Transfusions in Sickle Cell Disease: How, When and Why

Transcription

1 Transfusions in Sickle Cell Disease: How, When and Why James R. Eckman, MD Professor Emeritus of Hematology and Medical Oncology Emory University School of Medicine This work is supported by the Centers for Disease Control and Prevention under Cooperative Agreement # 5 NU58 DD The contents are solely the responsibility of the author and do not necessarily represent the official views of the CDC or the Department of Health and Human Services. Disclosures Dr. James Eckman, Personal/Professional Financial Relationships with Company Industry Name(s) Role External Industry Relationships * Equity, stock, or options in biomedical industry companies or publishers** None Board of Directors or officer None Royalties from Emory or from external entity None Industry funds to Emory for my research None Other None No off label use of therapies 1

2 Learning Objectives Provide information to patients, family and other healthcare providers regarding the important role of transfusion in improving health in sickle cell disease. Describe the complications of transfusion and apply strategies for their prevention and management. Relay the role of healthcare providers, patients, families, care providers, and the community in optimizing transfusion therapy in sickle cell disease. Transfusion Recommendations NHLBI guidelines for SCD Yawn et al. JAMA 2014;312(10): British Journal of Haematology, 2017, 176, British Journal of Haematology, 2017, 176,

3 Why Transfuse in Sickle Cell Disease Increase hemoglobin level and improve oxygen delivery to the tissues. Dilute out the red cells containing sickle hemoglobin to increase blood flow; treating and preventing complications How Do You Transfuse in Sickle Cell Disease Simple or Top Up Exchange transfusion: Manual Exchange transfusion: Automated also called erythrocytopheresis 3

4 WHOLE BLOOD VISCOSITY Erslev in Williams, Beutler, Erslev. Hematology Schmalzer et al. Transfusion 27:228, How Do You Transfuse in Sickle Cell Disease Simple transfusion advantages More rapid and less expensive Less exposure to blood Exchange transfusion advantages Decreases percent Hb S more efficiently Less iron loading 4

5 Transfusion Indications Correction of acute anemia Indication Type of Transfusion Evidence Grade Aplastic crisis Simple 1B Acute splenic sequestration Acute hepatic sequestration Delayed hemolytic transfusion reaction with life-threatening anemia Simple Simple Simple 1B 1B 1B Severe anemia in pregnancy Simple 1C Acute bleeding SS patients elective low or medium risk surgery Simple Simple or Exchange 1C 1A Modified from Davis et al. Br J Haematol 2017;176: Transfusion Indications Reduce the Hb S percentage Indication Type of Transfusion Evidence Grade Acute chest syndrome Acute stroke or TIA Prevention of primary stroke & silent cerebral infarct Secondary stroke prevention Acute multi-organ failure Simple or Exchange Exchange Simple or Exchange Simple or Exchange Simple* or Exchange 1B 1B 1A 1B 1C Acute intrahepatic cholestasis Exchange 1C Modified from Davis et al. Br J Haematol 2017;176:

6 Transfusion Indications Reduce the Hb S percentage Indication Type of Transfusion Evidence Grade Severe sepsis Exchange 2C Elective low and medium risk surgery in Hb SC patients Exchange 1C Elective high risk surgery in all phenotypes Exchange 1C Pregnancy with sickle complications (e.g. painful crises, ACS, stroke) Pregnancy with high obstetric, medical or fetal risk ACS and pain crisis prevention unresponsive to hydroxyurea Simple or Exchange Simple or Exchange Simple Exchange 1B 1C 2C Modified from Davis et al. Br J Haematol 2017;176: Sickle Cell Disease Other indications Acute Simple Transfusion Symptomatic anemia Severe anemia and hypoxia Chronic Transfusion Chronic renal failure Chronic cardiac decompensation Chronic pulmonary insufficiency Cerebral angiopathy Modified from Wayne, Kevy, Nathan. Blood 81:1109,

7 Complications of Transfusion Alloimmunization Delayed Transfusion Reactions Autoimmune Hemolytic Anemia Iron Overload Transmission of Infection Hepatitis C and B Human Immunodeficiency Virus Other Agents Bacteria, parasites, CMV, EB Cardiovascular Complications ABO Blood Groups Antibodies are detected against antigens absent from blood cells within the first few months of life naturally occurring antibodies are made in response to gut flora with antigens resembling the A or B antigen IgM is the major class of antibody produced against ABO blood groups 14 7

8 Typing Determined Phenotypically or Genotypically 15 Minor Blood Groups Antibodies are formed in response to previous transfusions or pregnancy. Over 600 potential antigens but many fewer are clinically important. Antibody screen is used to detect antibodies to minor antigens Transfused blood is matched so units lack antigens for which the recipient has antibodies. 16 8

9 Blood Group Frequency Varies With Geography 17 Hemoglobin Disorders Are Geographic Diseases Sickle Cell. Barnhart, Henry, Lusher. Eds. Upjohn, Kalamazoo MI,

10 Sickle Cell Disease Alloantibody Response Transfusion Number RBC Antibodies WBC Antibodies None 0 % 29 % < 50 units 10 % 33 % u 25 % 48 % u 46 % 34 % > 200 u 57 % 71 % Reisner et al. Tissue Antigens 30:161, 1987 Alloimmunization 107 Sickle Cell Patients Antibody Percent of Patients Anti - K 16.8 Anti - E 14.9 Anti - C 10.3 Anti - Jk b 6.5 Anti - Fy a 3.7 Anti - M 2.8 Anti - Le a 2.8 Anti - S 1.9 Anti - FY b 1.9 Vichinsky et al. New Engl J Med 322:1617,

11 Alloimmunization in Sickle Cell Antigen Patients, % N = 158 Donors, % N = 200 P Value K 2 9 < E < 0.01 Jk b < Fy a < M < 0.01 Le a NS S < Fy b < Vichinsky et al. New Engl J Med 322:1617, 1990 Pathophysiology of Delayed Hemolytic Transfusion Reaction Primary Exposure Evanescence Secondary Exposure Anamnestic response (DHTR) Ross Fasano

12 Delayed Hemolytic Transfusion Reaction (DHTR) The most feared transfusion complication in SCD patients Hyperhemolysis (bystander hemolysis) unique to SCD VOC 5-14 d post-trxn => ACS => MSOF => Death (6%) Ab-Negative DHTR: Process attributed to antibody-independent macrophage activation. Characterized by PS exposure and eryptosis Autoantibodies: further complicate clinical picture, and potentially contribute to hyperhemolysis DHTR Treatment: Remains controversial because the exact mechanisms remain unclear EPO / IVIG / Steroids / Rituxan / Eculizumab / Bortezomib (?) Avoidance of RBC transfusion 23 Alloimmunization is a Real Problem Aygun et al. Transfusion 2002;42:

13 Extended Phenotypic Matching LaSalle-Williams Transfusion 2012;51: Extended Phenotypic Matching LaSalle-Williams Transfusion 2012;51:

14 NHLBI guidelines for SCD Yawn et al. JAMA 2014;312(10): British Journal of Haematology, 2017, 176, Patients with SCD must also have extended red blood cell (RBC) antigen typing performed, which may assist with further serological testing and selection of red cell units if there are haemolytic reactions and complex transfusion requirements (Grade 1C). If transfusion is needed, patients with SCD should be given ABOcompatible, extended Rh- and Kell-matched units. If there are clinically significant red cell antibodies(current or historical) then the red cells selected should be negative for the corresponding antigens (Grade 1C). All patients with SCD should carry a transfusion card indicating that they have special requirement and, in particular, giving information of any alloantibody (Grade 2C). All clinicians managing patients with SCD should be aware of the risk of haemolytic transfusion reactions to ensure prompt recognition and management. Close liaison is needed with haemoglobinopathy specialists and blood services for investigation and management (Grade 1C)

15 Transfusion in Sickle Cell Transfuse D, C/c, E/e, Kell similar units Transfuse exclusively with phenotypically similar blood after the first alloantibody Some advocate phenotypically similar blood for all transfusions All patients keep and clinicians take a detailed transfusion history Recruit for blood donation from family and the African American population *Eckman and Reid, Charache, Lubin NIH Pub No , IRON LOADING FROM TRANSFUSION There is 200 mg iron in 1 unit PRBC (from 420 ml of donor blood) 0.47 mg iron/ml of whole blood 1.16 mg iron/ml of pure red cells In thalassemia major (splenectomized), if mean Hb 12 g/dl ~300 ml PRBC/kg/y (0.4 mg iron/kg/d from transfusion) Add 1-4 mg/d from gut absorption Total mg/kg/d But wider variability in transfusion mg/kg/d PRBC = packed red blood cells; Hb = hemoglobin. Porter. Br J Haematol. 2001;115:

16 How do you monitor the patient for iron overload? Number of units transfused Serum ferritin level Measured liver iron concentration Cardiac T2* for determination of heart iron quantification Other 31 FERRITIN AS A MONITOR OF IRON LOADING Reflects Iron stores Inflammation and tissue damage Recent chelation Ascorbate status Plasma ferritin (µg/l) 24,000 12, Hepatic Iron Stores and Plasma Ferritin Sickle cell anemia (n=37) Thalassemia major (n=74) ,000 16,000 Hepatic iron (µg Fe/g liver) Brittenham et al. Am J Hematol. 1993;42:81. 16

17 MAINTENANCE OF LOWER FERRITIN LEVEL PREDICTS SURVIVAL AT UCLH Survival probability Ferritin <2500 μ/l on more than two thirds of occasions Ferritin >2500 μ/l on more than one third of occasions Years of follow up UCLH = University College London Hospital. Porter. Unpublished data. LIVER IRON CONCENTRATION PREDICTS TOTAL BODY IRON Body iron stores (mg/kg) Sample <1 mg Dry Weight (n=23) r= Hepatic iron concentration (mg/g dry weight) Body iron stores (mg/kg) Sample >1 mg Dry Weight (n=25) r= Hepatic iron concentration (mg/g dry weight) Body iron (mg/kg) = 10.6 hepatic iron concentration (mg/g dry weight) Angelucci et al. N Engl J Med. 2000;343:

18 Hepatic iron (µmol/g wet weight) LIVER IRON AND RISK FROM IRON OVERLOAD HH heterozygotes Threshold for cardiac disease and early death Normal 10 Thalassemia major Increased risk of complications 20 Age (y) Hepatic iron (mg/g dry weight) HH = hereditary hemochromatosis. Adapted from Olivieri and Brittenham. Blood. 1997;89:739. NHLBI guidelines for SCD Yawn et al. JAMA 2014;312(10):

19 Multi-site transfusion in SCD patients N = 42 SCD pts N = 150 SCD pts Harm SK, et al. Am J Clin Pathol Management of Iron overload Clinicians must keep records Patients and their families need to record every transfusion received Erythrocytopheresis can minimize iron overload in chronically transfused patients Once iron overload is documented chelation therapy is required and may be life-long in individuals receiving simiple transfusions Strict adherence to chelation is critical for a positive outcome. 19

20 Questions? Comments? Thank for your attention! More resources at Scinfo.org 20