Chapter 442. Transfusion Medicine

Transfusion of blood components is essential for treating children with various neonatal and pediatric disorders. Neonatal and pediatric transfusion practices can be classified into two age groups: infants up to 4 months of age and infants/children greater than 4 months of age. This chapter addresses specific aspects of pediatric transfusion medicine, namely the constituents of blood, indications, physician ordering, component preparation in blood banks, administration, and potential adverse events in each age group. It is important to note that prior to ordering or administering any blood product or component, informed consent explaining indications, treatment plan(s), benefits, and risks must be obtained unless a transfusion is required in an emergency.

Composition and Volume

Packed red blood cells (pRBCs) are the most commonly transfused component of whole blood. They are derived by centrifugation or, less frequently, are acquired directly from the donor by apheresis techniques, known as non-whole blood derived. See Table 442-1 for types of pRBC products, volume per unit, dosage, hematocrit and storage solution, and storage periods. Diverse anticoagulant preservative solutions are used to conserve red blood cells and may uniquely affect each neonatal/pediatric recipient. While additive solutions (AS) have evolved to extend the shelf life of red cells, the safety of the concentration of adenine and mannitol in AS and their associated renal toxicity when given to neonates has come into question. Additionally, the use and safety of AS-preserved pRBCs in massive transfusions for trauma, cardiac surgery, or exchange transfusions for infants less than 4 months old has not been established. The use of AS-preserved red cell units in this population in specific clinical situations must be approached with caution.2-5

It is imperative that pediatricians understand the diverse anticoagulant preservative solutions used to conserve red blood cells (RBCs) and the effect these solutions may have on the recipient. Historically, pRBCs for pediatric patients were stored in citrate, phosphate, dextrose, and adenine (CPDA-1) anticoagulant preservative solution.6 As additive solutions (AS) evolved in order to extend the shelf life of pRBCs, many investigators began to question the safety of these solutions in neonates. Of special concern were the levels of adenine and mannitol in AS and the association with renal toxicity. Specifically, mannitol’s potent diuretic effect can potentiate adverse fluctuations in the cerebral blood flow of preterm infants. Investigations on the risks of AS-containing transfusions have demonstrated their safety for neonates receiving small volumes (5–15 ml/kg) of pRBCs. Preparations of pRBC with additive solutions AS-1 and AS-3 caused no ill effects in infants receiving small volume. Transfusions of pRBC with AS-1 or AS-3 were as effective in increasing the hemoglobin levels as red cells stored in CPDA-1.2,6,7These findings were further validated by Luban and colleagues using theoretical calculations that revealed no substantial risk from the additive solutions to neonates receiving small-volume transfusions.3 However, removal of the AS supernatant is recommended for neonates with renal or hepatic insufficiency, particularly if the administration of multiple transfusions is anticipated from the same donor unit. The safety of AS-preserved pRBCs in massive transfusions vis-à-vis trauma, cardiac surgery, or exchange transfusions in neonates less than 4 months of age has not been established. Therefore, the use of AS-preserved pRBC units should be approached with caution in specific clinical situations.2–5

Storage Effects on pRBCs and Whole Blood

In general, packed red blood cells (pRBCs) are transfused to replenish blood volume and increase red cell mass, thereby increasing the oxygen-carrying capacity required to maintain adequate tissue oxygenation. Most donated blood is collected in an anticoagulant (citrate) and preservative (phosphate, dextrose, adenine) solution that upholds fluidity and red cell viability by means of replenishing ATP and maintaining a neutral pH. The storage conditions alter the red cell membrane while the supernatant around the red cells accumulates, increasing levels of potassium that can cause hyperkalemia in patients with a small plasma volume. Storing RBCs can also affect 2,3-diphosphoglycerate (2,3-DPG) levels within the red cell, which can interfere with hemoglobin function and adversely affect patients with acute hypoxia and those requiring large-volume transfusions of stored pRBCs. Nonetheless, the transfusion of stored pRBCs has been justified, as 2,3-DPG can regenerate within 24 hours, thereby restoring the hemoglobin function of the stored pRBCs.

The availability of whole blood for transfusions in hospitals varies. Health care facilities that treat neonates and pediatric patients do not customarily receive or store whole blood, as these facilities tailor the preparation of blood components specific to the patient’s unique transfusion needs. Moreover, many problems have been documented with the storage and use of whole blood, such as the loss of platelet function after 24 hours of storage at 4°C and loss of 5% to 30% viability of factors V and VIII after 21 days of storage. Instead, whole blood is now usually used with autologous donation for surgical procedures and, in some institutions, in the cardiopulmonary bypass circuit for pediatric cardiac surgery patients.

Indications for Transfusion of pRBCs in Patients Less Than 4 Months of Age

Packed RBCs are the most commonly transfused product during the neonatal period,8 chiefly for symptomatic anemia or after a 10% reduction of blood volume from iatrogenic or other losses. Guidelines for managing pRBC transfusion in neonates have been published9-13 and are primarily based on clinical practice rather than on evidence. See eTable 442.1 for the most recently published guidelines.14

Indications for Transfusion of pRBCs in Patients Older Than 4 Months of Age

The transfusion indications for pediatric patients older than 4 months are similar to adult pRBC transfusions. However, significant differences exist, namely blood volume, the ability to tolerate blood loss, and age-appropriate hemoglobin and hematocrit levels. A reduction of red cell mass, resulting from surgery, anemia of chronic diseases, hematologic malignancies, or slowly developing anemia is the most common indications for a red cell transfusion in this population. See eTable 442.2 for transfusion parameters for children older than 4 months of age.14

Ordering

ABO and Rh compatibility tests as required by the AABB (previously known as the American Association of Blood Banks) are listed in Table 442-2.15 At the earliest indication for a nonurgent pRBC transfusion, a type and screen should be ordered to determine the recipient’s ABO/Rh antigen type. The recipient’s serum should be “screened” with the indirect antiglobulin test (IAT) for unexpected alloantibodies that may have resulted from previous receipt of red cells. A type and crossmatch is performed to determine the patient’s type of ABO and Rh antigens, to screen for antibodies to unexpected red blood cell minor antigens, and to identify compatible red cells for transfusion.16 Crossmatched red cells may be issued more easily and rapidly when the antibody screen is negative and the crossmatch is nonreactive. A positive antibody screen requires assessing the significance of the antibody detected (ie, its capability of causing intravascular or extravascular hemolysis) prior to selecting donor red cell units for crossmatch.

Once the specificity of the antibody is determined, antigen-negative red cells can be selected. Exclusive of emergent transfusions, crossmatch testing must be done prior to issuing any red cell unit. In the event of an urgent red cell transfusion, when there is insufficient time to obtain ABO/Rh typing, a physician may order the emergency release of this product(s). For an emergency release order, group O (universal donor) and Rh-negative, uncrossmatched red cells are issued. This group and type (group O, Rh negative) of packed red blood cells (pRBCs) are scarce and valuable, so their availability may be limited. The next and most appropriate choice for red cell product in an emergency is group O and Rh-positive pRBCs. However, pediatric transfusion medicine specialists restrict the use of this group/type to male recipients in order to avoid the risk of immunizing an Rh-negative female who may, in the future, carry an Rh-positive fetus. An exposure of Rh-positive pRBCs to an Rh-negative female predisposes her fetus to developing hemolytic disease of the newborn. In somewhat emergent situations in which the time prior to transfusion is limited, the blood bank staff is required to provide type-compatible or type-specific blood (ie, O donor cells to an A, B, or AB recipient; A donor cells to an A recipient; and B donor cells to a B recipient). In less emergent scenarios, screening and crossmatching are not performed prior to product dispensation, yet type-compatible blood (O type for A, B, or AB recipients; A type for A recipients; and B type donor cells for B recipients) is issued by the blood bank.

Dosage, Blood Bank Preparation, Administration

The standard dose of red cells for infants less than 4 months of age is approximately 10 ml/kg, administered over a 2- to 4-hour period. This dose and rate can be transfused safely without additional processing, such as washing or resuspending the cells in another solution. Premature infants with severe hepatic or renal compromise require removal of the additive solution and resuspension of RBCs in saline or albumin. In larger volumes, such as for exchange transfusions, cardiac surgery, extracorporeal membranous oxygenation (ECMO), or massive transfusion, RBCs in extended storage media are not recommended.17 Infants older than 4 months of age and children with good cardiac and vascular function can tolerate an infusion of 10 to 20 ml/kg of pRBCs. As in younger infants, the pRBCs may be infused over 2 to 4 hours unless underlying disease deems other infusion strategies. The older child’s increased blood and plasma volume render the anticoagulant preservative solutions less important. A nonbleeding patient who receives a 10 ml/kg dose of pRBC will likely achieve a rise in hemoglobin concentration of 1 to 2 g/dl, or a 3% to 6% increase in hematocrit level. If the transfusion results in a poor increment, one can suspect peripheral destruction of the red cells or blood loss.

Preparation

For the prevention of transfusion errors, accurate component and recipient identification is imperative; the blood sample must be labeled with the recipient’s name and hospital identification number as taken from, and thus exactly matching, the hospital identification band always worn by the patient. Initial patient testing on the plasma or serum from either the infant or mother must include ABO and D typing of their red blood cells (RBCs) and a screen for unexpected RBC antibodies. Nonetheless, prior to issuing nongroup type O RBCs, the infant’s plasma or serum is tested to detect passively acquired maternal anti-A or anti-B. Of note, crossmatch compatibility testing and repeat ABO and D typing may be omitted during any hospitalization, as long as any of the following criteria are met: (1) the antibody screen is negative; (2) the transfused RBCs are group O, ABO identical or ABO compatible; or (3) the RBCs are either D negative or the same D type as the patient.14 However, before issuing nongroup O type RBCs, testing of the infant’s plasma or serum is required to detect passively acquired maternal anti-A or anti-B; this test should also include the antiglobulin phase. In the presence of an antibody, ABO-compatible RBCs are administered until the acquired antibody is no longer detected.14

As referenced in Table 442-1, pRBC units are supplied in volumes of 250 to 350 ml. The anticoagulant preservative solution used accounts for the variations in volume. The typical amount of blood ordered for infants either younger or older than 4 months of age is less than 250 ml and up to 350 ml. In facilities that support the blood products for neonatal and pediatric patients, small-volume aliquoting is used to (1) deliver an accurate volume of blood for a child/infant, (2) avoid an overtransfusion, (3) prevent product wastage, and (4) minimize donor exposures and donor-related risks to this neonatal population.18-22 To accomplish this latter goal, many hospitals assign a single pRBC unit to a single infant (or more than one infant) until the entire unit is utilized.19,23 Several acceptable technical approaches exist to produce a small-volume aliquot; once generated, the aliquot is relabeled with its proper expiration date, its origin, and disposition of the unit(s).

Administration

At the bedside, one must verify the recipient’s identity, matching the identity and hospital identification number with the corresponding name and number on the donor unit. Such corroboration is vital for avoiding a mistransfusion attributed to clerical errors, which account for a majority of fatal hemolytic transfusion reactions.23 All blood components are administered through a standard in-line filter that removes particles that may have accumulated during storage. Prior to initiating a transfusion, the patient’s vital signs are measured; the infusion is then started slowly while observing the patient for a potential transfusion reaction over the first 15 minutes. If a transfusion reaction is suspected, the infusion is slowed further or halted altogether. A slow infusion rate (~ 2 ml/kg per hour) is recommended for patients with severe anemia or heart failure, thereby reducing the risk of volume overload. Patients who experience acute hemorrhage or hypovolemia require rapid infusion of pRBCs to restore intravascular volume. Regardless of the indication, once a transfusion has been initiated, it must be completed within 4 hours to minimize the risk of bacterial contamination, which increases exponentially when pRBCs are subjected to room temperature for longer than 4 hours. RBCs should not be infused too rapidly or pushed through a very small needle, as this may cause hemolysis and a transfusion reaction.

Autologous Donation

Candidates for preoperative whole blood (WB) collection are stable patients who will undergo an elective surgical procedure that may potentially require a blood transfusion (eg, orthopedic surgery). Autologous donation has been shown to significantly reduce patient exposure to allogeneic red cell minor antigens and infectious pathogens.24 Two requisites must be met prior to donating autologous blood: the patient’s hemoglobin level should be at least 11g/dl, and the donation should occur more than 4 weeks prior to the surgical procedure so as to allow adequate time for compensatory erythropoiesis. Common recommendations for autologous WB donation include weekly collection and dietary iron supplements. The WB product is stored at 4°C for up to 35 days, after which it must be frozen or discarded. If the autologous product is not used for its intended recipient, it cannot be crossed over for allogeneic use, because the strict criteria and guidelines used for the general donor population are not applied to autologous donors. Absolute contraindications to autologous donation include (1) infection or the risk of bacteremia, (2) aortic stenosis, (3) unstable angina, (4) active seizure disorder, (5) myocardial infarction, (6) cerebrovascular accident during previous 6 months, (7) high-grade left main coronary artery disease, (8) cyanotic heart disease, (9) uncontrolled hypertension, and (10) significant pulmonary or cardiac disease.

Chronically Transfused Patients: Sickle Cell Disease and Thalassemia

Many patients with hemoglobinopathies, such as sickle cell disease (SCD) and thalassemia, require chronic RBC transfusion therapy to treat their disease. Chronic transfusion therapy is designed to mitigate tissue hypoxia and to suppress endogenous hemoglobin production. One therapeutic goal of chronic transfusions is to reduce the risk of stroke by decreasing the percentage of RBCs containing hemoglobin S, thereby diminishing sickling and preventing a rise in blood viscosity.25-28 Chronic transfusions have been shown to reduce the risk of recurrent stroke to less than 10% when hemoglobin concentrations are maintained between 8 and 9 g/dL and when hemoglobin S level is less than 30%. The method of transfusion can be a simple additive or a partial exchange transfusion once every 3 to 4 weeks. Chronic erythrocytapheresis (the simultaneous removal and replacement of a recipient’s RBCs with those of a donor), using a machine, may prevent iron overload and decrease the amount of hemoglobin S in patients with SCD. When chronic transfusions are employed for stroke prevention, they must be continued indefinitely to prevent recurrences.25,26 When orders are written for a pRBC transfusion, the unit(s) should ideally be screened for hemoglobin S and leuko-reduced to prevent HLA alloimmunization and platelet refractoriness, especially when contemplating stem cell transplantation.

RBC alloimmunization and alloantibody formation occurs more often in patients with SCD than any other patient group.29-31 Its frequency varies with each child’s disease process and is influenced by factors such as the child’s age at first transfusion, number of transfusions received, and the ethnicity of all donors and recipients.16 Common RBC antigens that elicit antibody production include Rh, Kell, Duffy, and Kidd system antigens. In order to reduce the rate of alloimmunization, many sickle cell treatment centers perform thorough RBC phenotyping prior to starting any transfusion therapy, using a preferential selection of phenotypically matched units.26,32 However, for those patients who are not yet alloimmunized, this strategy remains controversial, as it is difficult to obtain phenotypically compatible units.25,33

Persons with thalassemia and severe anemia require packed red blood cells transfusions to improve tissue oxygenation and to suppress ineffective extramedullary erythropoiesis in the liver, spleen, and bone marrow. A child’s normal growth and development can be supported with the maintenance of hemoglobin levels between 8 and 9 g/dL. Some chronic transfusion protocols target higher hemoglobin levels (11–12 g/dL) in an effort to decrease iron absorption from the gastrointestinal tract. Unfortunately, iron overload is an inevitable and serious complication of pRBC transfusions in this population and must be treated with chelation therapy beginning early in childhood.34,35

Massive Transfusion

Administering red blood cell products in amounts greater than or equal to the patient’s estimated blood volume (75–80 ml/kg) is termed massive transfusion and may cause a host of complications, including (1) hypothermia secondary to the rapid infusion of cold blood products; (2) dilution and depletion of hemostatic coagulation factors, predominantly after replacing 1 to 2 total blood volumes of the patient; (3) metabolic derangements such as hypocalcemia resulting from citrate anticoagulants that bind to free calcium; and (4) dilutional thrombocytopenia. Evidence of these complications is confirmed by specific laboratory tests, such as (1) prolonged clotting times (PT/PTT), (2) hypofibrinogenemia, (3) thrombocytopenia, and (4) hypocalcemia. These complications can occur when massive transfusions are utilized to establish extracorporeal membrane oxygenation (ECMO), during cardiopulmonary bypass, or secondary to trauma. Other blood products such as platelets, frozen plasma products (FFP), and cryoprecipitate are part of the arsenal in a massive transfusion.

Component and Volume

In the United States, both pooled platelet concentrates (known as random donor or whole blood–derived platelets) and apheresis platelets, known as single-donor platelets, are available. Platelet concentrates are derived from whole blood drawn from a donor, whereas single-donor platelets are collected via an apheresis machine that returns the remaining whole blood components to the donor. These two methods of platelet collection yield distinctly different amounts of platelets per unit. One platelet concentrate contains approximately 7 × 1010platelets, whereas one single donor apheresis platelet contains 3 to 6 × 1011platelets. Pooling of 5 to 8 platelet concentrates from different donors is required to equal the same amount of platelets in an apheresis platelet transfusion. Platelets have a short shelf life (limited to 5 days) and are stored at room temperature and preserved with constant, gentle agitation. The various types of platelet products are listed in Table 442-3, with their approximate volumes, compositions, dosage, and storage periods.

Indications

Normal peripheral blood platelet counts vary in all age groups from 150,000 to 450,000 per μl. The threshold to transfuse platelets in premature neonates is higher than in other age groups, given the risk of intracranial/ventricular hemorrhage (ICH/IVH). When the platelet count falls below 50,000/μl, there is a clinically significant risk of an IVH (particularly in infants who weigh less than 1.5 kg at birth).36 However, prophylactic platelet infusion is controversial, because although this procedure can increase platelet counts and shorten bleeding times, it has not been shown that it reduces the incidence of IVH.37 In contrast, neonates, children, and adolescents can tolerate platelet counts as low as 10,000/μl without the risk of major bleeding. The most common rationale for transfusions is preventing potential bleeding.38 For stable patients, recent studies support a platelet threshold of 10,000/μl when there are no coexisting conditions.39-41 Currently, the same thresholds are used for children/adolescents who have thrombocytopenia secondary to chemotherapy. For children and adults with fever, active bleeding, or coexisting coagulation defects, a platelet count of 20,000/μl is considered the threshold at which to transfuse. Indications for platelet transfusion are shown in eTable 442.3.

Ordering

When possible, platelets should be ABO and Rh matched, as this secures the best response and minimizes the potential for red cell hemolysis.

The potential of a fatal outcome from receiving ABO/Rh-incompatible platelets is not as great as when one receives ABO/Rh-mismatched red cells. However, if platelet Rh type is mismatched, Rh immunoglobulin should be administered to counter any red blood cell contamination of the platelet product. Of significance in receiving ABO-mismatched platelets is a potential or eventual platelet refractory state.42 In addition, hemolysis of red blood cells, leading to death, has been reported in children who have received either large volumes of ABO-incompatible plasma or plasma with high-titer isohemagglutinins, each of which is more likely to occur with an apheresis platelet product rather than with pooled platelet concentrates.43 Thus, the optimal strategy for preventing platelet- and HLA-alloimmunization are leuko-reduced, ABO-matched units.

For the neonate and small child, incompatible platelet products, whether apheresis or a platelet concentrate, should be volume reduced to eliminate most of the incompatible plasma. However, the process of volume reduction decreases the number and optimal functioning of platelets and shortens their expiration to 4 hours. Consequently, volume reduction is not routinely recommended for older children or adult patients who receive ABO-mismatched platelet products. For additional details on the volume-reduction of platelet products, see the “Clinical Service and Blood Bank Evaluation of Acute Transfusion Reactions” section later in this chapter.

Dosage, Blood Bank Preparation, Administration

The customary dose for a platelet concentrate is 10 ml/kg, which typically yields approximately 10 × 109cells. Platelets obtained from a single donor may contain a slightly lower dose than the platelet concentrate. Some facilities categorize platelet apheresis products into patient subsets by weight and are ordered as “quarters” or “halves.” Alternatively, a 70-kg adult body surface area (BSA) of 1.7 m2 can be used to estimate the BSA of a neonate or child to approximate the appropriate pediatric dose. When a patient is suspected of being platelet refractory, the clinician must anticipate the time required (up to several hours or even days) to obtain and prepare either crossmatched or HLA-matched platelets.

A strategy that allows the clinician the ability to assess the platelet transfusion outcome is to calculate the corrected count increment (CCI) by measuring the post-transfusion platelet count obtained within 15 minutes up to 1 hour after completing the transfusion. The CCI formula can help determine if the patient is platelet refractory or has an adequate rise in platelet count for the dose given; the CCI is based on the patient’s body surface area (BSA).

If the CCI is less than 5000 to 7500/μl for 2 successive days, the patient is considered refractory. The blood bank staff should be notified when a patient is suspected of platelet refractoriness so that procurement of crossmatched or HLA-matched platelets can be anticipated. Such products require hours, if not days, to obtain and prepare.

Component and Volume

Granulocyte products are obtained by automated leukapheresis, yielding approximately 300 ml of granulocytes, RBCs (6–7 g/dl of hemoglobin per unit), platelets, and citrated plasma. Prior to leukapheresis of donors, the volunteers receive corticosteroids (dexamethasone) or a growth factor such as G-CSF that stimulates a greater production of granulocytes. Oral dexamethasone has been demonstrated to increase baseline peripheral blood granulocytes two- to threefold (1.7 × 109). Donors stimulated with G-CSF have been shown to yield a seven- to tenfold increase from the baseline (4–5 × 1010). The combined use of dexamethasone and G-CSF is superior, in that this combination produces a nine to twelvefold increase in circulating granulocytes in the donor. The collection of granulocytes for an individual donor is typically scheduled one collection daily, for 4 to 5 days. The final granulocyte count for a collection depends on the total volume of blood processed and on the peripheral blood neutrophil count at the start of the donation. A continuous-flow blood-cell separator can process from 7 to 12 liters of blood over a 2- to 4-hour period.44

Indications

Clinical indications for granulocyte transfusions include severe neutropenia (< 0.5 × 109 polymorphonuclear cells [PMNs]/μL) for any of the following conditions: (1) progressive, documented bacterial, yeast, or fungal infection that is nonresponsive to antimicrobial therapy 48 hours after initiation of antibiotic treatment; (2) a protracted period of neutropenia in stem cell transplant recipients; (3) congenital granulocyte dysfunction; and (4) bacterial infection in neonates.45 Prophylactic granulocyte transfusions are not recommended.46

Ordering

Granulocytes are considered an unlicensed product and as such have no official Food and Drug Administration (FDA) product specifications. However, AABB standards require the collected product to contain at least 1 × 1010granulocytes in more than 75% of units sampled.47 Ideally, the ordering physician will notify the hospital blood bank, which then notifies the blood center of the request for granulocytes. The blood center contacts potential ABO-compatible donors (from a registry) to prevent a reaction with the red cells in the end product. Thus, a crossmatch is necessary on the unit prior to its use. In addition, immunocompromised recipients of granulocytes are at risk of acquiring transfusion-associated graft versus host disease (TA-GVHD) due to the predominance of donor T lymphocytes in the product; thus, irradiation of all granulocyte products is recommended. In addition, granulocytes should not be infused through a leukocyte-reduction filter.48 Moreover, granulocytes need not be HLA matched unless the patient is known to be HLA alloimmunized. Lastly, most blood centers require a signed emergency release by the ordering physician, as the product must be infused soon after collection and prior to completion of all infectious disease testing by the blood center.

Dosage, Blood Bank Preparation, Administration

The average dose for a neonate or child is 1 to 2 × 109 granulocytes/kg/day.1 Administration of granulocytes is recommended for a period of 4 to 7 days in an effort to increase the granulocyte count of severely neutropenic patients not responding to antibiotic/antifungal treatment. Once the product arrives at the hospital blood bank, it must be kept at room temperature and issued as soon as possible, or within 24 to 48 hours after its collection. It is difficult to accurately predict the post-transfusion increment of granulocytes, which has not been well correlated with the granulocyte dose administered. Thus, the clinical significance of granulocyte transfusions is hard to assess, and most clinicians strive for a sustained post-transfusion granulocyte count above 500 PMN/μl (0.5 × 109 /L). This transfusion outcome is increasingly feasible with the collection of large numbers of granulocytes from donors given steroid and G-CSF stimulation. The occurrence of adverse events with granulocyte administrations is limited to anecdotal evidence that administration of Amphotericin B concurrent with that of granulocytes has been linked to pulmonary toxicity. Thus, it is generally recommended that granulocyte transfusions be administered after a minimum of 4 hours after an Amphotericin B infusion.48 Other potential adverse reactions from granulocytes include fever, dyspnea, rigors, and hypotension. They may be mitigated by reducing the infusion rate, administering antihistamines, corticosteroids, and meperidine.

Composition and Volume

The aqueous, acellular portion of whole blood is known as plasma. Albumin is the most abundant of the plasma proteins. Other plasma proteins include complement, predominantly C3, in addition to enzymes, transport molecules, immunoglobulins (gamma-globulins), and coagulation factors. Coagulation factors in plasma include (1) fibrinogen; (2) factor XIII; (3) von Willebrand factor; (4) factor VIII, primarily bound to its carrier protein vWF (~ 100 ng/ml); and (5) vitamin K–dependent coagulation factors II, VII, IX, X.1 Plasma products are mainly produced from whole blood and less frequently from plasmapheresis collections. The designation of a plasma product as either fresh frozen plasma (FFP) or F24 plasma is determined by the time after collection to the time of freezing. FFP is frozen within 6 to 8 hours of collection, while F24 is frozen within 24 hours after collection. FFP and F24 are virtually equivalent. Another FDA-approved plasma product is cryo-reduced plasma (CRP), also known as cryosupernatant, which is depleted of its cryoprecipitate fraction. Table 442-4 provides a list of plasma-derived products, with their appropriate volumes, composition, and storage periods.

Indications

Specific indications for FFP and F24 include (1) bleeding diatheses associated with acquired coagulation factor deficits, such as end stage liver disease, massive transfusion,49 and disseminated intravascular coagulation (DIC); (2) the rapid reversal of warfarin effect; (3) plasma infusion or exchange for thrombocytopenic purpura (TTP); (4) congenital coagulation defects, except when specific factor therapy is available; and (5) C1-esterase inhibitor deficiency. Refer to eTable 442.4 for more detailed indications for plasma products.

Ordering

Despite a lack of formal compatibility testing for plasma, the ordering physician must be aware of isohemagglutinins that can cause hemolysis and accordingly must order ABO-compatible plasma for the recipient. Nevertheless, when a recipient’s ABO type is unknown prior to a plasma infusion, AB plasma, lacking in isohemagglutinins, may be administered. Rh alloimmunization rarely results from an Rh mismatch of plasma products, because there are few RBCs in plasma.

Dosage, Blood Bank Preparation, Administration

Dosing of both FFP and F24 is uniform (10–20 ml/kg) among neonates, children, and adults. It typically yields a 30% increment in coagulation factor concentrations. Nonetheless, a clinically significant coagulopathy may require multiple doses of plasma to correct this state. The need to thaw either of these products, which can take 20 to 40 minutes to complete, requires advance notification. Rapid infusion of plasma products is acceptable, and doses may be administered repeatedly, depending on the half-life of the factor deficiency being treated.

Composition and Volume

Cryoprecipitate is an insoluble precipitate that is formed by thawing FFP and then refreezing it in 10 to 15 ml of plasma within 1 hour. This processing produces a plasma-based product containing the highest concentrations of factor VIII (80–150 U/unit), vWF (100–150 U/unit), fibrinogen (~250 mg/unit), factor XIII (150–250 U/unit) and fibronectin ~2 mg/ml. Cryoprecipitate can be stored at temperatures less than or equal to –18°C and can be maintained for up to 1 year.

Indications

The development of safer and more specific factor concentrates has limited the indications for cryoprecipitate primarily to fibrinogen replacement, owing to its high fibrinogen content. The etiology of such a deficiency may be congenital or acquired, namely (1) dysfibrinogenemia; (2) DIC; (3) orthotopic liver transplantation; and (4) poststreptokinase therapy, which may cause hyperfibrinogenolysis. It is also effective in the rare patient with factor XIII deficiency. With the advent of heat-treated, plasma-derived von Willebrand–containing factor products and recombinant factor VIII products, cryoprecipitate no longer has a therapeutic role in treating von Willebrand disease and hemophilia A in the United States. See eTable 442.5 for more detailed indications for cryoprecipitate.

Ordering

Cryoprecipitate units have a small volume (10–30 ml) in contrast to other plasma products, pRBCs, and apheresis platelets. As a result, the isohemagglutinins anti-A and anti-B are present in small quantities. Similarly to plasma products, compatibility testing is not absolutely required for cryoprecipitate, but it is recommended by the AABB standards for the pediatric patient.

Dosage, Blood Bank Preparation, Administration

The dose of cryoprecipitate required depends on the clinical necessity. In both children and adults, a 1 unit/10 kg dose will increase the fibrinogen level by 60 to 100 mg/dl. However, in a neonate, a single unit dose will increase the fibrinogen level by more than 100 mg/dl. The dosing frequency varies, from once every 8 to 12 hours to up to several days, depending on the cause of the hypofibrinogenemia. Cryoprecipitate is prepared in the blood bank by thawing and pooling several units, which are then issued as one unit. As with other frozen plasma products, component preparation can take 20 to 30 minutes. Cryoprecipitate can be administered by rapid infusion or slowly over 2 to 4 hours, depending on the clinical indication.

Composition

Albumin, the most abundant of the plasma proteins (3500–5000 mg/dl), is an acellular product whose primary function is to maintain plasma colloid oncotic pressure. The liver is responsible for albumin synthesis. The product is made by separating albumin from human plasma through a cold ethanol fractionation procedure. The life span of the albumin molecule is approximately 15 to 20 days. Commercially available formulations of human albumin preparations include a 5% solution, a 25% solution, and a plasma protein fraction 5% solution (PPF). All preparations are manufactured from pooled plasma and have a balanced physiological pH and contain 145 mEq of sodium and less than 2 mEq of potassium per liter. Additionally, these preparations are free of preservatives or coagulation factors.

Indications

Albumin, in adult and pediatric medicine, is widely used in (1) adult respiratory distress syndrome (ARDS); (2) priming a cardiopulmonary bypass pump; (3) fluid resuscitation for shock, sepsis, and burns; (4) neonatal kernicterus; and (5) enteral feeding intolerance (eTable 442.6). Albumin is also administered subsequent to a large-volume paracentesis in patients with nephrotic syndrome that is resistant to diuretics and for volume/fluid replacement in plasmapheresis. Albumin is not indicated for correcting nutritional hypoalbuminemia or hypoproteinemia, nutritional deficiency requiring total parenteral nutrition, wound healing, or a simple volume expander for a surgical or burn patient. Additionally, albumin is not used in the blood bank to resuspend RBCs.

Ordering

As an acellular product, albumin is virtually devoid of blood group isohemagglutinins, so ABO or Rh compatibility is not a requisite prior to its dispensation. The clinical indication dictates the albumin’s percent solution and volume required.

Dosage and Administration

The dose of albumin recommended for children with hypoproteinemia is 0.5 to 1 g/kg per dose, given over 2 to 4 hours. It may be repeated 1 to 2 times in a 24-hour period. The total dose should not exceed 250 grams in a 48-hour period.

Composition

Intravenous immune globulin, or IVIG, is acquired by fractionating large pools of human plasma. Similar to native immunoglobulins, IVIG has a half-life of 21 to 25 days. In vivo clearance of immunoglobulins is accentuated in states of increased metabolism such as fever, infection, hyperthyroidism, or burns. Numerous FDA-approved preparations of IVIG are commercially available, the differing manufacturing processes of which have their theoretical advantages and disadvantages. The ideal IVIG product typically (1) contains each IgG subclass; (2) retains Fc receptor activity; (3) has a physiological half-life; (4) demonstrates virus neutralization, opsonization, and intracellular killing; and (5) possesses antibacterial capsular polysaccharide antibodies. Additionally, the product should be devoid of transmissible infectious agents and vasoactive substances. While each manufacturer strives for this optimal composition, some brands produced have profiles more suitable for treating specific disease states. The immunomodulatory effects of IVIGs are not well understood. Postulated mechanisms of action include autoantibody inhibition, increased IgG clearance, complement activation modulation, macrophage-mediated phagocytosis inhibition, cytokine suppression, superantigen neutralization, and modulating B- and T-cell function.

Indications

The use of intravenous immune globulin (IVIG) is approved for immune thrombocytopenic purpura (ITP), congenital or acquired immunodeficiencies (eg, severe combined immunodeficiency [SCIDS] or pediatric HIV), and Kawasaki disease.50 Despite these clinical applications, more than 50% of the IVIG produced yearly is used for off-label indications.51

Ordering

Unless otherwise specified by the physician, the IVIG product stocked in the blood bank is appropriate for most clinical indications. Certain disease states, however, such as renal insufficiency and IgA-deficiency, require specific product knowledge. See eTable 442.751 for licensed products and their specifications. Physicians administering IVIG must be acquainted with the potential side effects directly related to IgG aggregates and dimer formation, combined with complement activation. Adverse symptoms to IVIG typically include mild and transient headache, fever, flushing, and hypotension. Amelioration or avoidance of these unfavorable symptoms can be accomplished by reducing the infusion rate or changing the brand of IVIG. More serious adverse reactions to IVIG include renal failure, aseptic meningitis, and thromboembolic events. In addition, recipients who have an IgA deficiency and receive an IgA-containing product have been reported to experience severe anaphylactic reactions. Other less common, yet serious, reactions include pulmonary edema, fluid overload, eczema, arthritis, and transfusion-related acute lung injury (TRALI).

The administration of IVIG can also cause the passive transfer of blood group antibodies such as anti-A and anti-B (IgG class) and non-ABO antibodies such as anti-Kell, anti-C, and anti–Lewisb. This transfer of antibodies can result in positive antibody screens; positive DATs; and, in rare instances, hemolytic anemias secondary to anti-D or anti-A. For this reason, close observation of the hemoglobin level is advised after treatment with IVIG. In the mid-1990s, transmission of hepatitis C with the administration of IVIG was a serious problem. Consequently, manufacturers implemented methods such as pasteurization or solvent/detergent treatment and improved donor screening to safeguard against the transmission of hepatitis C and other viruses.

Dosage and Administration

The specific disease process necessarily dictates the type and dose of IVIG. The dose can range from daily infusions of 400 mg/kg per day, given for 5 days, up to 1 gm/kg per day for 1 to 2 days for ITP, and one dose of 2 gm/kg for Kawasaki disease. The dosing for pediatric HIV is 200 to 400 mg/kg every 2 to 4 weeks, whereas for congenital immunodeficiencies, a dose of 300 to 400 mg/kg is recommended monthly and adjusted to achieve suggested trough IgG levels between 400 and 500 mg/dl. For pediatric bone marrow transplant recipients, data extrapolated from the adult experience suggests a dose of 500 to 1000 mg/kg weekly be used to prevent graft versus host disease (GVHD) and infection.

Leukoreduction, CMV serological testing, gamma-irradiation, plasma volume reduction, and washing of cellular products (pRBCs and platelets) are specialized processes performed to prevent specific transfusion complications.

Leukoreduction

Leukoreduction, the process of removing the leukocytes (WBCs) from the cellular component of blood, is performed at blood centers prior to storage of components and is known as prestorage leukoreduction. Leukoreduction is undertaken to prevent or delay the complications such as febrile nonhemolytic transfusion reactions (FNHTRs), human leukocyte antigen (HLA) alloimmunization, transfusion transmitted cytomegalovirus (TT-CMV) or herpes-related viruses, and transfusion-related immunomodulation (TRIM). A study of leukoreduced pRBCs stored at 4°C for 42 days showed a WBC reduction of 3.2 logs, with individual reduction of monocytes, lymphocytes, and neutrophils of 4.1, 3.8, and 2.5 logs, respectively.52 The widespread occurrence of WBC-associated complications led Great Britain and Canada to implement universal prestorage leukoreduction for all blood components. In the United States, neither the AABB nor the FDA have mandated prestorage leukoreduction for all blood components. Despite a recent Canadian study of universal leukoreduction that revealed no change in mortality or rate of bacteremia, U.S. blood centers currently leukoreduce all pRBC and platelet products.53 These investigators did attribute a decrease in retinopathy of prematurity and bronchopulmonary dysplasia (BPD) as well as shorter hospitalization to the practice of universal leukoreduction.53

Cytomegalovirus (CMV) Prevention

The transmission of CMV occurs in a myriad of ways, including in utero, during the birth process, with breast-feeding, close contact with mothers or nursery staff, or transfusion. With current and applied blood banking technologies, the occurrence of transfusion-transmitted CMV is between 1% and 3%.54Manifestations of CMV infection or disease in neonates are quite variable and range from asymptomatic seroconversion to death. The rate of symptomatic transfusion-transmitted CMV (TT-CMV) infection in infants is low when compared to the high incidence of seropositivity in adults. Moreover, symptomatic CMV infection is uncommon in neonates born to seropositive mothers due in part to protective antibodies stemming from the mother. The risk of TT-CMV infection is higher in multitransfused low birth weight infants (LBWI) of less than 1200 grams born to seronegative mothers.54-56 Thus, the recommendation for LBWI born to CMV-seronegative mothers is to receive CMV reduced-risk blood transfusions. Two other strategies to prevent TT-CMV include using blood from CMV-seronegative donors or leukocyte-reduced components, as CMV is associated with leukocytes.57-59 Other processes such as deglycerolized and washed RBCs have been demonstrated to reduce the risk of TT-CMV but are logistically more cumbersome than WBC filtration.

Irradiation

The prevention of transfusion associated (TA) GVHD is the primary purpose for irradiating cellular blood components and is intended for use in immunocompromised recipients. Effective treatment for TA-GVHD is limited, so mortality rates are as high as 80% to 90%. Thus, it is imperative prior to transfusion to identify individuals most vulnerable, to prevent this noninfectious hazard of transfusion. (See eTable 442.8 for guidelines to identify those who should receive irradiated cellular blood products.) Despite varying opinions and practices among experts, the policies of blood banks will necessarily reflect their resources and the particular needs of the patient population they serve.

Plasma Volume Reduction

Plasma volume reduction of cellular blood components is a process generally used for premature infants who have renal ischemia or compromised cardiac function. In 1993, the AABB Committee on Pediatric Hemotherapy recommended that volume reduction of platelet concentrates be reserved for infants with total body fluid restrictions.36 The methods for platelet volume reduction have been published.60 Nonetheless, optimal centrifugation rates and preparation methods remain unclear.39

Washing

Saline washing of red blood cells (RBCs) and platelets is used to reduce the risk of adverse reactions to plasma or anticoagulant preservative solutions. Specifically for neonates, washing RBCs or platelet components is performed to remove maternal plasma, additive solutions, and high levels of potassium. The importance of removing maternal plasma lies in preventing hemolytic disease of the newborn and neonatal alloimmune thrombocytopenia, while potentially reducing the lifelong risk of transfusion related acute lung injury (TRALI). Washing RBCs and platelets is also performed for all recipients who have had a severe allergic or anaphylactic transfusion reaction, to reduce the risk of recurrence. Of note, washing RBCs does not adequately leukoreduce this product to prevent WBC-associated complications, nor does it protect against the development of TA-GVHD.61

Transfusion reactions are categorized as noninfectious versus infectious complications of transfusion (eTable 442.9). Acute hemolytic transfusion reactions (AHTRs) are noninfectious reactions that result from the transfusion of ABO-incompatible red cells. In acute hemolytic reactions, intravascular hemolysis results from IgM anti-A or anti-B reacting with their cognate antigen on the donor red cells. Intravascular hemolysis can also occur by passive IgM anti-A or anti-B transfer of incompatible donor plasma that reacts with the recipient’s red cells, which carry the cognate antigen. The release of free hemoglobin into the intravascular space activates the coagulation cascade and releases vasoactive amines, resulting in fever, chills, nausea and vomiting, chest or back pain, and anxiety. As a result, laboratory tests may reveal hemoglobin in the urine and low haptoglobin in the serum. The severity of the reaction can be mitigated by the timely cessation of the transfusion. However, the infusion of a large volume of incompatible blood or plasma can result in acute renal failure, shock, disseminated intravascular coagulation (DIC), and death. Acute intravascular hemolysis can be mediated by a nonimmune cause such as physical or thermal injury to donor RBCs during storage (inappropriate temperature storage or mixing of hypotonic fluid with RBCs) or transfusion method (red cells being pressurized through a fine-gauge needle).

Delayed hemolytic transfusion reactions (DHTRs) can occur 3 to 10 days after a red cell transfusion, owing to non-ABO antigens. These IgG-mediated reactions can cause severe hemolysis. A DHTR can occur in a previously sensitized recipient, whose incompatible minor RBC antigens go undetected during routine antibody screening and produce an anamnestic antibody response. Detection of a DHTR may be delayed, as recipients are initially asymptomatic. However, they subsequently develop hyperbilirubinemia, do not achieve the expected transfusion outcome, or merely have an unexplained decline in hemoglobin level 1 to 2 weeks post-transfusion. Confirmation of a DHTR is made with a positive direct antiglobulin test (DAT) and a potentially positive antibody screen. Thereafter, antibody specificity must be identified and future pRBC transfusions should be devoid of that specific RBC antigen.

Transfusion-related acute lung injury (TRALI) is a noninfectious complication of transfusion and is currently the leading cause of transfusion-related deaths reported to the FDA.61 As defined by the National Heart, Lung and Blood Institute (NHLBI), TRALI is a “new acute lung injury (ALI) that develops with a clear temporal relationship to transfusion, in patients with or without alternate risk factors for ALI.” Contrastingly, the Canadian Consensus Conference on TRALI in 2004 defined it as “a new episode of ALI that occurs during or within 6 hours of a completed transfusion which is not temporally related to a competing etiology for ALI.” A diagnosis of TRALI is confirmed by clinical and radiographic findings. Recipients may exhibit shortness of breath resulting from noncardiogenic pulmonary edema, fever, and hypotension. At present, the pathogenesis, treatment, and prevention of TRALI are not well understood.

Transfusion-associated circulatory overload (TACO) is another noninfectious complication that can result from transfusing excessive fluid in a disproportionate time. Patients at greatest risk for developing TACO are those with underlying cardiovascular disease.

Infectious organisms transmissible in blood include viruses, bacteria, parasites, spirochetes, and prions (eTable 442.10). The three most common transmitted viral pathogens that have caused significant morbidity and mortality are HIV, hepatitis C (HCV), and hepatitis B (HBV). Significant advances in safety/testing, such as nucleic acid testing (NAT), have greatly reduced the risk of disease transmission in the United States. See eTable 442.11 for a list of transfusion-transmitted viral agents.

Once a transfusion reaction is suspected, the transfusion must be immediately terminated and further evaluation for classification of reaction is undertaken. The assessment for all febrile reactions or suspected acute hemolytic transfusions includes four essential steps. First, the donor unit must be verified with the recipient. Second, the ABO and Rh types of both the recipient and the donor are reconfirmed. Third, a visual inspection of the recipient’s plasma for free hemoglobin is performed. And, fourth, a DAT on the recipient’s post-transfusion specimen is performed (eTable 442.12).61 The most common cause of severe febrile reactions with platelet transfusions is most likely attributed to bacterial contamination, as they are stored at room temperature. If a recipient of platelets develops a fever or manifests signs of infection or endotoxin-mediated shock, a Gram stain and blood culture are obtained from both the patient and the donor product in order to determine the source of contamination. Supportive care for the patient includes but is not limited to intravenous antimicrobial therapy.