Chapter 5

Matt Emery

Blood and Blood Components

PERSPECTIVE
The era of modern blood transfusion began in the early 1900s with discovery of the ABO red cell antigen system. By World War I it was known that adding citrate enabled the storage of anticoagulated blood. Blood banking in the United States began during the 1930s. Energetic pioneers such as John Lundy of the Mayo Clinic gained a wealth of clinical experience, prompting dissemination of expert-based advice, such as Lundys recommendation that blood transfusion was appropriate when a patients hemoglobin (Hgb) was less than 10g/dL or when a patient lost more than 15% of circulating blood volume. These recommendations were not, however, based on rigorous controlled trials. Rapid expansion of blood banking occurred after World War II, and in subsequent decades research focused on such critical issues as prolonging the storage life of blood products, component therapy, and reducing the risk of transfusion reactions and transfusion-related infections.1,2 More recently, at a time when nearly 14 million units of packed red blood cells (PRBCs) are transfused yearly in the United States, attention has turned toward evaluating the efficacy of more restrictive transfusion policies, rethinking the overall risk-benefit ratio of blood products, and developing bloodless alternatives.1,3-7

refrigerated at 1 to 6C (usually 4C), cell metabolism con tinues and changes occur (collectively referred to as the storage lesion). Documented alterations are numerous and include a decrease in pH and in the level of 2,3-diphosphoglycerate (2,3-DPG). In addition, the deformability of RBCs makes them, over time, more spherical and rigid, thereby increasing resistance to capillary flow. With time, many of these changes are reversed in vivo. The decrease in 2,3-DPG, for example, results in a left shift in the hemoglobin-oxygen dissociation curve (less oxygen is released at a given partial pressure of oxygen [Po2]), but the ability to synthesize 2,3-DPG is regained over the first 24 hours after transfusion.10 The relationship between overall oxygen transport and oxygen delivery to tissues is complex. Depletion of S-nitrosohemoglobin during storage alters oxygen-dependent regulation of microcirculatory blood flow (hypoxic vasodilation).11 There is ongoing debate about whether and when these and other changes are clinically significant, and how they might be overcome.12-16 Additional well-established changes include cell leakage of potassium, although the amount ( 6mEq/U17) is readily tolerated by most otherwise healthy patients. PRBCs contain essentially no functional platelets or granulocytes.

Blood Typing PATHOPHYSIOLOGIC PRINCIPLES Blood Banking3

Blood centers, such as those of the American Red Cross and Americas Blood Centers, process more than 90% of the units collected in the United States. Traditional allogenic donation methods still predominate, but increasing use is being made of red cell apheresis technology, by which red cells are separated from the blood at the time of collection, with the rest returned to circulation. This allows collection of about two transfusable units during a single donation. Blood collection bags contain an anticoagulant-preservative of citrate, phosphate, dextrose, and adenine (CPDA-1), ensuring a shelf life (viability of at least 70% of the RBCs 24 hours after infusion) of 35 days and hematocrit of 70 to 80% for PRBCs.8 Additive solutions (Adsol, Nutricel, Optisol) provide additional nutrients, extending maximum storage to 42 days and lowering viscosity, which makes infusion easier.9,10 Storage impairs red cell function. Transfused blood delivers oxygen to the tissues less efficiently. Even though blood is
42

A basic knowledge of compatibility testing allows emergency physicians to order blood bank products and services appro priately. Identified red blood cell (RBC) antigens include the ABO and related carbohydrate antigens (H, P, I, and Lewis), the 48Rh system antigens, and more than 200 non-ABO/Rh antigens. When a clinician anticipates that transfusion might be indicated, a type and screen can be ordered, and a blood specimen from the patient is sent for the following tests: ABO grouping, Rh typing, and an antibody screen for unexpected (non-ABO/Rh) antibodies. Completion of these steps speeds the delivery of crossmatched blood if it is subsequently required. ABO incompatibility results in acute hemolysis, the most serious transfusion reaction. ABO grouping requires that the recipients red cells be tested with anti-A and anti-B serum, and that their serum be tested with A and B red cells.8 Patients form antibodies at about 6 months of age against the A and B antigens they lack. Those with type AB blood form no ABO group antibodies. Patients who are type O have antibodies against both. The major clinically

significant Rh antigen is the D antigen. Rh typing can usually be determined by adding a commercial reagent (anti-D) to recipient RBCs. The antibody screen identifies clinically significant unexpected antibodies in the patients serum. These antibodies form when a patient responds to a foreign RBC antigen, usually due to prior exposure, such as with allogenic transfusion, pregnancy, or organ transplant. The antibody screen is performed by mixing commercial RBC reagents (mixtures of red cells expressing clinically significant antigens) with the patients serum. The incidence of these unexpected antibodies in the general population is low (<12%), but a positive screen mandates further compatibility testing.10,17 The type and screen allows quicker selection of appropriate banked blood for complete crossmatch if a transfusion is ordered. Ideally, blood identical to the patients own ABO and Rh group is used. Local blood supplies, however, might dictate that a nonidentical, but compatible, unit be used. Patients with blood group AB, for example, can receive blood from any of the ABO groups. Men, and women beyond childbearing age, who are Rh-negative and have no preformed Rh (anti-D) antibodies may receive either Rh+ or Rh blood. When a blood transfusion is ordered, a formal crossmatch is done by mixing recipient serum with donor RBCs as a final compatibility test prior to transfusion. This can be done using a Coombs test (with serum incubated to 37C), or the more rapid immediate spin crossmatch at room temperature, which will detect only ABO incompatibility. The more thorough Coombs test can detect incompatibilities that were missed with the antibody screen.17

lent to the patients blood volume with stored RBCs within a 24-hour period.8 In addition to storage lesion problems, hypothermia can result when patients receive more than 100mL/min of cold blood for 30 minutes. This can be prevented by warming the blood to 37C with a blood warmer. Transiently decreased levels of ionized calcium may result from the citrate preservative. Clinical signs of hypocalcemia include circumoral tingling, skeletal muscle tremors, and QT segment prolongation. Calcium administration is guided by determination of ionized calcium levels and clinical findings.18 Dilutional thrombocytopenia may result, but platelet concentrate is not indicated unless there is evidence of microvascular bleeding. If disseminated intravascular coagulation (DIC) develops, platelet concentrate, FFP, and cryoprecipitate may be required.18

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Chapter 5 / Blood and Blood Components

Administration Legal Aspects

Before a blood product can be infused, two qualified personnel check it at the bedside to prevent a potentially fatal clerical error. This check includes recipient and unit identification, as well as confirmation of compatibility, and the expiration date.8 At times a patient may arrive from a transferring facility with typed and crossmatched blood. If the blood is administered immediately in the emergency department, the hospital blood bank is not involved and accepts no responsibility for the blood. If the blood is not used immediately and the blood bank is asked to hold the blood for the patient, it is processed and crossmatched as for other issued blood and quarantined for 24 hours. It can be sent back to the blood bank to have this done only if (1) it has been constantly maintained at a temperature between 1 and 6C, (2) all container seals are intact, and (3) tubing segments have remained attached to the blood container.8

Special Clinical Circumstances

To select the most appropriate blood product in the emergency setting, clinicians must consider the patients hemodynamic stability and the amount of time available to intervene.17

Universal Donor Group O

Universal (group O) blood is used when RBCs must be given at once to hemorrhaging, unstable patients. Premenopausal females (adults and children) need group O Rh-negative blood, whereas men and all other women may receive O Rh-positive blood, which is more common. Conversely, the universal type for fresh frozen plasma (FFP) is type AB, since it contains no antibodies to either A or B antigens. If the patients condition can be initially stabilized with crystalloid infusion, type-specific blood (using ABO and Rh testing) should be available within 15 minutes of receiving a sample of the patients blood. An antibody screen and immediate spin crossmatch take approximately 45 to 60 minutes. The recipients serum is screened for unexpected antibodies as described earlier. An immediate spin crossmatch is then performed at room temperature if the antibody screen is negative. If the antibody screen is positive, however, the antibody is identified using more elaborate procedures, and a complete crossmatch (using a Coombs test with incubated serum) is required. This process can take up to several hours.17

Infusion Adjuncts
Urgent transfusion situations require flow rates faster than gravity can provide. An administration set with an in-line pump that is squeezed by hand is the simplest method to speed infusion. Pressure bags are also available that completely encase the blood bag and apply pressure evenly to the blood bag surface. If external pressure is anticipated, large-bore needles are recommended for venous access to prevent hemolysis.8 If only a small-gauge needle is available, the transfusion may be diluted with normal saline, but this may cause unwanted volume expansion. In elective transfusions, no significant hemolysis occurs when small-gauge needles are used and when the maximum rate of infusion is less than 100mL/hr.8

MANAGEMENT Decision-Making
When considering the use of blood component therapy, the patients age, severity of symptoms, cause of the deficit, underlying medical condition, ability to compensate for decreased oxygen-carrying capacity, and tissue oxygen requirements are all considered. Clinical evaluation, including appearance (pallor, diaphoresis), mentation (alert, confused), heart rate, blood pressure, and the nature of the bleeding (active,

Massive Transfusion
Abnormalities from massive transfusion are rarely seen during a patients initial resuscitation in the emergency department, but the physician should be aware of potential problems. Massive transfusion has been defined as transfusion equiva-

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controlled, uncontrolled), can be supplemented by laboratory evaluation of Hgb, hematocrit, platelets, and clotting functions. A review of relevant literature underscores the difficulty of making firm recommendations. Only recently5,7,19,20 have randomized controlled trials investigated the efficacy of various transfusion triggers in the critical care and surgical setting. The largest randomized trial in adult patients to date, the TRICC (Transfusion Requirements in Critical Care) trial,5 demonstrated that in the critical care setting, a transfusion threshold of 7g/dL was as safe as a threshold of 10g/dL, although subgroup analysis generated some concern that patients with ischemic heart disease may benefit from a higher transfusion threshold.21 In a large, retrospective analysis of patients hospitalized with acute myocardial infarction, anemia appeared to raise the risk of death, and transfusion for a hematocrit of 33% or less improved overall mortality rates.22 It is debatable, however, whether these results can be generalized to the emergency department setting. Further research is urgently needed.1 The list of known and suspected risks associated with transfusion, on the other hand, is long and growing. Recent concerns include Transfusion Related Acute Lung Injury (TRALI) and immune modulation.23 As a result, recent guidelines generally recommend a restrictive strategy for most patients, utilizing transfusion triggers more stringent than those traditionally followed.24 Recommendations for the use of FFP likewise have long been more expert-based than evidence-based.25,26

Fresh Frozen Plasma

Current practice dictates that FFP be given to patients with evidence of coagulopathy (international normalized ratio [INR] >1.52.0) who are either actively bleeding (absolute indication) or require an invasive procedure (relative indication).28,29 Most clinicians consider active bleeding to include clinically significant hemorrhage, not minor degrees of oozing. If a specific factor deficiency is identified (e.g., hemophilia), targeted replacement of that factor, if available, is more practical. FFP should not be used for volume expansion.

Platelets
Platelet transfusion is indicated prophylactically when the count is less than 10,000/mL, and this includes a margin of safety, as it appears that hemostasis is well-maintained even at counts of 5000/mL. Platelet counts of 40,000 to 50,000/mL are sufficient to perform invasive procedures.30 Platelets have traditionally been given to adults in a dose of 6U of platelet concentrate (i.e., a six-pack of platelets), which typically raises the platelet count about 40,000 to 60,000/ mL. This practice is not, however, evidence-based.30 Because hemostasis is maintained with platelet counts as low as 5000/ mL, it seems likely that smaller, more frequent platelet transfusions should be equally efficacious, but more cost-effective in hospitalized patients. This may be impractical, of course, in outpatients. An ongoing randomized trial addresses this issue by assigning patients to low-, medium-, and high-dose platelet regimens.31 Lastly, if immune-mediated consumption is the cause of thrombocyopenia, transfusion is generally ineffective.

Whole Blood
Whole blood is not as economical as component therapy, although there has recently been renewed interest in the benefits of using fresh whole blood in military field hospitals.16 In the United States it is rarely used.

Autotransfusion
Autotransfusion may be used in the emergency setting in the event of severe chest trauma. This strategy has numerous advantages: immediate availability, blood compatibility, elimination of patient-to-patient disease transmission, avoidance of the storage lesion, less risk of circulatory overload, and fewer direct complications (e.g., hyperkalemia, hypothermia, hypocalcemia, and metabolic acidosis). There is also greater acceptability to some patients whose religious convictions prohibit transfusions.31,33 Widespread use has not occurred, however, because of the limited number of appropriate trauma patients, the training required to operate the equipment, and the time required for equipment setup.34

Packed Red Blood Cells

PRBCs are given to improve oxygen delivery to tissues at the microvascular level. Controversies regarding efficacy were discussed earlier; absent further research, the recommendations of the American Society of Anesthesiologists seem reasonable: transfusion is rarely needed with a Hgb concentration greater than 10g/dL and almost always needed when the Hgb is less than 6g/dL.27 Patients with a Hgb between 6 and 10mg/dL require careful clinical judgment. Ischemic heart disease may render patients more intolerant of anemia, although more research is needed to clarify whether transfusion benefits these patients. Lastly, most emergency physicians would still transfuse a patient with ongoing hemorrhage and unstable vital signs despite adequate fluid resuscitation, and would occasionally consider withholding transfusion for Hgb levels even lower than 6g/dL in a young, healthy, asymptomatic patient without ongoing hemorrhage.

Therapeutic Modalities Packed Red Blood Cells

In acute hemorrhage, PRBCs are used to supplement initial crystalloid replacement. In an average adult, 1U of PRBCs increases the Hgb by about 1g/dL or the hematocrit by about 3%.35 A similar increase in pediatric patients is obtained by administering 3mL/kg. PRBCs are run through a filter with a large-bore intravenous line with normal saline. Lactated Ringers solution can lead to clotting secondary to the added calcium, and hemolysis may result with a hypotonic solution. Medications should not be added to the unit or pushed through the transfusion line unless it has been thoroughly flushed. Most transfusions are given over 60 to 90 minutes (not longer than 4 hours). Unused blood should be returned promptly to the blood bank because any units unrefrigerated for more than 30 minutes are discarded.8

Artificial Oxygen Carriers

Research into both hemoglobin-based oxygen carriers and perfluorocarbon emulsions is ongoing, but as yet none are approved for general clinical use in the United States. Several problems remain unsolved. Hemoglobin-based carriers, for example, have been found to cause vasoconstriction through nitric oxide (NO) scavenging,19 endothelin release, and peripheral alphaadrenergic receptor sensitization. Perfluorocarbon emulsions require relatively high partial pressure of oxygen (Po2) levels. When used clinically, pure oxygen is usually administered to patients.6

Fresh Frozen Plasma

A unit of FFP typically has a volume of 200 to 250mL, is ABO compatible, and is given through blood tubing within 2 to 6 hours of thawing.8 It contains all clotting factors. One unit of activity for any coagulation factor is equal to the clotting activity found in 1 mL of FFP. It should be given in doses calculated to achieve a minimum of 30% of plasma factor concentration, traditionally calculated as 10 to 15mL/kg of FFP. When used for the urgent reversal of warfarin anticoagulation, 5 to 8mL/kg of FFP is considered sufficient.29 Recent research, however, has questioned this,36 and indicates that screening tests such as INR and activated partial thromboplastin time (aPTT) do not correlate well with clinical risk of bleeding, and large amounts of FFP (possibly as high as 30mL/kg) may be needed to raise factor levels adequately to achieve hemostasis.37 The need to correct the INR for invasive procedures such as central line placement has also been questioned.38

Platelets
Crossmatching is unnecessary, but Rh-negative patients should receive Rh-negative platelets because there may be enough cells in the platelet concentrate to cause Rh sensitization. In adults the traditional dose has been 4 to 6U (a six pack of platelets), and in children it is 1U/10kg body weight. As noted earlier, however, consider giving smaller, more frequent transfusions in hospitalized patients. In frequently transfused patients it is often desirable to reduce human leukocyte antigen (HLA) sensitization. The use of leukoreduced, HLAmatched, cellular products decreases the risk of HLA antibody-induced immune destruction.8

OUTCOMES
Adverse effects of RBC transfusion can be divided into immune-mediated and non-immune-mediated categories, as well as acute, delayed, and chronic effects.

Immune-Mediated Adverse Effects Acute

Intravascular Hemolytic Transfusion Reaction. Intravascular hemolytic transfusion reaction is the most serious transfusion reaction. It is usually the result of ABO incompatibility, most often due to error. The resulting antigen-antibody reaction leads to the intravascular destruction of transfused red cells, producing hemoglobinemia and hemoglobinuria. The onset of symptoms is immediate and may include fever, chills, headache, nausea, vomiting, a sensation of chest restriction, severe joint or low back pain, and a burning sensation at the site of the infusion.17,39 Clinical effects can include hypotension, DIC, and acute tubular necrosis. Treatment includes stopping the transfusion immediately, replacing all old tubing with new, and initiating vigorous crystalloid fluid therapy. Diuretic therapy should be used to maintain urine output at 1 to 2mL/kg/hr. Pressor agents may be needed to sustain the blood pressure and protect the kidneys. Blood and urine specimens should be sent to the laboratory, as well as the remainder of the transfusion and the blood tubing. Detecting free Hgb (blood and urine) and a positive Coombs test on post-transfusion, but not pretransfusion specimens confirms the diagnosis.17 Febrile Transfusion Reaction. This is the most common and least serious transfusion reaction and is defined as a 1C temperature elevation associated with transfusion that has no other

medical explanation. Reactions are believed to result from antileukocyte antibodies, most commonly as a result of prior transfusion. Treatment is symptomatic with an analgesicantipyretic and an antihistamine. The use of leukoreduced RBCs can decrease, but not eliminate, the risk of this re action.10,17 If a febrile reaction occurs in a first-time transfusion, it should be treated in the same way as an intravascular hemolytic reaction until proven otherwise. Allergic Reactions (Urticaria to Anaphylaxis). Urticaria, or hives, may occur during a transfusion without other signs or symptoms and with no serious sequelae. It is generally attributed to an allergic, antibody-mediated response to a donors plasma proteins. The transfusion does not need to be stopped, and treatment with an antihistamine is usually sufficient. If the patient has a known history of urticaria, the antihistamine should be administered before the transfusion. Occasionally, full anaphylaxis may be caused by an anti-immunoglobulin A (IgA) reaction to IgA in the donors blood components. The patient is likely to have a genetic IgA deficiency and display hypotension, respiratory and gastrointestinal symptoms, but no fever. Treatment is with epinephrine and corticosteroids. Future transfusions should be with washed RBCs, and plasma products should be from other IgA-deficient individuals.10 Transfusion-Related Acute Lung Injury. TRALI, now considered the leading cause of transfusion-related mortality,40 presents abruptly during, or within 6 hours of, the transfusion of plasmacontaining blood products. These include PRBCs, FFP, platelets, and cryoprecipitate. The initial clinical presentation is that of a noncardiogenic pulmonary edema, with dyspnea, hypoxemia, and bilateral infiltrates on chest radiograph. Fever, hypotension, and transient leukopenia may also be seen. Other causes of acute lung injury should be ruled out. The underlying pathophysiologic mechanism is a subject of continuing debate and could involve multiple insults. Proposed theories include a reaction between transfused antibodies and granulocyctes in the recipient, as well as the effects of biologically active factors that accumulate in stored blood such as cytokines and lipids.41 One strategy suggested for reducing TRALI has been to use only male donors for plasma in order to avoid allotypic leukocyte antibodies which can occur in women as a result of prior pregnancies.42 Appropriate treatment consists of stopping the transfusion, notifying the blood bank, and providing respiratory support, which may include intubation and mechanical ventilation. It is safe to continue transfusion of blood products from a different donor, if necessary.43 Complete resolution is typically seen within 48 to 96 hours. Overall prognosis is better than would be expected with many other causes of acute lung injury, with a reported mortality rate of 6% in one series.44 Survivors rarely show long-term adverse effects.

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Chapter 5 / Blood and Blood Components

Delayed
Extravascular Hemolytic Transfusion Reaction. These result from a nonABO-mediated immune reaction, most often due to an anamnestic response in a patient previously sensitized to red cell antigens by transfusion, pregnancy, or transplant. This prior exposure may result in antibody levels that are too low to detect with the antibody screen. Following repeat exposure from transfusion, however, antibody levels rise, and extravascular hemolysis occurs days to weeks later. Less commonly, primary alloimmunization can occur after transfusion. The patient may have fever, anemia, and jaundice. Symptoms are not usually severe. Rare cases of oliguria or DIC can occur, however. Because the hemolysis is extravascular, hemoglo binemia and hemoglobinuria are typically not present.10 Many

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PART I Fundamental Clinical Concepts / Section One Critical Management Principles

cases are subclinical, but management may require monitoring of hematologic and renal labs, maintenance of urine output, and additional red cell transfusions. Care is needed for subsequent transfusions to provide antigen-negative blood, which can be discussed with the blood bank.45 Transfusion-Associated Graft-Versus-Host Disease. This rare, but lifethreatening, complication results when transfused lymphocytes proliferate and attack the recipient. Cell-mediated immunodeficiency puts the patient at risk, as does having an HLA type that is identical between donor and recipient (most often among first-degree relatives). Symptoms, which begin 3 to 30 days following transfusion, include fever, erythematous skin rash, diarrhea, elevated liver enzymes, and pancytopenia. The only effective treatment is bone marrow transplant, and most deaths result from coagulopathy or infection. Efforts are therefore directed at prevention by using gamma irradiation of all cellular components, which renders the donor lymphocytes incapable of proliferating. The use of leukocytepoor components is also advocated. This condition should be kept in mind when considering transfusion in anemic leukemia or lymphoma, especially in patients who have recently received chemotherapy.10 Consultation with an oncologist prior to transfusion should be strongly considered in these complex cases.

the transfusion, and carries a 60% mortality rate.23 Risk is higher, however, with platelets, which are stored at a higher temperature, and may occur as frequently as 1 per 1000 to 2000U.23 During or after the transfusion, the patient may develop rigors, vomiting, abdominal cramps, fever, shock, renal failure, and DIC. When a septic transfusion reaction is considered, vigorous resuscitative therapy and broadspectrum antibiotics should be started and the transfusion stopped.10 Other Effects. Although infrequent, the following complications can occur secondary to multiple-unit transfusions: hypocalcemia, hyperkalemia and acidosis, hypothermia, microembolization, and coagulopathies. Treatment is specific to the symptom and problem.

Chronic
Risk of Transmission-Transmitted Viruses. Improved techniques for selecting and testing blood donors have dramatically reduced the risk of viral transmission of disease by transfusion. The blood supply in the United States has never been safer.23 Current estimates for the risk of acquiring hepatitis C and HIV from transfusion are approaching 1 in 2 million. The risk of hepatitis B infection, however, remains closer to 1 in 200,000 to 500,000.46 Cytomegalovirus (CMV) can be transmitted by blood transfusion as well. Those at risk include recipients of allogeneic stem cell or solid-organ transplantation, and neonates. CMV-negative blood products should be considered in these patients.18,23 Recently, West Nile virus has emerged as a risk, although one that varies considerably by geography and season (as high as 1233 per million units in one metropolitan area during the epidemic of 2002).23 Transfusion-related infection with West Nile virus, however, has been virtually eliminated by the use of system-wide nucleic acid amplification testing.46 The references for this chapter can be found online by accessing the accompanying Expert Consult website.

Non-Immune-Mediated Adverse Effects Acute

Circulatory Overload. Chronically anemic, normovolemic elderly patients are at greatest risk for developing congestive heart failure with the rapid infusion of blood. Taking 4 hours to infuse a unit and using diuretics (if needed) should prevent this complication.10 Bacterial Contamination. Bacterial contamination, most commonly with Yersinia enterocolitica (which grows well in cool, iron-rich environments), occurs in fewer than 1 per million units of stored RBCs, but typically results in symptoms during