Critical Care Medicine

Pediatric Transfusion Management

Pediatric Transfusion Management

Synonyms

Blood administration, transfusion, blood product handling

Related Conditions

Pediatric: trauma, surgery (general, orthopedic, neurosurgery, plastics, urologic, oropharyngeal, cardiovascular), extracorporeal membraneous oxygenation (ECMO), therapeutic apheresis (leukopheresis, erythrocytapheresis, plasma exchange), sepsis, renal failure (dialysis dependent), oncology, sickle cell disease/hemoglobinopathies, stem cell transplantation, respiratory failure/pneumonia

1. Description of the problem

Core Transfusion Medicine Concepts

What every clinician needs to know about red blood cell antigens (ABO) and the plasma they come in (anti-A IgM, anti-B IgM, and anti-A, B IgG):

The ABO antigens (oligosaccharides) of the ABO blood group (Type A, B, AB, and O) are the most clinically significant antigens in all of transfusion practice.

For example, if you are blood type A there is A antigen on your red blood cells and tissues. In the next 3 months to 1 year of age anti-B will begin to form in the plasma due to exposure of the gut to different microbes that on the outer surface look similar to the B antigen. The predominant isohemagglutinin will be anti-B IgM.

The universal donor of red blood cells is Group O blood type. There aren't any antigens on the red cell surface of those cells so they can go into any recipients plasma. The recipient can have anti-A or anti-B of any type and those antibodies will not have a target to cause hemolysis. However, the same cannot be said for the plasma of an O donor. The O plasma has anti-A and anti-B and anti-A, B IgM and IgG antibodies.

Different individuals have different titers of these antibodies and they are hemolytic antibodies. This means if a red blood cell with an A antigen or a B antigen or both A and B antigens mixes with the O plasma an acute hemolytic transfusion reaction can occur potentially killing the patient.

The universal donor of plasma is therefore AB plasma since AB donors have A and B antigens on the surface of their red blood cells but no isohemagglutinins in their plasma. This explains why O red blood cells can be given in an emergency because no cross matching of the RBCs with the donor plasma/serum is necessary because O red blood cells are compatible with all blood types. AB plasma is given in an emergency because it does not have isohemagglutinins and won't cause a hemolytic transfusion reaction in the recipient no matter what their ABO blood type may be.

Figure 1 is the best way to conceptually think about all blood types. It also give the rule of "4"s so you can remember the rarest and most common ABO types. This is just an approximation of all blood donors. 44 % are type A, 4+4=8% are type B, and 4% are type AB, and finally 44% are O blood type.

Figure 1.

ABO group antigens and isohemagglutinins in corresponding plasma of patients and approximate incidence of each ABO blood type

The RBC surfaces are self explanatory with the distinct antigens.

The plasmas of each blood type, recipient or donor, are what most people forget about and are the most critical. A mis-match of RBCs or plasma (such as with platelet transfusion and plasma transfusions) can be just as hemolytic and cause mortality in the patient.

  • Anti-A and anti–B can generally be detected in serum after the first few months of life.

  • Antibody production reaches the adult level at 5-10 years of age.

  • IgM is the major class of antibody produced in group A and group B people; small amounts of IgG are also present.

  • IgG is the dominant class of antibody in group O people (anti-A,B), and is responsible for ABO hemolytic disease of the newborn - hyperbilirubinemia - and can lead to a manual exchange transfusion in the PICU with readmission.

  • Both classes agglutinate RBCs best at room temperature or below, and activate complement at 37°C.

What Blood Products are Available in their Hospital's Blood Bank?

Possibilities include but are not limited to:

Whole blood, packed red blood cells (pRBCs), platelets in two types (apheresis platelets (AP) and whole blood derived platelets (WBDP) , frozen plasma (fresh frozen plasma (FFP) and frozen plasma (F24)), liquid plasma, cryoprecipitate, cryo-poor plasma, granulocytes, albumin.

What is in Each Blood Product?

Figure 2

Figure 2.

Contents of blood products

1. Whole Blood

Factors V and VIII decrease to 5-30% by day 21

Cytokines accumulate and contribute to WBC-related complications

2. pRBCs

Anti-coagulant preservative solutions (pRBC storage solutions)

Citrate, phosphate, dextrose (CPD, CP2D, CPDA-1)

  • Shelf-life 21 days, volume 250 ml

  • Shelf-life 35 days usually yield Hct~70%, volume 250 ml

Adsol (AS-1, AS-3, AS-5)

  • Additive solution licensed in US (1980s) contains mannitol, phosphate buffer, adenine, NaCl and dextrose

  • Increases red cell shelf life to 42 days

  • Preserves metabolism of red cells with slower K+ leak

  • Addition of 100 ml AS dilutes RBC so Hct~ 50 - 60%

  • Volume usually 350 ml

  • 10 ml/kg of CPDA-1 unit raises Hgb 2 gm/dL and AS raises Hgb 1.5 g/dL

Liquid pRBCs

  • Shelf-life/volume depends upon anticoagulant preservative solution

  • After whole blood donation unit is spun down and pRBCs go to bottom of unit

  • Platelet-rich plasma is removed (supernatant) and additive solution is added to pRBCs if necessary

Cryopreserved pRBCs

  • Glycerol is a cryoprotectant, allows for long-term frozen storage of rare pRBCs (e.g. frozen, 40% glycerol, store @ -65°C stored for 10 years)

  • Glycerol washed away after thawing

  • ~90% leukoreduced

  • Platelets and CMV destroyed

  • Must be transfused within 24 hrs

  • Indicated for anemic patients with rare blood types or multiple alloantibodies

RBC unit storage lesions (pathophysiologic changes during storage on shelf in blood bank)

During liquid preservation of pRBCs the following metabolic changes occur:

  • extracellular potassium rises

  • extracellular free Hgb rises

  • intracellular 2,3 DPG falls returns to normal levels 24 hours after transfusion

  • intracellular pH falls

Sequelae of RBC storage lesion

Cardiac arrhythmia and neonatal deaths have occurred subsequent to transfusion of stored (35 day old) RBC prompting recommendation to use younger RBC for transfusions of neonates < 5 days old.

Events above occurred with transfusion of large volume pRBC > 20 ml/kg, stored in CPDA-1.

K+ leak is slower with AS stored RBCs thus, many think that transfusion of > 5 days old is safe for neonates, as long as the volumes are 10 -20 ml/kg aliquots.

3. Platelets

Figure 3. Plasma exchange device-centrifugation process

Figure 3.

AP on left and WBDP on right - notice difference in volume which translates to approximately 6-8 times more platelets in each AP versus WBDP a. AP - Apheresis platelets also known as Single Donor Platelets - made from a single donor and contains and adult dose of platelets in 1 unit = 3 x 1011 platelets per unit at a minimum.

Figure 4. Centrifugation device for blood separation

Figure 4.

Centrifugation device for blood separation.

1 units of SDP = 6-8 units of RDPs

1 RDP unit = 50-60 ml

1 SDP unit = 300-600 ml

AP platelets are leukoreduced when they come out of the machine whereas WBDP need to go through a filter after collection and separation from whole blood to then be leukoreduced prior to storage. Figure 5. WBDP composition/separation

Figure 5.

WBDP composition/separation

Made from a whole blood donation. Once blood is collected a hard spin is performed and RBCs go to bottom of unit. Platelet-rich-plasma(PRP) is on top and then removed. Then PRP is spun and platelets go to bottom and plasma is left at top. Plasma is removed and approximately 50ml of plasma and platelets are left at bottom of unit which comprises the platelet concentrate (PC). This unit is not leukoreduced and needs to be filtered with a leukoreduction filter prior to storage.

4. Frozen Plasma

Figure 6. Frozen plasma

Figure 6.

Frozen plasma

  • Production:

    • FFP: frozen within 8 hrs of collection at <-18°C from CPD, CP2D or CPDA-1 whole blood or frozen within 6 hrs from ACD plasma

    • F24 plasma: frozen within 8–24 hrs after collection

  • Viral testing only, no viral inactivation

  • Volume: 150–300 ml per unit

  • Contents: contains all factors:

    • 1 IU/ml of clotting factors (labile and nonlabile)

  • Thaw:

    • FFP thaw @ 30-37°C; store @ 1-6°C for 24 hrs

    • F24 Thaw @ 30-37°C; store @ 1-6° for 5 days

  • Expiration:

    • FFP: 12 MOS @ -18°C for 7 yrs @ -65°C

    • F24 : 12 mos. @ -18°C

5. Liquid Plasma

Production: Cold insoluble portion of plasma that remain after FFP has been allowed to thaw at 1-6°C. Separated from plasma and refrozen.

  • PLASMA REMOVED FROM WHOLE BLOOD UP TO 5 DAYS AFTER EXPIRATION DATE, BUT NEVER FROZEN

  • Expire: 5 days post original expiration date @1-6°C

  • Elevated potassium and ammonia and low factor VIII (vs. FFP)

  • Sent to manufacturer for fractionation

  • Derived from donor plasma

    • Prepared by cold alcohol fractionation

  • Pasteurized by heating to 60° C for 10 hours

    • destroys viruses

  • 5% or 25% solution

    • (5% is oncotically and osmotically equivalent to plasma)

Indications

  • Hypovolemia with hypoproteinemia

    • Thermal injury, nephrotic syndrome, shock

Contraindications

  • Long-term therapy for chronic or nutritional hypoalbuminemia

6. Cryoprecipitate

Production from cold insoluble portion of plasma that remain after FFP has been allowed to thaw at 1-6°C. Separated from plasma and refrozen.

  • Viral testing - no viral inactivation process

  • Volume: 10-20 mL (may need diluent if amount of plasma is less than 15 mL)

  • Contents: 80-100 units factor VIII; 150-250 mg fibrinogen;

    • 80 units of von Willebrand Factor (40-70% of the original amount in the unit)

    • 40-60 units of factor XIII (20-30% of the original amount) 30-60 mg fibronectin

  • Thaw: 37°C waterbath; store 6 hrs room temperature

  • Pool: 4 hours @ 20-24°C

  • Preparation Time: 10-20 minutes

Figure 7

Figure 7.

Cryoprecipitate

7. Cryo-poor Plasma

  • Cryoprecipitated antihemophilic factor (AHF) precipitates out when FFP is thawed between 1-6°C

  • The 10-15 ml of cryo. is removed and the FFP is refrozen within 1 hour

  • Expires: 12 mos @ -18°C (24 hr thawed)

  • Thaw @ 37°C; store @ 1-6°C

  • Use: TTP patients (lacks the high molecular weight multimers of vWF and contains the metalloprotease enzyme)

8. Granulocytes

  • Collected by apheresis techniques from volunteer donors.

  • Transfuse within 6-10 hours of collection, without leukoreduction filter for optimal beneficial effect.

  • WBCs should be stored at room temperature with as little agitation as possible.

  • Donor WBC mobilization can be stimulated with dexamethasone alone or with dexamethasone plus G-CSF.

  • Dex + G-CSF donor stimulation can yield neutrophil collection ranges between 3 to 10 x 1010 neutrophils.

  • Ideal WBC product dose is 1 x 109 neutrophils/kg or 15 ml/kg.

  • WBC transfusions with low or high neutrophil counts have not consistently been demonstrated to increase the survival rates of neutropenic septic neonates or children.

9. Albumin

  • Derived from donor plasma

    • Prepared by cold alcohol fractionation

  • Pasteurized by heating to 60° C for 10 hours

    • destroys viruses

  • 5% or 25% solution

    • (5% is oncotically and osmotically equivalent to plasma)

Indications

  • Hypovolemia with hypoproteinemia

    • Thermal injury, nephrotic syndrome, shock

Contraindications

  • Long-term therapy for chronic or nutritional hypoalbuminemia.

How are Each of the Blood Products Stored?

Which Blood Products Require Testing Prior to Use?

Erythrocytes

Routine pre-transfusion testing required. ABO is the only system that the reciprocal antibodies are present in the sera/plasma of most individuals with no previous exposure

Platelets

Testing of patient’s ABO type is necessary, but no crossmatching is done unless patient is in an immune refractory state. For children, goal is to transfuse ABO type specific or compatible platelets due to their small plasma volume.

Frozen Plasma/Cryo

ABO type is necessary, no crossmatching performed. Goal to transfuse ABO type specific or compatible plasma.

Granulocytes

ABO typing and crossmatch must be done on all granulocyte transfusions due to the contaminating red blood cells in the product.

Blood Product Dosing and Expected Post-transfusion Outcome for respective laboratory monitoring parameter

Knowing the patient's weight is absolutely critical as it is with all pediatric dosing of medications etc.

pRBCs

5,10,15, sometimes 20 ml/kg per dose: expect 1-2 gm/dL rise in hemoglobin level post transfusion if no bleeding

Platelet concentrate

10 ml/kg

  • If give 0.1-0.2 units/kg it will raise post-tx platelet count by 50-100,000/microliter in patients with hypoproliferative thrombocytopenia induced by chemotherapy

Platelet pheresis

10-15 ml/kg

Frozen plasma

10 ml/kg will raise factor levels approximately 15-20%

Cryoprecipitate

1-2 units (each approximately 5-15 ml in volume total)/ 10 kg rise in fibrinogen of 60-100 mg/dL.

2. Emergency Management

Clinical features for transfusion indications below:

anemia, thrombocytopenia, coagulopathy, prolong neutropenia, hyperleukocytosis

Indications for transfusion

Note: These are usually rules of thumb not hard and fast. The indications are usually established by local practice the medical executive team of each hospital. One should go to the transfusion committee at their respective hospitals to obtain a copy of the transfusion indications use for each blood product. The Joint Commission requires that these are established at each hospital and monitored by the organization.

A. Packed Red Blood Cell Transfusion

  1. Improved oxygen carrying capacity to maintain adequate hemoglobin and relieve symptomatic anemia (i.e. congestive heart failure)

  2. Maintain adequate pre-operative hemoglobin > 8 g/dL

  3. Chronic transfusion, every 2-4 weeks for different complications in certain diseases such as sickle cell anemia, beta-thalassemia major, severe hereditary spherocytosis, myelodysplasia, etc.

Autologous Packed Red Blood Cells

Useful in older children for orthopedic surgery, scoliosis repair, marrow-donor harvest

Directed Donors

Test requirements impossible for emergent transfusion, relative should not be used as blood donor for potential stem cell transplant due to potential for transplant rejection, recognize that first time donors can exhibit higher rates of infectious disease markers (i.e. HIV, HCV, HBV) than repeat volunteer donors.

B. Platelet Transfusion

With Thrombocytopenia

  • Platelet count 5-10,000/μl with failure of platelet production

  • Platelet count < 30,000/μl in neonates with failure of platelet production

  • Platelet count < 50,000/μl in stable premature infant with:

    • Active bleeding

    • Before intensive procedure with failure of platelet production

  • Platelet count < 100,000/μl in sick premature infant with:

    • Active bleeding

    • Before an invasive procedure in patient with DIC

Without Thrombocytopenia

  • Active bleeding with qualitative platelet defect

  • Unexplained excessive bleeding in patient undergoing cardiopulmonary bypass

  • Patient undergoing ECMO with:

    • Platelet count < 100,000/μl

    • Higher platelet count and bleeding.

C. Frozen Plasma Products

INDICATIONS: FFP and F24

1. Congenital or acquired coagulation factor deficiency with active bleeding or prior to an invasive procedure when the specific concentrates are not available

2. Massive blood transfusion with coagulopathy

3. Multiple acquired coagulation defects (i.e. liver disease or DIC)

4. Deficiency of ATIII, protein C, or protein S when a concentrate is not available

5. Plasma exchange for TTP

6. Rapid reversal of warfarin effect

NON-INDICATIONS: FFP and F24

1. Volume expansion

2. Nutrients

3. Immunodeficiency (use fractionated IgG)

4. Wound healing

5. Reconstitution of RBCs (except for neonatal RBC exchange)

Cryoprecipitate

INDICATIONS

1. Congenital or acquired hypofibrinogenemia

2. Factor XIII deficiency (1 unit/10-15 kg q 2 weeks)

3. Topical hemostatic or adhesive agent (fibrin glue) combined with thrombin

4. Wound or bone healing (fibronectin)

5. Uremic bleeding unresponsive to dialysis or DDAVP

6. Hemophilia A and vWD; only when virus-inactivated concentrates are unavailable

NON-INDICATIONS

1. Deficiency of Factors II, V, VII, X or XI

2. Hemophilia A (Factor VIII deficiency)

3. Hemophilia B (Factor IX deficiency)

4. vWD responsive to DDAVP

5. Sole treatment of DIC

6. Don't use for any deficiency in which a viral-inactivated concentrate is available or in which the factor is not present in cryoprecipitate.

D. Granulocytes

1. Neonates and children with neutropenia or granulocyte dysfunction with bacterial sepsis and lack of responsiveness to standard antimicrobial therapy (neutrophil + band count < 3 x 109/L)

2. Bacterial sepsis, no response to antibiotics, (neutrophil + band count < 5 x 109/L)

3. Neutropenic neonates or children with fungal disease not responsive to standard therapy.

E. Therapeutic Pheresis

Therapeutic Plasma Exchange (TPE)

Medical Evidence
ABO incompatible stem cell transplant Category II
Autoimmune hemolytic anemia: cold/warm Category III
Aplastic anemia: pure red cell aplasia Category III
TTP Category I
Pediatric Autoimmune neuropsych disordersassociated with strep infection: Sydenham'schorea: Severe PANDAS, severe SC Category I
Sepsis Category III
Leukapheresis: Hyperleukocytosis
Leukostasis Category I
Prophylaxis Category III
Erythrocyte exchange transfusion
Sickle cell disease Category I
Life and Organ Category II
Prevention of iron overload Category II

Emergency Management of Bleeding with Massive Transfusion Effect

The transfusion of packed RBC products greater than or equal to the patient’s estimated blood volume (75 to 80 ml/kg) is termed a “massive transfusion”, and brings with it a host of complications.

1. hypothermia secondary to the rapid infusion of cold blood products

2. dilution and depletion of hemostatic coagulation factors, particularly after replacing 1-2 total blood volumes of the patient

3. metabolic derangements (i.e. hypocalcemia resulting from citrate anticoagulants that bind to free calcium)

4. dilutional thrombocytopenia.

Evidence of these complications can be monitored and detected with specific laboratory tests:

1. prolongation of clotting times (PT/PTT)

2. hypofibrinogenemia

3. thrombocytopenia

4. hypocalcemia

Note: Blood warmers are highly recommended in the prevention of hypothermia. Blood components such as platelets, frozen plasma products (FFP) and cryoprecipitate are part of the arsenal in a massive transfusion, the specific needs of the patient of which should be guided by the laboratory results and estimates of RBC units per total blood volume of the patient.

Critical to remember: Any of the complications mentioned may occur as a result of massive transfusions utilized to establish extracorporeal membrane oxygenation (ECMO), during cardiopulmonary bypass, or secondary to trauma.

Blood Product choices

O negative emergency release packed red blood cells are always available - these can be given prior to knowing the patient's blood type.

AB negative plasma is the universal donor of plasma and can be given without a patient's blood type as well.

Once the patient's blood type is established then type specific or compatible products may be administered. All blood products can be IV pushed or put through a rapid infuser. Platelets are the most sensitive to rapid administration so there can be loss of potency when platelets are pushed hard or go through a rapid infuser.

Communication with the blood bank personnel is critical because all plasma products FF/F24 and cryoprecipitate are frozen and need to be thawed in a controlled setting for issue. This takes time and as was stated earlier in this chapter must be type specific or compatible. That being said letting the blood bank know ahead of time of having a massive transfusion protocol or algorithm that lets the blood bank stay ahead with regard to thawing plasma is extremely helpful in mitigating the effects of massive transfusion secondary to pRBC transfusion.

Multiple studies in the mid-to-late 2000's from both military and civilian experiences around the world have noted in adults that resuscitation with a 1:1:1 ratio of RBCs:plasma:platelets during massive transfusion improves morbidity and mortality in patients. This has not been shown in children but multiple pediatric institutions have been applying a similar algorithm and looking at outcomes.

At a minimum it is recommended that a trauma center dealing with children should establish within their institution with trauma surgeons, operating room staff including anesthesiologists, emergency department personnel and the blood bank transfusion medicine specialists together agree on execution of these algorithms.

Pathophysiology

Blood Product Special Processing: Irradiation, Leukoreduction, Volume reduction, Washing

A. Irradiation

Purpose: prevents transfusion-associated graft versus host disease (TA-GVHD) in at risk patients by rendering long-lived T-cells that are in the donor RBC or platelet incapable of proliferating and destroying the recipients bone marrow and other organs.

Some facts

a. Blood from relatives should be irradiated (directed donors) because they can cause TA-GVHD as well

b. Immunocompromised patients cannot effectively eliminate donor lymphocytes

c. Rarely, immunocompetent patients do not see closely HLA-matched donor lymphocytes as foreign

d. Donor-T cells proliferate, attack host (marrow also unlike GvHD) > 90% fatal

e. Completely eliminated by 25 Gy gamma-irradiation of units prior to transfusion

Specific Indications

Accepted

1. Immunocompromised transplant recipients

2. Hodgkin's disease

3. Donations from relatives, HLA-matched donors

4. Intrauterine transfusions

5. Neonatal exchange transfusions, ECMO

6. Congenital cell-mediated immunodeficiencies (i.e. SCIDS)

Potential

1. Immunosuppressive therapies and radiation therapy patients

2. AIDS

3. Hematologic malignancies

4. Low birth weight neonates < 1500 grams.

B. Leukoreduction

Process

Reduce by filtration in packed red blood cell and platelet units the number of WBCs. The number is reduced to < 5 x 106WBCs per unit after filtration. The filtration is done prior to storage in the hospital blood bank to lessen the cytokines release from broken WBCs and decrease fragments of WBCs in the supernatant of the blood component.

Purpose

To mitigate or prevent the following complications:

1. Febrile non-hemolytic transfusion reactions

2. Transfusion-transmitted CMV (CMV is latent in monocytes one of the WBCs filtered out)

3. HLA-alloimmunization (the WBCs have the HLA antigens on them and can cause HLA alloimmunization with platelet refractory side effects - platelets have class I HLA on them).

C. Volume reduction - "hyperpacking"

Process

Centrifugation of platelets or packed red blood cells and then removal of most of the supernatant

Purpose

To reduce the amount of supernatant to go into the recipient but will recipient with still receive some of the volume

1. good for patients with volume overload issues such as congestive heart failure, stem cell transplant patients during time engraftment period, edematous patients

2. almost critical for ABO out-of-group platelet transfusion (i.e. if O platelet due to shortage of platelets needs to be transfused into an A patient and the Anti-A part of the plasma in the product needs to be decreased as to not precipitate a acute hemolytic transfusion reaction).

D. Washing

Process

Elimination of all supernatant in cellular products such as packed red blood cell units and platelets

Purpose

To eliminate all plasma and supernatant from donor units

1. removes plasma proteins that cause allergic reactions

2. removes IgA for patients who have experienced anaphylaxis due to being IgA deficient

3. removes high levels of extracellular K+ from RBC units that have been sitting on the shelf for a long time or have been on shelf irradiated for a long time (irradiation potentiates the leakage of K+ into the supernatant).

Epidemiology

Complications of Transfusion Reactions

Noninfectious Complications of Transfusion

1. Hemolytic Transfusion Reactions

A. Acute hemolytic transfusion reactions (AHTR) usually occur secondary to ABO incompatibility resulting from clerical error during patient identification. This reaction can be avoided with accurate labeling of the patient’s pre-transfusion blood specimen and assuring that the information on the donor unit precisely corresponds with the information on the patient’s identification band.

In AHTR intravascular hemolysis ensues in the patient’s plasma due to IgM anti-A and/or anti-B reacting with their cognate antigen on the donor RBCs. Intravascular hemolysis can also occur by passive IgM anti-A and/or anti-B transfer of incompatible donor plasma (product) or plasma-containing product reacting with the recipient’s red blood cell containing the cognate antigen. The release of free hemoglobin into the intravascular space activates the coagulation cascade and release of vasoactive amines.

Symptoms include: fever, chills, nausea and vomiting, chest and/or back pain, and anxiety.

Laboratory tests: are usually positive for hemoglobin in the urine and a low haptoglobin in the serum.

Severe complications can be avoided if the transfusion is immediately stopped and the volume of incompatible RBCs received is small. In the event of the infusion of larger volumes of incompatible blood or plasma, acute renal failure, shock, DIC, and death may occur.

Note: AHTRs can occur as a result of non-immune mediated causes such as physical or thermal injury to donor RBCs either during storage or transfusion, and includes inappropriate temperature storage, hypotonic fluid that mixes with RBCs, and/or pressurized administration of RBCs through a fine-gauge needle.

B. Delayed hemolytic transfusions (DHTR) occur 3–10 days after a transfusion of RBCs. These reactions are usually secondary to non-ABO antigens and are IgG-mediated which causes extravascular hemolysis. DHTR may occur when anamnestic antibody production occurs in response to incompatible minor RBC antigens that were undetectable during routine antibody screening.

Symptoms: can be asymptomatic and later develop hyperbilirubinemia, and may not achieve the expected transfusion outcome or have an unexplained fall in their hemoglobin level 1–2 weeks after the RBC transfusion.

Lab testing: Blood bank testing can confirm this type of reaction with a positive DAT and a potentially positive antibody screen. Once the antibody has been identified, the specificity of the antibody can be determined and future pRBC transfusions for this recipient should be devoid of the specific RBC antigen.

2. Non-hemolytic Transfusion Reactions

A. Febrile non-hemolytic transfusion reactions (FNHTR) can occur with either a RBC or platelet transfusion, and is defined as a temperature increase of greater than 1° C (1.8° F) associated with a transfusion that cannot be attributed to any other cause. FNHTR is a diagnosis of exclusion. Leukocyte contamination from the donor is usually the cause. Another major cause of fever without hemolysis related to the transfusion is bacterial contamination of any blood component resulting in a septic transfusion reaction.

Symptoms: attributable to either leukocytes or bacteria include: chills, fever, headache, nausea and vomiting.

Treatment: A patient with this reaction typically responds to antipyretics, such as Tylenol. Pre-storage leukocyte reduction helps avoid most febrile non-hemolytic transfusion reactions.

B. Allergic reactions attributed to soluble antigens in the donor plasma that reacts with IgE that is bound to the recipient’s mast cells and cause histamine release.

Symptoms: The mild local cutaneous symptoms of this reaction can include urticaria (hives), rash or generalized flushing, pruritus, and/or localized swelling. Respiratory symptoms may range from dyspnea, cough, or hoarseness to wheezing, stridor, chest tightness or pain. Gastrointestinal signs of this type of reaction may include nausea, cramping, emesis, and/or diarrhea. Cardiac indications can include tachycardia and/or other arrhythmias.

Treatment: This type of reactions should illicit an immediate, and potentially a temporary halt of the infusion. Intravenous access should be maintained in the event the reaction becomes more severe and/or progresses to anaphylaxis, and requires a saline infusion. Antihistamines should be administered, and in the event the urticaria remits, the transfusion may be restarted. An anaphylactic reaction is considered a medical emergency and can manifest with severe, life-threatening symptoms such as severe hypotension, laryngeal edema, and respiratory failure.

C. Anaphylaxis reactions can occur with the transfusion of any blood component and must be immediately stopped if this reaction is even remotely suspected.

Treatment: Immediate supportive care should be instituted with antihistamine administration, subcutaneous, intramuscular, or intravenous epinephrine and, if necessary, fluid resuscitation. The cause of an anaphylactic reaction may lie in IgA deficient patients who house IgG antibodies to IgA. Other etiologies of an anaphylactic reaction are: a) recipient antibodies to other serum proteins absent in the recipient; b) transfused allergens; c) passive transfer of IgE; or d) mast cell activation by anaphylatoxins.

Note: Once a recipient experiences an anaphylactic reaction, avoidance of all plasma-containing products is recommended, particularly if the reaction was caused by anti-IgA antibodies. Thereafter, strict washing of cellular blood products (RBCs and platelets) is suggested and should be implemented for these patients.

3. Pulmonary Reactions

A. TRALI is the leading cause of transfusion-related deaths reported to the FDA in 2003. Two definitions of TRALI exist. One, from the National Heart, Lung Blood Institute (NHLBI) defines this as a “new acute lung injury (ALI) that develops with a clear temporal relationship to transfusion, in patients without or with alternate risk factors for ALI”.

The second, from the Canadian Consensus Conference on TRALI in 2004, states that this is “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.” The diagnosis of TRALI is considered clinical and radiographic, not defined by any laboratory measures.

Recipients of allogeneic blood transfusions, if they are enduring a TRALI reaction, experience shortness of breath that results from non-cardiogenic pulmonary edema, fever, and hypotension. The pathogenesis, treatment and prevention of TRALI are not well understood. Does not respond to diuretics.

B. TACO Another non-infectious transfusion reaction is transfusion-associated circulatory overload (TACO) and is characterized by transfusion of too much fluid to the recipient over a short period of time. Patients with underlying cardiovascular disease are at greatest risk for this type of non-infectious transfusion reaction. Responds to diuretic therapy.

Infectious Complications of Transfusion

A. Viruses

Hepatitis B, C (HBV, HCV)

Retroviruses: HIV-1 and HIV-2, human T-cell leukemia viruses, types I and II (HTLV-I/II)

Cytomegalovirus (CMV), parvovirus, and Epstein-Barr virus (EBV)

(mainly in immunosuppressed recipients)

B. Bacteria

Associated asymptomatic bacteremia in blood donors (Yersinia enterocolitica, salmonella, and other gram-negative organisms)

Blood collection contamination with skin flora or processing of components

C. Parasites

Malaria, babesiosis, Trypanosoma cruzi, leishmaniasis

D. Spirochetes

SyphilisE. Prions

Creutzfeldt-Jakob disease (CJD)

New variant CJD (nvCJD)

Special considerations for nursing and allied health professionals.

Table I.

Blood Component Storage
Blood Component Storage Temperature Storage Duration Storage Conditions
Whole blood 1-6°C 35 days CPDA-1
Packed red blood cells 1-6°C 35 days     42 days CPDA-1 additive solution (AS)
Platelets (apheresis or whole blood derived) 22°C 5 days Gas exchange/ constant agitation/ plasma
Frozen Plasma (FFP and F24) -18°C/thawed 1 year/24 hrs plasma frozen in 8 or 24 hrs
Cryoprecipitate -18°C/thawed 1 year/24 hrs precipitate frozen
Plasma-derived factor products 1-6°C or 22°C depending on manufacturer as per manufacturer Lyophilized and mixed with diluent

See Table II

Table II.

Current Risk Estimates of Viral Transmission by Transfusion
Viral/Infection Estimated Risk products tranfused 2007
Human immuodeficiency virus (HIV) approximately 1.5 to 1.8 million
Hepatitis C (HCV) 1:1.4 million
Hepatitis B (HBV) 1:144,000 among all donors and 1:205,000 for repeat donors

What's the evidence?

Core Transfusion Medicine Concepts

Josephson, CD, Castillejo, MI, Grima, K, Hillyer, CD. "ABO-mismatched platelet transfusions: Strategies to mitigate patient exposure to naturally occurring hemolytic antibodies". Transfus Apher Sci. vol. 42. 2010. pp. 83-88.

(Provides a discussion about ABO antigens and antibodies and their potential to cause acute hemolytic transfusion reactions in when out-of-ABO group plasma is given with out-of-group platelet transfusions. Emphasizes key concepts of transfusion medicine that all physicians who transfuse blood products should know.)

Strauss, RG, Burmeister, LF, Johnson, K. "Feasibility and safety of AS-3 red blood cells for neonatal transfusions". J Pediatr. vol. 136. 2000. pp. 215-9.

(Goes over the safety profiles for neonates to receive AS-3 red blood cell storage solutions and compares it to CPDA-1 red cell storage solutions. Gives important dosing information about keeping AS-3 units out of being massively transfused > 20 ml/kg at one time to a neonate.)

Goodstein, MH, Herman, JH, Smith, JF. "Metabolic consequences in very low birth weight infants transfused with older AS-1 preserved erythrocytes". Pediatr Pathol Lab Med. vol. 18. 1999. pp. 173-85.

(Goes over the safety profiles for neonates to receive AS-1 red blood cell storage solutions and compare it to CPDA-1 red cell storage solutions. Gives guidance about dosing for neonates.)

Luban, NLC, Strauss, RG, Hume, HA. "Commentary on the safety of red cells preserved in extended-storage media for neonatal transfusions". Transfusion. vol. 31. 1991. pp. 229-35.

(Insight into expert opinions regarding transfusion of red cell storage media other than CPDA-1 to neonates.)

Josephson, CD, Hillyer, CD, Strauss, RG, Luban, NLC. Handbook of Pediatric Transfusion Medicine. vol. 3. Elsevier Academic Press. 2004. pp. 34-37.

(Chapter provides all relevant information on blood products and how they should be tailored for children. This entire book, not only this chapter, is an excellent resource for Pediatric Transfusion Medicine.)

Transfusion Guidelines/Indications for Transfusion

Roseff, SD, Luban, NLC, Manno, CS. "Guidelines for assessing appropriateness of pediatric transfusion". Transfusion. vol. 42. 2000. pp. 1398-413.

(Easy to follow guidelines by three well respected experts in Pediatric Transfusion Medicine field.)

Wong, CC, Luban, NLC, Mintz, PD. "Intrauterine, Neonatal, and Pediatric Transfusion". Transfusion Therapy: Clinical Principles and Practice. AABB Press. 2005. pp. 159-201.

(Excellent resource for in depth explanations about transfusion in the setting of intrauterine, neonatal, and pediatric transfusion.)

Josephson, CD, Su, LL, Hillyer, KL, Hillyer, CD. "Transfusion in the Patient with Sickle Cell Disease: A Critical Review of the Literature and Transfusion Guidelines". Transfus Med Rev. vol. 21. 2007. pp. 118-33.

(Modern review of all evidence for indications to transfuse red blood cell products to children and adults with sickle cell anemia. The transfusions are for both acute and chronic complications and have huge applicability in the intensive care setting, especially as they apply to acute stroke and acute chest syndrome which require red blood cell exchange transfusion.)

New, HV, Standworth, SJ, Engelfriet, CP, Reesink, HW, McQuilten, ZK, Savoia, HF, Wood, EM, Olyntho, S, Trigo, F, Wendel, S, Lin, Y, Hume, H, Petaja, J, Krusius, T, Villa, S, Ghirardello, S, von Lindern, J, Brand, A, Hendrickson, JE, Josephson, CD, Strauss, RG, Luban, NL, Paul, W. "Neonatal transfusions". International Forum. Vox Sanguinis. vol. 14. 2008. pp. 23-0410.

(This article give insight into the controversies that exist around transfusing neonates around the world. Experts discuss their opinions about all blood components and what evidence exists for the neonatal transfusion guidelines that are published.)

Slichter, SJ, Kaufman, R, Assmann, SF, McCullough, J, Triuluzi, D, Strauss, RG, Gernsheimer, TB, Ness, PM, Brecher, ME, Josephson, CD, Konkle, B, Woodson, RD, Ortel, T, Hillyer, CD, Skerrett, DL, McCrae, K, Sloan, SR, Uhl, L, George, JN, Buchannan, G, Manno, C, McFarland, JG, Hess, JR, Leissinger, C, Granger, S. "Effects of Platelet Dose on Transfusion Outcomes (The PLADO TRIAL, A Transfusion Medicine/Hemostasis Clinical Trials Network Study)". N Engl J Med. vol. 362. 2010. pp. 600-13.

(A ground-breaking article about platelet dosing for children and adults with hypoproliferative thrombocytopenia that have under gone stem cell transplant or chemotherapy for malignancy. The findings for patients who received prophylactic platelet transfusions for 10,000 or less platelet trigger dose by body surface area that it didn't matter what dose, high, medium or low dose platelets the bleeding risk for grade 2 or higher (WHO classification) does not influence bleeding risk.)

Josephson, CD. "Neonatal and Pediatric Transfusion Medicine". Technical Manual. AABB Press. 2008.

(Comprehensive chapter about transfusing neonates and pediatric patients.)

Hillyer, KL, Hare, VW, Josephson, CD, Harris, SB, Hillyer, CD. "Partners for Life: the transfusion program for patients with sickle cell disease". Immunohematol. vol. 22. 2006. pp. 108-11.

(This article provides insights not only about how patients with sickle cell Disease in Atlanta, GA, but in many programs around the US implement strategies to mitigate red blood cell alloimmunization.)

Emergency Management of Bleeding with Massive Transfusion Effect

Borgman, MA, Spinella, PC, Perkins, JG. "The ratio of blood products transfused affects mortality in patients receiving massive transfusions at a combat hospital". J Trauma. vol. 62. 2007. pp. 805-813.

(Military experience substantiating a new strategy to help combat dilutional coagulopathy by providing evidence that a 1:1:1 ratio of RBC to plasma to platelet ratio improves morbidity and mortality in the combat situation.)

Holcomb, J, Hess, J. "Early massive trauma transfusion: state of the art". J Trauma. vol. 60. 2006. pp. S1-S2.

(A review of massive transfusion and the way to address treatment.)

Shaz, BH, Dente, CJ, Nicholas, J, MacLeod, JB, Young, AN, Easley, K, Ling, Q, Harris, RS, Hillyer, CD. "Increased number of coagulation products in relationship to red cell products transfused improves mortality in trauma patients". Transfusion. vol. 50. 2010. pp. 493-500.

(A prospective civilian study that show feasibility and improved outcomes with implementing a massive transfusion protocol that uses a 1:1:1 RBC to plasma to platelet ratio at a level 1 trauma center in the US.)

Blood Product Special Processing: Irradiation, Leukoreduction, Volume reduction, Washing

Josephson, CD, Shaz, BH, Hillyer, CD, Shaz, BH, Zimring, JC, Abshire, TA. "Washed blood products". Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects. Elsevier Science. 2009. pp. 227-230.

(Discusses details of indications for washing cellular products. Excellent handbook for intensive care physicians.)

Josephson, CD, Hillyer, CD, Shaz, BH, Zimring, JC, Abshire, TA. Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects. Elsevier Science. 2009. pp. 231-234.

(Discusses specific indications for volume reduction of cellular blood products. Excellent handbook for intensive care physicians.)

Transfusion Reactions

Josephson, CD, Hillyer, CD, Shaz, BH, Zimring, JC, Abshire, TA. Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects. Elsevier Science. 2009. pp. 309-310.

Josephson, CD, Hillyer, CD, Hillyer, CD, Shaz, BH, Zimring, JC, Abshire, TA. Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects. Elsevier Science. 2009. pp. 317-322.

Josephson, CD, Hillyer, CD, Shaz, BH, Zimring, JC, Abshire, TA. "Delayed Hemolytic Transfusion Reactions". Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects. Elsevier Science. 2009. pp. 323-326.

Josephson, CD, Hillyer, CD, Shaz, BH, Zimring, JC, Abshire, TA. "Septic Transfusion Reactions". Transfusion Medicine and Hemostasis: Clinical and Laboratory Aspects. Elsevier Science. 2009. pp. 335-338.

Transfusion Risks

Dodd, RY. "Current risk for transfusion transmitted infection". Curr Opin Hematol. vol. 14. 2007. pp. 671-676.

(Article proves current risks of transfusion in the US. Roger Dodd the author is a national and international authority on transfusion transmitted disease.)

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