Review. Blood Components for Hemostasis. RBC Transfusion. Karen W. Eldin, MD 1, and Jun Teruya, MD, DSc 1,2 ABSTRACT

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1 Blood Components for Hemostasis Karen W. Eldin, MD 1, and Jun Teruya, MD, DSc 1,2 ABSTRACT We present an overview of revised indications and doses for routinely transfused blood components. Targeted blood component therapy is one of the earliest models of personalized medicine, striving to achieve the tenets of the right dose at the right time for the right reason to the right patient. Despite rigorous quality assessment and federally mandated regulatory requirements, blood component therapy has fallen short of this goal. Transfusion support practices largely are Targeted blood component therapy, with or without administration of pharmaceutical hemostatic agents, strives to minimize blood exposure and risk for serious adverse transfusion complications. Integration of the clinical condition and laboratory findings guide targeted blood component therapy, improving clinical response, patient safety, and resource allocation. In the United States most blood is collected as whole blood and separated after collection into various components. The derived components may either DOI: /LMNU4K1ZERN1CDKV Abbreviations RBCs, red blood cells; HIV, human immunodeficiency virus; TRALI, transfusion-related acute lung injury; HTRs, hemolytic transfusion reactions; HLA, human leukocyte antigen; CMV, cytomegalovirus; VWF, von Willebrand factor; ADP, adenosine diphosphate; TAS, transfusionassociated sepsis; NSAID, nonsteroidal anti-inflammatory drug; DDAVP, desmopressin acetate; TTP, thrombotic thrombocytopenic purpura; HELLP, hemolysis, elevated liver enzymes, and low platelet count; HUS, hemolytic uremic syndrome; HIT, heparin-induced thrombocytopenia; ITP, immune thrombocytopenia; PTP, post-transfusion purpura; WHO, World Health Organization; CCI, corrected count increment; DIC, disseminated intravascular coagulation; FFP, fresh frozen plasma; TPE, therapeutic plasma exchange; VKA, vitamin K antagonism; PT, prothrombin time; INR, international normalized ratio; TACO, transfusion-associated circulatory overload; FDA, US Food and Drug Administration; PCC, prothrombin complex concentrate; EACA, e-aminocaproic acid; TXA, tranexamic acid; rfviia, recombinant Factor VIIa 1 Department of Pathology & Immunology, 2 Departments of Pediatrics and Medicine, Texas Children s Hospital and Baylor College of Medicine, Houston, Texas *To whom correspondence should be addressed. jteruya@bcm.edu dictated by expert opinion and tradition with few evidence-based recommendations. Blood component transfusions, while mostly regarded as safe, are not without risk for serious adverse outcomes. Pharmaceutical agents commonly used either in lieu of, or in addition to, transfusion support will also be discussed. Keywords: hemostasis, transfusion, guidelines, plasma, platelet, pharmaceutical agents provide a single therapeutic dose (red blood cells [RBCs]) or a fraction of a dose (plasma, platelets, frozen plasma derived cryoprecipitate). Increasingly, components are selectively collected via apheresis (derived from Greek, meaning to carry away ) techniques. While apheresis has several advantages, including increased frequency for platelet and plasma donations, single donor platelet products, prestorage leukocyte reduction (in some instances), and improved inventory management, apheresis collections are generally not amenable to off-site blood collections, are more costly, and have unique donor risks (extracorporeal circuit and citrate infusion) relative to whole-blood donations. 1 All human blood components carry a risk for adverse events, traditionally divided between transfusion-transmitted infections and non-infectious risks. Transfusion transmitted viral infections include human immunodeficiency virus (HIV), hepatitis B, and hepatitis C, although these risks continue to decline due to advances in donor selection and combination testing (antibody, antigen, and/or nucleic acid based viral detection). Transfusion-associated bacterial sepsis currently is the most serious infectious transfusion complication, and together with transfusion-related acute lung injury (TRALI) and hemolytic transfusion reactions (HTRs), they account for the majority of transfusion-related deaths. 2 RBC Transfusion Product Options Most RBC products are obtained from whole blood donations. Various anticoagulants and preservatives extend Fall 2012 Volume 43, Number 6 Lab Medicine 237

2 the shelf life of RBCs, currently up to 42 days with cold storage. RBC products may be modified to meet specific patient needs by irradiation, washing, or leukoreduction. In many centers, RBCs are leukocyte reduced to minimize the risk of nonhemolytic febrile transfusion reactions, human leukocyte antigen (HLA) alloimmunization, transmission of cytomegalovirus (CMV), and immunomodulation. Indications Hemoglobin levels of 7-9 g/dl (estimated hematocrit: 21%-27%) are adequate for tissue oxygenation and are not associated with increased mortality in stable intensive care patients. 3 However, indications for red-cell transfusion in bleeding or coagulopathic patients go beyond the oxygen-carrying capacity of erythrocytes. The importance of erythrocytes in primary hemostasis has been demonstrated in in vivo and in vitro studies. 4-6 Intravascular RBCs likely serve as micro-mixers in the blood, expediting delivery of coagulation factors and platelets to the vessel wall and allowing interaction with disrupted endothelium and initiation of clot formation. Erythrocyte concentration, measured by the hematocrit, is the primary determinant of blood viscosity, impacting shear stress in the blood vessel wall (ie, frictional drag force per unit area) and platelet activation by von Willebrand factor (VWF). 7 In addition to shear-mediated platelet activation, RBCs participate in platelet aggregation via chemical mediators (adenosine diphosphate [ADP] release) 8 and may participate in hemostasis by exposing procoagulant phospholipids. 9 Transfusion of RBCs alone when the hematocrit is less than 30% has corrected uremic bleeding 10 and reduced the risk of hemorrhage in anemic and thrombocytopenic patients. 11 Contraindications Transfusion is not without risk, thus RBC transfusion should not be used to treat anemia associated with iron, folate, or vitamin B12 deficiencies. Instead, these deficiencies should be treated by appropriate supplementation. Dosage One unit of RBCs in an adult (without ongoing blood loss or hemolysis) should increase hemoglobin by 1 g/dl (or 3% rise in hematocrit). In pediatric patients, dosing is based on weight (10-15 ml/kg) and the expected increase in hemoglobin per unit is 2 g/dl. In the absence of massive hemorrhage, measurement of a post-transfusion hemoglobin or hematocrit is recommended before transfusion of additional RBC units. Nonemergent increases in hemoglobin and hematocrit levels may be achieved by nontransfusion alternatives such as administration of recombinant human erythropoietin or iron therapy. Complications Acute hemolysis with multiorgan failure, and sometimes death, is a rare but serious complication associated with RBC transfusion. Acute hemolysis may be immune-mediated (most often related to ABO incompatible transfusion) or non immune-mediated (hypertonic solutions, malfunctioning blood warmer, or transfusion through small bore peripheral venous access). Transfusion of incompatible blood is usually a consequence of human error and strict adherence to patient identification procedures are necessary throughout the entire process of sample collection, laboratory testing, and issuance of the transfused blood product. Platelet Transfusion Product Options Platelet products in the United States are typically collected by apheresis (single donor platelets); fewer are pooled whole blood derived platelet concentrates. Platelets collected by apheresis reduce the number of donors to which a patient is exposed, but both products are equally efficacious: selection depends on availability and cost considerations. 11,12 In the United States, platelets are suspended in donor plasma and ABO compatibility is a consideration to avoid complications of transfusion of ABO-incompatible plasma. ABO compatible platelet transfusions also demonstrate better platelet recovery and a decreased incidence of alloimmunization. 12 While ABO identical platelet concentrates are preferred, lack of availability occasionally necessitates out-of-group transfusions (Table 1). Though platelets do not express the RhD antigen, RhD-negative individuals (particularly women of childbearing age) traditionally receive RhD-negative products because of risk for RhD alloimmunization due to contamination of the platelet product with RBCs. Table 1. ABO Platelet and Plasma Compatibility Patient ABO O A B AB Unit ABO (in order of preference) O, A, B, AB A, AB, O a B, AB, O a AB, O a a Negative or low titer anti-a/a, B group O plasma/platelets. Group O platelets may also be volume-reduced or washed. 238 Lab Medicine Fall 2012 Volume 43, Number 6

3 Platelet products have a shelf life of 5 days; use of older units entails concerns for patient safety and product efficacy. Room temperature (20º-24ºC) storage in a plasma-rich environment promotes bacterial growth and consequent risk for transfusion-associated sepsis (TAS). Bacterial testing of platelet products reduces, but does not eliminate, the risk of TAS. 13 In addition, platelets are anucleated cell fragments with a limited metabolic capacity, so their viability deteriorates quickly (platelet storage lesion). Techniques to prolong storage and halt or attenuate platelet degeneration are being actively investigated. 14 Platelets may be processed in many of the same ways as RBCs (ie, washed, leukocyte reduced, or volume-reduced) to meet specific patient needs. Centrifugation of washed or volume reduced platelets may result in platelet activation and loss of as much as 20% of the product, so it should only be performed in cases of severe allergic reactions or out of group transfusions in neonates. Indications Bleeding in a patient with severe thrombocytopenia or platelet dysfunction is the clearest indications for therapeutic platelet transfusion. Prophylactic platelet transfusion in nonbleeding patients with thrombocytopenia or platelet dysfunction is somewhat controversial. In certain patients, notably those with hematologic malignancies and neonates, the majority of platelet transfusions are prophylactic. 15,16 When to initiate a platelet transfusion (the trigger) and how much to transfuse (dose) are based primarily on opinion rather than evidence-based guidelines. Transfusion triggers may include fever or sepsis, actual or impending vascular insults, and the location of bleeding (Table 2). A minimum platelet count of 5000 per ml is needed to maintain hemostasis and prevent spontaneous hemorrhage in adults. Thus, prophylactic transfusions in patients with platelet counts less than /mL provide an adequate safety margin to prevent bleeding in otherwise stable patients. 17 Platelet dysfunction, regardless of platelet count, occasionally occurs. Most cases of platelet dysfunction are acquired as a result of cardiopulmonary bypass surgery, aspirin or other nonsteroidal anti-inflammatory drug (NSAID) use, antibiotic therapy, uremia, or antiplatelet medications; these may increase the risk of new bleeding or aggravation of underlying hemorrhage. Congenital platelet dysfunction is rare but may be caused by receptor defects (ie, Bernard-Soulier syndrome or Glanzmann thrombasthenia) or storage pool disorders. Automated platelet function testing, platelet aggregation studies, and thromboelastography are useful laboratory methods for evaluating platelet dysfunction and can be used to guide and monitor therapy. Desmopressin acetate (DDAVP) is usually administered as first-line therapy to reverse acquired platelet dysfunction; however, additional management may include platelet transfusions, antifibrinolytic agents, or recombinant factor VIIa (see the subsection Pharmaceutical Agents). Contraindications Platelet transfusions are contraindicated in certain thrombocytopenic conditions because of harmful outcomes or established poor response. Thrombotic thrombocytopenic purpura (TTP), other microangiopathies (ie, hemolysis, elevated liver enzymes, low platelets [as part of the syndrome consisting of hemolysis, elevated liver enzymes, and low platelet count (HELLP)], hemolytic uremic syndrome [HUS]) and heparin-induced thrombocytopenia (HIT) are conditions that can be worsened by addition of platelets that can serve as a substrate for thrombosis (as expressed by the fuel for the fire analogy). In patients with immune thrombocytopenia (ITP) or post-transfusion purpura (PTP), platelet transfusion should only be used when severe thrombocytopenia and active bleeding are present. Dosage A dose of platelets collected by apheresis contains approximately platelets and is equivalent to pools of 4 to 6 platelet units derived from whole blood. In an adult, one dose of platelets should increase the platelet count by to per ml. Pediatric dosing typically is based on weight (10 ml/kg) or 1 whole blood derived dose equivalent per 10 kg, and the expected increase in platelet count is /mL. Lower dose platelet transfusions ( /transfusion/m 2 of body surface area) appear adequate in the prevention of World Health Organization (WHO) grade 2 or greater Table 2. Indications for Platelet Transfusions Platelet Transfusion Indication Adult 15,17 Neonate 15,16 Prophylactic transfusion, stable patient <10,000/µL <30,000/µL Febrile, septic, or increased risk <20,000/µL <50,000/µL of bleeding Invasive procedures <100,000/µL Catheter placement <25,000/µL Liver biopsy or major surgery <50,000/µL Active bleeding, massive transfusion No lower threshold established Bleeding into critical sites (intracranial, No lower threshold established intraocular, or pulmonary hemorrhage) Active bleeding with known or suspected Consider hemostatic agents platelet dysfunction Fall 2012 Volume 43, Number 6 Lab Medicine 239

4 bleeding 17 but result in smaller and more frequent transfusions with associated risks (alloimmunization and infection). Cost/benefit studies comparing dose-based (less costly) versus unit-based (more costly) pricing models have been inconclusive. 17 Monitoring the efficacy of prophylactic platelet transfusions is problematic because its impact on bleeding cannot be assessed since the patient was not bleeding before transfusion. Therefore the pre- to post-transfusion increase in the platelet count is the only routinely available measurement of the efficacy of prophylactic platelet transfusions, but the measurement may not be clinically relevant. Patients may not achieve the expected posttransfusion increase in platelet count for a variety of reasons, termed platelet refractoriness, which can be immune- or nonimmune-mediated. In alloimmune-mediated platelet refractoriness due to anti-hla and/or antiplatelet antibodies, the patient may benefit from HLA-matched, antigen-negative, or cross-match compatible platelets. These products are rare and costly, so careful evaluation of the indications for transfusion is advisable to minimize expense and prevent wastage. Calculation of the corrected count increment (CCI) 10 to 60 minutes after transfusion (ie, early post-transfusion) with ABO-matched platelets is useful for distinguishing immune from nonimmune mechanisms. The CCI is calculated as follows: CCI = Body surface area (m 2 ) x [(plt count post- plt count pre) x ] Number of platelets transfused (10 11 ) Poor early recovery, defined as CCI less than 5000 on two consecutive occasions, is most likely associated with an immune etiology, while later ( 24 hours) poor recovery is more often associated with nonimmune consumptive etiologies (ie, sepsis, splenomegaly, chronic disseminated intravascular coagulation [DIC], or drug-related). Consultation with the transfusion medicine service is recommended for any unusual needs and for assistance in the evaluation and management of the platelet refractory patient. Complications TAS occurs more frequently with platelets because they are stored at room temperature. Since the implementation of bacterial testing of platelet products, the incidence of TAS has decreased but it remains one of the main causes of fatal adverse transfusion events. 2 Platelet transfusions may also cause allergic reactions and TRALI due to their plasma content (as we will describe in the following section, in the Complications subsection). Plasma Transfusion Product Options Plasma is the noncellular fraction of blood and contains activators and inhibitors of the coagulation cascade, in addition to complement, immunoglobulins, and albumin. Different plasma products are classified according to their storage condition and time interval from collection to freezing. Plasma frozen within 8 hours of collections is called fresh frozen plasma (FFP) and plasma frozen within 24 hours of collection is designated FP24. Once a frozen unit of plasma is thawed, it may be kept refrigerated for as long as 24 hours retaining the designation FFP or FP24, but after refrigerated storage for more than 24 hours (ie, as long as 5 days), the unit is referred to as thawed plasma. FFP retains the most activity of clotting factors, including the labile coagulation factors V and VIII. FFP, FP24, and thawed plasma are available from most transfusion services. The functional activity of the coagulation factors in these products are similar and they may be used interchangeably in most patients. 18 Cryoprecipitate-reduced plasma (also known as cryo-poor plasma) is the plasma remaining after preparation of cryoprecipitate. This product is rarely used except as replacement fluid during therapeutic plasma exchange (TPE) for TTP. However, cryo-poor plasma is not superior to FFP in the treatment of TTP; the use of cryo-poor plasma for that purpose has been questioned. 19 Indications There are two principal uses for plasma transfusion: to replace fluid in patients undergoing TPE and to replace coagulation factors in a bleeding patient when a specific factor concentrate is not available. The benefits of plasma as a replacement fluid in patients undergoing TPE are well established. However, it is estimated that greater than 90% of plasma is used to treat acquired bleeding disorders such as vitamin K deficiency, vitamin K antagonism (VKA), liver disease, DIC, and dilutional coagulopathy. 20 A considerable proportion of plasma transfusions (as many as 43%) 21 are given prophylactically to patients with normal or mildly deranged coagulation parameters with no clinical signs of bleeding. Multicenter reviews of adult 21 and pediatric 22 FFP transfusion patterns consistently demonstrate wide variability in the uses of FFP, suggesting that uniform clinical indications and/or guidelines do not exist; both reviews concluded that most FFP transfusions were of unproven clinical benefit. Laboratory measures 240 Lab Medicine Fall 2012 Volume 43, Number 6

5 of coagulation include the prothrombin time (PT) and its derived international normalized ratio (INR). Although an INR greater than 1.5 is often cited as a trigger for plasma transfusion, no evidence-based guidelines to support this trigger exist, and elevations of the PT and INR are poor indicators of bleeding risk. 23 PT can be prolonged due to the presence of lupus anticoagulant without any coagulation factor deficiencies. Attempts to correct a mildly prolonged INR to below 1.5 using plasma transfusions are not considered necessary or helpful. 24 Factors V and VIII are labile and may decrease during storage of thawed plasma. Factor VIII is not produced by the liver and its synthesis does not depend on vitamin K, so decreased levels of this factor in plasma products are inconsequential when plasma transfusion is used to treat liver failure or vitamin K deficiency or antagonism. Plasma transfusion is not an acceptable treatment for hemophilia A or B; recombinant factor VIII or IX, or factor specific concentrates should be administered instead. Decreased factor V levels may be corrected with plasma transfusion, and the higher factor V levels in FFP make it the optimal choice in those cases. Approximately 20% of factor V is sequestered in the alpha granules of platelets, so platelet transfusions may benefit patients with congenital or acquired factor V deficiencies. 25 In the absence of clinically significant bleeding, and when there are no immediate plans for invasive procedures, vitamin K should be administered to treat vitamin K deficiency or VKA. VKA reversal in a bleeding or preoperative patient may require plasma transfusion, although prothrombin complex concentrates may be more effective (see the section Pharmaceutical Agents). Contraindications Plasma should not be used as a volume expander, source of nutrients or immunoglobulin, or to facilitate wound healing. Plasma transfusion is not useful for correction of a mildly prolonged INR (ie, 1.5 or less) in a nonbleeding patient. Dosage Dose and frequency of plasma transfusion depends on the patient s plasma volume, desired factor activity, and factor half-life (Table 3). A unit of FFP typically has a volume of 200 to 300 ml; a jumbo (ie, apheresis-derived) unit may be as much as 600 ml in volume. FFP contains roughly 1 IU per ml of coagulation factors. An ideal dose of plasma is 10 to 20 ml/kg; however, adherence to this dosing ratio is common only in infants and children. Unit dosing is more common in adults; a typical dose is 2 to 4 units of plasma. It has been pointed out 21 that unit dosing frequently results in less than the optimal 10 ml/kg dose (ie, underdosage), exposing patients to unnecessary transfusion-associated risks without clinical benefit. Complications Adverse events associated with plasma-rich transfusions (ie, plasma and platelet products) vary from common mild allergic reactions to rare severe anaphylactic or anaphylactoid reactions to plasma proteins. Respiratory distress may result from transfusion-associated circulatory overload (TACO) or TRALI. TRALI is characterized by noncardiogenic pulmonary edema occurring within 6 hours of transfusion in the absence of pre-existing acute lung injury and not associated with another risk factor for acute lung injury. The mechanism of TRALI is incompletely understood but is hypothesized to involve both recipient and donor factors. The patient usually has a priming event such as sepsis, surgery, or trauma that may alter endothelial and/or leukocyte properties. Transfusion of plasma containing leukocyte alloantibodies (ie, anti-hla or antineutrophil antibodies) results in leukocyte activation in the microvasculature of the lung and results in capillary leakage. 2 Antileukocyte antibodies may be generated in response to pregnancy or transfusion, and multiparous women are considered higher-risk donors. Though TRALI occurs more commonly in transfusions with plasma-rich products, it also occurs with red-cell transfusions despite their lower plasma content. In recent years, TRALI surpassed acute hemolytic transfusion reactions as Table 3. Plasma Factor and Inhibitor Composition a Coagulation Factors Biological Levels to Achieve and Inhibitors a Half-life, h Hemostasis Fibrinogen (Factor I) mg/dl Factor II % Factor V % Factor VII b % Factor VIII b,c % Factor IX b,c % Factor X % Factor XI % Factor XIII b,c % von Willebrand factor c % Protein C c % Protein S 42 60% Antithrombin b,c % a Dosing formula for adults: assume 1U/mL (1%) concentration in plasma: total blood volume (TVB) = 70 ml/kg body weight in kg; total plasma volume = TBV (1-hematocrit/100); volume of plasma replacement = (desired factor levelpatient factor level) TPV. b Human derived, virally inactivated concentrate available. c Recombinant factor available. Fall 2012 Volume 43, Number 6 Lab Medicine 241

6 the most common cause of transfusion-related deaths. The increased incidence of TRALI likely reflects better recognition of this entity within the transfusion medicine and clinical communities. Excluding plasma donations from multiparous females (some regions collect plasma only from male donors) has reduced US Food and Drug Administration (FDA) reported TRALI fatalities. 2 Cryoprecipitate Transfusion Product Options Cryoprecipitate (previously known as cryoprecipitate antihemophilic factor) is the insoluble material that precipitates from plasma thawed at 1º to 6ºC; its principal components are factor VIII, VWF, fibrinogen, fibronectin, factor XIII, and platelet microparticles. Cryoprecipitate is refrozen at -18ºC and thawed before use. The volume of 1 unit normally is 10 to 15 ml; 5 to 10 units of cryoprecipitate are usually combined for an adult dose. Single units of cryoprecipitate have a shelf life of 6 hours after thawing, whereas pooled units expire 4 hours after being thawed and pooled. Because of the short shelf life, significant amounts of cryoprecipitate are wasted due to expiration (as much as 25% in our institution). Although the short shelf life is mainly due to the labile factor VIII, cryoprecipitate is no longer a recommended treatment for hemophilia A. Indications Historically, cryoprecipitate was used to replace factor VIII or VWF in deficient individuals. Today, the primary use of cryoprecipitate is for fibrinogen replacement in bleeding patients with acquired hypofibrinogenemia (fibrinogen <100 mg/dl). Cryoprecipitate also is used in massive transfusion protocols and to treat post cardiac surgery hemorrhage, uremic bleeding, acquired hypofibrinogenemia due to DIC, hemorrhage after thrombolytic therapy, and venomous snake bites. 26 However, as with some other blood components, many of the indicated uses for cryoprecipitate are not evidence based. Contraindications Cryoprecipitate is no longer used to replace factor VIII or VWF in patients with congenital deficiencies of these factors. In developed countries, human-derived viral inactivated or recombinant products are recommended to treat these factor deficiencies. Fibrinogen concentrate and recombinant or human-derived factor XIII are also available in the United States. Cryoprecipitate is a poor source of vitamin K dependent factors and should not be used for warfarin reversal. Disturbingly, Pantanowitz et al 27 discovered during an audit of inappropriate cryoprecipitate transfusions that it was misused for warfarin reversal in 6 of 12 (50%) instances. Dosage and Complications A dose of 1 unit per 5 to 10 kg should raise fibrinogen levels by 60 to 100 mg/dl, assuming ideal recovery. ABOcompatible products are generally not required in adults because cryoprecipitate has a low anti-a or anti-b titer. Infants and neonates should receive ABO compatible products to avoid risk of hemolysis. Each unit of cryoprecipitate has the same risk of transfusion-transmitted infection as a unit of RBCs (ie, 5-10 donor exposures for pool of cryoprecipitate). Pharmaceutical Agents Increasingly, hemostatic agents are available from the pharmacy as well as the blood bank. These pharmaceutical agents include vitamin K, DDAVP, lysine analogues, recombinant factors VIIa, VIII, IX, XIII subunit a, and antithrombin, and human plasma derived factors VIII, IX, and XIII, VWF, fibrinogen, antithrombin, and protein C. Human plasma derived factors undergo various manufacturing procedures to ensure viral inactivated, purified concentrates with a low risk of infectivity. The concentrates may be factor specific (factors VIII, IX, and XIII, fibrinogen, antithrombin, and protein C) or represent a combination of factors (VWF/factor VIII and prothrombin complex concentrates). Off-label use of these products (usually in combination with traditional blood components) is common in acute hemorrhage or anticoagulant reversal. Selected products are briefly reviewed in the following section. 1-deamino-8-D-arginine Vasopressin (Desmopressin or DDAVP) DDAVP stimulates release of preformed factor VIII and VWF from cellular stores. It is commonly used as the primary therapy in patients with type 1 von Willebrand disease. Acquired platelet dysfunction, due to aspirin use or uremia, often responds to DDAVP. DDAVP is typically administered intravenously, resulting in immediate increases in factor VIII and VWF that persist for 6 to 12 hours. Tachyphylaxis can occur with repeated doses due to exhaustion of endothelial reserves of the two factors. 242 Lab Medicine Fall 2012 Volume 43, Number 6

7 Vitamin K Vitamin K is an essential cofactor in γ-carboxylation of procoagulant factors II, VII, IX, and X and anticoagulant proteins S, C, and Z. Vitamin K deficiency may be acquired in prolonged antibiotic therapy, poor dietary intake, malabsorption, and liver disease, or it may be iatrogenic (VKAs). Both conditions produce a hypocoagulable state mediated by a balanced reduction of all vitamin K dependent factors and a resulting increase in INR. Patients on VKA with supratherapeutic INRs, with or without bleeding, may require vitamin K replacement. In the United States, vitamin K replacement (phytonadione) is available in oral, intramuscular, subcutaneous, and intravenous preparations. Intramuscular administration of vitamin K is not recommended for anticoagulated patients but is reserved primarily for neonates. Correction of VKA by oral vitamin K administration requires as long as 24 hours, but reversal within 6 to 8 hours can be achieved with intravenous administration. FFP transfusion, administration of prothrombin complex concentrate (PCC), and/or recombinant factor VIIa may be initiated to rapidly reduce the INR, but concurrent vitamin K administration is necessary to avoid rebound coagulopathy or bleeding. Prothrombin Complex Concentrate (PCC) PCCs are pooled human plasma derived concentrates containing 3 or 4 vitamin K dependent coagulation factors. The concentration of factor VII distinguishes between 3-factor (ie, low or trace factor VII) and 4-factor (ie, adequate factor VII) concentrate. Only 3-factor concentrate is approved for use in the United States for the prevention and control of bleeding in patients with congenital factor IX deficiency (hemophilia B) when factor IX-specific concentrate is not available. Common off-label uses of PCC include VKA reversal and as an alternative to FFP in acute bleeding because of the time required to thaw, ABO compatibility issues, and high-volume doses associated with FFP. INR reversal is often dramatic with 4-factor PCC, but decreases in INR may not correlate with cessation of bleeding. Studies comparing PCC to FFP can be difficult to interpret because administration of FFP and vitamin K, in addition to PCC, is common. 28 There is no evidence supporting addition of recombinant factor VIIa to 3-factor PCC to simulate a 4-factor PCC; also, combination of PCCs with other procoagulants (including human or recombinant factor products, antifibrinolytics, protamine, and DDAVP) should be avoided. 28 PCCs (3- and 4-factor concentrates) have similar risks for venous and/or arterial thrombosis. Lysine Analogue Antifibrinolytics Plasminogen and plasmin bind fibrin via lysine-binding sites, resulting in fibrinolysis and clot digestion. The lysine analogue antifibrinolytics, e-aminocaproic acid (EACA) and tranexamic acid (TXA) competitively inhibit plasminogen and plasmin, stabilizing the clot. Antifibrinolytics are indicated in congenital protein deficiencies that cause hyperfibrinolysis but also are widely used to treat systemically acquired hyperfibrinolysis due to extracorporeal devices or in liver transplantation. EACA and TXA may be administered orally, intravenously, or topically. Antifibrinolytics stabilize the clot but leave thrombin generation intact, and widespread thrombosis has been described when antifibrinolytics are used in DIC. Clot formation in the urinary tract may result in urinary obstruction; consequently antifibrinolytics are used cautiously in urologic surgery. Fibrinogen Concentrate Purified human fibrinogen is commercially available in a reduced volume and typically has 10 times the final fibrinogen concentration of FFP. Fibrinogen levels fall with bleeding, fibrinolysis, and dilutional coagulopathy; replacement with FFP and/or cryoprecipitate is included in many massive transfusion protocols. A systematic review of fibrinogen concentrate studies demonstrated good efficacy and safety of this product compared to FFP; 29 however, studies that directly compare fibrinogen concentrate to cryoprecipitate and FFP are needed. Recombinant Factor VIIa (rfviia) rfviia generates a localized thrombin burst by complexing with tissue factor at the site of vascular injury, resulting in thrombin-mediated platelet activation, activation of the coagulation cascade, and fibrin cross linking. rfviia is approved for use in the United States for the treatment of high titer inhibitors in hemophilia patients and patients with congenital factor VII deficiency. In 2005, the FDA issued a warning due to reports of thrombotic events associated with off-label usage of rfviia. Despite concerns over its safety, rfviia use increased 143-fold during the period from 2000 to 2008; 97% of its use was off-label. 30 rfviia has been used to treat bleeding from massive trauma or surgery, postpartum hemorrhage, intracranial hemorrhage, vitamin K antagonist reversal, and Glanzmann thrombasthenia, among other uses. Recommendations for off-label dosing vary widely, from very low doses for prophylaxis to very large doses in massive hemorrhage. Administration of concurrent blood products is common, providing substrates for rfviia-mediated clotting (ie, platelets and fibrinogen). A recent systematic review of off-label rfviia 31 use found no consistent benefits in the therapy and, at best, only modest benefits in the prophylactic use, leading the authors to conclude that off-label rfviia use should be restricted to clinical trials. Many physicians have observed cessation of dramatic Fall 2012 Volume 43, Number 6 Lab Medicine 243

8 bleeding and shortening of PT after administration of rfviia and may be reluctant to embrace this conclusion. The controversy will only be resolved by appropriate clinical trials that confirm or refute the efficacy and safety of rfviia use for indications not currently approved. Until those studies are complete, rfviia should be reserved for life-threatening hemorrhage refractory to traditional management or when compatible blood components are not available. Summary Appropriate selection of blood components prevents unnecessary transfusions, minimizes the risks for adverse transfusion events, improves management of limited blood bank resources, and decreases the cost of health care. Targeted studies will help define appropriate transfusion doses and triggers and will benefit patient care. Advances in the development of purified concentrates of human coagulation factors offer the promise of standardized dosing and improved patient safety. Moreover, pharmaceutical agents, alone or in combination with blood components, are useful in reducing hemorrhage related to surgery, trauma, or anticoagulation. LM To read this article online, scan the QR code. References 1. Devine DV, Serrano K. Preparation of blood products for transfusion: Is there a best method? Biologicals. 2011;40: Vamvakas EC, Blajchman MA. Transfusion-related mortality: the ongoing risks of allogeneic blood transfusion and the available strategies for their prevention. Blood. 2009;113(15): Hébert PC, Wells G, Blajchman MA, et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. N Engl J Med. 1999;340(6): Andrews DA, Low PS. Role of red blood cells in thrombosis. Curr Opin Hematol. 1999;6(2): Valeri CR, Cassidy G, Pivacek LE, et al. Anemia-induced increase in the bleeding time: implications for treatment of nonsurgical blood loss. Transfusion. 2001;41(8): Eugster M, Reinhart WH. The influence of the haematocrit on primary haemostasis in vitro. Thromb Haemost. 2005;94(6): Hathcock JJ. Flow effects on coagulation and thrombosis. Arterioscler Thromb Vasc Biol. 2006;26(8): Valles J, Santos MT, Aznar J, et al. Erythrocytes metabolically enhance collagen-induced platelet responsiveness via increased thromboxane production, adenosine diphosphate release, and recruitment. Blood. 1991;78(1): Peyrou V, Lormeau JC, Héault JP, et al. Contribution of erythrocytes to thrombin generation in whole blood. Thromb Haemost. 1999;81(3): Weigert AL, Schafer AI. Uremic bleeding: pathogenesis and therapy. Am J Med Sci. 1998;316(2): Liumbruno GM, Bennardello F, Lattanzio A, Piccoli P, Rossetti G. Recommendations for the transfusion of plasma and platelets. Blood Transfus. 2009;7(2): Slichter SJ. Evidence-based platelet transfusion guidelines. Hematology Am Soc Hematol Educ Program. 2007: Jenkins C, Ramírez-Arcos S, Goldman M, Devine DV. Bacterial contamination in platelets: incremental improvements drive down but do not eliminate risk. Transfusion. 2011;51(12): Shrivastava M. The platelet storage lesion. Tranfus Apher Sci. 2009;41(2): Estcourt LJ, Stanworth SJ, Murphy MF. Prophylactic platelet transfusions. Curr Opin Hematol. 2010;17(5): Strauss RG. Platelet transfusions in neonates: questions and answers. Expert Rev Hematol. 2010;3(1): Slichter SJ. New thoughts on the correct dosing of prophylactic platelet transfusion to prevent bleeding. Curr Opin Hematol. 2011;18(6): Scott E, Puca K, Heraly J, Gottschall J, Friedman K. Evaluation and comparison of coagulation factor activity in fresh-frozen plasma and 24-hour plasma at thaw and after 120 hours of 1 to 6ºC storage. Transfusion. 2009;49(8): Raife TJ, Friedman KD, Dwyre DM. The pathogenicity of von Willebrand factor in thrombotic thrombocytopenic purpura: reconsideration of treatment with cryopoor plasma. Transfusion. 2006;46(1): Tavares M, DiQuattro P, Nolette N, et al. Reduction in plasma transfusion after enforcement of transfusion guidelines. Transfusion. 2011;51(4): Stanworth SJ, Grant-Casey J, Lowe D, et al. The use of fresh-frozen plasma in England: high levels of inappropriate use in adults and children. Transfusion. 2011;51(1): Puetz J, Witmer C, Huang Y-SV, Raffini L. Widespread use of fresh frozen plasma in US children s hospitals despite limited evidence demonstrating a beneficial effect. J Pediatr. 2012;160(2): Tripodi A, Caldwell SH, Hoffman M, Trotter JF, Sanyal AJ. Review article: the prothrombin time test as a measure of bleeding risk and prognosis in liver disease. Aliment Pharmacol Ther. 2007;26(2): Holland LL and Brooks JP. Toward rational fresh frozen plasma transfusion: the effect of plasma transfusion on coagulation test results. Am J Clin Pathol. 2006;126(1): Camire RM. A new look at blood coagulation factor V. Curr Opin Hematol. 2011;18(5): Callum JL, Karkouti K, Lin Y. Cryoprecipitate: the current state of knowledge. Transfus Med Rev. 2009;23(3): Pantanowitz L, Kruskall MS, Uhl L. Cryoprecipitate: patterns of use. Am J Clin Pathol. 2003;119(6): Patanwala AE, Acquisto NM, Erstad BL. Prothrombin complex concentrate for critical bleeding. Ann Pharmacother. 2011;45(7-8): Kozek-Langenecker S. Sørensen B, Hess JR, Spahn DR. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Crit Care. 2011;15(5):R239. [Epub ahead of print October 14, 2011.] 30. Logan AC, Yank V, Stafford RS. Off-label use of recombinant factor VIIa in U.S. hospitals: Analysis of hospital records. Ann Intern Med. 2011;154(8): Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Use of recombinant factor VIIa for the prevention and treatment of bleeding in patients without hemophilia: a systematic review and meta-analysis. CMAJ. 2011;183(1):E9-E19. Epub November 15, Lab Medicine Fall 2012 Volume 43, Number 6