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Every year more than 5 million individuals in the United States are transfused with allogeneic and autologous blood components. In spite of extensive donor screening and laboratory testing, a small number of transfused patients experience adverse transfusion reactions. An adverse reaction is defined as any unfavorable event that occurs during or after a transfusion. The cellular or fluid portions of the blood, anticoagulant-preservative solution, metabolic by-products, and circulating or contaminant microorganisms may cause adverse reactions. When an adverse transfusion reaction occurs, medical, nursing and laboratory personnel must be prepared to recognize and treat them. Because the signs and symptoms of different types of adverse reactions overlap and their severity can vary considerably, all transfusions must be carefully monitored and stopped as soon as symptoms of a reaction appear. Early recognition is the key to minimizing serious complications. Signs and symptoms of a transfusion reaction include:
Nursing Action For any acute reaction other than hives, the nursing or medical staff should take the following action:
Laboratory Response The Transfusion Service staff will immediately determine whether hemolysis has occurred. If possible, testing should be performed by someone other than the person who completed the original testing. Laboratory evaluation of a suspected hemolytic reaction should follow a hierarchic approach. Testing is divided into Tier One and Tier Two. First Tier testing is designed to detect hemolysis, but cannot differentiate immune from other causes of hemolysis. Negative first tier testing rules out hemolysis. Second tier testing is performed if first tier testing indicates that hemolysis occurred. It is intended to establish the diagnosis of immune hemolysis. Tier One Testing Tier one testing encompasses:
If the DAT is positive on the post-reaction specimen, a pre-transfusion reaction sample should be tested for comparison. If the post transfusion DAT is positive, but the pre-transfusion DAT is negative a hemolytic transfusion reaction is possible. Since circulating antibody or complement coated red cells may be rapidly cleared, the DAT may be negative especially if the specimen was drawn several hours after the suspected reaction. If incompatible transfused cells have been partially destroyed, the DAT may have a mixed field appearance. The DAT will be positive if at least 10% of a patient's red cells are coated with IgG. If both the pre and post-transfusion DAT are positive, the test is not helpful in diagnosis of a hemolytic transfusion reaction, because the DATmay be the result of:
Tier Two Testing If any part of Tier One testing is positive or the patient's medical condition strongly suggests a hemolytic reaction, then Tier Two testing is undertaken.
If hemolysis is observed in the blood bag, red blood cells may have been hemolyzed because the unit was improperly transported, stored, warmed or mixed with a hypotonic IV solution. In a hemolytic reaction, DAT may be positive and antibody screen negative. In this situation, a red cell eluate can be used for antibody identification. Pre and post crossmatches should be performed, including the antiglobulin phase, to detect an antibody to a low frequency antigen or an error in pretransfusion testing. Whenever possible, the pre-transfusion crossmatch should be repeated with cells from a retained segment. If an incompatibility is found, a second crossmatch should be performed with the pre-transfusion serum and donor unit red cells to see if incompatibility was present prior to transfusion.
Acute Hemolytic Reactions without Detectable Antibody Occasionally, a severe hemolytic reaction occurs, but the serological workup does not detect a red cell antibody. Sometimes the use of antibody enhancement techniques such as Polybrene, polyethylene glycol (PEG) or enzyme treated red cells reveals the causative antibody, which usually has specificity for C, E, e, S, Jka, or Jkb. However, in many cases these techniques are not helpful. HLA antibodies may be responsible for some of these hemolytic reactions. HLA A28, B7 and B17 are present on red cells and are termed Bgc , Bgb and Bga, respectively. Bg antigens are excluded from antibody screening cells. If one of these patients requires additional urgent transfusion, the best option is to provide phenotypically matched red cell units. Reporting of Adverse Reactions
Types of Transfusion Reactions Clinical and laboratory personnel must be familiar with the different types of transfusion reactions so that the most appropriate testing and treatment are instituted. For this discussion, reactions have been classified as acute or delayed. Acute Reactions Allergic Reactions Simple allergic reactions are the second most common type of transfusion complication. Allergic reactions occur most commonly after the transfusion of components containing large volumes of plasma such as fresh frozen plasma, single donor platelets or pooled random donor platelet concentrates. Transfusion of red blood cells is less commonly associated with allergic reactions because they contain so little plasma. Etiology: Allergic reactions are attributed to soluble substances in donor plasma (e.g. food allergens, drugs or ethylene oxide) which react with IgE antibody bound to basophils or mast cells in the recipient's blood. This interaction results in the release of C3a, C5a, histamine, prostaglandin D2, leukotrienes C4 and D4 and a variety of other cytokines. These substances produce an immediate type hypersensitivity reaction by increasing vascular permeability, promoting bronchial smooth muscle contractions, and stimulating mucus secretion by nasal and bronchial glands. Histamine release causes hives, itching, and rarely, laryngeal edema. Symptoms: Hives (urticaria) or other rash (erythema), itching (pruritis), and wheezing are most common. Allergic reactions can occur during or up to 3 hours post-transfusion. The shorter the time interval between the start of the transfusion and the onset of the allergic reaction, the more severe the reaction. In more severe reactions, anxiety, dyspnea, palpitations, fever and chills may accompany urticaria. Consequences: Allergic reactions are not usually dangerous, but they do cause discomfort and anxiety. Urticaria is not a manifestation of a hemolytic reaction, so it is not usually necessary to discontinue the transfusion. Lab Data: No laboratory testing is necessary. Treatment:
Anaphylactic Reactions Anaphylactic reactions can be associated with almost any type of blood component and are life-threatening. Etiology: Quantitative IgA deficiency ( < 0.5 mg/dL) or an IgA subclass deficiency puts a patient at higher risk of having an anaphylactic reaction. Approximately 1 in 600 people are IgA deficient. Such persons may form IgG antibodies against IgA. When anti-IgA antibody binds to IgA in transfused plasma, complement is activated and severe anaphylaxis can occur. Although IgA deficiency is the most well known cause of anaphylactic reactions, other causes have also been reported.
Symptoms: Sudden onset of flushing and hypertension followed by hypotension, tachycardia, widespread edema, laryngeal edema, bronchospasm, shock, and sometimes GI symptoms such as abdominal cramping, nausea, vomiting, and diarrhea can occur within minutes of starting the transfusion. Consequences: Potentially fatal due to shock or respiratory failure. Early recognition and treatment are critical. Lab Data: Tier One testing should be performed to rule out a hemolytic reaction. No evidence of RBC serological incompatibility will be found in an anaphylactic reaction. IgA deficiency is diagnosed by measuring quantitative immunoglobulin levels. If IgA is deficient, serum can be further tested for anti-IgA antibodies. Treatment:
Febrile Nonhemolytic Reactions Febrile reactions are the most common type of transfusion reaction reported to the Blood Bank. Because their symptoms of fever and chills also occur with acute hemolytic reactions, it is essential to evaluate all such reactions immediately. Etiology: Most febrile reactions that occur during transfusion of red blood cells are caused by the interaction of leukocyte antibodies in the recipient's plasma with donor leukocytes, stimulating the release of pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF). Patients who have had multiple prior transfusions or pregnancies are more likely to have these antibodies. Two thirds of these antibodies have HLA specificity, while one third are specific for platelet or granulocyte antigens. Antibodies usually reach detectable levels within 1 to 2 weeks after transfusion and are often transient. The transient nature of these antibodies may explain why only 1 in 7 patients experience repeat febrile reactions. At least 2 mechanisms are responsible for febrile reactions to platelet transfusions. Approximately 95% of reactions are caused by cytokines that accumulate in the platelet concentrate during storage. Most of these cytokines do not reach detectable levels until day 3 of storage and they reach high levels by day 5. Transfusion of high levels of these cytokines produces fever. The second mechanism that is responsible for 5% of platelet associated febrile reaction is the interaction of donor leukocytes with anti-leukocyte antibodies in recipient plasma, similar to febrile reactions induced by red cells. Symptoms: A febrile reaction is defined as an increase in temperature >1oC above the pre-transfusion temperature either during or up to several hours after the transfusion. Fever may persist for 8 to 12 hours. Chills may precede the fever or occur up to 30 minutes after the onset of fever. In some patients, headache, flushing, or tachycardia may accompany fever and chills. Patients who are febrile at the onset of transfusion or have been febrile in the preceding 24 hours, are more prone to febrile reactions. Consequences: It is important to recognize and report febrile reactions because they may be the first indication of a septic or hemolytic transfusion reaction. A febrile reaction, by itself, is not usually serious, although the patient will have discomfort. Lab Data: Tier One testing is performed. A febrile reaction will not have any evidence of hemolysis or serological incompatibility. Treatment:
The best way to prevent severe febrile reactions is to use prestorage leukocyte reduced single donor platelets. Bedside leukocyte reduction of platelets does not reduce the incidence of febrile reactions. If a patient continues to have febrile reactions to leukocyte reduced single donor platelets, it may be helpful to remove plasma from the platelet unit immediately prior to transfusion. Alternatively, platelets can be washed. Both plasma reduction and washing may activate platelets and decrease their hemostatic effectiveness. If a patient continues to experience febrile reactions even after receiving leukocyte reduced blood components, it may be necessary to pre-medicate them with 650 mg acetaminophen and 25 mg of diphenhydramine. Pre-medication should be used judiciously since it may mask the early signs and symptoms of a hemolytic reaction. Acute Hemolytic Transfusion Reaction (AHTR) Today, 1 in 38,000 red cell units is transfused to the wrong patient. When the wrong unit of blood is given, it is ABO-incompatible 1 in 3 times. Two thirds of these erroneous transfusions are caused by a clerical or management error in identifying the patient, blood sample or blood component and one third are due to an error in the transfusion service. Of these ABO-incompatible transfusions, about 10% are associated with a fatal hemolytic transfusion reaction. Occasionally, a non-ABO antibody may also trigger acute intravascular hemolysis. Usually, however, these other antibodies (primarily of the IgG class) are associated with extravascular hemolysis. They bind to red cells and may activate complement. Antibody coated red cells are sequestered in the retroendoctrilal system where they are phagocytized by macrophages. Very rarely, an antibody from transfused donor plasma may be implicated in an acute hemolytic reaction. Etiology: The pathophysiology of acute hemolytic reactions involves 3 phases.
Consequences: The morbidity and mortality of hemolytic reactions is proportional to the amount of incompatible blood transfused. Symptoms and signs may occur after transfusion of as little as 1 mL of incompatible blood. Pronounced signs and symptoms are common after 5 to 20 mL. Life-threatening consequences include acute renal failure, shock and DIC. The risk of a fatal reaction is much higher after transfusion of more than 200 mL of incompatible blood. Lab Data: When a hemolytic reaction is suspected, immediate action must be taken to determine its etiology and minimize its consequences.
A plasma haptoglobin should be performed on both pre and post-transfusion serum specimens. After transfusion of several units of stored blood, the post-transfusion haptoglobin level may be decreased to 50% of the pre-transfusion level, even though the units were compatible. After hemolysis, the pre-transfusion level will be within the reference range of 100 to 150 mg/dL and the post-transfusion level will be zero. If hemolysis has occurred coagulation tests including PT, aPTT, fibrinogen, platelet count and D-Dimer should be ordered to determine if DIC is occurring. BUN and creatinine should be monitored to assess renal function. Treatment: The transfusion should be stopped immediately, but the IV line should be kept open with Normal Saline infusion, since hypotension and shock may occur. Saline, should be infused to maintain urine output at 100 mL/h in adults for at least 24 to 48 hours. EKG, BP, cardiac output and urine output should be monitored. Although there is no good evidence that the use of diuretic agents can reverse acute renal failure once it has developed, it is reasonable to attempt a trial of furosemide, 80 to 400mg IV, in the early oliguric phase in the hope of inducing a diuresis. Childhood dose is 1 to 2 mg/kg. If shock occurs, dopamine, 1 ug/kg/minute, may be given after blood volume is restored. Dopamine combats both shock and renal failure, but requires careful hemodynamic monitoring. Medical consultation should be obtained for management of renal failure and/or DIC.
Nonimmune Hemolysis When symptoms of hemolysis are observed and antibody detection tests are negative, other causes of hemolysis should be investigated including:
The administration of hypotonic solutions with whole blood or red blood cells can cause hemolysis. Solutions containing 5% dextrose are most frequently associated with hemolysis. Besides its osmotic effect, dextrose appears to directly damage red cell membranes, reducing RBC survival. Five or 10% dextrose in water or in 0.45 or 0.225% saline causes red blood cells to swell, resulting in decreased in vivo survival. Blood remaining in the administration set tubing should be examined for hemolysis. If the administration set was previously used for infusion of a hypotonic or dextrose solution, hemolysis may be seen in the tubing but not in the blood bag. Other IV solutions, besides drugs, can also cause adverse effects. Simultaneous administration of hypertonic hyperalimentation or lipid solutions and blood transfusions through multi-lumen catheters has been associated with severe acanthocytosis. The calcium content of Ringer's lactate solution can cause clots to form if it is added to blood component bags or tubing, because of the recalcification of citrated anticoagulated plasma. Patients with intrinsic red cell defects, such as glucose-6-phosphate dehydrogenase deficiency or sickle cell anemia, may experience intravascular hemolysis unrelated to transfusion. Myoglobinemia, secondary to trauma, may be mistaken for hemolysis. Symptoms: Hemoglobinuria is present, but other symptoms of acute hemolysis are absent. Consequences: Nonimmune hemolysis is usually limited. The cause of hemolysis needs to be corrected in order to minimize complications. Lab Data: Hemoglobinuria and hemoglobinemia are observed, but no serological incompatibility is detected. Tier one and tier two testing are completed to rule out an acute hemolytic reaction. Treatment: Usually no treatment is necessary, but patient must be monitored for significant hemolysis. If hypotension or renal failure occur, see treatment of acute hemolytic reactions above. Prevention: Blood Bank transfusion policies are designed to avoid many situations that contribute to non-immune hemolysis. Careful adherence to policies and patient monitoring will minimize this problem. Transfusion Related Acute Lung Injury (TRALI) TRALI, also known as noncardiogenic pulmonary edema, is indistinguishable from adult respiratory distress syndrome (ARDS). The frequency of TRALI remains uncertain, but has been estimated to be 1 in 5000 plasma-containing transfusions. Virtually every type of blood component has been implicated in TRALI including red blood cells, fresh frozen plasma, cryoprecipitate, platelet concentrates, apheresis platelets, and rarely IVIG. Etiology: Unlike other immunologic transfusion reactions, the antibodies implicated in TRALI are usually of donor origin. The etiology of TRALI is attributable to the presence of anti-HLA and/or anti-granulocyte antibodies in the plasma of multiparous females or donors who have received previous transfusions. Once transfused to recipients, these antibodies cause complement activation, pulmonary leukostasis, release of granulocyte enzymes and damage to the pulmonary microvasculature. This injury leads to fluid accumulation, inadequate oxygenation, and reduced cardiac return. Other suggested causes include cytokines in donor units, lipids with granulocyte priming activity in donor units, recipient granulocyte or HLA antibody, and use of extracorporeal perfusion circuits. Symptoms: Typically, patients develop acute respiratory distress manifested as severe hypoxemia, hypotension, cyanosis, fever, chills and severe bilateral pulmonary edema within 1 to 6 hours after transfusion of a plasma-containing blood component. Chest x-rays demonstrate a "whiteout" picture without evidence of fluid overload or congestive heart failure. There are no other signs of left heart failure. Unlike ARDS, TRALI is usually transient. Edema fluid clears rapidly and pO2 levels return to their pretransfusion levels within 72 hours. Consequences: Between 6 and 10% of cases are fatal. TRALI must be recognized promptly and treated appropriately. The patient's physician should be notified immediately. Lab Data: There is no evidence of RBC serological incompatibility. The remaining unit should be returned to the hospital transfusion service so that donor plasma can be tested for granulocyte antibodies. Recipient plasma may also be tested for granulocyte antibody. Crossmatching recipient lymphocytes or granulocytes with serum from the implicated donor may provide supportive evidence of TRALI. Treatment: The transfusion should be stopped. Symptomatic support includes oxygen administration and possibly intubation with mechanical ventilation. Diuretics are not useful in treatment of TRALI because the underlying pathology involves microvascular injury, rather than fluid overload. Corticosteroids are often used empirically but their effectiveness has not been proven. Prevention: If antibodies are present, the blood center should be notified so that the donor will be permanently deferred from future donations. Patients who develop TRALI are unlikely to have another reaction because it is most often donor specific. Circulatory Overload Circulatory overload may occur when excessive volumes of blood or components are administered too quickly. This complication occurs most frequently in patients with severe chronic anemia because they have an expanded blood volume. Infants, elderly adults, and patients with heart or kidney disease are also more prone to develop circulatory overload. When too much blood is transfused too quickly, these patients cannot handle the volume increase and consequently develop heart failure and acute pulmonary edema. Symptoms: Symptoms include dyspnea, orthopnea, wheezing, tightness in the chest, dry cough, headache, cyanosis, tachypnea, and rapid increase in blood pressure. Peripheral and pulmonary edema may also develop. Consequences: Usually not serious if intervening steps are taken. Potentially life-threatening if not promptly recognized. Lab Data: No evidence of serological incompatibility. Treatment:
Bacterial Contamination Blood components are sterile. However, if bacteria are introduced into donor units during collection, processing, or pooling, they may cause sepsis or life-threatening endotoxic shock. Etiology: Donors who have recently recovered from gastroenteritis may be asymptomatic but still be bacteremic. Bacteria that cause low grade or asymptomatic infections in donors, such as Salmonella or Yersinia, are most often implicated. Bacteremia may also occur during the incubation periods of upper respiratory tract infections and following dental procedures. Contamination of the donor unit at the time of collection is probably the most common cause of contamination. A small core of skin containing bacteria may enter the phlebotomy needle during skin puncture. Bacterial contamination can also occur during manufacturing of blood bags. Needles, anticoagulant-preservative solution or the plastic bags and tubing may become contaminated with airborne or waterborne bacteria. Finally, contamination can take place during processing of the unit at the blood bank or transfusion service. During storage, bacteria multiply and may secrete toxins. Upon transfusion, contaminated units may cause sepsis. Platelet concentrates are more prone to bacterial contamination than red blood cells or plasma components because they are stored at room temperature. The risk of contamination is greater for pooled random donor platelet concentrates than for single donor platelets collected by apheresis. Gram negative bacteria are most often isolated from contaminated units of red blood cells, since they can proliferate in the cold. Symptoms: Sepsis due to contaminated blood components should be suspected if a patient develops high fever, rigors, and profound hypotension shortly after starting a transfusion. Shock, hemolysis, renal failure, and disseminated intravascular coagulation are also frequently present. Consequences: Transfusion of a bacterially contaminated blood component is potentially fatal. It must be recognized and treated immediately. Lab data: The transfusion should be stopped immediately and the bag, tubing and other fluids being administered should be returned to the transfusion service for immediate investigation. The bag should be inspected for discoloration, clots or hemolysis. A Gram stain and blood culture should be performed on an aliquot of blood from the bag and from the recipient. The Gram stain will be negative in one third of cases even though contamination is present. The most commonly detected bacteria are listed in the following table.
Before starting antibiotic therapy, a blood culture should be obtained from the patient. Isolation of the same organism from the blood bag and the patient establishes the diagnosis of bacterial contamination with a high degree of certainty. If the patient is receiving antibiotics at the time of transfusion, blood cultures from the patient may be negative for the organism in question. Treatment: The patient's physician should be notified immediately. If the patient is not already being treated with IV antibiotics, they should be started as quickly as possible. Prevention: All policies involving collection, handling, and storage of blood components must be carefully followed. All blood components should be inspected prior to transfusion for any abnormal color, opacity, hemolysis or clots. Suspect units should not be issued for transfusion. The infusion set should be primed and the blood bag spiked using aseptic technique. Transfusions should be begun as soon as the units are available and the transfusion completed within 4 hours to prevent possible bacterial proliferation. If the transfusion cannot be started within 30 minutes the unit should be promptly returned to the Blood Bank for proper storage. If a unit is contaminated, all other blood components from that donation should be immediately recalled. A method to limit or detect bacteria in all platelet products must be implemented by March 2004. Patients undergoing rapid, massive transfusion may develop metabolic complications such as hypocalcemia, hyperkalemia, hypothermia, or dilutional deficiencies of platelets or clotting factors. This is discussed further in the section on Massive Transfusion. Citrate toxicity The anticoagulant-preservative solution in blood bags contains more citrate than is needed to prevent blood clotting during storage. Excess citrate binds calcium and magnesium in the recipient's blood and can cause hypocalcemia and hypomagnesemia. Symptoms: The most frequent effects are circumoral paresthesia, tremor and arrhythmia. Lab Data: Decreased plasma ionized calcium and magnesium. Treatment: Treatment consists of slowing the infusion. If symptoms are not alleviated, the patient can be treated with 10 mL calcium gluconate or 2.5 mL of 10% calcium chloride IV after every liter of blood transfused. Prevention: Usually the liver metabolizes citrate so quickly, these adverse effects do not occur. Most patients can tolerate 1 unit of blood every 5 minutes or up to 20 units in 2 hours before hypocalcemia and hypomagnesemia occur. Patients who are massively transfused and have liver failure or slowed metabolism due to hypothermia may become hypocalcemic or hypomagnesemic more quickly. Hypothermia Red blood cells are stored at 4oC and do not warm up much beyond 10oC if they are transfused rapidly. Symptoms: Many of the arrhythmias attributed to hypocalcemia and hypomagnesemia may be accentuated by hypothermia. Consequences: Hypothermia may impair drug metabolism, impair platelet function and coagulation. Tissue oxygen delivery is reduced, while oxygen consumption increases due to shivering. At body temperatures of 25 to 30o C, cardiac output decreases and ventricular irritability increases. Patients may develop ventricular fibrillation. Lab Data: None. Treatment: Warming fluids and inspired gases, increasing ambient temperature and applying warming blankets directly to the patient are also effective treatments. Prevention: Infants and elderly patients are at greatest risk of hypothermia, particularly during massive transfusion of blood components. Other situations where cold blood may induce arrhythmias include exchange transfusions and transfusion of multiple units through central IV lines. In all of these cases, blood should be warmed to 37oC with an electronic in-line-warming device. Hyperkalemia During storage in the cold, the red cell membrane sodium-potassium pump is inhibited and potassium leaks out of red cells at a rate of 0.5 to 1 mEq/L per day.
Hyperkalemia from red blood cell transfusions is theoretically possible, but is of clinical concern only in patients who are unable to handle an additional potassium load such as neonates, burn victims or patients with renal failure. Hyperkalemia may occur during massive transfusion in patients with renal failure or multiple trauma. Symptoms: Hyperkalemia, along with acidosis, hypocalcemia and hypothermia, can cause arrhythmias. ECG shows peaked T waves and widened QRS interval. Treatment: Once adequate perfusion is reestablished and acidosis is resolved, hyperkalemia dissipates. In some cases, there may even be a rebound hypokalemia, presumably due to the uptake of potassium by transfused cells to replace what was lost during storage. Prevention:
Air embolism has become a very rare complication since the introduction of plastic blood bags. It may occur in association with intraoperative RBC recovery or during the use of rapid infusion devices. Symptoms: If air embolism occurs, the patient becomes cyanotic and dyspneic and may develop shock. Consequences: Cardiac arrest may ensue. Lab Data: DIC may occur. Treatment: Patients should be treated by lowering their head and laying them on their side so that air will collect in the right atrium, away from the pulmonary valve. Prevention: Proper use of infusion pumps, cell salvage devices and tubing couplers should prevent air embolism. Delayed Reactions Hemolytic Transfusion Reaction Delayed hemolytic reactions occur in patients who have undetectable levels of antibody when pretransfusion testing is performed, so that seemingly compatible units of red blood cells are transfused. Exposure to antigen positive red blood cells provokes an anamnestic response and an increased synthesis of the corresponding antibody. After several days, the antibody titer becomes high enough to hemolyze transfused red cells. During a 19 year period, the Mayo Clinic encountered 559 delayed immune reactions to transfusion associated with antibodies of potential clinical significance. Only 35% showed any signs of hemolysis and were classified as delayed hemolytic reactions. The remaining 65% were classified as delayed serologic reactions because they had alloantibody formation with a positive DAT, but no evidence of hemolytic anemia. Symptoms: In most cases, delayed hemolytic reactions are asymptomatic and the only noticeable sign is a more rapid fall in the post-transfusion hemoglobin level than is clinically expected. Occasionally a patient experiences a flu-like illness. Fever is the most common symptom, followed by jaundice. In rare instances, hemolysis may be brisk (especially when Kidd antibodies are implicated) resulting in fever, hemoglobinemia and hemoglobinuria. Consequences: Generally, delayed hemolytic reactions do not result in serious adverse sequelae. Ocasssionally, the decrease in a patient's hemoglobin associated with a delayed hemolytic transfusion reaction can be misdiagnosed as internal bleeding. Lab Data: Delayed hemolytic transfusion reactions are most often detected by the blood bank when laboratory tests reveal a positive direct antiglobulin test and/or an indirect antiglobulin test. Other lab findings include decreasing hemoglobin or hematocrit, increasing indirect bilirubin, and positive antibody screen posttransfusion. Treatment: Treatment is rarely necessary. Urine output and renal function should be monitored. Transfusion of antigen negative blood may be necessary for treatment of anemia. Prevention: It is critical that the responsible antibody is identified and all additional units are negative for the corresponding antigen. When RBC antibodies are identified, physicians should inform their patients and counsel them to provide this information when they are hospitalized elsewhere. Carrying a transfusion alert card is recommended. Physicians whose patients tell them about previously identified antibodies should immediately notify the Transfusion Service. Transfusion Associated Graft Versus Host Disease Etiology: Transfusion associated graft versus host disease (TA-GVHD) occurs when viable donor T lymphocytes engraft and multiply in a recipient incapable of eliminating them. Donor T cells initiate a cell mediated immune response directed at recipient tissue antigens. The recipient's inability to eliminate these donor lymphocytes may result from severe immunodeficiency or an inability to immunologically recognize the transfused cells as foreign. An example of the former is a bone marrow transplant recipient whose immune system has been ablated by chemotherapy. The latter situation occurs in immunocompetent patients who receive directed donations of red cells from first degree relatives or HLA matched platelets. It seems to occur when the donor is homozygous for one of the recipient's HLA haplotypes. For example, if a donor is homozygous for an HLA haplotype (e.g. HLA A2 A2, B7, B7) and a recipient is heterozygous (HLA A2, A19, B7, B57) the recipient would not recognize donor lymphocytes as foreign, but donor lymphocytes would recognize recipient lymphocytes as foreign. The relative risk of TA-GVHD varies with the relationship of donor and recipient.
Other risk factors for the development of TA-GVHD include transfusions for cardiovascular surgery or cancer and use of fresh blood. Symptoms: TA-GVHD shares many of the same features as graft versus host disease occurring after bone marrow transplantation. Patients with TA-GVHD and BMT-GVHD display the classic signs of fever, erythematous maculopapular skin rash, diarrhea, hepatomegaly, and elevation of liver enzymes. If engraftment occurs in a BMT patient, bone marrow and lymphocytes are of donor origin. So while the host's skin, liver and GI tract are attacked, the bone marrow and lymph nodes are spared. In TA-GVHD, donor lymphocytes also seek to destroy the host's bone marrow, thymus, lymph nodes and spleen. Therefore, patients with TA-GVHD frequently have lymphadenopathy and severe pancytopenia. Comparison of Transfusion & Transplantation GVHD
Consequences: The response to therapy is poor and mortality is 90%. Most patients die from severe pancytopenia and infection. Prevention: TA-GVHD can be prevented by gamma irradiation (2500 cGy per unit for 1 to 5 minutes) of cellular blood components including red blood cells, platelets, and granulocytes to inactivate lymphocytes. Fresh frozen plasma and cryoprecipitate do not need to be irradiated. Leukocyte reduction by filtration does not remove sufficient numbers of lymphocytes to prevent graft versus host disease. Treatment: No treatment has proven to be effective. Iron Accumulation Iron overload is not a problem in patients receiving only a few units of blood, but is a predictable consequence of chronic red cell transfusion therapy. Etiology: Each unit of red blood cells contains about 250 mg of iron complexed with hemoglobin. Transfusion hemosiderosis may become apparent after about 100 units of blood. Organ damage may already be advanced at the time of diagnosis. Organ toxicity begins when reticuloendothelial sites of iron storage become saturated and iron becomes deposited in other cells. Iron causes oxidative damage to liver, heart and endocrine glands. Consequences: The most serious complication is cardiotoxicity, which causes arrhythmias, congestive heart failure and death. Hepatic injury, diabetes mellitus and adrenal insufficiency may also occur. Lab Data: Long term ferritin monitoring is helpful in assessing total body iron burden. Long term maintenance of serum ferritin below 300 ng/mL is associated with improved survival. Treatment: Treatment with iron chelation agents, such as parenteral deferoxamine, should be initiated early in the course of chronic transfusion therapy. Prevention: The best way to prevent iron overload is to limit the number of transfusions as much as possible. Transfusion transmitted infectious diseases usually share the following properties:
Viruses Transmitted by Transfusion
Hepatitis Before the late 1970's, the risk of transmitting hepatitis by transfusion was very high because of blood collection from prisoners and paid donors and the lack of sensitive serological tests. Between 1965 and 1972, approximately 1 in 60 units of blood transmitted hepatitis. The change to an all-volunteer blood supply and the introduction of a third generation test for HBsAg in the mid 1970's led to a marked reduction in transfusion transmitted hepatitis B infection. The risk decreased even further with the implementation of ALT and anti-HBc tests in 1987 and 1988 as surrogate markers for hepatitis C. Today the risk of transmitting hepatitis B is only 1 case per 205,0000 units and it accounts for only 10% of post-transfusion hepatitis cases. Further reduction may occur, as hepatitis B vaccination becomes more widespread. In the late 1970's, approximately 10% of patients who were transfused with multiple units of red cells became infected with hepatitis C. The introduction of more stringent donor eligibility criteria and both serological and nucleic acid tests hepatitis C virus antibody and RNA has reduced the risk of transmission to about 1 infection per 2,000,000 units transfused. The natural history of transfusion acquired HCV is similar to that of HCV acquired through other modes of transmission. Approximately 50% of patients will develop chronic elevations of liver enzymes and 10% of these will develop cirrhosis. Transmission of hepatitis A by blood transfusion has been estimated to occur with a frequency of 1 case per 1 million units transfused. Hepatitis A is seldom transmitted by transfusion because its viremic phase lasts only 7 to 10 days, a chronic carrier state does not exist, and many transfusion recipients have protective immunity. Most cases of post-transfusion hepatitis A have occurred in neonatal ICUs. HIV-1 The risk of transmitting HIV-1 by transfusion has almost been completely eliminated over the past 20 years. The risk has decreased from 1 case per 100 transfused units in 1983 to 1 case per 2 million today. The risk declined dramatically with the identification and deferral of donors with high-risk behavior in 1983 and the introduction of HIV-1 antibody testing in 1985. In late 1995, blood banks began to test donors for p24 antigen to identify donors in the window period of an early infection who did not have detectable antibody. P24 antigen testing decreased the window period from 22 to 16 days. In late 1999, blood banks introduced nucleic acid testing for HIV-1 RNA to further reduce the possibility that a unit collected during the window period might be transfused. The window period is now estimated to be 11 days. HIV-2 HIV-2 also causes AIDS and can be transmitted by blood. The FDA licensed the first combination test kit for detecting antibodies to HIV-1 and HIV-2 on September 25, 1992. All blood centers were required to implement this combination test by June 1993. Very few cases of HIV-2 have been detected in the United States. The risk of transmitting HIV-2 by blood transfusion is very small. HTLV In 1988, the first generation HTLV-1 antibody test was licensed in the U.S. to screen blood donors for human T cell lymphotropic virus type 1 (HTLV-1), which is a retrovirus that has been associated with adult T cell leukemia (ATCL) and a neurological syndrome, HTLV-I associated myelopathy (HAM). Cellular blood products including red blood cells, platelets and granulocytes can transmit HTLV-1. Plasma components such as FFP and cryoprecipitate do not. Storage of cellular components for more than 14 days appears to decrease infectivity. Between 20 and 60% of recipients who received HTLV-1 positive units prior to the introduction of testing, have seroconverted. Another related virus, HTLV-2, was originally isolated from patients with hairy cell leukemia. It is transmitted by blood and sexual intercourse. Most males in the United States with HTLV-2 infection have a history of drug abuse, while most infected females have a history of sexual contact with a known IV drug user. Because this virus is closely related to HTLV-1, the HTLV-1 antibody test detects the majority of HTLV-2 positive blood donors. A separate test that could specifically identify HTLV-2 antibody was implemented in 1992. Disease associations arising from HTLV-I or HTLV-II infection are much less frequent than HIV. It has been estimated that 4% of individuals infected with HTLV-I at birth may progress to ATCL during their lifetime, usually after an incubation period of at least 20 to 30 years. HAM has been estimated to occur in 0.25% of persons infected with HTLV-1 after an incubation period of months to years. A similar neurological syndrome has been documented as a result of HTLV-II infection. However, there is no evidence linking HTLV-II infection with ATCL. CMV Cytomegalovirus (CMV) is present within the leukocytes of at least 60% of adult blood donors. However, only 1% of seropositive units is infectious. Only cellular blood components transmit CMV infection. Clinical disease is rare in immunocompetent recipients presumably because they have protective CMV antibody levels. Adverse effects are usually limited to heterophile negative mononucleosis syndromes or mild hepatitis. Transfusion transmitted CMV infections can cause serious illness in CMV negative patients who are immunocompromised, such as premature infants ( < 1250 g), bone marrow and solid organ transplant recipients and CMV negative AIDS patients. Clinical manifestations include hepatitis, retinitis, pneumonitis, encephalitis and GI tract disease. Intrauterine infection may cause jaundice, thrombocytopenia, cerebral infarction and mental retardation. The risk of transfusion associated CMV infection may be essentially eliminated by transfusing blood components that are leukocyte reduced (< 5 x 106 WBCs) or are CMV seronegative. It is not necessary to supply seronegative plasma products, since transmission of CMV requires leukocytes. West Nile Virus WNV is a mosquito-borne virus that was associated with meningitis and encephalitis in over 4,000 individuals in 39 states in 2002. During 2002, WNV transmission by transfusion was identified in at least 21 cases, transmitted by blood components from 14 donors. Red blood cells, platelets, and fresh frozen plasma have been implicated in transfusion-transmitted disease. During last year's epidemic, it was estimated that 4 donors per 100,000 were infected with WNV. In the most severely affected communities at the peak of the epidemic, the donor infection rate may have approached 200 per 100,000. Nucleic acid tests (NAT) for WNV in donated blood were implemented on July 1, 2003. During the first year of testing, the detection rate was 1 case per 10,000 donors. Physicians are also encouraged to report to the hospital transfusion service suspected cases of WNV occurring within 28 days after transfusion. Parvovirus B19 Parvovirus B19 is a small nonenveloped virus with a single-stranded DNA genome. It is classified as an erythrovirus because it is highly tropic for erythroid progenitor cells and because complete replication of B19 has been found only in these cells. The cellular receptor for B19 is the blood group P antigen. Individuals who lack the P antigen on their erythroid cells are not susceptible to infection. Parvovirus is detected in the blood of approximately 1 in 35,000 donors. B19 is a common contaminant of pooled plasma or plasma derivatives. Solvent detergent treated plasma and factor VIII concentrates have induced B19 viremia in recipients. Because parvovirus B19 is tropic for erythroid progenitor cells, individuals who have a shortened red cell survival time are at risk for B19 induced anemia due to red cell aplasia. Maternal B19 infection during the first half of pregnancy can result in hydrops fetalis. Aplastic crises may develop in patients with sickle cell disease. Immunocompromised patients may develop severe chronic anemia due to persistent B19 infection. FDA does not mandate screening for B19, but it does recommend that plasma pools have less than 10,000 genome copies per mL. Variant Creutzfeldt-Jakob disease Bovine spongiform encephalopathy (BSE), also known as mad cow disease, is a transmissible spongiform encephalopathy that is responsible for the human neurodegenerative disorder known as variant Creutzfeldt-Jakob disease (vCJD). BSE first appeared in cattle in the United Kingdom (UK) in 1986. The origin of BSE is thought to be cattle feed containing meat & bone meal supplements contaminated by scrapie infected sheep carcasses. Similarly, vCJD was transmitted to humans through consumption of beef products contaminated by infected neural tissue, such as hot dogs, sausages, lunchmeat, meat pies and various canned meat goods. BSE infections in the UK have decreased substantially since 1992 due to slaughter of infected animals and changes in animal feed production. BSE has not occurred in the US or other countries that do not import live cattle, beef products, or livestock nutritional supplements from the UK. The incubation period of vCJD is not known. If large numbers of infected persons are silently incubating the disease, human to human iatrogenic spread may be possible .The disease could unknowingly be spread during invasive medical and surgical procedures and donation of organs, tissues and blood. In December 2003, the United Kingdom Health Secretary reported the world's first possible case of variant Creutzfeldt Jakob disease (vCJD) by transfusion of red blood cells. The blood donor, who was free of symptoms at the time of donation, donated in March 1996. The donor developed vCJD in 1999 and eventually died from it. The recipient was transfused with the unit of blood during surgery in 1996 and died from vCJD in the autumn of 2003. At least 15 other people are known to have received blood from donors who subsequently developed vCJD. So far none has yet developed the disease, but all recipients are being notified and counseled. No sensitive screening tests currently exist. The FDA has taken several measures to prevent future transmission. In 1999, FDA mandated that blood centers must defer donors who:
Syphilis Only two documented cases of syphilis transmission by transfusion have been reported. The last case reported in the United States occurred in 1965. Today, the risk appears more theoretical than real for several reasons:
Lyme disease is caused by a spirochete, Borrelia burgdorferi, that is transmitted to man by tick bites. It is the most commonly reported tick-borne disease in the U.S. The spirochete can remain viable in stored blood for 60 days. Some concern has been raised about the possibility of transmitting Lyme disease by transfusion in endemic areas. Ten components of blood that were donated by infected National Guardsmen were transfused prior to recall. None of the recipients became clinically ill. The risk of transfusion transmitted infection is appears to be very small. This is most likely due to the fact that less than 1% of donors in endemic areas test positive for Borrelia burgdorferi antibodies. Also, spirochetemia occurs only during the earliest stage of disease and is accompanied by flu-like symptoms and rash, which are reasons for donor deferral. Malaria Approximately three cases of transfusion malaria are reported per year in the United States, indicating a risk of about one case per 4 million units transfused. Of 93 cases of transfusion transmitted malaria reported between 1963 to 1999,
Babesia microti Babesia microti is an intra-erythrocyte parasite that causes a malaria-like illness. It is transmitted to man by the deer tick. Endemic areas in the United States include northeastern coastal areas and parts of Wisconsin and Minnesota. Infected persons may remain asymptomatic for many months and could qualify as blood donors. Babesia microti can survive in stored red blood cells for more than a month. Screening tests for Babesia microti antibodies are not available. Permanent deferral of donors with a history of babesiosis appears to be a sufficient safeguard at the present time, since only seven cases of transfusion babesiosis have been reported in the United States. Trypanosoma cruzi Transfusion transmitted Chagas disease appears to be rare in the United States at the present time, but is much more common in Latin America. Approximately 20,000 cases of transfusion induced Chagas diseases occur per year in Latin America, where between 5 and 9% of donors test positive. Seven transfusion-associated cases have been documented in the North America since the 1980's. Most cases were associated with platelet transfusions. More cases may occur in the future, especially in areas with large numbers of Latin American immigrants, such as Washington D.C. and Southern California. Presently, individuals with a history of Chagas disease are permanently deferred from donating blood. Screening tests for antibodies to Trypanosoma cruzi may become necessary in the future, since persons with acute infections remain asymptomatic for long periods of time and Typanosoma cruzi, the parasite which causes Chaga's disease, can survive for several weeks in refrigerated blood. One in 7500 donors in Los Angeles and 1 in 9000 donors in Miami test positive antibodies to Trypanosoma cruzi. |
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