The Washington Manual of Oncology, 3 Ed.

Transfusion Medicine

Ronald Jackups • George Despotis

 I. RED BLOOD CELLS (RBCs). The therapeutic goal of a blood transfusion is to increase oxygen delivery according to the physiologic need of the recipient. It is difficult to determine an appropriate transfusion threshold, however, because the benefits of blood are hard to define and measure. In a multi-institutional Canadian study, 418 critical care patients were to receive red cell transfusions when the hemoglobin (Hgb) level decreased to less than 7 g/dL, with Hgb maintenance in the range of 7 to 9 g/dL, and 420 patients were to receive transfusions when the Hgb was less than 10 g/dL, with Hgb levels maintained in the range of 10 to 12 g/dL. There was a trend in reduced 30-day mortality rate in the patients randomized to the conservative Hgb threshold (18.7% vs. 23.3%; p = 0.11), indicating that a transfusion threshold as low as 7 g/dL is as safe as a higher transfusion threshold of 10 g/dL in critical care patients without active end-organ ischemia (N Engl J Med 1999;340:409). These findings of tolerance of lower hemoglobin levels were also replicated recently in additional trials. An important confounding factor in the efficacy of red cell transfusions involves the variable capacity of red cell units to enhance or provide tissue oxygenation based on 2,3-diphosphoglycerate (DPG) levels, which vary with the age of the red cell units. Clearly, more data are needed to characterize how these red cell storage changes impact on the clinical efficacy of red cells transfusion on tissue oxygenation.

 Data on morbidity also are unclear. Silent perioperative myocardial ischemia has been observed in patients undergoing noncardiac as well as cardiac surgery. Hemoglobin levels in the range of 6 to 10 g/dL as well as clinical signs or indicators of end-organ ischemia other than [Hgb] may identify patients who may benefit from blood transfusion. Accordingly, elderly patients undergoing elective, noncardiac surgery have been shown to be at risk for intraoperative or postoperative myocardial ischemia with hematocrits less than 28%, particularly in the presence of tachycardia. This finding was also recently confirmed in the study involving the postoperative period after orthopedic surgery. In this study, transfusion was more commonly triggered by the development of symptoms (e.g., threefold increase in bleeding, twofold increase in angina, 10-fold increase in congestive heart failure, and two-and-a-half-fold increase in the development of hemodynamic instability) in the patient cohort whose Hgb trigger was set at 8 g/dL (N Engl J Med 2011;365:2453). Therefore, in the absence of a physiologic need such as end-organ ischemia in a stable, nonbleeding patient, correction of anemia may not be indicated and may, in fact, predispose patients to adverse outcomes. However, when clinicians implement lower transfusion thresholds, the implementation of a proactive surveillance program should be considered to detect important symptoms of organ ischemia of dysfunction.

 Guidelines for blood transfusion have been issued by several organizations including a National Institutes of Health consensus conference on perioperative transfusion of red cells, the American College of Physicians, the American Society of Anesthesiologists, AABB (formerly known as American Association of Blood Banks), and the Canadian Medical Association. These guidelines consistently recommend that blood should not be transfused on a prophylactic basis and suggest that in patients who are not critically ill, a Hgb level of 6 to 8 g/dL is well tolerated and acceptable. Adherence to these guidelines has raised questions about whether transfusion is now underused. A Hgb level of 8 g/dL seems an appropriate threshold for transfusion in surgical patients with no risk factors for critical or target (end-organ) ischemia, whereas a higher threshold may be more appropriate for patients who are considered at higher risk or, more importantly, patients who develop symptoms consistent with organ ischemia. However, prophylactic transfusion of blood cannot be endorsed, particularly because studies have found an association between transfusion and less favorable outcomes in critically ill patients. It is unlikely that one specific hemoglobin value can be used as a universal threshold for transfusion.

1. TRANSFUSION THERAPY
2. General considerations. The transfusion of blood or blood components has inherent risks, summarized in Table 39-1. Informed consent (a clear explanation of relative benefits, risks, and alternatives regarding the transfusion to the patient) is mandatory, and is accompanied in many institutions by a consent form that documents the conversation and patient acceptance. In the elective transfusion setting, alternatives to blood transfusion have previously included autologous or directed (from a donor known to and selected by the patient) blood. However, recent evidence indicates that this approach may not be as safe in part related to the fact that these represent first time donations (Transfusion 2013;53:1250). Another important measure for any blood management program includes, when feasible, the evaluation of patients with respect to uncovering treatable anemias (e.g., iron, folate, B₁₂, and erythropoietin) before initiating blood transfusion.

 Risks, side effects, and indications of blood and blood products are available in the Circular of Information for Blood and Blood Products, issued jointly by the American Red Cross, America’s Blood Centers, and the AABB and approved by the US Food and Drug Administration (FDA), and can be obtained from hospital transfusion services. Administration of blood must be preceded by confirmation that two unique identifiers (such as name and hospital number or social security number) match between the patient and the blood-unit label, immediately before initiating infusion of the blood unit. The blood must be infused through a dedicated intravenous line with no other concurrent drugs or fluids, except 0.9% NaCl (normal saline) except when approved for use by the FDA. Signs should be recorded immediately before transfusion and within 5 to 10 minutes after starting; some institutions require the patient to be also carefully monitored, and at regular intervals (e.g., hourly or more frequently as predicated by the patient’s condition) thereafter. Each blood unit should be administered within 4 hours. A standard macroaggregate filter (170 to 260 µm) is used to prevent infusion of fibrin, cell clumps, and debris.

^aKaufman RM, Djulbegovic B, Gernsheimer T,et al. Platelet transfusion: a clinical practice guideline from the AABB [Epub ahead of print]. Ann Intern Med 2014. http://www.ncbi.nlm.nih.gov/pubmed/25383671.

 An order for blood type and screen involves testing the patient’s RBCs blood type for the A, B, and D (Rh) antigens, whereas the antibody screen involves testing the serum/plasma for the presence of alloantibody against other (minor) RBC antigens. The frequency of detecting such alloantibodies varies between patient populations (e.g., 0.2% of healthy donors, vs. 1% to 1.5% in the general population vs. up to 8.4% of patients who receive blood) and is related to previous exposure from pregnancy or transfusion. A cross-match order leads to in vitro testing of the patient’s serum against donor RBCs to confirm compatibility between the blood unit selected and the patient.

1. Complications of transfusion
2. The Transfusion Medicine Service typically provides clinicians with a list of distinct diagnostic criteria (e.g., cardiopulmonary or allergic symptoms along with signs of hemodynamic, respiratory, and/or febrile reactions) with respect to early identification of transfusion reactions to alert medical personnel regarding potential problems with the transfusion. These criteria include a temperature elevation of greater than 1°C; the appearance of symptoms (e.g., shortness of breath, nausea/vomiting, pruritus, pain at infusion site, back pain, and palpitations); or signs (changes in vital signs, rash, hives, edema, or stridor) indicating a change in the patient’s clinical status. When a transfusion reaction is considered, the transfusion must be stopped immediately, and a physician is notified to assess the patient’s status. The transfusion is terminated if there is a significant change in the patient’s clinical status during the transfusion. At that time, the blood bag, patient blood samples, and urine are sent to the blood bank, where patient and blood-unit identification are reverified; direct antigen test, blood group confirmation, and potential repeat antibody screen testing are repeated; serum and urine are inspected for signs of hemolysis; and the residual contents of the blood bag may be cultured. The patient’s blood should be drawn for blood culture if fever or blood pressure changes occurred during the transfusion.
3. Nonhemolytic febrile-associated transfusion reactions (NHFTRs) are characterized by fever (i.e., at least a one degree rise in temperature), which may or may not be associated with other signs and symptoms. These types of reactions used to occur in 0.5% to 2% of RBC transfusions and in 8% to 30% of platelet transfusions in the era prior to use of leukoreduced blood. Within certain populations such as multiparous women and frequently (or chronically) transfused patients, the prevalence can be higher. These reactions are generally mild and occur during the latter part of the transfusion. The potential mechanisms involve either recipient antibodies against donor leukocyte antigens and/or soluble cytokines (interleukins and tumor necrosis factor) contained within the blood component, or both. Symptoms are treated with acetaminophen (650 mg) for fever, and occasionally, rigors and chills may require meperidine (25 to 50 mg i.v.). Although these reactions are typically mild and self-limiting, if the rise in temperature is related to infusion of blood component contaminated with bacteria, there may be a more profound presentation with high fevers and hemodynamic instability related to sepsis (refer to infectious complications of transfusion).
4. Nonhemolytic allergic transfusion reactions (NHATR) are invariably accompanied by pruritus, rash, or hives consistent with urticaria and on occasion, histamine release results in more significant and on occasion life-threatening perturbations such as severe bronchospasm, angioedema involving swelling of supraglottic structures (e.g., glossal, epiglottis, and other pharyngeal structures), or substantial hemodynamic compromise such as severe hypotension with reflex tachycardia or, on occasion, myocardial depression. While mild allergic reactions occur in 0.5% to 2% of RBC transfusions and in 8% to 30% of platelet transfusions, severe reactions occur at a much lower frequency (0.3% to 0.01% of transfusions) and are typically related to allergy to one or more unidentified donor plasma proteins. Therapy depends on the severity of signs and symptoms and includes either continued monitoring or with progressive symptoms beyond a rash, antihistamine therapy involving both an anti-H1 antagonist diphenhydramine (25 to 75 mg), p.o. or i.v. when the patient is NPO, and an anti-H2 blocker such as ranitidine (50 mg) or pepcid (20 mg). For more severe reactions, SQ or IV epinephrine and glucocorticoids should be considered for severe allergic reactions involving hemodynamic perturbations while inhaled beta agonist therapy to abate either bronchospasm (e.g., albuterol) or stridor (e.g., racemic epinephrine). The transfusion may be continued at the discretion of the physician, particularly in patients with prolonged transfusions with mild dermatologic reactions. Some patients may benefit from prophylactic treatment with antihistamine agents shortly before transfusion, to prevent or attenuate reactions. Bedside leukodepletion filters are infrequently utilized (i.e., >90% of blood is leukoreduced prior to storage) for patients with a history of two or more febrile reactions but prevent only 50% of reactions, because they affect only those due to antibodies against leukocytes. However, severe hypotension can occur in susceptible patients (e.g., patients on angiotensin-converting enzyme [ACE] inhibitors) and is secondary to the hemodynamic effects of bradykinin, which is released due to the filtration process and by sustained blood levels as related to reduced clearance (i.e., as related to the use of ACE inhibitors). The clinical manifestations include vital sign instability, particularly, hypotension. Bedside leukodepletion filters should therefore be avoided in patients with cardiovascular compromise and in those treated with ACE inhibitors.

 Severe anaphylactic reactions have been observed (i.e., generally with the first or second transfusion) in patients with immunoglobulin A (IgA) deficiency who have no detectable IgA levels and who have developed anti-IgA antibodies and receive blood products (all of which contain IgA). If IgA deficiency is considered, both IgA levels (i.e., with a method that can detect levels as low as 0.05 mg/dL as highlighted by Vassallo RR) and anti-IgA antibody testing should be pursued. Patients with suspected IgA deficiency should receive washed cellular blood components until the diagnosis is confirmed, at which time, components from IgA deficient donors may be potentially procured from the American Red Cross if available.

4. Acute hemolytic transfusion reactions are caused by preformed antibodies (IgM or IgG antibodies against A or B antigens, or complement-fixing IgG antibodies against minor RBC antigens, such as Kidd) in the patient and are characterized by complement-mediated intravascular hemolysis subsequent to initiation of the transfusion. Hypotension, fever, nausea/vomiting, and back and/or chest pain may develop, along with hemoglobinuria, renal failure, and disseminated intravascular coagulation (DIC). If such a reaction is suspected, the transfusion should be immediately terminated. Treatment includes resuscitative measures, support of the cardiovascular system with intravascular volume and vasopressor therapy, and preservation of renal function with i.v. hydration, along with alkalinization of urine (i.v. sodium bicarbonate therapy) and administration of hemostatic blood components in the setting of bleeding and laboratory evidence of hemostatic factor deficiency secondary to DIC.
5. Delayed hemolytic transfusion reactions (DHTRs) are usually detected 7 to 21 days after RBC transfusion. They are related to a primary or anamnestic IgG response on exposure to minor RBC antigens, the latter seen particularly in patients previously exposed to such antigens through pregnancy or previous blood transfusion. Clinical manifestations may include an unexplained and perhaps severe (i.e., dependent on the number of incompatible units transfused) posttransfusion anemia, icterus, or jaundice (due to accelerated intravascular RBC destruction), a failure to increase Hgb (1 g/dL/U) levels after RBC transfusion, or most commonly in asymptomatic patients through serologic evidence (i.e., the appearance of a new alloantibody on antibody screen before subsequent transfusion). Occasionally, the reactions can be clinically severe, with renal impairment and even reported deaths (Table 39-2). Treatment in these cases is the same as for acute reactions. Patients should be informed that they have an allergy (e.g., antibody to non-ABO antigens) to prevent subsequent DHTRs since many of these antibodies (50%) fade within 3 to 6 months and therefore lead to negative antibody screens obtained at the same or another institution.
6. Transfusion-related acute lung injury (TRALI) is an underrecognized and serious reaction to transfusion often due to an antihuman leukocyte antigen (HLA) or antineutrophil (HNA) antibody from a donor (usually a multiparous woman) that reacts to the corresponding antigen on recipient leukocytes. Alternatively, transfusion of accumulated lipids or cytokines in the plasma of stored blood products has also been implicated as a cause of TRALI, especially when related to transfusion of platelet units. In addition, there is substantial evidence to suggest that TRALI represents a two-hit mechanism and that the patient’s underlying condition (e.g., sepsis, systemic inflammatory response, major surgical intervention) predisposes patients to an exaggerated response to the primary trigger (e.g., anti-HLA/HNA antibodies, biologically active lipids or cytokines, etc.) that leads to an increase in adverse consequences. This has been recently supported in the cardiac surgery environment; Vlaar et al. demonstrated a 2.4% incidence of TRALI in 668 patients undergoing cardiac surgery. In this cardiac surgical series, TRALI was associated with substantial (i.e., fourfold and twofold) increase in ICU and hospital lengths of stay, doubling of ventilation intervals and a fourfold higher mortality. In addition, TRALI was only associated with anti-HLA antibodies using multivariate statistical methodology. TRALI is now the leading cause of transfusion-related mortality in the United States, exceeding the number of deaths due to transfusion of ABO-incompatible or bacterially contaminated units. Most studies have indicated that plasma is associated with roughly 50% of TRALI cases, whereas apheresis or whole blood platelets are the next most common precipitant, and packed red cells and cryoprecipitate are rare causes of TRALI. Other publications, however, have indicated the highest incidence with platelets (1:400 platelet units), but this has not been uniformly reported. Clinical manifestations of TRALI include fever, hypotension, tachycardia, and noncardiogenic pulmonary edema that can lead to profound hypoxemia and respiratory distress necessitating intubation and mechanical ventilatory support in 70% of patients. Chest radiographs demonstrate a noncardiogenic pattern of bilateral infiltrates without cardiomegaly consistent with acute respiratory distress syndrome. Typically, signs and symptoms of TRALI occur within 2 hours of receipt of the blood product, but can occur up to 6 hours following transfusion. Treatment is supportive, and while more than 70% of patients require mechanical ventilation, most patients are extubated within 24 to 72 hours.

Established indications

Prevention of recurrent nonhemolytic febrile transfusion reactions to RBC transfusions

Prevention or delay of alloimmunization to leukocyte antigens in select patients who are candidates for transplantation or transfusion on a long-term basis

Indications under review

Prevention of the platelet-refractory state caused by alloimmunization

Prevention of recurrent febrile reactions during platelet transfusions

Prevention of cytomegalovirus transmission by cellular blood components

Not indicated for

Prevention of transfusion-associated graft-versus-host disease

Prevention of TRALI due to the passive administration of antileukocyte antibody

Patients who are expected to have only limited transfusion exposure

Acellular blood components (fresh frozen plasma, cryoprecipitate)

 In patients who meet the clinical criteria for TRALI, confirmation first requires the identification of potentially involved blood products and their respective donors. Other banked blood products from the donor(s) suspected in a TRALI case must be quarantined during evaluation. To implicate a donor in a case of TRALI, the presence of an anti-HLA or antineutrophil antibody with specificity to an antigen expressed by the recipient is required. Implicated donors are typically permanently deferred from further donation.

 To date, measures to prevent TRALI have focused on the identification and deferral of donors at high risk to form anti-HLA or antineutrophil antibodies. The United Kingdom adopted a policy to manufacture and import male donor plasma only, whereas centers in Spain screen previously pregnant donors for anti-HLA antibodies and, if positive, do not manufacture plasma products from these donors. Data from the SHOT UK Surveillance program (i.e., years 1996 to 2006) involving 206 cases of TRALI demonstrated a substantial (i.e., 80%) decline in the incidence of TRALI after implementation of exclusive use of male donor plasma in the United Kingdom in 2003. Accordingly, in 2007, the American Red Cross has also adopted the use of plasma from only male donors as well. However, this risk still persists with the use of AB plasma; despite the fact that AB plasma represents 4% of all plasma transfused, 50% of the TRALI cases were observed with AB plasma from female donors who had HLA or HNA antibodies (Transfusion 2013;53:1442). This has led to preferential utilization of non-AB plasma in an attempt to mitigate this risk. In multiparous donors from the United States, the incidence of anti-HLA antibodies is approximately 25% and, therefore, policies to exclude high-risk donors can potentially adversely affect the supply of blood products, especially platelets. It is currently unclear which preventative measures such as anti-HLA/HNA testing versus use of platelet additive solution for platelets will be implemented to definitively decrease the incidence of TRALI from platelet derived from female donors.

7. Volume overload with symptoms and signs of congestive heart failure can be seen in patients with cardiopulmonary compromise, particularly in elderly patients with substantial anemia who already have expanded plasma volume, patients with substantial renal dysfunction, or patients who have received excess fluids prior to transfusion. Diuretic therapy should be used prophylactically in such patients to minimize this complication. The distinction between volume overload and TRALI can be difficult. Recently, a small study involving 19 patients suspected to have transfusion-associated circulatory overload (TACO) found beta natriuretic peptide (BNP) to be 81% sensitive and 89% specific in the diagnosis of volume overload following a transfusion. Therefore, along with essential clinical data, BNP may be a helpful marker to distinguish TACO from TRALI, although future studies are needed validate this approach.
8. Transfusion-associated graft-versus-host disease (GVHD) is a syndrome in which donor lymphocytes that share an HLA haplotype with the patient’s lymphocytes successfully engraft and attack the host (patient) with clinical manifestations of rash, pancytopenia, and liver and gastrointestinal damage (diarrhea). This appears to be unique to immunocompromised patients such as solid organ or bone marrow transplantation patients, and patients with certain malignancies (Hodgkin’s disease, non-Hodgkin’s lymphoma, leukemia, and multiple myeloma), particularly in those undergoing intensive chemotherapy (e.g., fludarabine or myeloablative therapy). Interestingly, a patient with human immunodeficiency virus (HIV) infection has not yet been reported to have this complication, probably because of the suppressive effect of HIV infection on donor lymphocytes. Mortality is in excess of 80% and is usually secondary to bone marrow failure. This complication can be prevented by irradiation of blood products for patients at risk. On the basis of the pathogenesis, directed blood transfusions from any blood relative of the transfusion recipient also must be irradiated.
9. Posttransfusion purpura (PTP) is a rare complication, which is manifested by a profound immune-mediated thrombocytopenia that is observed 7 to 10 days after blood transfusion. Platelet alloantibodies within the recipient initiate the destruction of allogeneic platelets and are thought to trigger a complement-mediated consumption of the patient’s own platelets. Most commonly, recipients lack human platelet antigen (HPA)-1a, which is present in approximately 99% of whites. Although controversial, additional platelet transfusions with HPA-1a–positive units may increase complement generation, so further transfusions are often withheld unless an HPA-1–negative donor is identified. The treatment for PTP is intravenous IgG (IVIG), and if this fails, plasma exchange may be initiated to eliminate the antibody after 4 to 5 procedures.
10. Infections
11. Human immunodeficiency virus infection. Since the recognition that HIV infection is transmissible by blood, major advances in blood safety have been made. With the implementation of nucleic acid testing (NAT) for direct detection of viral (HIV and hepatitis C) contamination, the window period (time from infection to detectability by testing) is 11 days for HIV and 8 to 10 days for hepatitis C. Following the institution of NAT testing, the estimated risk for HIV and hepatitis C transmission is 1:1.5 × 10⁶ and 1:1.2 × 10⁶, respectively. In contrast, the risk of hepatitis B approximates 1:293,000. The risk of fatality from acute hemolytic transfusion reaction (usually due to ABO incompatibility secondary to patient or blood-unit misidentification) approximates 1:1.5 × 10⁶, which approximates the estimated death risk from viral transmission. Nevertheless, prudent utilization of transfusion support is important because blood is a scarce resource and because of possible, unknown future blood risks.
12. West nile virus (WNV). Queens, New York, was the epicenter of a WNV epidemic in 1999, which thereafter spread to numerous states throughout the country. The first of the cases of transfusion-transmitted WNV was reported in 2002, when 23 transfusion recipients who developed symptoms of a viral illness within 4 weeks of transfusion and then had laboratory confirmation of WNV. The cases were linked to 16 donors who were viremic at the time of collection (N Engl J Med 2003;349:1236). NAT testing of blood donors was started in 2003, and data from the American Red Cross reported 540 positive donations in 2003 and 2004. It is not clear whether NAT testing for WNV in blood donors will need to continue as the number of WNV cases throughout the country has declined since 2002.
13. Cytomegalovirus (CMV) infection. CMV infection has been a substantial cause of morbidity and mortality for immunocompromised oncology patients. Patients who receive allogeneic bone marrow/stem cell transplantation are at risk because of cytotoxic preparative regimens, immunosuppressive therapy (cyclosporine and corticosteroid), and/or GVHD. Up to 60% of this patient population will experience CMV infection, with half of them developing CMV disease. Even with the use of CMV-negative blood products, CMV seroconversion has been reported in 1% to 4% of CMV-negative donor–recipient transplantation patients.

 CMV infection and CMV disease are much less common in patients undergoing conventional chemotherapy or autologous bone marrow/stem cell transplantation, and are not thought to be a significant clinical problem.

 A randomized, controlled clinical trial in allogeneic bone marrow transplantation patients compared the value of CMV-seronegative blood products with unscreened blood products that were subjected to bedside leukofiltration. Four (1.3%) of 252 patients in the CMV-seronegative cohort developed CMV infection, with no CMV disease or fatalities; 6 (2.4%) of 250 patients in the leukoreduced cohort developed CMV disease, of whom 5 died. A much larger study would have to be performed to eliminate a type II statistical error with the insignificant rise in CMV infection of 40%. The filtered cohort had an increased probability of developing CMV disease by day 100 (2.4% vs. none; p = 0.03). Even when the investigators eliminated CMV infections that occurred within 21 days of transplantation, two cases of fatal CMV disease occurred in the filtered arm as compared with none in the leukoreduced arm. The conclusion by the authors of this study that leukoreduced blood products are “CMV safe” remains controversial. In a consensus conference held by the Canadian Blood Service, 7 of 10 panelists concluded that patients considered at risk for CMV disease should receive CMV-seronegative products, even when blood components are leukoreduced.

4. Bacterial contamination. The risk of platelet-related sepsis is estimated to be 1:12,000 for apheresis platelets but is greater with transfusions of pooled platelet concentrates from multiple donors (e.g., 1:2,000 after receiving six concentrates). Transfusion-related sepsis was the second leading cause of transfusion-associated fatalities from 1990 to 1998. In descending order, the organisms most commonly implicated in fatalities (as reported to the FDA) are Staphylococcus aureus, Klebsiella pneumoniae, Serratia marcescens, and Staphylococcus epidermidis. Platelets are prone to bacterial contamination because they are stored at 20°C to 24°C (room temperature). There is an increasing risk of bacterial overgrowth with time and, consequently, the shelf life of platelets is limited to 5 days. However, with new procedures, this may be extended to 7 days. In 2004, AABB implemented standards that require blood banks to perform bacterial testing of platelets. The bacterial testing systems are inoculated 24 hours after collection (to allow for bacterial growth) and then incubate for an additional 24 hours. Approximately 1:2,000 platelet units are found to be bacterially contaminated and often bacteria are detected after the 24-hour incubation and subsequent transfusion. Late positive tests likely indicate a reduced bacterial load and a smaller risk of sepsis. When platelets are released from bacterial testing, only 3 days remain of the 5-day shelf life, which challenges blood banks to maintain an adequate platelet inventory without substantial wastage. The use of rapid culture technology has been shown to reduce the transfusion of bacterially contaminated components (i.e., especially platelets with Gram-negative organisms), and this has also been accompanied by diminishing rates of septic reactions via hemovigilance programs. However, ongoing reports of culture negative products leading to either septic reactions or being associated with positive outdate cultures underscore persistent limitations in this technique. Recently, the FDA has approved a bacterial testing system that prolongs the shelf life of platelets to 7 days, which is currently being utilized in some centers.

 Another method to reduce the risk of transfusion-associated sepsis is photochemical treatment of platelet products. Photochemical treatments utilize ultraviolet (UV) light and psoralen to inactivate a broad range of Gram-negative and -positive organisms, as well as viruses. Treatment of platelet concentrates with amotosalen (a synthetic psoralen) and UVA light will result in a >4.5-log reduction in bacterial pathogens. Two randomized, controlled trials have evaluated the safety and efficacy of platelet concentrates treated with psoralen and UVA and both concluded that platelet products treated with photochemical inactivation were as efficacious as conventional platelets in achieving hemostasis with a comparable safety profile. Further studies are needed to better elucidate the role of pathogen inactivation in platelet products to reduce transfusion-associated sepsis and the risk reduction, if any, these methods provide in addition to the AABB-mandated bacterial cultures. In addition, Benjamin et al. have demonstrated that diversion pouches in conjunction with bacterial culture at the time of collection can minimize the rate of bacterial contamination of donated blood.

 The clinical presentation of bacterially contaminated platelet infection can range from mild fever (which may be indistinguishable from febrile, nonhemolytic transfusion reactions) to acute sepsis, hypotension, and death. Sepsis caused by transfusion of contaminated platelets is underrecognized in part because the organisms found in platelet contamination are frequently the same as those implicated in “catheter” or “line” sepsis. The overall mortality rate of identified platelet-associated sepsis is 26%.

 In the clinical setting, any patient in whom fever develops within 6 hours of platelet infusion should be evaluated for possible bacterial contamination of the component, and initiation of empiric antibiotic therapy should be considered. Because of their storage at room temperature, platelets are more prone to bacterial infection than are other blood products. FATRs occur in only 0.5% of red cell transfusions; of these, 18% and 8% of patients experience a second and third Febrile Transfusion Reaction (FTR),, respectively. Approximately 18% of platelet transfusions are associated with FTR, although the prevalence of platelet-associated FTR can be as high as 30% in frequently transfused populations such as oncology patients. Reactions characterized as severe occur in only 2% of platelet transfusions, and bedside leukofiltration has not been found to reduce the overall prevalence of FTR. Risks of transfusion-transmitted diseases are the same as those for red cells and are summarized in Table 39-1.

1. Plasma therapy. Plasma therapy should be administered to patients who have abnormal prothrombin time (PT) or partial thromboplastin time (PTT) assays in the setting of correction with a mixing study and clinically significant hemorrhage. The most common setting is in patients with liver disease who have multiple coagulation deficiencies, along with ongoing consumption due to impaired reticuloendothelial system (RES) clearance of substances activating the coagulation system. Another setting is in vitamin K deficiency. Vitamin K is derived from dietary sources and from intestinal bacteria, so that deficiency is caused by either poor dietary intake and/or with concomitant antibiotic therapy (e.g., intubated or cachectic patients treated with prolonged and multiple antibiotic therapy). Patients who have had Coumadin overdose or who are sensitive to this agent can also have markedly elevated international normalized ratio (INR) values. Parenteral vitamin K (5 to 10 mg s.q. or i.v. daily) administration should be considered in both patients with liver disease (impaired enterohepatic circulation of bile salts leading to deficiency of vitamin K and the vitamin K–dependent coagulation factors II, VII, IX, and X) and patients with Coumadin overdose. For patients with life-threatening hemorrhage, 15 mL/kg of plasma will increase factor levels by 20% to 30%, but there are limitations with plasma related to time required to obtain and administer the units as well as the propensity for fluid overload in susceptible patients (e.g., patients with poor myocardial function or patients who require larger doses). Recent guidelines have highlighted the potential usefulness (Grade 2c recommendation) of three and four factor concentrates that can be used to immediately reverse the effects of warfarin with minimal requirements for volume; the newer factor concentrates may also attenuate thrombotic risk since they also contain substantial quantities of protein C and S.
2. Platelet transfusions
3. Platelet-transfusion practices
4. Threshold for transfusion. Several studies have evaluated prophylactic platelet-transfusion practices and thresholds for patients who are thrombocytopenic due to myelosuppressive therapy. One study found that most patients undergoing stem cell transplantation were transfused prophylactically with platelets when their platelet counts were between 10 × 10⁹/L and 20 × 10⁹/L, indicating that a threshold of 20 × 10⁹/L was most common. Only 9% of hemorrhagic events reported in this study occurred when platelet counts were less than 10 × 10⁹/L.

 Two prospective, randomized studies evaluated the relative merits of platelet-transfusion thresholds of 10 × 10⁹/L versus 20 × 10⁹/L for leukemia patients undergoing chemotherapy. One found that the lower transfusion threshold was associated with 22% fewer platelet transfusions. No differences between the two patient cohorts were seen with respect to hemorrhagic complications, number of red cell transfusions, duration of hospital stay, or mortality. In a second study, a platelet threshold of 10 × 10⁹/L was safe and effective when compared with a threshold of 20 × 10⁹/L. Two (1.9%) of the 105 patients in this study died of hemorrhagic complications; each patient had a platelet count greater than 30 × 10⁹/L at the time of death. However, these studies were not adequately powered to detect a difference in fairly infrequent but catastrophic complications (e.g., subarachnoid bleeds). Nevertheless, it seems that other patient-related factors (i.e., qualitative platelet abnormalities, von Willebrand disease, or other hemostatic system defects) may play a role with respect to bleeding complications in the setting of thrombocytopenia.

5. Platelet dose. Standards of the AABB require that 75% of single-donor platelet (SDP) or apheresis products contain more than 3 × 10¹¹ platelets and that 75% of platelet concentrates (i.e., six pack is equivalent to a SDP) contain more than 5.5 × 10¹⁰ platelets. However, there is a broad range of platelet doses in several clinical trials, indicating that there is no consensus for a standardized platelet-transfusion dose.

 High-dose platelet therapy was investigated in a clinical trial that randomized patients with hematologic malignancies to prophylactic platelet transfusions with standard, high, and very high platelet doses (4.6 × 10¹¹, 6.5 × 10¹¹, and 8.9 × 10¹¹ platelets, respectively) to maintain a platelet count of 15 × 10⁹ to 20 × 10⁹/L. The high and very high platelet dose cohorts had greater platelet-count incremental increases and prolonged time to next transfusion when compared with the standard platelet dose cohort. However, as the platelet dose increased, the ratio of median number of platelets transfused/median transfusion interval decreased, suggesting that lower platelet doses may decrease the overall number of platelets required to maintain a platelet count of 15 × 10⁹ to 20 × 10⁹/L.

 Mathematical modeling of platelet survival predicts that lower doses of prophylactic platelet therapy (approximately 2 × 10⁹ vs. 4 × 10⁹) transfused to maintain a platelet count of 10 × 10⁹/L would decrease platelet usage by 22%. To evaluate the effects of low-dose platelet therapy on platelet utilization and risk of hemorrhage, a randomized study in thrombocytopenic patients receiving high-dose chemotherapy or a stem cell transplant compared low-dose (approximately 2 × 10¹¹) with standard-dose (approximately 4 × 10¹¹) platelet therapy. Over the course of their hospitalization, patients in the low-dose arm required 25% fewer platelet units and had a comparable number of bleeding events to the standard-dose group. Further studies of platelet-transfusion dosage strategies are needed to determine an optimal dose.

2. Platelet refractoriness. Infusion of an SDP generally results in a platelet count rise of 30,000 to 60,000/µL. Platelet refractoriness is defined as a reduced or absent rise in platelet count, especially when measured within 1 hour of transfusion. The differential diagnosis of platelet refractoriness in oncology patients includes infection, DIC, thrombotic thrombocytopenia purpura (TTP), splenomegaly, drugs, or antibody-mediated mechanisms. The first step in managing patients who respond poorly to platelet transfusions is to identify the specific cause of platelet refractoriness, which first requires the measurement of a corrected count increment (CCI), which accounts for the dose of platelets and the recipient size. Platelet refractoriness is typically defined as a CCI of less than 5,000 to 7,500 on two occasions when the patient receives ABO-compatible platelets.

 Upon diagnosis of platelet refractoriness, the causative factor must be sought. In multiply transfused patients, a poor response to transfusion may be commonly due to anti–HLA-related antibodies. Antibody-mediated accelerated clearance of platelets is supported by a poor increment when the count is obtained within 30 to 60 minutes after transfusion, in contrast to other potential causes like DIC that may result in an initial (30 to 60 minutes) increase in platelet count, followed by accelerated clearance over the next few hours. The formation of antibodies to HLA antigens occurs when there is exposure to foreign HLA molecules through pregnancy or transfusion. As platelets express HLA class I antigens, the presence of these antibodies may result in platelet refractoriness. Leukocytes present in transfused products have been implicated in the formation of HLA antibodies and, therefore, a large, randomized trial was conducted to examine the benefit of leukoreduced blood products in the reduction of platelet alloantibodies. The TRAP study (Trial to Reduce Alloimmunization to Platelets) found that clinical platelet refractoriness associated with HLA antibody seropositivity was reduced from 13% of patients transfused with unprocessed platelet concentrates to 3% to 5% of patients receiving leukoreduced apheresis platelets, leukoreduced platelet concentrates, or psoralen-/UVB-treated platelets. Notably, there was no difference in the rate of hemorrhage or overall mortality between the groups. The authors concluded that leukoreduced blood helped prevent the formation of alloantibodies.

 Alloantibodies to HLA antigens can be detected by methods of lymphocytotoxicity, enzyme-linked immunosorbent assay (ELISA), or flow cytometry. If HLA alloantibodies are found, providing matched platelets at the A and B loci can improve platelet increments. Alternatively, if specificity of the HLA antibody can be determined, antigen-negative platelets may be effective. In fact, some centers utilize cross-match procedures to identify platelet units that will improve responsiveness to platelet transfusion. The largest obstacle to providing HLA-matched platelets is a limited donor pool, which can be mitigated through single antigen mismatches with cross-reactive groups (CREGs). CREGs are structurally similar HLA antigens that react with common antisera. Transfusing alloimmunized patients with selectively HLA-mismatched platelets can increase the number of potential donors while improving platelet increments.

 Persistent refractoriness to platelet transfusions despite HLA-matched platelets is not uncommon in heavily alloimmunized patients. Although many immunosuppressive medications have been tried in this circumstance, the only therapy that has demonstrated some success is IVIG. Case reports and small series comprise most of this literature and the efficacy of IVIG in the treatment of alloimmunized patients is variable between reports. IVIG should not be used as a first-line therapy for alloimmunized patients; however, it has a role in patients who are persistently refractory to well-matched platelets or who are refractory and have active bleeding.

 Although alloantibodies are an important cause of platelet refractoriness, in some cases patient-specific factors can also influence the response to transfusion. In patients undergoing stem cell transplantation, the type of therapy administered and extent of disease are important predictors of platelet increment following a transfusion. A study of stem cell transplant recipients noted that factors usually associated with patient response to platelets (history of previous transfusion, pregnancy, the presence of HLA, or platelet-specific antibodies) did not significantly correlate with CCI. Rather, patient-specific variables such as disease status (advanced rather than early), conditioning regimen (including total body irradiation or not), progenitor cell source (bone marrow rather than peripheral stem cell), and type of transplant (allogeneic vs. autologous) are significant predictors of platelet refractoriness in patients undergoing stem cell transplantation.

1. Special blood products
2. Washed RBCs are rarely indicated, except in patients with severe or recurrent idiosyncratic reactions to plasma or platelets, in patients with IgA deficiency or in patients who cannot tolerate potassium loads especially with older RBC units (e.g., end-stage renal disease).
3. Irradiation of blood products eliminates engraftment by immunologically competent donor lymphocytes and is recommended for immunocompromised patients (high-dose chemotherapeutic regimens, immunosuppressive therapy in allogeneic transplantation, or fludarabine therapy), and any patient receiving directed transfusions from a blood relative.
4. Leukoreduced blood products (i.e., defined as 99.9% of white blood cells [WBCs] removed) have been recommended for the following patients: (a) patients with previous febrile transfusion reactions not prevented by acetaminophen and diphenhydramine therapy; (b) patients undergoing red cell-exchange transfusions; (c) patients for whom cross-match compatible blood is difficult to obtain; (d) patients who are candidates for solid organ (kidney, heart, and lung) or stem cell (aplastic anemia) transplantation; and (e) patients who should receive CMV-negative blood (e.g., platelets) when CMV-seronegative products are unavailable.

 III. APHERESIS. Apheresis is a procedure that removes a specified component of whole blood. It can be broadly classified into plasmapheresis (removal of plasma) and cytapheresis (removal of cells). Whole blood is continuously (i.e., 50 to 100 mL/min) removed from the patient either through a central venous catheter or a peripheral vein with a large bore needle and enters the pheresis machine through an extracorporeal circuit. Within the machine, the components of blood are separated by centrifugation, the desired portion (plasma, platelets, white cells, or red cells) is removed, and the remainder is then returned to the patient along with replacement solutions (e.g., plasma, albumin, or hetastarch) and donor red cells (i.e., with a red cell exchange). In the case of plasmapheresis, filtration instead of centrifugation can be used and similarly a replacement fluid is necessary, which may be albumin, plasma, or a combination.

1. Plasmapheresis. In general, plasmapheresis is used to remove disease-inducing antibodies or antigen-antibody complexes (e.g., vasculitis) and the amount of antibody removed per procedure depends on the vascular distribution of the pathologic antibody. IgG is 45% intravascular and approximately five procedures (i.e., using a 1.5-plasma volume exchange) are necessary to remove 90% of the antibody; in contrast, IgM is 80% to 90% intravascular and requires two to three procedures to remove 90% of the antibody. Plasmapheresis is used to treat many disease states in patients with cancer diagnoses. The frequency of required maintenance procedures also depends on the half-life of the specific immunoglobulin class (i.e., 21 days for IgG vs. 10 days for IgM and IgA).

 Waldenstrom’s macroglobulinemia (WM) is a low-grade lymphoma often associated with hyperviscosity symptoms due to excess IgM. If patients with WM present with symptoms of hyperviscosity (dizziness, shortness of breath, bleeding, confusion, visual changes) related to high IgM levels, emergent plasmapheresis can markedly improve symptoms. Additionally, patients with WM who cannot tolerate other therapies may be maintained on a chronic program of plasmapheresis to control symptoms. Plasmapheresis is also effective in the treatment of hyperviscosity associated with multiple myeloma; however, IgG or IgA paraproteins may require multiple procedures for symptom resolution. Recently, a randomized, controlled trial investigated the role of plasmapheresis in acute renal failure of multiple myeloma. Patients were randomized to conventional therapy (supportive care plus treatment of multiple myeloma) or to conventional therapy plus five to seven plasma exchange procedures. No significant differences in dialysis dependence, glomerular filtration rate, or death were noted between the plasmapheresis and standard therapy cohorts. Finally, plasmapheresis can be utilized in stem cell transplantation patients who receive a transplant from an ABO-incompatible donor. In the case of a major incompatibility (A donor → O recipient), recipient isohemagglutinins (anti-A) may persist until erythroid engraftment (A cells) occurs, with resultant potentially life-threatening hemolysis. This incompatibility may also lead to a protracted red cell engraftment period. Alternatively, if the donor is O and the recipient is A blood group, a minor incompatibility is present at the time of transplantation. However, donor lymphocytes (which produce anti-A) are delivered along with stem cells, and approximately 10 days after transplantation, synthesize anti-A in quantities sufficient to cause clinically significant hemolysis. This phenomenon is referred to as passenger lymphocyte syndrome and can also be seen after solid organ transplantation. Monitoring forward/reverse blood types, blood counts, lactate dehydrogenase (LDH), and direct antigen test results in susceptible patients (e.g., those with anti-A or anti-B titers >1:8) can allow early identification of patients who might require apheresis management for these hemolytic processes. In major or minor incompatibilities, plasmapheresis can effectively remove the isohemagglutinins and help abate hemolysis. However, if hemolysis is related to IgG (anti-A or anti-B), then plasmapheresis may not be immediately effective (i.e., since five procedures are required for a log reduction in IgG levels). In the case of ABO incompatibility and substantial hemolysis, urgent red cell exchange with O units may be indicated to abate hemolysis and reduce hemolytic-related sequelae.

5. Cytapheresis is used to collect peripheral blood stem cells for transplantation as discussed in Chapter 5. Outlined in the Chapter 35 is leukoreduction for hyperviscosity of acute leukemia.

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