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Transfusion Medicine
Blood transfusion can be lifesaving and is currently the safest it has ever been. However, blood transfusion is associated with multiple adverse outcomes, including both noninfectious and infectious complications. The benefits and risks of transfusion can be considered for each patient using evidence-based, multidisciplinary approaches to reduce unnecessary transfusions and improve patients’ outcomes. As a result, the number of units of blood transfused has declined substantially in the United States and worldwide. In the United States, for example, about 10.6 million units of red blood cells (RBCs) are now transfused annually, a decrease from the high of 14.8 million units in 2008.
Blood Components
The majority of blood collections are whole blood, which can then be separated into plasma, platelets, and red blood cell (RBC) components. In the United States, 85% of RBC units are manufactured from whole blood and more than 90% of platelet components are collected by apheresis.
The majority of blood is transfused as component therapy, tailored to the need of a specific patient. Blood components such as RBCs, plasma, platelets, or granulocytes are obtained either from donation of whole blood or via apheresis ( Table 162-1 ). Each component is stored under their respective optimal conditions; RBCs are refrigerated with additive solutions to improve long-term storage, plasma is frozen to preserve clotting factors, and platelets are stored at room temperature to preserve function and post-transfusion survival. As needed, components can be modified (e.g., irradiated) or selected (e.g., hemoglobin S negative) to meet specific patient requirements.
TABLE 162-1
BLOOD PRODUCT CHARACTERISTICS
| PRODUCT | VOLUME | COMPOSITION | STORAGE CONDITIONS | STORAGE LENGTH | COMMENTS |
|---|---|---|---|---|---|
| Red blood cells | 300-350 mL | 200 mL RBCs, 30-40 mL plasma, 100-110 mL anticoagulant and additive solution |
1-6° C | CPD: 21 days CPDA-1: 35 days AS: 42 days |
|
| Platelets | 50 mL per whole blood derived platelet component; 200-400 mL/apheresis component | Platelets suspended in sufficient plasma or platelet additive solution | 20-24° C with constant gentle agitation | 5 days or 7 days with additional bacterial mitigation Pooled in an open system: 4 hrs |
|
| Plasma | 200-250 mL | One mL of plasma contains one unit of coagulation factor activity | −18° C; 1-6° C after thawing | Frozen shelf life: 1 yr FFP/FP24/PF24RT24 after thaw: 24 hrs Thawed plasma: 5 days |
|
| Cryoprecipitate | 10-15 mL/unit | 80-120 units Factor VIII, >150 mg Fibrinogen, Factor XIII, vWF |
−18° C; room temperature after thawing | Frozen shelf life: 1 yr Thawed/pooled in an open system: 4 hrs Thawed/pooled in a closed system: 6 hrs |
|
AS = additive solution; CPD = citrate-phosphate-dextrose (anticoagulant); CPDA = citrate-phosphate-dextrose-adenine (anticoagulant); FFP = fresh frozen plasma; RBCs = red blood cells; vWf = von Willebrand factor.
Whole Blood
Whole blood contains RBCs, platelets, and plasma. It is stored refrigerated unless used shortly after collection. The shelf-life depends on the storage conditions and preservation solution used. Whole blood provides oxygen-carrying capacity (RBCs) and coagulation support (plasma and platelets). Whole blood has largely been replaced by individual blood components because most patients only require one component (RBCs, platelets, or plasma).
However, whole blood can be useful particularly for trauma patients. The military uses a walking donor program for fresh whole blood, which is stored at 22° C for less than 24 hours. This product has addressed blood component shortages, particularly for platelet products, in austere environments. For civilian trauma, some institutions use cold stored (2° to 6° C) whole blood, which may or may not be leukoreduced (i.e., depleted of leukocytes).
Red Blood Cell Components
RBC components are usually prepared from whole blood by removing 200 to 250 mL of plasma after centrifugation. RBC components can also be manufactured by apheresis, which can collect two components from a single donor. RBC components are stored at 1° to 6° C, which allows for 42-day storage. General characteristics of RBC components include 130 to 240 mL of RBCs, 50 to 80 g of hemoglobin, and 150 to 250 mg of iron per unit. The total volume (250 to 350 mL), and hematocrit (55 to 80%), vary depending on the volume of blood collected (450 versus 500 mL) and the specific preservative and additive solution used, which also determine its shelf life. RBCs have a hematocrit of 65 to 80% and a shelf life of 21 days when stored in citrate-phosphate-dextrose (CPD), a hematocrit of 65 to 80% and a shelf life of 35 days when stored in CPDA-1, and a hematocrit of 55 to 65% and a shelf life of 42 days when stored in additive solutions. In the United States, most RBC components are stored in additive solutions and contain small amounts of plasma, platelets, and leukocytes, unless the latter have been removed by leukoreduction filtration (which also removes platelets). Canada and many countries in Europe have a universally leukoreduced blood supply.
Red Blood Cell Component Modification
RBCs and other blood components can be modified to mitigate the complications of transfusion, such as transmission of infectious agents, and to enhance the preservation of rare components. Modified blood components include leukoreduced, irradiated, pathogen reduced, frozen (also known as cryopreservation), and washed components.
Leukoreduction
To remove 99.9% of the white blood cells (yielding <5 × 10 6 white blood cells per component), most RBC and platelet components transfused in the United States are leukoreduced. This process decreases the risk of febrile nonhemolytic transfusion reactions, transfusion-transmitted cytomegalovirus (CMV) and other leukocyte-transmitted infections, HLA alloimmunization, and a transient depression of the immune system after transfusion.
Irradiation and Cryopreservation
Irradiation of cellular blood components prevents transfusion-associated graft-versus-host disease (GVHD). Irradiation of RBCs shortens their storage period.
Freezing of RBCs extends their storage capability to 10 or more years. RBCs with rare phenotypes can therefore be frozen and banked for prolonged periods and be more readily available for patients who have antibodies to high-frequency antigens or rare combinations of antigens. After thawing, frozen RBCs must be washed to remove the cryoprotectant (glycerol). Because washed cellular blood components are depleted of plasma proteins, they are the preferred products for patients with a history of allergic, anaphylactoid, or anaphylactic reactions. Washed RBCs expire 24 hours after washing.
Pathogen Reduction
Pathogen reduction inactivates nucleic acids in viruses and bacteria and thus reduces the risk of transfusion-transmitted pathogens, both known and unknown. It also inactivates residual white blood cells, thereby eliminating the need for irradiation. Pathogen-reduced platelets and plasma are used preferentially in some European countries and are increasingly being used in the United States. Pathogen-reduced plasma, particularly plasma treated with a solvent detergent, has a very low adverse event rate. RBC components derived from pathogen-reduced whole blood are approved in Europe, the Middle East, and Africa and are undergoing clinical trials for approval in other countries. Pathogen-reduced RBCs have a shortened shelf-life. In the United States, pathogen-reduced cryoprecipitate is approved for use in acquired fibrinogen deficiency or for replacement of factor XIII or von Willebrand factor when specific factor concentrates are not available.
Platelet Components
Platelet components can be produced from whole blood or apheresis collections and generally have a volume of approximately 300 mL. Platelets derived from whole blood are commonly referred to as random donor platelets , platelet concentrates , or buffy coat platelets . Each unit derived from whole blood contains approximately 0.5 × 10 11 platelets. Typically 5 units are pooled to provide a therapeutic dose of 3.0 × 10 11 platelets. Platelets collected by apheresis (or plateletpheresis) are referred to as single donor platelets or apheresis platelets . The required minimum content for a platelet component collected by apheresis is 3.0 × 10 11 platelets, but many apheresis-derived platelet collections contain two or three times the required minimum and are therefore split to make multiple platelet components from a single collection. Outside the United States, platelets are made from whole blood using the buffy coat method. These are then pooled and stored in either platelet additive solution or a single donor’s plasma. Platelet components can be stored for up to 7 days.
Platelet components are screened for the presence of bacteria to prevent septic transfusion reactions. Also, platelet and plasma components are prepared to reduce the risk of transfusion-related acute lung injury by selecting male or never-pregnant female donors or testing previously pregnant donors for HLA antibodies. Finally, platelets stored in platelet additive solutions have less plasma and thus are less likely to result in allergic reactions and hemolytic reactions due to ABO incompatibility between the donor and recipient.
Another product modification, cold-stored platelets, is emerging for use in trauma or during major bleeding. In the United States, cold-stored (1° to 6° C) platelets are approved with a 14-day shelf life when standard room temperature platelets are not available. These platelets remain in circulation less than 24 hours compared to 5 to 7 days for platelets stored at room temperature.
Plasma Components
Plasma components can be produced from whole blood after centrifugation and removal of RBCs or by apheresis. Notably, the following information applies to the United States, but other countries have simpler terms for their plasma components. Fresh frozen plasma (FFP) is frozen at −18° C or colder within 8 hours of collection. Plasma frozen at −18° C or colder within 24 hours of collection is referred to as plasma frozen within 24 hours after phlebotomy. Plasma frozen within 24 hours after phlebotomy held at room temperature up to 24 hours after phlebotomy prepared from apheresis collections is also available. Once frozen, plasma has a frozen shelf life of 1 year. Prior to transfusion, plasma must be thawed to 30° to 37° C, a process that takes 20 to 30 minutes. Thawed plasma should be transfused immediately or stored at 1° to 6° C for up to 24 hours. Thawed plasma can be stored for up to 4 additional days at 1° to 6° C to prevent wastage. FFP contains approximately 1 IU/mL of each clotting factor. From a clinical perspective, all plasma products are essentially equivalent.
Other plasma components which are less commonly used include cryoprecipitate-reduced plasma and liquid plasma . Cryoprecipitate-reduced plasma, which is the plasma remaining after cryoprecipitate is removed, is mostly deficient in factor VIII, fibrinogen, von Willebrand factor, factor XIII, and fibronectin. The sole clinical indication for cryoprecipitate-reduced plasma is in the treatment of thrombocytopenic thrombotic purpura ( Chapter 158 ). Liquid plasma, stored at 1° to 6° C, is separated from whole blood and transfused no later than 5 days after the expiration date of the whole blood. This product contains viable lymphocytes, so it requires irradiation to prevent transfusion-associated graft-versus-host disease in high-risk recipients, such as patients who are immunocompromised.
Cryoprecipitate
Cryoprecipitate is manufactured by thawing FFP at 1° to 6° C. During this thawing process, a precipitate forms (the cryoprecipitate), is separated, and is refrozen. Cryoprecipitate is selectively enriched in fibrinogen, fibronectin, factor VIII, von Willebrand factor, and factor XIII. Cryoprecipitate and its supernatant (cryoprecipitate-poor plasma) are separately refrozen and stored for up to 1 year after collection.
Each unit of cryoprecipitate contains at least 150 mg fibrinogen and 80 IU of factor VIII. A single 10 to 15 mL unit of cryoprecipitate should increase the fibrinogen concentration by approximately 50 mg/dL per 10 kg of body weight. Most blood centers provide prepooled cryoprecipitate, which typically consists of 5 units of cryoprecipitate and which is easier for the hospital transfusion service to prepare. For adult patients, the typical order is a dose of 5 to 10 units of cryoprecipitate.
Granulocytes
Granulocytes have a 24-hour shelf life and are stored at room temperature without agitation. Mostly they are collected by apheresis using hydroxyethyl starch to improve collection. In order to increase the number of granulocytes collected, the donor may be stimulated with steroids to yield components with approximately 1 × 10 10 granulocytes and donors stimulated with steroids and granulocyte colony-stimulating factor (G-CSF; Chapter 142 ) to yield components with approximately 1 × 10 11 granulocytes. Apheresis granulocytes have approximately 200 mL volume, 10 to 50 mL of RBCs, 3 × 10 11 platelets (equivalent to a platelet component), and plasma. All granulocytes should be irradiated, cannot be leukoreduced, and should be transfused as soon as possible.
Pretransfusion Testing
Routine pretransfusion testing of blood components includes receipt of an appropriately labeled patient specimen by the transfusion service, testing of the patient’s specimen for ABO group and D type and for the presence of unexpected antibodies, and crossmatching of RBC components with the patient’s sample.
In emergency situations and before crossmatch compatible blood components are available, group O RBCs and group AB plasma (some institutions use group A plasma) may be appropriately transfused.
Critical to safe blood transfusion is a properly labeled pretransfusion blood specimen from the intended transfusion recipient. Most hemolytic transfusion reactions are caused by misidentification or labeling errors in pretransfusion blood specimens. Radio-frequency identification technology improves the safety and efficiency.
A “type and screen” involves typing the patient’s RBCs for ABO and Rh (also known as RhD or D) type, as well as screening the patient’s plasma for clinically significant RBC antibodies. A “type and crossmatch” also includes the selection, crossmatching, and reserving of appropriate RBC components for the transfusion recipient. Many institutions have a maximum surgical blood order schedule, which indicates when a type and screen is ordered and how many components should be reserved for each type of surgical procedure.
RBC antibodies of clinical significance are formed in response to pregnancy or transfusion; they may cause hemolysis or shortened survival of transfused RBCs carrying the reciprocal antigen (i.e., acute or delayed hemolytic transfusion reaction). For this reason, the intended recipient’s plasma is screened for the presence of these unexpected antibodies prior to RBC transfusion. If a patient has a clinically significant antibody, the transfusion service will select and reserve the appropriate RBC components that do not carry the reciprocal antigen. The process of identifying a patient’s RBC antibody and crossmatching the appropriate RBC components can take hours or even days, depending on the antibody or antibodies found. It can be particularly problematic when the intended recipient has autoantibodies ( Chapter 146 ).
How far in advance a specimen can be drawn is determined by institutional policies. In patients with a negative antibody screen and no history of transfusion or pregnancy in the preceding 3 months, specimens may be drawn up to 1 month before surgery. However, if the patient has been transfused or has been pregnant in the preceding 3 months, a pretransfusion specimen is valid only for 3 days. Most hospitalized patients require a new specimen every 3 days.
ABO/D Compatibility
Individuals naturally have antibodies against the ABO groups they do not carry (i.e., group O individuals have anti-A and anti-B, group A individuals have anti-B, group B individuals have anti-A, and group AB individuals have none). RBC components must be major ABO compatible and usually D compatible. Group O is the universal RBC component because the RBCs carry no A or B group antigens, whereas group AB RBCs can only be transfused to group AB individuals, group A RBCs can only be transfused to group A or AB individuals, and group B RBCs can only be transfused to group B or AB individuals. Incompatible RBC transfusions may result in acute hemolytic transfusion reactions.
In contrast, D-negative individuals do not make anti-D unless exposed to D-positive RBCs through previous pregnancy or transfusion. D-negative females of childbearing potential must receive D-negative RBCs, unless unavailable in emergency situations, to prevent anti-D formation which may result in hemolytic disease of the fetus and newborn. If there is a shortage of D-negative RBCs, males and females not of childbearing potential (usually defined as age ≥50 years old) can receive D-positive components. The risk of anti-D formation from D-positive RBC unit is about 10 to 20%.
Plasma, which contains antibodies, should be minor ABO compatible such that group AB plasma is the universal product. Group A plasma can be transfused to group A or O individuals, group B to group B or group O individuals, and group O to group O individuals. Group A plasma is being used in massive transfusion settings due to the limited availability of group AB plasma (4% of the population is group AB). This practice appears safe, particularly given that these patients are receiving group O RBCs and are switched to type-specific components once the blood type is known. Plasma is not D-matched because no RBCs are in the product.
Platelets are typically transfused with ABO matching. ABO compatibility results in higher post-transfusion platelet count increment. To decrease the risk of hemolytic transfusion reactions from incompatible plasma, low titer (of anti-A) group O products are used. Risk of anti-D with D-positive to D-negative patients is less than 1%. Granulocytes should be major ABO compatible due to their contamination with RBC and subsequent risk of acute hemolytic transfusion reaction.
Blood Safety
Adverse events of blood transfusion occur in 0.2% of transfusions, and about 7% of these events are serious. Adverse events can be classified as acute (within hours) or delayed (days to years), and as noninfectious or infectious ( Table 162-2 and Table 162-3 ). Infectious risks include emerging infections, such as Babesia , and traditional infections, such as hepatitis B or C. With improvement in donor screening for transmissible diseases, more focus has been on reducing noninfectious transfusion reactions. ,
TABLE 162-2
NONINFECTIOUS TRANSFUSION-ASSOCIATED EVENTS
| TRANSFUSION-ASSOCIATED ADVERSE EVENT | RISK PER UNIT TRANSFUSED IN THE UNITED STATES |
|---|---|
| Acute hemolytic transfusion reaction | ≈1 : 110,000 transfusions |
| Febrile nonhemolytic transfusion reaction | ≈1 : 1100 |
| Allergic transfusion reaction | ≈1 : 1200 ≈1 : 15,500 severe |
| Transfusion-associated circulatory overload | ≈1 : 9000 |
| Transfusion-related acute lung injury | ≈1 : 140,000 |
| Hypotensive transfusion reactions | ≈1 : 32,000 |
| Transfusion-associated dyspnea | ≈1 : 28,000 |
| Delayed hemolytic transfusion reaction | ≈1 : 32,000 |
| Delayed serologic transfusion reaction | ≈1 : 8000 |
| Transfusion-associated graft-versus-host disease | <1 : 10,000,000 |
| Post-transfusion purpura | ≈1 : 10,000,000 |
TABLE 162-3
INFECTIOUS DISEASE WINDOW PERIOD AND RESIDUAL RISK
| TEST | WINDOW PERIOD (DAYS) | RESIDUAL RISK OF TRANSFUSION |
|---|---|---|
| HIV MP-NAT | 9 | ≈1 : 1,800,000 |
| HIV EIA | 21 | |
| HCV MP-NAT | 7 | ≈1 : 1,600,000 |
| HCV EIA | 51-58 | |
| HBsAg | 30-38 | ≈1 : 300,000 |
| HBV NAT | 40-50 (MP) and 15-34 (ID) | ≈1 : 1,500,000 |
| HTLV | 80 | ≈1 : 3,300,000 |
| Syphilis | 1 reported case in the United States in the last 50 years | |
| Chagas disease | 7 reported cases in the U.S.; none since testing | |
| WNV NAT | Last case in 2012 | |
| Bacterial contamination | 1 : 200,000-1,000,000 with addition of multiple mitigation strategies |
EIA = enzyme immunoassay; HBsAg = hepatitis B virus surface antigen; HBV NAT = hepatitis B virus nucleic acid test; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HTLV = human T-cell leukemia-lymphoma virus; ID = individual donor nucleic acid testing; MP-NAT = mini-pool nucleic acid testing; WNV NAT = West Nile virus nucleic acid test.
Noninfectious Adverse Effects of Blood Transfusion
Acute Hemolytic Transfusion Reaction
Acute hemolytic transfusion reactions occur when preformed recipient antibodies bind to transfused RBC antigens, thereby resulting in the formation of an antigen-antibody complex. This complex activates the complement cascade and causes intravascular hemolysis. Most commonly, acute hemolytic transfusion reactions are severe reactions due to ABO incompatibility, usually because transfused RBC antigens are incompatible with the recipient’s plasma (e.g., group A RBCs into group O recipient), and less commonly when transfused plasma contains antibodies against the recipient’s RBC antigens (e.g., group O plasma into group A recipient). Acute hemolytic transfusion reactions can also be associated with antigen-antibody complexes outside of the ABO system. The destruction of RBCs also may result in mechanical hemolysis unrelated to the transfusion.
The incidence of acute hemolytic transfusion reactions is approximately 1 : 110,000 transfusions, and these rates have substantially decreased over time. About 70% of transfusion reactions are due to RBCs and 30% due to platelet transfusions. ABO-incompatible RBC transfusions most commonly occur with mistransfusion, when the patient receives an incorrect unit. Mistransfusion is usually caused by human error, including improper identification of the intended recipient during pretransfusion sample collection, improper ABO typing of the blood component or the intended recipient, or improper identification of the recipient or the blood component at the time of transfusion.
Clinical Manifestations and Diagnosis
The signs and symptoms of acute hemolytic transfusion reactions are fever, chills/rigors, anxiety, chest and abdominal pain, flank and back pain, nausea, vomiting, dyspnea, hemoglobinuria, diffuse bleeding, and oliguria/anuria. If an acute hemolytic transfusion reaction is suspected, the transfusion should be stopped immediately, the reaction should be reported to the transfusion service for investigation, and the unit should be returned to the blood bank. Diagnosis is based on laboratory evidence of hemolysis (e.g., decreased hemoglobin, decreased haptoglobin, hemoglobinuria, and elevated lactate dehydrogenase) and evidence of incompatible blood transfusion (e.g., positive direct antiglobulin test and incompatible crossmatch). Approximately 50% of ABO-incompatible RBC transfusions have no adverse effect, but 5% are fatal.
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