Transfusion is a routine medical procedure in which donated blood is provided to you through a narrow tube placed within a vein in your arm. This potentially life-saving procedure can help replace blood lost due to surgery or injury.
A transfusion is defined as an infusion of whole blood or any one of its components. Transfusions like any other medical intervention have benefits and risks. Hemolytic transfusion reactions are one of the possible complications from transfusions. Hemolysis is described as rupture of red blood cells and leakage of their contents. The site of hemolysis can be intravascular (in circulation) or extravascular (in the reticuloendothelial system). Hemolytic transfusion reactions can be immune or non-immune mediated.[rx][rx][rx]
Blood transfusion is the process of transferring blood products into one’s circulation intravenously.[rx] Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but modern medical practice commonly uses only components of the blood, such as red blood cells, white blood cells, plasma, clotting factors, and platelets.
Types of blood transfusions
According to the American Red Cross, there are four common types of blood transfusions:
- Red blood cell transfusions: A person may receive a red blood cell transfusion if they have experienced blood loss, if they have anemia (such as iron deficiency anemia), or if they have a blood disorder.
- Platelet transfusions: A platelet transfusion can help those who have lower platelet counts, such as from chemotherapy or a platelet disorder.
- Plasma transfusions: Plasma contains proteins important for health. A person may receive a plasma transfusion if they have experienced severe burns, infections, or liver failure.
- Whole blood transfusion: A person may receive a whole blood transfusion if they have experienced a severe traumatic hemorrhage and require red blood cells, white blood cells, and platelets.
Before a blood transfusion, a healthcare professional will remove the white blood cells from the blood. This is because they can carry viruses.
That said, they may transfuse white blood cells called granulocytes to help a person recover from an infection that has not responded to antibiotics. Healthcare professionals can collect granulocytes using a process called apheresis.
Acute Transfusion Reactions
Mild allergic: Attributed to hypersensitivity to a foreign protein in the donor product.
Anaphylactic: Similar to a mild allergic reaction, however resulting in a more severe reaction. Sometimes this can occur in a patient with IgA deficiency who makes alloantibodies against IgA and then receives blood products containing IgA.
Febrile non-hemolytic: Generally thought to be caused by cytokines released from blood donor leukocytes (white blood cells).
Septic: Caused by bacteria or bacterial byproducts (such as endotoxin) which may contaminate blood.
Acute hemolytic transfusion reactions: Can result in intravascular or extravascular hemolysis, depending on the specific etiology (cause). Immune-mediated reactions are often a result of recipient antibodies present to blood donor antigens. Non-immune reactions are possible, and occur when red blood cells are damaged before transfusion (e.g., by heat or incorrect osmotic conditions).
Transfusion-associated circulatory overload (TACO): Occurs when the volume of the transfused component causes hypervolemia (volume overload).
Transfusion-related acute lung injury: Acute lung injury is due to antibodies in the donor product (human leukocyte antigen or human neutrophil antigen) reacting with antigens in the recipient. The recipient’s immune system responds and causes the release of mediators that lead to pulmonary edema. Possibly contributing to this are clinical conditions that predispose the patient including infection, recent surgery, or inflammation.
Delayed Transfusion Reactions
Delayed hemolytic transfusion reaction: Typically caused by an anamnestic response to a foreign antigen that the patient was previously exposed to (generally by prior transfusion or pregnancy).
Transfusion-associated graft-versus-host disease: Results from engraftment of donor lymphocytes (commonly found in cellular blood products) into an immunocompromised recipient’s bone marrow. The donor lymphocytes recognize the patient as foreign and react against the recipient’s body. The patient’s immune system is unable to clear the foreign lymphocytes. This is rare but often fatal.
Transfusions of Whole Blood
Whole blood refers to human blood transfusion from a standard blood donation.
Whole blood can be separated into its components: red blood cells, plasma, and platelets.
Blood can be transfused in either its relatively unprocessed form as whole blood or through the administration of its processed and separated cellular or plasma components.
Plateletpheresis is a more efficient way to extract platelets than whole blood extraction because plateletpheresis produces platelets that are more highly concentrated.
The blood is separated into distinct plasma and cellular layers by centrifugation, sedimentation, or simply through gravity over a longer period of time.
Whole blood transfusion has similar risks to a transfusion of red blood cells and must be cross-matched based on blood type to avoid hemolytic transfusion reactions and other complications.
- buffy coat: The fraction of an anticoagulated blood sample that contains most of the white blood cells and platelets following density gradient centrifugation of the blood.
- centrifuge: A device in which a mixture of denser and lighter materials (normally dispersed in a liquid) is separated by rotation around a central axis at high speed.
- plasma: The straw-colored/pale-yellow liquid component of blood that normally holds the blood cells of whole blood in suspension.
Blood transfusions are a key therapeutic component to treating those with excessive blood loss from severe injury or surgery. Whole blood refers to blood drawn directly from the body from which none of the components, such as plasma or platelets, have been removed. The blood is typically combined with an anticoagulant during the collection process but is otherwise unprocessed. Whole blood may also be altered and processed for use in blood transfusion.
Historically, blood was transfused as whole blood without further processing. Most blood banks now split the whole blood into two or more components, typically red blood cells and a plasma component such as fresh frozen plasma, which is extracted frozen plasma from the blood splitting process.
Platelets for transfusion can also be prepared from the buffy coat of whole blood, which has therapeutic benefits for those with platelet disorders or impaired clotting ability. Some blood banks have replaced this with platelets collected by plateletpheresis, a process in which platelets are extracted during initial blood collection. Plateletpheresis is more efficient because whole blood platelets typically aren’t concentrated enough to have a useful effect, while plateletpheresis platelets are highly packed and concentrated. It also minimizes the chance of platelet transplant rejection because a single donor will be able to contribute enough platelets via plateletpheresis.
The collected blood is generally separated into components by one of three laboratory methods:
- Centrifuge quickly separates whole blood into plasma, buffy coats, and red cells by using centrifugal force to drop the cellular components to the bottom of a container.
- Sedimentation, in which whole blood sits overnight, causing the red blood cells and plasma to settle and slowly separate by the force of normal gravity.
Whole blood transfusion has similar risks to those of transfusion of red blood cells. It must be cross-matched on the basis of blood type to avoid hemolytic transfusion reactions. Most of the indications for use are identical to those for red blood cells. Whole blood is not used because the extra plasma can contribute to transfusion-associated circulatory overload (TACO), a potential complication that can dangerously increase blood pressure, causing pulmonary edema and acute respiratory distress.
Whole blood is sometimes “recreated” from stored red blood cells and fresh frozen plasma for neonatal transfusions. This provides a final product with a very specific hematocrit (percentage of red cells) with type O red cells and types AB plasma to minimize the chance of complications.
Whole blood is typically stored under the same conditions as red blood cells and can be kept up to 35 days if collected with CPDA-1 storage solution or 21 days with other common storage solutions such as CPD. If the blood will be used to make platelets, it is kept at room temperature until the process is complete. This must be done quickly to minimize the warm storage of RBCs in the unit.
Plasma and Blood Volume Expanders
A volume expander is a type of intravenous therapy that provides a fluid replacement for the circulatory system.
During blood loss, the amount of oxygen that can be delivered to the tissues is reduced due to lost red blood cells and decreased blood volume, which also causes a decrease in blood pressure.
Although they cannot replace lost red blood cells, blood volume expanders can help improve oxygen delivery in instances of blood loss by increasing blood volume and blood pressure so that blood can flow to the tissues.
Survival is possible with low red blood cell and hemoglobin levels as long as blood volume and blood pressure are maintained so blood continues to reach tissues.
Hypovolemic shock occurs when tissue oxygenation drops due to a decrease in blood volume.
Crystalloid volume expanders are aqueous solutions of mineral salts or other water-soluble molecules. Although they decrease the osmotic pressure by diluting the red blood cells, they increase both vascular and interstitial volume.
Colloid volume expanders contain larger insoluble molecules, such as gelatin or hydroxyethyl starch, and theoretically increase the intravascular volume but not interstitial and intracellular volumes.
- crystalloid: Aqueous solutions of mineral salts or other water-soluble molecules, such as saline solution.
- hypovolemic shock: Shock due to decreased blood volume, such as through severe bleeding or vomiting. It activates dangerous compensatory mechanisms that maintain blood flow to the brain while causing other organs to fail.
- colloid: Blood volume expander containing larger insoluble molecules that exert osmotic pressure.
When blood is lost, the greatest immediate need is to stop further blood loss, then lost volume must be replaced. Blood volume is directly proportional to the blood pressure in the body, and when both decrease the flow of blood to important tissues may be inhibited. The remaining red blood cells can still oxygenate body tissue. A volume expander is a type of intravenous therapy that provides blood volume for the circulatory system. It may be used for fluid replacement.
Blood Volume and Oxygen Transport
Normal human blood has a significant excess oxygen transport capability because not all of the hemoglobin molecules are loaded with oxygen under normal conditions. As long as pulmonary function is sufficient for gas exchange and there is enough blood volume to have sufficient blood pressure, very low hemoglobin levels will be enough to sustain the patient. Those with low hemoglobin content will not be able to tolerate situations where a greater amount of oxygen is required (exercise, for example) until their hemoglobin levels are restored.
The body has compensatory feedback mechanisms to deal with lower hemoglobin levels. For instance, the heart pumps more blood with each beat, which increases blood pressure. Blood pressure is detected by the renal system, which increases blood volume and blood pressure by excreting less water during blood filtration. As a result of partial pressure gradient changes, more oxygen is released to the tissues. These adaptations are so effective that if only half of the red blood cells remain, oxygen delivery will still be around 75% of normal. A patient at rest only uses 25% of the oxygen available in their blood. In extreme cases, patients have survived with a hemoglobin level of about 1/7 the normal (i.e. 2 g/dl), although levels this low are very dangerous.
When blood loss is significant, the red blood cell level ultimately drops to a level that is too low for adequate tissue oxygenation. This is marked by hypoxia and hypovolemic shock, a condition in which tissue oxygenation drops from a lack of blood volume and harmful compensatory mechanisms activate, causing more damage. In these situations, the only alternatives are blood transfusion, packed red blood cells, or oxygen therapy.
Types of Volume Expanders
There are two main types of volume expanders: crystalloids and colloids. Crystalloids are aqueous solutions of mineral salts or other water-soluble molecules. Colloids contain larger insoluble molecules, such as gelatin; blood itself is a colloid. There are also a few other volume expanders that may be used in certain situations:
- Colloids: These solutions preserve a high-colloid osmotic pressure (protein-exerted pressure) in the blood, while this parameter is decreased by crystalloids due to hemodilution. The higher osmotic pressure from colloids draws fluids inward, preventing it from leaking out into the tissues as easily, which increases intravascular blood volume.
- Crystalloids: The most commonly used crystalloid fluid is normal saline, a solution of sodium chloride at 0.9% concentration, which is close to the concentration in the blood (isotonic). Saline solution is administered intravenously (IV drips) and increases both intravascular and interstitial volume. They decrease osmotic pressure by diluting the blood.
- Dextrose Water: This solution contains dextrose, a form of glucose. It is given to patients who have dangerously low blood sugar levels (important for cellular metabolism) as well as low blood volume.
Another common volume expander includes hydroxyethyl starch (HES/HAES, common trade names: Hespan, Voluven) which is considered a colloid. An intravenous solution of hydroxyethyl starch is used to prevent shock following severe blood loss caused by trauma, surgery, or another problem. It increases the blood volume, allowing red blood cells to continue to deliver oxygen to the body. When tissue blood perfusion is maintained, shock is averted as the dangerous compensatory mechanisms of shock aren’t activated.
Blood Groups and Blood Types
Red blood cells have surface-expressed proteins that define the self/not-self nature of the cells.
Surface-expressed proteins called antigens on red blood cells determine an individual’s blood type. There are two types of antigen groups: the ABO system antigens and a Rhesus D antigen.
Exposure to a blood group antigen that is not recognized as self will cause the immune system to make specific antibodies to the new blood group antigen, often leading to the destruction of the cells.
Knowing an individual’s antigen type is important to ensure compatibility if a transfusion is needed.
Blood type is inherited. O type is the most common despite being a recessive gene because it is more highly expressed in the gene pool, while type A and type B are dominant (and type AB is codominant) but are less common because they are less expressed in the gene pool.
Individuals may also be positive or negative for the rhesus D antigen in addition to their blood type. Rhesus D complications are common during fetal development if the parents differ in rhesus antigen expression.
- antibodies: Also known as an immunoglobulin (Ig), a large Y-shaped protein produced by B-cells that is used by the immune system to identify and neutralize foreign objects such as bacteria and viruses.
- antigen: A substance that induces an immune response, usually foreign.
Red blood cells have surface-expressed proteins that act as antigens, which are molecules that can illicit an immune system response. Red blood cells belong to different groups on the basis of the type of antigen that they express. Blood type determines compatibility for receiving blood transfusions from other people.
The ABO Blood Group System
If an individual is exposed to a blood group antigen (A or B) that is not recognized as self, the individual can become sensitized to that antigen. This will cause the immune system to make specific antibodies to a particular blood group antigen and form an immunological memory against that antigen. These antibodies can bind to antigens on the surface of transfused red blood cells (or other foreign tissue cells), often leading to destruction of the cells by recruitment of other components of the immune system.
Knowledge of an individual’s blood type is important to identify appropriate blood for transfusion or tissue for organ transplantation. There are four blood types that differ based on the antigen expressed by the red blood cell and by the type of associated antibody found in the plasma. The type of antigen determines which blood types that blood type may safely be donated to, while the type of antibody determines which types of antigen (and types of blood) will be rejected by the body.
- Blood group A individuals have the A antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the B antigen. Therefore, a group A individual can only receive blood from individuals of groups A or O types and can donate blood to individuals of groups A or AB.
- Blood group B individuals have the B antigen on the surface of their RBCs, and blood serum containing IgM antibodies against the A antigen. Therefore, a group B individual can only receive blood from individuals of groups B or O and can donate blood to individuals of groups B or AB.
- Blood Group AB individuals have both A and B antigens on the surface of their RBCs, and their blood serum does not contain any antibodies against either A or B antigen. Therefore, an individual with type AB blood can receive blood from any group, but can only donate blood to another group AB individual. AB blood is also known as the “universal receiver.”
- Blood group O individuals do not have either A or B antigens on the surface of their RBCs, but their blood serum contains IgM antibodies against both A and B antigens. Therefore, a group O individual can only receive blood from a group O individual, but they can donate blood to individuals of any ABO blood group (i.e. A, B, O, or AB). O blood is also known as “universal donor.”
Blood types are inherited and represent genetic contributions from both parents. The gene that codes for blood type contain three alleles: IA and IB which give type A and B blood and are dominant, and I, which is recessive, and codes type O. Children will have blood types similar to their parents based on inheritance. The I allele is far more commonly expressed in the gene pool than IA and IB, which is why type O blood is the most common type despite being a recessive phenotype. Type AB is the rarest because it is the combination of less commonly expressed alleles, and is the result of codominance between IA and IB alleles.
Many people also have the rhesus D (Rh) antigen expressed by their red blood cells. Those that have Rh antigens are positive for Rh, while those that don’t have it are Rh-negative (ie. type O+ is type O with rhesus, type A- is type A without rhesus). Rh-positive individuals do not have the antibodies for the Rh factor but can make them if exposed to Rh. Besides being a consideration for blood transfusion, parents who differ based on Rh status must be cautious to ensure that maternal antibodies do not destroy their child’s red blood cells during fetal development, which can cause hemolytic anemia.
Typing and Cross-Matching for Transfusions
Blood banks test donor blood to ensure recipient compatibility, reducing the risk of hemolytic reaction, renal failure, and death.
Transfusion medicine is important to treat those with blood loss.
Given enough time, cross-matching is performed to ensure that donated blood will not cause a transfusion reaction.
Cross-matching involves mixing a sample of the recipient’s serum with a sample of the donor’s red blood cells and checking if the mixture agglutinates due to antibody reactivity.
If a transfusion with non-matched blood occurs, the patient risks red blood cell destruction, renal failure, shock, and death.
- hemolysis: The destruction of red blood cells from pathological causes, such as infection or immune system mediated damage.
- agglutinate: The act of red blood cells clumping together due to antibody reactivity.
Transfusion medicine is extremely effective at treating those with severe blood loss. Transfusions are often a required component of major surgeries. Due to the different antigen blood types, blood must be cross-matched during processing to avoid potential complications.
The Cross-Matching Process
Much of the routine work of a blood bank involves testing blood from both donors and recipients to ensure that every recipient is given blood that is compatible and is as safe as possible. Several laboratory tests allow cross-matching of compatible blood between donor and recipient. Patients should ideally receive their own blood or type-specific blood products to minimize the chance of a transfusion reaction. Risks can be further reduced by cross-matching blood, but this process isn’t always performed if time is short and the need for transfusion has not been anticipated.
Cross-matching involves mixing a sample of the recipient’s serum with a sample of the donor’s red blood cells and checking if the mixture agglutinates, or forms clumps. These clumps are the result of antibodies binding the red blood cells together. If agglutination is not obvious by direct vision, blood bank technicians check for agglutination with a microscope. If agglutination occurs, that particular donor’s blood cannot be transfused to that particular recipient. In a blood bank, it is vital that all blood specimens are correctly identified, so labeling has been standardized using a barcode system known as ISBT 128. The blood group may be included on identification by military personnel in case they need an emergency blood transfusion.
Potential Transfusion Complications
If a patient receives blood during a transfusion that is not compatible with his or her blood type, severe problems can occur. Acute hemolytic transfusion reactions occur if donated blood cells are attacked by matching host antibodies. This can cause shock-like symptoms, such as fever, hypotension, and disseminated intravascular coagulation from immune system-mediated endothelial damage. Transfusion reactions are also associated with acute renal failure. Lung injury is common as well, due to pulmonary edema from fluid overload if plasma volume becomes too high or neutrophil activation during a transfusion reaction. If the donated blood is contaminated with bacteria, it may induce septic shock in the patient.
Transfusion adverse events
Negative reactions to receiving a blood transfusion are very rare. They are known as ‘transfusion adverse events’.
Most transfusion adverse events are mild – such as itching, fever, hives or rash – and can be treated easily. The most common adverse reaction to a blood transfusion is a mild fever, which occur in less than one in 1,000 transfusions. Most transfusion adverse events occur within 24 hours of a transfusion.
Severe reactions are very rare, but can be life-threatening. They need immediate treatment. A severe reaction may involve:
- breathing difficulties – which may be caused by severe allergic reaction (anaphylaxis), bacterial infection, red cell breakdown or transfusion-related acute lung injury (TRALI)
- high fever and shaking
- low blood pressure
- dark urine
- aches and pains.
If you experience any symptoms of a negative reaction to transfusion, let your health care team know immediately.
There are multiple complications of blood transfusions, including infections, hemolytic reactions, allergic reactions, transfusion-related lung injury (TRALI), transfusion-associated circulatory overload, and electrolyte imbalance.[rx][rx][rx]
According to the American Association of Blood Banks (AABB), febrile reactions are the most common, followed by transfusion-associated circulatory overload, allergic reaction, TRALI, hepatitis C viral infection, hepatitis B viral infection, human immunodeficiency virus (HIV) infection, and fatal hemolysis which is extremely rare, only occurring almost 1 in 2 million transfused units of RBC.
For comparison, the lifetime odds of dying from a lightning strike are about 1 in 161,000.
List of approximate risk per unit transfusion of RBC (adapted from AABB clinical guidelines published JAMA November 15, 2016).[rx]
Adverse Event and Approximate Risk Per Unit Transfusion of RBC
Febrile reaction: 1:60
Transfusion-associated circulatory overload: 1:100
Allergic reaction: 1:250
Hepatitis C infection: 1:1,149,000
Human immunodeficiency virus infection: 1:1,467,000
Fatal hemolysis: 1:1,972,000
Febrile reactions are the most common transfusion adverse event. Transfusing with leukocyte-reduced blood products, which most blood products in the United States are, may help reduce febrile reactions. If this occurs, the transfusion should be halted, and the patient evaluated, as a hemolytic reaction can initially appear similar and consider performing a hemolytic or infectious workup. The treatment is with acetaminophen and, if needed, diphenhydramine for symptomatic control. After treatment and exclusion of other causes, the transfusion can be resumed at a slower rate.
Transfusion-associated circulatory overload is characterized by respiratory distress secondary to cardiogenic pulmonary edema. This reaction is most common in patients who are already in a fluid overloaded state, such as congestive heart failure or acute renal failure. Diagnosis is based on symptom onset within 6 to 12 hours of receiving a transfusion, clinical evidence of fluid overload, pulmonary edema, elevated brain natriuretic peptide, and response to diuretics.
Preventive efforts, as well as treatment, include limiting the number of transfusions to the lowest amount necessary, transfusing over the slowest possible time and administering diuretics before or between transfusions.
Allergic reaction, often manifested as urticaria and pruritis, occurs in less than 1% of transfusions. More severe symptoms, such as bronchospasm, wheezing, and anaphylaxis are rare. Allergic reactions may be seen in patients who are IgA deficient as exposure to IgA in donor products can cause a severe anaphylactoid reaction. This can be avoided by washing the plasma from the cells prior to transfusion. Mild symptoms, such as pruritis and urticaria can be treated with antihistamines. More severe symptoms can be treated with bronchodilators, steroids, and epinephrine.
Transfusion-related lung injury (TRALI) is uncommon, occurring in about 1:12,000 transfusion. Patients will develop symptoms within 2 to 4 hours after receiving a transfusion. Patients will develop acute hypoxemic respiratory distress, similar to acute respiratory distress syndrome (ARDS). Patients will have pulmonary edema without evidence of left heart failure, normal CVP. Diagnosis is made based on a history of recent transfusion, chest x-ray with diffuse patchy infiltrates, and the exclusion of other etiologies. While there is a 10% mortality, the remaining 90% will resolve within 96 hours with supportive care only.
Infections are a potential complication. The risk of infections has been decreased due to the screening of potential donors so that hepatitis C and human immunodeficiency virus risk are less than 1 in a million. Bacterial infection can also occur, but does so rarely, about once in every 250,000 units of red cells transfused.
Fatal hemolysis is extremely rare, occurring only in 1 out of nearly 2 million transfusions. It is the result of ABO incompatibility, and the recipient’s antibodies recognize and induce hemolysis in donor’s transfused cells. Patients will develop an acute onset of fevers and chills, low back pain, flushing, dyspnea as well as becoming tachycardic and going into shock. Treatment is to stop the transfusion, leave the IV in place, intravenous fluids with normal saline, keeping urine output greater than 100 mL/hour, diuretics may also be needed and cardiorespiratory support as appropriate. A hemolytic workup should also be performed which includes sending the donor blood and tubing as well as post-transfusion labs (see below for list) from the recipient to the blood bank.
Retype and crossmatch
Direct and indirect Coombs tests
Complete blood count (CBC), creatinine, PT, and PTT (draw from the other arm)
Haptoglobin, indirect bilirubin, LDH, plasma free hemoglobin
Urinalysis for hemoglobin
Electrolyte abnormalities can also occur, although these are rare, and more likely associated with large volume transfusion.
Hypocalcemia can result as citrate, an anticoagulant in blood products binds with calcium.
Hyperkalemia can occur from the release of potassium from cells during storage. Higher risk in neonates and patients with renal insufficiency.
Hypokalemia can result as a result of alkalinization of the blood as citrate is converted to bicarbonate by the liver in patients with normal hepatic function.