An acute hemolytic transfusion reaction (AHTR), also called immediate hemolytic transfusion reaction, is a life-threatening reaction to receiving a

blood transfusion Blood transfusion is the process of transferring blood products into a person's Circulatory system, circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used ...

. AHTRs occur within 24 hours of the transfusion and can be triggered by a few milliliters of blood. The reaction is triggered by host antibodies destroying donor red blood cells. AHTR typically occurs when there is an ABO blood group incompatibility, and is most severe when type A donor blood is given to a type O recipient.

Signs and symptoms

Early acute hemolytic transfusion reactions are typically characterized by fever, which may be accompanied by rigors (chills). Mild cases are also typically characterized by abdominal, back, flank, or chest pain. More severe cases may be characterized by

shortness of breath Shortness of breath (SOB), known as dyspnea (in AmE) or dyspnoea (in BrE), is an uncomfortable feeling of not being able to breathe well enough. The American Thoracic Society defines it as "a subjective experience of breathing discomfort that con ...

, low blood pressure, hemoglobinuria, and may progress to shock and

disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking Microvessel, small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems ...

. In anesthetized or unconscious patients,

hematuria Hematuria or haematuria is defined as the presence of blood or red blood cells in the urine. "Gross hematuria" occurs when urine appears red, brown, or tea-colored due to the presence of blood. Hematuria may also be subtle and only detectable with ...

(blood in the urine) may be the first sign of AHTR. Other symptoms include nausea, vomiting, and

wheezing A wheeze is a clinical symptom of a continuous, coarse, whistling sound produced in the respiratory airways during breathing. For wheezes to occur, part of the respiratory tree must be narrowed or obstructed (for example narrowing of the lower ...

Causes

The most common cause of acute hemolytic transfusion reaction is ABO incompatibility, which is typically due to human error that results in a recipient receiving the incorrect blood product. Rarely, other blood type incompatibilities can cause AHTR, the most common of which is Kidd antigen incompatibility. Rh, Kell, and Duffy antigen incompatibility have also been implicated in AHTR.

Mechanism

Acute hemolytic transfusion reactions result when

antibodies An antibody (Ab) or immunoglobulin (Ig) is a large, Y-shaped protein belonging to the immunoglobulin superfamily which is used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that caus ...

against A and/or B antigens (isohemagglutinins) present in the recipient's blood destroy the respective donor

red blood cell Red blood cells (RBCs), referred to as erythrocytes (, with -''cyte'' translated as 'cell' in modern usage) in academia and medical publishing, also known as red cells, erythroid cells, and rarely haematids, are the most common type of blood cel ...

s. This is mediated through the antibodies IgM (and to a lesser extent IgG) which cause activation of the complement cascade, with complement C5-C9 forming the membrane attack complex which leads to pore formation and red blood cell lysis. The lysed red blood cells release free hemoglobin into the bloodstream, overwhelming hemoglobin binding proteins such as

albumin Albumin is a family of globular proteins, the most common of which are the serum albumins. All of the proteins of the albumin family are water- soluble, moderately soluble in concentrated salt solutions, and experience heat denaturation. Alb ...

, haptoglobin, and hemopexin, with the excess free hemoglobin leading to renal vasoconstriction (via nitric oxide scavenging), which then leads to

acute tubular necrosis Acute tubular necrosis (ATN) is a medical condition involving the death of tubular epithelial cells that form the renal tubules of the kidneys. Because necrosis is often not present, the term acute tubular injury (ATI) is preferred by pathologis ...

and

acute kidney injury Acute kidney injury (AKI), previously called acute renal failure (ARF), is a sudden decrease in renal function, kidney function that develops within seven days, as shown by an increase in serum creatinine or a decrease in urine output, or both. ...

. The antibodies also activate the

coagulation cascade Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulat ...

(blood clotting system) via

factor XII Coagulation factor XII, also known as Hageman factor, is a plasma protein involved in coagulation. It is the zymogen form of factor XIIa (), an enzyme of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by ' ...

, which can lead to disseminated intravascular coagulation and kidney damage. Isohemagglutinins also activate the complement cascade via C3a and C5a, which then promote inflammatory

cytokine Cytokines () are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

release from

white blood cell White blood cells (scientific name leukocytes), also called immune cells or immunocytes, are cells of the immune system that are involved in protecting the body against both infectious disease and foreign entities. White blood cells are genera ...

s. C3a and C5a also activate

mast cells A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem cell that is a ...

which release

serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...

and

histamine Histamine is an organic nitrogenous compound involved in local immune responses communication, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Discovered in 19 ...

, which along with fragments of red blood cells that were destroyed, further stimulate the release of inflammatory cytokines. These inflammatory cytokines include IL-1, IL-6, IL-8, and

TNF-alpha Tumor necrosis factor (TNF), formerly known as TNF-α, is a chemical messenger produced by the immune system that induces inflammation. TNF is produced primarily by activated macrophages, and induces inflammation by binding to its receptors o ...

, which cause increased capillary permeability and vasodilation leading to symptoms of low blood pressure, fever, chest pain, nausea, vomiting, and wheezing.

Diagnosis

The diagnosis of AHTR is made with microscopic examination of the recipient's blood and a direct antiglobulin test (direct Coombs test) which detects IgG antibodies or complement bound to red blood cells and is usually diagnostic of acute hemolytic transfusion reactions. The donor and recipient blood can be re-tested with a type, crossmatch, and antibody screen to determine the cause of the reaction. The donor blood should be examined for any labelling error or other possible errors from the blood bank, which may help prevent other mislabeled blood products from being distributed. Testing the donor blood using a

gram stain Gram stain (Gram staining or Gram's method), is a method of staining used to classify bacterial species into two large groups: gram-positive bacteria and gram-negative bacteria. It may also be used to diagnose a fungal infection. The name comes ...

and

blood culture A blood culture is a medical laboratory test used to detect bacteria or fungi in a person's blood. Under normal conditions, the blood does not contain microorganisms: their presence can indicate a bloodstream infection such as bacteremia or ...

can also help to rule out an infectious cause of the symptoms (such as the donor receiving infected blood). Testing for urine or plasma free hemoglobin may also assist in the diagnosis.

Treatment

Initial treatment for any type of transfusion reaction, including AHTR, is discontinuation of the transfusion.

Fluid replacement Fluid replacement or fluid resuscitation is the medical practice of replenishing bodily fluid lost through sweating, bleeding, fluid shifts or other pathologic processes. Fluids can be replaced with oral rehydration therapy (drinking), intravenous ...

and close monitoring of vital signs are important. People with AHTR are managed with

supportive care Symptomatic treatment, supportive care, supportive therapy, or palliative treatment is any medical therapy of a disease that only affects its symptoms, not the underlying cause. It is usually aimed at reducing the signs and symptoms for the co ...

, which may include

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics ...

s, blood pressure support, and treatment of disseminated intravascular coagulation (with

fresh frozen plasma Fresh frozen plasma (FFP) is a blood product made from the liquid portion of whole blood. It is used to treat conditions in which there are low blood clotting factors (INR > 1.5) or low levels of other blood proteins. It may also be used as the r ...

cryoprecipitate Cryoprecipitate, also called cryo for short, or Cryoprecipitate Antihemophilic factor (AHF), is a frozen blood product prepared from blood plasma. To create cryoprecipitate, plasma is slowly thawed to 1–6 °C. A cold-insoluble precipita ...

, and

platelet transfusion Platelet transfusion, is the process of infusing platelet concentrate into the body via vein, to prevent or treat the bleeding in people with either a thrombocytopenia, low platelet count or poor platelet function. Often this occurs in people ...

). The use of steroids, intravenous immune-globulins (

IVIG Immunoglobulin therapy is the use of a mixture of antibodies (normal human immunoglobulin) to treat several health conditions. These conditions include primary immunodeficiency, immune thrombocytopenic purpura, chronic inflammatory demyelin ...

) or plasma exchange is not supported by evidence.

Furosemide Furosemide, sold under the brand name Lasix among others, is a loop diuretic medication used to treat edema due to heart failure, liver scarring, or kidney disease. Furosemide may also be used for the treatment of high blood pressure. It can ...

is the diuretic of choice in treatment of AHTR with decreased urine output, because it increases the amount of blood that reaches the

renal cortex The renal cortex is the outer portion of the kidney between the renal capsule and the renal medulla. In the adult, it forms a continuous smooth outer zone with a number of projections ( cortical columns) that extend down between the pyramids. I ...

Mannitol Mannitol is a type of sugar alcohol used as a sweetener and medication. It is used as a low calorie sweetener as it is poorly absorbed by the intestines. As a medication, it is used to decrease pressure in the eyes, as in glaucoma, and to l ...

may also be used.

Dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

is used for blood pressure support because it causes

vasodilation Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel wa ...

(dilation of blood vessels) in the kidneys as well as increasing the

cardiac output In cardiac physiology, cardiac output (CO), also known as heart output and often denoted by the symbols Q, \dot Q, or \dot Q_ , edited by Catherine E. Williamson, Phillip Bennett is the volumetric flow rate of the heart's pumping output: tha ...

(amount of blood pumped by the heart each minute).

Prognosis

The severity and prognosis of acute hemolytic transfusion depends on the rate of blood administration and the total volume of the transfusion. The levels of anti-A and anti-B antibodies in the recipients blood may also predict the prognosis, with higher levels of antibodies thought to portend a more severe course. Approximately 2% of cases are fatal. Reactions that begin sooner are typically more severe.

Epidemiology

Acute hemolytic transfusion reaction is estimated to occur in 1 in 38,000 to 1 in 70,000 transfusions. An estimated 41% of ABO-incompatible transfusions result in AHTR.

References

{{Transfusion medicine Transfusion reactions Complications of surgical and medical care Transfusion medicine