Transfusion Therapy : Blood and Blood Products

Transfusion of blood components (red cells, white cells, platelets, whole plasma, or plasma fractions) is commonplace in the emergency department (ED). Annually in the United States, 15 million blood donations take place and 14 million units of red blood cells (RBCs) are transfused. Although acute hemorrhage is the most common emergency indication for blood transfusion, more nonemergency transfusions and blood component therapy now occur in the ED as a result of the general migration of health care away from inpatient settings. Technical advances have made component therapy directed at specific acute and chronic pathologic conditions practical, safe, and affordable.

Background

RBC Antigens and Antibodies

The first documented transfusion took place in the early 1600s, and sporadic advancement in transfusion medicine occurred over the next three centuries, mainly dabbling in cross-species whole blood transfusions. It was not until the early 1900s that the Austrian Karl Landsteiner found that an individual's serum reacted with the red cells of some but not all other individuals, thereby discovering the red cell antigen-antibody system.

RBC membranes contain a series of glycoprotein moieties, or antigens, that give the cell an individual identity. Two different genetically determined antigens, type A and type B, occur on the cell surface. Any individual may have one, both, or neither of these antigens. Because the type A and type B antigens on the surface of the cell make the RBC susceptible to agglutination, these antigens are termed agglutinogens. The presence or absence of agglutinogens is the basis for the ABO blood group classification, and the blood types are named accordingly as A, B, or AB. Blood type O contains neither the A nor the B agglutinogen. These blood type antigens are represented in Fig. 28.1 .

Figure 28.1, Blood group types and their associated antibodies and antigens.

Within the first year of life, antibodies begin to form against the standard red cell agglutinogens that are not present in the individual patient. These agglutinins are γ-globulins of the immunoglobulin (Ig) M and IgG types and are probably produced by exposure to agglutinogens in food, bacteria, or exogenous substances other than blood transfusions. In the absence of type A agglutinogens (blood types B and O), anti-A antibodies, or agglutinins, spontaneously develop in the plasma. Similarly, in the absence of type B agglutinogens (blood types A and O), anti-B antibodies develop. When both A and B agglutinogens are present (blood type AB), no agglutinins are formed. Blood groups and their genotypes and constituent agglutinogens and agglutinins are shown in Fig. 28.1 .

The reaction between red cell antigens and the corresponding agglutinins results in red cell destruction when noncompatible blood types are mixed. As many as 300 different red cell antigens have been identified, but clinically the A and B antigens are most important; severe, potentially fatal agglutination can occur with the first transfusion of ABO-incompatible blood. The Rh system is likewise very important because there is a chance that transfusion of Rh-positive blood to an Rh-negative patient will result in the formation of Rh antibodies. These antibodies are capable of causing severe hemolysis following a second exposure to the Rh antigen. Of the 40 antigens in the Rh system, D is the most antigenic, but others can also stimulate the production of antibodies in recipients lacking the antigen and thus complicate future transfusions. Other antigen systems in which antibodies could potentially cause hemolytic reactions are the Kell (K and k alleles), Duffy (Fy ^a and Fy ^b ), Kidd (Jk ^a and Jk ^b ), and MNS (M and N and closely linked S and s) systems. Other antigen systems are rarely of clinical importance in transfusion therapy, except in certain patient populations who may require repeated transfusions, such as those with sickle cell anemia.

Crossmatching

Compatibility testing, or crossmatching, involves mixing the donor's RBCs and serum with the serum and RBCs of the recipient to identify the potential for a transfusion reaction. The end point of all crossmatches is the presence of RBC agglutination (either gross or microscopic) or hemolysis. Testing is performed immediately after mixing, after incubation at 37°C for varying times, and with and without an antiglobulin reagent to identify surface immunoglobulin or complement. Each unit of blood product, when properly crossmatched, can be administered with the expectation of safety. Full crossmatching takes approximately 45 minutes to complete.

Types of RBC Preparations

Whole Blood

The normal blood volume of a healthy adult and healthy child is approximately 70 mL/kg and 80 mL/kg, respectively. Though intuitively an ideal transfusion agent, whole blood is seldom used except for autologous transfusions (e.g., autotransfusion) and for exchange transfusions. Whole blood is not indicated for the treatment of hypovolemic shock, which can be treated effectively with a combination of crystalloids (e.g., lactated Ringer's [LR] solution, 0.9% sodium chloride), colloids (e.g., plasma protein, albumin), and packed RBCs (PRBCs). It is also not indicated for the correction of thrombocytopenia, replacement of coagulation factors, or treatment of anemia. The incidence of transfusion reactions following transfusion with whole blood is approximately 2.5 times greater than that with PRBCs. Whole blood contains antigenic leukocytes and serum proteins, which carry higher risk (approximately 1%) for an allergic reaction. Nevertheless, warm fresh whole blood has seen increased popularity in military settings and has been proposed as an alternative to component therapy for civilian use in massive transfusion protocols. Other methods of whole blood transfusion, including autologous transfusion in massive hemothorax, are being explored as promising alternatives to minimize reaction to whole blood transfusion.

Packed Red Blood Cells

PRBCs are prepared by centrifugation and removal of most of the plasma from citrated whole blood. One unit of PRBCs contains the same red cell mass as 1 unit of whole blood at approximately half the volume and twice the hematocrit (55% to 80%) in 250 mL of volume. One unit of PRBCs raises the hematocrit approximately 3% in an adult or increases the hemoglobin level of a 70-kg individual by 1 g/dL. In children, there is an approximate rise in hematocrit of 1% for each 1 mL/kg of packed cells. For example, if 5 mL/kg of PRBCs is transfused, the hematocrit will rise by approximately 5%. Actual changes depend on the state of hydration and the rate of bleeding. Because most of the plasma has been removed, PRBCs cause fewer transfusion and allergic reactions than whole blood does.

PRBCs contain less sodium, potassium, ammonia, citrate, hydrogen ions, and antigenic protein than whole blood does. This may offer advantages in patients with reduced cardiovascular, renal, or hepatic function. The rate of urticaria is still relatively high at 1% to 3% of transfusions, but the incidence of adverse reactions to packed cells is approximately one third of that noted with whole blood. The benefit of increased hemoglobin must be weighed against the potential for volume, electrolyte, and acid-base imbalances following PRBC administration. In cases of massive transfusion (>10 units), there is a significant risk for metabolic and respiratory acidosis, as well as hypocalcemia, which can reach life-threatening levels. Although underlying illness or injury obviously plays a major role in the cause of death, the overall mortality of patients requiring massive PRBC transfusions is approximately 60%.

Transfusion of PRBCs is indicated to provide additional oxygen-carrying capacity and expansion of volume. Packed cells are most commonly used to treat acute hemorrhage and anemia that is not amenable to nutritional correction. When treating acute hemorrhage, PRBCs are usually given: (1) if the hemoglobin level falls below established critical levels for that particular given patient population (see the section on Transfusion Thresholds ), (2) after rapid crystalloid infusion fails to restore normal vital signs, or (3) concurrently with crystalloid infusion in the treatment of obvious life-threatening blood loss.

Specially prepared or screened types of red cells are listed in the following sections. Their indications for use are presented in Box 28.1 .

Box 28.1

Abstracted from Williamson LM, Warwick RM: Transfusion-associated graft-versus-host disease and its prevention, Blood Rev 9:251–261, 1995; and Cushing MM, Ness PM: Principles of red blood cell transfusion. In Hoffman R, Benz EJ, Shattil S, et al, editors: Hematology: basic principles and practice , ed 5, Philadelphia, 2009, Churchill Livingstone/Elsevier, pp 2210–2216.

Indications for the Use of Specialty Red Blood Cells for Transfusion

Irradiated

Neonates
Patients with hematologic malignancies
Stem cell–transplant patients
Directed donations from family members
HLA-matched platelets
Patients with cellular immune deficiency

Washed

Recipients with a history of severe allergic transfusion reactions
IgA-deficient patients
Paroxysmal nocturnal hemoglobinuria

Leukocyte Reduced

Multiple-transfused patients
Multiparous females
Cancer patients undergoing chemotherapy

CMV and EBV Seronegative

Seronegative patients who are currently pregnant
Premature or low–birth-weight infants
Bone marrow or organ transplant recipients
Immunosuppressed patients

CMV , Cytomegalovirus; EBV , Epstein-Barr virus; HLA , human leukocyte antigen; IgA, immunoglobulin A ; RBCs , red blood cells.

Washed RBCs

After centrifugation, red cells can be washed to further remove leukocytes, platelets, microaggregates, and plasma proteins. Washing reduces the titer of anti-A and anti-B, thereby permitting safer transfusion of type O PRBCs into non-O recipients.

Leukocyte-Reduced RBCs

Leukocyte-reduced blood products contain less than 5 × 10 ⁶ leukocytes/unit, whereas standard RBC units contain 1 to 3 × 10 ⁹ leukocytes. Reduction can be performed at the time of collection, in the transfusion laboratory, or at the bedside during transfusion. Leukocyte-reduced products are used to decrease the likelihood of febrile reactions, immunization to leukocytes, and transmission of disease. Currently, approximately 60% to 75% of the U.S. blood supply is leukoreduced. Several groups advocate the use of 100% leukocyte-reduced blood products because of the many adverse transfusion reactions that are associated with leukocytes. Non–leukocyte-reduced products are virtually the exclusive method of transmission of several viruses, including human T-lymphotropic virus 1 and 2, Epstein-Barr virus (EBV), and cytomegalovirus (CMV). Additionally, they help reactivate and disseminate CMV and human immunodeficiency virus (HIV). Moreover, increased rates of bacterial contamination and postoperative and line infections have been associated with the use of non–leukocyte-reduced products. Furthermore, leukocytes lead to human leukocyte antigen (HLA) alloimmunization, which results in increased graft rejection and platelet refractoriness.

Irradiated RBCs

Blood products can be irradiated to reduce the risk for graft-versus-host disease (GVHD) in susceptible patients. Irradiation destroys the donor lymphocytes' ability to respond to host foreign antigens. Box 28.1 lists the indications for use of irradiated PRBCs.

Infectious Complications of Transfusions

Though relatively uncommon, transmission of infectious diseases is the transfusion-related complication most feared by the lay public. Transmission of a wide variety of infectious diseases has been reported, but modern screening methods have sharply reduced the frequency of transmission. Viral illnesses remain the most problematic.

Between 1985 and 1999, 694 deaths associated with transfusion were reported to the Food and Drug Administration (FDA). Seventy-seven (11.1%) of these deaths were caused by bacterial contamination. However, sepsis is an uncommon occurrence because both the citrate preservative and refrigeration kill most bacteria. Concern over sepsis is responsible for the practice of completing transfusions within 4 hours and returning unused blood products to the blood bank refrigerator for future use only if they have been unrefrigerated for less than 30 minutes. Both gram-negative and gram-positive organisms are transmitted, with gram-negative virulence being more commonly associated with mortality. A prospective observational study found that the rate of nosocomial infections was significantly higher in patients receiving blood transfusion. Leukoreduction did not significantly reduce the rate of infection. A 2001 multicenter study by the Centers for Disease Control and Prevention further evaluated the risk for bacterial contamination in the blood pool. The results showed the rate of bacterial sepsis to be much lower than previously thought. Only 0.21 cases and 0.13 deaths per million red cell transfusions occurred. The rate was slightly higher for platelet transfusions, with 10 cases and 2 deaths per million transfusions. Mandatory screening of platelets for bacterial contamination began in 2004 and has further reduced the rate of reported death.

Syphilis may theoretically be transmitted by transfusion, but both refrigeration and citrate markedly reduce the survival of Treponema pallidum . Thus, transmission is only a concern with fresh blood or platelet transfusions. The incubation period for syphilis transmitted by transfusion is 4 weeks to 4 months, and the initial clinical manifestation is commonly a rash. No cases of transfusion-transmitted syphilis have been recognized for many years.

The risk for parasitic infection via transfusion is exceedingly low (<1 per 1,000,000), although prospective blood product donors who have been to an endemic region within 12 months or treated with malarial prophylaxis within 3 years are prohibited from blood donation. Those with a history of babesiosis or Chagas disease are permanently barred. Donors with a history of Lyme disease may donate if they are symptom free and have undergone a complete course of treatment.

Viruses are the organisms most likely to be transmitted by transfusion and are the agents with the greatest potential to cause serious disease. They include CMV, EBV, HIV, West Nile virus (WNV), and the hepatitis viruses.

Most blood products have the potential to transmit hepatitis. Routine testing of blood donors for hepatitis C virus (HCV) has occurred since 1991, but the initial screening tests were relatively inaccurate. Since April 1999, the use of nucleic acid amplification testing (NAAT) to detect HCV RNA has been mandatory. This test has essentially eliminated false positives and has a sensitivity of greater than 99%. The American Association of Blood Banks (AABB) reported the risk for transmission of HCV to be less than 1 per 1,000,000 transfusions. The incubation period for HCV is 2 to 12 weeks following parenteral infusion. The reported risk for transmission of hepatitis B virus (HBV) is higher at 1 per 137,000 transfusions.

Both CMV and EBV may cause a mononucleosis-like syndrome 2 to 6 weeks after a transfusion. Indications for CMV- and EBV-negative preparations are listed in Box 28.1 . Alternatively, leukocyte-reduced products can help protect against CMV and EBV.

The AIDS epidemic has affected transfusion therapy profoundly. In the United States, 3% of AIDS cases have been linked to blood products. The estimated likelihood of transmitting HIV through transfusion is 1 in 1,900,000. Currently, NAAT is used to detect HIV in blood. Because the test detects genetic material in lieu of antibody to the virus, it has significantly reduced the window period during which infection is undetected. Other methods of reducing transmission, including techniques to kill the virus in collected samples (viral inactivation) and the use of blood component substitutes, are being investigated.

Efforts to reduce the risk for transmission of HIV to the general population receiving blood products began early in the course of the epidemic and have had considerable success. Voluntary deferment of blood donation by high-risk groups was encouraged beginning in 1983, and formal screening of all blood products commenced in 1985.

Transmission of WNV by blood transfusion was first documented in the United States in 2002. Since 2003, universal screening for WNV by investigational NAAT occurs on all blood donations. From 2003 to 2005, 1400 potentially infectious donations were removed from the blood pool. Since that time, however, multiple cases of transfusion-associated transmission of WNV have been confirmed. This residual risk for transmission is due to blood units with low levels of viremia. Public health authorities continue to look for ways to eliminate this risk from the blood pool.

Emerging infectious risks to the blood supply are always under investigation. Blood-transmitted infections under current surveillance include parvovirus B19, dengue virus, and the prions that cause Creutzfeldt-Jakob disease. Although a viremic phase of human herpesvirus-8, avian flu (H5N1), H1N1, and Lyme disease has been well documented, no cases of transmission through transfusion have been noted.

A summary of infection risks associated with red cell transfusion is presented in Table 28.1 .

TABLE 28.1

Estimated Risks of Transfusion per Unit of Packed Red Blood Cells in the United States

RISK	RATE
Major allergic reactions	1/100
Anaphylaxis	1/20,000–50,000
Anaphylactic shock	1/500,000
Hemolytic reaction (minor)	1/6000
Hemolytic reaction (fatal)	1/100,000 allergic reactions
Death from sepsis (RBC)	1/5 million
Death from sepsis (platelets)	1/500,000
Parasitic infections (Lyme, malaria, Chagas)	<1/million—data lacking
Hepatitis C	<1/million
Hepatitis B	1/140,000
Parvovirus, Creutzfeldt-Jakob disease	Extremely rare—data lacking
HTLV 1/2 infection	1/200,000
HIV infection	1/2 million
West Nile virus	Extremely rare—data lacking
CMV/Epstein-Barr	Rare—data lacking
Acute lung injury	1/500,000
Graft-versus-host disease	Extremely rare—data lacking
Immunosuppression	Unknown
Syphilis	No cases reported currently

CMV, Cytomegalovirus; HIV, human immunodeficiency virus; HTLV, human T-cell lymphotropic virus; RBC, red blood cell.

Transfusion Reactions

Transfusion reactions can be divided into two phases: acute and chronic. The vast majority of transfusion reactions occur proximate to or concurrently with the administration of red cells. If the ED is the site for a nonemergency transfusion and the patient is otherwise stable enough for discharge, it is a common practice for the patient to be released shortly after the transfusion is completed.

Acute Reactions

Allergic

The most common manifestation of a minor allergic transfusion reaction is urticaria; however, wheezing and angioedema can also be observed. The allergic response is due to the presence of atopic substances that interact with antibodies in the donor or recipient plasma, but the severity is not dose related. Whenever a transfusion reaction is suspected, the first step in management is to stop the transfusion. Treatment is the same as for other allergic reactions and includes antihistamines, corticosteroids, and intramuscular (IM) or intravenous (IV) epinephrine if needed. For mild reactions (e.g., those limited to skin findings), the transfusion can be resumed once treatment has been given.

Anaphylactic

The reported incidence of transfusion-associated anaphylaxis is 1 in 20,000 to 50,000. Anaphylaxis occurs most commonly in IgA-deficient patients who have IgA-specific antibodies of the IgE class. Manifestations of an anaphylactic transfusion reaction include shock, hypotension, angioedema, dyspnea, bronchospasm, and laryngospasm. The symptoms are typically rapid in onset and begin within seconds to minutes of starting the transfusion. If this type of reaction occurs, the transfusion must be stopped immediately. Treatment includes airway management as necessary, IM or IV epinephrine, fluids, corticosteroids, and antihistamines, followed by appropriate supportive care and continued close observation. If a transfusion is still required, the patient needs to be pretreated with corticosteroids and antihistamines 30 to 60 minutes before the transfusion. Alternatively, or in addition, washed cellular products can be used.

Febrile (Nonhemolytic) Reactions

A febrile, nonhemolytic reaction is defined as an increase in temperature of 1°C or higher during or within 6 hours of the transfusion. The mechanism for this type of reaction is most commonly attributed to an interaction between recipient antibodies and donor leukocytes. This stimulates the release of cytokines such as interleukin-1, which ultimately produces a febrile response. Although this type of reaction is not life-threatening, it is difficult to distinguish from more serious transfusion reactions. Accordingly, all patients with a fever attributable to a transfusion must have the transfusion stopped. Symptoms can be treated with acetaminophen or nonsteroidal antiinflammatory drugs. There is no role for antihistamines in the treatment of this type of reaction. Although controversy exists, premedication with antipyretics and antihistamines may prevent these transfusion reactions.

Acute Hemolytic Reactions

An acute hemolytic reaction is usually the result of donor-recipient major ABO incompatibility. This in turn is most commonly the result of blood product misassignment related to clerical error. Hemolytic transfusion reactions are estimated to occur once per every 6000 blood units transfused, with a fatality rate of 1 per every 100,000 units transfused.

When incompatible blood is given, the result may range widely from no effect to death. If the recipient does not have antibodies (naturally occurring or acquired) directed against the foreign RBC antigen received, there will be no immediate reaction, but antibodies to the infused blood may develop within weeks, thus limiting the safety of subsequent transfusions from the same donor or same antigenic type. If the recipient's serum has preformed antibodies directed against the donor RBCs (e.g., an incompatibility in the major crossmatch), the recipient will begin to hemolyze the donor cells within seconds or minutes. In most cases of major crossmatch reactions, RBCs of the donor blood are agglutinated and hemolyzed. It is rare for transfused blood to produce agglutination of the recipient's cells because the plasma portion of the donor blood becomes diluted by the plasma of the recipient. This reduces the titer of the infused agglutinins to a level too low to cause significant agglutination. Because the recipient's plasma is not diluted to any significant degree, the recipient's agglutinins can react with donor cells. The end result of antigen-antibody incompatibility is red cell hemolysis. Occasionally this occurs immediately, but more often the cells first agglutinate. They are then trapped in small vessels and become phagocytized over a period of hours to days and release hemoglobin into the circulatory system. Clinical manifestations of acute hemolysis include chills, fever, tachycardia, abdominal pain, back pain, hypotension, fainting, and a feeling of “impending doom.” Derived from the liberation of intracellular material associated with hemolysis, vasoactive substances may cause hypotension and shock; other substances may precipitate disseminated intravascular coagulation and high-output cardiac failure. Acute renal failure may also result. The presence of hemoglobinemia and hemoglobinuria is essential in making the diagnosis. A decrease in hematocrit and haptoglobin or an increase in lactate dehydrogenase may also be seen.

Treatment of an acute hemolytic reaction begins with immediate cessation of the transfusion. The blood bank should be alerted immediately because a second patient is now at risk for receiving the wrong product. Resuscitation and supportive care along with close monitoring of laboratory values are essential. A sample of blood from the recipient needs to be obtained for a direct antiglobulin test, plasma-free hemoglobin, and repeated type and crossmatch. Urine can also be tested for free hemoglobin. Renal function and electrolytes should be monitored for evidence of renal failure and hyperkalemia. Dialysis is occasionally required. Fluid resuscitation and diuresis with normal saline are recommended to maintain urine output above 100 to 200 mL/hr. LR solution should be avoided because calcium can precipitate clotting.

Drug-Induced Hemolysis

Drug-induced hemolysis is not a transfusion reaction per se; however, it can be indistinguishable from an acute hemolytic reaction in patients receiving blood transfusions. In this case, both autologous and transfused cells are affected. A patient's serum can react with red cells in the presence of certain drugs. Two examples of drugs that can cause this type of reaction are cefotetan and ceftriaxone.

Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) refers to noncardiogenic pulmonary edema occurring during or shortly after the transfusion of blood products. A leading cause of transfusion-related mortality and morbidity, TRALI has been reported to occur in as many as 3% of patients receiving transfusions. TRALI appears to be associated with components from female plasma; preferential distribution of male plasma by the American Red Cross has recently decreased its incidence.

The potential for TRALI is one reason why some authorities are reluctant to transfuse high ratios of plasma to PRBCs in massive transfusion protocols. TRALI is thought to result from the activation of recipient neutrophils in the lung and the production of vasoactive mediators, which leads to increased pulmonary capillary permeability and leakage. Initial symptoms include respiratory distress, hypoxia, hypotension, fever, and bilateral pulmonary edema; however, the spectrum of TRALI can also include much milder reactions.

Treatment of TRALI is supportive and includes supplemental oxygen, endotracheal intubation, and cardiovascular support as necessary. Diuresis and corticosteroids are not effective.

Delayed Reactions

Delayed Hemolytic Transfusion Reactions

Even when major and minor crossmatches indicate compatibility, delayed hemolytic transfusion reactions can occur days to weeks after transfusion. This is due to antibody production by either the donor or recipient B cells in response to exposure to antigens on red cells. Usually seen in patients who have had multiple transfusions or in multigravida women, these reactions may be unavoidable without complete RBC antigen typing, a procedure occasionally indicated for recipients of repeated transfusions. An incompatibility in the minor crossmatch does not usually result in a serious reaction, although the recipient's red cells can be hemolyzed if the titer of the antibody is sufficiently large. Fortunately, 90% of transfusions are now given as PRBCs, which contain a very small volume of plasma, thus minimizing the chance of a transfusion reaction occurring as a result of donor sensitization.

The signs and symptoms of a delayed hemolytic reaction include low-grade fever, a decrease in hemoglobin, mild jaundice, a positive direct antiglobulin test, and elevation of lactate dehydrogenase.

Treatment of a delayed hemolytic reaction is not needed unless there is evidence of brisk hemolysis. In the case of brisk hemolysis, treatment consists of fluids, antigen-negative (type O) blood transfusions, or red cell exchange.

Graft-Versus-Host Disease

GVHD is a transfusion complication most commonly associated with allogeneic hematopoietic cell transfusions. However, it can occur whenever immunologically competent lymphocytes are transfused, especially in immunocompromised hosts. Donor lymphocytes engraft in the recipient and then attack host tissue. Symptoms are typically observed 7 to 14 days after the transfusion and include fever, rash, and diarrhea. Hepatitis and marrow aplasia also occur. GVHD is often fatal; failure of the host's marrow leads to overwhelming infection or bleeding. The use of gamma-irradiated cellular components prevents this complication by making the donor lymphocytes incapable of proliferating.

Posttransfusion Purpura

In rare cases, profound thrombocytopenia can develop 1 to 3 weeks after a transfusion associated with an antibody response to a platelet antigen. A probable pathophysiologic mechanism for this is the production of low-affinity antibodies that cross-react with autologous platelets. Eventually, as the immune response matures, the low-affinity antibody is eliminated and the thrombocytopenia resolves spontaneously. Only patients at risk for bleeding or hemorrhage need to be treated. Treatment consists of high-dose immune globulin, plasmapheresis, or platelet transfusion.

Miscellaneous Transfusion Issues

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here