Blood Transfusion Reactions Revisited

Edwin V. Rodriguez, MD
Pediatrician Pediatric Hematologist Diplomate, Philippine Pediatric Society Diplomate, Philippine Society of Hematology and Blood Transfusion Instructor IV, Departments of Pharmacology and Pediatrics UST Faculty of Medicine and Surgery

Blood is a perishable commodity for which there is NO ideal preservation.

Blood therefore must be used rationally. rationally.

Blood and blood components are similar to DRUGS.

Blood has both THERAPEUTIC INDICATIONS and ADVERSE EFFECTS.

Blood has THERAPEUTIC USES.

Blood can be used to TREAT anemia and clotting factor deficiencies.

Blood has unwanted adverse effects in the form of blood transfusion reactions.
Blood must then be used cautiously and consciously.

Blood transfusion must therefore be INDIVIDUALIZED.

Blood must be transfused on a casecaseto-case basis using the patient risktoriskbenefit ratio as a guide.

Transfusion
irreversible event that carries potential benefits and risks to the recipient intravenous administration of whole blood or components

Transfusion Reaction
any unfavorable transfusion-related event occurring in a patient during or after transfusion of blood components may be immune-mediated or non-immune mediated (mechanism/ pathophysiology) maybe acute or delayed (onset/ timing)

Blood Transfusion Reactions (BTRs)

occur within 24 hours after transfusion in 2% of cases may be life-threatening and even fatal require immediate recognition and management must be treated if indicated and prevented in transfusion practice

RISKS OF BLOOD TRANSFUSION

Risks of Immune-Mediated BTRs

NHFTR allergic IHTR DHTR fatal immediate BTR 1-2% 1-2% 1:6000 1:6000 1:100,000

BTR-Induced Morbidity and Mortality

acute hemolytic reaction delayed hemolytic reaction non-cardiogenic PE TA-GVHD and related donor 1:25,000 1:2500 1:1000 1:7000

TA-GVHD and unrelated donor 1:39,000

Transfusion Associated Deaths (TAD)

acute hemolysis (ABO incompatible blood component) acute pulmonary edema bacterial contamination delayed hemolytic reactions anaphylaxis external hemolysis acute hemolysis TA-GVHD

Differential Diagnoses of BTR

PNH AIHA G6PD malignant hyperthermia hemoglobinopathies RBC membrane defects

HEMOLYTIC TRANSFUSION REACTIONS

Hemolytic Transfusion Reactions (HTRs)

donor RBC infused is incompatible with an antibody pre-existing in the recipient resulting in intravascular destruction of RBC may lead to hypotension, shock, consumptive coagulopathy and acute renal failure

IMMEDIATE OR ACUTE HEMOLYTIC TRANSFUSION REACTIONS

Acute Hemolytic Transfusion Reactions (AHTRs)

rapid destruction of blood cells immediately after or within 24 hours of a transfusion commonly associated with whole blood transfusion mortality is high and depends on the amount of blood infused

Acute Hemolytic Transfusion Reactions (AHTRs)

Pathophysiology of AHTRs: transfusion of whole blood or RBC that are immunologically incompatible with antibodies pre-existing with the recipient commonly involve antibodies to A, Kell, Jk(a), Fy(a) ABO incompatibility accounts for 74% of all fatal reactions

Acute Hemolytic Transfusion Reactions (AHTRs)

Incompatible RBC infused binding of antibody to the surface of transfused cells by complement activation - intravascular hemolysis - release of hemoglobin, RBC stroma and enzymes Hemolysis primarily intravascular but extravascular component possible - antibody and complement coating of RBC - ingestion of mononuclear phagocytes of the RES

Acute Hemolytic Transfusion Reactions (AHTRs) Interplay of biochemical mediators:

anaphylatoxins: C3a, C5a histamine and serotonin kallikrein cytokines: TNF-alpha, IL-1, IL-8, MCP PF3 pro-coagulant and pro-inflammatory molecules

Acute Hemolytic Transfusion Reactions (AHTRs) Signs and symptoms of AHTRs:

Factors affecting clinical manifestations
antigen involved quantity of RBC infused titer of antibody thermal range of antibody activity

Acute Hemolytic Transfusion Reactions (AHTRs)

Signs and symptoms of AHTRs:
fever chills/ rigors anxiety and feeling of dread nausea and vomiting diarrhea pallor icterus chest pain hypotension flushing

Acute Hemolytic Transfusion Reactions (AHTRs)

Signs and symptoms of AHTRs:
diffuse bleeding hemoglobinuria, hemoglobinemia jaundice oliguria or anuria pain in the abdomen, flanks, back, head, infusion site shock (severe cases) pallor dyspnea

Acute Hemolytic Transfusion Reactions (AHTRs) Signs and symptoms of AHTRs:

Atypical presentation
anesthesized: changes in blood pressure, diffuse bleeding, hemoglobinuria, chills and rigors are NOT seen with paralysis

Acute Hemolytic Transfusion Reactions (AHTRs) Major complications of immune-mediated hemolysis:

hypotension vasoconstriction and renal ischemia activation of platelets and coagulation cascade resulting in DIC

Acute Hemolytic Transfusion Reactions (AHTRs)

Differential Diagnosis of AHTRs:
microbial contamination physical, chemical and drug-related damage to stored RBC AIHA: development of minor blood group antigens congenital hemolytic anemias microangiopathic hemolytic anemia PNH infections

Acute Hemolytic Transfusion Reactions (AHTRs) Prevention and Management of AHTRs:

Avoid blood transfusion. Define clear-cut indications for blood transfusion. Consider blood substitutes. Use autologous blood if feasible. Use a sensitive antibody screening tests. Avoid, trace, correct clerical errors. Implement strict quality assurance programs

DELAYED HEMOLYTIC TRANSFUSION REACTIONS

Delayed Hemolytic Transfusion Reactions (DHTRs)

occurs 3-10 days classically associated with previous immunization with transfusion or pregnancy but in whom the antibody was not detected in pretransfusion testing with generally milder clinical manifestations present with fever, unexplained anemia, jaundice, hemoglobinuria common with antibodies to Kidd and Rh antigens

Delayed Hemolytic Transfusion Reactions (DHTRs) previously called delayed blood transfusion incompatibility reaction common features of DHTRs:
previous alloimmunization due to previous pregnancies or transfusions low titer of reactivity allows antibody to be undetected or missed in pre-transfusion antibody screening or compatibility testing occurs 3-10 days after blood transfusion antibody undetected in previous pre-transfusion screening is readily identified in the post-transfusion sample

Delayed Hemolytic Transfusion Reactions (DHTRs) Prevention of DHTRs

Apply extensive phenotyping. Perform prophylactic antigen matching of donor RBC with recipients complete phenotype. Use artificial blood substitutes. Use more sensitive antibody screening tests.

IMMEDIATE NON-HEMOLYTIC NONTRANSFUSION REACTIONS

Febrile Non-Hemolytic Transfusion Reactions (FNHTRs)

temperature rise of at least 1C occurring with or without chills in association with transfusion or shortly thereafter (up to 4 hours) that is not attributable to other causes including hemolysis or underlying disease recurrence rate: 15% incidence: 0-5-1.4%

Febrile Non-Hemolytic Transfusion Reactions (FNHTRs) Pathophysiology of FNTHRs:

Donor white cells- donor cytokines - recipient antibodies and/ or cytokines - FNTHRs Donor white cells -- recipient antibodies/ and or cytokines -FNTHRs Donor white cells - FNHTRs Donor cytokines- recipient antibodies and/or cytokines FNHTRs Other donor biologic response modifiers- recipient antibodies and/or cytokines -- FNHTRs

Febrile Non-Hemolytic Transfusion Reactions (FNHTRs) Diagnosis of FNHTRs:

Clinical manifestations: newly developed fever, chills or both in a recipient during or shortly after transfusion Presence of fever in a recipient during transfusion warrants DISCONTINUATION of the transfusion. To avoid confusion, it is recommended that blood transfusion be done during an AFEBRILE period. Transfusion reaction evaluation should be initiated for temperature elevation greater than 1C during blood transfusion.

Febrile Non-Hemolytic Transfusion Reactions (FNHTRs)

Differential Diagnosis of FNHTRs:

HTRs Reactions to bacterially contaminated blood products Fever only temporally related to transfusion in addition to FNHTRs

Febrile Non-Hemolytic Transfusion Reactions (FNHTRs) Treatment of FNHTRs:

Immediate discontinuation of blood transfusion IV line should be maintained Formal transfusion reaction report should be initiated Pharmacologic antidotes: anti-pyretics, antihistaminics, steroids Clinical manifestations resolve with or without treatment and do not typically lead to additional or long-term adverse sequelae.

Febrile Non-Hemolytic Transfusion Reactions (FNHTRs)

Prevention/ Recurrence of FNHTRs:

pre-transfusion administration of antidotes
documented BTR, warrants pre-transfusion medications 30 minutes before blood transfusion

use leukocyte-depleted blood

removal of buffy coat sedimentation red cell washing

use of micro-aggregate filtration (leukoreduction)

Allergic and Anaphylactic Reactions

Types of allergic and anaphylactic reactions:
Uncomplicated allergic reactions consisting of localized or diffuse urticaria (IgE-mediated) Anaphylactic allergic reactions (IgE-mediated)
High potential for adverse events and outcomes including death Require immediate recognition and intervention Avoidance of all plasma-containing products

Anaphylactoid allergic reactions (non-IgE mediated)

Allergic and Anaphylactic Reactions

Diagnosis: Nephelometry for IgA detection Treatment:
Discontinuation of transfusion Antidotes: anti-histaminics, epinephrine

Prevention:
Avoidance of plasma-containing blood products Use immunodiffusion screening methods Use confirmatory passive hemagglutination assays Modification of transfused blood products (washing, autologous, freezing with deglycerolization)

Transfusion-Associated Lung Injury (TRALI)

occurs during or within 4 hours of transfusion also called non-cardiogenic pulmonary edema, pulmonary HPS reaction, allergic pulmonary edema; consists of symptoms of adult respiratory distress (ARDS) manifested radiographically by the presence of bilateral pulmonary infiltrates clinical manifestations: chills, fever, tachypnea, cough, tachychardia

Transfusion-Associated Lung Injury (TRALI)

Pathophysiology of TRALI: due to donor antibodies directed against WBC antigens donor profile: multiparous females, donors with multiple exposure to various HLA types involves antibodies directed toward NA2, NB2 and anti-5b (granulocytic antigens) antigen-antibody interaction leads to agglutinins trapped within the pulmonary circulation with resultant release of toxic substances and pulmonary edema

Transfusion-Associated Lung Injury (TRALI)

Treatment and Prevention of TRALI: Supportive care is advised. Endotracheal intubation may be needed. Resolution occurs in 81% of cases and happens usually within 3-5 days from onset. TRALI does not usually recur in the same patient when the reaction is due to recipient antibodies. TRALI is a donor-specific phenomenon.

Transfusion Associated Circulatory Overload (TACO)

incidence: 1 in 100 transfusions often unrecognized or mistaken with TRALI clinical manifestations: dyspnea, hypertension, tachychardia, cough, chest tightness, cyanosis iatrogenic transfusion reaction

Transfusion Associated Circulatory Overload (TACO)

Pathophysiology: Intravascular volume may be overtaxed by either an inappropriate rate of transfusion or an inappropriate volume of transfusion in addition to other infused substances - high CVP - LV failure - pulmonary congestion and edema

Transfusion Associated Circulatory Overload (TACO)

CXR: cardiomegaly, prominent pulmonary arteries and septal lines, diffuse clouding of both lung fields Timing:
immediate during blood transfusion delayed after 24 hours from blood transfusion

Patients with CHF or pulmonary disease are predisposed to these types of reactions.

Transfusion Associated Circulatory Overload (TACO) Treatment of TACO: Cessation or reduction of the rate or blood products. Use of diuretics Supportive therapy

Transfusion Associated Circulatory Overload (TACO) Prevention and Recurrence of Circulatory Overload:
Vigilant assessment and recording of fluid input and output Slowed infusion rates Diuretics Identification of high risk groups

Bacterial Contamination
Presentation and Prevalence: PRBC extremely severe transfusion reactions high mortality: 70% clinical manifestations: fever >38.5C, chills, hypotension begin during the transfusion, nausea, vomiting, dyspnea, diarrhea

Bacterial Contamination
Presentation and Prevalence: PRBC microbial contaminants: gram negative microbes (Yersinia enterocoliticaendotoxin)

Bacterial Contamination
Presentation and Prevalence: PRBC prediposing factor: PRBC stored >21 days which carried a high bacterial and endotoxin load pathophysiology: infusion of endotoxin followed by massive release of recipient cytokines (TNF-alpha) (TNF-

Bacterial Contamination
Presentation and Prevalence: PLATELET CONCENTRATES clinical manifestation: fever, chills, hypotension beginning during or shortly after transfusion mortality rate: 25% predisposing factor: platelet concentrates >3 days old

Bacterial Contamination
Presentation and Prevalence:
FFP AND CRYOPRECIPITATE clinical manifestations: wound infections, endocarditis, septicemia with unusual organisms several days after transfusion

Bacterial Contamination
Microorganisms Implicated
PRBC
Yersinia enterocolitica Enterobacter specie Pseudomonas putida, fluorescens

Platelet Concentrates
CONS

FFP and Cryoprecipitate

Pseudomonas cepacia, aeruginosa Borrelia burgdorferi

Bacterial Contamination
Mechanisms of Contamination: Donor bacteremia
Patients with gastroenteritis (Yersinia, Campylobacter) Patients with URI (Strep pyogenes) Patients with septicemia (Staph aureus) Patients with Lyme disease (Borrelia)

Bacterial Contamination
Mechanisms of Contamination: Donor bacteremia
Chronic low grade infection Toe ulceration (Serratia) Osteomyelitis (Salmonella) After dental or medical procedure (Staph aureus) Syphilis (Treponema)

Bacterial Contamination
Blood Collection
Inadequate skin disinfection (Staph epidermidis, aureus, diphteroids) Scarred phlebotomy site (enterococci, Staph) Contaminated vacuum tubes (Serratia) Contaminated apheresis solutions (Enterobacter)

Bacterial Contamination
Blood processing
Contamination during thawing (Pseudomonas)

Container damage or defect

Leaky seals (Serratia) Cracked vials (Enterobacter)

Blood bag manufacture

Contaminated bag exterior (Serratia) Contamination during manufacture and/ or fractionation (Pseudomonas)

Bacterial Contamination
Prevention of Transfusion-Associated TransfusionBacterial Sepsis:
Extensive donor screening Improved donor skin disinfection Removal of first aliquot of donor blood Limitation of component storage time Pre-transfusion detection

Bacterial Contamination
Altered blood processing
Leukocyte reduction Reduced holding temperature and time prior to component preparation Component storage temperature Waterbath disinfection

Chemical or photochemical decontamination

psoralens

Physically or Chemically Induced Transfusion Reactions (PCITRs)

heterogenous group of conditions including: physical RBC damage depletion and dilution of coagulation factors and platelets hypothermia citrate toxicity hypokalemia / hyperkalemia

Physically or Chemically Induced Transfusion Reactions (PCITRs)

Physical Damage to RBCs
intravascular lysis due to hypertonic or hypotonic
solutions heat damage from blood warmers, during shipping, in hot rooms freeze damage in absence of cryoprotective agent during shipping

Physically or Chemically Induced Transfusion Reactions (PCITRs)

Mechanical Damage
blood pumps, roller pumps
infusion under pressure through small bore needles

Physically or Chemically Induced Transfusion Reactions (PCITRs)

Patients with Intrinsic Abnormal Cells
congenital hemolytic anemias sickle cell crisis PNH or AIHA

Physically or Chemically Induced Transfusion Reactions (PCITRs)

Clinical manifestations: non-specific non facial/ generalized numbness, chills, muscle
twitching, perioral tingling, altered respiration. anxiety

Laboratory tests:
electrolyte levels, serum ionized calcium, blood pH,
blood glucose, urinalysis, hemoglobin, hematocrit, PLT count, PT, aPTT

Physically or Chemically Induced Transfusion Reactions (PCITRs)

Treatment of PCITRs:
correction of underlying cause preventive measures

Physically or Chemically Induced Transfusion Reactions (PCITRs)

Citrate toxicity

ACD/ CPD has 1.4-1.6 g of citrate - no toxicity 1.4 citrate > 100 mg/ dl - citrate toxicity Causes ADULTS rate of BT > 1 liter/ 10 min or BT volume exceeds 6 L administered in < 2 hours CHILDREN exchange transfusion - hypocalcemia

Physically or Chemically Induced Transfusion Reactions (PCITRs)

Clinical manifestations:
involuntary muscle tremors, cardiac arrhythmia,
ventricular fibrillation

ECG findings:
ST prolongation
T wave delay

Physically or Chemically Induced Transfusion Reactions (PCITRs)

Potassium toxicity:
Mechanism: high potassium load with prolonged
blood storage - hyperkalemia Clinical manifestations: cardiac excitability - cardiac standstill ECG findings: peak T waves Laboratory findings: hyperkalemia Management: calcium gluconate

DELAYED NON-HEMOLYTIC NONTRANSFUSION REACTIONS

Post-Transfusion Purpura (PTP)

Consists of profound thrombocytopenia occurring 1-2 weeks after transfusion Pathophysiology: Effect of antibody directed against donor platelet antigens that the recipient lacks Commonly associated with human platelet-specific alloantigen 1a (HPA-1a)

Post-Transfusion Purpura (PTP)

Pathophysiology: Causes destruction of both autologous platelets as well as donor platelets (innocent bystander effect)
Nonspecific antibody adherence Soluble proteins taken up by recipient platelets against which an antibody has been formed Immune complex deposition on platelet surfaces with resultant recipient platelet destruction

Post-Transfusion Purpura (PTP)

Treatment and Prevention of PTP:
IVIG plasmapheresis steroids avoidance of antigen-positive platelet transfusion with previous PTP

Post-Transfusion Purpura (PTP)

If PTP does not lead to death due to hemorrhage, it is a SELF-LIMITED disease with recovery within 4-5 days of therapy. Recovery may be hastened by the use of antigen-negative platelets if the specificity of the antibody has been determined and antigennegative platelets are available.

Transfusion Associated Graft versus Host Disease (TA-GVHD)

disorder marked by attack and destruction of recipient cells by engrafted immune cells remains a serious and common complication in transplantation

Transfusion Associated Graft versus Host Disease (TA-GVHD)

Criteria for diagnosis:
presence of immunocompetent cells in the graft capable of reacting against the recipient major histocompatibility differences between donor and recipient inappropiate recognition of self-antigens (autoimmunity) inability of the recipient to reject donor cells

Transfusion Associated Graft versus Host Disease (TA-GVHD)

Pathophysiology of GVHD: Immunocompetent donor lymphocytes that are not cleared because of a compromised host immune system go on to proliferate in the recipient --- attack and destruction of host tissues in target organs (liver, intestines, skin, lungs)

Transfusion Associated Graft versus Host Disease (TA-GVHD)

Pathophysiology of GVHD: One-Way HLA Match --- donor cells are homozygous for an HLA type + recipient cells which are heterozygous for the same HLA type --- recipient immune cells do not recognize the donor cells as foreign and fail to mount an immune response that would normally clear donor cells - donor cells respond to the mismatched haplotype - GVH reaction

Transfusion Associated Graft versus Host Disease (TA-GVHD)

Pathophysiology of GVHD: Role of dysregulated cell activation and cytokine release Upregulating effects: T-helper 1 cytokines - IL-2, gamma interferon, pro-inflammatory cytokines IL-1 and TNF-alpha Downregulating effects: T-helper 2 cytokines-- IL-4, IL-10

Transfusion Associated Graft versus Host Disease (TA-GVHD)

Clinical Manifestations of GVHD: onset: 7-10 days from transfusion fever reddish, raised rash spreading from trunk or face to extremities - bullous lesions -erythroderma hepatitis watery diarrhea (profuse) non-specific signs: anorexia, nausea and vomiting

Transfusion Associated Graft versus Host Disease (TA-GVHD)

Pancytopenia is the usual cause of death due to hemorrhage and overwhelming infection. Death occurs within 1-3 weeks after transfusion. Diagnosis of GVHD:
Identification of donor-derived lymphocytes in the circulation or tissues of the affected host. (PCR amplification strategy)

Transfusion Associated Graft versus Host Disease (TA-GVHD)

Treatment of GVHD:
Immunosuppressive therapy Patient Groups at RISK for developing transfusionassociated GVHD:
Selected immunodeficiency (congenital, HD, CLL on fludarabine) Newborns with erythroblastosis foetalis Recipients of intrauterine transfusions Recipients of hematopoietic stem cell transplants Recipients of blood products donated by relatives Recipients of HLA selected (matched) platelets or platelets known to be homozygous

Transfusion Associated Graft versus Host Disease (TA-GVHD)

Prevention of GVHD:
Gamma irradiation of blood components containing viable lymphocytes is 100% effective in preventing GVHD.
Prevention of lymphocyte proliferation through DNA crosslinkage. Uses 25 cGy to the midplane of the blood container with a minimum of 15 cGy to any point of the irradiated field Adverse effects: moderate decrease in survival of RBC and leakage of potassium from intracellular stores

Iron Overload
common in patients with chronic diseases requiring multiple and prolonged transfusions (thalassemia) on the average, 1 unit PRBC = 200 mg iron also transfusion hemosiderosis chronic iron overload leads to hepatic, cardiac and pancreatic disease. prevention: iron chelation therapy (desferoxamine)

Alloimmunization
results from prior exposure to donor blood components AE: difficulty in finding compatible RBC units because of the presence of clinically significant RBC antibodies, transfusion reactions or platelet refractoriness

Alloimmunization
Pathophysiology:
after first exposure to donor antigen recipient memory lymphocytes are invoked -moderate production of IgG and IgM on second exposure to donor antigen -rapid and large production of IgG within the first 2 days

Alloimmunization
Clinical manifestations:
mild to severe

Laboratory tests:
antibody screening

Alloimmunization
Treatment of Alloimmunization:
Accurate matching of donor and recipient RBC phenotypes

Immunosuppression
generalized non-specific effect diminishing the activity of the recipients immune system soon after blood transfusion pathophysiology: unknown rapid uptake of blood component cellular matter into the RES

Immunosuppression
clinical manifestations: non-specific blood component transfusion may increase risk of suppressive effect on the recipient treatment of immunosuppression: non-specific prevention risk-benefit ratio evaluated

IMMEDIATE BTR PROCEDURES AT BEDSIDE

Bedside BTR Procedures

1. STOP blood transfusion at once! 2. Keep IV line open with isotonic solution. 3. Seek medical attention. 4. Monitor clinical condition of patient. 5. Perform bedside clerical checks. 6. Return unit, set and attached solution to BB. 7. Collect appropriate blood specimens for evaluation. 8. Document BTR.

SAFETY DURING BLOOD TRANSFUSION

Safety During Blood Transfusion

Flow rates
Infuse the first 25 mL of blood (smaller volume for pediatric
patients) slowly at no more than 25 drops/ minute to allow for recognition of an acute adverse reaction. Remainder can be infused at 60-80 drops/ minute. Complete transfusion within 2 hours unless the patient can tolerate only gradual expansion of the intravascular volume. Transfusion should not exceed 4 hours. Platelets, plasma and cryoprecipitate are generally transfused at 10 mL/ min

Safety in Blood Transfusion

During the blood transfusion: Document patients vital signs.
Check for urticaria. During the infusion, VS should be documented after the 1st 15 and 30 minutes and hourly until 1 hour after completion of transfusion. Any transfusion that stops or slows the transfusion should be investigated.

Safety in Blood Transfusion

Measures to enhance blood flow:
elevate IV pole
change filter and tubing reposition patients arm change to a larger gauge needle

Safety in Blood Transfusion

Medications:
Do not add medications directly to a unit of blood during transfusion Medications by IV push:
stop transfusion clear the line at the medical injection site with 5-10 mL NSS administer the medication re-flush the line with NSS and re-start transfusion

SAFETY IS THE BEST POLICY.