TRANSFUSION

REACTIONS
DR. Abhineet
Dept. of Transfusion Medicine and Immunohematology
INTRODUCTION

 Transfusion reactions are defined as adverse events associated with the transfusion of
whole blood or one of its components.
 An adverse event is an unintended and deleterious occurrence associated with blood
component transfusion.
 It may occur before, during, or after a transfusion.
 Adverse events include incidents and adverse reactions.
 An incident is any error that could affect the quality or effectiveness of a blood product
or could have led to an adverse reaction to a transfusion recipient.
 An adverse reaction is a harmful effect observed in a transfusion recipient that is
temporally associated with a blood component transfusion
 INCIDENCE OF TRANSFUSION REACTION

Rates of Adverse Transfusion Reactions Reported to Haemovigilance Programme of

India from May 2016 to December 2017
Non-infectious Transfusion Reactions
Alloimmunization to RBC Antigens
 Alloimmunization is the development of non-ABO anti -bodies following RBC
transfusion, pregnancy, or transplantation.
 Increase the risk of acute and delayed haemolytic transfusion reactions.
 The incidence of alloimmunization varies markedly according to clinical setting studied
and condition of the patient.

 Incidence of alloimmunization:
• Healthy blood donors have an less than 0.3%,
• Unselected hospitalized patients who have had type and screen testing - 1% to 3%.
• Post-transfusion alloimmunization rate in surgery patients - 3%
• Chronically transfused patients with sickle cell disease, myelodysplastic syndrome,
thalassemia, or autoimmune haemolytic disease ->30%
 D antigen causes significant immunological response to RBC protein antigen.
 85% of healthy D-negative persons exposed to the D antigen will develop anti-D.
 Exposure to other antigens causes much lower sensitization
• anti-E in about 7%,
• anti-c in in about 3%.
• anti-K develops in about 10% of K-negative–exposed individuals
 Exposure to other minor blood group antigens produce alloimmunization <3% of
antigen-negative person
 The risk of an individual patient developing a non-ABO alloantibody depends upon
many factors:
• Underlying diseases condition
• Cause of anemia
• Total number of transfusions,
• Immunogenicity of the non-self RBC antigens to which the patient is exposed.
 RESPONDERS – individuals who are more susceptible than others to developing RBC
alloantibodies.
 Represent the majority of patients identified with alloantibodies.
 HYPER-RESPONDERS – 1/3rd of patients who are alloimmunized develop more than one
alloantibody.
Haemolytic Transfusion Reaction (HTR)

 Acute haemolytic transfusion reaction (AHTR)

 Delayed haemolytic transfusion reaction(DHTR)
Pathophysiology of HTR

 HTR is a systemic inflammatory response to antibody-mediated hemolysis.

 RBC alloantibodies mediate RBC destruction through activating the complement
cascade or through the Fc receptor (FcR)-mediated phagocytosis by macrophages, in
the spleen or liver.
 AHTRs and IgM alloantibodies are associated with intravascular hemolysis through
the complement activation pathway.
 DHTRs and IgG alloantibodies are associated with extravascular hemolysis through
the FcR pathway.
 After intravascular hemolysis, haptoglobin rapidly binds free hemoglobin.
 Haptoglobin-hemoglobin complexes are bound to CD163 on monocytes and
macrophages- initiates receptor-mediated uptake and intracellular degradation of
hemoglobin.
 Free hemoglobin is observed as visibly pink to red plasma (hemoglobinemia) , and as
brown to red discoloration of the urine (hemoglobinuria).
 Free hemoglobin causes multiple effects on circulating cells and endothelial cells that
trigger inflammatory response.
 Inflammatory response to hemolysis drives the clinical features of an HTR
Acute Hemolytic Transfusion Reaction (AHTR)

 Accelerated destruction of transfused RBCs due to antibody-mediated incompatibility.

 Alloantibodies in the recipient’s plasma bind to the corresponding antigen on the
transfused cells, which mediate hemolysis and removal from the circulation.
 Combination of signs and symptoms associated with hemolysis, biochemical evidence
of hemolysis, and serologic evidence of RBC incompatibility occurring during or
within 24 hours after transfusion.
 Majority of AHTRs is due to RBC transfusion, can also occur with incompatible
plasma-containing products.
 Severity of an AHTR is related to the amount of incompatible blood transfused.
Signs and symptoms

 Fever - most common symptom in AHTR, occurs with chills or rigors.

 Pain- flanks, lower back, abdomen, or infusion site.
 Hypotension - 10% of AHTR’s. Shock in small subset.
 Acute kidney injury - detected biochemically- elevated blood urea nitrogen (BUN) and
creatinine, decreased or absent urine output.
 Shock and disseminated intravascular coagulation (DIC) are the main causes of renal
dysfunction after haemolysis.
 Coagulation testing – aPTT , (PT), thrombin time, D-dimer, fibrinogen, and platelet
count are essential for diagnosis and management
Delayed Hemolytic and Serologic Transfusion
Reaction (DHTR)/ (DSTR)

 DHTR - positive DAT 24 hours to 28 days after transfusion with either a positive
eluate or a newly identified alloantibody in the plasma or serum and evidence of
haemolysis.
 Evidence of hemolysis:
• Inadequate rise in hemoglobin after transfusion
• Rapid drop in hemoglobin to the pretransfusion level
• Appearance of spherocytes on peripheral blood smear examination,
• Biochemical evidence of hemolysis.
 Most cases of DHTR appear 7–10 days post-transfusion
 Delayed serologic transfusion reaction (DSTR) is defined as the same serological
findings as DHTR but without evidence of haemolysis.
Management

 Stop transfusion immediately.

 Mannitol – to prevent renal failure
 Hypotension- IV fluids and vasoactive drugs eg. Dopamine
Transfusion-Related Acute Lung Injury
(TRALI)
 Aka non cardiac pulmonary edema.
 No diagnostic test for TRALI
 Diagnosis of TRALI is made according to clinical criteria that support the diagnosis
and, exclusion of other possible causes of acute lung injury (ALI).
 The NHSN Hemovigilance definition includes
(1) the absence of acute lung injury (ALI) prior to transfusion,
(2) ALI during or within 6 hours after transfusion,
(3) evidence of hypoxemia by blood gas or oxygen saturation testing
(4) radiographic evidence of bilateral pulmonary edema
(5) exclusion of circulatory overload and other causes of pulmonary edema
 “Possible TRALI” when the above criteria are present but another cause of ALI is also
identified.

 “Delayed TRALI” refers to when criteria for TRALI are present but the onset is 6–72
hours after transfusion

 Incidence of TRALI is difficult to precisely determine and ranges between 0.08% and
15% of patients receiving blood transfusion.
Signs and Symptoms

 Acute respiratory distress, including dyspnea, tachypnea, and hypoxemia.

 Fever
 Rigors
 Tachycardia
 Hypothermia
 Hypotension.
 Transient leukopenia and thrombocytopenia can be present in about 25% of patients.
Pathology

 Antibody mediated TRALI

 Non-antibody mediated TRALI

 “TWO HIT” or threshold model for the pathogenesis of TRALI.

Antibody mediated TRALI

 Anti- HLA class I and anti-neutrophil antigen (anti-HNA) alloantibodies from passive
transfusion of these antibodies from donors.
 Neutrophil activation via direct binding of anti-HNA antibodies or through indirect
binding of anti-HLA antibodies to endothelial cells and monocytes – neutrophil
activation.
 Antibodies to HNA-1, HNA-2, and HNA-3a are associated with the most severe/ fatal,
TRALI reactions.
 Antibodies to recipient HLA or HNA antigens must be detected in implicated donors in
the evaluation of TRALI cases to confirm the diagnosis of antibody-mediated TRALI.
 This testing is also useful to identify donors who pose a risk for TRALI to patients.
Non-antibody mediated TRALI

 Proinflammatory mediators accumulate in the blood product released by RBCs and

platelets during storage or as a result of erythrocyte and platelet aging.
 Activate endothelial cells in the pulmonary microcirculation that induce neutrophil
activation, capillary leakage, and pulmonary edema.
 Mediators – bioactive lipids derived from cell membranes and soluble
CD40(proinflammatory mediator produced by platelets)
 Platelet–neutrophil interactions.
 Microparticles, morphological and biochemical changes that increase adhesion of
RBCs and platelets to endothelial cells.
 Loss of Duffy antigen for chemokines on RBCs during storage may increase cytokine
availability for neutrophils
TWO-HIT hypothesis

 Neither all blood products nor all patients have an equal risk for TRALI
 The majority of blood products that contain anti-WBC antibodies do not cause TRALI,
even in patients with related antigens

 First hit involves Neutrophil attraction to the pulmonary alveolar capillary network.

 Second hit involves Neutrophil activation- cascade of proinflammatory events

culminating in pulmonary capillary damage and the development ofpulmonary edema
Management

 Oxygen therapy
 IV steroids
 Intubation
 Leukocyte reduced components use.
Transfusion-Associated Circulatory Overload
(TACO)

 TACO is an adverse reaction characterized by acute respiratory distress from

pulmonary edema caused by increased intravascular volume due to excessive
transfused fluid and/or too rapid of an infusion rate and

 The inability of the patient to accommodate the volume of transfused products due to
impaired pulmonary, cardiac, or renal function.

 TACO is the second most common cause of transfusion related deaths reported to the
FDA.
 Measurement of brain natriuretic peptide (BNP) NT-proBNP, may be helpful in the
diagnosis,
 Value of 1.5 times greater than the pretransfusion level supports diagnosis.
 Serial BNP level determinations following post transfusion pulmonary complications
for the assessment of TACO is recommended.
Management

 Stop the transfusion

 Place patient in a more upright posture,
 Administer supplemental oxygen,
 Stop infusion of other intravenous fluids,
 Administer diuretic medications
Transfusion-Associated Dyspnea (TAD)

 TAD is diagnosed when dyspnea occurs within 24 hours after transfusion and all other
diagnoses are excluded.
 Seen in allergic reactions, TACO, or TRALI, or could be related to the patient’s
underlying condition.
 Pathophysiology unknown
 Diagnosis should almost always be made with a qualification as “possible” or
“probable.”
 Associated most commonly with mild TACO
Hypotensive Transfusion Reaction

 Diagnosed when hypotension is seen alone during or within 1 hour after thetransfusion
is finished.
 Hypotension is defined by NHSN criteria
• In adults as a drop in the systolic BP of >30 mm Hg and systolic BP <80 mm Hg.
• In children,- 25% drop in the baseline systolic BP
 Increased bradykinin levels in stored blood products are hypothesized to be responsible
for the pathophysiology of these reactions
Febrile Nonhemolytic Transfusion Reaction
(FNHTR)

 One of the most common adverse transfusion reactions.

 FNHTR is defined as fever greater than 100.4°F (38°C) or a change of at least 1.8°F
(1.0°C) from the pretransfusion level occurring during or within 4 hours after the end of
the transfusion or chills and/or rigors are present.
 The frequency of FNHTR in the general hospital population is about 1 in 200 units
transfused.
 The incidence much higher in hematology/oncology patients and chronic transfusion
patients, eg. sickle cell disease
Signs and symptoms

 Fever
 Chills and rigors
 Headache
 Mild dyspnea
 Mild nausea / vomiting
 The change in temperature is usually modest (less than 2°C/3.6°F), but when it is
greater than 2°C, transfusion-transmitted bacterial infection must be excluded by visual
inspection of the product for discoloration or clots and culture of the implicated product
Pathophysiology

 Recipient anti-WBC antibodies triggering release of proinflammatory cytokines.

 Laboratory studies of platelet products showed direct relationships between the number
of residual WBCs in platelets, levels of proinflammatory cytokines, and storage time.
 Accumulation of proinflammatory cytokines is the result of metabolically active
residual WBCs in the products
 Room temperature storage and agitation have been shown to affect cytokine levels in
platelet components.
Management

 Antipyretics
 Rule out AHTR’s, TRALI and Sepsis
 No role of IV steroid and antihistaminic drugs.
Allergic Transfusion Reactions (ATRs)

 ATRs are the most common reactions seen with platelet and plasma transfusions,
occurring in about 2% of transfused platelets, second to FNHTRs in RBC transfusions
 Allergic reactions - generally mild to moderate reactions and refer to signs and
symptoms limited to the skin and gastrointestinal tract
 Anaphylactoid reactions - moderately severe reactions that include oral and throat
symptoms, more severe GI symptoms, and respiratory complaints, profound
hypotension and shock.
 A definite diagnosis of ATR includes the appearance of signs and symptoms during or
within2 hours after the end of transfusion and the exclusion of other possible drug,
environmental, and dietary causes.
Signs and symptoms
Pathophysiology

 IgE-mediated type I hypersensitivity reactions

 IgG, direct complement activation, and platelet-derived factors.
 Plasma protein polymorphisms might explain some intermittent ATRs seen in
repeatedly transfused patients.
Transfusion-Associated Graft-Versus-Host
Disease

 Clinical syndrome developing from 2 days to 6 weeks after transfusion characterized

by the typical skin rash seen and other forms of GVHD, diarrhea, fever, enlarged liver,
elevated liver enzymes, marrow aplasia, and/or pancytopenia.

 A definite diagnosis is made by skin or (occasionally) liver, biopsy showing

characteristic histological features.

 A probable diagnosis of TA-GVHD is made when the clinical criteria are met but
biopsy is negative or was not performed
Signs and symptoms

 Rash- begins as a maculopapular rash that starts over the trunk and then spreads to the
limbs
 Fever
 Increased liver enzymes
 Pancytopenia
 Diarrhea
Pathophysiology

 Related to recipient immune status

 Component characteristics,
 Donor-recipient HLA relationships
 Risk factors for TA-GVHD - Male sex, Age >70 years, cardiovascular surgery, whole
blood, and fresh blood products.
 Although the recipient is immunocompetent, donor lymphocytes are not recognized as
sufficiently foreign to be eliminated because of shared HLA antigens.
 Donor immunologically competent CD8+ cytotoxic T lymphocytes are directed against
recipient cell surface HLA antigen and mediate cell destruction.
Management

 Immunosuppressive medications.
 Hematopoietic stem cell transplantation (not very successful)
 Irradiation of cellular blood components is successful in preventing TA-GVHD
Post-Transfusion Purpura

 Severe and sudden drop in the platelet count, usually occurring 5 to 10 days after
transfusion due to alloimmunization to platelet-specific antibodies from prior
transfusion or pregnancy.

 NHSN definition - Thrombocytopenia to less than 20% of the pretransfusion count and
demonstration of alloantibodies against platelet specific antigens are required for
diagnosis.

 The implicated alloantibodies are directed against human platelet antigens HPA-1 or
HPA-3a
Signs and symptoms

 Thrombocytopenia is usually severe platelet counts less than 10,000.

 Purpura (slightly raised dark red–purple patches on theskin),
 Bleeding from mucous membranes (such as from the gums or nose),
 GI bleeding
 Hematuria
Management

 IV IG- most patients respond within hours of first infusion

 Plasma exchange with FFP in patients not responding to IVIG
Adverse Metabolic Effects of Transfusion

 Sodium citrate is an anticoagulant that is a component of all RBC preservative

solutions.
 Citrate binds to calcium and magnesium to prevent activation of coagulation factors.
 Normally, citrate is rapidly metabolized in the liver following transfusion.
 Excessive amounts of citrate can enter the circulation in massive transfusion or in
patients with severe liver disease.
Management / Prevention

 Hyperkalemia can be prevented in large volume RBC transfusions to infants by issuing

“fresh” RBC units (less than 7–10 days old).
 Washed RBCs.
 Calcium supplementation.
Infectious Transfusion Reactions
Transfusion-Transmitted Bacterial Infections
(TTBI)

 The NHSN Hemovigilance definition of TTBI requires laboratory evidence of the

pathogen in the recipient and demonstration of the pathogen in at least one or more of
the following:
• the transfused component,
• the donor at the time of collection,
• an additional component prepared from the same donation, or an additional recipient of
a component from the same donation
 A definitive diagnosis of TTBI also requires that the recipient did not have evidence of
infection with the same pathogen prior to the transfusion.
 Bacterial contamination of platelets is much more frequent.
Signs and symptoms

 Fever
 Chills and rigors
 Hypotension
Prevention

 Improved skin disinfection and initial aliquot diversion can reduce skin organism
contamination.
 Pathogen-reduction technologies - INTERCEPT system (Cerus Corporation), a
photochemical treatment process using a psoralen derivative, has been approved by the
FDA for use in the United States for treatment of plasma and platelets.
Hemovigilance
References

 Modern Blood Banking & Transfusion Practices Seventh Edition Denise

Harmening, PhD, MT(ASCP).
 Google images.