Harvey G. Klein MD1
1Chief of Transfusion Medicine, National Institutes of Health
The author has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Recombinant activated factor VII (rVIIa) has not been approved by the FDA for uses described in this chapter.
Transfusion medicine has evolved from the empirical administration of blood to a laboratory-based clinical discipline.1 The discovery of blood group antigens and the understanding of the host immune response to these antigens, the development of methods of anticoagulation and storage of blood, the creation of plastic bags that allow sterile separation of whole blood into components, and the advent of the automated blood cell separator all contributed to its advancement. The potential of blood to act as an agent of disease transmission has heavily shaped both the donation process and transfusion practice.2 Decisions about whether to transfuse involve weighing the benefits against the risks. This chapter provides a basis for these decisions, including indications for blood-component use, complications of transfusion therapy, and methods of reducing risks during the collection, processing, and preparation of blood components. Therapeutic removal of blood (phlebotomy) and components (apheresis) are also discussed.
The donation process for either whole blood or special products, such as single-donor platelets (SDPs) obtained by apheresis, is designed to protect both the donor and the recipient. Donor qualification includes stringent donor screening, physical examination, sensitization testing, donor tracing, and donor deferral when instances of disease transmission are discovered. This system of safeguards has made the United States blood supply extremely safe; however, it is not 100% effective. Approximately 2% of volunteer donors still conceal risks that would have led to deferral at the time of donation.3
Autologous and Directed Donation
Autologous donations and directed donations are two strategies adopted by patients seeking to minimize their real or perceived risk of infection from blood components.
Autologous Donation and Bloodless Surgery
In preoperative autologous donation, patients deposit their own blood, which is then available to them should they need transfusion therapy. Autologous blood avoids the risk of new viral infections and sensitization associated with allogeneic blood; however, it does not eliminate bacterial contamination or the risk of receiving the wrong unit of blood because of clerical error.4 Absolute contraindications to autologous donation include tight aortic stenosis, unstable angina, and active bacterial infection. Anemia and poor venous access frequently limit the number of units that can be collected; up to half of the collected units are not used. With the increasing safety of allogeneic blood, autologous donation should be limited to selected patients (i.e., those who undergo joint replacement and vascular and cardiothoracic surgery and who are not anemic at the time of the first donation).5 The advantages and disadvantages of preoperative autologous donation need to be weighed for individual patients [see Table 1].
Table 1 Advantages and Disadvantages of Preoperative Autologous Donation
Acute normovolemic hemodilution (ANH) is another form of autologous donation. In ANH, whole blood is removed from the patient immediately before surgery; the patient is infused with crystalloid solution to maintain normovolemia, and the whole blood that was removed is reinfused when needed, often at the conclusion of surgery. ANH can yield modest blood savings and minimize the risk of clerical error.6 For patients who experience massive bleeding during surgery, semiautomated collection devices can recover, process, and reinfuse blood lost at the operative site (a process referred to as intraoperative salvage).6,7 Centers that advertise bloodless surgery combine autologous strategies, erythropoietic support, and conservative transfusion thresholds to limit exposure to allogeneic blood.8
Blood donated for a specific patient is termed a directed donation; usually, it involves donations made by friends or family members of the intended recipient. Directed donation presumes that the recipient can identify donors who carry lower risk of infections than volunteer donors from the general population. However, prevalence data show that the risk of infectious disease from directed donors is no different from that of first-time donors.9 The current risk of infection via transfusion is so low [see Table 2] that directed donor programs are justified primarily by patient preferences or by the need for a selected donor serving as the only source of blood components to reduce the recipient's risk from exposure to multiple donors. The latter form of directed donation is most appropriate for neonatal transfusions, in which one of the biologic parents may provide all the needed blood components.10 In unusual circumstances, such as cases involving highly immunized patients or patients with rare blood types, directed donations from relatives or matched unrelated donors are medically indicated. However, the use of blood relatives as donors increases the risk of graft versus host disease, unless the blood is irradiated. In addition, transfusing a woman of childbearing age with blood from her spouse or her spouse's relatives increases the risk of hemolytic disease of the newborn in subsequent pregnancies.11
Table 2 Estimated Risks of Blood Transfusion per Unit Transfused
The combination of improved donor selection and postdonation testing has greatly decreased the infectious risks of allogeneic blood [seeTable 2]. Nine screening tests are applied to all donated blood, and supplemental assays, such as testing for cytomegalovirus, are used for special indications, such as stem cell transplantation.
Postdonation testing is essential for identifying donors likely to transmit blood-borne infections who are missed in the initial screening process. The risk of transfusion-transmitted viruses is now so low that estimates must be derived from mathematical models rather than from direct measurement of infected blood recipients.12
Screening for Hepatitis Viruses
Screening for hepatitis C began in 1990 with the availability of a serologic enzyme-linked immunosorbent assay (ELISA). The development of ELISA assays with improved sensitivity, associated confirmatory tests, and nucleic acid testing (NAT) for viral RNA and DNA has led to a reduction in the per-unit risk of hepatitis C virus (HCV) transmission to less than 0.0001% (1 per 1.6 million to 1 per 1.935 million).12,13Before these tests were available, the risk per unit was about 4%. Improved HCV testing has eliminated the need for surrogate tests, such as the measurement of alanine aminotransferase (ALT) levels and testing for antibody to hepatitis B virus (HBV) core antigen (anti-HBc). However, the test for anti-HBc is still used to detect recently infected donors who lack measurable circulating HBV surface antigen (HBsAg).14
The epidemiology of HCV infection is still poorly understood. The majority of transmissions are related to intravenous drug use.15 Sexual transmission occurs with enough frequency to warrant evaluation of partners and appropriate use of methods of barrier protection. Heterosexual transmission of HCV may be asymptomatic; a blood donation from a person who was infected with HCV via sexual contact but has not yet developed detectable antibodies is a potential risk to the blood supply. Therefore, persons who are sexual partners of known HCV-infected persons may be excluded from donation. Donors found to be positive for HCV on ELISA should undergo supplemental testing, such as with recombinant immunoblot assays (RIBA). Donors with positive supplemental test results are likely to have a chronic HCV infection; such persons are rejected as future donors, and they require further clinical evaluation and treatment.16 Donors with negative supplemental test results probably had false positive screening results and may be eligible for reentry into the allogeneic donor pool after 6 months. The infection status of donors with indeterminate supplemental results is best resolved by testing for HCV RNA; those with only a single band on the most sensitive supplemental test (RIBA-3) have a less than 4% chance of having circulating HCV RNA.17
Gene amplification methods for detecting HCV RNA are used on all blood products before those products are released for transfusion. These tests directly detect the presence of virus before antibody development, and their use is responsible for reducing the risk of HCV transmission to the current minuscule level. Correlation studies have shown that only 80% of samples with confirmed positive results on serologic testing for HCV are also found to be positive on NAT. This finding is consistent with previous estimates of the size of the population of persons who were previously HCV-positive persons but who are no longer infected.
HBV remains a major human pathogen with worldwide distribution that causes acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma.18 HBV is highly infectious and is readily transmitted by needle stick and sexual contact. The elimination of the practice of paying whole blood donors together with the development of modern testing methods for HBsAg and anti-HBc has reduced HBV infections to about one in 180,000 units transfused.19 However, donors with low levels of virus, especially during the incubation period, still transmit disease. HBV immunization of patients requiring multiple transfusions of blood or components has long been advised, and childhood immunization is now standard in the United States.
Because the viremic phase of hepatitis A virus infection lasts only about 17 days before signs and symptoms develop, hepatitis A transmission from single-donor components is rare. Pooled products, such as factor concentrates, however, carry a substantially higher risk.20
Hepatitis D is a defective virus that requires HBV to produce fulminating hepatitis; it is a concern only for patients already infected with HBV.
Screening for Retroviruses
All donated blood is screened for HIV-1, HIV-2, human T cell lymphotropic virus type I (HTLV-I), and HTLV-II. Data obtained nationally from American Red Cross donors indicate that the HIV infection risk has been reduced from two per 100 transfusions to about one per 2 million transfusions12; improved safety has been achieved by the exclusion of high-risk donors and the postdonation testing for HIV-1 and HIV-2 antibodies and use of NAT for viral RNA or DNA.12 In follow-up studies, 90% to 95% of recipients of blood that is seropositive for HIV become infected.21
To have predictive value, the ELISA screening test for HIV must be confirmed by some additional assay, most commonly the Western blot assay. Studies employing polymerase chain reaction (PCR) data, culture data, and donor review all indicate that donors with negative or indeterminate Western blot results are seldom, if ever, HIV positive.22 In a follow-up study of donors who tested positive for HIV on ELISA and whose Western blot results were indeterminate, HIV infection was confirmed in 45% of cases on subsequent ELISA testing. Of these patients, 84% still had indeterminate Western blot results, but none were shown to be HIV positive by PCR.23 There have been occasional false positive results of Western blot assays in low-risk donors.24 The possibility of a false positive result should be remembered when one is counseling low-risk donors who have had unexplained positive results on Western blot testing; these false positive results must always be confirmed by careful clinical follow-up.
In the United States, the prevalence of HTLV-I or HTLV-II in donors was about 0.03% in 1995. Data from 2001 suggest that the prevalence has been reduced to about 0.01%; about two thirds of these HTLV-positive patients have HTLV-II infection.12 HTLV is transmitted by cellular components, but not by cell-free plasma or plasma derivatives. Infectivity of cellular components declines with the length of refrigerated storage.23 Several longitudinal studies have defined the clinical consequences of HTLV-I/II infection; they are useful in advising donors who have had positive or indeterminate test results.25 In a prospective, longitudinal study comparing seropositive blood donors with seronegative blood donors, both viruses were associated with an increase in the incidence of some infectious diseases. No cases of adult T cell leukemia or lymphoma were identified; myelopathies, though rare, were associated with both HTLV types.26 The risk of HTLV-I/II transmission by blood components is one per 2,993,000. As with HIV, laboratory studies and epidemiologic investigations of HTLV-I/II indicate that patients with positive results on screening tests and negative or indeterminate results on supplemental testing are unlikely to have clinical sequelae; positive results in these patients are most likely false positives.27
Screening for Other Agents
West Nile virus
West Nile virus (WNV), a flavivirus imported into the United States in 1999, has become a significant transfusion risk; during periods of epidemics, its transmission rate has been estimated to be 3.02 per 10,000 donations in high-risk metropolitan areas.28 Approximately 80% of patients are asymptomatic, 20% experience a febrile illness, and about 1 in 150 develop meningoencephalitis. Elderly and immunosuppressed blood recipients are at particular risk. All blood donations are currently tested for WNV by NAT assays. Several thousand potential transmissions have been interdicted; however, transmissions of WNV continue by means of blood components that have low levels of virus.29
Chagas disease is caused by infection with the protozoan parasite Trypanosoma cruzi, which is found primarily in Latin America. The risk of severe heart or intestinal complications in infected persons is about 30%; complications usually occur long after the initial infection. Seven cases of transfusion-transmitted T. cruzi and five cases of transmission by organ transplantation have been documented in the United States and Canada, although the mild, nonspecific symptoms of early infection make it likely that many cases have gone unrecognized. A serologic blood screening test has been licensed and introduced by the major blood collectors.30
Emerging Infectious Diseases
Until either screening tests or sterilization procedures become available, epidemiologic considerations are the only possible protective strategy against newly recognized infections.31 For example, the recognition that WNV was transmitted by blood components prompted the introduction of screening questions to eliminate donors at risk for this disease; however, the screening questions proved largely ineffective. A nucleic acid-based test for WNV was introduced in June 2003, and it is now a standard screening test for all donated units.32
In the United Kingdom, another form of epidemiologic control was instituted to safeguard against possible transmission of infectious disease by blood transfusion. The incidence of variant Creutzfeldt-Jakob disease (vCJD), which is the human equivalent of bovine spongiform encephalopathy (mad cow disease), and the concern that vCJD may be transmissible by transfusion prompted in the United States the deferral of donors who had lived in or visited countries in which vCJD was reported; this restriction resulted in a reduction of 4% to 5% in the number of active blood donors. Because no screening assay for vCJD is available and because vCJD infection is uniformly fatal, such epidemiologic precautions were considered warranted. However, transmissibility of vCJD by blood transfusion has not been proved, and data are inconclusive and limited.33,34 Reports from the United Kingdom have identified three probable cases of transfusion-associated vCJD and one subclinical infection in a person who received a transfusion from a vCJD-positive donor.33,34 In 23 known recipients of blood transfusions from donors who subsequently developed vCJD, the risk of infection is probably high.33 However, potential blood donors who are rejected on the basis of epidemiologic risk of vCJD should be assured that their risk of having any form of CJD infection is low.
False Positive Test Results during Donor Screening
The causes of false positive test results for HCV and retroviruses are poorly understood. Influenza vaccines administered in 1992 were associated with an increase in false positive results for these viruses.35 However, the proteins responsible for cross-reactivity have not yet been identified. Tests for low-prevalence infections, even tests with excellent specificity and sensitivity, will always be associated with a substantial proportion of false positive results. Consequently, on the basis of test characteristics, as well as culture and PCR results, donors who are not at risk but who have had positive screening-test results and negative or indeterminate confirmatory-test results can be reassured that they are not infected.36 As PCR technology improves, it will probably become the most reliable means of establishing whether a positive result represents infection or is a false positive result. There are insufficient data on the screening test for WNV to determine the prevalence or underlying cause of false positive results.
Blood recipients are routinely tested to establish their ABO phenotype and Rh type. Establishing ABO type is essential because isoagglutinins (antibodies) against A or B antigens not present on a person's red cells are acquired during the first 2 years of life. These IgM antibodies can cause an immediate hemolytic reaction if ABO-incompatible red cells are transfused.
The terminal carbohydrate on these antigens determines specificity in the ABO system, with type A being associated with N-acetylgalactosamine and type B being associated with a terminal galactose. Persons with type O lack both of these terminal sugars. These residues are added by a glycosyltransferase, which was thought to be either nonfunctional or absent in type O persons. Yamamoto and colleagues used molecular techniques to prove that glycosyltransferase in type O persons is very similar to the transferase in type A persons.37 The type O glycosyltransferase is nonfunctional because of a single base deletion that produces a frameshift and a downstream stop codon.
All methods of ABO typing depend on demonstrating that the antigens found on the red cells are consistent with the expected isoagglutinins. D antigen specificity typing in the Rh system is done because of this antigen's potency as an immunogen. Antibodies to the D antigen are the most important cause of isoimmune hemolytic disease of newborns. Rh antigens are membrane glycolipids or glycoproteins. Antibodies against antigens of this class, which includes the Rh, Duffy, Kell, Kidd, and Lutheran systems, will usually cause shortened red cell survival. In contrast to antigens with carbohydrate-mediated specificity, glycolipid and glycoprotein antigens do not stimulate antibody formation unless the transfusion recipient was previously exposed to allogeneic red cells, either from transfusion or from fetal red cells during pregnancy or delivery.
D antigen typing is also done using agglutination techniques. In some cases, less antigenic forms of the D antigen, called weak D, require an antiglobulin reagent to enhance detection. Structural studies of the complementary DNA associated with the major Rh antigens (D, Cc, and Ee) have provided probes for direct genotyping.38 Molecular methods of prenatal Rh type determination have revealed that most Rh-negative persons lack the D gene. Some persons with the weak D phenotype have mosaic D genes because of exchange with some of the exons of the CcEe gene.
Because the genotypes of many of the clinically relevant red cell antigens are known, it is now possible to predict red cell phenotype by DNA analysis.39 Although DNA analysis for determining red cell phenotype is not yet widely available, it will be useful for recently transfused patients, for whom circulating allogeneic red cells complicate antigen phenotyping.
Screening for Antibodies
In addition to identifying patient ABO and D red cell phenotypes, blood banks must screen the patient's serum for red cell-specific antibodies, which can cause serious reactions with transfused red cells. Screening involves testing serum against indicator type O red cells displaying all the clinically important red cell antigens. Positive reactions are detected by adding an antiglobulin reagent (i.e., Coombs reagent) to the incubated mixture of type O red cells after it has been washed free of serum. Any observed agglutination is from the reaction of the antiglobulin reagent with antibody adsorbed on the surface of the indicator red cells [see 5:IV Hemoglobinopathies and Hemolytic Anemias]. Agglutination of the indicator red cells indicates the presence of other antibodies, which require identification. The absence of agglutination excludes all antibodies except those against antigens so rare that they are not displayed on the indicator red cells. Because the alloantibody concentration may fall below the level detectable by agglutination, a negative screen does not guarantee a compatible blood transfusion.
Use of type-specific blood removes the risk of ABO incompatibility; however, residual risk of an immunologic reaction from the antibodies to other red cell antigens remains. Such antibodies are present in about 3% to 5% of a random population; they are also present in 10% to 15% of persons who were recently transfused or women with a history of pregnancy. Screening for antibodies reduces the frequency of reactions to about 0.06%. Performing a full crossmatch, in which the recipient's serum is tested against the red cells actually being transfused, is of little additional benefit; a full crossmatch is used primarily to exclude technical errors, confirm ABO compatibility, and detect the rare antibody that is not detected by the screening.
Before receiving allogenic red cells, patients who have had a transfusion or have become pregnant within the past 3 months must be tested for new antibodies every 3 days. For patients not recently exposed to red cells, there is no consensus concerning the appropriate interval between red cell collection and use of the specimen in pretransfusion testing. Commonly, specimens are accepted 14 to 28 days before the date of use. However, one study showed that no new antibodies appeared in paired specimens collected up to 1 year apart, suggesting that a longer acceptance interval may be possible.40
Most blood donations undergo a centrifugal separation process that allows each component to be used for specific indications. Whole blood can be separated into red cells (which contain most of the leukocytes), platelet concentrates (which contain some leukocytes), and plasma. Plasma can be further separated into coagulation components and albumin. Each whole-blood unit can potentially support many recipients and clinical needs, maximizing use of each donation.
After 24 hours' storage, whole blood contains no active platelets, and after 2 days, the labile factors V and VIII are in decline. Therefore, except for some autologous blood programs that use whole blood rather than packed red cells, use of whole blood has now been almost completely supplanted by therapy employing specific blood components.
Red Blood Cells
The anticoagulant-preservative used determines the shelf life of red cells [see Table 3]. Citrate-phosphate-dextrose (CPD) with the addition of adenine (CPDA-1) increases storage time from 28 days to 35 days. Most red cells are now stored in CPD to which extra nutrients have been added, which increases storage time to 42 days. This additive solution sometimes contains additional saline, which can be removed if units with very high hematocrit (approximately 70%) are needed.
Table 3 Characteristics of Blood Products and Indications for Use
To prevent transfusion reactions or to delay alloimmunization, red cells are further processed by leukocyte reduction (see below) or washing to remove plasma proteins. Current filter technology reduces white cell counts to less than 5 × 106 cells per unit, a concentration that is sufficient to reduce febrile transfusion reactions and delay platelet alloimmunization and refractoriness. Washing red cells removes the plasma, leaving less than 0.5 ml per unit, a degree of plasma depletion usually effective in treating allergic transfusion reactions. Washing red cells requires at least 1 hour; it results in a loss of 10% to 15% of cells and usually shortens the product shelf life to 24 hours, because breaking the seal on the plastic bag that contains the red cells increases the risk of bacterial contamination. Leukocyte reduction can be accomplished during collection, immediately after collection in the blood bank, or at the bedside during product infusion. Prestorage or laboratory filtration is preferred to bedside filtration.41 Universal leukoreduction has been implemented in Canada and Europe, but it is not yet required in the United States because of concerns regarding cost-effectiveness.
Freezing is an alternative method for storing red cells. Red cells can be kept in a cryoprotectant (usually glycerol) for 10 years or more.42Freezing is therefore ideal for storing rare units or autologous units from persons with rare blood types, for whom it is difficult to find compatible allogeneic red cells. When a unit is at the end of its liquid storage shelf life, the cells can be rejuvenated with fresh media and nutrients; they can then be refrozen and stored. To be used, frozen red cells must be thawed and the glycerol removed; consequently, preparation time for this product is longer than for products stored in the liquid state.
Platelets can be provided either as platelet concentrates from a number of blood donors or from a single donor [see Table 3]. SDPs are collected by a continuous apheresis process that removes platelets and returns all other blood components. A single transfusion of platelet concentrates usually consists of platelets derived from four to six units of donated whole blood, which is about the same number of platelets contained in one SDP product. Platelets are suspended in 200 to 300 ml of plasma. The advantage of SDP therapy is the reduced risk of blood-borne infection and antigen exposure, because the product is from one donor rather than from four to six; disadvantages are a longer collection time, greater cost, and, often, limited supply.43 ABO Rh-compatible platelets should be used when possible, because significantly better therapeutic results are obtained from compatible transfusions.12,44
Fresh frozen plasma (FFP), which is plasma that is frozen within 8 hours of collection, contains all the procoagulants at normal plasma concentrations. Units of FFP prepared from whole blood generally contain 300 to 330 ml and contain virtually all plasma proteins in concentrations equivalent to those of fresh plasma. After thawing, FFP can be kept for 24 hours at 2° to 6° C and will retain 3 to 4 mg/ml of fibrinogen and 1 IU/ml of the other clinically important coagulation proteins.
Cryoprecipitate consists of the cryoproteins recovered from FFP when it is rapidly frozen and then allowed to thaw at 2° to 6° C. These cryoproteins include fibrinogen, factor VIII, von Willebrand factor, factor XIII, and fibronectin. About 40% of the components in FFP are recovered. The cryoproteins are suspended in a small amount of plasma that contains ABO isoagglutinin at the concentration found in normal plasma. A pool of 10 units of cryoprecipitate (each derived from one unit of FFP) contains an amount of fibrinogen equivalent to four units of FFP but in one fourth to one fifth the volume. Consequently, a cryoprecipitate pool permits more rapid replacement of fibrinogen than FFP but has the disadvantage of more donor exposures. After the cryoprecipitate is removed from FFP, the residual product is known as cryopoor plasma. Once frozen, cryopoor plasma has the same shelf life as FFP [see Table 4]. With the exception of a few cell-associated pathogens, such as HTLV I/II and malarial parasites, plasma components present the same risk of infectious disease transmission as does whole blood.
Table 4 Plasma and Recombinant Clotting Factors
Transfusion of Red Cells
Indications for Allogeneic Transfusion
Acute Blood Loss
The decision whether to use red cells depends on the etiology and duration of the anemia, the rate of change of the anemia, and assessment of the patient's ability to compensate for the diminished capacity to carry oxygen that results from the decrease in red cell mass.45Management of acute anemia caused by bleeding or operative blood loss will differ from management of chronic anemia to which the patient has adapted. However, the question underlying any red cell transfusion is whether there is sufficient oxygen delivery to tissues for current needs.
Compensatory mechanisms for acute blood loss include adrenergic response, leading to constriction of venous beds, which improves venous return; increased stroke volume, tachycardia, or both; and increased peripheral resistance, which eventually redistributes blood flow to essential organs. Also contributing to the maintenance of intravascular volume is the shifting of fluid to the intravascular space; this shifting occurs relatively rapidly from the extravascular space and more slowly from the intracellular to the extravascular space.37
A decrease in blood volume has distinct effects on oxygen delivery, depending on the volume of blood lost and the functioning of the compensatory cardiovascular responses. Restoration of intravascular volume, usually with crystalloid, ensures adequate perfusion of peripheral tissue and is the first treatment goal for a patient with acute blood loss. Whether red cell transfusion is required depends on the extent of blood loss and the presence of comorbid conditions that may limit host response to the blood loss. The American College of Surgeons has correlated blood loss with clinical findings. Loss of up to 15% of total blood volume (class I hemorrhage) usually has little effect; this amount is the maximum permitted in normal blood donation. A class II hemorrhage (15% to 30% loss) results in tachycardia, decreased pulse pressure, and, possibly, restlessness. A class III hemorrhage (30% to 40% loss) leads to obvious signs of hypovolemia; mental status often remains normal. Red cell transfusion is usually indicated when blood loss exceeds 30% in a patient without other significant comorbid conditions. However, the presence of serious cardiac, peripheral vascular, or pulmonary disease can lower this threshold. For example, anemic patients with significant coronary artery disease are more likely to have serious postoperative myocardial complications. One unit of red cells will raise the hemoglobin concentration about 1 g/dl in an adult.
The threshold for red cell transfusion has been evaluated in two randomized, controlled trials. In one study of transfusion after coronary artery bypass, patients who received transfusions for hemoglobin levels below 8 g/dl did no worse than patients who received transfusions for hemoglobin levels below 9 g/dl.46 The other trial compared outcomes in critical care patients who received transfusions when their hemoglobin level fell below either 7 g/dl or 10 g/dl.47 Enrollment in this study was limited to patients who were euvolemic at entry and whose hemoglobin levels were from 7 to 9 g/dl; patients who had undergone routine cardiac procedures or who were actively bleeding upon entry to the intensive care unit were excluded. There was no statistical difference in 30-day mortality for these two groups. However, in the subgroups of patients younger than 55 years and patients whose illness was less severe, as defined by standardized clinical criteria, Kaplan-Meier survival estimates were significantly better in the patients who were not transfused unless hemoglobin levels dropped below 7 g/dl. These results are provocative, but they must be interpreted cautiously. They do suggest that more restrictive transfusion policies may be safely adopted for selected patients. However, the enrollment criteria may have biased the findings, and this calls into question the applicability of these findings to other settings.
In the chronically anemic patient, an increase in red cell 2,3-diphosphoglycerate leads to a shift in the oxygen dissociation curve and improved delivery of oxygen to tissues. This adaptation augments the mechanisms for improved oxygen delivery described above. Indications for transfusion depend on clinical assessment of the adequacy of oxygen delivery and are also guided by the etiology of the anemia.45 In patients for whom the anemia can be reversed with iron, folic acid, or vitamin B12, transfusion therapy is indicated only when clinical conditions cannot be tolerated during the period in which the endogenous red cell mass is being regenerated. Patients with chronic renal disease are typically deficient in erythropoietin. Replacement therapy with exogenous erythropoietin [see 5:III Anemia: Production Defects] often obviates transfusion. It is rarely necessary to return the hematocrit to “normal” levels to provide clinically effective therapy. Patients with anemia that is a result of chronic disease such as rheumatoid arthritis, malignancy, or AIDS may also respond to erythropoietin.48
Relatively little is known about transfusion thresholds in specific medical illnesses. An observational trial has addressed the effect of anemia on the 30-day mortality of elderly patients hospitalized with acute myocardial infarction. Mortality was reduced in those patients who were transfused to a hematocrit of 30% to 33%, but transfusion had little or no effect on patients who presented with a hematocrit already in the 30% to 33% range.49
Indications for Autologous Transfusion
Whether the criteria for autologous transfusion should be the same as that for allogeneic transfusion remains unresolved. Although the risk associated with autologous blood is less than that associated with allogeneic blood, it is not zero. Errors in labeling, storage, and processing can still occur. For these reasons, many argue that uniform standards based on oxygen delivery should apply, regardless of the blood source. Others, citing the reduced risk, advocate returning most or all of the predeposited units to the patient. There is no clinical evidence that either transfusion policy is associated with better or worse patient outcomes.50
Transfusion of Platelets
In general, the decision to transfuse platelets rests on the answers to two questions: (1) Is thrombocytopenia the result of underproduction or increased consumption of platelets? and (2) Do the existing platelets function normally?
Indications for Transfusion
Low Platelet Count
Thrombocytopenia can result from decreased production caused by marrow hypoplasia or from increased consumption caused by conditions such as immune thrombocytopenic purpura (ITP). In a patient with ITP, surviving platelets are larger and younger and function better than would be expected given the platelet count; platelet transfusion is largely avoided or minimized for such a patient, although in life-threatening situations the transient increment from a platelet transfusion can prove vital. In contrast, with hypoplasia, hemostasis is more severely impaired, and the risk of bleeding is relatively higher. Platelet transfusions should be given to patients with clinically significant hemorrhage and severe thrombocytopenia. The decision to transfuse patients who have hypoproliferative thrombocytopenia prophylactically is generally initiated when the platelet count drops below a certain threshold. Published consensus guidelines provide an excellent summary of all aspects of platelet therapy.51
The time-honored transfusion threshold of 20,000/µl used for platelet prophylaxis was established on the basis of studies of patients receiving aspirin; the results of more recent controlled trials indicate that this threshold is high. The prevalence of bleeding increases significantly below a threshold of about 10,000 platelets/µl in otherwise asymptomatic patients.52 Transfusion at levels above 10,000 platelets/µl may be necessary in newborns; in patients with signs of hemorrhage, high fever, precipitous decline in platelet count, and additional hemostatic defects; and in patients undergoing invasive procedures.51
Platelet function is the second criterion for the transfusion of platelets. Transfusion is appropriate in a bleeding patient whose platelet count is adequate but whose platelets are dysfunctional as a result of medications such as aspirin or nonsteroidal anti-inflammatory drugs or as a result of bypass surgery. In a bleeding patient, if platelet dysfunction is the result of inherited or acquired defects, transfusion is indicated to provide a minimum number of normal platelets. Platelet function is abnormal in uremic patients, and definitive treatment requires correction of the uremia. Some studies suggest that interventions that increase von Willebrand factor levels, such as desmopressin (1-desamino-8-D-arginine vasopressin [DDAVP]), conjugated estrogen, or cryoprecipitate, may favorably influence platelet function in uremia.47 In vitro evidence suggests that DDAVP may improve platelet dysfunction caused by glycoprotein IIb or glycoprotein IIIa (GPIIb/IIIa) inhibitors (e.g., eptifibatide, abciximab, tirofiban) or aspirin.51
Contraindications to Platelet Transfusion
Proper investigation of the causes of thrombocytopenia will identify clinical situations in which platelets are traditionally withheld because they may contribute to the evolution of the illness. These disorders include thrombotic microangiopathies, such as thrombotic thrombocytopenic purpura (TTP), hemolytic-uremic syndrome, and HELLP syndrome (hemolysis, elevated liver enzymes, and a low platelet count). Patients with these disorders rarely bleed; when hemorrhage occurs, platelet transfusion may prove life saving. Posttransfusion purpura is usually unresponsive to platelet transfusions that are not matched to avoid the platelet-specific antigen, but it may respond to intravenous immunoglobulin (IVIg) or plasma exchange.53 Transfused platelets are short lived in patients with immune thrombocytopenia (e.g., ITP), but they cause no harm and may effect hemostasis temporarily when hemorrhage occurs.54
Response to Platelet Transfusions
Both platelet and host factors influence the response to platelet transfusions. Length of in vitro storage, storage temperature, adequacy of oxygenation, and extent of pretransfusion manipulation all influence in vivo survival. Important host factors that influence survival are body temperature, splenomegaly, ABO compatibility, and immune status.
A transfusion of appropriately stored fresh platelets—whether pooled concentrates or SDPs—should contain about 6,000/µl to 10,000/µl platelets per unit (5.5 × 1011 platelets). Thus, in an unsensitized 75 kg (165 lb) recipient, each unit should yield an increment of about 60,000 platelets/µl. A posttransfusion count is usually obtained after 1 hour; however, a count can be obtained as early as 10 minutes after transfusion. A case is considered refractory to platelet transfusions when the 1-hour posttransfusion increment is less than 10,000 platelets/µl after the patient is given 3.3 × 1011 freshly stored (< 48 hours) platelets.
Platelet Transfusions in Refractory Cases
Platelets have platelet-specific antigens, human leukocyte antigens (HLA), and blood group antigens. Immune response to any of these can contribute to platelet unresponsiveness. Platelet surfaces have only class I HLA antigens, of which only HLA-A and HLA-B are clinically important. Polymorphic antigens are found in association with each of the major platelet proteins: HPA1a/2a (formerly called PlA1/A2) and HPA4 (Pen) on glycoprotein IIIa, HPA3a/b (Bak system) on glycoprotein IIb, and HPA 2a/b (Sib and Ko) on glycoproteins Ia and Ib. Each of these antigen groups is associated with isoimmune neonatal thrombocytopenia. The prevalence of antibodies to platelet-specific antigens is increased for patients sensitized to HLA antibodies; therefore, antibodies to both sets of epitopes may contribute to refractoriness in patients who fail to respond to HLA-matched platelets.55
In cases that are refractory to platelet transfusions, treatment involves addressing nonimmune causes (e.g., fever, sepsis, bleeding, and disseminated intravascular coagulation [DIC]) and providing recently collected ABO-compatible components. If these strategies fail, minimization of the effects of HLA antibodies or platelet antigens through HLA typing, platelet crossmatching, or both is indicated.51,55Selecting platelets matched at the HLA-A and HLA-B loci may improve responsiveness in about half of patients with positive HLA antibody screens. Computed best-match selection programs prove useful when identical matches are unavailable.56 Unless contraindicated because of transplant considerations, an empirical trial of donations from family members may also be helpful.
In one study undertaken to determine the best method of treating refractory cases, platelet selection by crossmatching was compared with selection by HLA criteria. Selection by crossmatching was equivalent to HLA selection and yielded better results.57 Another study found that crossmatched platelets provided equivalent platelet increments that were independent of the grade of HLA match.58 Although these results are promising, the effectiveness of selection either by HLA and crossmatching or by crossmatching alone is often limited by nonimmune host factors.
Modifying the effects of alloimmunization is difficult. IVIg can improve platelet increments but not platelet survival. In some circumstances, response reflects an underlying autoantibody in addition to alloantibodies. Plasma exchange is of limited value because it is difficult to remove IgG antibodies. In some patients, the HLA antibodies responsible for refractoriness may regress over time; it is therefore important to periodically retest for the presence of HLA antibodies. If the HLA antibody screen becomes negative, a trial of non-HLA-matched (i.e., from random donors) platelets is warranted.
All in all, the best strategy is prevention, which can be achieved by avoiding unnecessary transfusions and using only leukocyte-depleted components. A randomized, prospective trial examined how best to prevent alloimmunization in newly diagnosed patients with acute myeloid leukemia. The study compared leukocyte reduction by filtration and by ultraviolet B irradiation of platelets; both methods were equally effective.59 In addition, the study found that platelets obtained from single random donors provided no additional benefit over pooled platelet concentrates from random donors.59 Although leukocyte reduction significantly reduced the occurrence of alloimmunization, it did not prevent secondary immune responses in patients already sensitized through either pregnancy or transfusion.59,60
Transfusion of Fresh Frozen Plasma, Plasma Derivatives, and Recombinant Products
Fresh Frozen Plasma
Despite a paucity of indications for FFP use, roughly four million units are transfused annually.12,44,61 FFP is most appropriate for replacing the multiple coagulation deficiencies that result from massive transfusion, liver disease, warfarin toxicity, or acute or chronic DIC. In addition, FFP can be used to treat thrombotic microangiopathies and specific factor deficiencies when factor concentrates are not available.62 After one blood volume exchange using only red cells, plasma components are diluted to about 40% of their original concentration; after two blood volume exchanges, plasma components are diluted to 15%. Prothrombin time (PT) and partial thromboplastin time (PTT) become prolonged when coagulation components are lower than 30%, but abnormal bleeding from dilution usually does not occur until these values are less than 17% of normal. Microvascular bleeding associated with a PT and PTT greater than 1.5 times normal is an indication for FFP. Whether FFP replacement is needed when PT and PTT are over 1.5 times normal but are not associated with bleeding is less clear-cut; paracentesis and thoracentesis did not cause increased bleeding in patients with PT and PTT that were up to twice normal values.63 No data support the use of FFP to correct slight prolongation of PT and PTT. In a prospective audit, transfusion of 1,091 units of FFP to correct mild abnormalities in coagulation values resulted in partial normalization of PT in a minority of patients and failed to correct the PT in 99% of patients.64
The FFP dose depends on whether a consumptive process, such as TTP or DIC, is being treated concurrently with the use of hemodilution. For a patient requiring hemodilution alone, 15 ml/kg will usually be sufficient. However, if a thrombotic microangiography is present, the dose is best guided by the effect of treatment on PT and PTT. If fibrinogen is lower than 80 mg/dl, cryoprecipitate may be required to rapidly increase fibrinogen; PT and PTT determinations are inaccurate at this level. However, four units of FFP can be used in most cases to provide the same amount of fibrinogen as one pooled unit of cryoprecipitate. Urgent reversal of the effects of warfarin can usually be accomplished with about 5 to 10 ml/kg of FFP.
Thrombotic microangiopathies [see 5:XIII Platelet and Vascular Disorders] are treated with either FFP transfusions or, more often, plasma exchange with either FFP or cryopoor plasma.60 The dose of either product is usually equal to a plasma volume exchange of 1.0 to 1.5, which is carried out daily until clinical improvement occurs.65
No factor XI concentrates are licensed in the United States. Therefore, FFP is the treatment of choice for factor XI deficiency. FFP is not used to replace antithrombin III, because a purified concentrate is available.66
Recombinant activated factor VII (rFVIIa) was approved in 1999 for the treatment of bleeding episodes in patients with hemophilia A or B who have antibodies (inhibitors) to factor VIII or IX, respectively.67 Recently, rFVIIa was approved by the Food and Drug Administration for use as replacement therapy in factor VII deficiency, whether the deficiency is acquired (e.g., as a consequence of liver disease) or inherited. In addition, rFVIIa is useful in the activation of the coagulation tissue factor pathway. For patients with inhibitors, rFVIIa is given at a dosage of 90 µg/kg as a slow I.V. push over 2 to 5 minutes; the dosage is repeated every 2 hours, as needed. For factor VII deficiency, the dosage is 20 to 30 µg/kg given as a slow I.V. push over 10 minutes; given in this manner, rFVIIa treatment will reduce the PT to normal within 20 minutes after administration. Depending on the clinical setting, the PT will become prolonged again 3 to 4 hours after treatment.
Off-label use of rFVIIa as a universal hemostatic agent has become increasingly common in the treatment of uncontrolled hemorrhage in patients who do not have a preexisting bleeding disorder and who are unresponsive to FFP.8,68,69,70 Because rFVIIa is believed to act primarily on the platelet surface, it is important that severe thrombocytopenia be corrected before administration of rFVIIa. Furthermore, rFVIIa has been associated with thromboembolic events and should be used cautiously in patients at increased risk, such as those with cardiovascular disease, cerebrovascular disease, or DIC.71 Its high cost and potential for contributing to the development of DIC should limit its use to carefully selected patients for whom other alternatives are not available [see Tables 4 and 5].
Table 5 Recombinant Factor VII (rVIIa) Indications and Dose
Factor VIII Concentrates
The introduction of plasma-derived factor VIII concentrates in the 1960s brought a significant improvement in the treatment of hemophilia A. Unfortunately, these concentrates were derived from large pools of donor plasma, and contamination of the factor with HBV, HCV, and, especially, HIV resulted in the widespread transmission of these infections in the hemophilia community. Since 1980, new methods of heat sterilization, solvent or detergent treatment, and immunoaffinity purification have yielded an array of factor concentrates that are highly purified and free from these infectious agents. The efficacy of these viral-inactivation methods has been validated by molecular testing for the presence of these pathogens and by longitudinal epidemiologic surveillance.72 There have been no documented transmissions since 1985. Recombinant factor VIII concentrates of ultra high purity (> 3,000 International Units of clotting factor activity per mg of protein) are now available and are used widely for newly diagnosed hemophilia patients [see Table 4]. The dosage is calculated on the assumption that that 1 U/kg body weight of factor VIII will raise the plasma activity by about 2%. The circulating half-life of factor VIII is 8 to 12 hours.
The factor VIII preparation Humate-P is also rich in von Willebrand factor and is approved for the treatment of von Willebrand disease. This product has the major advantage of being free of the risks of infection associated with cryoprecipitate. If Humate-P is not available, the factor VIII preparations Alphanate or Koate-DVI may be used, but they are not approved for this purpose and their efficacy is uncertain.
The advances in the safety and purity of factor VIII concentrates, especially in the case of the recombinant products, have increased the cost per unit fivefold to 10-fold.73
The possibility that a nonhuman source of factor VIII would be useful in the treatment of patients with acquired factor VIII inhibitors led to the development of a highly purified porcine factor VIII concentrate. This was shown to be effective for patients whose factor VIII antibody does not cross-react with the porcine product.74 About one third of patients develop antibodies to the porcine product, which limits its usefulness for repeat treatments.
Factor IX Concentrates
Factor IX complex concentrates contain about equal amounts of the vitamin K-dependent factors II, VII, IX, and X. These preparations are available in several degrees of purity, but all have the disadvantage of being thrombogenic when used for extended periods or in patients with liver disease. These concentrates can be used for urgent reversal of warfarin anticoagulation. Highly purified plasma-derived and genetically engineered factor IX preparations are free of this complication and are the products of choice in treating factor IX deficiency [seeTable 4].75 One U/kg of factor IX concentrate raises the plasma activity by about 1%; the half-life is approximately 18 hours.
Activated prothrombin complex concentrates (i.e., Autoplex-T and FEIBA) have been used to bypass the need for factor VIII in selected patients with hemophilia A and acquired inhibitors. This provides an alternative for patients who do not respond to rFVIIa or porcine factor VIII [see 5:XV Coagulation Disorders].
Transfusion of Granulocytes
A direct relationship between the number of circulating granulocytes and bacterial infection has been recognized for more than 40 years.76Granulocyte transfusion can be effective in the treatment of severely neutropenic patients (absolute neutrophil count < 500/µl) with bacterial or fungal infections. Transfusion of granulocytes in doses in the range of 4 × 1010 to 8 × 1010 can be obtained by apheresis of donors who have been pretreated with granulocyte colony-stimulating factor (G-CSF) and a single dose of dexamethasone.77 Granulocyte transfusions at these dose levels have been shown to produce measurable, sustained increments in neutrophils, even into the normal range. The indications and clinical benefits of granulocyte transfusion at these higher doses are still being determined. Randomized trials are required to fully define the clinical efficacy of granulocyte transfusions. After collection, granulocytes must be stored at room temperature and irradiated to prevent transfusion-associated graft versus host disease. Granulocyte concentrates contain large numbers of erythrocytes; crossmatching between the specimen and the potential recipient should be performed to ensure red cell compatibility. Administration of granulocytes from random donors to alloimmunized patients is inadvisable, because improvement will usually be negligible and severe reactions may result.78
Transfusion of Immune Globulin
Many human immune globulin preparations are available. Immune serum globulin, administered intramuscularly, is used to treat chronic immunodeficiency disease and for the prevention or alleviation of measles, tetanus, and rabies. Hepatitis A can now be prevented by vaccination [see 4:VII Acute Viral Hepatitis]. Alternatively, a traveler who will spend less than 3 months in an endemic area can receive 0.02 ml/kg of immune serum globulin. Hepatitis B immune globulin (HBIg) is used for postexposure prophylaxis against HBV infection [seeCE:V Adult Preventive Health Care]. HBIg is prepared from plasma with high titers of antibody to hepatitis B surface antigen. RhO(D) immune globulin is used to prevent the development of anti-RhO (anti-D) antibodies in Rh-negative women who have just given birth, undergone amniocentesis, or aborted, if the biologic father is thought to be Rh positive. Intramuscular preparations must not be administered intravenously.
Several intravenous preparations of immune globulin are available with concentrations ranging from 3% to 12%. Intravenous administration of human immune globulin promptly elevates circulating IgG levels and is preferable to intramuscular administration. The half-life is about 21 days. IVIg is used to treat congenital or acquired chronic immunodeficiency disease [see 6:VIII Deficiencies in Immunoglobulins and Cell-Mediated Immunity]. The intravenous dosage for such deficiency syndromes is 0.2 g/kg/month; however, the dosage can be raised to 0.3 g/kg/month, or the agent can be given more often if needed. IVIg is widely used to treat autoimmune disorders such as ITP, Guillain-Barre syndrome, and chronic, demyelinating polyneuropathy.79 Burgeoning off-label use has resulted in repeated product shortages.
The most common side effects of IVIg therapy—headache, nausea, and fever—usually respond to symptomatic treatment and reduction of the infusion rate. Rarer and potentially more severe side effects are anaphylactic reactions, hemolysis from anti-A and anti-B antibodies, and acute renal failure.79 Renal failure has been attributed to osmotic nephrosis caused by the high sucrose concentration in many IgG preparations. In one study, aseptic meningitis was the most common of the serious side effects, with a frequency of 11%; patients with a history of migraine had a significantly higher incidence of aseptic meningitis.80 Aseptic meningitis usually occurs within 24 hours after administration and does not respond to a reduction of the infusion rate. Patients may be required to stay in the hospital for symptomatic treatment; if further treatment is needed, changing the lot or preparation of IVIg may alleviate this side effect. Thromboembolism of unknown cause has also been reported, and manufacturers have called specific attention to this complication.81 Current manufacturing practices eliminate HCV from IVIg preparations.
Transfusion of Stem Cells
Stem cell transplantation, initially pioneered for use in leukemia, is used to treat a number of life-threatening, malignant, hereditary, and immunologic disorders [see 5:XI Hematopoietic Cell Transplantation].
Complications of Transfusions
Hemolytic Transfusion Reactions
Hemolytic transfusion reactions are classified as immediate or delayed, depending on their pathophysiology. Immediate hemolytic reactions may be caused by a preexisting antibody in the recipient that was not detected during pretransfusion testing or, more commonly, by transfusion of ABO-incompatible blood in error.82 Delayed hemolytic reactions are the result of an anamnestic response to an antigen to which the recipient is already sensitized. The renewed antigenic exposure in a person already sensitized to an antigen can result in stimulation of antibody to levels that can cause hemolysis. This is in contrast to an immune response during primary sensitization, which seldom causes hemolysis, because antibody levels develop at a much slower rate. Not all antibodies are clinically significant; the most common and important ones are in the Rh, Kell, Duffy, and Kidd systems.
Patients with sickle cell disease appear more likely than others to become alloimmunized and to have delayed hemolytic transfusion reactions, which often occur in association with occlusive pain crisis. These reactions are occasionally associated with severe hyperhemolysis involving autologous, as well as allogeneic, red cells; these episodes can be life-threatening. The cause of these episodes is unknown, but they have been attributed to so-called bystander hemolysis associated with abnormal function of CD59 (membrane inhibitor of reactive lysis [MIRL]), transfusion-associated marrow suppression, or both.83
Diagnosis of Hemolytic Reactions
The pathophysiologic differences between immediate and delayed hemolytic transfusion reactions account for some of their differences in clinical findings. Fever is a common sign associated with both immediate and delayed hemolytic transfusion reactions.
Clinically, hemolysis is likely to be more severe in immediate hemolytic reactions; clinical findings may include back pain, pain along the vein into which the blood is being transfused, diaphoresis, changes in vital signs, evidence of acute renal failure, respiratory compromise, and signs of developing DIC. Red or brown plasma points to hemoglobinemia from intravascular hemolysis, whereas red urine in the absence of red cells indicates that hemoglobin from lysed red cells is being cleared by the kidney (hemoglobinuria). Immune-mediated acute hemolytic reactions reflect a systemic inflammatory response that involves multiple organ systems. These findings are probably caused by immune complexes activating the complement and kinin systems, by the direct effects of red cell stroma on kidney function, and possibly by the release of inflammatory cytokines such as interleukin-1β (IL-1β), IL-6, and tumor necrosis factor (TNF).84
In delayed hemolytic reactions, hemolysis with hemoglobinemia and hemoglobinuria (sometimes associated with renal failure) also occurs, but it is less common and generally less severe. In many delayed hemolytic transfusion reactions, the only clinical findings may be mild anemia, a newly positive Coombs test result, and the appearance of a new antibody against red cell antigens. Many such reactions go undetected because they occur 5 days or more after transfusion, at a time when some patients have already been discharged from the hospital. When hemolysis is absent, these reactions are sometimes called delayed serologic transfusion reactions.85 At the Mayo Clinic, two surveys sought to identify the incidence of both kinds of delayed transfusion reactions. The most recent survey, covering the period from 1993 to 1998, revealed a relative increase in delayed serologic transfusion reactions and an associated decrease in delayed hemolytic reactions, with overall increases in the incidence of these reactions. The earlier survey, which covered the period from 1980 to 1992, revealed an association between delayed transfusion reactions and the presence of antibodies to Jka and Fya or antibodies with multiple specificity; this association was not found in the later survey. These changes probably result from improved systems for identifying clinically significant nonhemolytic antibodies.86
In some cases, antiglobulin testing may yield positive results after all the transfused cells have been cleared, often with only complement being detected on the red cells. This finding has been attributed to autoimmune hemolysis that sometimes accompanies the delayed transfusion reaction.
Treatment of Hemolytic Reactions
As soon as a hemolytic transfusion reaction is suspected, the transfusion should be immediately discontinued. The diagnosis can be confirmed or excluded by sending the remaining blood product, together with a freshly drawn posttransfusion specimen, to the blood bank. The blood bank rechecks all records, confirms the patient's type and antibody screen, checks for evidence of hemoglobin in the plasma, and rechecks the crossmatch and antiglobulin test results. These tests will confirm or disprove the diagnosis and identify the antibody causing the immediate hemolytic reaction, when present. Until these studies have been completed, any further blood products should be given only with the approval of the blood bank's medical director.
Acute hemolytic reactions
Acute hemolytic transfusion reactions constitute a medical emergency and should be managed with aggressive supportive care in an intensive care setting. Circulatory and ventilatory support may be required. Mannitol has been infused traditionally to encourage tubular urine flow. Little evidence supports the use of diuretics to increase renal blood flow or heparinization to treat DIC, although platelets and FFP may be needed to manage the coagulopathy. Until the antibody causing the immune hemolysis is identified, only type O red cells and AB plasma should be used.
Delayed hemolytic reactions
Managing delayed transfusion reactions is simpler because of the slower tempo at which these reactions develop. The diagnosis requires identifying a new antibody against red cell antigens and searching for clinical evidence of hemolysis. Treatment involves replacement with the appropriate antigen-negative blood components when transfusion is necessary. Acute renal failure and DIC are unlikely but would be managed as described for immediate hemolytic reactions. The severe, atypical delayed transfusion reactions sometimes found in patients with sickle cell disease may require aggressive transfusion support.
Prevention of Hemolytic Reactions
Prevention of immediate and delayed hemolytic transfusion reactions depends on recognizing their respective proximate causes. Immediate hemolytic reactions are usually caused by errors made during the procurement or processing of blood specimens, during pretransfusion testing, or during product infusion.82 In a review of transfusion-related deaths reported to the FDA between 1990 and 1998, approximately 50% were caused by clerical errors that led to transfusion of ABO-incompatible blood, a rate virtually unchanged since reporting began in 1976.87 Prevention of immediate transfusion reactions is best accomplished by following protocols for obtaining specimens from patients in adequate time before transfusion and checking to see that blood products are appropriate for the intended recipient.
Delayed transfusion reactions are the result of an anamnestic response of antibodies from a previous transfusion (or pregnancy) that are not present in detectable levels at the time the specimen is crossmatched. A careful transfusion history can best prevent delayed hemolytic reactions. Many patients will know whether there were difficulties involving blood obtained for transfusion. If a patient has a history of difficulty with crossmatches, the blood bank can obtain the details from the institution responsible for the previous transfusion. A proper transfusion history can uncover patients likely to have antibodies that the blood bank would not detect. For example, antibodies to Jka and Fya are typically hard to identify because they are quick to rise on stimulation and fall equally rapidly, making later detection difficult.
Febrile Transfusion Reactions
Febrile nonhemolytic transfusion reactions occur in 0.5% to 2% of all transfusions and are more likely to occur after platelet transfusions. Until recently, most febrile transfusion reactions were attributed to recipient antibody reactions against HLA antigens on donor leukocytes in the transfused product.88 It is now apparent that cytokines produced during storage may also contribute to these reactions.89 This conclusion is based on observations that platelet products associated with transfusion reactions have higher levels of inflammatory cytokines (e.g., IL-1β, TNF, IL-6, and IL-8) in the supernatant than are found in platelets that do not cause febrile transfusion reactions.
Diagnosis of Febrile Reactions
Febrile reactions are characterized by the development of fever during transfusion or within 5 hours after transfusion. These reactions may be limited to an increase in body temperature of 1° to 2° F but are often associated with chills and rigors. Febrile nonhemolytic reactions are a diagnosis of exclusion.
The differential diagnosis for a patient who develops fever in the setting of transfusion always includes hemolysis and unrecognized sepsis. When a febrile reaction is observed, immediate management consists of discontinuing the transfusion, obtaining appropriate cultures, and returning the component to the blood bank. The blood bank checks for evidence of incompatibility, obtains cultures from the product, and verifies that no errors have occurred in its preparation or administration. The probability that a febrile transfusion reaction has occurred is influenced by the type of product, the number of white cells contained therein, and the transfusion history of the recipient. Febrile reactions to products that have few or no white cells (e.g., leukoreduced red cells, frozen-deglycerolized red cells, or FFP) are unusual. Unmodified whole blood and red cells contain between 1.3 × 109 and 3 × 109 white cells and are much more likely to cause febrile reactions. In the case of transfused platelets, reactions can be from cytokines made during in vitro room temperature storage or from bacterial contamination.
Treatment of Febrile Transfusion Reactions
Febrile transfusion reactions are usually self-limited and respond to symptomatic management with antipyretics. However, symptoms may be of sufficient magnitude to require the use of 50 to 75 mg of meperidine by intravenous bolus. To prevent further occurrences, leukocyte-depleted components or premedication are indicated.
Prevention of Febrile Reactions
Newer designs of filters for leukocyte reduction decrease the white cell content to below the threshold for febrile transfusion reactions.90Because inflammatory cytokines may be involved in febrile transfusion reactions, methods are being implemented to accomplish leukocyte reduction either during or after collection but before storage. In a study comparing products that underwent leukocyte reduction either before storage or at the bedside, significantly fewer febrile reactions occurred in patients receiving prestorage leukocyte-depleted products; there was no difference in the number of allergic reactions.91
Prestorage leukocyte reduction is particularly important for platelets because platelets are stored at room temperature and accumulate significantly more cytokines than do red cells, which are refrigerated. Febrile transfusion reactions are also more likely with older components. Platelets that were used after they were in storage for 3 days or less have been found to cause significantly fewer febrile transfusion reactions than platelets that were used after longer storage periods.92 Unfortunately, testing for infectious diseases often takes 2 to 3 days, during which time the product cannot be used; it is therefore impractical to rely on younger products to reduce the risk of febrile transfusion reactions. Other benefits of leukocyte reduction include reduction of HLA alloimmunization; decreased transmission of leukocyte-associated viruses such as cytomegalovirus (CMV), Epstein-Barr virus, HTLV-I, and HTLV-II; and, possibly, reduction of immune modulation.
Whether these advantages justify leukocyte reduction for all blood products remains controversial; some physicians argue that the benefits do not justify the associated increased costs.93 Managing patients who continue to have febrile reactions after receiving leukocyte-depleted products is a clinical problem for which there are no clear solutions. In addition to premedication with antipyretics and steroids, use of HLA-matched components for patients who are known to have HLA antibodies may be helpful. Occasionally, use of washed products is beneficial, although 10% to 20% of the cells are lost in the washing process.
Transfusion-Related Acute Lung Injury
Transfusion-related acute lung injury (TRALI) is a clinical syndrome that presents as respiratory distress and hypoxemia with bilateral pulmonary infiltrates within 6 hours of transfusion.94 The clinical and radiographic picture is that of normal-pressure acute respiratory distress syndrome (ARDS); however, fever, hypotension, or hypertension may occur. The differential diagnosis is sufficiently broad to make the possible causal role of transfusion often go unnoticed. There is no diagnostic test for TRALI. Current evidence suggests that TRALI is associated with the interaction of antibodies (HLA class 1 or class 2 antibodies, monocyte antibodies, or granulocyte antibodies), with the corresponding antigens on leukocytes95; a recent study found such associations in 14 of 16 TRALI patients.96 These interactions cause endothelial injury, alveolar exudation, and the associated clinical findings of ARDS.
A second form of TRALI that involves two clinical events has been proposed.97 In this two-event model, which is based on clinical findings and rat lung studies, the first step is the priming of neutrophils by mediators that arise in certain clinical settings (e.g., recent surgery, massive transfusion, cytokine therapy, or infection).98 The primed neutrophils adhere to pulmonary endothelium and are activated by a second event, such as exposure to biologically active lipids from blood products.
Diagnosing TRALI depends on excluding cardiac and other causes of ARDS. Demonstration of antileukocyte antibodies helps confirm the diagnosis, but their absence does not exclude TRALI in the appropriate clinical setting. Early diagnosis is important because most patients will improve within 24 hours after supportive treatment is initiated. Unfortunately, a minority of patients develop TRALI in association with severe pulmonary edema and the filling of the trachea with fluid, for which no effective therapy exists. Mortality approaches 10%.
Allergic Transfusion Reactions
Allergic transfusion reactions are more common than febrile nonhemolytic transfusion reactions, occurring in 3% to 4% of transfusions. Allergic transfusion reactions usually present as pruritus and urticaria. A small percentage of patients have anaphylactoid symptoms, including wheezing, bronchospasm, and, occasionally, true anaphylaxis.99 These reactions have been attributed to an immune response to plasma proteins. However, one study suggested that they may instead be provoked by increased levels of RANTES (regulated on activation, normal T cell expressed and secreted), an inflammatory chemokine that is stored in platelet alpha granules and that accumulates during storage.100 This is an intriguing hypothesis, because RANTES is known to affect eosinophil and basophil function.
In most cases, symptoms of allergic reactions are local and do not require discontinuance of the transfusion if they are controlled with antihistamines. There is, however, no means as yet to identify the rare patient who will experience anaphylaxis. Certain protein deficiency states, such as haptoglobin and IgA deficiency, are associated with an increased likelihood of anaphylaxis, especially if the patient has a preformed antibody; however, many patients who are IgA deficient never have any difficulty.101
For most patients with urticaria, which seldom progresses to anaphylaxis, management is symptomatic. However, patients known to be IgA deficient should receive cells that have been washed thoroughly to remove plasma. When plasma products are required, they should be administered in a facility equipped to manage anaphylactic reactions. Using IgA-deficient plasma can minimize the risk, but such plasma is difficult to obtain and may require drawing from a rare donor pool, testing family members, or both.
Atypical Transfusion Reactions
Occasionally, patients have reactions that do not fit the categories already defined but clearly seem related to blood transfusion. These reactions have mainly consisted of severe hypotension after platelet infusions. No allergic features are present. The reactions are associated with blood-product infusions through bedside leukocyte reduction filters, and they often occur in patients who are receiving angiotensin-converting enzyme (ACE) inhibitors. A recent study suggests that such reactions may be caused by excessive accumulation of des-Arg9-bradykinin. This metabolite of bradykinin is known to be vasoactive and to be metabolized by ACE.102 Clinical observations suggest that atypical hypotensive reactions are more likely to occur in patients receiving ACE inhibitors during plasma exchange using albumin replacement solutions, hemodialysis, low-density lipoprotein apheresis, IgG-affinity column apheresis, and desensitization immunotherapy. These findings have led to the suggestion that ACE inhibitors be withheld for 24 hours before any of these procedures are initiated. Such reactions are sufficiently rare that it may be adequate to limit this restriction to patients who have already experienced one of these reactions.103
Transfusion-Associated Graft Versus Host Disease
Transfusion-associated graft versus host disease (TA-GVHD) is a feared consequence of transfusion therapy because mortality approaches 90%. TA-GVHD results from transfusing immunocompetent lymphocytes into a recipient who is unable to reject the allogeneic cells. The transfused lymphocytes engraft and proliferate, attacking host tissue antigens on the target organs.
Diagnosis and Identifying Patients at Risk
The diagnosis of TA-GVHD should be considered in any patient who presents after transfusion with fever, skin rash, and diarrhea and has pancytopenia and abnormal results on liver function testing.104 Signs and symptoms in neonates are similar to those in adults, but fever and rash develop later: in adults, fever occurs after a median of 10 days after transfusion; in neonates, fever occurs after 28 days, with rash appearing 1 to 2 days later. The diagnosis is generally made on the basis of clinical findings, and it can be confirmed with a biopsy that demonstrates cytogenetic evidence of donor lymphoid engraftment. TA-GVHD is best prevented by identifying potentially susceptible recipients. Patients who are at significant risk for TA-GVHD include premature infants receiving large doses of fresh allogeneic lymphocytes, patients with congenital defects in cellular immunity or immunity resulting from illness or chemotherapy, and patients who are unable to reject infused cells because of shared antigens with the allogeneic lymphocytes. Patients undergoing autologous or allogeneic bone marrow transplantation are particularly at risk. Many case reports document the association of Hodgkin disease with TA-GVHD, which occurs presumably as a result of acquired defects in T cell immunity. The intensive chemotherapy that is used to treat leukemia, high-grade lymphomas, and solid tumors may also set the stage for TA-GVHD. However, no cases have been identified in AIDS patients. One hypothesis explaining this surprising finding is that the HIV-mediated injury to CD4+ T cells blocks the development of TA-GVHD.105
Patients who are at risk for TA-GVHD because of receiving transfusions from a homozygous donor of a shared haplotype are the hardest to identify a priori. Donor lymphocytes are not rejected by the recipient but do respond to the nonshared recipient haplotype. This mechanism probably accounts for the majority of cases of TA-GVHD. The chances of receiving haplotype-homozygous blood from an unrelated donor vary with different populations. In Japan, the risk for adults may be as high as 1 in 874; it is estimated to be 1 in 102 in neonates because of the use of fresh whole blood from family members.106 In the United States, the risk for the white population is thought to be about 1 in 7,147. The risk increases if first-degree relatives are donors.
Once patients at risk are identified [see Table 6], pretreatment of all cellular transfused products with gamma radiation is indicated.107 No cases associated with FFP have been documented. On the basis of in vitro studies, the current recommended dose is 2,500 cGy, which does not affect red cell function or platelet survival if administered immediately before transfusion.108 However, irradiated red cells stored for 42 days show significant increases in plasma potassium and hemoglobin and a small but significant decrease in cell survival. Consequently, it is recommended that red cells be stored for no longer than 28 days after irradiation; however, most institutions prefer to irradiate immediately before product release. Platelets normally survive in storage for 5 days after being irradiated; they can be irradiated at regional centers before distribution.
Table 6 Patients for Whom Irradiated Blood Products Are Recommended
In addition to irradiation, leukocyte reduction may provide some protection against TA-GVHD, which is related to the dose of lymphocytes. However, filtration alone is not preventive and must never be used as a substitute for gamma irradiation. Because of the risk associated with a one-way HLA match, blood-bank standards require that family members' blood and the blood of directed donors be irradiated.
Treatment of TA-GVHD remains ineffective. Prevention by providing irradiated blood components to all recipients—the current practice in Japan—may become the most practical solution to this complication.107
Bacterial and Protozoan Infections
Platelets are associated with the majority of cases of transfusion-related sepsis because the platelets are stored at room temperature, which is conducive to bacterial proliferation.109 All platelet concentrates are currently screened for bacterial contamination; however, even the best available assays fail to detect low-level contamination. Controlling this problem requires improved disinfection of the donor's phlebotomy site, better detection of subclinical infection, and the development of methods for storage at lower temperatures or postcollection component sterilization. If sepsis is suspected in patients who have been given red cells, the possibility of Yersinia enterocolitica infection should be considered.110 This organism can grow in the cold, iron-rich environment provided by stored red cells. When such infections occur, the blood is almost always at least 2 weeks old; this period corresponds to the time needed for the usually small initial inoculum to reach clinically significant amounts. Malaria infections have been almost completely eliminated by predonation screening. T. cruzi can cause a chronic parasitic infection; the incidence of blood-borne transmission has increased to the point that pretransfusion testing for it has been introduced. Spirochetes do not tolerate refrigerated temperatures for longer than 80 hours, and syphilis is no longer considered a clinically significant source of blood-borne infection.111
CMV is a common blood-borne infection of no clinical consequence to healthy, immunocompetent recipients, but it can be a lethal problem for patients with either acquired or congenital immunodeficiency [see Table 7]. Judged on the basis of screening for antibody to CMV, more than 40% of healthy donors may have the potential to transmit CMV.112
Table 7 Patients for Whom Cytomegalovirus-Negative Blood Products Are Recommended
Although few institutions test directly for the virus, two approaches are used to prevent CMV transmission. The first is to use CMV antibody-negative components. The second, more practical approach is to use leukocyte-reduced components, because CMV is highly cell-associated. On the basis of a prospective, randomized study of more than 500 transplant patients, products that have undergone leukocyte reduction to the current standard of fewer than 0.5 × 106 leukocytes per milliliter are considered to be as effective as seronegative products in preventing CMV infection.113 It is unclear which approach provides the best protection against transfusion-associated CMV infection; however, both preparations should be considered CMV-safe rather than CMV-negative.114 Direct comparisons between seroconversion rates after transfusion of prestorage leukocyte-depleted components and CMV-negative products are required to settle this issue.
Immune Modulation as a Result of Transfusion
Evidence that transfusions result in modulation of host immunity has come from studies of transplantation, cancer recurrence, and posttransfusion infection rates.115 The effect was first observed in cadaver-kidney transplantation; patient survival was shown to increase with increased transfusions. Although this benefit became less important with the introduction of cyclosporine, Opelz and colleagues found increased cadaver-graft survival in transfused recipients whose immunosuppression regimen included cyclosporine.116
The hypothesis that immune modulation is related to infused white cells has been supported by studies in animal models and by clinical observations of tumor recurrence and posttransfusion infection rates. Bordin and colleagues have shown in a rabbit model that the number of pulmonary metastases is increased by allogeneic blood transfusions but not by blood from syngeneic littermates.117 This effect of allogeneic blood is abrogated by prestorage leukocyte reduction but not by poststorage reduction. Randomized clinical studies of posttransfusion infection and cancer recurrence have produced conflicting results.118 The conflicting data concerning the magnitude and clinical relevance of transfusion-induced immunomodulation have yet to be resolved. If leukocyte reduction is shown to reduce posttransfusion infections and cancer recurrence, the argument for universal leukocyte reduction of cellular blood products, which is already strong, would become irrefutable. Until this matter is settled, the possible immunomodulatory effect of blood transfusion is another reason to limit the use of allogeneic blood transfusion.
Apheresis therapy is the converse of transfusion therapy; it entails treating disease by removing plasma, specific antibodies, or cells. Apheresis has been applied to a broad spectrum of diseases [see Table 8]. Therapeutic apheresis has real risks and may provide little benefit. It is usually an acute intervention that is transiently effective, unless the underlying problem is being treated effectively. Consequently, it is important to identify criteria for both starting and stopping such treatment. Indications for apheresis that are approved by the American Association of Blood Banks and the American Society for Apheresis have been summarized.119
Table 8 Recommendations for Therapeutic Apheresis
Red Cell Exchange
Red cell exchange has been used primarily to treat or prevent complications of sickle cell disease. Although the molecular defect of sickle hemoglobin is simple, the pathophysiology of the vaso-occlusive crises is complex, involving hemoglobin polymerization, change in cell shape, adhesion to endothelial cells, and release of inflammatory cytokines. Clinical manifestations vary from patient to patient. Exchange transfusion aims to improve tissue oxygenation and prevent microvascular sickling by diluting the patient's abnormal red cells, which results in improved whole blood viscosity and rheology; red cell exchange may also be used to correct anemia. No clinical data support a single optimal level of hemoglobin A (HbA); however, as few as 30% of transfused cells markedly decrease blood viscosity; at mixtures of 50% or greater, resistance to membrane filterability approaches normal.120 Raising the level of HbA to between 60% and 70% while lowering the level of hemoglobin S (HbS) to 30% is generally efficacious.
Red cell exchange has been used to treat stroke, acute chest crises, and priapism. In patients with these disorders, the indications for red cell exchange—as compared with simple transfusion—are poorly defined. For example, in a randomized study of patients with sickle cell disease who are undergoing surgery, a conservative simple transfusion regimen was as effective as an aggressive exchange regimen with respect to perioperative nontransfusion-related complications. The patients in the aggressive regimen group received twice as many units of blood, had a proportionally increased red blood cell alloimmunization rate, and had more hemolytic transfusion reactions.121
Exchange transfusion has also been used for prophylaxis during pregnancy and before surgery. The only randomized trial of transfusion during pregnancy has shown that prophylactic transfusion sufficient to reduce the incidence of painful crises did not reduce maternal morbidity from other causes, nor did it reduce perinatal mortality.122
Long-term transfusion prophylaxis is unquestionably indicated for children at high risk for stroke, as determined by transcranial Doppler ultrasonography. A randomized controlled study demonstrated a risk reduction of 90% in the patients who were maintained at levels of 30% or less HbS by simple or exchange transfusion.123 In this group of children, transfusion therapy should begin before the first event, and it should be continued indefinitely. Red cell exchange leads to less iron accumulation than transfusion therapy, which is an advantage in the treatment of patients with sickle cell disease who require long-term therapy.124 Using Rh and Kell antigen-compatible red cells reduces the incidence of alloimmunization from 7% to 1%114 and should be standard practice.125
Red cell exchange is used as an adjunct to malaria treatment for critically ill patients with high levels (> 10%) of parasitemia and to lower blood viscosity acutely by removing red cell mass in patients with polycythemia and central nervous system signs and symptoms.
Leukapheresis is a treatment option for patients with acute leukemia who develop leukostasis syndrome. Leukostasis syndrome, which is caused by high levels of circulating leukocytes (especially blast cells), can lead to serious complications, including stroke, pulmonary dysfunction, and renal insufficiency. When the fractional volume of leukocytes (leukocrit) exceeds 20%, blood viscosity increases, and leukocytes can interfere with pulmonary and cerebral blood flow.126 Recent investigations of the expression and function of adhesion receptors on leukemic cells suggest that leukostasis may also be related to interactions between leukemic blast cells and endothelial cells mediated by locally released adhesion molecules.127
Leukostasis is a function of cell number and cell type. Myeloblasts are more likely to cause stasis than are an equivalent number of well-differentiated lymphocytes in a patient with chronic lymphocytic leukemia. Unless pulmonary or cerebral leukostasis is severe enough to cause progression in clinical findings, hydroxyurea will usually decrease the cell count sufficiently within 24 hours and is the treatment of choice. However, when clinical findings demand improvement within 4 to 8 hours, a combination of leukapheresis and hydroxyurea is usually needed. A single leukapheresis procedure generally reduces the leukocyte count by 20% to 50%, depending on the differing sedimentation characteristics of the specific blast cell population. Ordinarily, leukapheresis is initiated when the blast cell count is higher than 100,000/µl or when rapidly rising blast cell counts are higher than 50,000/µl, especially if central nervous system or pulmonary symptoms are evident.
Leukapheresis used as a method of mechanical cytoreduction in chronic leukemic processes has limited value. In a series of patients with chronic myeloid leukemia, the use of repeated leukapheresis procedures adequately reduced cell count; however, the median patient survival rate was not significantly different from that achieved with conventional chemotherapy.128
Therapeutic plateletpheresis is generally reserved for patients with myeloproliferative disorders and hemorrhage or thrombosis associated with increased numbers of circulating abnormal platelets. Many centers consider using plateletpheresis when the patient's peripheral platelet count is greater than 106/µl, although no consistent relation between the level of platelet elevation and the occurrence of symptoms has been found, and no generally accepted assay of platelet dysfunction predicts which patients are at risk.129,130 A single procedure can lower the platelet count by 30% to 50%. Attempts to maintain thrombocythemic patients at normal platelet counts by cytapheresis alone have not been successful; aspirin and cytoreductive chemotherapy should be instituted concurrently. Most patients with thrombocytosis, including patients with myeloproliferative disorders, do not develop symptoms; prophylactic plateletpheresis is unwarranted regardless of the platelet count.130
Plasmapheresis (Plasma Exchange)
Indications for Plasma Exchange
Neurologic diseases whose pathogenesis may be antibody-mediated are now the most common indications for plasma exchange. Myasthenia gravis occurs when antibodies to acetylcholine receptors cause abnormal neuromuscular transmission. Reductions in these antibody titers from plasma exchange are associated with clinical improvement. A randomized trial compared the use of plasma exchange with the use of IVIg therapy in the treatment of myasthenia gravis; the investigators noted a trend toward better results with plasma exchange.131
Similar findings were reported from much larger studies of Guillain-Barré syndrome, which is thought to be caused by antibodies to myelin. Two large series comparing plasma exchange with current best therapy showed faster improvement with the addition of plasma exchange. Randomized comparisons of plasma exchange and IVIg in the treatment of Guillain-Barré syndrome have shown these approaches to be equivalent; no additional benefit from using both therapies was shown.132,133
Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disorder that causes proximal and distal weakness; CIDP has a progressive or relapsing course and is sometimes associated with monoclonal gammopathies. CIDP responds to plasma exchange, except in patients with distal weakness and associated IgM monoclonal gammopathies134,135; such patients respond poorly to all modalities of therapy. IVIg therapy and plasma exchange have been shown to be comparably effective in CIDP.136
The use of plasma exchange in multiple sclerosis remains controversial. Meta-analysis of six controlled trials of plasma exchange provided some evidence of benefit, but the authors concluded that the subgroups of patients likely to benefit need further definition.137 A randomized study of plasma exchange in patients with acute inflammatory demyelinating central nervous system disease showed a significant benefit from the therapy. However, patients continued to experience relapse.138
The hematologic diseases that require plasma apheresis are those associated with obstruction of vascular flow by proteins as a result of increased viscosity or cryoprecipitation; antibody-mediated diseases that lead to destruction of the formed elements of the blood; and thrombotic microangiopathies.
In patients with TTP, plasma exchange with FFP replacement has been estimated to improve survival rates from 10% to more than 75%; TTP is the only hematologic condition in which a specific replacement solution seems to make a difference. Comprehensive reviews of the clinical and laboratory evaluation and treatment of patients with suspected TTP, including management with plasma exchange therapy, have been published.71,139 Treatment usually involves daily single-volume plasma exchange; the frequency and duration of treatment are guided by clinical response, an increase in platelet count (i.e., to 100,000/µl or more), and evidence of decline in hemolysis (as measured by normalization of serum L-lactate dehydrogenase [LDH] and decline in the number of schistocytes on the peripheral blood smear). Despite promising initial reports, the use of cryoprecipitate-poor plasma may not be more effective than the use of standard FFP as a specific replacement fluid for plasma exchange in patients with TTP.140,141
The effectiveness of plasma exchange in patients with TTP may derive from the removal of antibody to von Willebrand factor, replacement of the von Willebrand factor-cleaving zinc metalloprotease (ADAMTS13 [a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13]), or both.139,141 However, patients with clinical features of TTP and moderate ADAMTS13 deficiency—or even normal activity—may respond to plasma exchange. The results of plasma exchange in hematopoietic progenitor cell transplant recipients with clinical features of TTP have been disappointing.66
In patients with Waldenstrom disease, plasma exchange has produced clinical improvement; however, it does not affect the disease process. The benefit of plasma change is the result of rapid reduction of paraprotein concentrations and normalization or significant decrease of serum viscosity in patients with hyperviscosity syndrome.142 The concentration of paraprotein influences plasma protein viscosity, as does its heavy-chain class. IgM is the largest plasma protein and is nearly 100% intravascular; it is most likely to cause hyperviscosity. IgA and IgG3 are more likely to aggregate and are associated with hyperviscosity more often than other IgG subclasses. As in leukostasis, the choice between plasma exchange and chemotherapy is guided mainly by the clinical symptoms and their rate of progression. Plasma exchange can lower viscosity within hours, whereas most chemotherapy requires days.143
Despite the role that antibody and immune complexes play in hematologic cytopenia, there are no well-controlled studies supporting the use of plasma exchange. The available case reports usually describe the role of plasma exchange as being that of backup after failure of more established therapies. FFP or cryopoor plasma is used in replacement therapy for thrombotic microangiopathies. Case reports suggest that patients with severe preeclampsia, HELLP syndrome, or both may benefit from plasma exchange with FFP replacement if they fail to improve after delivery.144
Antibody-mediated renal, muscular, and cutaneous diseases
Despite promising reports from case studies, controlled trials of patients with pemphigus vulgaris,145 polymyositis, dermatomyositis,146 and Goodpasture syndrome147 have raised doubts concerning the value of plasma exchange. However, plasma exchange does appear to be valuable in stopping pulmonary hemorrhage in Goodpasture syndrome.
Immune complex diseases
The only indication for plasma exchange in rheumatoid arthritis and systemic lupus erythematosus is severe vasculitis that does not respond to other therapies. Plasma exchange is usually requested as an intervention of last resort.
Plasma exchange and selective removal of low-density lipoproteins (LDLs) have both been used to treat familial hypercholesterolemia [see9:VI Diagnosis and Treatment of Dyslipidemia]. Selective removal of LDLs can be accomplished by immunoadsorption, heparin precipitation, or dextran sulfate cellulose absorption, whereas plasma exchange causes significant reduction of both LDLs and HDLs. Other rare genetic storage diseases, such as Refsum disease (characterized by the accumulation of phytanic acid), benefit from mobilization of the toxic metabolite by plasmapheresis.
Complications of Plasma Exchange
The complications associated with plasma exchange are best divided into problems related to apheresis machines and problems related to venous access, type of replacement fluids, and anticoagulant.148 Apheresis machines accomplish cell and plasma separation by either centrifugation or membrane filtration. All systems monitor air and access pressure, allowing air emboli to be eliminated and access problems to be promptly recognized. Excess transmembrane pressure may cause red cell hemolysis, which leads to increased hemoglobin in the separated plasma. The majority of complications associated with plasma exchange result from the replacement fluid and anticoagulant used. Plasma removed by exchange is commonly replaced with 5% albumin, which carries no risk of infection and does not increase the citrate return but does dilute coagulation factors, causing mild coagulopathy for 24 to 48 hours. On an every-other-day treatment schedule, coagulation abnormalities are usually not clinically significant, but they may become significant if the patient is on a daily treatment schedule. Using FFP prevents dilutional coagulopathy but increases risks of blood-borne infection and allergic reactions. Peripheral venous access is often inadequate to maintain the required flow rates of 45 to 80 ml/min, necessitating central venous access with a large, double-lumen catheter; life-threatening or fatal complications from central catheter placement have been reported.149 Catheter malfunction should always be considered when a patient shows clinical evidence of hypovolemia, shock, or both while undergoing plasma exchange. The majority of complications, however, are side effects of the citrate anticoagulant.150 These can include paresthesias, abdominal cramps, and, in rare instances, cardiac arrhythmias or seizures. Citrate toxicity is usually managed easily by slowing the return rate and providing extra calcium, either orally or sometimes intravenously. Patients with renal failure who receive large amounts of citrate may develop a profound metabolic alkalosis.151
Future Prospects for Transfusion Therapy
The evolution of transfusion practice has been a steady progression from whole blood to components to fractionated and recombinant products designed for specific therapies. The search for a practical replacement for red cells that would allow stable storage, provide adequate oxygen delivery, and be free of significant toxins has been long and filled with substantial obstacles. Hemoglobin-based substitutes seem the most promising candidates, but concerns about efficacy and potential toxicity persist.152 In the case of coagulation components and other plasma proteins, recombinant products are beginning to provide highly specific treatment of clinical problems that are poorly managed by current therapy. Bioengineering holds the promise of improving the effectiveness of current recombinant products. Methods to remove or mask red cell antigens provide the promise of a so-called universal red cell.153 Pathogen reduction technologies seem likely to render cellular components as free of infectious transmission as their plasma counterparts.154
A major change in transfusion practice may evolve from the availability of cytokines that can modify endogenous production. Erythropoietin has changed the treatment of anemia associated with chronic renal disease; as a result, many dialysis patients no longer require transfusions. Erythropoietin can also facilitate patients' self-banking their blood for anticipated surgical needs. In some cases, erythropoietin use is accepted by Jehovah's Witness patients, thereby allowing such patients to undergo surgical procedures that would otherwise not be possible. The availability of myeloid growth factors has contributed substantially to the development of methods for collection, and it is possible that mobilizing leukocytes with growth factors can increase the effectiveness of granulocyte transfusions. Thrombopoietin may in time be used to enhance platelet apheresis collections. In very early studies, recombinant cytokines have been combined with hematopoietic progenitor cells to grow blood cells in culture; however, the prospects of making available millions of units of cultured red cells and platelets remains more a hope than a promise.
Even in an era of accelerating change, certain aspects of transfusion medicine will remain constant. The blood donor remains a linchpin that cannot be replaced by recombinant methodology. Transfusion practice has improved in safety, but there will always be residual risks. Each transfusion will require careful assessment of whether the risks to the recipient outweigh the benefits.
The author and editors gratefully acknowledge the contributions of the previous author, W. Hallowell Churchill, M.D., to the development and writing of this chapter.
Editors: Dale, David C.; Federman, Daniel D.