Blood Component Therapies

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151 Blood Component Therapies

James P. Isbister

Blood component therapy has had a central role in the development and practice of numerous medical advances, especially in modern surgery. It is only in more recent years that blood transfusion is no longer regarded as essential for a wide range of medical and surgical conditions. It is now possible for most uncomplicated major surgery to be conducted without allogeneic blood component therapy.1 Blood component transfusion is generally supportive therapy for the correction of one or more hematologic deficiencies until the basic disease process can be controlled or corrected. Appropriate attention to accurate diagnosis of the hematopoietic deficiency and consideration of the range of therapeutic options available and their potential hazards are essential before accepting blood component therapy as indicated.2

Blood component therapy and its immediate endpoints are part of a medical management process. Although appropriate endpoints may be achieved in terms of measurable parameters or immediate clinical response, the clinician needs evidence that these traditional surrogate endpoints are relevant and correlate with a beneficial final clinical outcome for the patient. The human immunodeficiency virus (HIV) crisis shocked clinical medicine into a realization that there were many transfusion practices exposing patients to potential hazards without evidence for identifiable short-term or long-term benefits.

Evidence-based medicine is increasingly influencing the practice of transfusion medicine. In many areas of transfusion medicine, evidence from prospective randomized trials is not available, and the clinician must base therapy on a good understanding of the problem in terms of pathophysiology and indicators of severity. Transfusion medicine decision making can be difficult, and there is ongoing debate regarding the indications for various allogeneic blood components. Unnecessary allogeneic transfusion can be avoided or minimized by giving attention to the clinical time frame, hematologic defect, alternatives, and knowledge about blood components and the potential hazards. There have been considerable advances in minimizing allogeneic transfusion and the development of “transfusion alternatives.” The concept of transfusion alternatives can be challenged as inappropriate, as most of the so-called alternatives are indeed optimal patient management. Emphasis away from the blood component to a focus on the patient’s blood (i.e., patient blood management) is the new paradigm. In managing a patient’s oxygen-carrying capacity, a three-pillar approach—optimizing red cell mass, minimizing blood loss, and tolerating anemia in the short term—results in avoidance of allogeneic transfusion in most uncomplicated elective surgical cases. This can be achieved by identifying patients at high bleeding risk, giving attention to surgical and anesthetic techniques (e.g., controlled hypotension, hypothermia prevention, reduction of venous pressure at operative site), and using pharmacologic agents to minimize blood loss. Autologous methodologies including perioperative hemodilution, blood salvage, fibrin glue, and platelet fibrin gel all may have a part to play.

image Guidelines for Blood Component Therapy

The following is a brief summary of the guidelines for use of commonly available blood components. An evidence-based approach to blood component transfusion has resulted in many long-standing transfusion dogmas being challenged and better guidelines for their use being developed for safe, effective clinical practice. Figure 151-1 illustrates the general approach to the decision to transfuse blood components, with the emphasis on patient blood management and how blood component therapy fits into the bigger picture.1

image

Figure 151-1 Overview of blood management and where blood component therapy may be appropriate.

Red Blood Cell Concentrates

Appropriate and inappropriate use of red blood cell (RBC) transfusions in acute medicine has received considerable attention in recent years; however, identifying the benefits of RBC transfusion in many circumstances has been difficult.2–3 The question of the lowest safe hematocrit continues to receive considerable attention. Pushing any aspect of a system to its limits risks “sailing close to the wind” and may be appropriate in some situations but potentially hazardous in others. In an otherwise stable patient, the transfusion of RBC concentrates is likely to be inappropriate when the hemoglobin level is above 100 g/L. Their use may be appropriate when hemoglobin is in the range 70 to 100 g/L if there are other defects in the oxygen transport system. The decision to transfuse should be supported by the need to relieve clinical signs and symptoms of impaired oxygen transport and to prevent morbidity and mortality, ultimately to improve clinical outcomes. The transfusion of RBC concentrates is likely to be appropriate when hemoglobin is less than 70 g/L and the anemia is not reversible with specific therapy in the short term, but lower levels may be acceptable in patients who are asymptomatic, especially in the younger age group.

Platelet Concentrates

Platelet transfusions may benefit patients with platelet deficiency or dysfunction, and there are some general recommendations for their use.4 Prophylactic transfusion of platelet concentrates is indicated in patients with bone marrow failure when the platelet count is (1) less than 10 × 109/L and there are no associated risk factors for bleeding or (2) less than 20 × 109/L in the presence of additional risk factors. However, recent evidence suggests lower levels may be tolerated if there is no clinical evidence of hemostatic failure.

In patients undergoing surgery or invasive procedures, the platelet count should be maintained at greater than 50 × 109/L. In patients with qualitative defects in platelet function, platelet count is not a reliable indicator for transfusion, and transfusion decisions and monitoring of efficacy should be based on the setting and clinical features.

Platelet transfusions are indicated in hemorrhaging patients in whom thrombocytopenia is secondary to marrow failure and is considered a contributory factor to the bleeding. In massively hemorrhaging patients, platelet transfusions in conjunction with correcting plasma coagulation factor deficits are indicated when the platelet count is less than 50 × 109/L or less than 100 × 109/L in the presence of diffuse microvascular bleeding. The transfusion of platelet concentrates is not generally considered appropriate when thrombocytopenia is due to immune-mediated destruction, in patients with thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, or in uncomplicated cardiac bypass surgery.

Fresh Frozen Plasma and Cryoprecipitate

Fresh frozen plasma is widely used, but there are limited specific indications for its use, and there is a dearth of evidence for efficacy in many clinical settings.5–6 The use of fresh frozen plasma may be appropriate in patients with a coagulopathy who are bleeding or at risk for bleeding when a specific therapy or factor concentrates are not appropriate or unavailable. Fresh frozen plasma generally is indicated in hemorrhaging patients for replacement of labile plasma coagulation factors (e.g., massive transfusion, cardiac bypass, liver disease, or acute disseminated intravascular coagulation [DIC]). Fresh frozen plasma is rarely indicated in vitamin K deficiency or reversal of warfarin therapy, because concentrates are now generally available.7 The use of fresh frozen plasma generally is not considered appropriate in cases of hypovolemia, in plasma exchange procedures (unless postexchange invasive procedures are planned), or in treatment of immunodeficiency states.

Compatibility tests before transfusion are not necessary, but plasma should be ABO group compatible with the patient’s RBCs, and volume transfused depends on the clinical situation and patient size. As a guide, initial dosing of 10 to 15 mL/kg is recommended, and efficacy should be monitored by laboratory tests of coagulation function.

Cryoprecipitate is prepared by thawing fresh frozen plasma between 1°C and 6°C and recovering the precipitate, which is refrozen. The component contains factor VIII, fibrinogen, factor XIII, von Willebrand factor, and fibronectin and is principally indicated for fibrinogen deficiency or dysfibrinogenemia when there is clinical bleeding, invasive procedures, trauma, or acute DIC. The role for cryoprecipitate will diminish as fibrinogen concentrates become increasingly used for hypofibrinogenemic states. Cryoprecipitate should not be used for the treatment of hemophilia or von Willebrand disease unless factor concentrates are unavailable.

Plasma-Derived Products

A wide range of highly purified plasma-derived blood products is available for use in numerous clinical conditions. It is beyond the scope of this chapter to discuss their use in detail; Table 151-1 summarizes commonly used fresh and plasma-derived blood products. Fibrinogen concentrate instead of cryoprecipitate is having an increasing role in the management of hypofibrinogenemic states, depending on local availability.

TABLE 151-1 Blood Products

Blood Product Main Indications
Whole blood* Rarely indicated in acute hemorrhage if other blood products are unavailable
Red blood cell concentrates* Hemorrhage and anemia
Leukocyte-depleted blood* In patients having febrile reactions, to avoid leukocyte immunization in selected patients (especially patients with hematologic malignancy). Universal prestorage leukodepletion is more widely used and has the added benefit of minimizing storage lesions.
Platelet concentrates* Thrombocytopenia due to marrow hypoplasia or platelet functional defect
Granulocyte concentrates* Occasionally in patients with sepsis associated with profound and prolonged neutropenia secondary to marrow suppression
Fresh frozen plasma* Specific or multiple plasma protein deficiencies (especially coagulation)
Cryoprecipitate* Hypofibrinogenemia and rarely in factor VIII and von Willebrand disease, when concentrates are unavailable
4% or 5% albumin solutions† Plasma volume expansion. Use is controversial, and the role of albumin solutions in critically ill patients remains under deliberation.30
Concentrated albumin† Severe hypoalbuminemic states with complicating hypovolemia
Concentrate of coagulation factors II, VII, IX, and X† Vitamin K–dependent factor II, IX, and X deficiency and reversal of oral vitamin K antagonists31
Specific factor concentrates† Factor VIII and IX concentrates have an established role in management of hemophilia, but others are in the process of establishing their clinical efficacy and indications.
Fibrinogen concentrates for hypofibrinogenemia and dysfibrinogenemia32
Antithrombin concentrates are available for thrombophilia due to antithrombin deficiency and are increasingly recommended in other disorders in which antithrombin may be depleted (e.g., DIC, MODS).31
Gamma globulin† Generally used intravenously for replacement in hypogammaglobulinemia or in high dosage in autoimmune disorders33
Specific immune gamma globulins† Rhesus prophylaxis, specific infection prophylaxis (e.g., tetanus, zoster, hepatitis B)

DIC, disseminated intravascular coagulation; MODS, multiorgan dysfunction syndrome.

* Fresh products.

† Fractionated plasma products.

Recombinant Blood Products

Development and introduction of recombinant blood components continues to be one of the most exciting advances in transfusion medicine. Recombinant growth factors (cytokines) such as erythropoietin and granulocyte stimulating factors have had a major impact on managing anemia and neutropenia. There are further promising recombinant cytokines in development that could have a role in countless clinical conditions, especially as antiinflammatory and tissue-protecting agents. Recombinant hemostatic factors have improved the management of hemophilia, and recent expansion of clinical indications for the use of recombinant activated factor VII (factor VIIa)—beyond treating hemophiliac patients with coagulation factor inhibitors—is having an impact on management of a range of hemostatic disorders.8 Because factor VIIa is dependent on tissue factor, which is usually available in limited quantities within the circulation, its clinical use is generally regarded safe from a thrombosis-inducing point of view, and its use is now being recommended as a “panhemostatic agent.” Factor VIIa initiates the extrinsic coagulation pathway only when complexed to tissue factor at sites of injury. It may have a role in a wide range of hemostatic disorders (e.g., massive blood transfusion, liver disease, uremia, severe thrombocytopenia, and platelet disorders). It has been difficult to establish a sound evidence base outside the hemophilia setting for the use of rVIIa, with most experience being observational and anecdotal. Randomized controlled trial results have shown a significant reduction in transfusion requirements but could not demonstrate a reduction in mortality. There is also an increased risk of thromboembolism.

Blood Substitutes

Efforts have been ongoing for many years to develop substitutes for RBCs and platelets, but results have been disappointing, and safety concerns have plagued clinical development. The development of substitutes for cellular blood components has also been slow, and as their introduction into clinical medicine remains in the research phase, the reader is referred to reviews for further information.

image Transfusion Management of Massive Acute Hemorrhage

In recent years there has been a reappraisal of guidelines for the use of blood components in acutely hemorrhaging patients. Guidelines are more focused on managing critical bleeding and avoiding the massive transfusion coagulopathy quagmire in which a patient spirals down into the “triad of death”: coagulopathy, acidosis, and hypothermia. Advances in patient retrieval, resuscitation protocols, techniques for rapid and real-time diagnosis, trauma teams, and early “damage-control” surgery have improved the management of acutely hemorrhaging patients. There is also greater attention and research being directed toward the nature of clear fluids and the importance of plasma viscosity, colloid oncotic pressure, and functional capillary density. Patients are now surviving increasingly larger volumes of blood transfusion, but sepsis, acute lung injury, and multiorgan failure remain challenges. Immediate lifesaving blood transfusion is increasingly being recognized as an independent risk factor for delayed morbidity and mortality.

Transfusion can be minimized with tolerance of hypotension until hemorrhage is controlled and acceptance of lower hemoglobin levels. The immediate posttransfusion function of stored red cells and hemoglobin in delivering oxygen to microcirculation and in oxygen unloading is also being questioned, with the storage age of RBCs possibly being associated with poorer clinical outcomes.9 Recent animal data point to the immediate clinical benefit of transfused red cells in treating hypovolemic shock relating more to reconstitution of the macrocirculation, with potentially adverse effects on the functional capillary density in the microcirculation.

A protocol approach to blood component therapy has generally not been recommended. However, this remains a controversial issue, with advocates for up-front protocol component therapy with red cell and hemostatic components, especially fresh frozen plasma with or without cryoprecipitate. With better understanding of coagulopathy in the critical hemorrhage setting and the importance of hypofibrinogenemia and hyperfibrinolysis, there is a reanalysis of the approach to blood component therapy. Failure of hemostasis is common in acutely bleeding patients and may be complex and multifactorial. Accumulating evidence supports the view that the pathophysiology of coagulopathy, when occurring in the context of critical hemorrhage, should be viewed as related to the primary insult or initiating event. A secondary coagulopathy may compound the problem in the resuscitated patient, such as massive stored blood transfusion, hemodilution, hypothermia, and continuing tissue hypoxia.10–11 The primary mechanisms of coagulopathy relating to the initiating event may relate to trauma, hypoxia, pregnancy, sepsis, envenomation, or antithrombotic agents.12–13 In all circumstances there is activation or inhibition of some aspect of the hemostatic system, and therapy is better informed if these varied mechanisms are better understood. Frequently, complex tests are required for definitive diagnosis, but the urgency of the situation cannot always wait for the results, and therapy may be initiated on clinical evidence with minimal laboratory information.

Many trauma patients have coagulopathy at presentation related to hypovolemic shock and not consumption or dilution. Recent evidence indicates that activation of the protein C system and hypofibrinogenemia due to secondary hyperfibrinolysis are important.14 Except when severe clotting test abnormalities are present, hemostatic laboratory parameters correlate poorly with clinical evidence of hemostatic failure. In the massively transfused patient, thrombocytopenia and impaired platelet function are the most consistent significant hematologic abnormalities, correction of which may be associated with control of microvascular bleeding. A problem with standard screening tests of coagulation function is they do not provide information about the formation of the hemostatic plug, its size, structure, or stability. Global tests of hemostatic plug formation and stability such as thromboelastography, thrombin generation tests, and clot waveform analysis in which changes in light transmission in routine activated partial thromboplastin time (APTT) are measured are of increasing use. With ongoing bleeding with associated microvascular oozing, various approaches may be taken. Having ensured that all identifiable hemostatic defects have been corrected, questions then arise as to the role of fresh blood and, more recently, recombinant activated factor VII.

image Hazards of Allogeneic Transfusion

It cannot be overemphasized that allogeneic blood transfusion is a tissue transplant that is probably associated with the greatest range of potential hazards of any medical intervention and should only be used in circumstances in which there is good evidence that clinical outcomes will be improved.15–16

The pathophysiology of transfusion reactions can be divided broadly into three categories:

1 Reactions may occur due to immunologic differences between the donor and recipient, resulting in varying degrees of blood component incompatibility. In general, for a reaction to occur, the recipient needs to have been previously immunized to a cellular or plasma antigen.17
2 A wide range of infectious agents may be transmitted by allogeneic blood component therapy.
3 Alterations in blood products due to preservation and storage may result in quantitative or qualitative deficiencies in the blood components that reduce transfusion efficacy and expose the patient to potentially adverse consequences from substances that accumulated during storage (Table 151-2).

TABLE 151-2 Red Blood Cell Storage Lesions and Possible Clinical Consequences

Storage Lesion Potential Clinical Consequences
Alterations in red blood cell structure and function:
ATP depletion Echinospherocyte formation, increased osmotic fragility, impaired RBC deformability with adverse effects on oxygen transport and delivery
Microvesiculation and loss of membrane lipid, lipid peroxidation and hemolysis, and irreversible damaged RBCs Reduced RBC viability and cell death
Hyperbilirubinemia, LDH, increased serum iron, free radical generation (?), hyperkalemia
Reduced 2,3-DPG Increased hemoglobin affinity for oxygen and impaired unloading
Decreased CD47 antigen (integrin-associated protein) expression Reduced posttransfusion survival due to premature clearance post transfusion
RBC adhesion to endothelial cells Adverse effects on microcirculatory hemodynamics
Storage temperature Hypothermia unless pretransfusion warming
Additives:
Citrate Hypocalcemia, acid-base imbalance, initial acidosis alkalosis
Glucose Hyperglycemia
Sodium Hypernatremia
Cytokines: IL-1, IL-6, IL-8, TNF Fever, hypotension, flushing
Enzymes: myeloperoxidase, elastase, arginase, secretory phospholipase A2 Transfusion-related immunomodulation, neutrophilia
Reactive proteins: defensins, annexin, soluble HLA, Fas ligand, soluble endothelial cell growth factor, and others Proinflammatory, potential “priming” for ARDS, TRALI, and MODS
Histamine and kinin accumulation Hypotension, anxiety, flushing, pain syndromes, proinflammatory
Microaggregates and procoagulants Blockade of reticuloendothelial system
Risk factor for development of ARDS, MODS, TRALI
Activation of hemostasis > DIC (?), VTE (?), arterial thrombotic events (?)

ARDS, acute respiratory distress syndrome; ATP, adenosine triphosphate; DIC, disseminated intravascular coagulation; 2,3-DPG, 2,3-diphosphoglycerate; HLA, human leukocyte antigen; IL, interleukin; LDH, lactate dehydrogenase; MODS, multiorgan dysfunction syndrome; RBC, red blood cell; TNF, tumor necrosis factor; TRALI, transfusion-related acute lung injury; VTE, venous thromboembolism.

In terms of causation of an adverse clinical event, the possible role of transfusion can be classified broadly into three categories on the basis of probability (Figure 151-2):

1 Definite—unifactorial. The well-understood and well-reported hazards of transfusion (i.e., immunologic, technical, infectious) are generally unifactorial, with a 1 : 1 well-understood deterministic causal relationship between the blood component transfused (usually a specific individual unit) and the adverse consequence for the patient. ABO blood group incompatibility, transfusion-related infection transmission, transfusion-associated graft-versus-host disease, and transfusion-related lung injury due to donor leukoagglutinins are examples in this category.
2 Probable—oligofactorial. Some adverse consequences of transfusion result from interaction with other insults, pathophysiology, or host factors, but the contribution of the transfusion usually can be specifically identified in a deterministic manner. Fever, allergic reactions, hypotensive reactions, pulmonary edema, some cases of transfusion-related lung injury, hyperbilirubinemia, and cytomegalovirus transmission are examples of this category.
3 Possible—multifactorial. Transfusion may contribute to a complication or poor clinical outcome. In these circumstances, a causal implication for transfusion is probabilistic (i.e., a risk factor), and it is not necessarily the major factor. Transfusion-induced immunomodulation and the clinical consequences of storage lesions fall into this category. The role of transfusion contributing to adverse clinical outcomes can only be identified from observational studies using powerful multifactorial statistical analysis, although some supportive evidence is available from a limited number of randomized controlled clinical trials.17 Potential adverse clinical consequences of the storage lesions fall into this group, with product preparation method, dosage, and age of blood component being relevant.9 Prevention of complications from the storage lesion and immunomodulation focus on the quality of preservation and minimizing transfusion rather than elimination of the risk, as is the case with ABO incompatibility or HIV.
image

Figure 151-2 Hazards of allogeneic blood transfusion. ARDS, acute respiratory distress syndrome; CMV, cytomegalovirus; GVHD, graft-versus-host disease; HIV, human immunodeficiency virus; MODS, multiorgan dysfunction syndrome; TRALI, transfusion-related acute lung injury; TRIM, transfusion-related immunomodulation.

Hemolytic Transfusion Reactions

Most severe acute hemolytic transfusion reactions usually have an identifiable and avoidable cause and result from an error at some point along the compatibility chain, most commonly incorrect patient identification. ABO incompatibility is the most common potentially fatal complication of blood transfusion, and meticulous attention to patient and sample identification is crucial. Various strategies are advocated to eliminate the possibility of ABO incompatibility, including bar coding, vein-to-vein patient identification, bedside compatibility testing, and double patient sample collection. All of these strategies have problems, however, and the human factor remains important.

Most delayed hemolytic reactions are also immune in nature and usually cannot be prevented because the blood is serologically compatible at the time of transfusion. The clinician should always be on the outlook for the possibility of hemolytic episodes in critically ill patients, however, because these are commonly due to reactions to blood transfusion or medications.

Clinical features of hemolytic transfusion reactions are as follows:

• Initial symptoms and signs: classic symptoms and signs of an acute hemolytic transfusion reaction include apprehension, flushing, pain (e.g., infusion site, headache, chest, lumbosacral, and abdominal), nausea, vomiting, rigors, hypotension, and circulatory collapse. In unconscious or anesthetized patients, these symptoms are unlikely to be noted.
• Hemostatic failure: coagulopathy due to DIC may be a feature, resulting in generalized hemostatic failure with hemorrhage and oozing from multiple sites. Because the responsible transfusion is likely to have been administered for hemorrhage, increasing severity of local bleeding may be the first clue to an incompatible transfusion, especially if the patient is under anesthesia.
• Oliguria and renal impairment: renal failure may complicate a hemolytic transfusion reaction, and early recognition and prevention are crucial. If circulating volume and urinary output are rapidly restored, established renal failure is unlikely to develop. Death from acute renal failure directly caused by an incompatible blood transfusion is preventable. It is likely to occur only if expeditious action is not taken or there are complicating clinical problems.
• Anemia and jaundice: a severe hemolytic transfusion reaction may be suspected from the development of jaundice or anemia.

Allergic and Anaphylactoid Reactions

Noncellular blood (plasma and plasma derivatives) components rarely are considered to be a major cause for adverse reactions to transfusion therapy, but considering the complexity of plasma and component preparation processes, a broad range of potential adverse effects is possible.18 Plasma reactions may be related to immunologic differences between the donor and the recipient; either the component is antigenic to the recipient or the plasma contains an antibody reacting with a recipient antigen. There may be physicochemical characteristics of the plasma component such as temperature, additives, alterations due to preparative processes, and accumulation of metabolites or cellular release products on storage. Clinical severity may range from minor urticarial reactions or flushing to fulminant cardiorespiratory collapse and death. Many such reactions are probably true anaphylaxis, but in others, mechanisms have been less clear, and the term anaphylactoid has been used.

Immunologic reactions to normal components of plasma may occur in two ways. First, plasma proteins may contain epitopes different from those on the recipient’s functionally identical plasma proteins (e.g., anti-immunoglobulin A [IgA] antibodies). Second, there may be antibodies in the donor plasma that react with cellular components of the recipient’s blood cells or plasma proteins (e.g., transfusion-related lung injury).

Various contaminants in donor plasma or plasma components related to the fractionation process may be implicated in some reactions. Processing of plasma and its freezing may lead to activation of some of the proteolytic systems. Of particular importance in this respect are the complement and kinin/kininogen systems. If these systems are activated, there may be generation of vasoactive substances and anaphylotoxins. Subjective sensations (that may be missed in an unconscious patient) and hypotension occurring during rapid infusion of a hypovolemic patient may be misinterpreted as further volume loss. Histamine levels may be increased in stored blood components, and histamine levels may correlate with nonfebrile, nonhemolytic transfusion reactions.

Transfusion-Related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) is a potentially severe complication of blood transfusion, characterized by acute respiratory distress arising within hours of a transfusion. Most patients who are well resuscitated improve within 48 hours and usually make a full recovery. The pathophysiology of TRALI is classically due to the presence of leukoagglutinating or human leukocyte antigen (HLA)-specific antibodies in the plasma of the donor of the implicated components. When complement is activated, C5a promotes neutrophil aggregation and sequestration in the lung microvasculature, causing endothelial damage. The concept of TRALI has been expanded to embrace a broader spectrum of acute lung injury after transfusion to include cases of posttransfusion lung injury in which other mechanisms may be responsible (e.g., anaphylactic reactions, cytokine reactions, platelet reactions, granulocyte transfusions, blood storage lesion).18 The patient’s lungs may be “primed” by other pathologic factors such as shock and sepsis, and transfusion becomes an additional risk factor.19

Posttransfusion Purpura

Posttransfusion purpura is a potentially life-threatening complication of transfusion in which platelet-specific alloantibodies develop at 5 to 10 days, with the patient developing severe thrombocytopenia. Paradoxically, in contrast to other immunologically mediated transfusion reactions, the patient’s own platelets are destroyed during the immunologic reaction. Early recognition of this rare complication, which typically occurs in women, is essential to minimize morbidity and mortality. Platelet transfusions are usually ineffective even if crossmatch compatible, and high-dose intravenous immunoglobulin (2 g/kg given over 2-5 days) is the recommended treatment.

Transfusion-Associated Graft-Versus-Host Disease

Transfusion-associated graft-versus-host disease is due to infusion of immunocompetent lymphocytes, precipitating an immunologic reaction against the host tissues. It is most commonly observed in immunocompromised patients but also may be seen in recipients of directed blood donation from first-degree relatives. This response is also occasionally seen when donor and recipient are not related; homozygosity for HLA haplotypes for which the recipient is heterozygous is responsible. Transfusion-associated graft-versus-host disease is generally a devastating and fatal condition, with onset of the syndrome 2 to 4 weeks after allogeneic transfusion. Presenting signs and symptoms are fever, liver function test abnormalities, profuse watery diarrhea, erythematous skin rash, and progressive marrow failure.20

Transfusion-Related Immunomodulation

Transfusion-related immunomodulation (TRIM) is an evolving and complex area of research and new knowledge.21 Leukocytes seem to be the main blood component responsible for the immunomodulatory effects of transfusion. Space does not permit detailed analysis; however, it is likely that prestorage leukodepletion minimizes the effects. Allogeneic transfusion has been shown to be an independent risk factor for postoperative infection, with many infections being distant from the wound site, suggesting a systemic reduction in host resistance. Immunomodulation also may be responsible for increased cancer recurrence rates after surgery, but this remains controversial. The possible role of TRIM in the association between allogeneic blood transfusion and poorer clinical outcomes is discussed later.

Fever

The term nonhemolytic febrile transfusion reaction defines an acute complication of blood transfusion characterized by fever with or without chills and rigors. These reactions are generally not life threatening, but they cause discomfort, involve the use of medications, and employ resources of medical, nursing, and laboratory personnel. The effects of rigors and pyrexia in critically ill patients are concerning, and temperatures above 38°C should not be ignored. Most febrile reactions are due to immunologic reactions against one or more of the transfused cellular or plasma components, usually leukocytes. The use of leukocyte-depleted blood products minimizes the likelihood of nonhemolytic febrile transfusion reaction.

Transfusion-Transmitted Infections

Transfusion-related infections have received much attention, and their recognition has been a driving force behind many changed blood donation and processing policies. The reader is referred to recent reviews of transfusion-transmitted infections.16,21–23

Bacterial Contamination

Bacterial contamination of stored blood can cause fulminant endotoxic shock. In recent years, the storage of platelets at room temperature has made this blood component particularly susceptible to bacterial contamination.24 The clinical features of transfusion-related endotoxic shock in a nonanesthetized patient include violent chills, fever, tachycardia, and vascular collapse with prominent nausea, vomiting, and diarrhea. Anesthetized patients may have delayed onset of symptoms, and in patients who are already febrile and on antibiotics, diagnosis can be elusive or missed.

Blood Storage Lesions and Potential Clinical Consequences

Blood is altered from the moment of its initial collection and subsequent storage. Physical and biochemical characteristics may be of particular importance when large volumes are infused rapidly. Warming of all rapid blood transfusions should minimize the possibility of hypothermia. Patients receiving massive blood component therapy are likely to be seriously ill and have multiple problems. Potential adverse effects must be considered in conjunction with the injuries and multiorgan dysfunction. It is not always possible to define complications caused or aggravated by massive blood transfusion.

The storage lesions progressively increase until the time of expiry, and the extent of these changes is determined by the specific blood component, preservative medium, container, storage time, and storage conditions.25 Storage results in quantitative or qualitative deficiencies (or both) in blood components, which may reduce the efficacy of a transfusion. Quantitative deficiencies may result in reduced RBC survival, failure to achieve anticipated endpoints, and excessive donor exposure, increasing immunization and infection risks. Qualitative deficiency includes decreased membrane flexibility and increased adhesion to endothelium, which may impair microcirculatory hemodynamics. Reduced 2,3-diphospho-glycerate decreases hemoglobin oxygen affinity, impairing oxygen unloading.

In parallel with these storage changes is an accumulation of degenerate material (e.g., microaggregates and procoagulant material), release of vasoactive agents, cytokine generation, and hemolysis (Figure 151-3). Many of the changes occurring during storage are related to the presence of leukocytes (especially granulocytes) and can be minimized by prestorage leukoreduction. The clinical significance of storage lesions continues to be debated. In some cases, the effects are widely accepted; in others, further studies are needed. There is evidence that the storage lesion is clinically significant in several respects.26 Transfusion may result in significant increases in unconjugated bilirubin and lactic dehydrogenase, neutrophilia, and saturation of serum iron. The transfusion of biologically active lipids in stored blood may be associated with development of acute lung injury in patients with predisposing conditions. Blood transfusion has been shown to be an independent risk factor for development of postinjury multiorgan failure and acute respiratory distress syndrome, and this relationship may be stronger with the age of the transfused blood. There is an increased rate of infection associated with transfusion of old blood after severe injury, suggesting that transfusion-related immunomodulation may not be related only to allogeneic transfusion but contributed to by the storage lesion. In some studies, transfusion of stored blood older than 15 days in trauma patients was a predictor of a greater likelihood of admission to the intensive care unit (ICU) and predicted a prolonged length of ICU stay. Further information about the storage lesion and the possible clinical implications is summarized in Table 151-2.

image

Figure 151-3 Red blood cell storage lesions. ARDS, acute respiratory distress syndrome; GIT, gastrointestinal tract; LDH, lactate dehydrogenase; MOF, multiple organ failure; RES, reticuloendothelial system; TRALI, transfusion-related acute lung injury.

The commonly recognized potential hazards of rapid blood transfusion are as follows:

• Citrate toxicity: a patient responds to citrate infusion by the removal of citrate and mobilization of ionized calcium. Citrate is metabolized by the Krebs cycle in nucleated cells, especially the liver. A marked elevation in citrate concentration is seen with transfusions of greater than 500 mL in 5 minutes; the citrate level rapidly falls when infusion is slowed. Citrate metabolism is impaired by hypotension, hypovolemia, hypothermia, and liver disease, and toxicity may be potentiated by alkalosis, hyperkalemia, hypothermia, and cardiac disease. There are many potential consequences of citrate-induced depression of ionized calcium, but a warm, well-perfused adult patient with normal liver function can tolerate a unit of blood every 5 minutes without requiring calcium replacement.
• Acid-base and electrolyte changes: transfusion of stored blood presents a patient with an appreciable acid load, which may be of particular importance if there is a preexisting metabolic acidosis. The acidity of stored blood is mainly due to the citric acid of the anticoagulant and the lactic acid generated during storage. Their intermediary metabolites are metabolized rapidly with adequate tissue perfusion, and citrate is metabolized into bicarbonate, ultimately resulting in metabolic alkalosis. Routine use of sodium bicarbonate is unnecessary, and acid-base abnormalities should be corrected only in the context of the clinical situation. The acid-base status of the recipient is more important and predominantly dependent on tissue perfusion. Although controversial, it is unlikely that the high serum potassium levels in stored blood have pathologic effects in adults, except in the presence of acute renal failure. In contrast, hypokalemia may be a problem 24 hours after massive transfusion as the transfused cells correct their electrolyte composition and potassium returns into the cells. The sodium content of whole blood and fresh frozen plasma is higher than normal blood levels, owing to sodium citrate. This fact should be taken into account when large volumes of plasma are being infused into patients who have disordered salt and water handling (e.g., renal, liver, or cardiac disease).

Hyperbilirubinemia

Hyperbilirubinemia is common after massive blood transfusion, because a significant proportion of RBCs transfused (30% if aged blood is used) may not survive, and the resulting bilirubin load causes varying degrees of hyperbilirubinemia. If the patient has been hypovolemic and shocked, biliary transport functions may be impaired, particularly in the presence of sepsis or multiorgan dysfunction. An important rate-limiting step in bilirubin transport is the energy-requiring process of transporting conjugated bilirubin from the hepatocyte to the biliary canaliculus. Bilirubin from destroyed transfused RBCs may be conjugated, but delayed excretion may lead to conjugated hyperbilirubinemia. A hemolytic transfusion reaction and resorbing hematoma also have to be considered as possible causes of hyperbilirubinemia.

Allogeneic Transfusion as An Independent Risk Factor for Poorer Clinical Outcomes

In recent years, experimental and clinical studies have identified blood transfusion as an independent risk factor for morbidity and mortality as well as increased admission rates to ICUs, increased length of hospital stay, and additional costs. The implication of RBC transfusion as part of the problem rather than optimal therapy has challenged long-held views about the safety of allogeneic blood transfusion. It has always been assumed that blood transfusion can only be of benefit to the bleeding or anemic patient, with immunologic and infection transfusion hazards well understood and minimized. There is thus increasing evidence that TRIM and the transfusion effects of storage lesions may be responsible for poorer clinical outcomes in a range of clinical settings.27–28 There is also an association of transfusion with a higher incidence of venous thromboembolism.29 The case for this association between blood transfusion and poorer outcomes is strengthening, and evidence for the efficacy of many transfusions is being reassessed, as are studies supporting restrictive red cell transfusion policies as not jeopardizing clinical outcomes. Until these concerns are resolved, a precautionary approach should be adopted, with avoidance or minimization of allogeneic transfusion and the use of appropriate patient blood conservation techniques whenever possible.

image Basic Immunohematology

RBC serology is a highly specialized area of knowledge, and it is not possible to expect clinicians to have more than a basic working knowledge essential for patient safety. This section summarizes core knowledge for the clinician.

Saline Agglutination

Safe RBC transfusion has revolved around the traditional serologic technique of saline agglutination. A saline suspension of RBCs is mixed with serum and observed for agglutination. Saline agglutination is used for ABO blood grouping and is one of the techniques for compatibility testing of donor blood.

Direct and Indirect Antiglobulin Test

In RBC serology, the antiglobulin test (Coombs test) is used to detect IgG immunoglobulins or complement components. The direct antiglobulin test (DAT) detects immunoglobulin or complement components present on the surface of the RBCs circulating in the patient. The result is positive in autoimmune hemolytic anemia and hemolytic disease of the newborn and during a hemolytic transfusion reaction. The indirect antiglobulin test (IAT) detects the presence of nonagglutinating antibodies in the patient’s plasma, usually IgG type. Antibody screening for atypical antibodies and pretransfusion compatibility testing are the main applications of the IAT.

Regular and Irregular (Atypical) Antibodies

The regular alloantibodies (isoagglutinins) of the ABO system are naturally occurring agglutinins present in all ABO types (except AB), depending on the ABO group. Group O people have anti-A and anti-B isoagglutinins, group A people have anti-B, and group B people have anti-A. Group A cells cause the most common and most dangerous ABO-incompatible hemolytic reactions. Atypical antibodies are not normally present in the plasma but may be found in some people as naturally occurring antibodies or immune antibodies. Immune antibodies result from previous exposure due to blood transfusion or pregnancy. Naturally occurring antibodies more frequently react by saline agglutination, and although they may be stimulated by transfusion, they usually are of minimal clinical significance. In contrast, many of the immune atypical antibodies are of major clinical significance, and their recognition is the raison d’être for pretransfusion compatibility testing and antenatal antibody screening. Most clinically significant immune atypical antibodies are detected by the IAT. Blood group antigens vary widely in frequency and immunogenicity The D antigen of the Rhesus (Rh) blood group system is common and highly immunogenic. When an Rh-negative (i.e., D-negative) patient is exposed to D-positive blood, there is a high likelihood of forming an anti-D antibody. For this reason, the D antigen is taken into account when providing blood for transfusion, in contrast to the numerous other RBC antigens that are less common or less immunogenic. Beyond the Rh (D), and sometimes the Kell (K) blood group antigens, it is not practical or necessary to take notice of other blood group antigens unless an atypical antibody is detected during antibody screening procedures.

Antibody Screen

On receipt of a blood sample by the transfusion service, the RBCs are ABO and Rh D typed, and the serum is screened for atypical antibodies. This screen consists of testing the patient’s serum with group O screening cells. The screening panel consists of RBCs obtained usually from two group O donors containing all common RBC antigens occurring with a frequency of greater than approximately 2% in the community. If an atypical antibody is detected on the antibody screen, further serologic investigations are done to identify the specificity of the antibody. These investigations are time consuming and when possible should be carried out electively.

Crossmatch (Compatibility Test)

The crossmatch is the final compatibility test between the donor cells and the patient’s serum. The crossmatch test tends to be overemphasized to the detriment of the antibody screen. With sophisticated knowledge of serology, the emphasis in the supply of compatible blood is now concentrated on the steps before the final compatibility crossmatch.

Type and Screen System

As precompatibility testing has assumed the major role in the selection of blood for transfusion, there has been a rethinking of policies relating to the supply of blood for elective transfusions. Whenever elective surgery is planned for a patient who is likely to require blood transfusion, the transfusion service must receive a clotted blood sample well before the anticipated time of surgery. Precompatibility testing should be carried out during routine working hours when facilities are geared for large workloads and enough staff are available to handle all contingencies.

Provision of Blood in Emergencies

When quick clinical and laboratory decisions are made under conditions of stress, it is frequently difficult for all involved personnel to appreciate the difficulties of others. The decision to give uncrossmatched or partially crossmatched blood or to wait for crossmatch-compatible blood is not easy, and certain basic serologic considerations may clarify for the clinician some of the problems faced by the serologist. Depending on the degree of urgency and extent of previous knowledge about the patient’s RBC serology, blood can be provided with varying degrees of safety. When a patient is exsanguinating and likely to die, however, giving ABO-compatible, uncrossmatched blood, especially if the antibody screen is negative, is safe and appropriate therapy.

Universal Donor Group O Blood

Group O blood under normal circumstances is ABO compatible with all recipients. The transfusions should be given as RBC concentrates screened for high-titer A or B hemolysins and used only in extreme emergencies. If the recipient is of childbearing age, every attempt should be made to give Rh D-negative blood until the patient’s blood group is known.

Abo Group-Specific Blood

Transfusion of blood of the correct ABO type circumvents the isoagglutinin problems alluded to earlier. Simple as this approach may seem, its safety depends on meticulous attention to grouping. Previous blood group information such as a “bracelet” group or “unofficial” group written in the patient’s records may be incorrect, and there may be considerable risk if blood is administered on the basis of this information alone.

Saline-Compatible Blood

Administration of saline-compatible blood is, for practical purposes, administration of ABO group-specific blood.

Key Points

1 An evidence-based approach to blood component transfusion has resulted in many long-standing transfusion dogmas assuming clinical efficacy of the labile allogeneic blood components (red cell, platelets, and fresh frozen plasma) in improving clinical outcomes.
2 The decision to transfuse red blood cell concentrates should be supported by the need to relieve clinical signs and symptoms of impaired oxygen transport and to prevent morbidity and mortality, with the aim of improving clinical outcomes.
3 Allogeneic blood transfusion may be an independent risk factor for adverse clinical outcomes.
4 The development of clinical practice guidelines for the use of blood components should focus on patient blood management, and transfusion of allogeneic blood should no longer be the default decision in the context of clinical uncertainty.
5 The classic symptoms and signs of an acute hemolytic transfusion reaction include apprehension, flushing, pain (e.g., infusion site, headache, chest, lumbosacral, abdominal), nausea, vomiting, rigors, hypotension, and circulatory collapse.
6 A clinician needs a basic working knowledge of red blood cell serology to ensure patient safety.

Annotated References

Isbister JP. Decision making in perioperative transfusion. Transfus Apher Sci. 2002;27:19-28.

This paper reviews in detail the transfusion decision-making process, overviewing all the interacting factors meriting consideration when assessing the need for transfusion of blood components.

Thomson A, Farmer S, Hofmann A, Isbister J, Shander A. Patient blood management—a new paradigm for transfusion medicine? Vox Sang ISBT Science Series. 2009;4:423-435.

This article reviews patient blood management, describing the evolution of transfusion medicine from a product focus to a problem-based patient focus.

Ganter MT, Pittet JF. New insights into acute coagulopathy in trauma patients. Best Pract Res Clin Anaesthesiol. 2010;24:15-25.

This paper is a good and well-referenced review of recent research that has improved our understanding of coagulopathies in trauma patients.

Zubair AC. Clinical impact of blood storage lesions. Am J Hematol. 2010;85:117-122.

With increasing concern about blood storage lesions, storage age of blood, and clinical consequences, this article provides the reader with a succinct and well-referenced review.

Buddeberg F, Schimmer BB, Spahn DR. Transfusion-transmissible infections and transfusion-related immunomodulation. Best Pract Res Clin Anaesthesiol. 2008;22:503-517.

As mentioned in the text, space has not permitted discussion of transfusion-transmitted infections. Basic information is available in this review, with significant references.

Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med. 2008;36:1-8.

This review is a good summary of recent evidence supporting the case that for ICU, trauma, and surgical patients, red blood cell transfusions are associated with increased morbidity and mortality.

References

1 Thomson A, Farmer S, Hofmann A, Isbister J, Shander A. Patient blood management—a new paradigm for transfusion medicine? Vox Sang ISBT Science Series. 2009;4:423-435.

2 Marik PE, Corwin HL. Efficacy of red blood cell transfusion in the critically ill: a systematic review of the literature. Crit Care Med. 2008;36(9):1-8.

3 Spiess BD. Red cell transfusions and guidelines: a Work in Progress. Hematol Oncol Clin North Am. Feb 2007;21(1):185-200.

4 Slichter SJ. Platelet transfusion therapy. Hematol Oncol Clin North Am. Aug 2007;21(4):697-729. vii

5 Kor DJ, Stubbs JR, Gajic O. Perioperative coagulation management–fresh frozen plasma. Best Pract Res Clin Anaesthesiol. Mar 2010;24(1):51-64.

6 Pape A, Stein P, Horn O, Habler O. Clinical evidence of blood transfusion effectiveness. Blood Transfus. 2009;7(4):250-258.

7 Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol. Feb 2008;83(2):137-143.

8 Grottke O, Henzler D, Rossaint R. Activated recombinant factor VII (rFVIIa). Best Pract Res Clin Anaesthesiol. Mar 2010;24(1):95-106.

9 Lee JS, Gladwin MT. Bad blood: the risks of red cell storage. Nat Med. 2010;16(4):381-382.

10 Maani CV, DeSocio PA, Holcomb JB. Coagulopathy in trauma patients: what are the main influence factors? Curr Opin Anaesthesiol. 2009;22(2):255-260.

11 Ganter MT, Pittet JF. New insights into acute coagulopathy in trauma patients. Best Pract Res Clin Anaesthesiol. Mar 2010;24(1):15-25.

12 Silver RM, Major H. Maternal coagulation disorders and postpartum hemorrhage. Clin Obstet Gynecol. Mar 2010;53(1):252-264.

13 Isbister GK. Procoagulant snake toxins: laboratory studies, diagnosis, and understanding snakebite coagulopathy. Semin Thromb Hemost. 2009;35(1):93-103.

14 Brohi K, Cohen MJ, Ganter MT, et al. Acute coagulopathy of trauma: hypoperfusion induces systemic anticoagulation and hyperfibrinolysis. J Trauma. 2008;64(5):1211-1217. discussion 1217

15 Hendrickson JE, Hillyer CD. Noninfectious serious hazards of transfusion. Anesth Analg. 2009;108(3):759-769.

16 Stramer SL. Current risks of transfusion-transmitted agents: a review. Arch Pathol Lab Med. 2007;131(5):702-707.

17 Hebert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999;340(6):409-417.

18 Triulzi DJ. Transfusion-related acute lung injury: current concepts for the clinician. Anesth Analg. 2009;108(3):770-776.

19 Frenette PS, Mohandas N. Bad blood: a trigger for TRALI. Nat Med. 2010;16(4):382-383.

20 Ruhl H, Bein G, Sachs UJ. Transfusion-associated graft-versus-host disease. Transfus Med Rev. 2009;23(1):62-71.

21 Buddeberg F, Schimmer BB, Spahn DR. Transfusion-transmissible infections and transfusion-related immunomodulation. Best Pract Res Clin Anaesthesiol. Sep 2008;22(3):503-517.

22 Stramer SL, Hollinger FB, Katz LM, et al. Emerging infectious disease agents and their potential threat to transfusion safety. Transfusion. Aug 2009;49(Suppl. 2):1S-29S.

23 Allain JP, Stramer SL, Carneiro-Proietti AB, et al. Transfusion-transmitted infectious diseases. Biologicals. Apr 2009;37(2):71-77.

24 Palavecino EL, Yomtovian RA, Jacobs MR. Bacterial contamination of platelets. Transfus Apher Sci. Feb 2010;42(1):71-82.

25 D’Alessandro A, Liumbruno G, Grazzini G, Zolla L. Red blood cell storage: the story so far. Blood Transfus. 2010;8(2):82-88.

26 Zubair AC. Clinical impact of blood storage lesions. Am J Hematol. Feb 2010;85(2):117-122.

27 Reeves BC, Murphy GJ. Increased mortality, morbidity, and cost associated with red blood cell transfusion after cardiac surgery. Curr Opin Anaesthesiol. 2008;21(5):669-673.

28 Koch CG, Li L, Sessler DI, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med. 2008;358(12):1229-1239.

29 Khorana AA, Francis CW, Blumberg N, Culakova E, Refaai MA, Lyman GH. Blood transfusions, thrombosis, and mortality in hospitalized patients with cancer. Arch Intern Med. Nov 24 2008;168(21):2377-2381.

30 Caironi P, Gattinoni L. The clinical use of albumin: the point of view of a specialist in intensive care. Blood Transfus. 2009;7(4):259-267.

31 Liumbruno G, Bennardello F, Lattanzio A, Piccoli P, Rossetti G. Recommendations for the use of antithrombin concentrates and prothrombin complex concentrates. Blood Transfus. 2009;7(4):325-334.

32 Weinkove R, Rangarajan S. Fibrinogen concentrate for acquired hypofibrinogenaemic states. Transfus Med. 2008;18(3):151-157.

33 Provan D, Chapel HM, Sewell WA, O’Shaughnessy D. Prescribing intravenous immunoglobulin: summary of Department of Health guidelines. Br Med J (Clin Res Ed). 2008;337:a1831.

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