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1494 SECTION 18: Hematologic and Oncologic Disorders TABLE 237-5 Additional Causes of Hemolysis Cause Disorder Comments Infection Malaria Protozoan infects and damages RBCs, producing “blackwater fever” or hemoglobinuria Babesiosis Protozoan infects and damages the RBC Clostridium perfringens Toxin lyses RBCs Leptospirosis Weil’s syndrome; toxin lyses RBCs Envenomation Hymenoptera stings Requires massive venom injection Brown recluse spider Part of systemic loxoscelism Pit viper; Crotalinae; Elapidae; Viperinae Intravascular RBC destruction Chemical exposure Arsine Hemolysis can present 24 h after exposure 43,44 Naphthalene Mothballs; well water contaminated by toxic dumps; can affect fetus in utero and neonates; patients with G6PD deficiency at higher risk Direct impact trauma March hemoglobinuria Runners, soldiers, karate, conga drummers 45; hemoglobinuria but usually not anemia45-47 Abbreviations: G6PD = glucose-6-phosphate dehydrogenase; RBC = red blood cell. The mortality rate in typical HUS is about 5% to 15%. Historically, patients with atypical HUS had a poor outcome, with permanent renal failure or neurologic damage occurring in about half of patients and a morality rate approaching 25%. Aggressive treatment, including eculi zumab, appears to significantly reduce the incidence of permanent renal failure and lower the death rate in atypical HUS. MACROVASCULAR HEMOLYSIS A prosthetic heart valve may create turbulent blood flow with high shear stress across the valve. Older-generation mechanical heart valves were subject to deterioration that produced subsequent hemolysis, but hemolysis associated with current prosthetic heart valve models is most often attributed to paravalvular leak. Such leaks may occur at the time of valve placement or develop later in the life of the prosthetic valve if infection or calcification promotes dehiscence. 40 Particularly after mitral valve replacement, hemolysis may occur at both clinically insignificant and significant levels. Macrovascular hemolysis can also occur after intracardiac patch repair or aortofemoral bypass; in patients with coarctation of the aorta, severe aortic valve disease, or ventricular assist devices ; and in patients requiring the use of extracorporeal circulation such as dur ing cardiopulmonary bypass, plasma exchange, or hemodialysis. 41,42 Mechanical sheer stress, chemical contaminant, and exposure to dialysis membranes are all factors contributing to hemolysis risk during hemo dialysis, although technologic advances have made these events rare. Patients with ongoing mild macrovascular hemolysis should receive supplemental iron and folate to promote healthy reticulocytosis. By reducing the heart rate, β-blocker therapy may decrease RBC shear stress in the presence of a prosthetic valve and thereby mitigate hemo lysis. Pentoxifylline, a xanthine derivative that reduces blood viscosity and improves RBC flexibility and deformability, can reduce hemolysis associated with prosthetic heart valves. 40 Hemolysis associated with extracorporeal circulation typically begins during the procedure, but such patients may or may not exhibit symptoms until hours afterward. ADDITIONAL CAUSES OF HEMOLYSIS Infection, envenomation, chemical exposure, and trauma can also result in hemolysis (Table 237-5). REFERENCES The complete reference list is available online at www.TintinalliEM.com. Transfusion Therapy Clinton J. Coil Sally A.

tients may or may not exhibit symptoms until hours afterward. ADDITIONAL CAUSES OF HEMOLYSIS Infection, envenomation, chemical exposure, and trauma can also result in hemolysis (Table 237-5). REFERENCES The complete reference list is available online at www.TintinalliEM.com. Transfusion Therapy Clinton J. Coil Sally A. Santen INTRODUCTION Modern transfusion practice uses blood collected using a preservative– anticoagulant combination (usually citrate phosphate dextrose or citrate phosphate dextrose adenine-1). The collected whole blood is tested for transfusion-transmitted diseases and most often separated into specific components supplied as standardized preparations termed “units” (Table 238-1). 1 Transfusion in the ED typically is done for acute blood loss and/or circulatory shock using packed red blood cells (PRBCs), with increasing interest in using stored whole blood in severely bleeding patients. 2 Coagulation factors derived from human plasma or manufactured with recombinant technology are used to treat hemorrhage associated with a deficiency of one or more factors or to reverse the effect of antithrombotic medications (see Chapter 239, “Thrombotics and Anti thrombotics”) (Table 238-2). Safe transfusion practice uses informed consent (patient is informed about the risks, benefits, and alternatives to transfusion) and steps to ensure that the correct blood product is delivered to the correct patient. A best practice is to use two individuals to verify the identification of the patient and the unit before transfusion. Bar code identification along with verification by one individual is an alternative to two-person verification. BLOOD TRANSFUSION  STORED WHOLE BLOOD There is increasing interest in the practice of whole blood transfusion early in the resuscitation of patients with hemorrhagic shock, often before their ABO group is known. 4,5 The possible advantage is that whole blood as the initial resuscitation fluid efficiently provides treat ment for blood loss, coagulopathy, and platelet hemostatic function to patients losing large volumes of blood. In addition, whole blood trans fusion is simpler to administer since all three components (red cells, platelets, and plasma) are in one bag. Whole blood transfusion has been used by the military to treat traumatic hemorrhagic shock since the Korean War. 6 Based on this experience, several civilian trauma and EMS systems have started using whole blood transfusion. In response, the American Association of Blood Banks issued standards for whole blood transfusion in Standards for Blood Banks and Transfusions, 31st edition, effective April 1, 2018. Whole blood transfusion uses either stored or fresh whole blood. 7 Stored whole blood has a shelf life dependent on the anticoagulant used—21 days for citrate phosphate dextrose or 35 days for citrate phos phate dextrose adenine-1—although the hemostatic function of stored whole blood degrades after 2 weeks of storage. Fresh whole blood is collected via donation from prescreened donors (“walking blood donors”) immediately before transfusion. Because fresh whole blood does not undergo testing before transfusion, it is used solely by the military for CHAPTER Tintinalli_Sec18_p1461-1522.indd 1494 8/2/19 8:37 PM

after 2 weeks of storage. Fresh whole blood is collected via donation from prescreened donors (“walking blood donors”) immediately before transfusion. Because fresh whole blood does not undergo testing before transfusion, it is used solely by the military for CHAPTER Tintinalli_Sec18_p1461-1522.indd 1494 8/2/19 8:37 PM CHAPTER 238: Transfusion Therapy 1495 TABLE 238-1 Blood Products Component Shelf Life Approximate Volume/Unit (mL) Approximate Content/Unit* Initial Dose Initial Dose Effect Without Ongoing Loss or Destruction of Red Cells or Platelets Stored whole blood (type O, with low titer of anti-A and anti-B antibodies used for emergency unmatched transfusions) 21 d for CPD and 35 d for CPDA-1 500 Red cells 35%–38%, platelet count 150,000–200,000/mm (150–200 × 10 9/L), coagulation factors approximately 85% of predonation levels Adult: 2 units Raises hemoglobin concentration approximately 2 grams/dL (20 grams/L) or hematocrit by 6% in adults Packed red blood cells 21–42 d 250–350 Red cells 65%–80% Plasma 10–20 mL Adult: 2 units Raises hemoglobin concentration approximately 2 grams/dL (20 grams/L) or hematocrit by 6% in adults Platelets (apheresis-collected single-donor platelet concentrate) 5 d 250–300 Platelets 3–6 × 10 11 1 unit or 5 mL/kg Raises platelet count by up to 50,000/mm 3 (50 × 109/L), but less in many cases Platelets (pooled donor platelet concentrate, rarely used in the United States) 5 d 50–60 Platelets 8–9 × 10 10 6 units or 5 mL/kg Raises platelet count by up to 50,000/mm 3 (50 × 109/L), but less in many cases Abbreviations: CPD = citrate phosphate dextrose; CPDA-1 = citrate phosphate dextrose adenine-1. *Unless specifically prepared, most blood-derived products contain small amounts of white blood cells, red blood cells, platelets, and plasma in addition to the specific component.

0/mm 3 (50 × 109/L), but less in many cases Abbreviations: CPD = citrate phosphate dextrose; CPDA-1 = citrate phosphate dextrose adenine-1. *Unless specifically prepared, most blood-derived products contain small amounts of white blood cells, red blood cells, platelets, and plasma in addition to the specific component. TABLE 238-2 Coagulation Factor Products Type of Product* Initial Dose Comments and Approved Indications Fresh frozen plasma (FFP) 4 units or 15 mL/kg Volume 200–250 mL/unit 1 unit contains about 200–250 units of each individual coagulator factor and 400–500 milligrams of fibrinogen Initial dose raises most coagulation factor levels approximately 20% Shelf life: 1 y frozen and up to 5 d after thawing Used for coagulation factor replacement Cryoprecipitate 1 unit per 5–10 kg body weight; typically 10 units in an adult Volume 30–40 mL/unit Each unit typically contains: factor VIII 80–140 units, fibrinogen 150–250 milligrams, von Willebrand factor 80–100 units, and factor XIII and fibronectin in variable amounts Initial dose increases fibrinogen 50–100 milligrams/dL (0.5–1.0 gram/L) Shelf-life: 1 y frozen and 4 h thawed Used for replacement of fibrinogen, factor XIII, factor VIII, or von Willebrand factor Fibrinogen concentrate (human) RiaSTAP ® (CSL Behring) Dosed to increase fibrinogen level from baseline to >150 milligrams/dL (1.5 grams/L) If baseline fibrinogen level unknown, administer 70 milligrams/kg Each vial contains 900–1300 milligrams of fibrinogen Used for acute bleeding episodes in patients with congenital fibrinogen deficiency Factor IX complex Profilnine SD ® (Grifols Biologicals) Bebulin VH® (Baxter Healthcare Corporation) Dosed according to desired factor IX increase Contains factors II, IX, and X Used in hemophilia B (factor IX deficiency) Prothrombin complex concentrate (human) Kcentra ® or Beriplex® P/N (CSL Behring) Octaplex® (Octapharma) Dosed in factor IX units according to pretreatment INR Contains factors II, VII, IX, and X and may also contain antithrombotic protein C and protein S Used for urgent reversal of bleeding due to vitamin K antagonist (e.g., warfarin) in adult patients Anti-inhibitor coagulant complex FEIBA NF® (Baxter) 50–100 units/kg Contains factors II, IX, and X, mainly nonactivated, and factor VII, mainly in activated form Used in hemophilia A or B patients with inhibitors Coagulation factor VIIa (recombinant) NovoSeven ® RT (Novo Nordisk) 90 micrograms/kg Bleeding episodes and perioperative management in hemophilia A or B patients with inhibitors Congenital factor VII deficiency Glanzmann’s thrombasthenia with refractoriness to platelet transfusions Bleeding episodes and perioperative management in adults with acquired hemophilia *Commercial trade names provided for ease of product identification. severely bleeding patients when stored blood or component therapy is not available (e.g., resuscitative care initiated in active combat zones). Fresh whole blood is not approved for civilian use by the American Association of Blood Banks or U.S. Food and Drug Administration. Although transfused whole blood can be matched to the blood type of the recipient patient before use, the most urgent need for whole blood transfusion is in the severely bleeding patient before blood typing (e.g., in the ambulance, helicopter, or ED). It is important to note that while Tintinalli_Sec18_p1461-1522.indd 1495 8/2/19 8:37 PM

whole blood can be matched to the blood type of the recipient patient before use, the most urgent need for whole blood transfusion is in the severely bleeding patient before blood typing (e.g., in the ambulance, helicopter, or ED). It is important to note that while Tintinalli_Sec18_p1461-1522.indd 1495 8/2/19 8:37 PM 1496 SECTION 18: Hematologic and Oncologic Disorders type O is the universal donor for red cells, it is not the universal donor for plasma (see later section “Fresh Frozen Plasma”). As a result, donated units of type O whole blood are tested for levels of anti-A and anti-B antibodies, and units with low titers of anti-A and anti-B antibodies are used in unmatched whole blood transfusion to decrease the risk of hemolytic transfusion reactions. Similar to unmatched PRBCs, men and women over age 50 years may receive Rh-positive blood, whereas women of childbearing age should receive Rh-negative blood. When unmatched stored whole blood transfusion is used, obtain a pretransfusion sample to establish the recipient’s blood group as it may be difficult to determine after transfusion. The practice of whole blood transfusion in civilian hospitals and EMS systems is currently limited to a few loca tions in the United States, but further expansion is anticipated.  PACKED RED BLOOD CELLS Adult total blood volume is approximately 2.5 L/m2, 75 mL/kg, or about 5 L in a 70-kg person. Although whole blood would seem ideal to replace red cells, the platelets and plasma present are not usually neces sary and could be separated and used for directed treatment of patients with thrombocytopenia or coagulopathy, respectively. Therefore, whole blood is most often fractionated to its components for storage and transfusion. PRBCs are prepared by the centrifugation of whole blood collected with the preservative and anticoagulant solution to remove approximately 80% of the plasma (Table 238-1). Emergency PRBC transfusion is usually performed for acute blood loss or profound anemia to restore intravascular oxygen-carrying capacity. A hemoglobin concentration of 7 grams/dL (70 grams/L) or greater is adequate to support oxygen delivery in most adults who are hemo dynamically stable. Substantial evidence supports that the hemoglobin threshold of 7 grams/dL (70 grams/L) for PRBC transfusion—termed a restrictive threshold—is safe and effective. 9,10 For patients with preexisting cardiovascular disease or who are undergoing orthopedic or cardiac surgery, the recommended transfusion threshold is a hemoglobin con centration of 8 grams/dL (80 grams/L). 8-10 There is inadequate evidence for the threshold that should be used in patients with acute coronary syndrome, hematologic or oncologic conditions, chronic transfusiondependent anemia, or severe thrombocytopenia (since anemia has been shown to reduce platelet effectiveness). For actively bleeding patients, transfusion is based on clinically estimated blood loss rather than hemoglobin levels, because the fall in measured hemoglobin will lag behind the clinical impact of acute blood loss. A loss of about 30% blood volume (1500 mL in an adult) generally produces symptoms and signs, but young, healthy patients can tolerate this degree of loss, especially when treated with crystal loid. However, patients with chronic illness such as underlying anemia, cerebrovascular disease, or cardiac diseases; those with pacemakers; and those on β-blockers or similar medications may not tolerate blood loss. Consider emergency PRBC transfusion for unstable trauma patients based on an inadequate response to an initial 2-L bolus of IV crystalloid (see Chapter 13, “ Approach to Traumatic Shock”).

ar disease, or cardiac diseases; those with pacemakers; and those on β-blockers or similar medications may not tolerate blood loss. Consider emergency PRBC transfusion for unstable trauma patients based on an inadequate response to an initial 2-L bolus of IV crystalloid (see Chapter 13, “ Approach to Traumatic Shock”). Use the anticipated clinical course to guide the decision to transfuse the patient with acute hemorrhage, with a lower threshold if the source of bleeding cannot be controlled immediately compared to a patient whose acute hemorrhage has stopped. Use the minimum amount of PRBCs to accomplish the desired clinical outcome. 9 A single PRBC unit will raise the hemoglobin by 1 gram/dL (10 grams/L) and hematocrit by 3% in adults. In children, 10 to 15 mL/kg of PRBCs will raise the hematocrit by 6% to 9% and the hemoglobin level by approximately 2 to 3 grams/dL (20 to 30 grams/L). One unit of PRBCs, approximately 250 mL in volume, is generally transfused over 1 to 2 hours in stable patients, with faster infusion rates in patients with hemodynamic instability. Single-unit PRBC transfu sions should not exceed 4 hours to prevent contamination. If a slow transfusion is desired (e.g., in a patient at risk for volume overload), the blood bank should be asked to split a unit so that the first half can be transfused over 4 hours while the second half waits in the blood bank refrigerator. During standard transfusions, the initial infusion rate is slower over the first 30 minutes so that if there is a transfusion reaction, the infusion may be stopped. Type, Screen, and Cross-Match PRBC transfusion requires match ing the recipient’s and donor’s red blood cells according to blood type (ABO and Rh) and screening the recipient’s plasma for antibodies to the minor red blood cell antigens. Screening is done using a mixture of commercially available red blood cells that have all the important minor antigens. If the screen is positive for antibodies, then the recipient’s plasma is cross-matched against the specific PRBC unit intended for transfusion. Blood type can be determined in approximately 15 minutes, whereas it takes about 45 to 60 minutes to perform a serologic crossmatch. If an anti–red blood cell antibody is found in the recipient’s plasma, cross-matching may take longer and require additional blood specimens from the patient. Type O Rh-negative (universal donor) PRBC may be used in critical circumstances because these transfused red cells do not contain major blood group antigens (A or B). Type O Rh-positive blood may be used if type O Rh-negative is not available, but should be avoided in girls and women of childbearing potential. Approximately 20% of Rh-negative patients transfused with 1 unit of Rh-positive PRBCs will develop anti- Rh(D) antibodies, creating the risk for hemolytic disease of the newborn with subsequent pregnancies. This is usually clinically inconsequential for men or postmenopausal women. Treated Red Blood Cells PRBCs may be further treated for specific clinical applications: leukocyte-reduced PRBCs, irradiated PRBCs, washed PRBCs, and frozen PRBCs. 8 Leukocyte-reduced PRBCs have 70% to 85% of the white cells removed in order to (1) decrease the occurrence of nonhemolytic febrile reactions due to cytokines from transfused white cells; (2) prevent sensitization to human leukocyte antigen antibodies found on white cells in patients who may be eligible for bone marrow transplantation; and (3) minimize the risk of intracellular virus trans mission, such as cytomegalovirus. Irradiation of PRBCs eliminates the capacity of T lymphocytes to proliferate, thereby preventing the donor’s T lymphocytes from reacting to the recipient’s cells and thus reducing the risk for graft-versus-host disease.

plantation; and (3) minimize the risk of intracellular virus trans mission, such as cytomegalovirus. Irradiation of PRBCs eliminates the capacity of T lymphocytes to proliferate, thereby preventing the donor’s T lymphocytes from reacting to the recipient’s cells and thus reducing the risk for graft-versus-host disease. Irradiated cells are used in transplant patients, neonates, and immunocompromised patients, and with directed donations from relatives of the patient. Washed PRBCs are indicated in patients who have a hypersensitivity to plasma, such as those with immunoglobulin A deficiency or persistent febrile reactions. For rare blood types, red cells may be frozen and saved for up to 10 years for later use.  MASSIVE TRANSFUSION Massive transfusion in adults is variously defined as either the replacement of one blood volume (approximately 10 units of PRBCs) within a 24-hour period, replacement of 50% of blood volume within 3 hours, or ongoing transfusion during a period of rapid bleeding, such as >150 mL/min. 12 If only PRBCs were used, platelets and coagulation factors lost or consumed would not be replaced, potentially increasing bleeding. Massive transfusion protocols using fixed ratios of PRBCs, platelets, and fresh frozen plasma (FFP) are in common use (see Chapter 13, “ Approach to Traumatic Shock”). 12 The optimal ratio of PRBCs to platelets to FFP is not estab lished.13 Some protocols include cryoprecipitate, fibrinogen concentrate, coagulation factor VIIa (recombinant), tranexamic acid, or prothrombin complex concentrate. 12 Although most research on massive transfusion protocols has been in trauma, many institutions use similar strategies for other causes of hemorrhagic shock, such as postpartum hemorrhage or massive GI bleeding. Draw sufficient specimens early in the course from massive transfu sion patients because once the patient has received close to one blood volume of transfused products, new blood specimens will contain so much donor blood that it will confuse further cross-matching of subse quent units. Hypothermia is a risk during massive transfusion, so blood and crystalloid should be warmed, in addition to instituting warming measures for the patient. Hypocalcemia from the preservative citrate chelating calcium may occur with a massive transfusion.  PLATELET TRANSFUSION Platelet transfusions are used either prophylactically to prevent bleeding in thrombocytopenia or therapeutically when patients with thrombo cytopenia are actively bleeding. One apheresis-collected, single-donor Tintinalli_Sec18_p1461-1522.indd 1496 8/2/19 8:37 PM

ccur with a massive transfusion.  PLATELET TRANSFUSION Platelet transfusions are used either prophylactically to prevent bleeding in thrombocytopenia or therapeutically when patients with thrombo cytopenia are actively bleeding. One apheresis-collected, single-donor Tintinalli_Sec18_p1461-1522.indd 1496 8/2/19 8:37 PM CHAPTER 238: Transfusion Therapy 1497 platelet concentrate is the standard product in developed countries (Table 238-1). Platelets collected from six different donors can be pooled to create one unit for transfusion, but this practice is not recommended because this increases the risk of disease transmission and transfusion reaction. One apheresis single-donor platelet unit will increase the platelet count by up to 50,000/mm 3 (50 × 10 9/L), an amount sufficient to pro vide prophylaxis or stop spontaneous and minor traumatic bleeding in most situations. Check platelet levels at 1 and 24 hours after transfusion completion because the response is variable. Transfused platelets should survive 3 to 5 days; failure of platelets to rise appropriately may be due to increased consumption of platelets from an underlying process, active thrombosis due to ongoing hemorrhage, destruction due to platelet antibodies, or sequestration due to hypersplenism. The decision to transfuse platelets depends on the severity of throm bocytopenia and clinical circumstances. Among the evidence-based guidelines issued by the American Association of Blood Banks in 2015 and by the British Committee for Standards in Hematology in 2016, the indications most relevant to emergency medicine are a combination of thrombocytopenia and bleeding or risk of bleeding ( Table 238-3). 15-17 Consult with a transfusion medicine specialist or hematologist if uncertain about platelet transfusion in a specific situation. There are variable recommendations concerning platelet transfusions in patients with nonfunctioning platelets, on antiplatelet medications, or with uremia, von Willebrand’s disease, or hyperglobulinemia. In von Willebrand’s disease, normal platelets may help deliver von Willebrand factor to the bleeding site. Conversely, in uremic patients, the transfused platelets may not function any better than native platelets. Platelets are of no benefit in patients with spontaneous cerebral hemorrhage associated with antiplatelet agents. Relative contraindications to the transfusion of platelets are disorders associated with platelet activation, such as thrombotic thrombocytope nic purpura or heparin-induced thrombocytopenia, in which transfusion may worsen thrombosis. In these conditions, ongoing bleeding or the need to perform procedures may necessitate platelet transfusion in consultation with the appropriate specialist. Platelet transfusions are usually ABO-type specific because the platelets are bathed in plasma, although a serologic cross-match is usually not done. As a result, patients receiving platelets are subject to many of the same complications described for plasma transfusion. Depending on availability, non–type-specific platelets may sometimes be transfused. This practice is usually avoided in children or patients receiving multiple transfusions because they are at higher risk for complications. Transfusing non–type-specific platelets may also shorten the half-life of the transfused platelets. As with PRBCs, platelets can be leukocyte reduced or washed. Patients who have had repeated transfusions may become alloimmunized and refractory to platelet transfusion, noted by the lack of expected rise in platelet count after transfusion. Such patients need human leukocyte antigen–matched or cross-matched platelets.

As with PRBCs, platelets can be leukocyte reduced or washed. Patients who have had repeated transfusions may become alloimmunized and refractory to platelet transfusion, noted by the lack of expected rise in platelet count after transfusion. Such patients need human leukocyte antigen–matched or cross-matched platelets. Other factors may affect the efficacy of platelet transfusion, including bacterial sepsis in the recipient, antibiotics forming an antigen complex epitope with the platelet, disseminated intravascular coagulation, and splenomegaly. COAGULATION FACTOR TRANSFUSION  FRESH FROZEN PLASMA FFP is obtained after the cells are separated from whole blood and then frozen within 8 hours of collection. 19 FFP takes approximately 20 to 40 minutes to thaw, and this process cannot be sped up through artificial heating. Once thawed, FFP can be transfused up to 5 days later. Trauma centers and other specialty hospitals may keep prethawed units of FFP available. Each unit of FFP has a volume of 200 to 250 mL and contains approximately 1 unit of each coagulation factor and 2 milligrams of fibrinogen per milliliter (Table 238-1). The increase in individual coagulation fac tors seen after FFP infusion varies with the specific factor. In general, 1 unit of FFP will increase most coagulation factors by 3% to 5% in a 70-kg adult. For clinically relevant correction of severe coagulation fac tor deficiencies, a dose of 15 mL/kg (or 4 units in a 70-kg adult) is often required (Table 238-1). Transfused FFP should be ABO type compatible; however, Rh com patibility is unnecessary. It is a misconception that type O plasma is a universal donor, as it is for PRBCs. This is not the case, because type O plasma contains antibodies to A and B blood group antigens. Type AB is the universal donor for FFP , and in emergencies, universal donor FFP can be given minutes after thawing. Because it is hard to maintain a supply of type AB plasma, type A plasma can be used for emergencies if the recipient is type B or AB. FFP is used for bleeding from warfarin-induced overanticoagulation when prothrombin complex concentrate is not available, for replacement of multiple coagulation deficiencies, for deficiency of an individual coagulation factor when a specific replacement is not available, and during massive transfusion (Tables 238-4 and 238-5). 21 Other possible indications for FFP include hereditary angioedema if C1 esterase inhibitor is not available (see Chapter 14, “ Allergy and Anaphylaxis”). 22 FFP is used during plasma exchange for treatment of diseases such as thrombotic thrombocytopenic purpura and Guillain-Barré syndrome. 23 FFP is not recommended to reverse anticoagulation from direct oral anticoagulants such as dabigatran, rivaroxaban, apixaban, or edoxaban (see Chapter 239, “Thrombotics and Antithrombotics”). 24 There is no evidence to support the use of FFP in coagulopathic patients for procedures such as central venous line placement.25 Clinically adequate hemostasis is generally present with functional coagulation factor levels 30% to 40% of normal, which corresponds to an INR of about 1.7; thus, FFP administration to reverse coagulopathy should be restricted to patients with an INR of ≥1.8.  CRYOPRECIPITATE Cryoprecipitate is the cold-insoluble protein fraction of plasma containing primarily factor VIII and fibrinogen. There is significant variability in volume and content of cryoprecipitate units prepared from different centers. 27 With the development of recombinant factor VIII products for use in hemophilia and fibrinogen concentrates for use in hypofibrino genemia, there is a lesser role for cryoprecipitate.

VIII and fibrinogen. There is significant variability in volume and content of cryoprecipitate units prepared from different centers. 27 With the development of recombinant factor VIII products for use in hemophilia and fibrinogen concentrates for use in hypofibrino genemia, there is a lesser role for cryoprecipitate. 28 Cryoprecipitate may be used in bleeding patients with fibrinogen levels <100 milligrams/dL (<1 gram/L) due to severe liver disease, uremia, disseminated intravascular coagulation, and dilutional coagulopathy, although there is controversy TABLE 238-3 General Indications for Platelet Transfusion •   Platelet count <5000/mm3 (<5 × 109/L) •   Platelet count <10,000/mm3 (<10 × 109/L) for therapy-induced thrombocytopenia (e.g., chemotherapy) •   Platelet count <20,000/mm3 (<20 × 109/L) with a coagulation disorder or low-risk procedure (including central line placement) •   Platelet count <50,000/mm3 (<50 × 109/L) with active bleeding, lumbar puncture, or major surgery •   Platelet count <100,000/mm3 (<100 × 10 9/L) with neurologic or ophthalmologic surgery, intracranial hemorrhage, or major multisystem trauma •   As part of a massive transfusion protocol •   Platelets are generally not indicated for ITP, TTP, or HIT, except in the context of ongoing severe bleeding Abbreviations: HIT = heparin-induced thrombocytopenia; ITP = immune thrombocytopenic purpura; TTP = thrombotic thrombocytopenic purpura. TABLE 238-4 General Indications for Fresh Frozen Plasma Transfusion •  Reversal  of warfarin overanticoagulation when PCC not available •  Bleeding  with multiple coagulation defects •  Correction  of coagulation defects for which no specific factor is available •  As  a component of a massive transfusion protocol •   As part of plasma exchange when treating thrombotic microangiopathies or neurologic disorders Abbreviation: PCC = prothrombin complex concentrate. Tintinalli_Sec18_p1461-1522.indd 1497 8/2/19 8:37 PM 1498 SECTION 18: Hematologic and Oncologic Disorders TABLE 238-5 Replacement Therapy for Congenital Factor Deficiencies Coagulation Factor Approximate Incidence* Replacement Therapy Factor I (fibrinogen) 1 per million Fibrinogen concentrate Cryoprecipitate (if fibrinogen concentrate unavailable) Factor II (prothrombin) 1 per 2 million PCC Factor V 1 per million FFP Factor VII 1 per 500,000 PCC Coagulation factor VIIa (recombinant) Factor VIII †

1498 SECTION 18: Hematologic and Oncologic Disorders TABLE 238-5 Replacement Therapy for Congenital Factor Deficiencies Coagulation Factor Approximate Incidence* Replacement Therapy Factor I (fibrinogen) 1 per million Fibrinogen concentrate Cryoprecipitate (if fibrinogen concentrate unavailable) Factor II (prothrombin) 1 per 2 million PCC Factor V 1 per million FFP Factor VII 1 per 500,000 PCC Coagulation factor VIIa (recombinant) Factor VIII † 1 per 5000–10,000 males Coagulation factor VIII (recombinant or human) Desmopressin for mild hemophilia von Willebrand’s disease ‡ Up to 1 per 100 persons Desmopressin von Willebrand factor (recombinant) or antihemophilic factor/von Willebrand factor complex (human); cryoprecipitate if either unavailable Factor IX† 1 per 30,000 males Coagulation factor IX (recombinant or human) Factor IX complex Factor X 1 per million FFP for minor bleeding episodes PCC for major bleeding Factor XI ‡ 3 per 10,000 Ashkenazi Jews FFP 1 per million in general population

1 per 5000–10,000 males Coagulation factor VIII (recombinant or human) Desmopressin for mild hemophilia von Willebrand’s disease ‡ Up to 1 per 100 persons Desmopressin von Willebrand factor (recombinant) or antihemophilic factor/von Willebrand factor complex (human); cryoprecipitate if either unavailable Factor IX† 1 per 30,000 males Coagulation factor IX (recombinant or human) Factor IX complex Factor X 1 per million FFP for minor bleeding episodes PCC for major bleeding Factor XI ‡ 3 per 10,000 Ashkenazi Jews FFP 1 per million in general population Factor XII 25 per 1000 No bleeding manifestations; replacement not required Factor XIII 1 per million FFP or cryoprecipitate Abbreviations: FFP = fresh frozen plasma; PCC = prothrombin complex concentrate; vWF = von Willebrand factor. *Source: van Herrewegen F, Meijers JC, Peters M, van Ommen CH: Clinical practice: the bleeding child. Part II: disorders of secondary hemostasis and fibrinolysis. Eur J Pediatr 171: 207, 2012. †See Chapter 235, “Hemophilias and von Willebrand’s Disease.” ‡Factor XI levels correlate poorly with bleeding complications; many patients have low levels but no bleeding complications. TABLE 238-6 General Indications for Cryoprecipitate Transfusion •  Bleeding  with a fibrinogen level of <100 milligrams/dL (<1 gram/L) •  Dysfibrinogenemia •   Bleeding in some subtypes of von Willebrand’s disease that are unresponsive to desmopressin, and factor VIII concentrates are unavailable over dosing and efficacy ( Table 238-6).27,29 The typical adult dose is 10 units, administered in two doses, each containing five pooled units.  FIBRINOGEN CONCENTRATE (HUMAN) Fibrinogen concentrate is derived from pooled human plasma and is used to treat bleeding episodes in patients with congenital fibrinogen deficiency.30 Fibrinogen has been investigated for benefit in other hemorrhagic conditions with an observed ability to reduce bleeding and transfusion requirements, but without a measurable effect on mortality.31 The advantages over cryoprecipitate are minimal risk of disease transmission due to viral inactivation, accurate dosing because each vial is assayed for fibrinogen content, a lower volume for infusion, no need for thawing, no requirement of ABO testing and compatibility, and a rapid reconstitution for infusion. Fibrinogen is dosed according the patient’s baseline fibrinogen level, the target level (in most circumstances >150 milligrams/dL), 32 volume of distribution, and body weight. If the baseline fibrinogen level is unknown, the initial dose is 70 milligrams/kg. The most common adverse reactions include allergic reactions, fever, chills, nausea, and vomiting.  FACTOR IX COMPLEX (HUMAN) Factor IX complex is derived from human plasma and primarily con tains factors IX, X, and prothrombin. This product is typically used to treat hemophilia B (factor IX deficiency) and has been studied to treat hemorrhage caused by excessive warfarin effect, because this product contains three of the four vitamin K–dependent coagulation factors. Factor IX complex is often identified as three-factor prothrombin complex concentrate to differentiate it from the four-factor prothrombin complex concentrate product.  PROTHROMBIN COMPLEX CONCENTRATE (HUMAN) Prothrombin complex concentrate is derived from human plasma and contains the four vitamin K–dependent clotting factors: prothrombin and factors VII, IX, and X. During development and introduction into clinical use, this product was usually identified as four-factor prothrombin complex concentrate to differentiate it from factor IX complex, or three-factor prothrombin complex concentrate. Some prothrombin complex concentrate formulations may also contain anticoagulant pro teins C and S and antithrombin, as well as heparin. Prothrombin complex concentrate is approved for urgent reversal of overanticoagulation from vitamin K antagonists (such as warfarin). The prothrombin complex concentrate dose is calculated from pretreatment INR values and administered using factor IX units.

gulant pro teins C and S and antithrombin, as well as heparin. Prothrombin complex concentrate is approved for urgent reversal of overanticoagulation from vitamin K antagonists (such as warfarin). The prothrombin complex concentrate dose is calculated from pretreatment INR values and administered using factor IX units. Prothrombin complex concentrate can also be used as part of a protocol for reversal of direct oral anticoagulants such as rivaroxaban, apixaban, edoxaban, or dabigatran in the setting of life-threatening bleeding. 24,34 Prothrombin complex concentrate does not require thawing, does not necessitate ABO-compatibility testing, and does not carry the risk of volume overload, all of which can hinder FFP use. Because the effects of prothrombin complex concentrate are transient, vitamin K should usually be coadministered for sustained warfarin reversal. Thrombosis is the major complication of prothrombin complex concentrate and is observed in approximately 2.5% of treated patients, although this inci dence is less than in similar patients treated with FFP .  ANTI-INHIBITOR COAGULANT COMPLEX Anti-inhibitor coagulant complex is derived from human plasma and contains the four vitamin K–dependent factors: factors II, IX, and X (mainly in nonactivated form) and factor VII (mainly in activated form). This product is commonly known as FEIBA, an abbreviation for factor VIII inhibitor bypassing activity, and has also been termed activated prothrombin complex concentrate. Anti-inhibitor coagulant complex is approved for use in hemophilic patients with inhibitors and has been studied for reversal of direct oral anticoagulants 35 and for treatment of bleeding in acquired hemophilia.36 The risk of adverse thromboembolic complications is low in patients with congenital hemophilia37 but higher in other populations.  COAGULATION FACTOR VII a (RECOMBINANT) Coagulation factor VIIa (recombinant) is approved for use in the treat ment of bleeding in hemophilia A and B patients who have developed inhibitor antibodies to factors VIII or IX, respectively. Other uses for this agent have been investigated, such as acquired hemophilia, coagulation support in liver failure, multisystem trauma, intracranial hemor rhage, and postpartum bleeding. 38-40 The major drawback to this product is risk of thrombosis (up to 4% in patients with acquired hemophilia). COMPLICATIONS OF BLOOD TRANSFUSIONS Up to 20% of all transfusions may result in some type of adverse reac tion.3,41 Most reactions are minor; serious reactions are uncommon, and life-threatening ones are rare ( Table 238-7).42 In critically ill patients, Tintinalli_Sec18_p1461-1522.indd 1498 8/2/19 8:37 PM

hemophilia). COMPLICATIONS OF BLOOD TRANSFUSIONS Up to 20% of all transfusions may result in some type of adverse reac tion.3,41 Most reactions are minor; serious reactions are uncommon, and life-threatening ones are rare ( Table 238-7).42 In critically ill patients, Tintinalli_Sec18_p1461-1522.indd 1498 8/2/19 8:37 PM CHAPTER 238: Transfusion Therapy 1499 TABLE 238-7 Transfusion Reactions Reaction Type Signs and Symptoms Management Evaluation Acute intravascular hemolytic reaction Fever, chills, low back pain, flushing, dyspnea, tachycardia, shock, hemoglobinuria Immediately stop transfusion. IV hydration to maintain diuresis; diuretics may be necessary. Cardiorespiratory support as indicated. Retype and repeat cross-match. Direct and indirect Coombs test. CBC, creatinine, prothrombin time, activated partial thromboplastin time. Haptoglobin, indirect bilirubin, lactate dehydrogenase, plasma free hemoglobin. Urine for hemoglobin. Delayed extravascular hemolytic reaction Often have low-grade fever but may be entirely asymptomatic Usually presents days to weeks after transfusion. Rarely causes clinical instability. Hemolytic workup as above to investigate the possibility of intravascular hemolysis. Febrile nonhemolytic transfusion reaction Fever, chills Stop transfusion. Initially manage as in intravascular hemolytic reaction (above) because cannot initially distinguish between the two. Can treat fever and chills with acetaminophen. Usually mild but can be life threatening in patients with tenuous cardiopulmonary status. Consider infectious workup. Premedication with acetaminophen can mask this reaction. Hemolytic workup as above because may not be able to initially distinguish febrile from hemolytic transfusion reactions. Allergic reaction Mild: urticaria, pruritus Severe: dyspnea, bronchospasm, hypotension, tachycardia, shock Stop transfusion. If mild, reaction can be treated with diphenhydramine; if symptoms resolve, can restart transfusion. If severe, may require cardiopulmonary support; do not restart transfusion. For mild symptoms that resolve with diphenhydramine, no further workup is necessary, although blood bank should be notified. For severe reaction, do hemolytic workup as above because initially may be indistin guishable from a hemolytic reaction. transfusion reactions may be difficult to identify; therefore, watch for unexpected changes in patient status during a transfusion. Two important first steps in any confirmed or suspected transfusion reaction are to (1) immediately stop the transfusion and (2) contact the blood bank that issued the transfusion product. 8 The blood bank physician is an important resource for managing the suspected transfusion reaction. A common error in management of a confirmed or possible trans fusion reaction is to abandon all transfusion. Typically, transfusion reactions, such as hemolytic reactions or transfusion-related acute lung injury, are due to the interaction between a particular unit and a particular patient. Even patients with severe reactions can safely receive future blood products if they are appropriately matched to the patient. One of the first steps in management of a transfusion reaction is to draw a new specimen to retype and cross-match new units so that transfusion can resume as soon as possible. Premedication with acetaminophen and/or diphenhydramine is done to prevent febrile and/or allergic transfusion reactions43; however, the effects are limited,44,45 and routine prophylactic premedication is not recom mended in patients without prior reactions. However, premedication may be used for patients with previous febrile or allergic transfusion reactions.

henhydramine is done to prevent febrile and/or allergic transfusion reactions43; however, the effects are limited,44,45 and routine prophylactic premedication is not recom mended in patients without prior reactions. However, premedication may be used for patients with previous febrile or allergic transfusion reactions.  HEMOLYTIC TRANSFUSION REACTIONS Hemolytic transfusion reactions occur when the recipient’s antibodies recognize and induce hemolysis of the donor’s red blood cells. 8,46,47 The reaction is usually immediate when antibodies already exist as anti-A or anti-B immunoglobulin M antibodies or immunoglobulin G antibodies in very high titer. Reactions can be delayed when there is an amnestic response to a transfused red blood cell antigen to which the recipient has been previously sensitized. 8,10 Immediate transfusion reactions caused by ABO incompatibility are usually the result of technical errors made during the collection of blood, pretransfusion testing, or patient identification, and are responsible for the majority of transfusion fatalities. With acute hemolytic reaction, most of the transfused cells are destroyed, which may result in activation of the coagulation system, disseminated intravascular coagulation, and release of anaphylatoxins and other vasoactive amines. Clinical features of an acute hemolytic reaction include back pain, pain at the site of the transfusion, headache, alteration of vital signs (fever, hypotension, dyspnea, tachycardia), chills, bronchospasm, pulmonary edema, bleeding due to developing coagulopathy, and evidence of new or worsening renal failure. Ongoing transfusion should be stopped immediately on first indication of potential problems . While laboratory confirmation is being performed, the sequelae of hemolysis are treated supportively. Check renal function, electrolytes, and coagulation status. Maintain renal blood flow and urine output with fluids, mannitol, and furosemide, as needed. Treat circulatory shock with IV infusions and vasopressors to support blood pressure. The remaining donor blood should be sent, along with a posttransfusion blood specimen from the recipient, to the blood bank. The blood typing and cross-match are repeated, the patient’s serum is tested for blood group alloantibodies, and the donor’s plasma is tested for the presence of antibodies that react with the patient’s blood. With intravascular hemolytic transfusion reactions, serum haptoglobin will be decreased, serum lactate dehydrogenase will be elevated, and a direct antigen (Coombs) test usually will be positive. The blood bank will be able to test the blood, review records, confirm blood types, and determine if the patient’s syndrome is from a transfusion reaction. Extravascular delayed hemolytic reactions occur in approximately 1 per 1000 to 6000 PRBC units transfused. Hemolysis most commonly occurs in the spleen and occasionally in liver and bone marrow. This type of reaction is less serious and rarely fatal. 8,10 It may be identified by a positive Coombs test, elevated unconjugated (indirect) bilirubin level, and less than expected increase in hemoglobin from the transfusion.  FEBRILE NONHEMOLYTIC TRANSFUSION REACTIONS Febrile transfusion reactions are characterized by fever during or within 4 hours of a blood transfusion. 8,10,46,47 Febrile reactions occur in <0.5% of FFP transfusions, <1% of red blood cell transfusions, and ≤5% of platelet transfusions. 8,48 Febrile transfusion reactions are more common in patients who have been exposed to foreign blood antigens, such as multiparous women or multiply transfused patients. Febrile transfusion reactions result from a combination of recipient antibody against donor leukocytes and the release of cytokines that are produced during storage.

nsfusion reactions are more common in patients who have been exposed to foreign blood antigens, such as multiparous women or multiply transfused patients. Febrile transfusion reactions result from a combination of recipient antibody against donor leukocytes and the release of cytokines that are produced during storage. Clinical presentation can range from a mild elevation in temperature to a high fever along with rigors, headache, myalgias, tachycardia, dyspnea, Tintinalli_Sec18_p1461-1522.indd 1499 8/2/19 8:37 PM