Transfusion Reactions

Transfusion-related complications occur during or after a blood product is given. These complications can be classified as immunologic, non-immunologic and acute, and delayed. Non-immunologic reactions are caused by the transmission of disease in blood products, and immunologic reactions are antigen-antibody–mediated. Symptoms can range from mild itching, chills, and urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) ( hives Hives Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives)) to high fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, severe shortness of breath, jaundice Jaundice Jaundice is the abnormal yellowing of the skin and/or sclera caused by the accumulation of bilirubin. Hyperbilirubinemia is caused by either an increase in bilirubin production or a decrease in the hepatic uptake, conjugation, or excretion of bilirubin. Jaundice, hypotension Hypotension Hypotension is defined as low blood pressure, specifically < 90/60 mm Hg, and is most commonly a physiologic response. Hypotension may be mild, serious, or life threatening, depending on the cause. Hypotension, or hemoglobinuria. Severe reactions can lead to death.

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Hemolytic Reactions

Acute hemolytic transfusion reaction

  • Etiology:
    • Type II hypersensitivity reaction Type II hypersensitivity reaction Type II hypersensitivity, also known as antibody-mediated cytotoxic hypersensitivity, is caused by immunoglobulin G (IgG) and IgM antibodies directed against antigens on cells or extracellular materials. The reaction leads to cytotoxic processes involving antibodies and the complement system. Type II Hypersensitivity Reaction→ targets the transfused RBCs
    • ABO blood group incompatibility causes intravascular hemolysis.
    • Host’s own antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins (immunoglobulin G (IgG)) detect and bind to antigens on donor RBCs, causing extravascular hemolysis.  
  • Signs and symptoms:
    • Start during the transfusion or within 1 hour after
    • Tachycardia
    • Tachypnea
    • Hypotension
    • Flank pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
    • Hemoglobinuria due to intravascular hemolysis
    • Jaundice due to the extravascular hemolysis (yellowing of the sclera and skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin)
    • Fever and chills
  • Management: 
    • Immediate cessation of transfusion 
    • Repeat typing and crossmatching to identify cause and record to prevent future reactions.
    • Supportive care:
      • Infusion of IV fluids to aid diuresis
      • Hypotension managed with IV fluids and vasopressors 
      • In case of disseminated intravascular coagulation Disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation ( DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation): Perform coagulation studies Coagulation studies Coagulation studies are a group of hematologic laboratory studies that reflect the function of blood vessels, platelets, and coagulation factors, which all interact with one another to achieve hemostasis. Coagulation studies are usually ordered to evaluate patients with bleeding or hypercoagulation disorders. Coagulation Studies and administer of fresh frozen plasma (FFP) and platelets Platelets Platelets are small cell fragments involved in hemostasis. Thrombopoiesis takes place primarily in the bone marrow through a series of cell differentiation and is influenced by several cytokines. Platelets are formed after fragmentation of the megakaryocyte cytoplasm. Platelets
  • Complications:
    • Hemoglobinuria can lead to renal tubular necrosis and renal failure.
    • DIC DIC Disseminated intravascular coagulation (DIC) is a condition characterized by systemic bodywide activation of the coagulation cascade. This cascade results in both widespread microvascular thrombi contributing to multiple organ dysfunction and consumption of clotting factors and platelets, leading to hemorrhage. Disseminated Intravascular Coagulation: severe hemolysis can lead to an accumulation of cytokines in the blood → hypercoagulation → microthrombi and hemorrhage → impaired perfusion of organs and tissue necrosis → multi-system organ failure
Hemolytic reaction symptoms

Signs and symptoms of acute hemolytic transfusion reactions

Image: “Main symptoms of acute hemolytic reaction” by Mikael Häggström. License: Public Domain, edited by Lecturio.

Delayed hemolytic transfusion reaction

  • Etiology:
    • Occurs in patients who have been sensitized to specific RBC antigens (previous transfusions, pregnancy Pregnancy Pregnancy is the time period between fertilization of an oocyte and delivery of a fetus approximately 9 months later. The 1st sign of pregnancy is typically a missed menstrual period, after which, pregnancy should be confirmed clinically based on a positive β-hCG test (typically a qualitative urine test) and pelvic ultrasound. Pregnancy: Diagnosis, Maternal Physiology, and Routine Care, or transplantations) 
    • Re-exposure stimulates rapid antibody production and leads to extravascular hemolysis.
  • Signs and symptoms: 
    • Starts days or weeks after the transfusion
    • Fever and chills
    • Jaundice 
    • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview
    • Hemoglobinuria
  • Management:
    • No treatment required
    • Antibody testing should be performed to prevent future reactions.

Nonhemolytic Reaction

Febrile nonhemolytic transfusion reaction (FNHTR)

  • Etiology:
    • Type II hypersensitivity reaction Type II hypersensitivity reaction Type II hypersensitivity, also known as antibody-mediated cytotoxic hypersensitivity, is caused by immunoglobulin G (IgG) and IgM antibodies directed against antigens on cells or extracellular materials. The reaction leads to cytotoxic processes involving antibodies and the complement system. Type II Hypersensitivity Reaction in which host antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins target donor leukocytes
    • Accumulation of cytokines (IL-1, IL-6, IL-8, and tumor necrosis factor Tumor necrosis factor Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF) ( TNF TNF Tumor necrosis factor (TNF) is a major cytokine, released primarily by macrophages in response to stimuli. The presence of microbial products and dead cells and injury are among the stimulating factors. This protein belongs to the TNF superfamily, a group of ligands and receptors performing functions in inflammatory response, morphogenesis, and cell proliferation. Tumor Necrosis Factor (TNF))) in the donor blood during storage produces an immune reaction in the recipient.
  • Signs and symptoms:
    • Start within 1–6 hours after transfusion
    • Fever and chills
    • Headaches 
    • Flushing
    • General malaise
  • Management:
    • Cessation of transfusion 
    • CBC to rule out acute hemolytic reaction (anemia, hyperbilirubinemia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia)
    • Acetaminophen Acetaminophen Acetaminophen is an over-the-counter nonopioid analgesic and antipyretic medication and the most commonly used analgesic worldwide. Despite the widespread use of acetaminophen, its mechanism of action is not entirely understood. Acetaminophen to aid with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
    • Prevention by leukoreduction of blood products

Allergic Reactions

  • Etiology:
    • Type I hypersensitivity reaction Type I hypersensitivity reaction Type I hypersensitivity reaction is an abnormal immune response triggered by exposure to specific antigens known as allergens. In this type of hypersensitivity reaction, the presentation of the antigen to the T-helper cells (Th cells) initiates a cascade of immunologic events leading to the production of antigen-specific IgE antibodies. Type I Hypersensitivity Reaction against plasma proteins in donor blood
    • In the case of IgA deficiency: the anti-IgA IgG antibodies Antibodies Immunoglobulins (Igs), also known as antibodies, are glycoprotein molecules produced by plasma cells that act in immune responses by recognizing and binding particular antigens. The various Ig classes are IgG (the most abundant), IgM, IgE, IgD, and IgA, which differ in their biologic features, structure, target specificity, and distribution. Immunoglobulins of the recipient detect the IgA on the surface of RBCs in the donor blood, triggering a mass release of cytokines → anaphylaxis
  • Signs and symptoms: 
    • Start during the transfusion or within 2 hours after
    • Minor allergic reactions: urticaria Urticaria Urticaria is raised, well-circumscribed areas (wheals) of edema (swelling) and erythema (redness) involving the dermis and epidermis with associated pruritus (itch). Urticaria is not a single disease but rather is a reaction pattern representing cutaneous mast cell degranulation. Urticaria (Hives) or pruritus
    • Life-threatening reaction (anaphylaxis):
      • Hypotension
      • Bronchospasm, wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing, or stridor
      • Nausea and/or vomiting
      • Shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock
      • Cardiac and/or respiratory arrest
  • Management:
    • Minor allergic reactions: antihistamines Antihistamines Antihistamines are drugs that target histamine receptors, particularly H1 and H2 receptors. H1 antagonists are competitive and reversible inhibitors of H1 receptors. First-generation antihistamines cross the blood-brain barrier and can cause sedation. Antihistamines (e.g., diphenhydramine)
    • Anaphylaxis: 
      • Epinephrine
      • Hemodynamic stabilization
      • Airway management

Other Types of Transfusion Reactions

Transfusion-related acute lung injury (TRALI)

  • Etiology:
    • Antibodies in the donor blood products target the neutrophils and pulmonary endothelial cells of the recipient.
    • Causes non-cardiogenic pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema
    • Can lead to acute hypoxemia
    • Activated neutrophils in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs may also secrete proteolytic enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes, leading to more tissue damage.
  • Signs and symptoms: 
    • Start during the transfusion or within 6 hours after
    • Respiratory distress or dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
    • Hypotonia
    • Fever
    • Hypotension (hypovolemia due to the accumulation of fluid in the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs)
    • X-ray shows bilateral infiltrates suggesting pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema.
  • Management:
    • Cessation of transfusion
    • Supportive care
      • Assisted ventilation or oxygen administration
      • Monitoring and regulation of hemodynamic parameters
      • IV steroids to aid with inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation
Transfusion-related acute lung injury chest x-ray

Chest X-ray of TRALI showing bilateral diffuse infiltrates (left); chest X-ray of the same subject after treatment (right)

Image: “Two chest X-rays X-rays X-rays are high-energy particles of electromagnetic radiation used in the medical field for the generation of anatomical images. X-rays are projected through the body of a patient and onto a film, and this technique is called conventional or projectional radiography. X-rays” by Altaf Gauhar Haji et al. License: CC BY 2.0, edited by Lecturio.

Graft-versus-host disease (GvHD)

  • Etiology:
    • Delayed transfusion reaction 
    • Donor’s T lymphocytes T lymphocytes T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells target the recipient’s tissues and organs and produce →  systemic inflammatory reaction.
    • Most commonly affected organs: skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, intestines, and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver
    • Immunocompromised or immunocompetent patients are most likely to develop this condition.
    • Can present acutely (< 100 days after transfusion/transplant) or chronically (> 100 days after transfusion/transplant)
  • Signs and symptoms:
    • Acute reaction
      • Starts < 100 days after transfusion/transplant
      • Pruritic, painful maculopapular rash
      • Nausea and/or vomiting
      • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea and cramping abdominal pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain
      • Jaundice
    • Chronic reaction
      • Starts > 100 days after transfusion/transplant
      • All symptoms seen in the acute reaction may occur. 
      • Scleroderma Scleroderma Scleroderma (systemic sclerosis) is an autoimmune condition characterized by diffuse collagen deposition and fibrosis. The clinical presentation varies from limited skin involvement to diffuse involvement of internal organs. Scleroderma-like skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin changes (lichenoid skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin changes)
      • Xerostomia (dry mouth) and xerophthalmia (dry eyes)
      • Bloody diarrhea (chronic enteritis similar to inflammatory bowel disease (IBD))
      • Weight loss
      • Muscle pain Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain and weakness
      • Bronchiolitis obliterans Bronchiolitis obliterans Bronchiolitis obliterans is an obstructive lung disease triggered by a bronchiolar injury, which leads to inflammatory fibrosis and narrowing of the distal bronchioles. The triggering bronchiolar injury is often due to inhalation of a noxious substance, infection, or drug toxicity. Bronchiolitis Obliterans (chronic/persistent cough, wheezing Wheezing Wheezing is an abnormal breath sound characterized by a whistling noise that can be relatively high-pitched and shrill (more common) or coarse. Wheezing is produced by the movement of air through narrowed or compressed small (intrathoracic) airways. Wheezing, and dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea)
  • Diagnosis:
    • CBC shows anemia, thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia, and/or leukopenia (acute reaction).
    • Spirometry may show obstructive lung disease (chronic reaction).
    • Biopsy of the transplanted tissue to confirm diagnosis 
  • Management:
    • 1st-line: corticosteroids 
      • Topical in the case of  < 50% skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin involvement
      • Systemic in the case of > 50% skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin involvement, gastrointestinal (GI) involvement, liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver involvement
    • 2nd-line: increased corticosteroid dose + immunosuppressant (e.g., cyclosporine)

Transfusion-associated circulatory overload (TACO)

  • Etiology:
    • Large transfusion volume
    • Fast infusion rate
    • Underlying renal or cardiovascular disease
    • Low body weight
    • Infant or elderly patients
  • Signs and symptoms: 
    • Start during the transfusion or within 6 hours after
    • Signs of hypervolemia 
      • S3 gallop
      • Shortness of breath
      • Jugular venous distention
      • Sudden hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
      • Tachycardia
      • Widened pulse pressure
      • Cough and/or dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea
    • X-ray shows bilateral infiltrates suggesting pulmonary edema Pulmonary edema Pulmonary edema is a condition caused by excess fluid within the lung parenchyma and alveoli as a consequence of a disease process. Based on etiology, pulmonary edema is classified as cardiogenic or noncardiogenic. Patients may present with progressive dyspnea, orthopnea, cough, or respiratory failure. Pulmonary Edema.
  • Management:
    • Diuretics (only method to counteract elevated blood volume)
    • Oxygen supplementation or assisted ventilation if necessary

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