Acute Transfusion Reactionsin the Setting of Incompatible Transfusion Differential Diagnosis • Pertinent positives • Pertinent negatives Occam’s razor* does not always apply * All things being equal, the simplest explanation is usually correct. Examples: Hyperhemolysis in Sickle Cell DHTR with aplastic crises
Adverse Reactions Signs and Symptoms • Nausea and/or vomiting • Generalized bleeding; DIC • Darkened urine; Hemoglobinuria • Apprehension; Sensations of impending doom • ANY adverse manifestation at time of transfusion should be considered 7
Acute immune-mediated hemolysis – Usually due to transfusion of ABO- incompatible red cells – May begin after infusion of as little as 10- 15 mL of blood – Symptoms may be misleadingly mild – Early recognition and vigorous treatment are critical 8
Acute immune-mediated hemolysis• Presentation may include any sign or symptom, but most typically: – Fever (may be the only symptom); chills – Hemoglobinuria, hemoglobinemia – Hypotension – Back or flank pain; pain at infusion site – Generalized bleeding/DIC – Renal failure
Adverse Reaction• Transfusion should be stopped• Labels, forms and patient identification should be rechecked at the bedside• Patient’s physician and blood bank should be notified immediately• Maintain I.V. line with normal saline until medical evaluation completed
Adverse Reaction• Collect post-transfusion samples and send to blood bank – Avoid traumatic venipuncture and mechanical hemolysis• Depending on facility policy, send blood product container, administration set and any attached fluids to the Blood Bank.• Urine sample may be useful for evaluation
AHTR as Systemic Inflammatory RXN Common Involvement Inflammatory Response AHTR TRALI Febrile Sepsis Allergic HypotensiveCapon, Goldfinger. Transfusion 1995:35;513-20
Reaction Fever &/or Cardiovascular chills/rigors Respiratory FNHTR* No Other Hemolysis TRALI Yes Hypotensive AHTR AHTR Bacterial Bacterial Other Anaphylactoid Volume Overload Other*FNHTR = Febrile, non-hemolytic transfusion reaction
Reaction Fever &/or Cardiovascular chills/rigors RespiratoryFNHTR No Other Hemolysis TRALI Yes Hypotensive AHTR AHTR Bacterial Bacterial Other Anaphylactoid Volume Overload Other Complete clinical assessment Ancillary laboratory testing
First Tier• Clerical Check - Bedside and Laboratory• Repeat ABO/Rh (pre/post)• Visual Check for Hemolysis• Direct Antiglobulin Test* * may be pos or neg with immune hemolysis due to RBC destruction
Second Tier• Repeat ABO/Rh units• Repeat antibody screen• Repeat special antigen typing• Full crossmatch • pre/post-reaction specimens
Third Tier• “Blood Bank Voodoo” • enhanced techniques• Clinical findings/history• Contributing factors• Ancillary tests-hemolysis• Other pertinent testing• Monitoring and treatment
Common Causes of Acute AdverseReactions - Immunologic • RBC incompatibility, i.e., RBC antibody • Antibody to plasma proteins • Antibody to donor leukocytes • Donor antibodies to patient leukocytes 19
Common Causes of Acute AdverseReactions – Non-Immunologic• Volume overload• Bacterial Contamination• Physical or chemical destruction of RBCs – Incompatible solutions or medications – Excessive heat – Freezing 20
Laboratory Evaluation Immediate Investigation: • Check for Clerical Errors • Check for Hemolysis • Check DAT for evidence of blood group incompatibility
Clerical Errors• The risk of getting the wrong unit of blood exceeds all transmissible disease risks combined.• 1990-1999 data: 1 in 19,000 units was administered to other than the intended recipient – 51% errors at patient care area – 29% errors in Blood Bank – 15% multiple, sequential errors Linden JV, Wagner K, et al. Transfusion 2000
Checking for Clerical Errors • Was the blood transfused to the intended recipient? • Was the correct unit tagged? • Was the correct unit issued? • Was the correct sample used for testing?
Visual Examination for Hemolysis • Plasma from post-transfusion sample is inspected for hemolysis – May appear pink to red if significant hemolysis has occurred in previous few hours – May appear deep red/brown or yellowish if hemoglobin has metabolized to bilirubin – Increase in bilirubin may begin as early as 1 hour after reaction, peaks in 5-7 hours and returns to normal within 24 hours (assuming normal liver function)
Direct Antiglobulin Test• Used as serologic check for incompatibility• Perform on post-transfusion specimen; test pre-transfusion DAT for comparison• DAT is likely to be positive if incompatible rbcs or incompatible plasma was transfused
Direct Antiglobulin Test• Incompatible red cell transfusion: – DAT may have a mixed-field appearance – If transfused cells were rapidly destroyed, post- reaction DAT may be negative – Time sample drawn is important, should be collected ASAP after reaction occurs – Type of AHG employed may affect results
Additional Evaluation – When?• If any of initial checks and tests give positive or suspicious results• Clinical presentation is consistent with a Hemolytic Transfusion Reaction (HTR)
Repeat ABO grouping• Standard 188.8.131.52 [26th edition] “For suspected hemolytic transfusion reactions…, a repeat ABO group determination shall be performed on the post-transfusion sample.”Also repeat ABO testing on pre-transfusion sample and blood from transfused unit or attached segment.
ABO grouping discrepancies• Error in patient/sample identification – Pretransfusion sample mislabeled – Sample mix-up in the laboratory – Transfusion given to wrong patient• Error in original ABO-group interpretation – Recording error – Problem solving incorrect• Error in blood product labeling
Additional InvestigationNon-Immune Acute Hemolytic Reaction:• Examine blood in container and lines for abnormal appearance, hemolysis• Check records for any incompatible fluids or medications which may have been administered with blood• Interview transfusionist/check records for details (use of infusion devices, blood product handling, etc.) Cont’ d
Additional Investigation Causes of Non-Immune Acute Hemolysis • Defective blood warmers or infusion pumps • Use of small bore catheters and/or pressure cuffs for infusion • Improper storage (too warm, too cold) – Use of solid ice or dry ice – Use of microwave ovens, heating pads, room heaters, hot water, etc. to warm blood Cont’d
Additional Investigation Causes of Non-Immune Acute Hemolysis • Incompatible fluids, solutions or medications given with blood, especially Lactated Ringer’s, 5% Dextrose, and hypotonic saline solutions. • The only approved solution for infusion with blood is 0.9% sodium chloride injection, USP (normal saline). 5% albumin may be used with physician approval.
Additional Investigations • Antibody Elution • Antibody Screen: on post, repeat pre • Crossmatch – On pre and post – With AHG, esp. if not done previously • Repeat Antigen typings on donor red cells (if applicable) • Examination of urine specimen
Hemoglobinuria vs Hematuria S.G. Sandler, D.A. Sandler. Emedicine.com 2003
Antibody Elution • Removal of red-cell-bound antibody • Common techniques include alteration in pH, heat, organic solvents, detergents, sonication • Heat and sonication methods not suitable for recovering IgG antibodies; not recommended for investigation of HTR
Antibody Elution • May be helpful even when DAT is negative • Test eluate for presence of antibody with: – Antibody screen – A1 and B cells (when appropriate) – Cells from transfused donor units – DAT negative, pre-transfusion autologous cells (if possible)
Antibodies other than ABO • Repeat antibody screen and crossmatches – Use segment from container – Test through AHG-phase – May want to use different test methods, phases • Type post-transfusion sample for corresponding antigen – May help determine if incompatible cells were eliminated or if some are still in circulation
Other Tests• Markers of hemolysis: – Lactate dehydrogenase (LDH) – Bilirubin – Haptoglobin• Most useful if pre- and multiple post-reaction values are available• Rising indirect bilirubin is associated with extravascular hemolysis and HTR caused by non-ABO antibodies Cont’d
Other types of reactions Delayed (>24 hours) – Decreasing Hgb/Hct level, or absence of anticipated post-transfusion elevation – Mild to moderate jaundice – Laboratory evidence of increased cell destruction (increased bilirubin, LDH, etc) – Fever – Hemoglobinuria – Demonstration of previously undetected rbc alloantibody in plasma or eluate
Non-Hemolytic reactions Anaphylactic Reactions Confirmed by demonstration of anti-IgA in the patient’s plasma or serum. Test is available in specialized reference laboratories. Screening for IgA deficiency should be the initial study. Most patients with IgA-related anaphylaxis have been IgA deficient. Subclass or allotype-specific antibodies may develop in patients with normal IgA levels
Non-Hemolytic reactions Bacterial Contamination – Onset typically rapid, occurring within 30 minutes of completion of transfusion – More common in components stored at RT – Examine returned unit for abnormal appearance (brownish or purple discoloration, clots, muddy appearance) – Gram’s stain and Culture of blood bag contents should be performed if clinical presentation suggests bacterial sepsis
Non-Hemolytic reactions TRALI – 3rd leading cause of transfusion-associated death (CBER, FY2001 and FY2002) – Suspect TRALI with any respiratory distress occurring during or following blood or blood component transfusion – Notify facility that supplied blood component; test remaining product or donor sample for antibodies to HLA and/or granulocyte antigens – Crossmatching donor sera with recipient lymphocytes or granulocytes can provide supportive evidence
Non-Hemolytic reactions Febrile, Non-Hemolytic (FNHTR) – Typically present with fever/chills towards ends of transfusion – May be due to recipient antibody to donor WBC antigen – May also be caused by infusion of cytokines released from WBCs during storage of component – Since fever may be initial symptom of acute HTR or septic reaction, prompt attention is warranted to r/o life-threatening reaction
Non-Hemolytic reactions Urticarial / Allergic (1% of transfusions) • Usual presentation: Hives, itching, flushing • Hypersensitivity immune response • If symptoms limited to urticaria, may restart unit after administration of antihistamines per physician order. • Report to blood bank; repeated urticarial reactions will be evaluated to determine if washed blood products are required.
Non-Hemolytic reactions Circulatory overload – Usually seen in patients with compromised cardiac or pulmonary status – Difficulty breathing, cough, cyanosis, tachycardia, hypertension, headache, congestive heart failure – Symptoms usually improve when infusion is stopped and patient is placed in sitting position
Transfusion Associated Circulatory Overload (TACO)• The primary symptoms of TACO are: dyspnea, orthopnea, peripheral edema, and rapid increase of blood pressure.• It is difficult to determine the incidence of TACO, but its incidence is estimated at about one in every 100 to 10,000 transfusions. The risk increases with patients over the age of 60 and patients with cardiac or pulmonary failure, or anemia.• Transfusion Associated Circulatory Overload is easily prevented by closely monitoring patients receiving transfusions and transfusing smaller volumes of blood at a slower rate.• Differentiation from TRALI: While both are related to transfusion medicine and both are important, TACO differs from TRALI in part by having longer hospital stays and increased morbidity.• The hypotension seen with TRALI and the hypertension seen with TACO provides a clinical differentiation of the two.
Peripheral Blood Smear Anisopoikilocytosis Spherocytes BasophiliaAABB has not reviewed this slide and expressly disclaims any liability arising from relying upon or using information contained herein. Please see the full disclaimer appearing on the Disclaimer slide of this presentation.
Reticulocyte Count• DHTR, unexplained anemia• Marrow responsive to anemia?• Response appropriate?Critical in hemoglobinopathies – Differential Diagnosis (DDx): DHTR with marrow suppression
Coagulation Studies Monitor for Disseminated Intravascular Coagulation (DIC)• Platelet count• Fibrinogen• PT and aPTT• D-dimer
Intrinsic Pathway XII Tissue Damage XIIa Intrinsic System (aPTT) XI XIaExtrinsic System (PT) IX Tissue Factor IXa VIIa X VIIIa VIII Xa Va II IIa Fibrinogen Fibrin
Extrinsic PathwayHgb Cytokines ex.TNF Monocyte XII XIIa Intrinsic System (aPTT) Tissue Factor XI XIaExtrinsic System (PT) IX IXa VIIa X VIIIa VIII Xa Va II IIa Fibrinogen Fibrin
WBC Procoagulant Activity Induced by ABO Incompatibility Davenport R, Polar TJ, Kunkel SL. Transfusion 1994;34:943-9WBC Procoagulant Activity ABO Incompatible ABO Compatible Time (hours)
The role of Disseminated IntravascularCoagulation in Shock Induced by Transfusion of Human Blood in Dogs Takaki A et al. Transfusion 1979;19:404-409. 5 min Unsensitized Dogs Sensitized DogsNote abrupt immediate drop in platelet count in both sensitized and unsensitized dogs
(-) CHARGED SURFACE Coagulation Assays ex. COLLAGEN PT, aPTT, fibrinogen XII Tissue Damage XIIa Intrinsic System (aPTT) XI XIaExtrinsic System (PT) IX Tissue Factor IXa VIIa X VIIIa VIII Xa Va II IIa Fibrinogen Fibrin
Generation and Breakdown of FibrinFibrinogen D E D a,b peptides thrombin D D E D D E D D E D D E D D E Protofibril Fibrin Bundles of protofibrils (14-22n)
Evaluation of DICDD EE D D 1. Fall in Fibrinogen thrombin fibrinopeptide 2. Generation of D D E D fibrinopeptides a & bD E D D E D D D E D Plasmin plasminogenD E D D 3. Generation of fibrin split products D-dimer (FDP) and d-dimers
Etiology Acute Renal Failure in HTR• Ischemic - Shock - Vasoconstriction afferent renal arteries o Cytokine mediated (ex IL-1) o Nitric oxide absorption• Hgb-induced nephrotoxicity• Tubular obstruction• All of the above
Sobatta& Hammerstein Histology AProximal tubulesGlomerulus RBC Pigment Cast Loops of Henle Loops of Henle stained with hemoglobin. Also shown is an isolated pigment cast of hemoglobin. DeGowin and Warner, Arch Int Med 1938; 609-630.
Normal kidney Kidney with AHTRnondilated tubules dilated, distended tubules DeGowin and Warner, Arch Int Med 1938; 609-630.
Infusion of Hemoglobin Leads to Vasoconstriction 148 8.5% 126SBP 93 78 8.3%DBP 67HR 56 8.3% Control Increases in systolic (SBP) and Period diastolic (DBP), with 15 gm decreases in heart rate (HR) Hgb Miller and McDonald, J Clin Invest 1951;1033-1040.
Plasma Hgb 175 mg/dlUrine 11.5 87% 1.5 ml/min 4.6Renal Blood Flow 673 67% 220 ml/min 2.5 hrs 15 gm Hgb Hemoglobinuria AABB has not reviewed this slide and expressly disclaims any liability arising from relying upon or using information contained herein. Please see the full disclaimer appearing on the Disclaimer slide of this presentation.
Treatment: KidneyHydration• Normal saline• Goal >100 mL urine/hr• If oliguric, consider addition of diuretics• If anuric, restrict after 1 liter
Treatment: KidneyDiuretics• Loop diuretics (Furosemide/Lasix)• Osmotic agents (Mannitol)• Additive, synergistic effects• Precautions – Not appropriate in all patients
Synergism with mannitol and furosemide Linear Dose-responsebetween urine production and dose/kg BW. Sirevella et al. Ann Thorac Surg. 2000
Furosemide (lasix) Loop diuretic • Acts at medullary portion of ascending limb of HenleAscending loop • Inhibits Na+, K+ readsorption of Henle • Increase osmosis, H20 loss (medulla)
Furosemide Administration Adults • 20-40 mg IV over 1-2 min • Can be repeated 2 hrs,Monitor dose to effectK+, Na+, glucoseUric acid, hx gout • Do not exceed 1 gm/day Renal InsufficiencyDrug InteractionsACE Inhibitors • 2.5 < 4 mg/min IV infusionCardiac glycosidesAminoglycosides Pediatric (Edema doses)LithiumIndomethacin • 1 mg/kg/dose IV q 4-12 hrs Ref. DrugPoints
Mannitol• Non-metabolized sugar• Excreted by kidney• Is not readsorbed• Osmotic loss of H2O• 50 gm Mannitol = 1 liter shift H20
Mannitol/Osmitrol AdministrationAdults• 200 mg/kg test dose over 3-5 min. or 50-100 gm as single dose• 30-50 ml urine (1-2 hrs)If no/little response• Second test dose• If no response, stop & re-evaluatePediatrics• 0.75 gm/kg over 3-5 min• If no response, stop
Contraindications Mannitol • Intracranial bleeding* • Pulmonary edema • Capillary leak syndromes • Heart failure* • Anuria • Increasing renal failure afterMonitorBlood pressure initiationRenal function • DehydrationFluid/electrolytes *Commonly used in cardiac surgery and neurosurgery
Intermittent Continuous Diuretics Infusion Solution: 1 gm furosemide per 500 ml 20% mannitol Rate: 0.3-0.4 ml/kg/hr Dopamine Rate: 0.2-0.3 mcg/kg/min Siverella et al. Ann Thorac Surg 2000; 69:501Prophylactic infusion of mannitol, furosemide and dopamine (Group B) significantly decreased the need for post- operative dialysis due to TCV surgery and pigment nephropathy (Hgb, myoglobin).
Treatment: DIC• Consider Heparin*• Blood product support for bleeding• Hematology consult*If bleeding despite factor replacement
Heparin binds Antithrombin III (ATIII) & IIa (thrombin) Induces change enzyme conformation ATIII Increases ATIII inhibitory activity 15-19 fold Heparin ATIII ATIII IIa Inhibition IIa binding XIIATIII is broad serine Tissue Damage XIIa Intrinsic System (aPTT) XIProtease inhibitor Extrinsic System (PT) XIa IXInhibitor of multiple Tissue Factor IXacoagulation factors VIIa X VIIIa VIIIin the extrinsic and Xaextrinsic pathways Va II IIa Fibrinogen Fibrin
Heparin Contraindications: • Cerebral hemorrhageLoading dose • Recent neurosurgery• 5000 units IV • Recent eye surgery • Recent organ biopsyContinuous drip • Major arterial injury• 500-1000 units/hr • Hx heparin-associated – Thrombosis (HITT) – ThrombocytopeniaMonitor • Allergic hypersensitivity• PTT > 1.5x nl range to heparin
Heparin Treatment of Intravascular CoagulationAccompanying Hemolytic Transfusion Reactions. Rock RC, Bove JR, Nemerson Y. Transfusion 1969 DIC following transfusion of 260 mls Group A blood to a Group O patient, treated with heparin Rise in fibrinogen after giving heparin
Heparin Treatment of Intravascular CoagulationAccompanying Hemolytic Transfusion Reactions. Rock RC, Bove JR, Nemerson Y. Transfusion 1969 DIC following transfusion of 2 units Fya incompatible blood, treated with heparin.
Summary• The importance of prompt recognition and reporting of suspected Transfusion Reactions cannot be over-emphasized.• Assess reactions quickly and efficiently to rule out the most serious causes first• Communicate results with responsible physicians so appropriate actions can be taken without unnecessary delay
Dr. Raúl H. Morales Borges Hematology/Oncology• American Red Cross • Ashford Medical Center – Biomedical Services – Suite # 107 – PR Medical Center – Condado, San Juan – Tel. 787-759-8100 – Tel. 787-722-0412 – Ext. 3873 – Fax 787-723-0554 – Dir. 787-993-3873 – Cel. 787-354-0758 – Cel. 787-505-5814 – email@example.com – Raul.Morales@redcross.org – ww.ihoapr.com