17: Blood Component Therapy

1. Type and screen. Whenever possible, samples from both mother and infant should be obtained for initial ABO group and Rh(D) type determinations.

   1. Investigations of the maternal sample should include:

      1. ABO group and Rh(D) type.

      2. Screen for unexpected red cell antibodies by an indirect antiglobulin technique (IAT).

   2. Investigations of the infant (or umbilical cord) sample should include:

      1. ABO group and Rh(D) type.

      2. Direct antiglobulin test (DAT) performed on neonatal red cells.

      3. In the absence of maternal serum or plasma, the infant's serum or plasma is screened for unexpected antibodies by an IAT.

      4. If a non–group-O neonate is to be transfused with non–group-O erythrocytes, which are incompatible with the maternal ABO group, then the neonate's serum or plasma must be tested for anti-A and anti-B using an IAT. If either antibody is detected, then donor erythrocytes that lack the corresponding antigen must be chosen for transfusion.

      5. Unexpected (or atypical) red cell antibodies are clinically significant antibodies other than anti-A and/or anti-B whose presence may be expected depending on the ABO group. Repeat ABO group and Rh(D) type determinations may be omitted throughout the remainder of the neonate's hospital admission or until age 4 months is attained, whichever occurs sooner.

2. Type and cross-match red blood cells (RBCs). Mix donor RBCs with maternal or infant serum or plasma (or both) and inspect for agglutination and/or hemolysis after incubation at 37°C (98.6°F). Infants very rarely make alloantibodies in the first 4 months of life. If the initial screen for red cell antibodies is negative, then there is no need to perform cross-matching during that period (or throughout the remainder of the neonate's hospital admission, whichever occurs sooner). If the initial screen for red cell antibodies is positive, then additional testing should be done.

   1. Perform testing to determine the specificity of any antibodies identified (involves reaction of maternal serum or plasma and/or umbilical cord serum or plasma against a panel of reagent erythrocytes of known antigen phenotype).

   2. Transfused red cells used must lack the corresponding antigen(s) or be compatible by antiglobulin cross-match until such antibodies are no longer demonstrable in the neonate's serum or plasma. The presence of multiple antibodies increases the difficulty of identifying compatible donors and delays blood availability.

1. Voluntary blood donations. These are from screened donors with a negative history for potentially blood transmissible diseases. All blood donors are tested using serological enzyme immunoassays (EIAs) and nucleic acid amplification testing (NAT) for viral risks that include HIV (1 and 2), hepatitis viruses B and C (HBV and HCV), human T-cell lymphotrophic viruses (HTLV [I and II]), and West Nile virus (WNV). The only screening assay for parasites currently is an EIA for antibodies to Trypanosoma cruzi (cause of Chagas disease). In addition, EIA or microhemagglutination testing for Treponema pallidum (syphilis) is still required. Testing obviously is not performed for all blood-borne threats; testing for the following viruses is not routinely done: cytomegalovirus (CMV), parvovirus B19, hepatitis A virus (HAV), hepatitis G virus (HGV, also known as GB virus-C [GBV-C]; no proven disease association), Torque teno virus (TTV or transfusion-transmitted virus; no proven disease association), Epstein-Barr virus (EBV), and human herpes virus-8 (HHV-8 or KSHV; associated with Kaposi's sarcoma and with multicentric Castleman's disease and primary effusion lymphoma in HIV-infected patients).

2. The residual risks of transfusion per unit transfused are estimated to be:

   1. HIV types 1 and 2. 1 per 1,467,000.

   2. HCV. 1 per 1,149,000.

   3. HBV. 1 per 280,000.

   4. HTLV types I and II. 1 per 2,993,000.

   5. West Nile virus. Risk for WNV varies with location, date, and test method (mini pool NAT vs individual NAT) and has been decreasing in recent years, so a single risk estimate applicable to the Unites States is not possible. Risk for transfusion-transmitted T. cruzi is unknown.

   6. For perspective, selected comparative mortality odds ratios are: anesthesia—1:7000–1:340,000; flood—1:455,000; and lightning strike—1:10,000,000.

Blood provided by a relative or friend of the family for a specified infant. This technique cannot be used in the emergency setting as it takes up to 48 hours to process the blood for use. There is no evidence that donor-directed transfusion is safer than blood provided by routine donation. Mothers are not ideal donors because maternal plasma frequently contains a variety of antibodies (against leukocyte and platelet antigens) that could interact with antigens expressed on neonatal cells. Similarly, transfusions from paternal donors present a risk because the neonate may have been passively immunized against paternal blood cellular antigens (by transplacental transfer of maternal antibodies against paternal antigens).

In adults, safety of transfusion is markedly enhanced with the use of autologous blood collected preoperatively.

1. The fetoplacental blood reservoir contains a blood volume of ∽110 mL/kg and 30–50% of this volume is contained in the placenta. Thus, placental blood is autologous blood. Approximately 20 mL/kg can be harvested at birth and used for future transfusion. The potential for bacterial contamination coupled with the additional expense of collection have limited the widespread adoption of placental autologous blood transfusion.

2. As an alternative, delayed cord clamping for 30–45 seconds after birth allows the transfer of a significant amount of blood from the placenta to the infant. The blood volume of a newborn subjected to delayed cord clamping is 15–30 mL/kg larger than that of neonates with early cord clamping. Beneficial effects from this procedure are a reduction in transfusions needed, decreased iron deficiency at a later age, and possibly decreased risk of intraventricular hemorrhage in preterm infants.

1. The following adverse reactions to blood transfusion are caused by passenger or contaminant leukocytes (white blood cells [WBCs])—whose numbers are maximal when fresh blood is used).

   1. Sensitization to human leukocyte antigens (HLAs)

   2. Febrile transfusion reactions

   3. Immunomodulation, which may increase the risk of postoperative infection

   4. CMV transmission

   5. Transfusion-associated graft-versus-host disease (TA-GVHD) from engraftment of donor T lymphocytes

2. HLA sensitization and febrile transfusion reactions are unusual in infants, while transfusion-transmitted CMV and TA-GVHD can be life threatening.

   1. At greatest risk of severe CMV infection are preterm infants (<1200 g) born to CMV-seronegative mothers.

   2. Patients at risk for TA-GVHD include recipients of donor-directed units from first- and second-degree blood relatives, HLA-matched platelets, intrauterine transfusions, and massive fresh blood transfusions or exchange transfusions, as well as patients with suspected or proven severe T-lymphocyte immunodeficiency states (eg, DiGeorge syndrome).

   3. For these high-risk patients, transfused blood components must be processed to remove passenger WBC.

      1. Leukoreduction (removal of passenger WBC)

         1. Such so-called leukoreduction is almost always performed by filtration of the blood component through proprietary hollow-fiber filters to which intact WBC adhere. (Centrifugation-based techniques are outdated.) Leukocyte counts can be reduced from 10⁹ to 4–6 × 10⁵ per RBC unit (4 log unit reduction) with third-generation filters.

         2. Leukoreduction is effective in reducing HLA alloimmunization and transmission of cell-associated viruses (especially herpes viruses [such as CMV and HHV-8] and EBV)—as well as preventing some febrile transfusion reactions.

      2. Gamma-irradiation of cellular blood components delivers a dose of 25 Gy and prevents subsequent WBC mitoses, and thereby TA-GVHD.

For patients >4 months, uncross-matched (or “emergency release”) blood is rarely transfused, because most blood banks can complete an IAT cross-match within 1 hour. In cases of massive, exsanguinating hemorrhage, “type-specific” blood (ABO and Rh[D]-matched only), usually available in 10 minutes, can be used. If this delay is too long (as in severe fetomaternal hemorrhage), type O Rh(D)-negative RBCs should be used.

1. Red blood cells

   1. Packed red blood cells (PRBCs)

      1. Indications. PRBC transfusions are given to maintain the hematocrit (Hct) at a level judged best for the clinical condition of the baby. The selected target Hct is quite controversial and may vary greatly among neonatal units. In general the goal is to maintain the Hct:

         1. >35–40% in the presence of severe cardiopulmonary disease. The severity of cardiopulmonary disease is assessed based on the level of respiratory support (intermittent positive pressure ventilation [IPPV], continuous positive airway pressure [CPAP], Fio₂) required, symptoms of unexplained apnea and/or tachycardia, and/or poor growth.

         2. 30–35% for moderate cardiopulmonary disease or major surgery.

         3. 20–25% for infants with stable, so-called asymptomatic anemia.

      2. Administration

         1. Type. PRBC transfused throughout infancy should be screened in order to exclude donations from blood donors containing hemoglobin S.

         2. Dosage. 10–20 mL/kg given over 1–3 hours (4 hours maximum). Use the following formula as a guide:

            Volume PRBC to transfuse (mL) = 1.6 × weight (kg) × desired rise in Hct (%)

   2. “Adsol” PRBCs. The traditional use of relatively fresh RBCs (<7 days storage) has been largely replaced by the practice of transfusing aliquots of RBCs from a dedicated unit of PRBCs stored for up to 42 days. This requires a sterile connecting device and is done to diminish the number of donor exposures among infants expected to require numerous transfusions during their stay in the neonatal intensive care unit (NICU) (infants whose birthweight is <1500 g). PRBCs are suspended in a citrate-anticoagulated storage solution at an Hct of 55–60% stored at 1–6°C. The storage or additive solutions (AS or Adsol-1, -3, or -5) contain various combinations of preservatives (dextrose, sodium chloride, phosphate, adenine, and mannitol).

   3. Citrate phosphate dextrose PRBCs. Because of concern about potential hepatorenal toxicity of adenine and mannitol, units of RBCs without extended storage medium are used for large-volume transfusions such as exchange transfusion and transfusions for major surgical procedures. PRBC units with only small amounts of adenine and devoid of mannitol have a hematocrit of 65–80% and a shelf life of 35 days. PRBC units with CPD formulations (citrate-phosphate-dextrose) lacking both adenine and mannitol also have a hematocrit of 65–80% but a shelf life of only 21 days. Washed Adsol PRBC units are an alternative if these other PRBC units are unavailable.

   4. Washed PRBCs. During storage, potassium is progressively released from RBCs so that, by the end of the storage period, extracellular (plasma) potassium levels approximate 50 and 80 mEq/L for Adsol and CPD units, respectively. This leakage is increased in irradiated blood. For small-volume transfusions the amount of infused K is, in general, of little clinical significance (0.3–0.4 mEq/kg per 15 mL/kg RBC transfusion). But it may become hazardous for larger transfusion volumes such as in exchange transfusion. In such an event and in the absence of fresh whole blood (<2–3 days old), RBCs (typically O Rh[D] negative) washed free of their potentially hyperkalemic supernatant using normal saline and then reconstituted to a hematocrit of 50–55% with fresh frozen plasma (typically AB, termed “reconstituted whole blood”) can be used. Irradiated reconstituted whole blood should be used for total exchange transfusion.

2. Plasma—fresh-frozen plasma (FFP), thawed plasma. Donated whole blood is centrifuged to separate the cells (RBCs) and the liquid (plasma). If the separation is done within 18 hours of the blood being donated and is frozen, it is called fresh-frozen plasma. FFP contains albumin, immune globulins, and clotting factors (some retain much of their activity after thawing, eg, von Willebrand factor [vWF]) and factors V, VII, and VIII (their activity may be reduced during processing before freezing).

   1. Indications

      1. Correction of coagulopathy due to inherited deficiencies of some clotting factors, vitamin K deficiency (hemorrhagic disease of the newborn), or disseminated intravascular coagulation (DIC). When available, clotting factor concentrates are preferred to plasma in case of inherited clotting factor deficiency. There are no single factor concentrates available for factors II, V, and X. Prothrombin complex concentrates containing factors II, IX, and X are used for factor II and X deficiencies.

      2. Prophylaxis for dilutional coagulopathy that may ensue during massive blood transfusion administered for replacement of blood loss in excess of half of the blood volume.

      3. Preparation of reconstituted whole blood from washed PRBCs for total exchange transfusion.

      4. Although FFP provides excellent colloid volume support, it is not recommended for volume expansion or antibody replacement because safer components are available for these purposes.

   2. Administration

      1. Transfused plasma should be ABO compatible with the patient's blood group. Incompatible antibodies in the donor plasma (such as anti-A or -B antibodies in group O plasma) may rarely, if given in sufficient volume, result in an acute hemolytic reaction in the transfused patient.

      2. Dosage: 10–20 mL/kg over 1–2 hours (4 hours maximum).

      3. Rapid transfusion may result in transient hypocalcemia due to the sodium citrate that is added to the original donated blood. If rapid infusion of FFP is needed, a small bolus of calcium chloride (3–5 mg/kg) may be considered.

3. Cryoprecipitate. Prepared from FFP by thawing it at 1–6°C. In this temperature range, a cryoprecipitate forms and is separated from so-called cryo-poor supernatant plasma by centrifugation. The pellet is then frozen as cryoprecipitate. Prior to use, it must again be thawed and dissolved off the interior surface of its plastic bag with normal saline (with a total volume of 10–15 mL). Cryoprecipitate is a concentrated source of the following blood clotting proteins: factor VIII, vWF, fibrinogen, and factor XIII (with some other proteins, eg, fibronectin).

   1. Indications

      1. To restore fibrinogen levels in patients with acquired hypofibrinogenemia (as occurs in DIC and massive transfusion)

      2. Factor XIII in deficient patients

   2. Administration

      1. Like plasma, it should be ABO compatible with the recipient's blood group.

      2. Dosage: 10 mL/kg (0.1–0.2 U/kg raises fibrinogen by 60–100 mg/dL).

      3. Infusion should be completed within 6 hours of thawing.

4. Platelets. Prepared from whole blood donations by centrifugation (termed “random donor”) or by automated apheresis (termed “single donor” or “platelets pheresis”). Each random donor unit contains 5.5 × 10¹⁰ platelets in 50–70 mL of anticoagulated plasma. Each single-donor unit contains 3 × 10¹¹ platelets, typically in 200–300 mL of anticoagulated plasma. Both are stored at room temperature (20–24°C) with agitation for a maximum of 5 days.

   1. Indications. There are no absolute guidelines regarding platelet counts that necessitate transfusion.

      1. In general, platelet transfusion is indicated for platelet counts below 50,000/μL.

      2. In the presence of active bleeding or prior to surgery, this “transfusion trigger” may be raised to 100,000, while in a nonbleeding, stable neonate platelet counts as low as 20,000–30,000 may be tolerated.

      3. In septic patients, platelet increments after transfusion may only be transient.

      4. Because of room temperature storage, bacterial contamination of platelet units is actively sought, typically by culture or direct testing of each component.

      5. Increased mortality and morbidity have been described among preterm infants receiving multiple platelet transfusions.

   2. Administration

      1. Infant and donor should be ABO identical if possible. When ABO-identical platelets are unavailable, group AB platelets are the most suitable substitute. However, the frequent unavailability of group AB platelets causes the use of group A platelets for group B recipients and vice versa. Group O platelets are the least suitable for non–group-O infants, as passively transfused anti-A or -B antibodies may lead to hemolysis.

      2. Rh(D)-negative platelets should be given whenever possible to Rh(D)-negative patients—especially female infants.

      3. For infants with alloimmune thrombocytopenia (AIT), platelets lacking platelet-specific antigens (HPAs) to which antibodies are directed are required. If such platelets are unavailable, then HPA 1a, 5b–negative platelets may be given since these will be compatible in 95% of AIT cases among Caucasians. If anti-HPA antibodies are not demonstrated, then anti-HLA antibodies may be present requiring HLA-matched platelets.

      4. Dosage: 10–20 mL/kg IV should raise neonatal platelet counts by 60,000–100,000/μL.

1. Acute intravascular hemolysis. Occurs due to incompatibility of donor RBCs with antibodies in the patient plasma. The most common antibodies responsible for complement-mediated acute hemolysis are isohemagglutinins (anti-A, anti-B). Newborns do not all make isohemagglutinins in high titer until 4–6 months of age.

   1. However, transfusion of ABO-incompatible donor RBCs (most commonly due to clerical error) may result in hemolysis if isoagglutinin titers are high enough. Accordingly, some neonatal units may transfuse all neonates with O Rh(D)-negative PRBCs (if the blood supplier can support this policy).

   2. Incompatible isoagglutinins are more often found in the neonatal circulation due to transfusion of the ABO-incompatible plasma in platelet units.

   3. Transplacental passage of group O maternal isohemagglutinins to a non–group-O fetus may also cause hemolysis of the neonate's own RBCs in the absence of transfusion (typically mild; “ABO HDFN”). Note that passively acquired anti-A and anti-B, whether of blood donor or maternal origin, are not detected by antibody screens but do cause incompatible cross-matches. Accordingly, cross-matches using an IAT are always necessary when clinically significant red cell antibodies, including isohemagglutinins, are present in neonatal plasma.

   4. Red cell T-antigen is present on all human erythrocytes but expressed only after exposure to neuramidinase produced by a variety of infectious organisms—in particular Streptococcus, Clostridium, and influenzae viruses. Anti-T antibodies are present in almost all adults but are not present in the plasma of infants until 6 months of age. Anti-T may be associated with hemolysis in patients whose red cells are “activated,” eg, infants with necrotizing enterocolitis (NEC) or sepsis. When intravascular hemolysis occurs and T activation of neonatal RBCs is identified through peanut lectin testing, donor RBCs and platelets should be washed prior to use.

   5. Possible symptoms of intravascular hemolysis include hypotension, fever, tachycardia, hematuria, and hemoglobinuria. Diagnosis may be confirmed by an elevated free serum hemoglobin, absent haptoglobin (if it is not congenitally absent, as in about 10% of African-American infants), as well as the presence of schistocytes on a peripheral blood smear.

2. Nonhemolytic febrile reactions. Usually mild, due to transfusion of cytokines released from donor WBCs during storage or of fragmented donor WBCs.

3. Allergic transfusion reactions. Unusual in neonatal transfusion recipients. Due to antibodies in the patient's plasma reacting to epitopes on donor plasma proteins.

4. Transfusion-associated acute lung injury (TRALI). Typically due to antibodies in donor plasma that react with the patient's HLA antigens. More likely to occur with blood components containing large amounts of plasma such as FFP or platelets.

5. Bacterial contamination. There is a small but potentially fatal risk of bacterial infection on the order of 1 per 8–13 million for PRBCs but of 1 per 300,000 for platelets (because of room temperature storage). Escherichia coli, Pseudomonas, Serratia, Salmonella, and Yersinia are the most commonly implicated bacteria.

6. Hypothermia. Large-volume transfusions of either reconstituted whole blood (exchange transfusion) or PRBCs (major surgery, large fetomaternal hemorrhages), which are stored at 1–6°C, will result in hypothermia unless a blood warmer is used.

7. Hyperkalemia. At risk are infants receiving a large transfusion of RBCs such as in exchange transfusion, major surgery, or ECMO/ECLS. Reconstituted whole blood (washed PRBCs [<14 days old] with Hct adjusted using FFP) is recommended. In some neonatal units, fresh whole blood (<2–3 days) may be available.