Chapter 48: Transfusion Therapy

Product: Whole Blood Administration

Whole blood is given over a maximum of 4 hours through a 170-μm filter^1,2,3

Preparation/Composition

1. Donor blood 450–550 mL containing red blood cells (RBCs), plasma, clotting factors, and anticoagulant

2. Platelets and granulocytes are not functional

Indications

RBC replacement in acute blood loss with pronounced hypovolemia

Notes

1. Whole blood is not routinely available and is rarely required in hematology-oncology patients. It is not a source of viable white blood cells (WBCs) or platelets

2. Shelf life: 21 days in CPD (citrate-phosphate-dextrose); 35 days in CPDA-1 (citrate-phosphate-dextrose-adenine) preservatives

Product: Red Blood Cells Preparation/Composition

1. RBCs obtained by apheresis collection or prepared from whole blood by centrifugation^1,2,3

2. RBCs collected in CPDA-1 anticoagulant have a hematocrit of 65–80% and a storage volume of 250–400 mL

3. RBC collections from which plasma has been removed and 100 mL of adenine-containing RBC nutrient solution (eg, AS-1) has been added, have a hematocrit of 55–60% and a volume of 300–350 mL

Administration

1. RBCs are administered over a maximum period of 4 hours through a 170-μm filter

2. Do not add medications to blood products. If needed to decrease viscosity, 0.9% sodium chloride injection is the only compatible intravenous solution that may be added to RBCs; however, this is rarely needed with current additive solutions

Indications

1. Improves oxygen carrying capacity in anemic patients

2. In most stable asymptomatic patients without cardiovascular disease, transfusion is initiated if hemoglobin is <7 g/dL

3. Transfusion thresholds in patients with cardiovascular disease who are asymptomatic are not well defined; results of clinical trials are awaited. Higher transfusion thresholds (9–10 g/dL) may be appropriate for patients with symptomatic cardiac disease^3,4,5,6

Notes

1. Patients with febrile nonhemolytic transfusion reactions benefit from leukoreduced blood products

2. Premedication with acetaminophen 650–1000 mg orally, may also be given

3. Patients with allergic transfusion reactions are treated with diphenhydramine 25–50 mg orally or intravenously

4. Shelf life: 35 days in CPDA-1; 42 days if stored in additive solutions like AS-1 (contains sodium chloride 154 mmol/L, adenine 2 mmol/L, glucose 111 mmol/L, and mannitol 41.2 mmol/L)

Product: Washed Red Blood Cells Preparation/Composition

Washing RBCs with 1 L 0.9% sodium chloride injection (0.9% NS) removes more than 98% of plasma proteins. RBCs are then resuspended in 0.9% NS at an approximate hematocrit of 75%^1,2

Indications

1. Patients with a history of severe or recurrent allergic reactions

2. For patients with paroxysmal nocturnal hemoglobinuria, routine washing of group-specific RBCs is not required

3. Washed RBCs are used to decrease potassium load in neonates with cardiac or renal disease

Administration

Washed RBCs must be transfused within 24 hours

Notes

1. RBCs washed with larger volumes of 0.9% NS (≥2 L) or units collected from IgA-deficient donors are required for patients with severe IgA deficiency

2. Shelf life: Washed RBCs have a shelf life of only 24 hours

Product: Leukocyte-Reduced Red Blood Cells Preparation/Composition

Contains <5 × 10⁶ WBCs per unit. Leukocyte reduction filters remove >99.9% of the contaminating leukocytes^1,2

Administration

The product is transfused over a maximum period of 4 hours through a 170-μm filter

Indications

1. Patients with recurrent febrile nonhemolytic transfusion reactions (FNHTR)

2. To decrease the likelihood of HLA alloimmunization and platelet transfusion refractoriness

3. To decrease the risk of transmission of cytomegalovirus (CMV) infection in high-risk CMV-seronegative patients

Notes

1. Prestorage leukoreduction is superior to bedside filtration

2. The use of bedside leukoreduction filters has been associated with “hypotensive” reactions and facial flushing

3. Shelf life: Depends on the preservative added; 35 days for CPDA-1; 42 days for additive solutions such as AS-1

Product: Frozen Deglycerolized Red Blood Cells Preparation/Composition

Goal: Remove glycerol in which RBCs are suspended^1,2

1. RBCs are frozen with glycerol as the cryoprotectant to maintain integrity after thawing

2. Deglycerolization is achieved by first thawing RBCs and then washing them with saline solutions of decreasing osmolarity to remove the glycerol

3. The final product has few leukocytes and <0.1% of the original plasma; however, it does not meet requirements of leukoreduced components

Administration

Deglycerolized RBCs must be transfused within 24 hours

Indications

Indications for use include:

1. Storing units with rare blood types

2. Storing autologous collections

Notes

1. As shelf life of deglycerolized RBCs is limited, transfusion of rare, frozen RBCs should be carefully planned to avoid wastage

2. Shelf life: Deglycerolized RBCs have a shelf life of only 24 hours

Product: Platelets Preparation/Composition

1. Single-donor apheresis platelets: Collected from single donors by apheresis. Contain ≥3 × 10¹¹ platelets in 250–300 mL plasma^1,2,7

2. Platelet concentrates (PC): Platelet concentrates prepared from units of whole blood. PCs contain ≥5.5 × 10¹⁰ platelets suspended in 45–60 mL of plasma. Pooled platelets (4–6 PC) have a shelf-life of 4 hours. An FDA-approved closed system for pre-storage pooled platelets with a shelf-life of 5 days from time of whole blood collection is available now

Administration

1. When administering PCs, an adult dose is obtained by pooling 4–6 units into a single pack

2. Use a standard 170-μm filter or a leukocyte reduction filter, and infuse within 4 hours

Notes

1. Platelets are not routinely recommended for correction of thrombocytopenia in patients with ITP or TTP in the absence of a risk for severe bleeding

2. Washed, irradiated, and leukoreduced platelets have indications similar to those described under RBCs

3. Platelet increments and HLA-matched platelets⁹

   Among chronically transfused patients, 20–30% will develop alloimmunization to HLA antigens and will not experience an increment in their platelet count when platelets from randomly selected donors are administered. Platelet count should be obtained 15–60 minutes after transfusion, and the corrected count increments (CCIs; see equation) should be calculated. CCIs should be obtained for 2 consecutive transfusions. In the absence of clinical causes such as splenomegaly, fever, or ongoing bleeding to explain a poor increase in the platelet count, patients with poor CCIs are usually found to have an immune-mediated cause for the poor increments. In these patients, platelet cross-matching is carried out to select compatible products. Alternatively, HLA and platelet antibody screening tests are done. If the HLA antibody screen is positive, patients are supported with HLA-matched platelet products. Rarely, antibodies may be directed against platelet-specific antigens, in which case phenotype-matched platelet donors are recruited. Immune globulin (human) does not produce sustained responses; its routine use in alloimmunized patients is not recommended

    

   

    

   Note: The number of apheresis units transfused can be entered as the denominator in the formula above. For example, if a patient (70 kg, 167.6 cm, BSA = 1.8 m²) has an incremental increase of 10,000/μL in platelet count following transfusion of a platelet product containing 3 × 10¹¹ platelets, the calculated CCI would be 6000. A CCI of <5000–7500/μL suggests platelet refractoriness

4. Shelf life: 5 days. Pooled platelets must be transfused within 4 hours

Indications

1. Actively bleeding patients with thrombocytopenia⁸

2. Actively bleeding patients with congenital or acquired platelet function disorders, regardless of platelet counts

3. Prophylactic treatment when:

   • Platelet counts are <10,000/μL in stable afebrile patients with hematologic disease without underlying coagulopathy

   • Platelet counts are <20,000/μL in patients with active mucosal bleeding or fever

   • Platelet counts are <50,000/μL in patients requiring line placement, invasive procedures or surgery

   • Platelet counts are <100,000/μL in patients requiring ophthalmic surgery, or surgical procedures involving the upper airway, brain, or spinal cord

Product: Fresh-Frozen Plasma (FFP) Preparation/Composition

Fresh-frozen plasma (FFP) (200–250 mL) is:^1,2

• Obtained by apheresis, or

• Prepared by centrifugation of whole blood and frozen within 8 hours after collection

• Plasma frozen within 24 hours (FP24) may be separated and frozen up to 24 hours after collection. Except for containing slightly lower levels of the labile factors V and VIII, FP24 is considered clinically equivalent to FFP

Administration

When replacing coagulation factors, a dose of 10–20 mL/kg is recommended, with periodic monitoring of coagulation tests to determine efficacy and appropriate dosing intervals. Attention to volume status and judicious use of a diuretic is essential to avoid volume overload (“TACO”—transfusion-associated circulatory overload)

Indications

1. Replacement of coagulation factors in patients with coagulopathy of liver disease, massive transfusion, warfarin overdose, and DIC. The INR should be >1.5, or the PT/PTT must be increased by at least 1.5 times the upper limit of normal ranges

2. Therapeutic plasma exchange in patients with TTP. Cryo-poor plasma is FFP from which the cryoprecipitate fraction has been removed through cold precipitation. This may also be used as the plasma exchange replacement fluid in patients with TTP

3. Patients with rare disorders, such as isolated factor (V, X, XI) deficiencies or C-1 esterase inhibitor deficiency

Notes

1. Vitamin K therapy should be used to correct altered PT/PTT in patients who are not actively bleeding. Similarly, FFP is unnecessary for patients with warfarin overdose in the absence of active bleeding or risk for bleeding from an emergent procedure. Patients with INR ≤5 are initially managed with cessation of therapy for 48 hours with watchful return of coagulation tests to baseline levels

2. FFP from IgA-deficient donors is indicated for patients with IgA-deficiency

3. Shelf life: One year when FFP is stored frozen at ≤−18°C (≤−0.4°F); 24 hours when thawed and kept at 1°–6°C (33.8°–42.8°F). Plasma can be relabeled as Thawed Plasma and stored for an additional 4 days at 1°–6°C. While ADAMTS13 levels are well preserved, Thawed Plasma prepared from FFP and stored for 5 days contains reduced levels of Factor V (>60%) and Factor VIII (>40%)

Product: Cryoprecipitate Preparation/Composition

1. Cryoprecipitate is the cold-insoluble precipitate formed when FFP is thawed at 1°–6°C (33.8°–42.8°F)^1,2

2. Cryoprecipitate contains 200–250 mg fibrinogen, 100–150 units factor VIII, as well as 40–70% of the VWF and 20–30% of the factor XIII present in a unit of FFP

Indications

1. Fibrinogen replacement during dilutional coagulopathy

2. The hypofibrinogenemia/dysfibrinogenemias of liver disease, DIC, and asparaginase therapy

3. Factor XIII deficiency

Administration

Each unit (bag) of cryoprecipitate increases fibrinogen level by 5–10 mg/dL. Six to 10 bags are pooled and infused as a single dose in a 70-kg adult

Notes

1. Cryoprecipitate is no longer used to treat patients with hemophilia A or von Willebrand disease (VWD)

2. Shelf life: 1 Year when kept frozen at ≤−18°C (≤−0.4°F); 6 hours after thawing when kept at 20°–24°C; (68°–75.2°F); 4 hours after pooling

Product: Granulocyte Transfusions Preparation/Composition

1. Large numbers of granulocytes can be collected from healthy donors by means of granulocyte colony-stimulating factor (G-CSF) plus corticosteroid marrow stimulation followed by large-volume leukapheresis^1,2

2. Product contains ≥1 × 10¹⁰ granulocytes suspended in 200–300 mL plasma

Indications

1. Severely neutropenic patients (ANC <500/mm³) with bacterial sepsis without improvement despite 48–72 hours of optimum antibiotic therapy, provided there is a reasonable expectation of bone marrow recovery

2. Possible role in severely neutropenic patients with serious fungal infection not responding to antifungal therapy

3. Patients with granulocyte function disorders such as chronic granulomatous disease with refractory bacterial or fungal infections may also benefit from granulocyte transfusions

Administration

1. Transfusions are given daily until clinical improvement or neutrophil recovery occurs

2. Given the large number of RBCs in the product, donors should be RBC crossmatch-compatible with a recipient

3. Granulocyte products are routinely irradiated

4. The product is stored at room temperature (outdated in 24 hours), and is preferably infused soon after its collection

5. Do not use leukocyte reduction filters; use standard 170-μm filters

Notes

1. HLA-matched granulocyte donors should be considered for HLA alloimmunized patients

2. CMV-seronegative donors should be selected for CMV-seronegative recipients

3. Severe febrile and pulmonary reactions may occur, especially in HLA alloimmunized patients. Amphotericin administration should be temporally separated by at least 2 hours separated from either before or after granulocyte infusion

4. Shelf life: 24 Hours

Product: Irradiated Cellular Blood Products Preparation/Composition

RBCs, platelets, and granulocytes are irradiated with 25 Gy of gamma radiation^1,2

Indications

1. Patients at risk for transfusion-associated graft-versus-host disease (TA-GVHD) must receive irradiated cellular products. These include:

   • Patients with a hematologic malignancy receiving myeloablative chemoradiotherapy

   • Patients undergoing autologous or allogeneic peripheral blood stem cell and bone marrow transplantation

   • Patients with Hodgkin and non-Hodgkin lymphoma

   • Patients with congenital severe immunodeficiency

   • Patients receiving fludarabine/cladribine

2. HLA-matched or cross-matched platelets and directed donations from blood relatives should be irradiated

3. Blood products are routinely irradiated for infants <4 months in age

Administration

The guidelines for administering irradiated products are similar to those described earlier for nonirradiated products

Notes

1. Plasma products such as FFP and cryoprecipitate need not be irradiated

2. Leukoreduction does not prevent TA-GVHD and should not be substituted for irradiation

3. Shelf life: RBCs must be used within 28 days after they are irradiated or before their original outdate, whichever is earlier. The shelf life of platelets and granulocytes is not affected by irradiation

Product: RH_o(D) Immune Globulin (RH_o(D) IgG) Preparation/Composition

High-titer IgG, anti-D immunoglobulin derived from pooled human plasma^1,2

Administration

Indications

Prophylaxis against alloimmunization to Rh_o(D) antigen in Rh_o(D)-negative individuals, especially children and women of childbearing age who have been exposed to Rh_o(D)-positive RBCs via RBC, platelet, or granulocyte transfusions

Notes

1. RH_o(D) immune globulin (human) is also given after miscarriage, termination of pregnancy, amniocentesis, chorionic villous biopsy, or other obstetric manipulations/trauma. Optimal RH_o(D) immune globulin (human) dosages vary with indication/gestation

2. RH_o(D) immune globulin (human) 250–375 IU/kg (50–75 mcg/kg) is FDA approved for use in RH_o(D)-positive nonsplenectomized patients with ITP. A 1–2-g/dL drop in hemoglobin may occur after therapy; patients should be monitored for hemolysis

Product: CMV-Negative Cellular Blood Products Preparation/Composition

1. RBCs, platelets, and granulocytes are collected from CMV-seronegative donors^1,2

2. Only 30–50% of donors are CMV-seronegative; hence, this product is frequently in short supply

3. Leukoreduced products are provided when CMV-seronegative products are unavailable

Indications

1. CMV-seronegative patients undergoing myelosuppressive chemotherapy and/or radiation therapy

2. CMV-seronegative, hematopoietic progenitor cell transplantation candidates, when the donor is CMV-seronegative. For T-cell–depleted transplants, CMV-seronegative products may be indicated even if the donor is CMV-seropositive

3. CMV-seronegative patients with immunodeficiency disorders

4. CMV-seronegative patients receiving solid-organ transplantations from CMV-seronegative donors

5. CMV-negative products are recommended for pregnant women, for all intrauterine transfusions, and transfusions in infants with very low birth weight

6. CMV-negative products are not indicated for CMV-seronegative, immunocompetent patients

7. CMV-negative products are not indicated for immunosuppressed patients, if they are CMV-seropositive

Administration

CMV-seronegative products are infused following the same guidelines described earlier for RBCs, platelets, and granulocytes

Notes

1. CMV is a cell-associated virus; hence, plasma products such as FFP and cryoprecipitate do not transmit CMV infection

2. Blood products that have been leukoreduced with third-generation filters are considered to be equivalent to CMV seronegative products. Several centers routinely use leukoreduced products in lieu of CMV-negative components¹⁰

3. Shelf life: Not affected by the CMV status of the blood product

Transfusion Complications: Acute Hemolytic Transfusion Reaction (AHTR)

General^11,18

1. The estimated risk per unit transfused is 1 in 25,000

2. Infusion of ABO-incompatible blood is the leading cause of AHTR. Phlebotomy errors and blood administration errors account for the majority of cases

3. Immune-mediated AHTR can result in intravascular or extravascular hemolysis

    Donor RBCs may be lysed by naturally occurring anti-A/anti-B alloantibodies, drug-induced antibodies, or RBC autoantibodies present in recipient plasma

    Recipient RBCs may undergo destruction if incompatible antibodies are present in plasma-containing products such as FFP and platelets, or plasma-derived products such as immune globulin (human)

4. Non–immune-mediated hemolysis may mimic AHTR:

    Donor RBCs may be lysed by the addition of medications or hypotonic solutions to a blood bag, malfunctioning blood warmers, and membrane damage in an extracorporeal circuit

    Recipient RBCs may be lysed by the administration of large amounts of hypotonic replacement fluids

5. Hemolytic transfusion reactions must be distinguished from episodes of hemolysis in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency or sickle cell disease

Pathophysiology

1. Antigen-antibody complexes are formed on the surface of RBCs, complement is activated, and RBCs are lysed

2. The free hemoglobin, C3a and C5a anaphylatoxins, TNF-α, IL-1, IL-6, and IL-8, when liberated, mediate hypotension, bronchospasm, renal ischemia, and activation of the coagulation cascade seen in AHTR

Clinical picture

1. Signs and symptoms include fever; rigors; severe anxiety; vomiting; pain in the chest, abdomen, flank or infusion site; dyspnea; hypotension; hemoglobinuria; and diffuse bleeding

2. Clinical presentation is more severe in immune-mediated compared with non–immune-mediated hemolysis. In general, the clinical course of intravascular hemolysis is more severe than extravascular hemolysis

3. Severity depends on the volume and rate of infusion of incompatible RBCs, and on the nature of the antigen and titers of antibody involved

Management

Clinical

1. Stop the transfusion. Replace the infusion set and keep intravenous line open with 0.9% sodium chloride injection

2. Assess cardiopulmonary status and provide support as necessary

3. Notify the blood bank, check the patient's identity with identifiers on the issued blood unit, and return the remaining blood product along with attached labels and infusion set

4. Draw and send to the blood bank fresh blood samples. Send additional samples to evaluate CBC, plasma hemoglobin, bilirubin, LDH, haptoglobin, electrolytes, BUN, and creatinine. A delayed urine sample is preferred for hemoglobin testing

5. Achieve brisk diuresis using furosemide 20–40 mg intravenously, dosed as needed to achieve and maintain a urine output >100 mL/hour

6. Provide maintenance intravenous fluid administered at a rate of 3000 mL/m² per day, and monitor fluid balance. Deteriorating renal function may require dialysis

7. Monitor for ongoing hemolysis and DIC

Blood bank

1. Clerical check is carried out to verify that all labels on the blood unit match the recipient

2. The posttransfusion plasma sample is visually inspected for hemoglobinemia

3. A direct antiglobulin test (DAT, direct Coombs test) is done on the posttransfusion sample. If positive, the eluate is examined to identify the coating antibody. However, the direct antiglobulin test may be negative if all incompatible RBCs have been hemolyzed

4. Additional testing may include reconfirmation of the ABO and Rh type of the patient (using both pre- and post-transfusion specimens) and of the donor unit. The antibody screen and cross-match may also be repeated to confirm donor-patient compatibility

5. Nonimmune hemolysis must be excluded when a work-up is negative for antibody-mediated RBC destruction

Transfusion Complications: Delayed Hemolytic Transfusion Reaction (DHTR)

General

1. A newly formed alloantibody or an anamnestic increase in the titer of a previously undetectable antibody results in the destruction of transfused RBCs 3–14 days after a serologically compatible RBC transfusion

2. Patients have typically been previously alloimmunized through transfusion or pregnancy

Pathophysiology

1. Antibodies are commonly directed against the Rh/Kell antigens and rarely fix complement

2. RBC destruction occurs extravascularly with minimal cytokine release

Clinical picture

1. Patients may be asymptomatic or may present with fever, jaundice, or malaise. Decreased hematocrit, reticulocytosis, hyperbilirubinemia, or elevated LDH may be seen on testing

2. In patients with sickle cell disease, DHTR may mimic a painful crisis or present with severe hemolysis

3. Intravascular hemolysis, renal dysfunction, and progression to DIC are rare with DHTR

Management

Clinical

1. Future RBC transfusions must be negative for the antigen against which the patient has made an antibody

Blood bank

1. A DAT is performed on the posttransfusion sample and any coating antibody identified. The antibody screen is also repeated on this sample

Transfusion Complications: Febrile Nonhemolytic Transfusion Reaction (FNHTR)

General

1. FNHTRs are fairly common (0.5% per unit transfused), with higher rates seen in frequently transfused patients and multiparous women

2. Other causes of fever, including bacterial contamination and AHTR must be ruled out

Pathophysiology

1. Antibodies in a patient's plasma directed against HLA/platelet/granulocyte antigens form antigen-antibody complexes on the surface of transfused platelets and granulocytes. Less commonly, such antibodies in the donor plasma can complex with corresponding antigens present on recipient cells. Complement activation follows with release of complement components and inflammatory cytokines

2. During the storage process, leukocytes can elaborate IL-1, IL-6, IL-8, and TNF-α, which are known to mediate FNHTR. Prestorage leukoreduction decreases the concentration of inflammatory mediators in the product

Clinical picture

1. An increase in temperature of ≥1°C (≥1.8°F) occurring during or for up to 4 hours after a transfusion

2. In addition to fever, the patient may have chills, rigors, headache, and severe anxiety

3. With continued infusion, high fever and debilitating symptoms may develop

Management

Clinical

1. Stop the transfusion, keep the line open with 0.9% sodium chloride injection, perform all clerical checks, and return the remaining product to the blood bank

2. Fever is usually self-limited and responds to antipyretics

3. Control of rigors may require Meperidine 25–50 mg by intravenous injection

4. Complete a work-up of AHTR if hemolysis cannot be ruled out

5. Obtain blood cultures if bacterial contamination is being considered in the differential diagnosis

6. Individuals with FNHTR benefit from premedication with Acetaminophen 650–1000 mg administered orally

Blood bank

1. Patients with frequent febrile reactions should receive leukoreduced products

Transfusion Complications: Allergic Transfusion Reaction

General

1. Similar to FNHTR, allergic transfusion reactions are fairly common, especially in chronically transfused patients

2. Severe IgA deficiency should be ruled out in patients with anaphylactic reactions

3. Rare cases of anaphylaxis mediated by antibodies to haptoglobin or complement component C4 have been reported in patients with deficiencies of these proteins

Pathophysiology

1. Hypersensitivity to allergens (eg, plasma proteins) or drugs in donor plasma

Clinical picture

1. Symptoms range from mild uncomplicated urticaria to fatal anaphylaxis

2. Mild allergic reactions are very common, limited to localized rash, pruritus, and flushing, and do not require detailed work-up

3. Infrequently, patients present with severe bronchospasm, tongue and laryngeal swelling, hypotension, vomiting, diarrhea, and shock

Management

Clinical: For uncomplicated allergic reactions

1. Stop transfusion. Administer Diphenhydramine 50 mg intravenously or another histamine (H₁) receptor antagonist. If symptoms improve, restart the transfusion

2. If symptoms reappear and progress on restarting the transfusion, stop the transfusion and do not restart

3. For future transfusions, premedicate the patient with Diphenhydramine 50 mg administered by intravenous injection or orally or another H₁-receptor antagonist, 30–45 minutes before a transfusion

4. For patients with recurrent reactions, in addition to prophylaxis with a H₁-receptor antagonist, consider administering intravenously a Histamine (H₂) receptor antagonist and Hydrocortisone 50–100 mg prior to the start of a transfusion

5. For patients with severe reactions to platelets, use volume-reduced or washed platelets; for severe reactions to RBCs, use saline-washed products

Clinical: For anaphylactoid and anaphylactic reactions

1. Stop transfusion; maintain intravenous access and initiate resuscitation with fluids, vasopressors, bronchodilators, and respiratory support as needed

2. Investigate whether the recipient is severely IgA deficient

3. If an allergen has not been identified, cellular components for future transfusions must be extensively washed. Adequate preparation of the patient is recommended with H₁- and H₂-receptor antagonists and steroids

4. For patients with severe IgA deficiency, all cellular products must be extensively washed and plasma must be obtained from IgA-deficient donors (see next section)

Transfusion Complications: Allergic Transfusion Reaction: Patients with IgA Deficiency (Transfusion Strategy for Patients with IgA Deficiency)

General

1. IgA deficiency affects approximately 1 in 600 people

2. IgA deficiency must be excluded when anaphylactic reactions develop to blood products

3. Patients with known IgA deficiency are usually managed with washed RBCs to avoid sensitization and subsequent anaphylaxis

4. Patients with severe IgA deficiency and anti-IgA antibodies are at risk for developing an anaphylactic reaction when receiving blood products containing IgA

Pathophysiology

1. IgA exists as 2 subclasses, IgA1 and IgA2; the IgA2 subclass is associated with 2 allotypic determinants, 2m [1] and 2m [2]

2. Anti-IgA antibodies may be class-specific (anti-IgA), subclass-specific (anti-IgA1 or IgA2) or allotype-specific (anti-IgA2m [1] or anti-IgA2m [2])

Clinical picture

1. Patients may present with severe bronchospasm, tongue and laryngeal swelling, hypotension, vomiting, diarrhea, and shock

Management

Clinical: For anaphylactoid and anaphylactic reactions

1. Stop transfusion; maintain IV access and initiate resuscitation with fluids, vasopressors, bronchodilators, and respiratory support as needed

2. For patients with severe IgA deficiency, all cellular products must be extensively washed, and plasma must be obtained from IgA-deficient donors

Blood bank: Guide to selecting components for patients at risk for IgA-anaphylaxis

RBCs

1. RBC units washed with 1–2 L of 0.9% sodium chloride injection have a 99% reduction in their plasma protein content. For IgA-sensitized individuals, it is recommended that RBCs be washed with greater volumes of saline (2–3 L) for satisfactory removal of IgA

2. Frozen deglycerolized RBCs are essentially free of IgA and are probably as safe as RBCs collected from IgA-deficient donors

3. Freezing of autologous units should be considered for IgA-sensitized individuals who have recurrent reactions with washed RBCs

Platelets

• Platelets can be rendered IgA-deficient by washing them free of the plasma IgA. Some hospital blood banks may not provide this service

Fresh-frozen plasma and cryoprecipitate

• Plasma-derived components such as FFP and cryoprecipitate should be obtained only from IgA-deficient donors

Immunoglobulins and plasma derivatives

• IgA-deficient products, chosen after scrutiny of a manufacturer's product insert and confirmed to contain <0.05 mg/dL of IgA, can be safely transfused in IgA-sensitized patients

Transfusion Complications: Transfusion-Associated Circulatory Overload (TACO)

General¹²

1. TACO, an under-recognized complication, occurs in up to 1% of transfusions. Elderly patients are at increased risk

Pathophysiology

1. A rapid increase in the intravascular volume in patients with severe chronic anemia or in those with compromised cardiorespiratory or renal function can precipitate acute pulmonary edema

Clinical picture

1. Signs and symptoms are those of congestive heart failure

Management

Clinical

1. The transfusion should be stopped

2. Provide supplemental oxygen, administer intravenous diuretics, and reassess fluid balance

3. Further transfusions may require more diuresis and slower infusion rates (1 mL/kg per hour)

4. The differential diagnosis includes transfusion-related acute lung injury (TRALI)

Transfusion Complications: Transfusion-Related Acute Lung Injury (TRALI)

General^11,13,14

Estimated incidence: 1 in 5000 transfusions of plasma-containing components

Pathophysiology

1. TRALI results from the transfusion of plasma containing blood components (RBCs, platelets, FFP, cryoprecipitate, or granulocytes) or plasma-derivatives like immune globulin (human)

2. Antibodies (HLA class I/II, antineutrophil) in donor plasma react with a patient's WBCs or antibodies in the recipient plasma to form complexes with donor leukocytes

3. Antigen–antibody complex formation and complement activation lead to aggregation, margination, and sequestration of neutrophils in the pulmonary microvasculature

4. Tissue-disruptive enzymes and free radicals released from neutrophils damage the vascular endothelium, and fluid extravasates into the interstitium and alveolar spaces

5. Alternatively, a lipid-priming agent in stored blood acting in concert with a “priming” lung injury that preceded the transfusion has been proposed in the two-hit hypothesis for the development of TRALI

Clinical picture

1. Signs and symptoms occur within 1–6 hours after starting transfusion

2. Fever and mild-to-moderate hypotension are frequently seen. Less frequently, hypertension is present

3. Respiratory distress can rapidly progress to severe hypoxemia and respiratory failure

4. Chest x-rays: Bilateral extensive whiteout pattern or more patchy changes

5. The pulmonary edema is noncardiogenic in origin. Central venous and pulmonary capillary wedge pressures are normal

6. A transient drop in WBC count has also been described

Management

Clinical

1. Achieve optimum oxygenation with rapid and intensive respiratory support

2. Exclude AHTR, anaphylaxis, bacterial contamination, and fluid overload

3. Most patients improve clinically and radiologically in 72–96 hours

4. Blood products may continue to be used cautiously. Leukoreduced components might be beneficial where TRALI is mediated by anti-HLA or antineutrophil antibodies present in the recipient

Blood bank

1. Other blood components prepared from an implicated donor are quarantined, and the blood donor center is notified

2. Donors are evaluated for anti-HLA and antineutrophil antibodies. If a specific antibody is identified, the patient is typed for HLA and neutrophil antigens to look for a match with the cognate antigen

3. Antibody-positive donors implicated in fatal TRALI are permanently deferred

4. Rarely, anti-HLA and anti-neutrophil antibodies present in the recipient may mediate TRALI

5. TRALI mitigation measures implemented by blood centers in the United States include the decision to minimize the preparation of high plasma-volume components like FFP and apheresis platelets from donors known to be leukocyte-alloimmunized or at increased risk of leukocyte alloimmunization

Transfusion Complications: Transfusion-Associated Graft-Versus-Host-Disease (TA-GVHD)

General

1. The provision of gamma-irradiated cellular blood components for all patient groups at risk for TA-GVHD effectively prevents this frequently fatal complication of transfusion

Pathophysiology

1. Similar to GVHD seen in the hematopoietic transplant setting, immunocompetent lymphocytes in a donor unit proliferate in a susceptible (immunodeficient or immunosuppressed) host and launch a destructive immune response against host tissues expressing foreign HLA antigens

2. In rare instances, a directed donation from a family member (donor with a homozygous haplotype) has caused TA-GVHD in an immunocompetent host (recipient heterozygous for the donor haplotype)

Clinical picture

1. Symptoms and signs appear 10–14 days after transfusion

2. Marrow hypoplasia is a distinguishing hallmark of TA-GVHD

3. The fulminant cutaneous, gastrointestinal, and hepatic manifestations of acute GVHD are also seen with TA-GVHD

4. More than 90% of patients have a fatal outcome

Management

Clinical

1. Unlike transplant-associated GVHD, TA-GVHD responds poorly to interventions

2. Responses have been reported to combination therapies involving lymphocyte immune globulin, antithymocyte globulin (ATG); cyclosporine; methylprednisolone; anti-CD3 monoclonal antibodies; nafamostat mesylate (not available in the United States); and filgrastim

3. Prevention of TA-GVHD is achieved by identifying all groups at risk and by the meticulous attention to irradiation of all cellular components transfused to these patients

Blood bank

1. The blood bank should be notified about all patients at risk for TA-GVHD even before any blood products are ordered

2. HLA-matched and cross-matched platelets and granulocyte products are irradiated

3. Patients receiving fludarabine or other purine analogs like cladribine for illnesses other than hematologic malignancies (eg, SLE) should also receive irradiated blood products

4. All cellular components from blood relatives are irradiated

5. HLA typing of patients' circulating lymphocytes may aid in the diagnosis of TA-GVHD

Transfusion Complications: Post-Transfusion Purpura (PTP)

General

1. PTP is a rare complication, presenting as sudden onset of severe thrombocytopenia 7–10 days after transfusion in a previously transfused or pregnant patient

2. Approximately 200 cases have been reported worldwide

Pathophysiology

1. In >90% of cases, platelet destruction is mediated by an alloantibody directed against the human platelet specific antigen, HPA-1a

2. Rapid destruction of the autologous HPA-1a–negative platelets by a poorly defined “innocent bystander” mechanism contributes to the thrombocytopenia

Clinical picture

1. Severe unexplained thrombocytopenia developing 7–10 days after transfusion of a blood product should raise the suspicion of PTP

2. Patients may be asymptomatic or may present with purpura, ecchymoses, mucosal bleeding, or life-threatening hemorrhage

Management

Clinical

1. The thrombocytopenia is usually self-limiting and spontaneously resolves in 2–3 weeks

2. Routine platelet transfusions do not improve platelet counts, may in fact be detrimental, and should be avoided if there is time to begin specific treatment

3. For patients with life-threatening hemorrhage, high-dose intravenous immune globulin (IVIG) (0.4 g/kg/day for 2–5 days or 1 g/kg per day for 2 days) is preferred over therapeutic plasma exchange as the first line of therapy. Platelet counts typically recover in 3–4 days. A second course of IVIG may be required in some patients

Blood bank

1. Antibody studies may show the presence of anti–HPA-1a platelet antibody. Rarely, other specificities like anti–HPA-1b and anti–HPA-5a have been implicated in PTP

2. Patients should preferably receive appropriate antigen-negative platelets

3. Transfused platelets from random donors may successfully increase platelet counts after IVIG therapy has been initiated

4. RBC requirements are best met by providing washed products

Transfusion Complications: Bacterial Contamination

General¹⁵

1. Until recently, an important cause of transfusion-related mortality

2. Mandatory bacterial testing of platelets in the United States, beginning March 2004, has significantly reduced this risk

3. Risk of bacterial contamination of platelets: Bacterial contamination is detected in approximately 1 in 5000 apheresis platelet collections using culture methods. However, current methods fail to detect all contaminated units. Using data from passive surveillance of transfusion reactions, this residual risk was estimated as approximately 1 in 75,000 septic reactions per distributed component.¹⁵

4. RBC units have a much lower risk of bacterial contamination

Pathophysiology

1. Bacteria enter donor units during collection process/component preparation

2. Components (eg, platelets) stored at room temperature are commonly associated with Gram-positive organisms such as Staphylococcus

3. Components (eg, RBCs) stored at 4°C (39.2°F) are associated with Gram-negative organisms, such as Enterobacter, Yersinia, Pseudomonas, and Serratia

Clinical picture

1. High fever, chills, rigors, dyspnea, hypotension, and shock may develop rapidly

2. Milder presentations, particularly in a previously febrile patient may go unrecognized

Management

Clinical

1. Stop the transfusion and resuscitate aggressively

2. Send the remaining product for bacterial culture; send patient samples for blood cultures

3. Commence broad-spectrum antibiotics to cover both Gram-positive and Gram-negative organisms; modify therapy based on culture results

Blood bank

1. The implicated product should be sent immediately for Gram's staining and culture

2. All other components (RBC, FFP, cryoprecipitate) made from the same donation should be quarantined

3. Depending on the identity of the organism, donor follow-up may be indicated. A review of all donor collection and processing procedures might also be appropriate in certain instances

Transfusion Complications: Other Infectious Risks of Transfusion

Viruses^16,17

1. All blood donations in the United States are tested for human immune deficiency virus (HIV-1/2), human T-cell lymphotropic virus (HTLV-I/II), hepatitis B virus (HBV), hepatitis C virus (HCV), West Nile virus (WNV), and Chagas infections

2. Routine testing for hepatitis A virus and parvovirus B19 is not done

3. On rare occasions, donors with window-phase infections can still transmit disease

4. Currently, the estimated risks of viral transmission from a blood unit are:

     HIV:  1 in 2.14 million

     HTLV:  1 in 3 million

     HBV:  1 in 488,800

     HCV:  1 in 1.94 million

Parasites

1. Posttransfusion malaria and babesiosis have been reported in the United States

2. Routine screening of donor blood for these agents is not carried out

Prions

1. A screening test for variant Creutzfeldt-Jakob disease (vCJD) is not currently available

2. Donor exclusion criteria are based on a history of travel and residence in Europe

3. Transfusion-transmitted vCJD has been reported from the United Kingdom¹⁷