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The purpose of this chapter is to provide some basic information about transfusion medicine (TM). In order to provide care to patients and direct a blood bank, training and/or experience in TM is necessary. Please refer to the suggested reading for additional information. Purposefully omitted in this chapter is a discussion of blood collection and donor as well as therapeutic apheresis.
The decision to transfuse blood must be conveyed to a blood bank as a written or electronic order by a physician. In emergent situations, a verbal request for blood may be appropriate, but this should be documented and followed by a written or electronic order as soon as possible. In order to provide compatible blood to a patient, a pretransfusion sample is required for blood bank testing. The sample must be labeled with the patient’s name as well as a second unique identifier such as the patient’s date of birth (DOB) or a medical record number. Most institutions also require additional information on the specimen such as
the identity of the phlebotomist and the date that the sample was drawn. Due to the potentially lethal consequences of incorrect patient identification during sample acquisition or errors during testing, most institutions require two blood bank specimens to be drawn and tested independently from a patient (preferably at different times). Additionally, the results of any testing performed should always be compared to any historical blood bank data available for the patient.
Pretransfusion testing needs to be performed using the patient’s red blood cells (RBC
) and either plasma or serum. Usually, hemolyzed or lipemic samples are not accepted by blood banks as testing such samples may yield inaccurate results. Once an appropriate specimen is received, testing is performed to determine the patient’s ABO group and Rh (D) type followed by screening of the patient’s plasma for unexpected red cell antibodies. After the testing is completed, a suitable unit of donor blood is selected for the patient and checked for compatibility by performing a crossmatch.
AGGLUTINATION (DAT AND IAT)
The majority of testing performed in blood banks involves looking for the presence or absence of agglutination using patient, donor, or reagent red cells and patient plasma or reagent antibodies. The goal of this testing is to predict compatibility of blood products upon transfusion. Agglutination is “clumping” of red cells caused by the binding of antibody to antigens on the red cell membrane. This usually occurs in two phases: (1) sensitization of the red cells by the antibody binding to antigens and (2) lattice formation that results in macroscopic agglutination. Centrifugation is usually necessary to bring red cells in close proximity for agglutination as there is a net negative charge on the surface of red cells that prevents their aggregation and agglutination. As it is possible for IgG
antibodies to result in red cell sensitization without agglutination, it is often necessary to add a secondary antibody to cause lattice formation. The secondary antibody required is an antibody to human globulins, specifically IgG
and complement. This anti-human globulin (AHG
) or Coombs reagent can be used to perform a direct antiglobulin test (DAT
) as well as an indirect antiglobulin (IAT
). When performing a DAT
is added to a patient’s RBCs that are suspected to be sensitized. This is unlike an IAT
is added to a suspension of reagent (or donor) red cells and the patient’s plasma that is suspected to contain an antibody to the reagent (or donor) red cells. In either test, the addition of AHG
will result in agglutination if the red cells are sensitized by the antibody. Although many institutions perform pretransfusion testing as described above in small test tubes, some larger institutions are performing some (or most) of their testing using newer technology (gel columns and solid-phase testing).
PERFORMING A TYPE AND SCREEN
Prior to transfusion of blood, a patient’s ABO and Rh type must be determined, and the patient’s plasma must be checked for expected and unexpected antibodies. The blood typing usually begins with the forward ABO grouping performed by testing a patient’s red cells for the presence of A and B antigens using commercially available anti-A and anti-B antibodies. Subsequently, a
reverse grouping is performed by checking the patient’s plasma for anti-A and anti-B antibodies using reagent group A and group B red cells. With rare exception, patients that lack A or B antigens on their red cells should have an antibody to the antigen that is not present (see Table 17-1
). Any discrepancy in the forward and reverse ABO grouping must be resolved prior to transfusion of blood products, and if urgent transfusion is necessary, group O red cells and group AB plasma should be provided prior to the resolution of this discrepancy.
TABLE 17-1. Antigens and Antibodies Present in Each ABO Blood Group
ABO Blood Group
In order to determine a patient’s blood type, the patient’s red cells must also be tested with anti-D to determine whether the patient expresses the D antigen on his/her red cells. If the patient’s red cells do not agglutinate with the anti-D reagent antibody, some institutions may perform weak D testing by adding AHG
. Weak D testing will detect patients that have a quantitative or qualitative difference in the D antigen expressed on their red cells. Patients that have a weak D phenotype do not have enough D antigen on their red cells to result in direct agglutination, and agglutination is seen only after the addition of AHG
. Patients that have a partial D phenotype have a qualitative difference in the D antigen that also requires AHG
for agglutination. Although some institutions will perform weak D typing on patients, it is not necessary to do so as weak D and partial D patients will otherwise be considered Rh negative and will receive D-negative blood products, which will be compatible with the patient and not result in any harm. The same holds true for pregnant patients; while it is not necessary to perform weak D testing, some institutions choose to do so. If a pregnant patient with a weak D phenotype is typed as D negative (because the institution does not perform weak D testing on patients), she will be treated with Rh immune globulin unnecessarily (as she is not able to be immunized to the D antigen), but this will likely not result in any harm to the patient (also see discussion on prenatal testing in this chapter). However, blood donors must be typed for the weak D antigen because red cells from a weak D donor can immunize Rh-negative patients to the D antigen.
Once the patient’s blood type (ABO and Rh) is determined, the plasma or serum must be checked for unexpected antibodies to non-ABO red cell antigens. The goal of the antibody screen is to detect clinically significant antibodies to red cell antigens that can cause hemolytic transfusion reactions (HTR
) and hemolytic disease of the fetus and newborn (HDFN
). Antibodies that bind to red cells at body temperature (37°C) and are detected using AHG
are more likely to be clinically significant than cold-reactive antibodies that do not result in agglutination at 37°C or the AHG
phase of testing. Some of the more
commonly encountered clinically significant antibodies include antibodies to D, C, E, c, e, S, s, K, k, Fya
, and Jkb
. Reagent red cells must be able to detect these antibodies as well as antibodies to M, N, P1, Lea
, and Leb
After a type and screen is completed, an appropriate blood product can be selected to transfuse the patient. Ideally, ABO-identical blood products should be transfused, but due to inventory management constraints, often, ABO-compatible (but not ABO-identical) products are issued for transfusion. Table 17-2
reviews the type of red cells and plasma that are compatible with each of the ABO blood groups.
Plasma, platelets, and cryoprecipitate can be transfused without a crossmatch. However, for RBC
transfusion, each unit of red cells should be crossmatched with the recipient’s plasma prior to transfusion in order to ensure compatibility. The type of crossmatch necessary depends on whether the patient’s antibody screen is positive or negative.
If the patient’s antibody screen is negative, generally, an immediate spin crossmatch is performed by simply mixing the red cells selected for transfusion with the patient’s plasma and checking for agglutination after centrifugation. An immediate spin crossmatch is essentially a second check of the donor and recipient’s ABO compatibility as agglutination will be seen if the patient’s plasma has ABO antibodies to cognate antigens on the red cells selected for transfusion. In some institutions, patients that have a negative antibody screen may be eligible for an “electronic crossmatch” if at least two verifications of the donor and patient blood type have been performed and if the institution has validated the blood bank information system to not allow an incompatible blood product to be issued to the patient. If the patient has had a positive antibody screen, a full Coombs crossmatch using AHG
must be performed. Many clinically significant non-ABO alloantibodies are IgG
antibodies and will not result in agglutination unless AHG
is added to the suspension of red cells and plasma. Thus, patients that have a positive antibody screen should have the crossmatch performed by incubating the patient’s plasma and donor red cells at body temperature followed by addition of AHG
The sample of blood used to perform the crossmatch (as well as the type and screen) must be recently acquired from the patient if the patient has been transfused or pregnant within the last 90 days. This is necessary because the patient may produce an antibody to an RBC
antigen within as little as a few days after being exposed to allogeneic red cells. Generally, a sample should not
be more than 3 days old if the patient has been recently transfused or pregnant, but a sample drawn up to several weeks prior to transfusion is acceptable if the patient has not had any recent exposure to allogenic blood through transfusion or pregnancy. It is also important to review the blood bank history to prevent the transfusion of RBCs that may have antigens that the patient previously had antibodies to. In these patients, the antibody titer may decrease in strength to below detectable levels, but subsequent exposure to the antigen can result in brisk antibody production and a delayed hemolytic transfusion reaction. Unlike RBC
transfusion, transfusion of other blood products does not require a recent sample because selection is based on the patient’s blood type and a crossmatch does not need to be performed.
TABLE 17-2. Blood Products That are Compatible with Each ABO Blood Group
Compatible Red Cells
A, B, AB, O
O, A, B, AB
TRANSFUSION OF BLOOD PRODUCTS
Transfusion of blood products carries significant risks. Thus, prior to any transfusions, the risks and benefits should be carefully assessed and blood products should be provided to the patient only if the benefits outweigh the risks. Today, transfusion of whole blood is exceedingly rare in the United States with the exception of massively bleeding trauma patients. Patients are usually transfused with the specific blood component that is required (e.g., packed red cells, plasma, platelets, or cryoprecipitate).
RED CELL TRANSFUSION
The goal of red cell transfusion is to increase oxygen delivery to tissues in patients when necessary. Red cell transfusion is appropriate for the treatment of anemia if it will ameliorate symptoms of anemia or aid in correcting or preventing the adverse physiologic consequences of anemia. Most patients will tolerate a loss of approximately 50% of their circulating hemoglobin before they start to experience significant consequences due to acute anemia. In acute blood loss, symptoms due to hypovolemia are usually seen before symptoms due to anemia. In chronically anemic patients (patients that become anemic over weeks or months), compensatory mechanisms allow patients to tolerate lower hemoglobin levels than patients that become acutely anemic. Considering the many variables involved, it is often challenging to determine whether tissue ischemia exists and whether it will be alleviated with red cell transfusion.
□ Who Should Be Suspected?
There is a significant variation in RBC
transfusion practices between institutions. Most studies that have audited transfusion of blood products have reported that there was unnecessary transfusion of patients. Consequently, there is a trend toward more conservative hemoglobin transfusion triggers. Authorities in transfusion medicine (TM) agree that most patients with a hemoglobin of <6 g/dL will need red cell transfusion and most patients with a hemoglobin of >10 g/dL will not require red cell transfusion. Although there is general agreement that, within this range, the transfusion of blood products needs to be individualized to the patient, most institutions have adopted a transfusion trigger of a hemoglobin of 7 g/dL for most hospitalized patients with the notable exception of patients with unstable cardiac disease (see Table 17-3
TABLE 17-3. Indications for Blood Transfusion and Special Product Processing
Red blood cells (after bleeding has stopped, one unit of packed RBC increases Hb 1 g/dL in an average-sized adult)
Active blood loss
Hct ≤ 21% or Hb ≤ 7 g/dL
Hct ≤ 24% or Hb ≤ 8 g/dL and symptomatic
Hct ≤ 25% or Hb ≤ 8.3 g/dL and acute coronary syndrome
Platelets ≤ 10,000/µL
Platelets ≤ 20,000/µL and sepsis, multisystem failure, or high risk for outpatient hemorrhage
Platelets ≤ 50,000/µL with surgery or active bleeding
Platelet function defect and symptomatic or impending surgery/invasive procedure Intraoperative hemostatic defect
Prolonged prothrombin time (e.g., liver disease) and symptomatic or invasive procedure planned
Factor XI or XIII deficiency
C1 esterase inhibitor deficiency (hereditary angioedema) and symptomatic Intraoperative hemostatic defect
Overdose of oral vitamin K antagonist with evidence of bleeding
Cryoprecipitate (contains fibrinogen, factors VIII and XIII, von Willebrand factor, and fibronectin)
Mild factor VIII deficiency and symptomatic or with surgery/invasive procedure (if factor VIII concentrate not available)
von Willebrand disease and symptomatic or with surgery/invasive procedure (if von Willebrand factor concentrate not available)
Hypofibrinogenemia and symptomatic or with surgery/invasive procedure Intraoperative hemostatic defect
Factor XIII deficiency
Special blood product processing (not routinely needed)
Irradiated blood products
Directed donor product from blood relative (to avoid graft versus host disease)
Intensive chemotherapy with marrow suppression
Stem cell transplant candidate or recipient
Newborn, prematurity, intrauterine transfusion
Washed blood cell products
Congenital IgA deficiency with anti-IgA antibodies
Repeated severe hypersensitivity transfusion reactions despite appropriate medication
Leukocyte-reduced blood products
≥2 documented febrile transfusion reactions
Chronically transfusion dependent
Transplant candidate or recipient
High cytomegalovirus risk
Patient is a pregnant woman
Newborn, premature, intrauterine transfusion
Patient undergoing splenectomy
Patient with congenital immune deficiency
The previous practice of using plasma as a volume expander has largely become extinct. Today, plasma is almost always transfused to patients due to a deficiency of one or more proteins present in normal plasma. The proteins that are most commonly repleted are coagulation factors. Other deficient proteins that may be repleted with plasma transfusion include ADAMTS13 in patients with TTP
and complement factors in patients with HUS
□ Who Should Be Suspected?
Despite the most common indication for plasma transfusion being the treatment of coagulopathy, there are no clear guidelines for the appropriate use of plasma in this setting. Thus, very often, plasma is transfused unnecessarily to patients that do not benefit from it.
A more proactive approach in regard to plasma transfusion is appropriate in bleeding patients that require massive transfusion of blood products. In such patients, if coagulopathy develops, it may result in excessive bleeding that can be life threatening and it may be extremely difficult to correct a severe coagulopathy. These patients have multiple factors contributing to the coagulopathy including dysfunction of the enzymes of the coagulation cascade (due to hypothermia and acidosis) and consumption of coagulation factors due to disseminated intravascular coagulation (DIC
□ Other Considerations
Several types of plasma products are available for transfusion. These include fresh frozen plasma (FFP
), frozen plasma 24 (FP24
), and thawed plasma (TP). FFP
is plasma that has been separated from a whole blood collection and frozen within 8 hours of collection. FP24
has been frozen within 24 hours of collection. Both of these products can be kept frozen up to 1 year; however, once thawed, they must be used within 24 hours. Thawed plasma is FFP
that has been thawed and relabeled as “thawed plasma” and now can be used for up to 5 days after thawing. The concentration of the majority of coagulation factors does not vary significantly between FFP
, and TP with the exception of factor V and factor VIII. FP24
and TP have lower concentrations of factor V and factor VIII as these two factors have the shortest in vitro half-life. However, factor V deficiency is rare and factor VIII is an acute-phase reactant that is often elevated in patients requiring plasma transfusion. Most often, the vitamin K-dependent factors (II, VII, IX, and X) are the factors that need to be replaced in order to correct coagulopathy. These factors are stable at refrigerator temperatures and not significantly decreased in FP24
□ Laboratory Findings
When assessing a patient for coagulopathy (usually an acquired coagulopathy), the most common laboratory tests ordered are a prothrombin time (PT)/international normalized ratio (INR
) and an activated partial thromboplastin time (aPTT
). The PT is very sensitive and will be abnormal before coagulopathy will result in bleeding. Generally, an increase in bleeding is not usually seen until the PT is more than 1.5 times the upper limit of the normal range (which usually corresponds to an INR
of approximately 2). In nonbleeding patients with
an elevated INR
due to warfarin use, simply holding warfarin or administration vitamin K will correct the coagulopathy without plasma transfusion. It is also important to note that plasma transfusion is significantly more effective in decreasing a patient’s INR
when the INR
is extremely elevated. As the patient’s INR
approaches 1.5, transfusion of plasma will result in a minimal decrease in the patient’s INR
compared to the same volume of plasma given to the same patient at a higher INR
. Another important consideration when transfusing plasma, especially prior to an invasive/surgical intervention is that the plasma should be transfused within a few hours of the intervention. The in vivo half-life of some of the coagulation factors that need correction (such as factor VII) is a few hours, and correcting the coagulopathy with plasma transfusion >8 hours prior to the invasive procedure will likely be of little benefit. Of note, the use of plasma for warfarin reversal has decreased significantly over the last few years due to the availability of four factor prothrombin complex concentrate (PCC
) in the United States.
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