior in-dated products when donor screen+ Lookback on all confirmed-positive donors prior units Confirmed=positive on second test (RIPA, IFA, other) 40 Include all frozen units?infectious, but data limited As far back as records go Lookback recipient testing: Few if any infected recipients without their own exposure risk have been found Donors in US not as infectious as Latin Amer donors More Emerging Agents AABB Task Force, Emerging Infectious Disease Agents Stramer SL, Transfusion 49(suppl), Aug 2009 Highest priority (in addition to vCJ D): Babesia 41 Dengue 2010: Chronic fatigue syndrome and XMRV Xenotropic murine-leukemia-virus-associated retrovirus Other MLV-related viruses? Babesia Intraerythrocytic parasite, regionally endemic Dozens of transfusion cases, several fatalities Current donor deferral for history of illness (AABB) Donor testing under consideration 42 Issues for evaluating past transfusions from +donors: Transmissions have been from RBCs only Illness incubation 1-9 weeks Recipient susceptibility factors (in tick inoculations): Infants, elderly, immunosuppressed, asplenic 9/21/2010 15 Dengue Flavivirus, arthropod-borne like WNV, tropical climes Endemic in Caribbean and US-Mexico border areas 40-80% antibody rates Puerto Rico donor pilot testing, Amer Red Cross 1 in 1400 donations viremic 43 1 in 1400 donations viremic Two transfusion infections seen in SE Asia Donor testing if done would be NAT Issues for evaluating past transfusions from +donors: Incubation period until illness 3-14 days Short-term viremia before-during infection/illness Perhaps 120d donor deferral after +NAT, like WNV? Chronic Fatigue Syndrome (CFS) and XMRV Gammaretroviruses: feline, murine leukemia (MLV) viruses Xenotropic Murine-leukemia-virus-associated RetroVirus CFS: >6 months of fatigue, weakness, myalgia, impaired memory or concentration, insomnia (CDC.gov) Some studies link XMRV to CFS and prostate cancer FDA/NIH PNAS 8/23/10 MLV l t d i RNA i 44 FDA/NIH, PNAS 8/23/10: MLV-related virus gag RNA in CFS patients 87%, blood donors 7% No evidence for transfusion transmission to date, but AABB, Canada, Australia/NZ blood services, 2010: Donor deferral for history of CFS diagnosis No guidance included on past donations of new deferrals Implication for past transfused units unknown at this time DuntulmCastle ruins (Clan MacDonald), Isle of Skye Harris (tweed) on horizon 9/21/2010 16 Outline Summary Recalls and market withdrawals Biological product deviation reports Estimated 1 in 320 blood components General management 46 Compliance, SOP, training, rapid action Physician notification Tangible risk of infection or adverse effect Selected problems High-risk transfusion More emerging infections 9/21/2010 1 Transfusion Transfusion Triggers Triggers 2010 ASCP Annual Meeting Friday, October 29, 2010 Phillip J. DeChristopher, MD, PhD Medical Director, Transfusion Medicine / Blood Bank / Apheresis Professor of Pathology Loyola University Medical Center Maywood, Illinois (T) 708-327-2609 E-mail: pdechristopher@lumc.edu Lecture Objectives Overview of Some Complications of Transfusion Blood Component Types to Consider Indications for Blood Use Non-indications for Blood Use Situations where Blood Use is Beneficial Simplified Principles of Blood Management Before You Pull that Trigger, Heres a Number of Things to Consider 9/21/2010 2 Adverse Effects of Allogeneic Transfusion 1 Infectious Complications Viral, bacterial contamination of platelets* (1:3000), others (vCJ D, WNV, Chagas Disease, babesiosis, Dengue fever) Febrile and allergic reactions Hemolytic transfusion reactions* (clerical error) Mistransfusion incidence 1:16,000 Other Microchimerism (50% of trauma pts @ discharge/ 30% @ 1 year) 2 , graft vs. host disease SIRS, TACO (1:350) 3 , TRALI 4 * * Leading causes of morbidity and mortality 1. Goodnough, Crit Care Med 2003;31(12S) 2. Utter, Transfusion 2006;46 3. Rana, Transfusion 2006;46 4. Toy, Crit Care Med 2005;33(4) Transfusion therapy is a set of processes, not just a product Recruitdonor Screendonor Collectunit Preparecomponents Infectious diseases Pre-TXtesting Medical reasonto TX Issueunit Administer atbedside Monitor &evaluate Product: Blood safety Entire process: Blood transfusion safety testing AfterS. Dzik, MD BloodTransfusionService, MGH, Boston Practice Guidelines are a Kind of Practice Parameter Standards Accepted principlesof patient management Practice variation NOT expected p Guidelines Recommendations / strategies for patient management Practice variation is reasonable Practice Options Practice variation expected Incorporate substantial patient- and physician-specific information 9/21/2010 3 Defining Practice Guidelines Consensus statements that are systematically developed to assist practitioner and patient decisions about appropriate health care for specific clinical appropriate health care for specific clinical circumstances Field MJ. Clinical practice guidelines: Directions for a new agency. Institute of Medicine, Washington, DC, National Academy Press. 1990. Grading the Level of Evidence Grade I Randomized, controlled trials Grade II-1 Non-randomized, controlled trials Non randomized, controlled trials Grade II-2 Controlled observational studies (e.g., cohort studies) Grade II-3 Uncontrolled observational studies Grade III Descriptive studies; expert opinion WW II Medic Administers IV Plasma to Wounded GI: The Value of Blood Transfusion was Recognized Before Randomized Controlled Trials 9/21/2010 4 Red Blood Cell Unit The 1988 NIH Consensus Conference on Perioperative RBC Transfusion Transfuse red blood cells to increase oxygen-carrying capacity in anemic patients ?Death knell to the 10/30 Rule NIH Consensus Development Panel. Perioperative red cell transfusions. JAMA 1988;260:2700-03. Differing Views on the RBC Transfusion Target The Internists View Anemia cannot be defined numerically RBC's are transfused to symptomatic, anemic patients A i d h l i l dt bidit & Anemia and hypovolemia lead to severe morbidity & mortality Promulgated a [Hgb] trigger of 7 g / dL as reasonable Blood transfusion is an outcome to be avoided American College of Physicians. Practice strategies for elective red blood cell transfusion practice policies. Ann Intern Med. 1992;116:403-06. 9/21/2010 5 Differing Views on the RBC Transfusion Target The Surgeons View - Developed 11 Policies Transfusion needs should be assessed on case-by-case basis Blood should be transfused 1 unit at a time Limit allogeneic exposure g p Transfusion trigger on a sliding scale, patient-specific Perioperative blood loss prevented or controlled Consider autologous alternatives Maximize oxygen delivery to surgical patient RBC mass increased or restored (e.g., use of Fe +2 or EPO) Document reasons for and results of transfusion Hospital transfusion policies developed cooperatively & reassessed regularly Spence RK. Blood Management Practice Guidelines Conference. Surgical red blood cell transfusion practice policies. Am J Surg. 1995;170(suppl. 6A):3S-15S. Differing Views on the RBC Transfusion Target The Anesthesiologists View [Hgb] is an inappropriate basis... for transfusion Promulgated 6 g / dL as reasonable laboratorytrigger Additional Influences urging decision to transfuse RBC Patients cardiopulmonary reserve The rate and magnitude of blood loss Oxygen consumption Atherosclerotic disease ASATask Forces Practice Guidelines for Perioperative Blood Transfusion and Adjuvant Therapies. Anesthesiology. 2006;105:198-208. Developing Transfusion Targets: Incorporating Laboratory Trigger Numbers & Clinical J udgment 9/21/2010 6 Developing Transfusion Targets: Incorporating Clinical Judgment Duration of anemia Ongoing indication of organ ischemia Patients intravascular volume Normovolemic anemia well-tolerated Potential or actual ongoing bleeding (rate and magnitude) Patients risk factors for complications of inadequate oxygenation Low cardiopulmonary reserve High oxygen consumption Who is At Risk from Intravascular Volume Depletion? Myocardial Ischemia Coronary artery disease V l l h t di Valvular heart disease Congestive heart disease Cerebral Ischemia History of TIAs Previous thrombotic stroke Heberts Randomized, Controlled Study in Critical Care Studied 838 euvolemic ICU patients admitted with [Hgb] <9.0 g/dL 418randomlyassignedtorestrictive transfusionarm 418 randomly assigned to restrictive transfusion arm RBC transfused only when [Hgb] fell <7.0 g/dL RBC maintained between 7 - 9 g/dL 420 assigned to liberal transfusion arm RBC transfused only when [Hgb] fell <10.0 g/dL RBC maintained between 10.0 - 12.0 g/dL Hebert PC, et al. N Engl J Med. 1999;340(6):409-17. 9/21/2010 7 Heberts Randomized, Controlled Study in Critical Care Study Variable % in Restrictive Transfusion Arm % in Liberal Transfusion Arm In-Hospital Mortality Rate 22.2 28.2 (p=0.05) APACHE <20 8.7 16.1 (p =0.03) Age<55 years 5.7 13.0 (p =0.02) 30-day mortality 18.7 23.3 (p =0.11) Clinically significant cardiac disease 20.5 22.9 (p =0.69)
Blood Transfusion in Elderly Patients with Acute MI Retrospective study 78,974 Medicare beneficiaries, > 65 years old Hospitalized with AMI Hospitalized with AMI Categorized according to hematocrit on admission Questioned an association between use of transfusion and 30-day mortality Found RBC transfusion decreased 30-day mortality in elderly patients with MI WuW-C, et al., N Engl J Med. 2001;345(17):1230-36. Association of Blood Transfusion with 30-Day Mortality in Elderly AMI Patients, by Hct 9/21/2010 8 Blood Transfusion in the Elderly with Acute Myocardial Infarction Data indicate a high prevalence of anemia among elderly with AMI (43% had Hct < 39%) Anemic patients had a higher 30-day mortality Blood transfusion is effective in reducing short term mortality rate among elderly, if their Hct is < 30.0% and may be effective for patients with Hcts as high as 33.0% Patients were less likely to receive transfusion if they were white, had cardiac arrest, had a DNR order or who had been admitted from nursing home Relationship of Blood Transfusion & Clinical Outcomes in Patients with ACS Anemic patients with ischemic heart disease: Is there definitive evidence to support transfusing RBC? Are we doing harm to such patients if we fail to transfuse for Hgb < 10 g / dL? Post hoc analysis of pooled data from 3 large Post hoc analysis of pooled data from 3 large international trials of patients with acute coronary syndromes Patients grouped as whether they received RBCs transfusion during hospitalization or not Of 24, 112 patients in 3 studies, 10% had at least 1 blood transfusion, complete data on transfusion & bleeding and outcomes RaoSV, et al., JAMA2004;292(13):1555-62 Blood Transfusion in Patients with ACS GUSTO IIb Trial strategies to open occluded arteries, heparin vs. hirudin PURSUIT Trial Platelet GPIIb/IIIa suppression using Integrilin (eptifibatide) PARAGON B Lamifiban vs. placebo All 3 trials treated with aspirin in (80 to 325 mg/dL) Transfusion data collected prospectively in each Endpoints: 30-day all-cause mortality 30-day death or MI Moderate bleeding not life threatening, required transfusion; only 1 st bleeding episode included in analysis 9/21/2010 9 Relationship of Blood Transfusion & Clinical Outcomes in Patients with ACS Study Variable Transfusion (medianof 3.6units/ transfusedpatient) No transfusion Age(yr) Female(%) 68.9 41.5 64.0 (p <.001) 33.6 (p <.001) Female(%) 41.5 33.6 (p .001) Black race(%) Body weight (Kg) Comorbidities (HTN, DM, stroke, hyperlipidemia) 5.1 74.0 27.9 3.9 (p <.002) 77.3 (p <.001) 20.6 (p <.001) Hematocrits (%), baseline/ nadir 39.9 / 29.0 41.7 / 37.6 (p <.001) 30-day MI 30-day death or MI 25% 29% 8%(p <.001) 10%(p <.001) Some Conclusions: Transfusion of Patients with Ischemic Heart Disease Transfused patients were 3.94 x more likely (OR 3.26 4.75) to die within 30 days At Hct < 25%, there was no relation between transfusion and death Data suggest Hcts as low as 25% may be tolerated in otherwise stable patients with ischemic heart disease Discrepancies vs. Wu, et al data: Admitting Hcts vs. developing anemia (drivers of anemia such as bleeding and procedures) Transfusion data probably incomplete Excluded patients younger than 65 years of age Excluded patients dying within 48 hours Pre-Op Hct & Post-op Outcomes in Older Patients undergoing Noncardiac Surgery Retrospective cohort study (132 U.S. VA Medical Centers) 310, 311 veterans, aged 65 years old Underwent major noncardiac surgery, 1997 2004 St tifi d ti t di t ti h t it Stratified patients according to preoperative hematocrit Outcome Measures: 30-day postoperative mortality 30-day composite postoperative mortality or cardiac events Found 30-day mortality and cardiac event rates increased monotonically (+ or -) with deviations from normal Hct WuW-C, et al., JAMA2007;297(22):2481-88. 9/21/2010 10 Baseline Patient Characteristics by Preoperative Hematocrit Level Hematocrit, % <39.0 39.0 53.9 >53.9 N =132, 970 N =176, 704 n =637 42.8% 56.9% 0.2% Mean age ~ 73 y/o Ca. 98% male; ca. 80% Caucasian Cohort with anemia had the most female & nonwhite patients, the highest prevalence of DM, cardiac disease, renal disease, infected wounds cancer and preoperative transfusions 30-Day Postoperative Mortality & Cardiac events by Hct Level Hct, % 30-Day Mortality Rates, % 30-Day Cardiac Event Rates, % Adjusted Odds Ratio < 18.0 35.4 14.6 2.42 18.0 20.9 26.8 8.6 1.68 24 0 26 9 14 9 4 4 1 33 24.0 26.9 14.9 4.4 1.33 30.0 32.9 8.4 3.1 1.21 36.0 38.9 3.5 1.8 1.12 45.0 47.9 1.5 0.9 1 (Ref.) 48.0 50.9 1.8 1.0 1.12 51.0 53.9 3.1 1.4 1.42 54 5.6 2.9 1.55 Issues Raised by the Wu Hct- Surgery Study in the Elderly Work highlights strengths of using high quality, large observational databases Allows for adjustments of many potentially confounding variables common to surgical practice The etiology and chronicity of abnormal Hcts could not be related to the outcomes No causality claimed, but authors provide several classic lines of cause-effect relationship: An appropriate temporal relationship A strong association of predictor and outcome An apparent dose-response relationship Biologic plausibility related to cardiac physiology 9/21/2010 11 Issues Raised by the Wu Hct- Surgery Study in the Elderly Epidemiologic features speak to a real relationship between Hct and outcome Defining anemia in the elderly may have important clinical implications p Is anemia simply a marker of other conditions that confer increased risk? National guidelines recommend treatment only when Hct is < 18% to 21%; the majority of deaths are associated with only modest degree of anemia (Hct 27.0% - 38.9%) If anemia were a modifiable risk factor, should preoperative transfusion be considered? Systematic Review of RBC Transfusion in the Critically Ill 45 studies with a median of 687 patients per study Outcome measures Mortality Infection MOF Syndrome ARDS Risks of RBC transfusion outweighed benefits in 42 of 45 studies!! Marik &Corwin, Crit Care Med 2008;36(9):2667-74. Association of Transfusion & Risk of Death Marik & Corwin, Crit Care Med 2008;36(9):2667-74. 9/21/2010 12 Association of Transfusion & Risk of Infectious Complications Marik & Corwin, Crit Care Med 2008;36(9):2667-74. Association of Transfusion & Risk Developing ARDS Marik & Corwin, Crit Care Med 2008;36(9):2667-74. Settings Wherein RBC Transfusion Appears to be Beneficial Neonates, especially premature neonates Massive transfusion Battlefield casualties T ( i ili ) Trauma (civilian) Surgery Obstetrical hemorrhage Liver transplantation Chemotherapy-induced myelosuppression, and stem cell transplantation Sickle cell disease (selected indications) 9/21/2010 13 Reality Testing of the RBC Transfusion Trigger Hemoglobin Level (g/dL) Transfusion Decision > 10 RBCs usually unnecessary 6 - 10 Grey Zone: Clinically correlate & individualize < 6 Almost always transfuse 3 Life-threatening DO NOT Transfuse Red Blood Cells To improve general well-being To promote wound healing In place of a hematinic In place of a hematinic Prophylactically, in the absence of signs, symptoms or risks For volume expansion, when oxygen- carrying capacity is adequate Comments about about Platelets 9/21/2010 14 Flavors of Platelet Concentrates Random-donor pools (pool size as low as 4) Apheresis platelets ( single donor ) ( g ) Pre-Storage RD Pools (leukoreduced, bacteriologically tested, counted for yield) Apheresis platelets, stored in InterSol, a platelet additive solution Platelet Concentrates All platelet concentrates have a 5-day Shelf Life All Adult Doses have a minimum count of 3 x 10 11 platelets Crossmatched and HLA-typed platelets are Apheresis, by definition Prophylactic Platelet Transfusion Dose 1271 patients with hypoproliferative thrombocytopenia Transfusion Trigger=10,000 / L Randomly assigned to 3 doses 1.1 x 10 11 / meter 2 2 2 x 10 11 / meter 2 Slichter, et al.,NEJM 2010;362(7): 600-13 2.2 x 10 / meter 4.4 x 10 11 / meter 2 Low dose led to decreased numbers of platelets transfused, but increased transfusions given Doses between 1.1 and 4.4 x 10 11 / meter 2 had no effect on the incidence of bleeding 9/21/2010 15 When You Think You are Observing Platelet Refractoriness Rule out clinical causes DIC states Sepsis, infection, fever Splenomegaly Splenomegaly Medications Repeat platelet counts 10 30 minutes, posttransfusion Please order a Panel Reactive Antibody Assay! Request specialized platelets only in the setting of documented immune-mediated refractoriness Deciding to Transfuse Platelets: Risk Assessment Issues Medical vs. Surgical patient Bleeding vs. Non-bleeding Risks in surgical / obstetric patients g p Type / extent of surgery Ability to control bleeding Actual / anticipated rate of bleeding Factors affecting platelet function, such as medications, extracorporeal circulation such as bypass, renal failure, etc. Bleeding Risks & Platelet Count are Approximately Correlated Platelet Platelet Count (10 Count (10 99 /L) /L) < 5 Likelihood of Spontaneous Hemorrhage High 5 10 10- 50 > 50 Increased with Trauma Surgery Ulceration Variably Increased Exceedingly Unlikely 9/21/2010 16 Recommendations for Platelet Transfusion Platelet Platelet Count (10 Count (10 99 /L) /L) < 5 10 20 Transfusion Decision Almost Always Prophylaxis Window 10 20 < 50 50 - 100 100 Prophylaxis Window for Medical Patients Usually Indicated for Surgery & Other Invasive Procedures Based on Risk of Bleeding Uncommonly Indicated: Consider with known platelet dysfunction & microvascular bleeding Avoid Transfusing Platelets In thrombocytopenia due to increased platelet destruction (immune or microangiopathic) Idiopathic thrombocytopenic purpura (ITP) p y p p p ( ) Thrombotic thrombocytopenic purpura (TTP) Other microangiopathies (HUS, HELLP) Platelet transfusion in these settings are rarely indicated and usually ineffective You incur all the risks, with little or no benefit Fresh Frozen Plasma Unit 9/21/2010 17 Where in the Classical Cascade Do the Coagulation Factors Belong? Extrinsic Pathway Factor I Factor II Intrinsic Pathway Factors I, II, V Factor VIII:C (also ac o Factor V Factor VII Factor X Ag:vWF) Factor IX Factor X Factor XI Factor XII Vitamin K-Dependent Factors (all Synthesized in the Liver) Factor II Factor VII Factor VII Factor IX Factor X Protein C Protein S Coagulation Factors Factor Common Name Half-Life I Fibrinogen 3 4 Days II Prothrombin 2 3 Days III Thromboplastin Available fromvarious tissues, suchas lung, brain, kidney IV Ionized Ca ++
Ubiquitous V Ac-globulin (proaccelerin) 12 36 hours VI Nonexistent -
9/21/2010 18 Coagulation Factors Factor Common Name Half-Life VII Proconvertin (Prothrombin Conversion Accelerator) 4 6 hours VIIIC Antihemophilic Factor 12 hours IX Christmas Factor 24 hours IX 24 hours X Stuart-Prower Factor 1 2 days XI Plasma Thromboplastin antecedent 2 3 days XII Hagemans (contact) factor 2 3 days XIII Fibrin Stabilizing Factor (Profibrinoligase) 3 5 days
Plasma Components Available in the United States other than FFP 24-Hour Plasma, known as FP24 Collected and separated from whole blood in a time frame >8 hours, but <24 hours F h lf lif i 1 h f Frozen shelf life remains 1 year, when frozen at < 18 o C Use just like FFP Delay time to freezing causes mild decrease in activity of the labile Factors, V & VIII 84%of Factor VIII left after 8 hours; 64%after 24 hours Plasma Components Available in the United States other than FFP Thawed Plasma Stored at 1 6 o C Label change required after 24 hours Used for up to 5 days (same indications as FFP) Factor V and Factor VIII are labile and progressively decrease over time Hemostatic levels of FV & FVIII still available 9/21/2010 19 Clinical Indications for Plasma Transfusion Multiple factor deficiency with active bleeding or prior to invasive procedure, and Documented laboratory evidence of ProlongedPT or PTT (15xmidpoint of thereference Prolonged PT or PTT (1.5 x midpoint of thereference range) Low Fibrinogen level Low specific coagulation factor assay(s) Typical clinical situations include Liver disease DIC states Massive hemorrhage & transfusion in trauma Clinical Indications for Plasma Transfusion Plasma exchange replacement fluid for treating microangiopathies (such as TTP, HUS, HELLP syndrome) Documented congenital or acquired coagulation factor deficiency Deficiency of Protein S, Protein C or AT (formerly known as AT-III) [AT and Protein C concentrates are available in the US] Clinical Indications for Plasma Transfusion Massive transfusion and evidence of both Continued (microvascular) bleeding C i fi i il bl / Coagulation deficiency or unavailable PT / aPTT Urgent reversal of Coumadin effect To stop Coumadin-therapy related intracranial bleeding) [Prior to surgery or other invasive procedure] (Frequently done, but remains controversial!) 9/21/2010 20 Misuses of Plasma Transfusion As a volume expander As a nutritional source Toenhancewoundhealing To enhance wound healing Not a suitable source of immunoglobulins (in patients with severe hypogammagloubulinemia) Mild to moderate prolongation of PT or aPTT prior to invasive procedures Defining the INR International Normalized Ratio = (Patient PT / control PT ) ISI , where ISI = International Sensitivity Index ISI, used by the local laboratory performing the PT measurement determinedfor eachcommercial batch measurement, determined for each commercial batch The ISI reflects the responsiveness of a given thromboplastin to a reduction in Vitamin K-dependent coagulation factors compared to WHO reference material. Highly sensitive thromboplastins (ISI ~1.0) are now made by recombinant technology with defined phospholipid content Lab Screening Tests as a Trigger to Transfuse Plasma No increased risk of hemorrhage / oozing if the PT / aPTT is no more prolonged than 1.3 X upper limit of reference range NOT an INR = 1.5 pp g - or - 1.5 X midpoint of reference range Abnormality Clinical Coagulopathy 9/21/2010 21 The INR of Fresh Frozen Plasma The INR of FFP is 1.1 (range 0.9 to 1.3) It is not surprising that giving FFP has little effect on minimally effect on minimally elevated PTs FFP will affect the INR only when there is a big difference between the FFP and the patients plasma And What if Plasma is Transfused? Mean change of 0.03 INR units / unit of FFP transfused Mildly abnormal PTs just dont change much with FFP transfusion INRs above 3 have a INRs above 3 have a more significant change per unit of FFP Mildly prolonged PT values (13 17 sec) do not correlate with RBC loss Only 10% of patients had the PT re-checked after transfusion!! Holland, et al., Transfusion 2005;45:1234-5 An Analysis of the Literature Normal vs. Abnormal Coagulation Tests Pre-procedure coagulation tests are lousy predictors of who is going to bleed Prophylactic plasma transfusion does not result in fewer bleeding events J Segal, W Dzik, et al., Transfusion 2005;45 (9): 1413-25. 9/21/2010 22 CRYOPRECIPITATED AHF Cold-insoluble portion of plasma processed from FFP Plasma proteins not soluble at 1 - 6 o C Estimated Contents of Plasma Factors in Cryoprecipitated AHF Constituent Constituent Fibrinogen Approximate Content 150 mg (minimum) Factor VIII:C Von Willebrand Factor Factor XIII 80 IU (minimum) 80 120 Units 40 60 IU Cryoprecipitate: Clinical Indications Hypofibrinogenemia E.g., in consumptive coagulopathies such as DIC Isolated fibrinogen deficiency with active bleeding Isolated fibrinogen deficiency with active bleeding or in patients at risk vonWillebrands Disease or Hemophilia A (use only when commercial concentrates are unavailable) Fibrin surgical adhesive Isolated Factor XIII deficiency 9/21/2010 23 Use of Blood Components: Use of Blood Components: Dosage Considerations Dosage Considerations Blood Component Blood Component RBC RBC Dosage: Goals Variable Number of Units: Reverse Symptomatic Anemia Enhance Oxygen-carrying Capacity Platelets Platelets Plasma Plasma Cryoprecipitate AHF Cryoprecipitate AHF - Use Apheresis Platelets or Pools - Provide 1Adult Dose at atime (nominally 3x 10 11 platelet count): To ReduceHighRisksof Bleeding 10 15 mL / Kg Body Weight: To Achieve Hemostatic Levels Provide 1 Adult Dose, pool of 5 units To Replete Fibrinogen Level What is Blood Management? 1 Blood management is an evidence-based, multidisciplinaryprocess that isdesigned to promote the optimal useof bloodproducts optimal use of blood products throughout the hospital. The goal of blood management is ensure the safe and efficient use of the many resources involved in the complex process of blood component therapy. 1 Boucher & Hannon, Pharmacotherapy 2007;27(10) Blood Management What is it? The promotion of the appropriate use of blood Improvement of patient outcomes by the d t f bl d prudent use of blood What is it not (but might include) Bloodless Medicine Bloodless Surgery No Blood 9/21/2010 24 Why Blood Management? Blood isa precious resource that saves lives Blood is often in short supply The number of eligible, willing blood donors is dropping The cost of blood continues to rise The decision to transfuse remains unavoidably unsafe, but some risks and complications may be avoidable Principles of Blood Management Focus on the patients best interest: Patient-Centered Grounded in scientific validation and evidence-based practice Use a multidisciplinary teamapproach p y pp Physician-driven Multidisciplinary and multi-professional Effective Achieve change through education & training Must have an institutional commitment to excellence Principles of Blood Management Operational Issues Risk reduction instituted in the preoperative setting Restricting certain medications or nutritional supplements Restrictions appropriate for the surgical procedure Use of surgical devices, medications and techniques to reduce blood loss Use of peri-operative blood salvage Planned cooperation among multiple levels of care 9/21/2010 25 Do Not Pull That Transfusion Do Not Pull That Transfusion Trigger Trigger Absent Patient Assessment Absent Patient Assessment Summary Summary Statements Statements Establish Institutional Guidelines based on available literature / experience Embrace / Implement / Teach Principles of Blood Management Avoid Transfusion Triggers Avoid Transfusion Triggers Transfuse Targets: Patient-centered Assessments when benefit > risk Transfuse the right patient, at the right time, with the right dose of the right component Minimize or avoid transfusion whenever possible ASCP 2010 Annual Meeting Selected Bibliography to Transfusion Triggers Friday, October 29, 2010 Phillip J. DeChristopher, MD, PhD
General Guidelines Miller Y, Bachowski G, Benjamin R, et al. Practice Guidelines for Blood Transfusion: A Compilation from Recent Peer-Reviewed Literature, Second Edition. Washington, DC: American National Red Cross, 2007.
Roseff SD. (Ed.), Pediatric Transfusion: A Physicians Handbook, Third Edition, Bethesda, MD: AABB Press, 2009.
Waters J H (Ed.), Perioperative Blood Management: A Physicians Handbook, 1 st Edition, Bethesda, MD: AABB Press, 2006.
American Society of Anesthesiologists Task Force on Perioperative Blood Transfusion and Adjuvant Therapies, Practice Guidelines for Perioperative Blood Transfusion and Adjuvant Therapies, Anesthesiology 2006; 105(1), 198-208.
Triulzi DJ (Ed.), Blood Transfusion Therapy, A Physicians Handbook, Seventh Edition, Bethesda, MD: AABB Press, 2002.
Guidelines for Use of Red Blood Cells Napolitano LM, et al., Clinical practice guideline: Red Blood cell transfusion in adult trauma and critical care, Crit Care Med 2009; 37:3124-57.
Marik PE and Corwin HL, Efficacy of red blood cell transfusion in the critically ill: A systemic review of the literature, Crit Care Med 2008; 36:2667-2674.
West MA, Shapiro MB, Nathens AB, et al., Guidelines for Transfusion in the Trauma Patient, J Trauma 2006;61:436-39.
Corwin HL and Hebert P. Avoiding a blood transfusion: How much is it worth? (Editorial). Crit Care Med 2005;33(3):672-74.
Guidelines for Use of Platelets Slichter SJ , et al., Dose of Prophylactic Platelet Transfusions and Prevention of Hemorrhage, N Eng J Med 2010; 362(7): 600-13.
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