RBC components suffer some cell loss during storage. The current technology with preservative solutions attempts to optimize cell quality and quantity by using strict criteria to determine the allowable storage time. Nonetheless, as RBC metabolism decreases progressively, a “storage lesion” results, with accumulation of a variety of undesirable substances and loss of cellular function.⁶ During storage, a slow rise in the concentration of potassium, lactate, aspartate aminotransferase, lactate dehydrogenase, ammonia, phosphate, and free hemoglobin and a slow decrease in pH and bicarbonate concentration occur. Cytokines and inflammatory mediators such as interleukin 1, interleukin 6, and tumor necrosis factor also accumulate. The pH of freshly stored blood in citrate solution is 7.16, which declines to approximately 6.73 at the end of the unit’s shelf life. As potassium leaks from RBCs during storage, levels as high as 25 mEq/L may result. However, each unit transfused supplies at most 7 mEq of potassium, which is usually well tolerated.

During the storage period there is also a progressive decrease in RBC-associated 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP).⁶ A decrease in 2,3-DPG increases the affinity of hemoglobin for oxygen, which shifts the oxygen dissociation curve to the left and decreases oxygen delivery to tissues. There is little evidence, however, that this transient increase in oxygen affinity has clinical importance. After infusion, 2,3-DPG gradually increases as the transfused RBCs circulate, with 25% recovery in 8 hours and full replacement by 24 hours.⁷ Decreased ATP during storage diminishes the viability of RBCs after transfusion and is one of the chief factors limiting storage time. There is no currently available storage or rejuvenation solution that optimizes these cellular constituents.

The majority of blood transfusions are in the form of PRBCs, the component indicated for normovolemic patients or those for whom intravascular volume constraints are necessary. Resuscitation in patients requiring increased oxygen-carrying capacity and volume is effectively achieved with the use of PRBCs and crystalloid or colloid solutions. Each unit of PRBCs is expected to raise the hemoglobin concentration by 1 g/dL and the hematocrit by 3% in stable, nonbleeding, average-sized adults.

Indications for Red Blood Cell Transfusion

Despite a long tradition of transfusion of RBCs in critically ill patients, the precise indications for transfusion remain a source of debate, and transfusion practices may vary widely among clinicians, ICUs, institutions, and geographic regions. Multiple observational studies document transfusion rates in ICU patients that vary from 17% to 53%,8–12 and the rate of transfusion increases with longer ICU length of stay.^8,13 There has been a trend over time for use of a lower transfusion threshold in critically ill patients.^14,15

RBCs should be transfused only to enhance tissue oxygen delivery, but the underlying physiology of anemia, the complex adaptations to anemia, and the potential advantages and disadvantages to particular groups of patients are not as well understood. Determining when an anemic patient would truly benefit from increased oxygen-carrying capacity remains an imprecise task. In addition, mounting evidence argues that transfusions may result in donor-recipient interactions deleterious to the critically ill patient, including the disruption of compensatory physiology, the immunomodulation caused by the presence of foreign cells, and the introduction of unintended plasma contents.

Compensatory mechanisms for acute and chronic anemia are complex and work in concert to maintain oxygenation within the microcirculation.16,17 Cardiovascular adjustments leading to increased cardiac output include decreased afterload and increased preload resulting from changes in vascular tone, increased myocardial contractility, and elevated heart rate. Lowered blood viscosity permits improved flow of RBCs within capillaries. Blood flow is redistributed to favor critical organs with higher oxygen extraction such as the heart and brain. Pulmonary mechanisms, though contributing relatively little to short-term oxygenation demands, exert potent effects on related metabolic variables. Finally, the hemoglobin molecule can undergo biochemical and conformational changes to enhance the unloading of oxygen at the capillary level. Increased synthesis of RBC 2,3-DPG in anemia results in a rightward shift of the oxyhemoglobin saturation curve and facilitates the release of oxygen to tissues. A rightward shift of the oxyhemoglobin curve can also occur with a decrease in pH (Bohr effect) but the clinical significance is small.¹⁶ All these mechanisms contribute to an oxygen reserve capacity that exceeds baseline requirements by approximately fourfold. Unfortunately, acute illness and chronic morbidities may limit these compensatory mechanisms in critically ill patients. Animal studies and case reports in patients refusing transfusion indicate that an extremely low hematocrit is tolerated if tissue perfusion is adequate.^17–19

Indirect measurements of tissue oxygen utilization can be derived if patients are monitored invasively with a pulmonary artery catheter, although use of this monitoring tool has significantly decreased in ICUs. Mixed venous oxygen content and arterial oxygen content can be calculated from measured variables. The oxygen extraction ratio (ER), defined as the ratio of oxygen consumption (VO₂) to total oxygen delivery (DO₂), can be used as a surrogate to determine adequacy of tissue oxygen delivery in the absence of low cardiac output. ER can be calculated by using venous and arterial partial pressures and oxygen saturation values:

where the arterial content of oxygen (CaO₂) equals 1.36 × hemoglobin × SaO₂ + 0.003 × PaO₂. The venous oxygen content (CvO₂) can be calculated by the same formula, replacing the values with mixed venous oxygen saturation () and venous partial pressure of oxygen (PvO₂). Because the contribution of dissolved oxygen in plasma to the oxygen-carrying capacity is negligible, ER can be estimated by: 1 – (). The total body ER at baseline is about 25%. A falling CvO₂ and an ER increasing to greater than 50% have been proposed as indicators of the need for RBC transfusion, but have never been validated in clinical studies.²⁰

Although RBC transfusion can increase oxygen-carrying capacity and thus oxygen delivery, it may not improve tissue oxygen consumption. Multiple case series evaluating the effects of RBC transfusion in critically ill patients have failed to document increased oxygen consumption or improvement in lactate level.21–25 Hypotheses to explain this discrepancy include an increase in blood viscosity limiting microvascular flow and impaired tissue and cellular oxygen utilization.

In practice, clinicians usually rely on the hemoglobin to determine when oxygen-carrying capacity is potentially compromised, despite the limitations noted earlier. Prior transfusion strategies often targeted a hemoglobin goal of greater than 10 g/dL with support of reports that anemia, defined by various criteria, is associated with increased mortality rate in critically ill patients,²⁶ mechanically ventilated COPD patients,²⁷ surgical patients who refuse transfusion,²⁸ and patients undergoing major noncardiac surgery.^29,30 However, the first large multicenter randomized trial of RBC transfusion strategies in the critically ill showed this liberal transfusion strategy may actually be unnecessary and potentially detrimental.³¹ The Transfusion Requirement in Critical Care (TRICC) trial compared a liberal (target hemoglobin, 10 to 12 g/dL) with a restrictive (target hemoglobin, 7 to 9 g/dL) RBC transfusion policy in 838 euvolemic patients with hemoglobin less than 9 g/dL within 72 hours of ICU admission. The primary outcome measure of 30-day all-cause mortality rate was not statistically different between the restrictive strategy and the liberal strategy (p = 0.11). A secondary outcome measure of overall hospital mortality rate was significantly lower in the restrictive strategy group (p = 0.05). The restrictive strategy was superior for subgroups of patients younger than 55 years and patients with lower (<20) APACHE (Acute Physiology, Age, and Chronic Health Evaluation) II scores. In addition, liberal transfusion was not associated with shorter ICU or hospital stays or less organ failure; longer mechanical ventilation times and cardiac events were more frequent in the liberal strategy group. A separate analysis of 713 patients in the study who received mechanical ventilation did not find any significant differences between treatment groups for the duration of mechanical ventilation or extubation success.³² Similarly, a subgroup analysis of 357 patients from the TRICC study with cardiovascular disease did not find any differences in mortality rates between the restrictive and liberal strategies.³³

The results of the TRICC study were replicated in a study of transfusion strategy in critically ill pediatric patients.³⁴ A liberal transfusion threshold of 9.5 g/dL was compared with a restrictive transfusion threshold of 7.0 g/dL. The primary outcomes of death and new or progressive multiple organ dysfunction as well as adverse events were similar in both treatment groups, but 54% of patients in the restrictive group did not receive transfusion as compared to only 2% in the liberal group (p < 0.001). Subsequent prospective randomized trials have validated the use of a restrictive transfusion strategy in other adult patient populations.^35–39 Although a small study of liberal (hemoglobin threshold of 10 g/dL) versus restrictive (hemoglobin threshold of 8 g/dL) transfusion in 120 hip fracture surgery patients raised concern for increased cardiovascular complications and mortality rate with a restrictive strategy,⁴⁰ a larger trial in 2016 high-risk patients undergoing surgery for hip fracture found no increase in mortality rate and no difference in functional recovery.³⁵ The Transfusion Requirements After Cardiac Surgery (TRACS) study compared transfusion thresholds of hematocrit less than 30% with hematocrit less than 24% from the start of surgery through the ICU stay.³⁶ There was no difference in the composite outcome of 30-day all-cause mortality rate and severe morbidity between the liberal and restrictive strategies, and fewer blood products were administered in the restrictive group. These results are similar to those in an earlier study in coronary artery bypass surgery patients that evaluated liberal and restrictive transfusion strategies in the postoperative period.⁴¹

The TRACS study and the analysis of patients with cardiovascular disease from the TRICC study suggest that RBC transfusion using a hemoglobin threshold of 7 to 8 g/dL in stable patients at risk for myocardial ischemia is well tolerated. However, these studies do not answer the question of whether patients with acute coronary syndromes (current or recent ischemia) would benefit from a liberal transfusion strategy. Results from retrospective and prospective observational studies of anemia and transfusion in acute coronary syndrome patients have yielded conflicting results.42–45 A recent prospective, randomized pilot study of 45 patients with acute myocardial infarction (MI) and hematocrit 30% or less compared a transfusion threshold of hematocrit less than 24% with hematocrit less than 30%.⁴⁶ The composite safety end point of in-hospital death, new MI, or new or worsening heart failure occurred in 38% of the liberal strategy patients versus 13% in the conservative strategy patients (p = 0.046). These results suggest that even in acute MI moderate anemia may not be as harmful as the risks involved with transfusions. Larger studies in the future should help determine whether a restrictive transfusion strategy should be adopted in patients with acute coronary syndromes.

Prior guidelines for transfusion of RBCs did not specifically address critically ill patients and were primarily based on consensus rather than evidence.47–51 Transfusion was usually recommended if hemoglobin was less than 6 or 7 g/dL and not indicated when hemoglobin was greater than 10 g/dL.^48,52 Guidelines of the American Association of Blood Banks⁴⁶ and the Society of Critical Care Medicine/Eastern Association for Surgery of Trauma⁵³ and a Cochrane review⁵⁴ provide an evaluation of clinical evidence and more specific recommendations that are applicable to the critically ill. A summary of the guideline recommendations is presented in Box 79.1. Transfusion of single units of RBCs is recommended except in the setting of acute hemorrhage.⁵³ Implementation of a restrictive transfusion practice as recommended by the guidelines could decrease patient RBC exposure by an estimated 40%.⁴⁶ The threshold for administration of RBCs should also be considered as part of a comprehensive, multidisciplinary patient blood management program to detect and treat anemia, reduce surgical blood loss, and optimize hemostasis.²

Box 79.1 Guideline Recommendations for Transfusion of Red Blood Cells

American Association of Blood Banks (2012)

• Adhere to a restrictive strategy in hospitalized, hemodynamically stable patients (strong recommendation)

• Adult ICU patients: consider transfusion when hemoglobin ≤7 g/dL

• Postoperative surgical patients: consider transfusion when hemoglobin ≤8 g/dL or for symptoms (chest pain, heart failure, orthostatic hypotension, tachycardia unresponsive to fluid resuscitation)

• Adhere to a restrictive strategy in hospitalized, hemodynamically stable patients with preexisting cardiovascular disease (weak recommendation)

• Consider transfusion when hemoglobin ≤8 g/dL or for symptoms

• No recommendation for a specific transfusion strategy in hospitalized, hemodynamically stable patients with acute coronary syndrome

Society of Critical Care Medicine/Eastern Association for Surgery of Trauma (2009)

• Transfusion is indicated for patients with hemorrhagic shock and may be indicated for patients with acute hemorrhage and hemodynamic instability or inadequate oxygen delivery.

• Transfusion when hemoglobin is <7 g/dL (restrictive strategy) is as effective as transfusion when hemoglobin is <10 g/dL (liberal strategy) in critically ill hemodynamically stable patients.

• Transfusion may be beneficial in patients with acute coronary syndromes with hemoglobin <8 g/dL on hospital admission.

ICU, intensive care unit.

Platelets

Platelet components are available as random donor units or single donor apheresis units. Because of the limited storage time and the increasing demand for this component, platelets are often subject to supply shortages. A random donor platelet concentrate is obtained by centrifugation from a unit of WB. This type of platelet concentrate contains up to 50% of the leukocytes from the WB unit. The average transfused dose of random donor platelets has been decreasing over time and is now 5 units in the United States.¹ If bags are entered for pooling before transfusion, the platelets must be administered within 4 hours. A single donor apheresis platelet unit contains the equivalent of 4 to 6 units of random donor platelet concentrates. This type of platelet concentrate is considered to be leukoreduced and no additional filtration is needed. Single-donor platelets offer the benefit of reducing the risk of multiple-donor exposure to the recipient, and may also be the only available alternative for recipients who have been alloimmunized by previous platelet transfusions. Apheresis platelets now account for 87% of all platelets transfused in the United States.¹

Platelets are stored at room temperature to avoid loss of function from refrigeration and are constantly agitated to maximize gas exchange. Some loss of viability and platelet numbers occurs during storage, but 5-day-old platelets still effect hemostasis. The plasma contained in platelet concentrates is a good source of stable coagulation factors and contains diminished but still potentially beneficial amounts of factors V and VIII. Platelet components may be modified by leukocyte reduction, irradiation, and washing similar to that for RBCs. Transfusion of ABO-compatible platelets is desirable but not essential. When ABO-mismatched platelets are given, removal of some of the incompatible plasma can be carried out prior to transfusion. Single donor apheresis platelets may be matched to an alloimmunized recipient for human leukocyte antigens (HLA) or platelet antigens. There is no contraindication to the use of Rh-positive platelets in Rh-negative patients. However, if Rh-positive random donor platelets are administered to Rh-negative women with childbearing potential, Rh immune globulin should be used prophylactically due to the small risk of Rh alloimmunization from RBCs that may be contained in the platelet concentrate. In similar circumstances, Rh immune globulin is not indicated if single donor apheresis platelets are transfused because they contain few RBCs.

Each unit of random donor platelets is expected to increase the platelet count by 10 × 10⁹/L in a typical 70-kg adult. A 1-hour posttransfusion platelet count should be obtained to determine the adequacy of response. The following equation, which relates platelet number and body size to the posttransfusion increment, can be used to assess the effectiveness of the transfusion:

A CCI of 10 × 10⁹/L or higher can be considered a good response, whereas a CCI of 5 × 10⁹/L or lower indicates a poor response to transfusion.⁵⁵ The increment in platelet count is higher with single-donor apheresis units, ABO-identical platelets, and platelets stored no longer than 3 days.^56,57 However, there is no advantage of these platelet characteristics on prevention of clinical bleeding.⁵⁶

Indications for Platelet Transfusion

Although the prevalence of thrombocytopenia in the critically ill varies with the definition used and clinical setting, thrombocytopenia is associated with platelet transfusions and increased mortality rate in ICU patients.58,59 Guidelines for transfusion of platelets are derived from consensus opinion and experience primarily in patients with chemotherapy-induced thrombocytopenia rather than critically ill patients.^48,60–63 Extrapolation of these guidelines to critically ill patients is problematic because the cause, risks, and consequences of thrombocytopenia may be different. Indications for platelet transfusions include active bleeding due to thrombocytopenia or functional platelet defects (therapeutic transfusion) or prevention of bleeding due to thrombocytopenia (prophylactic transfusion). The majority of platelet transfusions in the ICU are performed for prophylactic indications and often do not result in an increase in platelet count.⁶⁴

Suggested indications for platelet transfusion are summarized in Table 79.2. There is good evidence that medical or surgical patients with active bleeding and platelet counts of 50 × 10⁹/L or above will not benefit from transfusion if thrombocytopenia is the only abnormality. Prophylactic platelet transfusions are administered to prevent spontaneous bleeding or bleeding with invasive procedures. The threshold for platelet transfusion prior to invasive procedures is usually recommended as less than 50 × 10⁹/L, but transfusion decisions should take into account the type of procedure, bleeding risks associated with the procedure, consequences of bleeding, and concomitant factors affecting hemostasis. For critical invasive procedures in which even a small amount of bleeding could lead to loss of vital organ function or death, maintaining the platelet count greater than 50 × 10⁹/L is typically preferred. The presence of factors that diminish platelet function, such as certain drugs, foreign intravascular devices (e.g., intra-aortic balloon pump or membrane oxygenator), infection, or uremia, alter this requirement upward. Patients at risk for small but strategically important hemorrhage, such as neurosurgical patients, may need to be maintained at platelet counts of 80 to 100 × 10⁹/L.

Table 79.2

Indications for Platelet Transfusion

Clinical Situation	Platelet Count: × 10⁹/L
Therapeutic
Active bleeding	<50
Prophylactic
Spontaneous bleeding risk very high	0-10
Spontaneous bleeding risk high with concomitant coagulation abnormality, anticoagulant therapy, sepsis, fever, concurrent antibiotic use, rapidly decreasing count or planned invasive procedure	11-20
Planned invasive procedure	21-50
Consider with platelet dysfunction (uremia, antiplatelet drugs) and planned invasive procedure when other therapies are ineffective	>50

The most appropriate platelet count for procedures that may be performed in critically ill patients, such as placement of central venous catheters and arterial catheters, thoracentesis, and paracentesis, has not been defined. A retrospective study suggests that central venous catheters can be placed safely when the platelet count is greater than or equal to 20 × 10⁹/L.⁶⁵

Patients undergoing cardiac bypass surgery experience a drop in platelet count and often acquire a transient platelet functional defect from damage associated with the bypass apparatus.⁶⁶ Most patients do not experience platelet-associated bleeding, however, and prophylactic transfusion in the absence of bleeding is not warranted. In a patient who continues to bleed postoperatively, more likely causes are a localized, surgically correctable lesion or failure to reverse the effects of heparin. If these conditions are excluded, empiric transfusion of platelets may be justified.

Patients without hemorrhage who have platelet counts of 5 × 10⁹/L or lower are at increased risk for significant spontaneous bleeding, and the majority of guidelines propose prophylactic platelet transfusion to prevent hemorrhage at a threshold of 10 × 10⁹/L or less. The recommendations are based on experience in patients with hematologic malignancies and chemotherapy-induced underproduction of platelets. The prior practice of transfusion to maintain the platelet count above 20 × 10⁹/L derives from data published in 1962, which demonstrated an increase in spontaneous bleeding in leukemic patients at that level.⁶⁷ However, critical evaluation of the data reveals that serious hemorrhage was not greatly increased until counts fell to 5 × 10⁹/L or lower and that these patients received aspirin for fever, which might have compromised platelet function and enhanced bleeding.

A prospective study of a more conservative platelet transfusion protocol found that major bleeding episodes occurred on 1.9% of days with counts of less than 10 × 10⁹/L and on only 0.07% of days with counts of 10 to 20 × 10⁹/L.⁶⁸ Additional studies have confirmed the safety of using less than or equal to 10 × 10⁹/L as a prophylactic platelet transfusion threshold in patients with hematologic malignancies or stem cell transplants.^69–72 The trigger for prophylactic platelet transfusion of less than or equal to 10 × 10⁹/L, however, applies primarily to a specific population of stable thrombocytopenic patients. Factors such as fever, use of anticoagulant or antiplatelet drugs, and invasive procedures must be considered when generating a treatment plan for individual patients. Patients experiencing rapid drops in platelet count may be at greater risk than those at steady state and thus may benefit from transfusion at higher counts. Prospective studies in critically ill patients have not been reported. Benefits to the patient of more conservative use of platelet transfusion include decreased donor exposure, which lessens the risk of transfusion-transmitted disease; fewer febrile and allergic reactions that may complicate the hospital course; and the potential delay or prevention of alloimmunization to HLA and platelet antigens.⁷³

Patients thrombocytopenic by virtue of immunologic destructive processes such as idiopathic thrombocytopenic purpura (ITP) receive little benefit from platelet transfusions because transfused platelets are rapidly removed from the circulation. In the event of life-threatening hemorrhage or an extensive surgical procedure, transfusion may prove beneficial for its short-term effect but may require higher doses of platelets. Transfusion may be accomplished effectively by pretreatment with high-dose immunoglobulin or high-dose anti-D antiserum.74,75 Platelet transfusion is contraindicated in thrombotic thrombocytopenic purpura (TTP),⁷⁶ hemolytic-uremic syndrome, and heparin-induced thrombocytopenia. Cautious administration of platelets may be considered in cases of life-threatening thrombocytopenic bleeding.

The development of refractoriness to platelet transfusions due to alloimmunization is a serious event. Poor response to platelet transfusions due to increased platelet consumption also occurs with splenomegaly, fever, trauma and crush injury, burns, disseminated intravascular coagulation (DIC), concomitant drugs, and transfusion of platelets of substandard quality.⁷⁷ These factors should be identified and corrected if possible. Alloimmunization is characterized by the development of anti-HLA or platelet-specific antibodies, with resultant immune platelet destruction. As many as 70% of patients receiving multiple RBC or platelet transfusions become immunized.⁷³ Leukocyte depletion of transfused components can prevent or delay this phenomenon, but it is important to use leukoreduced components early in the course of transfusion therapy.^73,78 When patients fail to achieve expected increments after platelet transfusion, provision of ABO-specific platelet concentrates that are less than 48 hours old may improve the response. If no improvement is seen, the patient should be screened for HLA antibodies or be HLA typed and provided with HLA-compatible single-donor platelets. Alternatively, platelet crossmatching with the patient’s serum can be carried out. There is no advantage to unmatched single-donor platelets in this situation.

Plasma-Derived Components

Plasma

Standard FFP is prepared by centrifugation of WB or single-donor apheresis and is frozen within 8 hours of blood donation. Standard FFP contains all coagulation factors (including the labile factors V and VIII) and inhibitors, approximately 400 mg fibrinogen, complement, albumin, and globulins. By convention, the coagulation factors are present in concentrations of 1 U/mL. Plasma that is separated and frozen from refrigerated WB more than 8 hours but within 24 hours of phlebotomy is referred to as PF24. PF24 differs from standard FFP by having lower levels (approximately 15% to 25% reduction) of factors V and VIII, but the decrease in labile factor levels is not considered to be clinically significant. The processing technique for PF24 allows for clinical utilization of plasma collected at distant sites and increases the plasma supply. Cryoprecipitate-reduced plasma (also called cryopoor plasma) refers to FFP with the cold-induced precipitate removed. Cryopoor plasma will thus be deficient in factors VIII and XIII, fibrinogen, and von Willebrand factor. In the United States, FFP accounted for 54% of plasma transfusions and PF24 accounted for 39%.¹ The most common method of thawing FFP requires about 30 to 45 minutes in a 37° C water bath. Crossmatching to the recipient is not performed, but FFP must be ABO compatible. Standard FFP is as likely to transmit hepatitis, HIV, and most other transfusion-related infections as cellular components. The following types of pathogen-reduced plasma products are available in some countries outside the United States: solvent/detergent-treated plasma, methylene blue–treated plasma, psoralen- and ultraviolet light–treated plasma, and riboflavin- and ultraviolet light–treated plasma.⁷⁹

Indications for Fresh Frozen Plasma

FFP is frequently transfused inappropriately in critically ill patients who are not bleeding or in whom the international normalized ratio (INR) is less than 1.5.80,81 Guidelines for transfusion of FFP have been primarily based on expert opinion rather than clinical evidence (Box 79.2).^60,82,83 A summary of practice recommendations for specific clinical circumstances based on a systematic review is presented in Box 79.3. The review emphasized the lack of high-quality evidence on plasma infusion and the need for well-designed trials to address relevant knowledge gaps.⁸⁴

Box 79.3

Recommendations Regarding Fresh Frozen Plasma (FFP) Transfusion in Specific Conditions *

1. Suggest that FFP be transfused to trauma patients requiring massive transfusion

2. Cannot recommend for or against of FFP transfusion at a plasma-to-RBC ratio of 1:3 or more in trauma patients with massive transfusion.

3. Cannot recommend for or against FFP transfusion in patients undergoing surgery in the absence of massive transfusion.

4. Suggest FFP be transfused in patients with warfarin-related intracranial hemorrhage.

5. Cannot recommend for or against FFP transfusion to reverse warfarin in patients without intracranial hemorrhage.

6. Suggest against FFP transfusion in other groups of patients (in the absence of massive transfusion, surgery, bleeding, or overanticoagulation)

RBC, red blood cell.

^*Based on a systematic review.

Adapted from Roback JD, Caldwell S, Carson J, et al: Evidence-based practice guidelines for plasma transfusion. Transfusion 2010;50:1227-1239.

FFP should be administered only to provide coagulation factors or plasma proteins that cannot be obtained from safer sources. FFP is commonly used to treat bleeding patients with acquired deficiency of multiple coagulation factors, as in liver disease, DIC, or dilutional coagulopathy. However, changes in INR after FFP transfusion are usually minimal and not clinically significant when the pretransfusion INR is less than 2.0.81,85 FFP may be indicated for the provision of protein C or S in patients who are deficient and suffering acute thrombosis. FFP should be administered as boluses as rapidly as feasible so that the resulting factor levels achieve hemostasis. The use of FFP infusions is not helpful. Variable doses of FFP have been recommended including 2 units initially (probably underdosage) up to 10 to 15 mL/kg. However, some studies suggest that doses as high as 30 mL/kg may be needed to achieve adequate factor levels.⁸⁶ Due to the short half-life of factor VII, FFP should be infused every 6 to 8 hours if bleeding continues. FFP should not be used for volume expansion or as a nutritional source of protein. Anticoagulation induced by heparin, direct thrombin inhibitors (e.g., dabigatran), or direct factor Xa inhibitors (e.g., rivoraxaban) is not reversed by FFP.

Patients do not usually bleed as a result of coagulation factor deficiency when the INR is less than about 2.0, and even then the results are not always predictable.⁸⁷ The partial thromboplastin time (PTT) is also not useful in predicting procedural bleeding risk.⁸⁸ Prophylactic administration of FFP does not improve patient outcome in the setting of cardiac surgery unless there is bleeding with an associated documented coagulation abnormality.⁸⁹ FFP is often requested prophylactically before an invasive procedure when the patient exhibits mild prolongation in coagulation studies. Most of these procedures may be carried out safely without transfusing FFP.^87,90 A randomized trial of FFP versus no FFP in critically ill nonbleeding patients with INR between 1.5 and 3.0 scheduled to undergo central venous catheter placement, thoracentesis, percutaneous tracheostomy, or drainage of abscess or fluid is under way.⁹¹

Coagulation factors are normally present in the blood far in excess of the minimum levels required for hemostasis. As little as 10% of the normal plasma concentration of several factors will effect hemostasis. Conversely, FFP treatment of acquired multiple deficiencies, as in hepatic failure, is often ineffective because many patients cannot tolerate the infusion volumes required to achieve hemostatic levels of coagulation factors, even transiently.⁹² The plasma half-life of transfused factor VII is only 2 to 6 hours. It may be impossible to administer sufficient FFP every few hours without encountering intravascular volume overload. Finally, in some instances, transfusion of seemingly adequate volumes may still fail to correct the coagulopathy.⁹³ Careful documentation of both the need for FFP and the adequacy and outcomes of therapy is essential.⁹⁴

Transfusion of FFP is associated with significant adverse effects. It is the most commonly implicated blood product in the development of TRALI. Because of the large volumes that may be transfused, FFP administration is a risk factor for transfusion-associated circulatory overload (TACO). Allergic reactions to FFP are usually mild with the exception of anaphylactic reactions to IgA proteins that can occur when plasma is transfused in IgA-deficient patients.

Cryoprecipitate

A total of 1.1 million units of cryoprecipitate were transfused in 2008 in the United States at a mean average cost of $65.10/unit.¹ Cryoprecipitate is prepared by thawing and centrifuging FFP below 6° C and resuspending the precipitated proteins in a small volume of supernatant plasma. Each unit is a concentrated source of factor VIII (≥80 IU), von Willebrand factor (50% of original plasma content), fibrinogen (≥150 mg), factor XIII (30% of original plasma content), and fibronectin. It is considered to be leukoreduced without additional filtration. Cryoprecipitate offers the advantage of transfusing more specific protein and less total volume than an equivalent dose of FFP. Cryoprecipitate does not require crossmatching, but ABO compatibility with the recipient is preferred.

Indications for Cryoprecipitate Transfusion

In the past, cryoprecipitate was used to treat patients with inherited coagulopathies, such as hemophilia A, von Willebrand disease, and factor XIII deficiency. However, the availability of safer specific factor concentrates makes use of cryoprecipitate unwarranted for these conditions unless factor concentrates are unavailable. In the critical care setting, cryoprecipitate is most commonly used to replenish fibrinogen, especially in bleeding patients with hypofibrinogenemia caused by dilutional or consumptive coagulopathy. Transfusion of cryoprecipitate is usually recommended when fibrinogen levels are less than 100 mg/dL in the setting of bleeding or need for an invasive procedure.83,95,96 Cryoprecipitate also reportedly improves hemostasis in uremic patients, presumably by reversing the functional platelet defect,⁹⁷ but desmopressin⁹⁸ or conjugated estrogens exert similar effects and should be used preferentially to avoid potential transfusion-related complications. Similar to other blood components, cryoprecipitate is often transfused inappropriately.⁹⁹

The usual dose of cryoprecipitate to treat hypofibrinogenemia is 10 units to start, then 6 to 10 units every 8 hours or as necessary to keep the fibrinogen level above 100 mg/dL. The fibrinogen response will depend on the patient’s plasma volume (varies with gender and weight), initial fibrinogen level, and consumption of fibrinogen. A simple formula to start with dosing is number of units = 0.2 × weight (kg).¹⁰⁰ Each unit of cryoprecipitate carries a risk of disease transmission equivalent to that of 1 unit of blood.

Adverse Effects of Blood Component Transfusion

The decision to transfuse blood components must be made with full awareness of the potential risk to the recipient, as well as the expected benefits. For some patients, the benefit from transfusion of a blood product is so obvious that the associated risks are not significant in comparison to the consequences of withholding transfusion. However, the clinician’s knowledge of the incidence and management of the adverse effects to transfusion is vital, not only to ensure the best patient care but also to provide appropriate patient education and true informed consent.

Measurable reactions to transfusion occur in about 20% of patients; more serious adverse responses may be expected in only 1% to 2% of transfusions.¹⁰¹ The nature of these adverse reactions ranges from those that are common but clinically unimportant to those that may cause significant morbidity or death. The Food and Drug Administration reported 58 transfusion-related or potentially transfusion-related deaths in 2011.¹⁰² From 2007 through 2011, TRALI accounted for 43% of fatalities followed by acute hemolytic reactions in 23%.

Why blood component transfusions may be harmful in critical care patients is not well understood. With the modern techniques in screening, storing, and matching RBCs, the mortality rate directly attributable to transfusions is extremely low; however, retrospective data often link increased numbers of transfusions to increased mortality rates.8,9,12,103 It is difficult to distinguish whether this trend is a function of anemia as a signal for increased severity of illness versus an actual consequence of the transfusion. Nevertheless, the relationship between transfusions and increased mortality rates is concerning, and a better understanding would help both clinicians and patients understand the risks involved with transfusions, as well as to aid investigators to develop new methods of safer transfusions. Potential mechanisms of recipient harm include risk of infections or multiorgan failure via immunomodulatory effects from the introduction during transfusion of unintended lipid breakdown products, cell-signaling factors, and donor-recipient antigen-antibody interactions.

Acute Transfusion Reactions

The signs and symptoms of severe, life-threatening transfusion reactions are frequently indistinguishable from those of less significant reactions. However, every transfused patient who experiences a significant change in condition, such as an elevation in temperature, change in pulse or blood pressure, dyspnea, or pain, must be promptly and fully evaluated to identify the cause of the reaction and to institute treatment when necessary. The basic approach to all acute reactions should be to maintain a high index of suspicion for acute hemolytic reactions (with RBC components) by stopping the transfusion immediately, maintaining venous access with intravenous fluids, and informing the blood bank laboratory immediately so that the appropriate transfusion reaction protocol can be instituted and posttransfusion specimens obtained. Early recognition of severe transfusion reactions may be lifesaving.

Acute Hemolytic Transfusion Reaction

Acute hemolytic transfusion reactions (AHTRs) are caused by the recipient’s existing complement-fixing antibodies attaching to donor RBC antigens with resultant intravascular RBC lysis. Non-ABO incompatibility is now more commonly implicated than ABO incompatibility in these incidents.¹⁰² In addition to hemolysis, complement activation stimulates the release of inflammatory mediators and cytokines and can lead to hypotension and vascular collapse. Activation of the coagulation system may result in DIC and bleeding. Acute renal failure may also occur, presumably on the basis of immune complex interactions. Morbidity and mortality rates are directly related to the quantity of incompatible blood transfused, which is why prompt recognition and cessation of transfusion are imperative. Misidentification of the patient, or clerical error, at any time beginning with acquisition of the donor specimen through release of the unit and initiation of infusion is the major cause of AHTRs.¹⁰⁴ It is preferable to transfuse uncrossmatched group O RBCs than to chance ABO incompatibility caused by improper patient and specimen identification procedures.

The most common clinical sign of an AHTR is sudden onset of fever, with or without chills.¹⁰⁵ Other common signs and symptoms include back or flank pain, anxiety, nausea, light-headedness, dyspnea, and hemodynamic instability. In a comatose or anesthetized patient, these symptoms may not be evident; therefore, signs such as hypotension, hemoglobinuria, and diffuse oozing from puncture sites or incisions may be the only notable features.

Immediate management of suspected AHTRs includes cessation of the transfusion; the remainder of care is supportive. Rapid verification of patient and unit identification must be made, not only to confirm the suspected reaction but also to prevent a second patient from receiving a reciprocally incompatible unit if a clerical error has been made. Steroids, heparin, or other pharmacologic interventions have no role in treatment.

Febrile Nonhemolytic Transfusion Reactions

Febrile nonhemolytic transfusion reactions (FNHTRs) are the most commonly occurring acute reaction to RBC and platelet transfusions. These reactions can cause significant discomfort and must be investigated because they share manifestations with AHTRs and bacterially contaminated blood. Although a temperature increase of 1° C is often used to define an FNHTR, fever may be absent in patients pretreated with antipyretics. Additional clinical signs include chills or rigors usually beginning 1 to 2 hours after the start of the transfusion but occasionally delayed up to 4 to 6 hours. Associated manifestations may include nausea, vomiting, and dyspnea. FNHTRs occur in approximately 1.0% of transfusion episodes but are more common with platelet transfusions (4-31%).106,107 The cause of FNHTRs varies with the transfused product, but the release or presence of cytokines and pyrogens results in the clinical manifestations. This reaction to RBC transfusion is usually initiated by the interaction of recipient antibodies to donor leukocytes. Nonhemolytic transfusion reactions (NHTRs) with platelet products are most commonly initiated by leukocyte- or platelet-derived cytokines or other biologic response modifiers.¹⁰⁷ Management of NHTRs includes discontinuation of transfusion and initiation of the appropriate transfusion reaction evaluation. Antipyretics such as acetaminophen may be administered. Antihistamines are neither preventive nor therapeutic. Once acute hemolysis is excluded, transfusion of a new unit may be instituted. If repeated NHTRs become problematic, leukocyte-depleted blood components should be supplied. The implementation of universal leukocyte reduction results in a reduction in the frequency of all fever seen after transfusion by only about 12%.¹⁰⁸ Pretreatment with antipyretics or corticosteroids may also minimize FHTRs.

Anaphylaxis

Anaphylactic reactions to blood transfusions are rare but may be life-threatening. The usual cause is recipient antibody to a component of plasma that the patient lacks, most commonly antibody to IgA in IgA-deficient individuals. However, antibodies to other proteins (anti-haptoglobin) have been demonstrated and activated platelet membranes may also play a role.109,110 The highest rate of anaphylaxis occurs with platelets followed by FFP and RBCs. Signs and symptoms usually begin within minutes after transfusion is initiated and include severe anxiety, flushing, dizziness, dyspnea, bronchospasm, abdominal pain, vomiting, diarrhea, hypotension, and eventually shock. Fever and hemolysis do not occur. Management includes immediate cessation of transfusion and standard therapy for anaphylaxis. If anti-IgA antibodies are determined to be the cause of this reaction, the patient must receive blood components donated by IgA-deficient individuals or, if unavailable, specially prepared washed RBCs and platelet concentrates. Plasma-derived preparations, such as albumin, and immunoglobulins contain varying amounts of IgA and pose a substantial risk in these patients.

Allergic and Urticarial Reactions

Hives and pruritus are relatively common cutaneous adverse effects of transfusion and may occur with transfusion of RBCs, platelets, and FFP.¹⁰⁶ They are a hypersensitivity reaction localized to the skin, and their cause is unknown but may include both donor and recipient characteristics. These reactions consist of localized or generalized urticaria beginning shortly after the start of transfusion without fever or signs or symptoms of anaphylaxis or hemolysis. The transfusion should be temporarily interrupted, and antihistamines administered. If the hives resolve in a short time, the same unit of blood may be cautiously restarted. If repeated urticarial reactions occur, premedication with antihistamines may be effective.

Delayed Hemolytic Transfusion Reactions

Delayed hemolytic transfusion reactions (DHTRs) are an uncommon but probably underrecognized reaction to RBC transfusion that result from the stimulation of a primary or secondary (anamnestic) recipient antibody response to foreign RBC antigens. These antibodies are below the limit of detection at the time of transfusion but increase after transfusion. DHTRs typically occur 3 to 14 days after transfusion but may not be recognized because of the lack of a clear temporal association with transfusion. DHTRs are more likely in patients requiring frequent RBC transfusion.¹⁰⁶ Patients may be asymptomatic or experience fever, chills, and an unexplained decline in hematocrit.¹¹¹ Transient elevation in unconjugated bilirubin and lactate dehydrogenase may also occur. The diagnosis is established by a positive direct antiglobulin (Coombs) test resulting from recipient antibody coating donor RBCs. The specificity of the antibody is often against such RBC antigens as the Rh family, Kidd, Duffy, or Kell systems. Hemolysis may not occur, but if it does, it is likely to be extravascular and only rarely causes renal failure or DIC.

Prevention of these reactions is difficult. Alloimmunization to foreign RBC antigens occurs in approximately 1% of transfusions.¹⁰¹ Detection of delayed antibodies is the purpose for requiring a new blood bank specimen every 72 hours if the patient has recently been transfused. Permanent transfusion records should record the occurrence of delayed antibodies, even though they may not be apparent at a later crossmatch.

Transfusion-Associated Circulatory Overload

TACO is estimated to occur in 1:100 to 1:10,000 transfusions and accounts for 15% of transfusion-related fatalities in the United States between 2007 and 2011.¹⁰² It is more likely to occur with RBC or FFP transfusion due to the higher volumes of these blood components.¹¹⁰ Aside from the inherent volume of the blood components, the concurrently administered normal saline adds to the volume load. Risk factors for TACO include older age, critical care patients, cardiac and renal dysfunction, chronic anemia, increased volume of blood products, and increased rate of transfusion. Clinical manifestations of TACO include dyspnea, orthopnea, cough, and worsening oxygenation due to hydrostatic pulmonary edema. Management options include slowing the rate of transfusion and administration of diuretics. Careful attention to transfusion requirements and the use of volume reduction maneuvers available to the transfusion service can help minimize volume overload in most instances. TACO may be difficult to distinguish clinically from TRALI but TACO is less likely to be associated with fever and hypotension and more likely to be associated with a significantly elevated brain natriuretic peptide (BNP) and hypertension.

Transfusion-Related Acute Lung Injury

TRALI is now the leading cause of transfusion-related deaths in the United States.¹⁰² An increase in incidence of TRALI is likely related to an increased awareness of the syndrome rather than a true increase in frequency of reactions. The reported incidence of TRALI for all blood component transfusions is less than 0.1%, but in the critical care setting, it is reported to be as high as 8% per transfusion.¹¹² Products containing plasma (e.g., FFP and platelets) appear to have the highest risk, but the reaction has been seen with all types of blood components. Tranfusion of plasma from female donors also increases the risk of TRALI.^112,113 TRALI is defined as the development of acute lung injury (hypoxia and bilateral infiltrates of noncardiac cause) within 6 hours of transfusion in the absence of another more likely cause.^113,114

In patients without prior respiratory compromise, TRALI manifests as acute hypoxia with the development of rales and diffuse infiltrates on chest radiograph.¹¹⁵ Recognition of TRALI may be difficult in critically ill patients who may have other reasons for dyspnea or may already require mechanical ventilation. In addition, TRALI and TACO may be difficult to distinguish. Clinical features that favor TRALI over TACO include the presence of fever and leukopenia. Hemodynamic monitoring may aid in differentiation, but is not required for management.

Unlike other forms of acute respiratory distress syndrome (ARDS), TRALI is usually self-limiting and resolves within 1 to 4 days. However, reactions can be severe, and often may necessitate mechanical ventilation. Treatment consists of supportive care, including the prompt management of hypoxia. If mechanical ventilation is required, lung protective ventilation should be implemented, and daily spontaneous breathing trials should be performed to ensure timely extubation upon resolution. Because the inciting factor is derived from the donor product rather than the patient, additional blood products can still be transfused if necessary with low risk of redevelopment.

Studies have suggested several mechanisms in the development of TRALI. The presence of leukocyte antibodies in the donor blood has been consistently linked to many cases, although other triggers such as lipids and biologic response modifiers (cytokines) have also been implicated.116,117,113 When exposed to donor antibodies, neutrophils that are already recruited to the pulmonary vascular endothelium release inflammatory products, leading to injury of the endothelial cells and increased vascular permeability. Recipient factors are also involved, as blood products from the same donor do not consistently cause TRALI in different recipients. Critically ill patients may be more susceptible to TRALI owing to increased localization of neutrophils in the pulmonary vasculature.

To reduce the risk of TRALI, blood agencies are evaluating possible interventions to reduce the presence of leukocyte antibodies in the donated products. One strategy is to limit donation by multiparous women, who are at high risk of carrying antibodies.¹¹⁸ Decreasing the duration of storage of blood products may also be beneficial. The number of fatalities due to plasma has been decreasing in the United States, most likely due to reduced plasma transfusion from female donors.¹⁰²

Transfusion-Associated Graft-Versus-Host Disease

Transfusion-associated GVHD (TA-GVHD) is a rare and usually fatal immunologic complication of blood component transfusion.¹⁰⁶ Immunocompromised patients infused with blood components containing viable donor lymphocytes are at risk for engraftment of the allogeneic lymphocytes and ensuing rejection of recipient (host) tissues. Transfusion recipients who are at highest risk include bone marrow and organ transplant recipients, leukemia and lymphoma patients, and recipients of blood donated by relatives. TA-GVHD has been reported in patients after cardiac surgery who received designated donor blood from relatives; presumably, the HLA antigenic differences between donor and recipient were insufficient to stimulate a recipient immune response but sufficient to elicit a donor immune response.¹¹⁹ The onset of TA-GVHD is usually within 8 to 30 days after transfusion, and it is manifested as fever and skin rash, followed by diarrhea and evidence of liver dysfunction and bone marrow suppression. TA-GVHD differs from that seen in bone marrow transplantation (BMT) by its involvement of the marrow and far greater mortality risk. Treatment is largely ineffective, and mortality rate exceeds 90%.

Irradiation of blood components at 25 Gy prevents TA-GVHD by eliminating the donor lymphocyte mitogenic response. All cellular blood components should be irradiated before transfusion to high-risk patients. The functions of the cellular components of blood are unaffected, although damage to RBC membranes limits the duration of postirradiation storage of PRBCs to 28 days. Blood donated by a relative for any patient should be irradiated, as should HLA-matched or crossmatched platelet products.

Transfusion-Related Immunomodulation

Transfusion-related immunomodulation (TRIM) may potentially have significant adverse effects that affect patient outcome. Allogeneic RBC transfusion has been shown to suppress the recipient’s immune response, an effect first noted with kidney transplantation that resulted in increased survival of the transplanted kidney.¹²⁰ However, immunosuppression is generally undesirable in critically ill patients, even though the clinical impact of blood component transfusion is not well defined. As noted in previous sections, immunomodulation likely contributes to AHTRs, NHTRs, anaphylaxis, and TRALI. The major clinical issues regarding TRIM center around the association between blood product transfusion and increased risk of infection and increased and more rapid rates of tumor recurrence in surgical oncology patients. The largest prospective trial of colorectal cancer resection, for example, was negative,¹²¹ but a meta-analysis of existing data suggests that an adverse effect on recurrence does exist.¹²² Significant heterogeneity exists in the reported studies and makes definitive conclusions difficult.¹²³ Most retrospective and prospective trials of postoperative or critical care unit infections suggest an adverse effect of blood component transfusion.^124–126

The precise mechanism of the immunomodulation induced by transfusion has not yet been delineated, and several mechanisms may be involved.¹²³ Allogeneic plasma, leukocytes and substances that accumulate in stored blood components may contribute to TRIM. Alterations identified in laboratory and clinical transfusion recipients have included depression of the T-helper/T-suppressor lymphocyte ratio, decreased natural killer cell activity, diminished interleukin 2 generation, formation of anti-idiotype antibodies, impairment of phagocytic cell function, and chronic persistence of donor lymphocytes (microchimerism), suggestive of low-level GVHD. Difficulties in analysis of human data arise because patients requiring blood component transfusions have conditions that may induce immune changes. There is some evidence from two large clinical trials to suggest that leukocyte reduction of blood components reduces or eliminates this immunomodulatory effect but other results are conflicting.^127,128 Well-designed prospective trials are needed to more clearly elucidate the impact of any immunomodulatory effects of transfusing blood products.

Transfusion-Transmitted Infectious Diseases

Transfusion-associated acquired immunodeficiency syndrome (AIDS) has done more to revolutionize transfusion practice than any other transfusion risk by resulting in more conservative blood use, more stringent donor selection criteria, and improved screening tests. The result is that viral transmission rates are now difficult to measure, and the risk of transfusion-related infectious diseases is lower than ever.46,129 Bacterial infection has become the most common infectious risk.

Microbial and Endotoxin Contamination

Several fatalities are reported yearly from the transfusion of blood components contaminated with viable bacteria, with or without the accumulation of endotoxin.102,130 Platelet concentrates stored at room temperature are particularly prone to bacterial growth, with a reported incidence of 1.13 in 10,000 components with apheresis units having the highest contamination rate.¹³¹ Organisms isolated from platelets and implicated in fatal transfusion reactions include Staphylococcus and Streptococcus species and gram-negative bacilli. Fatalities resulting from bacterial contamination of refrigerated RBCs have occurred as well and more often involve cryophilic bacteria. RBC transfusions contaminated by Yersinia enterocolitica have been consistently reported for a decade.¹³² Transfusion reactions caused by bacterial or endotoxin contamination are fortunately quite rare, but the mortality rate exceeds 60%.

Signs and symptoms of reactions caused by microbial contamination overlap those of hemolytic transfusion reactions and consist primarily of fever and hypotension, along with other signs of endotoxic shock. A Gram stain of the implicated unit can be prepared immediately and, if positive, appropriate antibiotic and supportive therapy instituted. Autologous blood components may also be contaminated at the time of collection; therefore, reactions occurring in patients who are receiving their own blood should be evaluated as fully as though they were receiving allogeneic blood.

Hepatitis

The success of viral screening measures is most clearly illustrated by the fall in the risk for posttransfusion hepatitis over the past 2 decades. The elimination of paid donors in 1972 and the introduction of nucleic acid tests for hepatitis B virus (HBV) and hepatitis C virus (HCV) have resulted in a steady reduction in the rates of posttransfusion hepatitis. The estimated residual risk for HBV is 1 in 2.8 million to 1 in 3.6 million transfused blood components.¹³³ Although about 30% to 40% of HBV transmissions will result in acute hepatitis, chronic HBV infection develops in less than 10% of such patients. In contrast, the risk for chronic HCV infection after transfusion is higher, nearly 50%, and the long-term risk for mortality related to cirrhosis or hepatocellular carcinoma is about 15% over more than 20 years after posttransfusion hepatitis secondary to HCV.^134,135 The risk of HCV transmission is even lower than HBV with a residual risk estimate of 8.7 per 10 million transfused blood components.¹³⁶ The clinical course of hepatitis A is generally milder, and the lack of a chronic carrier state means that with donor screening for symptoms of the acute illness, the risk of transmission is rare.

Retroviruses

Retroviruses known to be capable of transmission by transfusion are human immunodeficiency virus (HIV-1, HIV-2) and human T-cell leukemia/lymphoma virus (HTLV I and II). Transfusion-associated AIDS was initially reported in late 1982.¹³⁷ The first report of an associated viral agent did not appear until late 1983, and in March 1985 the screening enzyme-linked immunosorbent assay (ELISA) to detect antibody to HIV-1 was licensed and immediately incorporated into the blood-screening process. Improved confidential donor screening also decreased the risk of infectious units appearing in the donor pool.¹³⁸ The discovery that heat treatment decreased transmission resulted in a reduction in transmission by plasma products, especially to persons with hemophilia. Removal of donor units with seropositivity by ELISA was insufficient to prevent transmission of HIV-1. Subsequent development of an assay for the p24 antigen and nucleic acid testing have lowered the risk of transfusion-associated HIV-1 infection to an estimated 1 in 1,467,000 transfused blood components.¹³⁶ Despite donor screening and sensitive assays, an extremely small but finite risk of HIV-1 transmission by screened blood transfusions remains. This risk is largely due to the eclipse period (interval between infection and development of detectable concentrations of HIV RNA in plasma) experienced by newly infected donors. The eclipse period for HIV-1 is estimated to be 9 days.¹³⁶

A second retrovirus, HIV-2, first described in residents of countries in West Africa and subsequently detected in migrants to western Europe, causes an immunodeficiency syndrome similar to that caused by HIV-1. Although very few cases of HIV-2 have been reported in the United States ¹³⁹ and there have been no reported transfusion-transmitted cases, experience with other retroviruses suggests that screening may prevent the majority of potential transmissions. Therefore, donated blood is now screened for the presence of HIV-2.

The retrovirus HTLV-I is the causative agent of adult T-cell leukemia (ATL) and is strongly implicated in the chronic, progressive neurologic disorder termed tropical spastic paraparesis or HTLV-I-associated myelopathy (TSP/HAM). HTLV-II has been linked to hairy cell leukemia, but no transfusion-transmitted cases have been reported. The virus exhibits strong serologic cross-reactivity with HTLV-I such that screening assays fail to distinguish between the two viruses. Transfusion-transmitted HTLV-I has been demonstrated.¹⁴⁰ TSP/HAM has developed in a small percentage of infected transfusion recipients, but no transfusion-associated cases of ATL have been seen. Approximately 0.025% of donors in the United States are seropositive for HTLV-I and HTLV-II¹⁴¹; further testing reveals the majority of them to be HTLV-II. Donated blood is currently screened for antibodies to HTLV-I and HTLV-II.

Cytomegalovirus

CMV is a human herpesvirus that establishes latent infection in the host’s tissues, particularly leukocytes, and is transmitted by all cellular blood components.¹⁴² Seropositivity, or the presence of antibody, denotes previous exposure to the virus but does not confer protective immunity. Secondary reinfection or reactivation of latent infection can occur. Antibodies to CMV persist for life and serve as a marker indicating the potential for transmission of live virus.

Immunocompetent recipients of transfused CMV-positive blood experience minimal morbidity and mortality risks. The majority are asymptomatic, whereas a heterophile-negative mononucleosis syndrome may develop in a few. Immunocompromised patients, however, may suffer life-threatening manifestations such as severe interstitial pneumonitis, gastroenteritis, hepatitis, or disseminated disease. Several groups of patients are at particular risk (Box 79.4),¹⁴³ and these patients should receive blood incapable of transmitting the virus. Screening of donated blood for CMV is not routine but can be performed quickly if necessary. Because the prevalence of donor seropositivity is quite high, CMV-seronegative blood may not be readily available. Blood that is leukocyte depleted may be as effective as seronegative blood in the prevention of CMV transmission, although a meta-analysis of clinical trials comparing the two methods suggests that CMV-negative blood products might have a slight advantage over leukocyte-depleted products.¹⁴⁴

Box 79.4 Patients for Whom Cytomegalovirus-Safe Blood Components Are Strongly Recommended

Seronegative pregnant women

Seronegative premature infants weighing less than 1200 g

Seronegative allogeneic or autologous bone marrow transplant recipients

Seronegative transplant recipients of seronegative organs

Parasites

Many blood-borne parasites may be transmitted by transfusion, although this is a rare occurrence in the United States because of donor screening questions and the low endemicity of implicated agents. Changing immigration patterns and global travel, however, make transfusion-transmitted parasites an increasing concern.

On a worldwide basis, malaria is the most important transfusion-transmitted infective parasite, although only a few cases are reported in the United States each year.¹⁴⁵ Such infections are manifested by delayed fever, chills, diaphoresis, and hemolysis, often masked by underlying medical conditions. Fatalities have occurred. Babesiosis, a tick-borne disease caused by Babesia microti, is endemic in regions of the northeastern United States. Transfusion-transmitted cases have been reported, with asplenic, elderly, or immunocompromised patients being particularly susceptible.¹⁴⁶ Babesiosis was the leading cause of infectious transfusion-related fatality in the United States from 2007 to 2011, and there are no effective methods of donor screening or testing.¹⁰² With increases in the number of Central and South American immigrants to North America, Chagas’ disease, transmitted by the protozoan parasite Trypanosoma cruzi, has emerged as a potential transfusion-transmissible infection.¹⁴⁷ Other parasitic diseases that have been transmitted by transfusion include toxoplasmosis, leishmaniasis, and Lyme disease.

Emerging Infections in Transfusion Medicine

Human parvovirus B19 has been recognized as a pathogen capable of transmission by transfusion, with typical clinical findings and the potential for aplastic anemia. Epstein-Barr virus infection with a typical mononucleosis-like illness has been reported after transfusion. West Nile virus can also be transmitted by transfusion. H2N1 influenza, severe acute respiratory syndrome (SARS), and other new viral infections should be capable of transmission by transfusion, although cases have not been reported and the prevalence of asymptomatic disease is unknown. A rising concern is the transmission of prion disease, either Creutzfeldt-Jacob disease or bovine spongiform encephalopathy (BSE). Donor referral criteria were implemented in 1987 for these diseases, and transfusion transmission of BSE has been reported in the United Kingdom.

Special Transfusion Situations in the Critical Care Setting

Massive Transfusion

Massive transfusion is commonly defined as the administration of blood components in excess of one blood volume or greater than or equal to 10 units PRBCs within a 24-hour period, although other definitions have been used in the literature and for resuscitation protocols.¹⁴⁸ Massive transfusion, especially in the range of 20 or more units of blood products, causes complications not generally seen in usual transfusion practice: accumulation of undesirable substances present within stored blood and dilutional depletion of normal blood constituents that are lacking in stored units. Trauma victims, surgical patients undergoing complex or emergent procedures, and patients with vascular or coagulation disorders may require massive transfusion in the critical care setting. The first priority in such patients is to stop the bleeding but transfusion of blood products occurs simultaneously to maintain hemostasis and ensure oxygen-carrying capacity. Survival is determined more by the nature and degree of the patient’s injuries or medical conditions than by the transfusions, but the presence of adverse effects of massive transfusion can complicate a patient’s course in the ICU.

Transfusion of large quantities of RBCs deficient in functional platelets often results in hemostatic defects and thrombocytopenia. Platelet counts consistently decrease in inverse proportion to the amount of blood administered, with the hemostatically significant level of 50 × 10⁹/L reached after 20 units.¹⁴⁹ Functional defects have also been noted.¹⁵⁰ Despite these laboratory changes, severe diffuse bleeding develops in less than 20% of massively transfused patients, and no laboratory studies alone are predictive. Prophylactic platelet transfusions were not shown to be of benefit in older studies.¹⁵¹ Platelet counts may return to hemostatically effective levels quickly in patients with normal marrow function.

Resuscitation of massively bleeding patients with PRBCs in combination with crystalloids will usually result in hemodilution to about 60% of normal coagulation factor levels after the transfusion of about 10 units; this factor level can usually maintain normal hemostasis. However, if crystalloids are given in excess of PRBCs less plasma protein may remain after 10 units are transfused. Bleeding is unlikely until prothrombin time (PT), INR, and PTT prolongations exceed 1.5 to 1.8 times the midpoint normal range, the equivalent of an INR approaching 2.0.¹⁴⁹ Prophylactic administration of FFP was also not effective in preventing diffuse bleeding in older studies.¹⁵² Based on the earlier studies, previous recommendations suggested that transfusion of blood components in massive bleeding should be based on measured or anticipated results of platelet count and coagulation studies (laboratory driven).

More recently some trauma centers have adopted a protocol approach (formula driven) to replacing platelets and plasma when massive transfusion is required, usually with a set ratio of RBC to platelet and FFP infusions (e.g., 3:1:1 or less).153,154 Variable ratios have been used and the optimal ratio of blood products is not defined. Although the published experiences from these retrospective, nonrandomized studies are generally positive, confirmation is needed from well-designed prospective randomized studies to avoid bias, particularly survival bias that favors higher plasma to RBC ratios.^155,156 Additional reports have also suggested that early transfusion of FFP may not improve outcomes and may predispose to organ failure.^157,158 Until higher quality evidence can support the use of specific blood product ratios in massive transfusion, it is difficult to support this practice.

Blood preservative solutions contain citrate, which anticoagulates stored blood by binding ionized calcium. WB contains approximately 1.8 g of citrate/citric acid per unit in the plasma fraction. Patients with normal liver function can metabolize the citrate load in 1 unit of WB in 5 minutes, but hepatic impairment may extend removal to 15 minutes or longer. Toxicity may result when citrate is administered in excess of the metabolic capacity, thereby causing a decrease in ionized calcium levels.¹⁵⁹ Although paresthesias, cramps, and myoclonus can result from citrate excess, the principal danger of hypocalcemia is depression of myocardial contractility and potential prolongation of the QT interval. Because the effects of citrate are transient and the use of PRBCs containing little residual citrated plasma is far more common than massive transfusion with WB, routine administration of calcium is not indicated; clinically significant rebound hypercalcemia may result. Calcium infusion should be limited to hypoperfused patients with hepatic or cardiac failure who manifest citrate toxicity. Hypomagnesemia is common in patients with massive transfusion, and it is often associated with hypocalcemia.¹⁶⁰ Citrate binds magnesium as well as calcium and may play a role in the development of hypomagnesemia.¹⁴⁸ Hypomagnesemia does not appear to impact outcomes in massively transfused patients.

Potassium leaks from RBCs during storage, and up to 7 mEq of extracellular potassium may accumulate in each unit. Irradiation of RBCs increases extracellular potassium. However, dangerous levels of potassium rarely develop in adults from transfused blood; the potassium level is more likely to be determined by the patient’s acid-base status.¹⁶¹ Studies of massively transfused patients have demonstrated a wide range of potassium levels, with hypokalemia seen as frequently as hyperkalemia. Because of the complexity of physiologic changes during resuscitation, it is impossible to predict the net effect of massive transfusion on serum potassium levels. Potassium levels need to be monitored closely in patients receiving large amount of PRBCs.

The pH of stored blood drops during storage, from 7.16 at the time of collection to as low as 6.73 after several weeks of storage. The administration of large quantities of acidic blood, together with the metabolic acidosis common in these patients before resuscitation, would lead one to expect worsening acidosis as the outcome of massive transfusion. However, patients are more likely to exhibit metabolic alkalosis at the end of the transfusion episode,161,162 partly because of improved tissue perfusion and the metabolism of citrate and lactate to bicarbonate. Patients in renal failure may be unable to handle the bicarbonate load and require dialysis. Acidosis persisting after transfusion suggests inadequate tissue perfusion.¹⁵⁹ Empiric administration of bicarbonate to counter the acid load is not warranted and may contribute to the deleterious effects of hypercapnia in patients with impaired ventilation.

RBC components are stored at approximately 4° C and require 30 to 45 minutes to warm to room temperature. Elective transfusions at standard flow rates are tolerated without the need to warm the blood; however, core body temperature, measured by esophageal probe, can fall to 30° C or lower with the administration of large volumes of cold blood over a period of 1 to 2 hours.¹⁶³ Adverse effects of hypothermia include a decreased heart rate and myocardial contractility, cardiac arrhythmias, increased affinity of hemoglobin for oxygen resulting in decreased tissue oxygen delivery, DIC, and impaired ability to metabolize the citrate load of stored blood. Both blood warmers and patient warming may be instituted during massive transfusion, and patient core temperature should be monitored during resuscitative efforts.

Whether massive transfusion in and of itself is a cause of ARDS is another source of controversy. There are theoretical reasons why massive transfusion might precipitate ARDS because all cellular transfusions contain damaged or activated WBCs, cell membranes, aggregated platelets, and microthrombi, all of which are capable of lodging in and damaging pulmonary capillaries. Despite this possibility, neither microfiltration of transfusions nor routine leukocyte depletion has shown a significant impact on the incidence of ARDS in massively transfused patients.¹⁶⁴ Certainly, other causes of ARDS exist in patients who undergo massive transfusion, and the possibility of TACO and TRALI should be considered in the evaluation of patients with hypoxia and diffuse pulmonary infiltrates after massive transfusion.

Autoimmune Hemolytic Anemia

Patients with autoimmune hemolytic anemia (AIHA) have an autoantibody, usually of broad specificity, that fixes itself to their RBCs and triggers extravascular immune-mediated destruction. Patients with AIHA have a positive direct antiglobulin test (DAT, commonly known as the Coombs test)¹⁶⁵ and varying degrees of hemolysis, and their autoantibodies cause agglutination of RBCs from all donors during crossmatching. If the hemolysis is brisk, patients may require RBC transfusion to support oxygen needs before medical management is effective. Hence, transfusion is difficult because agglutination during crossmatching interferes with proper definition of compatible units of RBCs and because the transfused RBCs are themselves subject to the same immune hemolysis as the host RBCs. Many blood banks have methods for depletion of autoantibodies from the recipient’s plasma and elution of antibodies from RBCs to arrive at a proper crossmatch.¹⁶⁶ Although such crossmatches are time consuming and not generally available on an emergency basis, they can be lifesaving. Criteria for transfusion should remain the same as for other recipients.

Necessary Transfusion of Incompatible Blood

RBCs are crossmatched for RBC antigens in the ABO and Rh₀(D) group and for other RBC antigens when antibodies are present. However, there are several hundred other RBC antigens in the human family and with repeated transfusion recipients may become alloimmunized to other antigens. Generally, alloimmunization occurs in approximately 1% of transfusions, but the prevalence of alloantibodies is higher in chronically transfused, relatively immunocompetent patients, especially African Americans, whose distribution of RBC antigens has significant variation from the white population. Alloimmunization may present difficulties in crossmatching of blood to the point that compatible blood must be obtained from rare-donor registries, if at all. In some patients the alloantibody is never precisely identified, yet the majority of blood available for transfusion is incompatible. The delay engendered by working with multiple or unidentified antibodies may be unacceptable in some critical care situations in which the need for oxygen-carrying capacity leaves no choice but to transfuse incompatible blood. The behavior of these antibodies in the laboratory may assist in predicting the clinical outcome of the incompatible transfusion.¹⁶⁷ Special procedures such as clearance studies, flow cytometry, and in vivo crossmatching (cautious administration of a small aliquot of blood, with subsequent observation of serum and urine for evidence of hemolysis) are useful if time permits.

Emergency transfusion of type O, Rh-negative uncrossmatched blood is generally reserved for the resuscitation of trauma patients, for whom the delay in crossmatching may be life-threatening. The risks of alloimmunization to non-ABO antigens are generally accepted as low and a recent study found antigen-incompatible RBCs were transfused in 2.6% of patients who required emergency blood release.¹⁶⁸ Even Rh-positive type O RBCs may be used because rates of alloimmunization to Rh₀(D) are low under the circumstances of emergency transfusion.

Transfusion in Patients with Disseminated Intravascular Coagulation

DIC is a common disorder in critically ill patients that may manifest as severe hemorrhage or thrombosis. Therapy is primarily directed at treating the cause and supporting the patient. Supportive therapy includes the transfusion of blood components needed to correct the bleeding diathesis caused by the consumption of platelets and fibrinogen, in addition to PRBCs to restore oxygen-carrying capacity. Platelets and fibrinogen (as cryoprecipitate) are the most common components used to treat the coagulopathy, but their use risks increasing the microvascular thrombosis of DIC. Heparin anticoagulation is controversial and may increase the risk of bleeding, especially if depleted factors are not replenished. No clinical trials support the routine use of heparin, and randomized trials of other components and coagulation inhibitors have uniformly been negative.

Hepatic Failure

Cirrhotic patients or those with fulminant hepatic failure have a variety of hemostatic disorders that complicate transfusion management of a bleeding patient.¹⁶⁹ Hepatic synthesis of coagulation factors may be markedly diminished, thereby necessitating replacement by FFP or cryoprecipitate. Patterns of factor diminution may vary between acute hepatic necrosis and chronic cirrhosis.¹⁷⁰ Associated hemodynamic alterations may make it impossible to administer the volumes required for effective hemostasis, however, and any effect is transient. The use of factor concentrates or antifibrinolytic agents may precipitate thrombosis. Activation of fibrinolysis and decreased clearance of activated factors may produce or mimic chronic DIC, thus further exacerbating the factor deficiencies and impairing coagulation. Abnormal platelet function and thrombocytopenia may contribute to the coagulopathy of liver disease, with concomitant splenomegaly reducing the effectiveness of platelet transfusions. As with DIC, blood product transfusions for coagulopathy of hepatic failure have not demonstrated any long-term benefits, and should be considered only to achieve emergent hemostasis.

Alternatives to Transfusion of Blood Components

The safest transfusion is one that is not given. Therefore, alternatives to blood component therapy continue to be sought. It may be possible to limit blood component exposure by the appropriate use of pharmacologic agents that promote hemostasis and the administration of recombinant hematopoietic growth factors to stimulate marrow hematopoiesis.

Blood Substitutes

Two types of alternative oxygen carriers are being evaluated for clinical use, but no oxygen-carrying blood substitute is currently approved for use in the United States.171,172 Perfluorocarbons are hydrophobic molecules with high oxygen-carrying capacity that have to be administered as an emulsion to be soluble in plasma. The perfluorocarbon solutions have failed to demonstrate any utility as intravascular oxygen carriers because of their unfavorable P-50 (oxygen half-saturation pressure) and oxygen off-loading characteristics. The other type of preparation that has been explored in clinical trials is cell-free hemoglobin solutions cross-linked or polymerized by chemical manipulation to prevent rapid clearance from the circulation. Known as hemoglobin-based oxygen carriers (HBOCs), they are intended to provide short-term oxygen-carrying capacity for acutely ill patients and have the advantage of not requiring cross-matching and no risk of infection. Although these proposed products may have a longer shelf-life and are easier to transport, they have many drawbacks. Most have a circulatory half-life of only about 24 hours. The oxygen dissociation curve for these substitutes is also frequently not favorable: either a high FIO₂ is required to “load” these molecules or they are less likely to deliver oxygen efficiently at lower PO₂ levels. Certain preparations of HBOCs are currently in clinical trials. Main concerns for HBOCs have been unfavorable side effects including hypertension, increased cardiovascular mortality risk, and renal dysfunction. Because the hemoglobin source is reclaimed bovine or human RBCs, it is unlikely that patients who do not accept blood components because of their religious beliefs (Jehovah’s Witnesses) will accept these types of hemoglobin solutions.

Desmopressin

The synthetic vasopressin analog, desmopressin (DDAVP), increases plasma factor VIII : c and promotes the release of von Willebrand factor from endothelial stores.¹⁷³ DDAVP has provided effective hemostasis in bleeding patients with mild hemophilia A and type I von Willebrand disease and has been used as prophylaxis for patients undergoing surgery. DDAVP reportedly improves platelet function in some patients with qualitative platelet disorders associated with uremia, cirrhosis, and aspirin ingestion. Studies of its efficacy in cardiopulmonary bypass procedures are conflicting, but a subset of these patients may benefit. The chief drawback to its use is tachyphylaxis, which develops in essentially all cases after short-term repeated administration.

Legal Issues in Transfusion Medicine

Most states regulate blood banking and medical practice, but blood products are regarded as a service, not as a commodity, so standard product liability does not pertain to blood components.¹⁸³ However, negligence in the course of preparing, testing, transferring, crossmatching, and administering blood products is still a potential cause for legal action. Every clinician who orders transfusions must be aware that blood components, like drugs, are approved for specific uses and that the indications should be clearly documented in the medical record.

The informed consent of the patient is an important area of potential liability. The Joint Commission has required written patient consent for blood transfusions since 1996. What constitutes adequate informed consent and who is responsible for advising the patient are still debated. Elements of informed consent include an understanding of the need for transfusion, its risks and benefits, and the alternatives, including the risk of not undergoing transfusion, as well as the opportunity to ask questions. Whether the clinician documents informed consent with an individual progress note in the patient record or with a standardized form is generally established as institutional policy. Similarly, institutions vary with respect to policies for consenting adults who are temporarily incompetent, such as sedated patients in the ICU.

A competent adult patient may refuse blood transfusion, and Jehovah’s Witnesses commonly do so for religious reasons. Case law is clear in upholding this right of the patient,¹⁸⁴ which extends to care given at such time as the patient may become incompetent (i.e., comatose) after such refusal was expressed before becoming incompetent. Courts will usually order a lifesaving transfusion for minors. Exceptions have been made in the case of some “emancipated minors” who are at the age of reason. Most states have evoked a “special interest” in the welfare of a fetus in ordering transfusions to pregnant women.

The advent of sentinel event reviews and other quality management procedures for patient safety has had an impact on transfusion practice as well. Procedures for patient identification before surgical procedures, including devices such as bar code readers, have also been applied to transfusion practice.

Key Points

• Blood components should be prescribed like therapeutic agents as part of a blood management program.

• RBC transfusion can be considered when the hemoglobin is less than or equal to 7 g/dL for the majority of hemodynamically stable ICU patients. A transfusion threshold of less than 8 g/dL may be appropriate for patients with symptomatic cardiovascular disease and postoperative surgical patients.

• Platelet transfusions are indicated for patients who have active bleeding due to thrombocytopenia or functional platelet defects and for the prevention of bleeding due to thrombocytopenia.

• FFP is indicated for the repletion of coagulation factors in bleeding patients deficient in those factors or to provide specific plasma proteins that cannot be obtained from safer sources.

• Cryoprecipitate is a concentrated source of fibrinogen and selected coagulation factors. Cryoprecipitate may be more helpful than FFP in correcting the hypofibrinogenemia of dilutional or consumptive coagulopathy.

• Adverse reactions to blood components occur in 1% to 2% of transfusion episodes. Adherence to routine protocols for the evaluation of transfusion reactions may save lives.

• Transmission of infectious agents by transfusion has been markedly reduced, and bacterial infection is now the most common infectious complication of transfusion.

• Adverse effects unique to massive transfusion are likely to complicate the management of critically ill or severely injured patients. Component therapy for such patients should remain conservative pending the outcome of prospective studies.

• Informed consent for blood transfusion is a standard of practice. A competent adult has the legal right to refuse blood transfusion.