Adverse Effects of Transfusion

Adverse Effects of Transfusion (Transfusion Reactions)

Associated Risks

• Immediate: Immune or non-immune reaction during a current transfusion.
• Delayed: Immune or non-immune reaction after the transfusion.

Transfusion Reactions

Immediate (Acute)

• Immunologic:
  • Hemolytic
  • Febrile
  • Allergic
  • Transfusion-Related Acute Lung Injury (TRALI)
• Non-Immunologic:
  • Bacterial Contamination
  • Transfusion-Associated Circulatory Overload (TACO)

Delayed

• Immunologic:
  • Hemolytic
  • Graft vs Host Disease (GVHD)
  • Cytomegalovirus (CMV)
• Non-Immunologic:
  • Iron Overload
  • Disease Transmission

Common Procedure for a Transfusion Reaction

1. Stop the transfusion.
2. Open the IV line for medication administration, if needed.
3. Monitor the patient.
4. Blood Bank performs Transfusion Reaction Investigation.
5. Blood/blood component (including IV set) returned to the Blood Bank, when indicated.

Immediate Transfusion Reactions

Acute Hemolytic Transfusion Reaction (AHTR)

• Signs & Symptoms:
  • Feeling of heat along the infusion arm
  • Anxiety / Apprehension / Immediate "Feeling of Doom"
  • Tachycardia / Dyspnea
  • Severe hypotension / Shock / Drastic drop in blood pressure
  • Hemolysis (Intravascular) / Hemoglobinemia / Disseminated Intravascular Coagulation (DIC)
  • Low Back Pain
  • Chest Pain
  • Hematuria (bloody urine)
  • Kidney Failure
  • Could cause death
• Common Cause:
  • ABO Incompatibility (as little as 5-20 mL of RBCs transfused)
  • Human Error (70% Causes):
    • Mis-identification of Patient
    • Staff Hurriedness and Wrong Patient Transfused
    • Patient Relocated and Wrong Patient Transfused
    • Mass Casualties and Poorly-Identified Patient
• Main symptoms:
  • Systemic: Chills, Fever
  • Vascular: Hypotension, Uncontrollable bleeding, Increased heart rate
  • Chest: Constricting pain
  • Transfused vein: Heat sensation
  • Lumbar region: Pain
  • Urinary: Hemoglobinuria, Hyperbilirubinemia
• Treatment:
  • Administer, when appropriate:
    • Diuretics
    • Analgesics
    • Pressors for hypotension
  • Infusion of hemostatic components, if bleeding
• Prevention:
  • Proper Identification of Patient / Ensure Positive Identification; Do NOT Use Room # as an Identifier
  • Mass Casualties - Triage Properly and Properly Identified Patient
  • Properly labeled specimen
  • ABO Match to Patient / Accurate Testing
  • Accurate labeling of unit to patient

Transfusion Fatality

• For FY 2021, incident is 1:2.4 million RBC transfusions & is the third leading cause of transfusion-related mortality in the USA
• Most common cause for Transfusion Fatality:
  • Wrong blood in tube (WBIT) - 1:1,303 - 2,262 samples; about 53% of WBIT errors result in violation of protocol
    • Always properly identify the patient using the attached wrist band or ask the question, "What is your name?". DO NOT ASK, "Are you John Doe?".
    • Always label the specimen tube at the patient's bedside.
  • Lack of electronic systems for patient identification
  • Failure to perform the final bedside check
  • Manual laboratory processes
• FDA CBER, Summary of Fatality Reports for FY 2021 AHTR, Ziman, A., 2023 Fall
• Lab Sem., UCLA, Oct. 21, 2023.Transfusion deaths (5) in 2021:
  1. "O" patient received 1 "B" RBCs - mix-up in sample
  2. "O" patient received 1 "A" RBCs - administration error caused by switched blood cooler
  3. "AB" patient received 1 "O" platelets - anti-A titer was 512
  4. "O" patient in critical condition received 3 "B" RBCs - BB error due to patient with similar name
  5. "A" patient in MTP situation received 1 B RBCs - "B" unit was tagged for a different patient

Febrile (Non-Hemolytic) Transfusion Reaction

• Signs & Symptoms:
  • Fever
  • Chills
  • Headache
  • Anxiety
  • Tachycardia
  • Fever (temp rise at least 1^{\circ} C or 1.8^{\circ} F)
  • "Fever-Chill" Reaction
  • Dyspnea
  • Flushing
  • Hypertension
• Common Cause:
  • WBCs Found in Blood / Blood Components
  • Platelets Found in Blood / Blood Components
• Treatment:
  • Antipyretic medication (Usually Tylenol)
• Prevention:
  • Transfuse Leuko-reduced Blood / Blood Components

Allergic Reaction

• Signs & Symptoms:
  • Urticaria / Sudden Rash Appearance
    • Neck Area
    • Arms
    • Chest / Back Area
  • Itching / Pruritis
  • Flushing
• Advanced Signs & Symptoms:
  • Dyspnea
  • Throat Swelling / Tongue Swelling
  • Hypotension
  • Cardiac Arrhythmia
• Mild allergic (urticarial, cutaneous) transfusion reactions
  • Very commonly reported reaction (1-3%)
  • Usually localized hives
  • Mechanism: Type 1 (IgE-mediated) hypersensitivity to transfused plasma proteins
  • Treatment options: Diphenhydramine
  • May restart transfusion after hives clear.
• Common Cause:
  • Something in the donor's blood that caused the recipient to react
  • Plasma proteins (IgA Deficiency - rare genetic condition) - very severe and is life threatening
• Treatment for a Mild Rxn:
  • Antihistamines, e.g., Benadryl
  • Slow down transfusion rate
• Treatment for a more Severe Rxn:
  • Diphenhydramines or epinephrine
• Treatment for Severe IgA Deficiency:
  • Usually the patient will have a medical history of being IgA deficient and precautions are taken when transfusion is indicated
  • Rare condition
• Prevention:
  • For patients with a history of allergic reactions, the patient is given antihistamine / Benadryl prior to transfusion.
  • Give IgA deficient blood / blood products; rare donor
  • In RBC products, additive solutions, e.g., Adsol® is used to replace residual plasma component.
  • In platelet products, InterSol®, a platelet additive solution, replaces the plasma component.

Transfusion-Related Acute Lung Injury (TRALI)

• Aka, TRALI
• The second leading cause of transfusion-related mortality in the USA in 2021
• Incidence - 1:5,000 transfusion
• Signs & Symptoms:
  • Occurs during or within 6 hrs following transfusion
  • Respiratory Distress / Severe Hypoxemia / ARDS (Acute Respiratory Distress Syndrome)
  • Dyspnea or Tachypnea
  • Hypotension
  • Pulmonary Edema
• Figure 1 - Pre-and post-transfusion X-rays of a patient with TRALI. Bilateral lung infiltrate with pulmonary edema is an essential criterion for the clinical diagnosis of TRALI. Radiographic discrepancies can be seen in the first hours after transfusion, with progression of the alveolar and interstitial infiltrate throughout the lung. Radiographic findings tend to be more specific than the results of physical examinations. TRALI: transfusion-related acute lung injury.
• Common Cause:
  • HLA antibodies found in blood / blood products - donors were usually from multiparous females
• Treatment:
  • O2 support
  • Mechanical Ventilatory Support / Intubation
  • Improvement seen within 48 hrs from treatment
• Prevention:
  • Blood products from males
  • Blood products from females tested for HLA Abs

Bacterial Contamination

• Sign & Symptoms:
  • Fever (can be a low-grade fever, i.e., only 1^{\circ} C rise)
  • Rigor (sudden feeling of chilliness)
  • Shivering
  • Hypotension / Shock
  • Tachycardia
  • Dyspnea
• Bacterial contamination reaction.
  • Although uncommon, but this type of specific reaction can have a rapid onset and high mortality in recipients.
  • The presence of bacteria in transfused blood may lead either to febrile reactions in the recipient (due to pyrogens) or serious manifestations of septic or endotoxic shock.
  • Commonly caused by endotoxin produced by bacteria capable of growing in cold temperatures such as Pseudomonas species, E. coli, Yersinia enterocolitica.
• Common Cause
  • TYPES OF BACTERIA
    • PACKED RBC; Yersinia enterolotica
    • PLATELETS; Pseudomonas fluorescnes, Serratia liquefaciens, Stahplycoccus epedermidis, Staphylococcus aureus, Bacilus cereus, Propionibacterium spp, Micrococcus spp, Group C Streptococcus
• Treatment:
  • Initiate IV antibiotic therapy
• Prevention:
  • Use aseptic technique, when collecting donor blood
  • Use sterile docking technique, when transferring aliquots of products
  • Use bacterial tests prior to transfusion
  • Use Pathogen Reduction Technology (PRT)

Transfusion-Associated Circulatory Overload (TACO)

• Aka, TACO
• The leading cause of transfusion-related mortality in the USA in 2021
• Signs & Symptoms:
  • Occurs within 12 hrs following transfusion
  • Respiratory Distress / Hypoxemia accompanied by cough, chest tightness
  • Dyspnea
  • Hypertension
  • Jugular Vein Distention
  • Pulmonary Edema
• Common Cause:
  • Fluid overload from blood transfusion, either by a single unit or multiple units
• Treatment:
  • Place patient in the upright (sitting) position
  • Administer O2, when indicated
  • Administer diuretics, when indicated
• Prevention:
  • Reduce the amount of fluid intake at one time

Delayed Transfusion Reactions

Delayed Hemolytic Transfusion Reaction (DHTR)

• Usually caused by undetected RBC antibody, e.g., anti-Jka
• Patient is usually asymptomatic with only a drop in Hgb / Hct
• Occurs (in general) about 7 - 10 days post-transfusion; DHTR caused by anti-Jka is known to occur up to 14 days later
• Usually, extravascular hemolysis is seen
• Lab test evidence:
  • Normal colored serum; except anti-Jka is known to cause a smoky-grey serum
  • Positive DAT (weak positive is common)
  • Weak reacting Ab; C' is bounded to RBC
• Patient is usually asymptomatic with only a drop in Hgb / Hct and / or indirect hyperbilirubinemia
• However, if patient is symptomatic, the common symptoms are:
  • Fever
  • Malaise

AHTR vs DHTR

Transfusion Reaction Workup

1. Unit (usually the IV set is still attached) must be returned to the Blood Bank
2. Check all clerical information - (TRF, unit, requisition, testing worksheet, specimens, sign-out sheet - lab / nurse; nurse / nurse)
3. Patient Testing:
   • Visual inspection for hemolysis in spun-down sample
   • Perform DAT, when indicated (elution, when indicated)
   • Perform ABO / Rh, when indicated
   • Perform ABS, when indicated (Ab ID, when indicated)
4. Unit
   • Perform ABO / Rh, when indicated

Basic Testing Steps

1. Clerical Check:
   • Check that postreaction sample matches transfusion documentation and blood bag (when available)
   • If discrepancy, request redraw and notify TS physician. Take necessary steps to prevent another adverse event if another patient is involved.
2. Hemolysis Check:
   • Visual check for free hemoglobin (pink or reddish discoloration of the plasma).
   • If hemolysis present, notify TS physician and proceed to secondary testing if requested.
   • If hemolysis present on second draw, notify TS physician and proceed to secondary testing if requested.
3. Direct Antiglobulin Test (DAT):
   • Detects presence of red blood cells sensitized in vivo.
   • If negative but HTR is suspected, notify TS physician and proceed to secondary testing if requested.
   • If positive, notify TS physician and proceed to secondary testing if requested.
4. ABO Testing:
   • Verify patient ABO typing.
   • If discrepancy, request redraw and notify TS physician. Take necessary steps to prevent another adverse event if another patient is involved and proceed to secondary testing if requested

Transfusion-Associated Graft Versus Host Disease (TA-GVHD)

• Occurs in immunosuppressed recipients (e.g., neonates, cancer patients on chemotherapy).
• Fatality is extremely high (> 90%) once the disease progresses.
• The common cause is the transfusion of donor T-lymphocytes (T-cells) into an immunocompromised recipient whose own immune system fails to suppress the transfused donor T-cells. The donor T-cells acknowledge the "foreign" environment (not in the original donor's body), rapidly replicate, and begin to attack the recipient's organs & skin.
• Manifestation - 2 days to 6 weeks following transfusion
• Signs & Symptoms:
  • Rash & Fever
  • Diarrhea
  • Pancytopenia
  • Liver Dysfunction / Jaundice

TA-GVHD PATHOGENESIS

• Transplanted immune cells (graft or donor) recognize patient's (host) cells as foreign.
• Primarily T cell mediated disease
• 3 phases
  • 1: conditioning regimen damages and activates host tissues to secrete cytokines that upregulate MHC antigens
  • 2: donor T cell activation
  • 3: Multiple inflammatory cascades
• Th1 CD4 -> TNFa, IL1 -> apoptosis
• Because the mortality rate is extremely high related to this disease, prevention is the best treatment.
• Prevention treatments:
  • Irradiated Blood / Blood Components
  • HLA-matched organ donor
• Treatment:
  • Administration of anti-rejection medication therapy, e.g., immunosuppressants, prior to and following transplantation

Cytomegalovirus (CMV) Infection

• Cytomegalovirus (CMV) Infections
  • Is cause by a virus, herpesvirus
  • Can cause death in neonates and in allogeneic Bone Marrow Transplant (BMT) patients
• CMV is primarily found in WBCs
• Signs & Symptoms:
  • Infant - rash; jaundice; enlarged liver / spleen; pneumonia; seizures
  • Adults - sometimes asymptomatic; can exhibit flu-like / mononucleosis symptoms; leukopenia; gastroenteritis, or pneumonia.
• Common Cause:
  • Transfusion of CMV positive blood where blood donor was not tested for CMV / donor status for CMV is unknown
• Manifestation - 20 - 60 days following transfusion
• Treatment:
  • Antiviral therapy (oral or IV)
• Prevention:
  • Serologic test for CMV. If found negative, blood is labeled as "CMV Neg."
  • Use of LR blood products are considered "CMV Safe" in some

Post-Transfusion Purpura (PTP)

• Delayed immune complication presented
• Thrombocytopenic Purpura appears
• Bleeding from mucous membranes (e.g., nose or gums), GI bleeding, hematuria
• Occurs 5 - 10 days post-transfusion
• Usually Febrile Reaction symptoms
• Usually caused by platelet Ab, i.e., anti-HPA-1a
• Treatment - IV Ig

Nonimmune Transfusion Adverse Effects

Iron Overload / Hemasiderosis

• Condition typically seen in chronically-transfused patients, e.g., Sickle Cell, Thalassemia, etc.
• Liver & cardiac iron concentration noted with MRI; Fe+2 lab test elevated
• Treatment
  • Reduce frequency of transfusion - by erythropoietin administration; stimulates patient to make his / her own RBCs
  • Infusion of iron-chelating agents

Iron Overload / Hemosiderosis Symptoms

• Chronic fatigue
• Frequent infections
• Nerve system disorders
• Joint pain
• Hair or skin pigment changes

Air Embolus

• Air infusion via IV line
• Signs & symptoms
  • Sudden shortness of breath
  • Coughing
  • Hypotension
  • Acute cyanosis
• Treatment
  • Lay patient on left side for mild cases
  • Hyperbaric chamber treatment for severe cases

Hypocalcemia

• Rapid infusion of citrate as seen in massive transfusions
• Signs & symptoms
  • Tingling sensation / Paresthesia
  • Cardiac arrhythmia
  • Tetany
• Treatment
  • Infusion of calcium supplements

Hypothermia

• Rapid infusion of cold blood / blood products
• Signs & symptoms
  • Feeling cold / shivering
  • Cardiac arrhythmia
• Treatment
  • Use blood warmer

Other Transfusion Adverse Effects

Disease Transmission

• Certain diseases can be transmitted via a blood / blood component transfusion.
• In the 1970s, Hepatitis B was a transmissible disease
• In the 1980s, HIV became a disease that was transmitted via a blood transfusion
• In the 1990s, Hepatitis C was a transmissible disease
• While the above time periods showed what was prevalent during that time, even today, there are still those risks that exist.
• Today, worrisome diseases are:
  • Herpes Simplex Virus (both HSV1 & HSV2)
  • Group B Streptococcus (GBS)
  • Cytomegalovirus (CMV)*. In particular, these diseases can be passed onto the developing fetus during gestation or during birth.
• Molecular diagnostic tests* are used to help detect these diseases and provide a rapid result to the treating clinician.
• MLO, The Rise of Molecular Diagnostics for Common Maternal & Fetal Tests, May 2022, vol. 54, no. 5