1) Risk of passenger WBC from blood units: Alloimmunization; CMV transmission; Febrile reaction (leukocyte/cytokinemediated)

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1 Transfusion Medicine UpToDate: Introduction: Risk Factors: Indications for Irradiated Blood Products: - Peripheral stem cell or bone marrow transplantation - Hematologic malignancies - HLA-matched directed donation - Fludarabine therapy - Congenital immunodeficiency - Newborn,premature infants Blood Products (one unit): - Whole Blood: 450ml, used for massive transfusion or exchange transfusion - Packed RBC: 250ml with Hct 80% (1 unit) - Leukocyte-reduced PRBC: As above but less WBC Febrile reaction, CMV transmission, HLA alloimmunization. - Leukocyte-reduced, γ-irradiated PRBC: tgvhd - Frozen RBC: 150ml, plasma and WBC depleted rare donor - Washed RBC: plasma depleted severe allergic reactions or anaphylactic reaction in pts with IgA deficiency - Pooled platelet: ml from 4-8 donors (1 unit) - Single donor platelet: ml from 1 donor (1 unit) - HLA-matched single donor platelet: ml from 1 donor, indicated for patients refractory to platelet transfusion owing to the presence of anti-hla antibody. - FFP (1 unit): 250ml (Do NOT make FFP from female donor with multiple pregnancies.) - Cryoprecipitate (1 unit): 150mg fibrinogen 1) Risk of passenger WBC from blood units: Alloimmunization; CMV transmission; Febrile reaction (leukocyte/cytokinemediated) Transfusion-induced GVHD (t-gvhd) Thus, Leukoreduction all above except t-gvhd. tgvhd requires irradiation of blood products. 2) Risk of platelet transfusion refractory: fever, infection, bleeding, amphotericin, vancomycin, VOD, portal hypertension with hypersplenism Biology: 1) ABO Blood Group/IgM: - A antigen: terminal N-acetylgalactosamine - B antigen: terminal Galactose - O: negative both A and B antigen (univeral donor) - AB: presence of both A and B antigen (universal recipient) - Intravascular hemolysis: IgM mediated complement activity. - In type O patients, IgG antibody is more prevalant. Thus, frequency of ABO hemolysis disease of newborn occurs in blood group O mothers carrying non blood group O fetus and newborns. Page 1 of 9

2 2) Weak A Antigen (Type A2): - Have detectable anti-a IgM, therefore, only A2 or O type blood is used for transfusion. 3) Rh System/IgG: antigen encoded by RhD and RhCE genes. - Rh (+): D+, CE + - Rh (-): D-, CE + * D gene deletion (European descent) or D gene mutations (Asian or African descent) negative D * RhCE: C, E, c, e. - Rh null (absence of all Rh proteins) stomatocytes low-grade hemolysis 4) Weak D (Du) and Partial D: both typed as Rh (+) - Weak D: structurally normal ( D expression) NOT able to produce anti-d Ab. Therefore, OK to receive Rh-(+) postive blood, and NO need for RhoGAM during pregnancy. - Partial D: structually different D able to produce anti-d Ab. Therefore, MUST receive Rh-(-) blood for transfusion, and MUST use RhoGAM during pregnancy. ** Rh IgG, a/w Hemolytic Disease of Newborn and Delayed Hemolytic Transfusion Reaction. Prevention: RhD immunoglobulin (RhoGAM) 300 μg given at 28wks of pregnancy and again at delivery if the newborns are Rh(+) and mother Rh(-). ** Pearls for Practice: - For recipient (pt): use reagents that do not pick up weak D. - For donor: use reagents that have ability to detect all weak D. 5) Minor Protein Antigens: IgG - Kell: 10%, most prevalant minor Ag hemolytic dz of newborns: In contrast to anti-rh hemolytic dz of newborn, it is also a/w BM hypoproliferation because the kell Ag present on the fetal hemotopoitic stem cells. McLeod Phenotype: Kx protein deficiency Kell Ag antigen Congenital acanthocytes and neurological dysfunction. - Kidd: Delayed hemolytic transfusion reaction (DHTRs) - Duffy: Acute or delayed hemolytic transfusion reactions Hemolytic disease of fetus or newborns Duffy protein - Receptor for malarial parasite (Plasmodium vivax). - MNSs: MN Ag, Ss Ag. * Ab against MN Ag: if not reactive at 37C, rarely clinically significant * Ab against Ss Ag: Hemolytic transfusion reaction and hemolytic dz of fetus or newborns 6) Minor Carbohydrate Antigen: IgM - Lewis Antigen (LeA and LeB): Ag for cold-reacting IgM * It is also a receptor for H.Pylori on gastric mucosa. Page 2 of 9

3 - P antigen (I/i ) * Receptor for parvovirus B19: modulate the cell susceptibility to HIV * Cold agglutinin to i(small) Ag: a/w EBV infection * Cold agglutinin to I(big) Ag: a/w Mycoplasma penumonia - I (big) Ag antigen IgM-mediated autoimmune hemolytic anamia (AIHA). - Paroxysmal cold hemoglobinuria (PCH): also called Donath-Landsteiner antibody or horror autoxicu only exception that antibody produced is IgG, rather then IgM for cold agglutinin. Symptoms: Diagnosis: See individual transfusion reactions below. Can be mild to severe. A. Blood Bank Testing: 1) ABO Typing and Crossmatch: - Forward Typing: "Pt's RBC + anti-igm Ab" test for Pt's RBC Ag - Reverse Typing: "Pt's serum + test RBC" test for pt's serum Ab - Discrapancy between forward and reserse typing: ABO mismatched BMT, Recent transfusion history, Newborn (delayed maturing Ab production) 2) Rh Typing: - One step only (Forward testing): Anti-D reagent include a mixture of IgG and IgM antibodies. If (-) by DAT, proceed to IAT for weak D Ag. 3) Crossmatching: - "Pt's serum + donor RBC" immediate spin watch for agglutination. - Full Crossmatch: if (-) for above proceed to IAT watch for agglutination (This applies whn when pt has positive antibody screen.) 4) Antibody Screen: screen for minor Ags. - 1st step (screening): "Pt's serum + test RBC (type O)" if (+), go to 2nd step - 2nd step (specificity): using a larger panel of RBC with known Ag specificities. 5) Pre-transfusion blood test for infectious agents: - HIV-1,HIV-2, HBV (HBc, HBsAg), HCV, HTLV-I/II, PKTP (Syphilis) B. Supply RBC to transfusion-dependent patients: - Provide blood with extended matching to include D, C, E, c, e, K, Fy, Kidd C. Autoimmune Hemolytic Anemia: - All crossmatching will be incompatible. - If unable typing give Group O, Rh negative blood - May need more extensive minor Ag typing if pt previously transfused to exclude possible alloantibodies. - For cold autoimmune hemolytic anemia, use warm blood. Pathology: A. Antiglobulin Test (Coombs Test): 1) Direct Coombs (DAT): detect nonagglutinating Abs (IgG) or complement on RBC Page 3 of 9

4 surface. 2) Indirect Coombs (IAT): detect antibodies in the patient's sera. Used to do compatibility testing; also used to type for minor antigens (Rh, Kell, Duffy) B. Donors: - Universal RBC donor: O type - Universal plasma donor: AB-positive - Universal platelet donor: does not exist, b/c platelet product contains substantial quantities of both plasma ( ml) and cells. * Group AB platelet yield a decreased platelet count increment when transfused to all but type AB recipients. Prognosis: Tx Principle: - Most transfusion reactions have good prognosis. - Some can be fetal such as TRALI, anaphylatic reaction due to mismatch. A. Platetet Transfusion: 1) Overview: - Platelet expresses ABO antigen, but not Rh antigen. - Platelet alloimmunization: major cause for platelet transfusion refractory after multiple transfusions. 2) Guideline for PLT Transfusion: 2.1 Prophylactic platelet transfusion: 10, 000 is the usual cutoff - Higher if blast crisis, APL induction, procedures, concurrent coagulopathy, anemia, fever, hypertension, acute pulmonary processes. - For active bleeding: keep platelet > 50,000 to 100,000/ul 2.2 Invasive procedure: * > 50,000/μl for LP, indwelling lines, epidural anesthesia, gastroscopy and biopsy, transbronchial biopsy, laporotomy,or liver biopsy * >100,000/μl for brain and eye surgery 2.3 Surgery in patients on plavix or other antiplatelet agents: If surgery can not be delayed until drug wash out consider platelet transfusion 2.4 Qualitative PLT Disorders: DDAVP first, correct HCT to >30% consider plt transfusion when other measures failed 3) Contraindication for platelet transfusion - DIC, TTP, HIT 4) Platelet transfusion: - Platelet Products: Single-Donor Platelet (SDP) 6 Pooled Units; Platelet phresis product - Choice of pooled platelet (6-pack) vs SDP: no difference in benefit. - Dosing? Triggers? 5) Platelet Transfusion Refractoriness: Page 4 of 9

5 - Cause: platelet allo-immunization (see above) * Abx to HLA-A or B, not class II HLA major cause. * Abx to HPA (human platelet antigen) minor - Definition: 1hr post trx corrected pletelet increments <5000/μl after 2 consecutive transfusions most predictive for the presence of alloantibody to HLA. * Corrected Count Increment (CCI) = (post-trx platelet # - pre-trx platelet #) x BSA/# of platelet infused - DD for platelet transfusion refractoriness: * Abx to HLA (major cause). Ab againat HPA is a very uncommon cause (3-8%). * Splenomegaly, DIC, fever, sepsis, bleeding, amphotericin B - 1hr post transfusion platelet number: * If decreased, check antibody against HLA. * If not decreased, likely due to consumption. - Management: A trial of HLA-matched platelet transfusion (HLA-A, and HLA-B match); alternatively, use Ag-negative platelet - Prevention: use leukocyte reduced or tirradiated platelet product, or use only phresis platelet (not the platelet from whole blood) 6) Posttransfusion Purpura (PTP): donor platelet destroyed by allo-abx against HPA (GPIIb/IIIa), followed by destruction of the pt's own Ag-negative platelet (similar to ITP). - Sx: Suden onset of severe thrombocytopenia (<5000) 7-10 days post-trx, persist for days, web purpura, seen commonly in female previously transfused or pregnant; also a/w acute febrile transfusion reactions. - Dx: (+) Anti-HPA-1a (>90%), never anti-hpa-1b - Tx: steroid, IVIg, plasma exchange, HPA and HLA compatible platelet transfusion - Prevention: For RBC transfusion use washed RBC (remove platelet) or autologous blood. For platelet transfusion use alloantigen-negative platelets (HPA-1b donor). Woman who has child with neonatal alloimmune thrombocytopenia should be cautioned of risk of post transfusion purpura in future with transfusion. ** Neonatal alloimmune thrombocytopenia (NAIT) occurs in first pregnancy - early in contrast to Rh disease. HPA1a alloimmunization is most frequent. Risk of ICH in subsequent fetal-antigen (+) pregnancies is 100%. - Therapy: maternal 12 wks, fetal transfusion B. Transfusion of Plasma Products: 1). FFP (fresh frozen plasma): - Indicated for multiple factor deficiencies (liver dz, DIC, warfarin, vit K deficiency, massive blood transfusion, plasma exchange) - Thawed FFP (labeled as thawed plasma) vs. FFP: Thawed FFP expires in 24hrs, with shelf life of 5 days. - Note: After thawing, ADAMTS13 is stable up to 5 days. So, thawed FFP can be used in emergency situation such as plasma exchange for TTP. But do NOT use thawed FFP for other factor deficiencies (factor V deficiency or hemophilia A). Factor decifiencies should be treated with fresh FFP if VIII concentrate is not available. Page 5 of 9

6 2). Cryoprecipitate: - Concentrates: fibrinogen, factor VIII, vwf, factor XIII, fibronectin - Unlike FFP, it does not contain physiological anticoagulants such as protein C, S, etc. - Indication: severe hemorrhagic DIC, congenital or acquired hypofibrinogenemia, vwf disease, hemophilia, quanlitative platelet dysfunction due to uremia * Do not use cyrorecipiate in liver dz. C. Blood Transfusion in Special Clinical Situations: 1). Aplastic Anemia: - Higher incidence of graft rejection: due to recipient-derived T cells (immunoactive to stem cells). - Limit blood transfusion for aplastic patients who are candiadte for transplant. - Avoid transfusion from blood products of family members as this will risk of graft rejection through alloimmunization to minor HLA Ags. - All blood products should be irradiated, leuko-reduced. For platelet transfusion, SDP preferred over pooled platelet products whever possible. Both graft failure if transplant. RBC transfusion only for symptomatic anemia. * Recipient residual T cells that are responsible for dz pathogenesis will cause graft rejection. 2). ABO Incompatible and Hematopoietic Stem Cell Transplantation (HCST): 2.1 Blood Transfusion after HSCT: - All blood products should be γ-irradiated prevent t-gvhd - All blood products should be leuko-reduced prevent CMV infection in CMV(-) recipients 2.2 ABO Incompatible: - Major ABO Incompatible recipient Abx attact donor RBC deplete donor RBC - Minor ABO Incompatible donor Abx attact recipient RBC deplete donor plasma 2.3 Donor Selection: - FIRST: match HLA NEXT: Graft source, CMV status NEXT: donor Age, Gender LAST: ABO compatibility * For myeloablative HSCT: Do NOT require ABO matching b/c ABO antigens NOT expressed on HSC. ABO-matched or mismatched transplant no difference in OS or transplant-related mortality in myeloablative HSCT. * For nonmyeloabalative HSCT: ABO incompatibility non-relapse mortality, acute GVHD, and transplant-related mortality in first year after transplant. So, Major ABO Mismatch: PRCA (erythroid progenitor cells express ABO antigens), profound reticulopenia with normal wbc and platelet - 10% incidence. Other cell lines recover ok but slower. Minor ABO Mismatch: acute hemolytic anemia (not common). Risk factors for hemolysis in minor ABO mismatch HSCT: non-hla matched sibling donor, CsA without MTX, PRBC instead of marrow. Steps for ABO incompatible HSCT: Page 6 of 9

7 1. Remove incompatible red cells or plasma from donor prior to infusion. Major mismatch remove RBC; Minor mismatch remove plasma; Bidirectional remove both 2. Use of blood product after after ABO incompatible HSCT: keep Hb>9.5 - Major mismatch: A or B O; AB B, A, or O * RBC: use type O; Plasma: donor compatible - Minor mismatch: O A, B,or AB; A or B AB * RBC: donor compatible; Plasma: host compatible - Bi-directional mismatch: A B; B A * RBC: type O; Plasma: type AB 3) Autoimmune Cytopenia after HSCT - ITP: responds to standard therapy for de novo ITP - AIHA: Cold-reactive IgM occur earlier 2-8 months post transplant; Warm auto-abx occur later (after 6 months) post transplant. Unrelated donor is a risk factor 4) ABO Incompatible Solid Organ Transplants: - Major ABO mismatch graft rejection (some but not all organ). ABO antigen expressed on all solid tissues - Minor ABO mismatch immune hemolysis due to passenger lymphocyte syndrome as in HSCT. * with graft lymphocyte content (Heart/Lung > Liver > Kindey) * with use of cyclosporine without antiproliferative agent * More common after O A than O B 5) Sickle Cell Disease: - Prone to alloimmunization against RBC antigens - Transfusion Indication: stroke, acute chest syndrome, aplastic anemia, pre-op - Use extended-match RBC prevent alloimmunization - DHTR: cause significant morbidity in sickle cell patients (little morbidity in nonsickle cell popuation) - Hyperhemolysis: occurs 7-10 days post transfusion severe anemia, reticulocytopenia, Hct lower than pre-transfusion level. Tx: no more transfusion, steroid, IVIG, ESA 6). Massive Transfusion: coagulopathy, thrombocytopenia, hypocalcemia 7). Cardiopulmonary Bypass: platelet abnormality (dysfunction and aggregation), platelet transfusion if bleeding D. Transfusion Reactions: 1). Hemolytic Transfusion Reactions: 1.1 Acute Hemolytic: ABO major mismatched blood intravascular hemolysis of donor RBC (IgM to ABO Ags) - Sx: fever, chill, back pain, hemoglobinuria (dark urine), hemoglobinemia, Page 7 of 9

8 hypotension. DIC in OR. - DAT (+) for complement. 1.2 Delayed Hemolytic (DHTR): 7-10 days post-trx in previously transfused or pregnant patients extravascular hemolysis (IgG to Rh, Kidd, Duffy, Kell, MNs), "IgG to Kidd" fix complement intravascular hemolysis. - DAT (+) and IAT (+); Spherocytes in delayed reaction 1.3 Passive administration of isoagglutins in FFP and platelets. 2) Febrile Reactions: - Cause: Ab to residual WBC (HLA) in blood product cytokine release febrile reaction. - Seen often in multiparous women and patients with h/o multiple transfusions - Tx: stop blood transfusion. Prevention use leukocyte depleted blood. 3) Allergic Reactions: - Cause: plasma protein in blood product allergic (or anaphylactic) reaction in multiple transfused patients. * Allergic reaction hives * Anaphylactic reactions occurs in IgA-deficient patients - Tx: Rx antihistamine. Prevention washed RBC and plasma product from IgAdeficienct donor. 4). Transfusion-Related Acute Lung Injury (TRALI): - Path: Antigranulocyte/HLA antibodies in bloor product activate recipient WBC cytokine release non-cardiac pulmonary edema severe respiratory compromise ( ARDS, but rapid resolution in hrs). Donor usually multiparous female. - Classic Sx: occurs within 4-6 hrs; fever; hypoxemia (PAO2/FIO2 <300, O2Sat <90% RA); CXR bilateral infiltrates with pulmonary edema; pulmonary artery pressure. - Tx: supportive O2, diuretics, or vent - Prevention: no more plasma-containing product from that donor. Use blood products from male donor only, or screen for HLA antibody for female donor. 5). Infectious complications - Bacterial, Protozoal, Hepatitis, HIV, HTLV-1 (human T-cell lymphotropic virus 1), West Nile virus, Parvovirus B19, CMV - Prevention: CMV-seronegative products is superior to leukoreduced blood product 6). Transfusion-associated GVHD (t-gvhd): - Cause: Passenger T-lymphocyte in donor blood pruduct 8-10 days post TRX GVHD (commonly seen in severe immune suppressed patients. - Classic Sx: "skin rash, diarrhea, abnl LFT" - Dx: skin biopsy, molecular technique (HLA typing) - Prevention: use leukoreduced and irradiated blood product Follow-Up: - Monitor transfusion reaction Page 8 of 9

9 - Monitor iron overload for multiple transfusion - Monitor autoantibody production. Pharmacology: Page 9 of 9