Secondary Logo

Journal Logo

Cardiovascular Anesthesiology: Special Article

Current Status of Pharmacologic Therapies in Patient Blood Management

Goodnough, Lawrence Tim MD*; Shander, Aryeh MD

Author Information
doi: 10.1213/ANE.0b013e318273f4ae
  • Free
  • SDC
  • Take the CME Test

Patient blood management is a multiprofessional (physicians, nurses, perfusionists, pharmacists) and multidisciplinary (e.g., transfusion medicine specialists, surgeons, anesthesiologists, and critical care specialists) approach that is hospital-wide and patient-centered6 on management of anemia, perioperative blood conservation and surgical hemostasis, and blood use. Professional societies such as the Society for the Advancement of Blood Management,1,7 the American Association of Blood Banks,8 and the Network for Advancement of Transfusion Alternatives,9 as well as hospital accreditation organizations such as the Joint Commission10 and Department of Human Health Services,11 have each developed initiatives in patient blood management.

ESAs, recombinant activated Factor VII (rFVIIa), hemostatic agents, (e.g., aprotinin), parenteral iron therapy, and artificial oxygen carriers have each undergone reevaluation regarding their relative benefits and risks as potential alternatives to allogeneic blood transfusion. In this review, we summarize the current roles of these pharmaceutical interventions in patient blood management.


The current status for approval of ESAs is summarized in Table 1.12 ESAs have been approved in patients undergoing elective surgery12,13 and in oncology patients with chemotherapy-induced anemia, based on prospective randomized trials that demonstrated reduced allogeneic blood transfusion in patients receiving such therapy.14–16 ESAs were first demonstrated and approved for use to increase the hemoglobin (Hgb) levels in patients with end-stage chronic kidney disease (CKD) undergoing dialysis17 and without dialysis18. Before the introduction of ESAs, dialysis patients with CKD commonly required blood transfusion support and its associated complications with significant morbidity19 such as iron overload.20 Since 1992, approximately 90% of patients undergoing dialysis in the United States are now managed with ESA therapy to address anemia of CKD.21 Similarly, in a Cochrane review22 for oncology patients, transfusion requirements in this setting have also been significantly reduced with ESA therapy, for a relative risk reduction observed (relative risk = 0.64; 95% confidence interval, 0.60–0.68).

Table 1
Table 1:
Erythropoiesis Stimulating Agents: Current Approval Status

Subsequent to Food and Drug Administration (FDA) approval for the use of ESA to reduce allogeneic blood transfusion in these clinical settings, clinical trials were undertaken in an attempt to further demonstrate long-term improved patient outcomes with ESA therapy (Table 2).23–36 In elective surgery patients scheduled for elective spine surgery, blood transfusion and patient outcomes were compared for ESA and placebo-treated cohorts. These patients did not receive anticoagulation prophylaxis for thrombotic adverse events (in contrast to the clinical trials in joint replacement patients that resulted in approval for the use of ESAs in elective surgery). This study 16 ANESTHESIA & ANALGESIA documented a higher incidence of deep vein thrombosis in patients receiving epoetin alfa compared with placebo. However, the rates of clinically relevant deep vein thrombosis and other thrombovascular events were similar between the treatment groups and well within published rates for this population. The authors concluded that antithrombotic prophylaxis should be considered when ESAs are used in surgical patients, including those who undergo elective spine surgery. Accordingly, the prescribing information for these agents was modified in the label on the basis of these findings.

Table 2
Table 2:
Postapproval Clinical Trials of ESA

The investigations in CKD24–29 and oncology30,31,33–37 patients focused on whether targeting or maintaining Hgb levels within normal or at the upper range of normal could benefit patients by improving patient survival. However, more “aggressive” anemia management in these trials was associated with increased morbidity (thrombosis or cardiovascular events) or increased mortality in the ESA-treated cohorts. In patients with end-stage CKD (estimated glomerular filtration rate < 60 cm3/min per 1.73 m)2 and Hgb < 12 g/dL), ESA treatment was associated with an increased risk of acute stroke, with the greatest effect among patients who also had a diagnosis of cancer.38 The risks of death or cardiovascular events were associated with a poor initial hematopoietic response, as doses of ESAs were escalated to meet target Hgb levels.28

Literature reviews and meta-analyses of ESA trials for both approved and off-label oncology settings have studied survival and other safety outcomes.22,32,39–45 One of these indicated that for Phase III controlled trials of ESA therapy (chemotherapy, radiotherapy, and anemia of cancer patients),42 mortality was higher in the ESA cohorts compared with the placebo cohorts (hazard ratio 1.10; confidence interval, 1.01–1.20; P = 0.03). Overall, 3 meta-analyses41,42,44 indicated increased risk of mortality with use of ESA, whereas two43,45 indicated that ESA did not significantly affect mortality. The mechanisms behind any ESA-associated increase in morbidity and mortality outcomes are unclear. One hypothesis is that ESAs stimulate disease progression and/or thrombosis by activating erythropoietin receptors (EPO-Rs) present in tumor cells or associated vascular endothelium.46

In a follow-up retrospective analysis of EPO-R expression in tumor samples from patients in the Erythropoeitin in Head and Neck Cancer Study (ENHANCE),43 locoregional progression-free survival was decreased in patients treated with ESAs only in the subpopulation of patients whose tumors expressed EPO-R,47 suggesting a potential direct tumor effect of ESA therapy on tumor progression; however, the antibody used to detect EPO-Rs in tumors lacks specificity.48,49 EPO-R mRNA levels vary as much as 30-fold among breast cancer and head and neck cancer specimens and vary between tumor epithelial and endothelial cell fractions. Solid tumors can be segregated by their overall EPO-R levels,50 suggesting known heterogeneity in tumor vasculature. Other investigators, however, have found no evidence that EPO-R is functionally expressed in tumors51 or is present in nonhematopoietic cells.52

In a meta-analysis of Phase III trials that reported survival and venous thromboembolism outcomes, 52 trials with 13,611 patients and 38 trials with 8172 patients, respectively, were analyzed by comparing ESAs with placebo or standard of care for the treatment of anemia among patients with cancer.41 Patients who received ESAs had increased risks of venous thromboembolism (7.5% vs. 4.9%; relative risk, 1.57 [1.31–1.87]) and increased risk of mortality (hazard ratio, 1.10 [1.01–1.20]). These findings, coupled with the 8 clinical trials in oncology patients that followed patients for clinical outcomes when ESA therapy was designed to sustain or achieve Hgb levels within the normal range, raised concerns about the safety of ESA administration to patients with cancer. Whether recommended Hgb levels are beneficial for survival independent of reduced exposure to allogeneic blood transfusions is the subject of ongoing clinical studies.

FDA approval of ESAs in cancer patients with chemotherapy-induced anemia continues to be based on their demonstrated benefit of reducing/avoiding the need for RBC transfusions (and not other possible benefits such as improved quality of life). Based on the above evidence, the labeling for use of ESAs in perisurgical, CKD, and oncology settings has been modified to reflect guideline updates,53,54 black box warnings, and FDA-mandated risk evaluation and mitigation strategies by treating physicians that include patient educational materials and cautionary text in consent forms. The revised labels also reflect safety concerns regarding target Hgb levels > 12 gm/dL. Similar black box warnings based on safety concerns have been inserted into the labels for use of ESAs in patients with end-stage kidney disease and in patients undergoing elective surgery.55 The black box warnings and updated guidelines remind treating physicians that the use of ESAs should be based on the initiation of therapy in patients whose Hgb levels are <10 g/dL or who have symptomatic anemia; and to target minimal ESA dosage toward RBC responses sufficient for patients to benefit from ESA therapy by avoidance of or reduced allogeneic blood transfusions.

One concern has been that if ESA use is reduced significantly, then the rate of RBC transfusions in patients will increase in these settings. After the National Coverage Decision in July 2007, effects of reimbursement changes on ESA use were found in oncology patients aged 65 years and older; that is, a 31% increase in transfusions was observed.56 Similarly, recent evidence from the U.S. Renal Data System for the first 9 months of 2011 suggests that the share of patients covered by Medicare who received blood transfusions increased by 9% to 22% over the corresponding months in 2010.57 These data suggest that more stringent Hgb levels, coupled with payer restrictions such as the National Coverage Decision dialysis rule changes, have also been associated with increased blood transfusions in dialysis patients. The prospect of increased RBC transfusion rates should be taken seriously, given the large body of evidence linking blood transfusions with potentially untoward patient outcomes as well as the negative and potentially destabilizing effect of the increased demand on blood inventory. It should be noted that the data indicate a <10% margin between the total numbers of blood units collected and transfused in the United States.58 These observations have led to concerns that controversies over use of ESA therapy as an alternative to RBC transfusion will inflict collateral damage to the blood supply.59 In clinical practice, the increased risks of death and thromboembolic events should be balanced against the benefits of treatment with ESAs, considering each patient’s clinical circumstances and preferences.60 The approved dosage for epoetin alfa in oncology patients is 600 units/kg at weekly intervals for 4 weeks.


The relationship between erythropoietin, iron, and erythropoiesis and the presence of iron-restricted erythropoiesis has important implications in anemia management. Iron-restricted erythropoiesis can occur in the following: absolute iron deficiency, functional iron deficiency, and/or iron sequestration (Fig. 1).61 Absolute iron deficiency is common in women, children, and the elderly. Functional iron deficiency occurs in patients with significant erythropoietin-mediated erythropoiesis or ESA therapy, even when storage iron is present. Iron sequestration, mediated by hepcidin, is an underappreciated but common cause of iron-restricted erythropoiesis in patients with inflammation.

Figure 1
Figure 1:
Iron deficiency syndromes. The relationships between absolute iron deficiency, iron sequestration, and functional iron deficiency are illustrated. Patients can have ≥1 combinations that all result in iron-restricted erythropoiesis. Adapted from Goodnough LT.61

Conditions contributing to the development of absolute iron deficiency have been reviewed.62 Blood loss is a major cause of iron deficiency (e.g., female patients with menses, patients with chronic occult gastrointestinal blood loss, and community blood donors) and is important not only because of its prevalence but also because proper diagnosis and management of the bleeding lesion are important.63–65 Therapeutic management is primarily focused on repletion of iron stores. Most iron-deficient individuals without inflammation respond well to oral iron therapy, but administration of IV iron may be beneficial in patients with inflammation.66–69

The development of functional iron deficiency (in which increased demand for iron by the erythron exceeds rates of mobilization of iron from storage) in healthy subjects61 is observed by a reduction in transferrin saturation (TSAT) within 1 week of initiation of ESA therapy. The decrease in TSAT is also demonstrated in patients undergoing aggressive autologous blood donation, with or without ESA therapy.70 A decline in serum ferritin also occurs, reflecting shift of iron from storage pools into newly synthesized Hgb.71 An enhanced RBC production is seen in response to parenteral iron therapy in CKD patients treated with ESA therapy, demonstrating that this functional iron deficiency can be ameliorated with IV iron therapy with increases in serum iron and TSAT.72

While sequestration of iron has long been known to be central to the pathogenesis of the anemia of chronic disease,73 understanding of the regulation of iron homeostasis has changed substantially in the last 10 years.74–77 Hepcidin is a small peptide hormone secreted mainly by hepatocytes and has emerged as the central regulator of iron absorption, and plasma iron levels. Hepcidin production is strongly increased by inflammation and infection. Hepcidin exerts its effect by binding and degrading the iron exporter, ferroportin,76 thus reducing the iron available for erythropoiesis.77 Hepcidin acts to sequester iron by inhibiting storage iron egress from hepatocytes and macrophages into plasma, and also inhibits absorption of dietary iron from duodenal enterocytes.

The development of a sensitive, accurate, and reproducible immunoassay for human hepcidin has allowed definition of physiologic and pathologic changes of hepcidin in healthy volunteers and in patients.78 The assays will be useful in improving our understanding of the pathogenic role of hepcidin in various iron disorders, and in the development of appropriate therapeutic interventions. In contrast to changes in ferritin levels, changes in hepcidin concentrations are the cause of, rather than the result of, iron disorders. Hepcidin antagonists may be an effective treatment for patients with inflammatory anemia.79

The diagnostic and therapeutic implications for consi derations in iron-restricted erythropoiesis depend on the assessment of whether the patient has absolute iron deficiency, an iron sequestration syndrome, and/or functional iron deficiency. Traditional biochemical assays including serum iron, total iron-binding capacity, iron saturation percentage, and serum ferritin are not always helpful in evaluating the iron status in patients with inflammation.67 An algorithm for anesthesiologists’ evaluation of preoperative anemia in patients scheduled for elective surgery has been developed and published by a consortium of European Societies, in which the algorithm is centered on an evaluation for iron-restricted erythropoiesis.80

Expected changes in iron variables in various clinical conditions, and in the potential use of hepcidin assays for hepcidin-targeted therapies and iron therapies in patients with various forms of anemia, are summarized in Table 3.61,67,81 As the pathogenic mediator of inflammation, hepcidin would be expected to be high in iron sequestration syndromes. It is noteworthy that hepcidin levels are reliably elevated in patients with anemia of inflammation (AI) compared with normal values, and are low or undetectable in patients with absolute iron deficiency. However, in patients who have mixed problems, AI coexisting with absolute iron deficiency, or functional iron deficiency, hepcidin levels alone may not reliably distinguish among iron deficiency syndromes.82,83 Because hepcidin levels are affected by iron stores, this assay may also identify patients most likely to respond to iron therapy or identify patients at risk for iron loading.78

Table 3
Table 3:
Potential Role of Iron Therapy in Management of Anemia

Even under the best of circumstances, oral iron is not well tolerated, and patients are often nonadherent.84 In addition, hepcidin response in inflammatory conditions inhibits gastrointestinal absorption of oral iron. While evidence in rodents suggests that in the presence of both iron deficiency and inflammation, hepcidin levels are more responsive to the erythropoietic demands for iron than to inflammation and that oral iron can be absorbed,67 oncology patients respond better to IV iron therapy than to oral iron supplementation in chemotherapy-induced anemias treated with ESA.68,85–87 Despite these beneficial effects, IV iron administration may generate oxidative stress and other inflammatory changes. Long-term effects of the IV iron preparations will require careful study in relevant clinical settings.88,89

Therapy with ESAs in management of the anemia of chronic renal failure has led to substantial clinical experience in supplemental IV iron therapy in this setting.73,90 Hyporesponsiveness to ESA therapy is a common phenomenon91,92 attributable to a variety of comorbid conditions, but is particularly related to functional iron deficiency.70,71 Patients with anemia undergoing dialysis may show suboptimal or no response to oral iron therapy for several reasons. During ESA therapy, although absorption of iron can increase up to 5-fold93 presumably as a result of hepcidin suppression by increased erythropoiesis, continuing external iron losses as a result of hemodialysis and blood testing can exceed the intake.94,95 Furthermore, some patients have poor compliance with iron therapy or significantly reduced gastrointestinal iron absorption. Absorption of oral iron can be enhanced with ascorbate by at least 30%, because it reduces ferric iron to ferrous iron.95 Iron absorption and release from stores may be impaired because of high hepcidin levels from diminished clearance by the kidneys not completely corrected by routine hemodialysis, as well as from inflammation. Indeed, overexpression of hepcidin in mice blocked the hematopoietic response even to large doses of ESA.74

IV iron administration has been successful in renal dialysis patients undergoing ESA therapy96 and is recommended for management of anemia by the National Kidney Foundation Guidelines.97 Patients treated with IV iron (100 mg twice weekly) achieved a 46% reduction in ESA dosage required to maintain hematocrit levels between 30% and 34%, compared with patients supplemented with oral iron.98 To further address the management of iron-restricted erythropoiesis in CKD patients undergoing dialysis, a randomized, controlled trial evaluated the effectiveness of IV iron supplementation in patients with ferritin levels between 500 ng/mL and 1200 ng/mL.99 The administration of IV iron (and increasing the dose of ESA by 25%) resulted in a greater correction of anemia compared with increasing the dose of ESA alone. After the end of the trial, there was greater success in reducing the dose of ESA in the patients receiving IV iron, compared with the non iron-treated arm.

In patients with malignancy and chemotherapy-induced anemia, clinical trials have studied IV iron in the setting of therapy with ESAs. In one study85 of patients undergoing chemotherapy, 155 patients were treated with ESA and were randomized to receive no iron, oral iron, or IV iron. There were significant improvements in Hgb levels and hematopoietic responses in both patient groups treated with IV iron, compared with those receiving oral iron or no iron therapy.

Iron-restricted erythropoiesis has been shown to be a consideration at the time of cancer diagnosis, even before initiation of ESA therapy: 17% of patients were found to have serum ferritins <100 ng/mL and 59% had TSAT <20% at diagnosis.37 In addition, renewed attention has been placed on the relationship between ESA dose and RBC production responses in ESA-treated patients.100 Recent controversies regarding the safety of ESA therapy in patients with malignancies and chemotherapy-induced anemia101 have led to the development of guidelines by the American Society of Hematology/American Society of Clinical Oncology53 and the National Comprehensive Cancer Network54 that recommend iron studies be obtained at baseline to identify patients who are candidates for supplemental iron therapy; and that if subsequent Hgb levels after 4 weeks of ESA therapy indicate no response (<1 g/dL increase in Hgb), then IV iron supplemental therapy should be considered, along with an increase in ESA dose.

IV iron therapy also improved responses to ESA therapy in patients with inflammatory bowel disease compared with responses in a similar patient group who receive oral iron supplementation.102 Decreased reticulocyte Hgb is an indicator of the inadequacy of iron supply in the face of increased iron demand stimulated by ESA therapy.103 The requirement for a kinetic balance between iron delivery and level of erythropoietin stimulation may explain the need for IV iron supplemental therapy in ESA-treated patients, even those with replete iron stores.96 The clinical response to the combination of IV iron and ESA therapy may be attributed to the ability of the parenteral route to circumvent the inflammation-induced block to intestinal iron absorption and to deliver sufficient iron to the reticuloendothelial system, and the ability of ESA therapy to mobilize the iron from the reticuloendothelial system via transferrin into RBC precursors.69,104,105 It is not clear how IV iron can enhance the effect of ESAs even in the face of apparently increased iron stores. It is possible that the additional iron load in the reticuloendothelial system increases iron efflux from macrophages, perhaps by increasing the translation of ferroportin mRNA.

Currently approved IV iron preparations are listed in Table 4.69,106,107 The risk–benefit profile of IV iron continues to undergo evaluation in renal dialysis patients,96,108 as well as in patients with anemia caused by other chronic diseases.74 Iron dextran was the most widely used IV iron until the introduction of ferric gluconate, and then iron sucrose, to the U.S. market. Shortly thereafter, the use of iron dextran in dialysis patients decreased substantially because of the view that iron dextran carried a greater risk of severe reactions. Information in a retrospective analysis by Chertow et al.109 of 50 million doses of IV iron found that low molecular weight (LMW) iron dextran was safer than high molecular weight iron dextran, with the latter agent accounting for the majority of reported serious adverse events attributed to iron dextran.

Table 4
Table 4:
Currently Available IV Iron Preparations

The clinical setting for which IV iron is to be used should determine which preparation is chosen. For total dose infusion, IV iron is required because the iron salts cause dose-dependent gastrointestinal or vasoactive reactions at doses > 200 mg to 400 mg.110 The preferred dextran is the LMW preparation because as above, the high molecular weight preparation is associated with a significantly higher incidence of serious acute events.109,111 For patients receiving cyclical therapies such as cancer chemotherapy or dialysis, the iron salts or LMW iron dextran can be used as 100-mg to 400-mg infusions.93,110,112 In clinical settings such as preoperative patients, pregnancy, menometrorrhagia, gastric bypass, and uncomplicated iron deficiency in those intolerant to oral iron, however, a total dose infusion of LMW iron dextran is more convenient, equally effective, and less costly. Three studies comparing LMW iron dextran with the 2 salts show no difference in effectiveness or toxicity among the 3 products, but demonstrate considerable savings and increased convenience with LMW iron dextran.113–115 Similar strategies can be used with the other available IV iron preparations (Table 4). For example, rapid, large, dose administration of ferric carboxymaltose was found to be more effective than oral iron therapy in correcting anemia and replenishing iron stores in women with dysfunctional uterine bleeding.116

IV iron can allow up to a 5-fold erythropoietic response to significant blood loss anemia in normal individuals.117,118 A greater rate of RBC production is probably not possible unless red marrow expands into yellow marrow space, as is seen in patients with hereditary anemias.119,120 One potential limitation to IV iron therapy may be that much of the administered iron ends up in the reticuloendothelial system as storage iron, from where it is not readily available for erythropoiesis,120 particularly if hepcidin concentrations are elevated. For patients with absolute iron deficiency, 50% of IV iron is incorporated into Hgb within 3 to 4 weeks.121 However, for patients with AI, IV iron is mobilized less rapidly from the reticuloendothelial system. Nevertheless, when iron dextran was given IV to patients with anemia of rheumatoid arthritis122 and inflammatory bowel disease,123 Hgb concentrations increased significantly.


Prothrombin Complex Concentrates

Prothrombin complex concentrates (PCCs), single-factor concentrates, and recombinant coagulation factors are approved and routinely used in the treatment of inherited coagulation factor deficiencies. Some of these products have also been approved as hemostatic agents in acquired coagulopathies, such as acute reversal of warfarin coagulopathy,124 or may be considered (but are not approved) for acute reversal of oral Xa inhibitor therapy.125 Currently approved PCCs are summarized in Table 5.

Table 5
Table 5:
Currently Approved Prothrombin Complex Concentrate Products

PCCs are either activated (i.e., to allow for bypassing inhibitors to Factor VIII or Factor IX in the treatment of patients with hemophilia A or B), or are nonactivated: some of these PCCs are approved for use in Factor IX deficiency (hemophilia B), of which some are approved for reversal of warfarin coagulopathy. The nonactivated PCCs are further categorized on the basis of the presence (4-factor) or absence (3-factor) of sufficient levels of Factor VII.126 PCCs that contain all 4 (including Factor VII) of the vitamin K–dependent clotting factors are approved in the European Union (EU),127 variably in other countries such as Canada and Australia, and are not yet approved in the United States. A 4-factor PCC product (Beriplex, CSL Behring, King of Prussia, PA)128 is currently undergoing regulatory review in the United States for emergency reversal of warfarin coagulopathy in patients with major bleeding128 and also for perioperative management of patients receiving warfarin therapy.129 Three-factor PCCs are approved in the United States only for the replacement of Factor IX. Use of these 3-factor PCCs for reversal of warfarin is controversial; although they can be demonstrated to normalize International Normalized Ratio (INR),130 one report showed a suboptimal effect in correcting INR because of minimal increments in levels of Factor VII.126 In contrast, 4-factor PCCs are approved outside the United States for replacement of the vitamin K–dependent clotting factors (II, VII, IX, X).131,132 A recent study demonstrated an effect of 4-factor PCC in acute reversal of rivaroxaban (Xa inhibitor) but not dabigatran (thrombin inhibitor) therapy in normal volunteers.125

Guidelines from a number of medical societies on the use of PCCs in these settings have been published. Five guidelines (Table 6)133–138 have recommended that PCC can be given as an alternative to fresh frozen plasma (FFP) to increase levels of the vitamin K–dependent clotting factors. The most recently updated guidelines from the American College of Chest Physicians138 recommend PCC therapy instead of plasma therapy for acute reversal of warfarin coagulopathy; however, currently, only 3-factor PCCs are approved in the United States. These have been demonstrated to be inferior to plasma therapy for acute warfarin reversal.126 Accordingly, in one review, the authors have published their own hospital’s trauma Coumadin protocol with a recommendation of concomitant administration of a 3-factor concentrate (4000 IU) and rVIIa (1.0 mg).139 However, another review140 concluded that PCC should be compared directly in randomized, controlled trials with other treatment strategies including FFP and rFVIIa, and should evaluate the effect on patient outcomes rather than simply the normalization of the INR, which has been used as a surrogate end point.141 This lack of consensus on the role of PCC therapy relative to plasma therapy is in part attributed to the variability in the contents and levels of clotting factors in these preparations;126,142 their regulatory approval status for different countries; their lack of availability among hospital formularies, particularly in smaller community hospitals; and their potential risks of thrombogenicity.

Table 6
Table 6:
Published guidelines for acute reversal of warfarin coagulopathyin patients with intracerebral hemorrhage

Product information for activated PCCs such as Factor VIII inhibitor bypass activity (FEIBA VH Immuno, Baxter, Vienna, Austria) and Autoplex-T (Baxter, Roundtree, IL) state, under warnings, that they “must be used only for patients with circulating inhibitors to one or more coagulation factors and should not be used for the treatment of bleeding episodes resulting from coagulation factor deficiencies in the absence of inhibitors to Factors VIII or IX.”143,144 In addition, the presence of disseminated intravascular coagulation is a stated contraindication to their use in the package inserts. Nevertheless, despite the even greater potential risk of thrombogenicity compared with nonactivated PCCs, use of FEIBA has been recommended for reversal of warfarin in life-threatening bleeding if 4-factor PCCs are not available.145 A chart review of 72 patients who received FEIBA for warfarin reversal compared with 69 patients who were treated with FFP in life-threatening bleeding, indicated faster and more effective reduction of INR with FEIBA, but similar survival rates and length of hospital stay between the cohorts. However, 7% of the FEIBA-treated patients suffered potentially related adverse events.145

The safety of PCC concentrates in the setting of emergency reversal of warfarin coagulopathy remains a subject of debate. A recent prospective study of 173 patients treated with PCC found that 4.6% of patients had a thrombotic event, but it attributed these adverse events to cessation of anticoagulant therapy for underlying and continuing risks of thrombosis.146 A recent study in a pig model of coagulopathy with blunt liver injury found that whereas 35 IU/kg PCC improved coagulation and attenuated blood loss, increased doses (50 IU/kg) of PCC therapy seemed to increase the risk of thromboembolism and disseminated intravascular coagulation.147 Thrombogenicity has been a recognized problem for patients,148,149 in part related to the presence of activated clotting factors (for which heparin and antithrombin III have been added to some preparations150); and also in part because of the presence of other preexisting thromboembolic risk factors that resulted in initiation of warfarin in these patients (e.g., venous thrombosis, atrial fibrillation) or new, concurrent risk factors (e.g., trauma, head injury).

The reported incidence of thromboembolic events published between 1998 and 2008 ranged from 0% to 7% (overall weighted mean of 2.3%), with higher and repeated dosing potentially associated with higher risk.140 Multinational trials on patients receiving a 4-factor PCC product at various infusion speeds for urgent vitamin K antagonists reversal have supported the safety and effectiveness of rapid infusion of PCC in these patients.151,152 However, noteworthy for one recommendation is “whenever possible, patients receiving PCCs should be under low dose heparin prophylaxis,”142 underscoring that use of PCCs in this setting is accompanied by risks of thrombosis. A recent review153 of 8 clinical studies identified a thromboembolic event rate of 0.9% associated with PCC therapy. Studies of optimal dosing strategies for PCC, including fixed versus variable (weight-based) dosage, provide a basis for future research.154

As pooled blood product derivatives, PCCs also have potential risks of transmitting infectious agents.155 Various processing methods such as nanofiltration, solvent detergent treatment, or vapor heating have been used to inactivate pathogens in commercially available PCCs and pooled plasma products.156 The cost-effectiveness of such products with pathogen reduction technology is an area of current debate.157,158


Reducing and/or avoiding blood loss is a key component of patient blood management.2 Under physiologic conditions, hemostasis is achieved through constriction of damaged vessels, formation of platelet plug, and activation of coagulation factors resulting in the formation of a stabilized fibrin clot at the site of bleeding. Parallel to this, the fibrinolytic system is activated to control clot formation and propagation and dissolve the unnecessary (and potentially dangerous) clots.159,160 Hemostatic agents exploit these physiologic pathways to tip the balance toward forming and maintaining clots, thereby reducing bleeding.160,161

The most widely studied and used hemostatic agents are the antifibrinolytics. As the name implies, these agents act by inhibiting the physiologic fibrinolytic pathway that is responsible for limiting and dissolving clots. Aprotinin is a serine protease inhibitor that directly inhibits plasmin (and many other serine proteases), whereas lysine analogous, ε-aminocaproic acid (EACA), and tranexamic acid (TXA), act through interfering with the activation of plasminogen to plasmin and its binding to fibrin clots.162 In addition, aprotinin inhibits the contact activation pathway and may attenuate the inflammatory response in cardiopulmonary bypass (CPB).163 Aprotinin was removed from the market in 2007, but a reexamination of the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study164 and other data have led to a reversal of this decision and reintroduction of aprotinin in Canada and Europe for cardiac surgery. TXA and EACA have also been extensively reported in clinical investigations on antifibrinolytics in various patient populations.165

Renewed interest in antifibrinolytics, especially TXA, comes from the Clinical Randomization of an Antifibrinolytic in Significant Haemorrhage-2 (CRASH-2) trial in which more than 20,000 bleeding (or at risk of bleeding) trauma patients were randomized to receive TXA versus placebo. It was noted that despite no difference in bleeding and transfusions, early treatment with TXA compared with placebo was associated with a risk of death of 14.5% vs 16%, respectively.166 Nevertheless, acceptance of the CRASH-2 study results remains slow in the United States despite widespread implementation of TXA into clinical practice in Europe.

Further studies have analyzed bleeding and transfusions in other settings. Crescenti et al.167 randomized 200 patients undergoing radical retropubic prostatectomy to TXA versus placebo and observed a perioperative transfusion rate of 34% vs 55% in the study arms, respectively, with no increased risk of thromboembolic events. Zufferey et al.168 studied 110 patients undergoing surgery for hip fracture and reported a significantly lower RBC transfusion rate in patients randomized to TXA versus the placebo arm; however, the rate of occurrence of vascular events in the 6-week postoperative period was 16% in the TXA arm versus 6% in the placebo arm. This observation did not reach statistical significance, underscoring the need for further studies with larger sample sizes. Another study evaluating 900 prospective controlled cases of combat injuries found that TXA was independently associated with survival (odds ratio, 7.23), with a lower unadjusted mortality rate (17.4%) compared with the no-TXA group (P = 0.03). The authors called for inclusion of TXA in trauma protocols.169 Many European and Canadian massive transfusion protocols include TXA as part of their management. Investigation through a large randomized trial170 of postpartum hemorrhage, still the number one cause of mortality in the parturient, is in progress.

A systemic review of trials in off-pump coronary artery bypass graft (CABG) surgery concluded that TXA administration (1–2 g loading dose and 200–400 mg/h) was associated with significantly less risk of transfusion with no increased risk of complications.171 Another meta-analysis of 252 randomized, controlled trials (including the CRASH-2 study) has concluded that aprotinin was marginally superior to lysine analogs with regard to reducing blood loss. Compared with placebo, RBC transfusion was reduced by 34%, 39%, and 19% in patients treated with aprotinin, TXA, and EACA, respectively. Contrary to the other recent reports, aprotinin was not found to be associated with increased risk of mortality, myocardial infarction, stroke, or renal dysfunction in the meta-analysis when compared against placebo, although the authors raised issues with the adequacy of the data. On the other hand, lysine analogs were associated with decreased risk of mortality compared with aprotinin, a finding heavily influenced by the data from the BART study.172

Another meta-analysis focusing primarily on the safety of TXA confirmed less mortality in patients treated with TXA compared with no treatment, but also indicated a nonsignificant trend toward increased neurologic complications including seizures.173 Overall, the available data support the safety and effectiveness of lysine analogs for reducing blood loss and improving the outcomes of the patients. Again, it should be noted that Health Canada has recently reversed its decision on suspending aprotinin from the market, and has allowed its use as a hemostatic agent to reduce surgical blood loss in patients undergoing low-risk CABG procedures, while placing a boxed warning on the product labeling and requesting the manufacturer to conduct additional safety and effectiveness studies.174 Similarly, on the basis of a new review of data from the BART study and other evidence and by noting a number of problems with the BART study, the European Medicines Agency recently recommended that the suspension of aprotinin for patients undergoing cardiac bypass surgery be lifted.175


Desmopressin (a long-acting vasopressin agonist) is indicated to maintain hemostasis in patients with hemophilia A or mild to moderate type-1 von Willebrand disease with Factor VIII activity >5%.176 Although desmopressin contributes to hemostasis through increasing the levels of von Willebrand factor and Factor VIII and improving platelet function among other less understood mechanisms, its effects are far more diverse and include inducing the production of nitric oxide (resulting in vasodilation) and increasing the level of tissue plasminogen activator.177 Desmopressin has been used as a hemostatic agent in patients without preexisting coagulation disorders undergoing high blood loss surgeries such as cardiac, spinal, and orthopedic procedures. A meta-analysis of 38 randomized, placebo-controlled trials indicated that desmopressin (usually at a dose of 0.03 μg/kg) had a statistically significant (albeit clinically modest) effect on reducing perioperative bleeding and transfusion of blood components (reducing approximately 80 mL in blood loss and 0.3 units in transfusions).178 There was no significant increased risk of thromboembolic complications,178 a concern that had been reported in earlier studies.179 Some reports suggest that patients with platelet dysfunction (e.g., due to aspirin) are more likely to benefit from desmopressin although more data are needed.179 However, its routine use as a prophylactic hemostatic agent is still debated and not currently recommended in cardiac surgeries.180

Other Factor Concentrates

Various concentrated or recombinant coagulation factors are available and routinely used in the treatment of congenital deficiencies; some of these factors have also been considered and investigated as potential hemostatic agents. Fibrinogen concentrate is currently approved in the United States for treatment of bleeding in patients with congenital fibrinogen deficiency.181 However, given the assertion that acquired fibrinogen deficiency may be present in patients undergoing various high blood loss procedures, use of fibrinogen concentrate as a hemostatic agent is under investigation. In a pilot study, thromboelastometry-guided administration of fibrinogen concentrate to patients undergoing aortic valve operation and ascending aorta replacement to achieve a high-normal plasma level resulted in less blood loss and transfusions.182 Another study by this team reported that administration of fibrinogen concentrate in patients with decreased platelet function with bleeding after CABG surgery was associated with less transfusion of allogeneic blood components.183 Encouraging reports have been published on the use of fibrinogen concentrate as a hemostatic agent in bleeding trauma patients, but the evidence is still far from conclusive in these and other patient populations.184–186 Finally, fibrinogen concentrates have been reported to be an effective addition to conventional treatments for obstetrical hemorrhage associated with hypofibrinogenemia.187,188 Fibrinogen concentrates are used in certain countries where cryoprecipitate is not available.

Factor XIII concentrate and recombinant forms are available for clinical use in Europe, but still await regulatory approval in the United States. Factor XIII is primarily used for prophylactic treatment of patients with congenital deficiency of Factor XIII. However, its special mode of action through cross-linking fibrin and improving the clot firmness may be a promising process to exploit for hemostasis, particularly in procedures associated with extensive perioperative blood loss. In a preliminary study in patients undergoing CABG with CPB, administration of Factor XIII was suggested to be effective in reducing postoperative blood loss and transfusions, only in patients with lower than normal Factor XIII.189 More recently, a placebo-controlled, proof-of-concept, randomized trial in 22 patients undergoing elective gastrointestinal cancer surgery has indicated that early administration of Factor XIII during surgery may be able to promote fibrin clot firmness and reduce fibrinogen consumption and blood loss.190 The blood conservation guidelines from the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists have recommended Factor XIII as a hemostatic agent to stabilize the clots in bleeding patients undergoing cardiac surgery when other treatments have not yielded satisfactory results.180 A Phase-II, multinational, randomized, placebo-controlled trial on the safety and effectiveness of recombinant Factor XIII in reducing transfusions in 479 patients undergoing heart surgery with CPB did not indicate any effectiveness.191 At this point, it seems that more data are needed to support its routine use as a hemostatic agent.

Topical Hemostatic Agents

Topical application of hemostatic agents provides a way of maximizing the local effects of these agents while minimizing their (potentially unwanted) systemic effects. Although there are a multitude of publications demonstrating bleeding cessation with a variety of topical agents, few if any address the use of topical agents, other than the antifibrinolytics, as a direct effect on transfusion reduction. In one systematic review,192 the authors report the effectiveness of topical agents in transfusion reduction and point out the paucity of strong trials in this area. As part of a multimodal approach to blood conservation in cardiac surgery, topical agents have been and continue to be recommended.180 In a placebo-controlled, randomized trial of 124 total knee arthroplasty patients (with a high patient dropout rate of 20%), topical application of TXA (1.5 g or 3.0 g of TXA in 100 mL normal saline solution applied topically to the joint for 5 minutes at the end of surgery) reduced postoperative blood loss by 20% to 25% depending on the dose, without any reported side effects.193 A meta-analysis of 8 trials on 622 on-pump cardiac surgery patients concluded that topical application of aprotinin or TXA to the mediastinum or pericardial cavity was associated with an average of 220 mL reduction in 24-hour postoperative blood loss via chest tube and avoidance of transfusion of 1 unit of RBC per patient with no reported adverse effects.194 It is interesting to note that one of the analyzed trials compared topical versus systemic aprotinin and found similar results.195

Several other topical products are available in the form of tissue sealants and adhesives for clinical use today. Topical hemostats generally act by compressing the bleeding vessels (directly or indirectly as a result of swelling of the sealant and compression of the adjacent tissues), activating/aggregating platelets, and providing a physical scaffold for better clot formation. In addition, some incorporate various procoagulant factors for more effective hemostasis. The matrix of these products is commonly made of collagen, gelatin, or polysaccharides (e.g., cellulose, chitin). Some other topical agents are made of synthetic or semisynthetic compounds such as cyanoacrylate, polyethylene glycol, and a mixture of albumin and glutaraldehyde that are polymerized to form tissue adhesives.196–198 Thrombin and fibrinogen are increasingly used as part of topical sealants (or on their own such as topical thrombin spray) to enhance the hemostatic effects of these products.199–201

Several randomized, controlled trials have demonstrated the safety and effectiveness of tissue sealants and adhesives, although negative results have also been reported. For example, in a study of 415 patients undergoing elective cardiac and aortic procedures, use of a thrombin-containing gelatin-based sealant was associated with better and faster hemostasis and less postoperative bleeding and transfusions.202 Similarly, use of fibrin sealants (potent topical hemostatic products containing both thrombin and fibrinogen) was found to reduce perioperative blood loss by more than 20% in 81 patients undergoing total hip replacement.193 On the other hand, a randomized, controlled trial of 300 patients undergoing liver resection failed to show any difference between fibrin sealant and placebo with regard to transfusion, postoperative and total drainage, complications, and postoperative morbidity,203 although the coupled use of an argon beam coagulator or a bipolar surgical sealer in all patients might have contributed to lack of significant differences between the study arms.204

However, trials evaluating the topical hemostatic agents are relatively small, and recent meta-analyses pooling data from several studies focusing on their effect on blood loss or transfusions are largely lacking. A 2003 meta-analysis of 7 trials on the effects of fibrin sealants on perioperative transfusion concluded that these products reduced allogeneic RBC transfusions by 54%, but it also noted the limited sample size and lack of blinding as causes for concern on methodological robustness of the studies.205 A 2009 update of this meta-analysis evaluated data from 18 trials and concluded that fibrin sealants reduced allogeneic RBC transfusions by 37% and reduced blood loss by an average of 161 mL per patient. The effect was even larger in a subset of trials focusing on orthopedic surgeries. Despite more convincing data, the call for larger and better- designed trials remains.206

The topical hemostatics are generally safe and the complications are mostly limited to issues related to local compression (for products that swell after application) and residual risk of disease transmission (for products derived from human or animal sources).198 The fibrin sealant meta-analysis could not find an association between use of fibrin sealants and increased risk of infections, hematoma formation, or death.206 Induction of inhibitory antibodies is also a concern, particularly in the case of bovine thrombin with potential cross-reactivity against the human native protein, which could result in coagulopathy and bleeding. This complication resulted in issuing a black box warning on the package insert of topical bovine thrombin. The risk appears to be vastly eliminated when recombinant human proteins are used.207,208 A study of data from 8 clinical trials on topical recombinant thrombin (used as part of sealants or directly applied) has concluded that recombinant thrombin was well tolerated. New thrombin antibodies emerged in less than 1% of the patients, and these antibodies were not neutralizing and hence not expected to negatively affect coagulation.209

Local infiltration of vasoconstrictors such as epinephrine has been used in clinical practice for years to reduce bleeding, namely in skin incisions and oral/dental surgeries.210 These topical hemostatic agents can be highly effective,211 but they must be used carefully to avoid systemic reactions, particularly in patients with cardiovascular comorbidities.212–214

Recombinant Activated Factor VII

rFVIIa is thought to act via 2 mechanisms, both of which are to increase coagulation activation to the site of tissue damage.215 First, rFVIIa complexes directly with tissue factor (TF) released from the subendothelium at sites of vascular disruption. The TF-rFVIIa complex then activates the remainder of the common coagulation cascade via activated Factor X. Alternatively, rFVIIa may bind to activated platelets, which also concentrates Factor X activation to sites of tissue injury. The Factor Xa generated by these 2 mechanisms ultimately drives the thrombin burst, which cleaves fibrinogen to fibrin, thus initiating the formation of the fibrin meshwork critical to secondary coagulation and clot stabilization. The potential role for rFVIIa in TF-independent clotting has raised concern for its site specificity and the risk for off-target thrombosis. Accordingly, the FDA required the addition of a black box warning to the package insert in 2005, warning physicians of the risk of thromboembolic complications when the agent is used, in view of these safety concerns for thromboembolic adverse events, along with continued uncertainty regarding its level of effectiveness in off-label settings.

Approved indications of rFVIIa in the United States and EU include treatment of bleeding episodes (or prevention of bleeding from invasive procedures) in patients with congenital hemophilia A or B with inhibitors to Factors VIII or IX, patients with congenital Factor VII deficiency, and in patients with acquired hemophilia. In addition, it is approved in the EU in the treatment of Glanzmann thrombasthenia for patients with an inherited qualitative platelet defect. However, these approved indications accounted for only 3121 (4.2%) of 73,747 cases reported to use rFVIIa in the United States from 2000 to 2008.216

Off-label use of rFVIIa in a variety of other clinical settings has continued to increase rapidly (Fig. 2). For example, use of rFVIIa in patients not receiving warfarin who had spontaneous intracranial hemorrhage (ICH) increased 8-fold, from 250 cases in 2004 to 2010 cases in 2008, accounting for 11% of all off-label rFVIIa usage. This activity reflected a large dose-seeking clinical trial in patients with spontaneous ICH that initially showed promise217 in reducing the volume of hemorrhage and improved patient outcomes (reduced mortality, long-term disability); however, the subsequent trial,218 although it confirmed reduced hematoma growth, was unable to demonstrate improved patient outcomes (reduction of severe disability or death at 90 days).

Figure 2
Figure 2:
Estimated annual in-hospital cases of recombinant Factor VIIa use for hemophilia and off-label indications. Cases signify the number of hospitalizations during which recombinant Factor VIIa was used. All cases for each year are depicted. The width of each segment represents the number of cases for each category, as indicated by differential shading. Hemophilia includes hemophilia A and B, and trauma includes body and brain trauma. ICH = intracranial hemorrhage. Adapted from Logan AC et al.216

Other off-label categories include cardiovascular surgery and trauma in an attempt to address uncontrolled hemorrhage in these settings. Gill et al.219 reported significant reductions in bleeding, transfusion requirements, and reexploration when rFVIIa was used postoperatively in high-risk bleeding cardiac surgical patients. Finally, early reports of the off-label use of rFVIIa in the successful management of warfarin-associated ICH in patients with refractory bleeding led to the development of policies for oversight of its off-label use.220 A subsequent systematic literature review found only limited available evidence for 5 off-label clinical settings (Fig. 2), in which no mortality reduction was found to be associated with rFVIIa use in these settings.221

The potential role of rFVIIa therapy in patients taking oral thrombin or Xa inhibitors who have hemorrhagic complications remains undefined. A recent case report suggested that the combination of rFVIIa and hemodialysis was effective in management of dabigatran-associated bleeding in a patient after cardiac surgery222 but the patient also received multimodal therapy.

Case reports have described the successful use of rFVIIa in patients with warfarin-associated anticoagulation and ICH,223–225 and studies have indicated that doses of 15 µg/kg to 20 µg/kg rFVIIa can normalize INR values when used to treat warfarin-associated deficiencies of functional vitamin K–dependent clotting factors.226 Nonetheless, concerns have been raised whether the effect goes beyond mere normalization of INR, and whether patient outcomes are improved.227 The uncertainty on whether the demonstrable effects of rFVIIa on INR correction are accompanied by adequate restoration of thrombin generation228 compared with PCCs, or improvement in bleeding times in reversal of warfarin in normal subjects,229 are reasons why 2 guidelines135,137 and 1 evidence-based review227 have recommended against the routine use of rFVIIa for warfarin reversal in patients with ICH.135

The safety profile of rFVIIa in controlled trials in patients with spontaneous ICH suggests that an increased risk of thrombotic arterial events may be underreported by treating physicians.230 Thromboembolic events associated with rFVIIa were reported to the FDA in approximately 2% of treated patients in clinical trials, but sufficient data were not available to identify the incidence in patients who received rFVIIA for warfarin reversal.231 A review of 285 trauma patients revealed that 27 (9.4%) had thromboembolic complications after administration of rFVIIa, including 3 patients who were treated for warfarin reversal.232 Levi et al.233 recently analyzed 35 randomized trials of rFVIIa with 4468 subjects and found that 11.1% had thromboembolic events. Rates of venous thromboembolic events were similar for subjects who received rFVIIa compared with placebo (5.3% and 5.7%, respectively); arterial events, however, were significantly higher (5.5% vs 3.2%, P < 0.003) in subjects receiving rFVIIa compared with placebo, particularly for older patients and/or higher doses.

Artificial Oxygen Carriers

Total oxygen carried by the blood is the sum of oxygen carried by Hgb molecules (normally confined within RBCs) and the oxygen dissolved in the plasma. The former component is determined by the Hgb concentration in blood and the percentage of Hgb oxygen saturation, whereas the latter component is directly related to the partial pressure of oxygen in the blood.234,235 Under physiologic conditions, each gram of Hgb is capable of binding approximately 1.34 mL oxygen, whereas each mL of plasma is capable of dissolving approximately 0.03 mL oxygen at 37°C and arterial partial pressure of oxygen in the blood of 100 mm Hg.234,236 Hence, most of the oxygen molecules (approximately 98%) are transported in blood via the first mechanism.236 Both mechanisms have been used as means for urgent increasing of the oxygen delivery in cases of severe anemia when blood oxygen content cannot meet the tissue demands and when blood transfusion is not an option. For example, in hyperbaric oxygen therapy, oxygen at above atmospheric pressure is administered to increase the amount of oxygen dissolved in plasma and causes a boost in tissue oxygen delivery that may indeed be enough to save a severely anemic patient from imminent death or ischemic complications.237 On the other hand, products known as artificial oxygen carriers achieve this by supplying additional Hgb molecules (first mechanism), or by providing an inert medium capable of dissolving substantial amounts of oxygen (second mechanism).

Although no artificial oxygen carrier is currently approved by the FDA for clinical human use in the United States, this is a field of active research with several products in various stages of development. The future of artificial oxygen carriers seems promising, given several potential advantages of such products. Some aspects that make the artificial oxygen carriers particularly appealing include: prospect of being free of most or all of the infectious risks of allogeneic blood; no need to perform blood grouping and cross-match; extended shelf-life and possibility of storage at room temperature; potential for virtually unlimited supply; and possibility of development of homogenous and standardized products with controlled characteristics optimized to achieve the goal of oxygen delivery without raising all other complexities of allogeneic blood that have been rightfully likened to a tissue transplant.1,236,238,239

Perfluorocarbon (PFC) emulsions are the most studied products that can boost oxygen delivery by increasing the amount of dissolved oxygen. To maximize their effectiveness, use of these oxygen carriers must be coupled with oxygen and increased FIO2 to further increase the amount of dissolved oxygen. Although PFCs are biologically inert, the same does not necessarily apply to other chemicals present in these products (e.g., surfactants added for emulsification). The PFCs that have reached clinical trial include Fluosol-DA (Alpha Therapeutics, Los Angeles, CA) and Oxygent (Alliance Pharmaceutical Corporation, San Diego, CA; and Perftoran [OJCS SPF Perftoran Russian, Moscow, Russia] outside of the United States).240 Fluosol-DA was initially used to improve oxygen delivery to the heart muscle during percutaneous transluminal coronary angiography, but it was subsequently withdrawn because of difficulties in storage and preparation, and lack of need in angioplasty. Oxygent has been shown in numerous studies to be able to improve oxygen delivery and replace and reduce transfusions, with overall mild side effects with the exception of a reported increase in stroke.236 Transient thrombocytopenia is a common side effect of PFCs, possibly related to increased platelet destruction because of changes in platelet membrane in presence of PFCs.241

On the other hand, Hgb-based oxygen carriers (HBOCs) dramatically increase oxygen delivery through increasing the Hgb level. The Hgb may be from human, animal, or recombinant sources. Despite effective oxygen transportation, HBOCs have been associated with complications such as vasoconstriction (initially attributed to extravasation of the HBOC to interstitial space and scavenging nitric oxide),242 hypertension, and renal, pancreatic, and liver injury. To minimize toxicity and associated complications, approaches such as purification, polymerization, cross-linking, conjugating with other macromolecules, and encapsulating in vesicles or other nano-particles have been pursued in various generations of HBOCs.243

Three products, HemAssist (Baxter, Deerfield, IL), Hemopure (Biopure, Cambridge, MA; now, OPK Biotech, Cambridge, MA), and PolyHeme (Northfield, Evanston, IL) are among the most extensively clinically investigated HBOCs. HemAssist (also known as diaspirin cross-linked Hgb or DCLHb) was produced from outdated human allogeneic blood units and had an Hgb concentration of 10 g/dL.244 The product underwent relatively extensive animal and human studies, including a U.S. multicenter, randomized trial on 112 patients with traumatic hemorrhagic shock using normal saline as the control treatment, which indicated a 72% higher mortality rate in the DCLHb group and resulted in premature termination of the study.244,245 Another prematurely terminated multicenter trial in Europe on 121 trauma patients with severe hemorrhagic shock concluded that treatment with DCLHb (versus standard therapy) reduced the use of transfusions, without improving morbidity or mortality.246 Two follow-up studies by the investigators reanalyzed the data from these 2 trials, and concluded that for the most part, DCLHb use was not associated with arterial blood pressure variation, base deficit, or lactate abnormalities (indicative of poor perfusion), and as such, they concluded that increased mortality in the DCLHb arm is not directly related to the vasoconstrictive effect of the product.245,247 The manufacturer has suspended the development of HemAssist.

Hemopure (also known as HBOC-201) is polymerized, purified bovine Hgb with an Hgb concentration of approximately 13 g/dL and extended shelf-life. A Phase-III, randomized trial on 688 orthopedic surgery patients with RBC transfusion as the comparator reported that HBOC-201 was highly effective in eliminating the need for transfusions, but it was also associated with increased risk of adverse events (namely, increased systolic and diastolic blood pressure) and serious adverse events (cardiac events and strokes). The authors attributed the increased risk of unfavorable outcomes partially to imbalances in patients’ age, intravascular volume overload, and undertreatment with the product.248 Further randomized trials on HBOC-201 were abandoned in the United States out of concerns with the product’s safety. However, the FDA provided a per-patient approval to use HBOC-201 on compassionate basis in patients with life-threatening anemia who could not have been transfused, and a report of 54 such cases has suggested that earlier administration of HBOC-201 to patients likely to have Hgb concentrations below critical levels is associated with better survival.249 HBOC-201 became the first product in this class to be approved for human use in South Africa (2001) and Russia (2011) for treatment of acute anemia. However, the product’s website in South Africa lists it as “unavailable” as of November 2011 ( A related product, HBOC-301 (Oxyglobin) is the first product approved in the United States and the EU for veterinary use, with promising results from ongoing investigations.250–252

PolyHeme is based on cross-linked and polymerized human Hgb sourced from outdated allogeneic RBC units, with an Hgb concentration of 10 g/dL.244 In a Phase-III, multicenter trial in the United States, 714 trauma patients with hemorrhagic shock were randomized to field resuscitation with PolyHeme or crystalloid and reported lower use of allogeneic blood transfusions but a moderately higher risk of adverse events and serious adverse events (notably, myocardial infarction) in patients randomized to receive PolyHeme. However, the authors concluded PolyHeme had a favorable benefit-to-risk ratio in patients in need of transfusion when blood transfusion was not available.253 A post hoc analysis of the data by the investigators suggested that PolyHeme was able to sustain postinjury survival longer compared with the control treatment.254 It should be pointed out that the design of this trial, including the waiver of informed consent, the potential for increased adverse events, and the continued use of the compound when blood was available, has generated ethical controversies.255–257 The manufacturer of PolyHeme eventually filed for bankruptcy.

Despite effectiveness in reducing allogeneic transfusions, clinical use of all major HBOCs appears to be marred with increased risk of morbidity and mortality. A 2008 meta-analysis of 16 trials on 5 different HBOCs (including the 3 products discussed here) indicated that regardless of the individual product or indication studied, use of these HBOCs was associated with significantly higher risk of death (relative risk of 1.30) and myocardial infarction (relative risk of 2.71) combined with the controls.258 Although the methodology of this meta-analysis and the validity of the conclusions have been criticized, there is little doubt regarding the risks and complications of these products.259,260 Nonetheless, there are also reports of patients with exceedingly low Hgb (even 2–3 g/dL) who survived on HBOCs.249,259,261 The brief overview of these once promising artificial oxygen carriers summarizes the complexities faced by research and development efforts in this field. Although a new generation of products is in development, currently these products can be considered to help patients survive critically low Hgb levels when blood transfusions are not available, as “oxygen bridges” until compensatory erythropoiesis can be achieved with the use of such agents as ESA and IV iron therapies.

Intravascular volume expanders can also serve as pharmacologic alternatives to blood transfusion. Hemospan is a polyethylene glycol-modified human Hgb with improved half-life in blood circulation and relatively high affinity for oxygen, which may make it more effective in delivering oxygen to hypoxic and ischemic tissues. In 2 related randomized trials in a total of 841 patients undergoing hip arthroplasty, Hemospan use was shown to be more effective in preventing hypotensive episodes and reducing the duration of such episodes, compared with hydroxyethyl starch. While serious adverse events occurred similarly in both study arms, the incidence of nonserious adverse events such as nausea, oliguria, and hypertension was higher in patients randomized to receive Hemospan hydroxyethyl starch.262,263 Currently, a Phase-II, randomized, controlled trial to evaluate the safety and effectiveness of Hemospan in trauma patients with shock is underway outside the United States.


Health care faces new challenges in delivery of care and resource utilization. The change from “volume-based” to “values-based” care necessitates shared decision making between patient and clinicians to achieve the best outcome.264,265 In light of this, we have presented a review of the pharmacologic and hemostatic agents that are used in patient blood management with an emphasis on their clinical utility as alternatives to allogeneic blood transfusion. Both patients and physicians will require effective information to make the most appropriate health decisions in the context of informed consent.266 As patient blood management evolves, understanding the relative benefits and risks of pharmacologic alternatives to blood compared with the relative benefits and risks of blood transfusion becomes imperative.


Name: Lawrence Tim Goodnough, MD.

Contribution: This author helped write the manuscript, and review, and approve the final draft.

Attestation: Lawrence Tim Goodnough approved the final manuscript.

Conflicts of Interest: Lawrence Tim Goodnough is a consultant for CSL Behring, Amgen, Pharmacosmos, and Luitpold.

Name: Aryeh Shander, MD.

Contribution: This author helped write the manuscript, and review and approve the final draft.

Attestation: Aryeh Shander approved the final manuscript.

Conflicts of Interest: Aryeh Shander has potential conflicts or relevant competing interests that should be known by the Editor for CSL Behring, OPK Biotech LLC; Ethicon; and American Regent.

This manuscript was handled by: Jerrold H. Levy, MD, FAHA.


1. Goodnough LT, Shander A. Blood management. Arch Pathol Lab Med. 2007;131:695–701
2. Goodnough LT, Shander A. Patient blood management. Anesthesiology. 2012;116:1367–76
3. Hofmann A, Farmer S, Shander A. Five drivers shifting the paradigm from product-focused transfusion practice to patient blood management. Oncologist. 2011;16 Suppl 3:3–11
    4. Goodnough LT, Brecher ME, Kanter MH, AuBuchon JPTransfusion medicine.. First of two parts–blood transfusion. N Engl J Med. 1999;340:438–47
      5. Goodnough LT, Brecher ME, Kanter MH, AuBuchon JPTransfusion medicine.. Second of two parts–blood conservation. N Engl J Med. 1999;340:525–33
        6. Adams KW, Tolich D. Blood transfusion: the patient’s experience. Am J Nurs. 2011;111:24–30
        7. Society for the Advancement of Blood Management (SABM). Available at: Accessed March 2, 2012
        8. Ness PM. A new section on blood conservation: liberalizing transfusion. Transfusion. 2004;44:631
        9. Network for Advancement of Transfusion Alternatives (NATA). Available at: Accessed March 2, 2012
        10. Joint Commission Patient Blood Management Performance Measures Project Jan 3, 2011. Available at:
        11. United States Department of Health and Human Services. . The 2007 National Blood Collection and Utilization Report 2010. Available at:
        12. Goodnough LT, Monk TG, Andriole GL. Erythropoietin therapy. N Engl J Med. 1997;336:933–8
        13. Laupacis A, Fergusson DErythropoietin to minimize perioperative blood transfusion: a systematic review of randomized trials.. The International Study of Peri-operative Transfusion (ISPOT) Investigators. Transfus Med. 1998;8:309–17
        14. Glaspy J, Bukowski R, Steinberg D, Taylor C, Tchekmedyian S, Vadhan-Raj S. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. Procrit Study Group. J Clin Oncol. 1997;15:1218–34
        15. Vansteenkiste J, Pirker R, Massuti B, Barata F, Font A, Fiegl M, Siena S, Gateley J, Tomita D, Colowick AB, Musil JAranesp 980297 Study Group. . Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst. 2002;94:1211–20
        16. Seidenfeld J, Piper M, Flamm C, Hasselblad V, Armitage JO, Bennett CL, Gordon MS, Lichtin AE, Wade JL 3rd, Woolf S, Aronson N. Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials. J Natl Cancer Inst. 2001;93:1204–14
        17. Eschbach JW, Egrie JC, Downing MR, Browne JK, Adamson JWCorrection of the anemia of end-stage renal disease with recombinant human erythropoietin.. Results of a combined phase I and II clinical trial. N Engl J Med. 1987;316:73–8
        18. Eschbach JW, Abdulhadi MH, Browne JK, Delano BG, Downing MR, Egrie JC, Evans RW, Friedman EA, Graber SE, Haley NRRecombinant human erythropoietin in anemic patients with end-stage renal disease.. Results of a phase III multicenter clinical trial. Ann Intern Med. 1989;111:992–1000
        19. Shander A, Cappellini MD, Goodnough LT. Iron overload and toxicity: the hidden risk of multiple blood transfusions. Vox Sang. 2009;97:185–97
        20. Eschbach JW, Adamson JW. Iron overload in renal failure patients: changes since the introduction of erythropoietin therapy. Kidney Int Suppl. 1999;69:S35–43
        21. Pisoni RL, Bragg-Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F, Bommer J, Cruz JM, Kerr PG, Mendelssohn DC, Held PJ, Port FK. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004;44:94–111
        22. Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B, Bennett CL, Langensiepen S, Hyde C, Engert A. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. 2006;98:708–14
        23. Stowell CP, Jones SC, Enny C, Langholff W, Leitz G. An open-label, randomized, parallel-group study of perioperative epoetin alfa versus standard of care for blood conservation in major elective spinal surgery: safety analysis. Spine. 2009;34:2479–85
        24. Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339:584–90
        25. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan DCHOIR Investigators. . Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355:2085–98
        26. Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag ACREATE Investigators. . Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–84
        27. Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, Feyzi JM, Ivanovich P, Kewalramani R, Levey AS, Lewis EF, McGill JB, McMurray JJ, Parfrey P, Parving HH, Remuzzi G, Singh AK, Solomon SD, Toto RTREAT Investigators. . A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361:2019–32
        28. Solomon SD, Uno H, Lewis EF, Eckardt KU, Lin J, Burdmann EA, de Zeeuw D, Ivanovich P, Levey AS, Parfrey P, Remuzzi G, Singh AK, Toto R, Huang F, Rossert J, McMurray JJ, Pfeffer MATrial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) Investigators. . Erythropoietic response and outcomes in kidney disease and type 2 diabetes. N Engl J Med. 2010;363:1146–55
        29. Lewis EF, Pfeffer MA, Feng A, Uno H, McMurray JJ, Toto R, Gandra SR, Solomon SD, Moustafa M, Macdougall IC, Locatelli F, Parfrey PSTREAT Investigators. . Darbepoetin alfa impact on health status in diabetes patients with kidney disease: a randomized trial. Clin J Am Soc Nephrol. 2011;6:845–55
        30. Hedenus M, Adriansson M, San Miguel J, Kramer MH, Schipperus MR, Juvonen E, Taylor K, Belch A, Altés A, Martinelli G, Watson D, Matcham J, Rossi G, Littlewood TJDarbepoetin Alfa 20000161 Study Group. . Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Br J Haematol. 2003;122:394–403
        31. Leyland-Jones B, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G, Makhson A, Roth A, Dodwell D, Baselga J, Biakhov M, Valuckas K, Voznyi E, Liu X, Vercammen E. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol. 2005;23:5960–72
        32. Untch M, Fasching PA, Konecny GE, von Koch F, Conrad U, Fett W, Kurzeder C, Lück HJ, Stickeler E, Urbaczyk H, Liedtke B, Salat C, Harbeck N, Müller V, Schmidt M, Hasmüller S, Lenhard M, Schuster T, Nekljudova V, Lebeau A, Loibl S, von Minckwitz GArbeitsgemeinschaft Gynäkologische Onkologie PREPARE investigators. . PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel and CMF versus a standard-dosed epirubicin/cyclophosphamide followed by paclitaxel ± darbepoetin alfa in primary breast cancer–results at the time of surgery. Ann Oncol. 2011;22:1988–98
        33. Overgaard J, Hoff C, San Hansen H. Randomized study of the importance of novel erythropoiesis stimulating protein (Aranesp) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): the Danish Head and Neck Cancer Group DAHANCA 10. Eur J Cancer. 2007;7:Abstract 6LB
        34. Thomas G, Ali S, Hoebers FJ, Darcy KM, Rodgers WH, Patel M, Abulafia O, Lucci JA 3rd, Begg AC. Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol. 2008;108:317–25
        35. Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, Szechtman B, Roa W, Mulroy L, Rudinskas L, Gagnon B, Okawara GS, Levine MN. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 2007;25:1027–32
        36. Smith RE Jr, Aapro MS, Ludwig H, Pintér T, Smakal M, Ciuleanu TE, Chen L, Lillie T, Glaspy JA. Darbepoetin alpha for the treatment of anemia in patients with active cancer not receiving chemotherapy or radiotherapy: results of a phase III, multicenter, randomized, double-blind, placebo-controlled study. J Clin Oncol. 2008;26:1040–50
        37. Glaspy J, Crawford J, Vansteenkiste J, Henry D, Rao S, Bowers P, Berlin JA, Tomita D, Bridges K, Ludwig H. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer. 2010;102:301–15
        38. Seliger SL, Zhang AD, Weir MR, Walker L, Hsu VD, Parsa A, Diamantidis CJ, Fink JC. Erythropoiesis-stimulating agents increase the risk of acute stroke in patients with chronic kidney disease. Kidney Int. 2011;80:288–94
        39. Ross SD, Allen IE, Henry DH, Seaman C, Sercus B, Goodnough LT. Clinical benefits and risks associated with epoetin and darbepoetin in patients with chemotherapy-induced anemia: a systematic review of the literature. Clin Ther. 2006;28:801–31
        40. Seidenfeld J, Piper M, Bohlius J, Weingart O, Trelle S, Engert A, Skoetz N, Schwarzer G, Wilson J, Brunskill S, Hyde C, Bonnell C, Ziegler KM, Aronson NComparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment.. (Comparative Effectiveness Review No. 3; prepared by Blue Cross and Blue Shield Association Technology Evaluation Center Evidence-based Practice Center under Contract No. 290–02–0026). 2006 Rockville Agency for Healthcare Research and Quality, Available at: Accessed on November 13, 2012
        41. Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, Barnato SE, Elverman KM, Courtney DM, McKoy JM, Edwards BJ, Tigue CC, Raisch DW, Yarnold PR, Dorr DA, Kuzel TM, Tallman MS, Trifilio SM, West DP, Lai SY, Henke M. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008;299:914–24
        42. Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke M, Weingart O, Kluge S, Piper M, Rades D, Steensma DP, Djulbegovic B, Fey MF, Ray-Coquard I, Machtay M, Moebus V, Thomas G, Untch M, Schumacher M, Egger M, Engert A. Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet. 2009;373:1532–42
        43. Henke M, Laszig R, Rübe C, Schäfer U, Haase KD, Schilcher B, Mose S, Beer KT, Burger U, Dougherty C, Frommhold H. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255–60
        44. Tonelli M, Hemmelgarn B, Reiman T, Manns B, Reaume MN, Lloyd A, Wiebe N, Klarenbach S. Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis. CMAJ. 2009;180:E62–71
        45. Ludwig H, Crawford J, Osterborg A, Vansteenkiste J, Henry DH, Fleishman A, Bridges K, Glaspy JA. Pooled analysis of individual patient-level data from all randomized, double-blind, placebo-controlled trials of darbepoetin alfa in the treatment of patients with chemotherapy-induced anemia. J Clin Oncol. 2009;27:2838–47
        46. Hadland BK, Longmore GD. Erythroid-stimulating agents in cancer therapy: potential dangers and biologic mechanisms. J Clin Oncol. 2009;27:4217–26
        47. Henke M, Mattern D, Pepe M, Bézay C, Weissenberger C, Werner M, Pajonk F. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol. 2006;24:4708–13
        48. Elliott S, Busse L, Bass MB, Lu H, Sarosi I, Sinclair AM, Spahr C, Um M, Van G, Begley CG. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood. 2006;107:1892–5
        49. Elliott S, Busse L, McCaffery I, Rossi J, Sinclair A, Spahr C, Swift S, Begley CG. Identification of a sensitive anti-erythropoietin receptor monoclonal antibody allows detection of low levels of EpoR in cells. J Immunol Methods. 2010;352:126–39
        50. Miller CP, Lowe KA, Valliant-Saunders K, Kaiser JF, Mattern D, Urban N, Henke M, Blau CA. Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial. Stem Cells. 2009;27:2353–61
        51. Swift S, Ellison AR, Kassner P, McCaffery I, Rossi J, Sinclair AM, Begley CG, Elliott S. Absence of functional EpoR expression in human tumor cell lines. Blood. 2010;115:4254–63
        52. Sinclair AM, Coxon A, McCaffery I, Kaufman S, Paweletz K, Liu L, Busse L, Swift S, Elliott S, Begley CG. Functional erythropoietin receptor is undetectable in endothelial, cardiac, neuronal, and renal cells. Blood. 2010;115:4264–72
        53. Rizzo JD, Brouwers M, Hurley P, Seidenfeld J, Arcasoy MO, Spivak JL, Bennett CL, Bohlius J, Evanchuk D, Goode MJ, Jakubowski AA, Regan DH, Somerfield MRAmerican Society of Hematology and the American Society of Clinical Oncology Practice Guideline Update Committee. . American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update on the use of epoetin and darbepoetin in adult patients with cancer. Blood. 2010;116:4045–59
        54. NCCN Clinical Practice Guidelines in Oncology. . NCCN guidelines: cancer-and chemotherapy-induced anemia. Version2.2012. Available at: Accessed on November 13, 2012
        55. Unger EF, Thompson AM, Blank MJ, Temple R. Erythropoiesis-stimulating agents–time for a reevaluation. N Engl J Med. 2010;362:189–92
        56. Hess G, Nordyke RJ, Hill J, Hulnick S. Effect of reimbursement changes on erythropoiesis-stimulating agent utilization and transfusions. Am J Hematol. 2010;85:838–43
        57. . Unintended consequence for dialysis patients as drug rule changes. Available at: New York Times. Accessed May 16, 2012
        58. U.S. Department of Health & Human Services. . The 2007 National Blood Collection and Utilization Survey Report. 2010 Washington DC U.S. Department of Health & Human Services
        59. Adamson JW. Erythropoietic-stimulating agents: the cancer progression controversy and collateral damage to the blood supply. Transfusion. 2009;49:824–6
        60. Goodnough LT, Shander AS. Erythropoeisis stimulating agents, blood transfusions, and the practice of medicine. Am J Hematol. 2010;85:835–7
        61. Goodnough LT. Iron deficiency syndromes and iron-restricted erythropoiesis (CME). Transfusion. 2012;52:1584–92
        62. Goodnough LT. The new age of iron: evaluation and management of iron-restricted erythropoiesis. Semin Hematol. 2009;46:325–7
        63. Annibale B, Capurso G, Chistolini A, D’Ambra G, DiGiulio E, Monarca B, DelleFave G. Gastrointestinal causes of refractory iron deficiency anemia in patients without gastrointestinal symptoms. Am J Med. 2001;111:439–45
        64. Acher PL, Al-Mishlab T, Rahman M, Bates T. Iron-deficiency anaemia and delay in the diagnosis of colorectal cancer. Colorectal Dis. 2003;5:145–8
        65. Raje D, Mukhtar H, Oshowo A, Ingham Clark C. What proportion of patients referred to secondary care with iron deficiency anemia have colon cancer? Dis Colon Rectum. 2007;50:1211–4
        66. Goodnough LT, Morris D, Koch TA, He A, Bregman DB. Hepcidin levels predict non-responsiveness to oral iron therapy in patients with iron deficiency anemia. Am J Hematol (in press).
        67. Goodnough LT, Nemeth E, Ganz T. Detection, evaluation, and management of iron-restricted erythropoiesis. Blood. 2010;116:4754–61
        68. Auerbach M, Ballard H, Trout JR, McIlwain M, Ackerman A, Bahrain H, Balan S, Barker L, Rana J. Intravenous iron optimizes the response to recombinant human erythropoietin in cancer patients with chemotherapy-related anemia: a multicenter, open-label, randomized trial. J Clin Oncol. 2004;22:1301–7
        69. Auerbach M. Ferumoxytol as a new, safer, easier-to-administer intravenous iron: yes or no? Am J Kidney Dis. 2008;52:826–9
        70. Mercuriali F, Zanella A, Barosi G, Inghilleri G, Biffi E, Vinci A, Colotti MT. Use of erythropoietin to increase the volume of autologous blood donated by orthopedic patients. Transfusion. 1993;33:55–60
        71. Eschbach JW, Haley NR, Egrie JC, Adamson JW. A comparison of the responses to recombinant human erythropoietin in normal and uremic subjects. Kidney Int. 1992;42:407–16
        72. Spinowitz BS, Kausz AT, Baptista J, Noble SD, Sothinathan R, Bernardo MV, Brenner L, Pereira BJ. Ferumoxytol for treating iron deficiency anemia in CKD. J Am Soc Nephrol. 2008;19:1599–605
        73. Means RT Jr. Commentary: an anemia of chronic disease, after all? J Investig Med. 1999;47:203
        74. Weiss G, Goodnough LT. Anemia of chronic disease. N Engl J Med. 2005;352:1011–23
        75. Ganz T. Hepcidin and iron regulation, 10 years later. Blood. 2011;117:4425–33
        76. Nemeth E, Ganz T. The role of hepcidin in iron metabolism. Acta Haematol. 2009;122:78–86
        77. Andrews NC. Forging a field: the golden age of iron biology. Blood. 2008;112:219–30
        78. Ganz T, Olbina G, Girelli D, Nemeth E, Westerman M. Immunoassay for human serum hepcidin. Blood. 2008;112:4292–7
        79. Sasu BJ, Cooke KS, Arvedson TL, Plewa C, Ellison AR, Sheng J, Winters A, Juan T, Li H, Begley CG, Molineux G. Antihepcidin antibody treatment modulates iron metabolism and is effective in a mouse model of inflammation-induced anemia. Blood. 2010;115:3616–24
        80. Goodnough LT, Maniatis A, Earnshaw P, Benoni G, Beris P, Bisbe E, Fergusson DA, Gombotz H, Habler O, Monk TG, Ozier Y, Slappendel R, Szpalski M. Detection, evaluation, and management of preoperative anaemia in the elective orthopaedic surgical patient: NATA guidelines. Br J Anaesth. 2011;106:13–22
        81. Nemeth E. Targeting the hepcidin-ferroportin axis in the diagnosis and treatment of anemias. Adv Hematol. 2010;2010:750643
        82. Young B, Zaritsky J. Hepcidin for clinicians. Clin J Am Soc Nephrol. 2009;4:1384–7
        83. Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, Sonnweber T, Eberwein L, Witcher DR, Murphy AT, Wroblewski VJ, Wurz E, Datz C, Weiss G. Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood. 2009;113:5277–86
        84. Bonnar J, Goldberg A, Smith JA. Do pregnant women take their iron? Lancet. 1969;1:457–8
        85. Henry DH, Dahl NV, Auerbach M, Tchekmedyian S, Laufman LR. Intravenous ferric gluconate significantly improves response to epoetin alfa versus oral iron or no iron in anemic patients with cancer receiving chemotherapy. Oncologist. 2007;12:231–42
        86. Hedenus M, Birgegård G, Näsman P, Ahlberg L, Karlsson T, Lauri B, Lundin J, Lärfars G, Osterborg A. Addition of intravenous iron to epoetin beta increases hemoglobin response and decreases epoetin dose requirement in anemic patients with lymphoproliferative malignancies: a randomized multicenter study. Leukemia. 2007;21:627–32
        87. Bastit L, Vandebroek A, Altintas S, Gaede B, Pintér T, Suto TS, Mossman TW, Smith KE, Vansteenkiste JF. Randomized, multicenter, controlled trial comparing the efficacy and safety of darbepoetin alpha administered every 3 weeks with or without intravenous iron in patients with chemotherapy-induced anemia. J Clin Oncol. 2008;26:1611–8
        88. Jurado RL. Iron, infections, and anemia of inflammation. Clin Infect Dis. 1997;25:888–95
        89. Bishu K, Agarwal R. Acute injury with intravenous iron and concerns regarding long-term safety. Clin J Am Soc Nephrol. 2006;1 Suppl 1:S19–23
        90. Sadjadi SA. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis. 1995;26:1000–1
        91. Adamson JW. Hyporesponsiveness to erythropoiesis stimulating agents in chronic kidney disease: the many faces of inflammation. Adv Chronic Kidney Dis. 2009;16:76–82
        92. Skikne BS, Cook JD. Effect of enhanced erythropoiesis on iron absorption. J Lab Clin Med. 1992;120:746–51
        93. Fishbane S, Frei GL, Maesaka J. Reduction in recombinant human erythropoietin doses by the use of chronic intravenous iron supplementation. Am J Kidney Dis. 1995;26:41–6
        94. Wingard RL, Parker RA, Ismail N, Hakim RM. Efficacy of oral iron therapy in patients receiving recombinant human erythropoietin. Am J Kidney Dis. 1995;25:433–9
        95. The National Kidney Foundation Diseases Outcomes Quality Initiative (KDOQI). . KDOQI clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease. Am J Kidney Dis. 2006;47:S11–145
        96. Silverberg DS, Iaina A, Peer G, Kaplan E, Levi BA, Frank N, Steinbruch S, Blum M. Intravenous iron supplementation for the treatment of the anemia of moderate to severe chronic renal failure patients not receiving dialysis. Am J Kidney Dis. 1996;27:234–8
        97. The National Kidney Foundation Diseases Outcomes Quality Initiative (NKF-KDOQI). . NKF-KDOQI clinical practice guidelines for anemia of chronic kidney disease: Update 2000. Avaiable at: Accessed May 16, 2012
        98. Coyne DW, Kapoian T, Suki W, Singh AK, Moran JE, Dahl NV, Rizkala ARDRIVE Study Group. . Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol. 2007;18:975–84
        99. Gasché C, Dejaco C, Waldhoer T, Tillinger W, Reinisch W, Fueger GF, Gangl A, Lochs HIntravenous iron and erythropoietin for anemia associated with Crohn disease.. A randomized, controlled trial. Ann Intern Med. 1997;126:782–7
        100. Goodnough LT, Skikne B, Brugnara C. Erythropoietin, iron, and erythropoiesis. Blood. 2000;96:823–33
        101. United States Food and Drug Administration. . Follow-up to the January 3, 2008 communication about an ongoing safety review on erythropoiesis-stimulating agents (ESAs) epoetin alfa (marketed as Procrit, Epogen) Darbepoetin alfa (marketed as Aranesp). Available at: Accessed January 26, 2012
        102. Weiss G, Houston T, Kastner S, Jöhrer K, Grünewald K, Brock JH. Regulation of cellular iron metabolism by erythropoietin: activation of iron-regulatory protein and upregulation of transferrin receptor expression in erythroid cells. Blood. 1997;89:680–7
        103. Thomas C, Thomas L. Anemia of chronic disease: pathophysiology and laboratory diagnosis. Lab Hematol. 2005;11:14–23
        104. Pak M, Lopez MA, Gabayan V, Ganz T, Rivera S. Suppression of hepcidin during anemia requires erythropoietic activity. Blood. 2006;108:3730–5
        105. Delaby C, Pilard N, Gonçalves AS, Beaumont C, Canonne-Hergaux F. Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin. Blood. 2005;106:3979–84
        106. Shander A, Spence RK, Auerbach M. Can intravenous iron therapy meet the unmet needs created by the new restrictions on erythropoietic stimulating agents? Transfusion. 2010;50:719–32
        107. Auerbach M, Goodnough LT, Picard D, Maniatis A. The role of intravenous iron in anemia management and transfusion avoidance. Transfusion. 2008;48:988–1000
        108. Hillman RS, Henderson PA. Control of marrow production by the level of iron supply. J Clin Invest. 1969;48:454–60
        109. Chertow GM, Mason PD, Vaage-Nilsen O, Ahlmén J. Update on adverse drug events associated with parenteral iron. Nephrol Dial Transplant. 2006;21:378–82
        110. Chandler G, Harchowal J, Macdougall IC. Intravenous iron sucrose: establishing a safe dose. Am J Kidney Dis. 2001;38:988–91
        111. Mamula P, Piccoli DA, Peck SN, Markowitz JE, Baldassano RN. Total dose intravenous infusion of iron dextran for iron-deficiency anemia in children with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2002;34:286–90
        112. Macdougall IC, Roche A. Administration of intravenous iron sucrose as a 2-minute push to CKD patients: a prospective evaluation of 2,297 injections. Am J Kidney Dis. 2005;46:283–9
        113. Critchley J, Dundar Y. Adverse events associated with intravenous iron infusion (low-molecular-weight iron dextran and iron sucrose): a systematic review. Transfus Altern Transfus Med. 2007;9:8–36
        114. Moniem KA, Bhandari SU. Tolerability and efficacy of parenteral iron therapy in hemodialysis patients, a comparison of preparations. Transfus Altern Transfus Med. 2007;9:37–42
        115. Sav T, Tokgoz B, Sipahioglu MH, Deveci M, Sari I, Oymak O, Utas C. Is there a difference between the allergic potencies of the iron sucrose and low molecular weight iron dextran? Ren Fail. 2007;29:423–6
        116. Van Wyck DB, Mangione A, Morrison J, Hadley PE, Jehle JA, Goodnough LT. Large-dose intravenous ferric carboxymaltose injection for iron deficiency anemia in heavy uterine bleeding: a randomized, controlled trial. Transfusion. 2009;49:2719–28
        117. Hamstra RD, Block MH. Erythropoiesis in response to blood loss in man. J Appl Physiol. 1969;27:503–7
        118. Crosby WH. The metabolism of hemoglobin and bile pigment in hemolytic disease. Am J Med. 1955;18:112–22
        119. Beutler E. The utilization of saccharated Fe59 oxide in red cell formation. J Lab Clin Med. 1958;51:415–9
        120. Wood JK, Milner PF, Pathak UN. The metabolism of iron-dextran given as a total-dose infusion to iron deficient Jamaican subjects. Br J Haematol. 1968;14:119–29
        121. Beamish MR, Davies AG, Eakins JD, Jacobs A, Trevett D. The measurement of reticuloendothelial iron release using iron-dextran. Br J Haematol. 1971;21:617–22
        122. Bentley DP, Williams P. Parenteral iron therapy in the anaemia of rheumatoid arthritis. Rheumatol Rehabil. 1982;21:88–92
        123. Schreiber S, Howaldt S, Schnoor M, Nikolaus S, Bauditz J, Gasché C, Lochs H, Raedler A. Recombinant erythropoietin for the treatment of anemia in inflammatory bowel disease. N Engl J Med. 1996;334:619–23
        124. Goodnough LT, Shander AS. How I treat warfarin-associated coagulopathy in patients with intracerebral hemorrhage. Blood. 2011;117:6091–9
        125. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573–9
        126. Holland L, Warkentin TE, Refaai M, Crowther MA, Johnston MA, Sarode R. Suboptimal effect of a three-factor prothrombin complex concentrate (Profilnine-SD) in correcting supratherapeutic international normalized ratio due to warfarin overdose. Transfusion. 2009;49:1171–7
        127. Pabinger I, Brenner B, Kalina U, Knaub S, Nagy A, Ostermann HBeriplex P/N Anticoagulation Reversal Study Group. . Prothrombin complex concentrate (Beriplex P/N) for emergency anticoagulation reversal: a prospective multinational clinical trial. J Thromb Haemost. 2008;6:622–31
        128. . Efficacy and safety study of BERIPLEX® P/N compared with plasma in patients with acute major bleeding caused by anticoagulant therapy. Available at: Accessed December 6, 2011
        129. Douketis JD. Perioperative management of patients receiving anticoagulant or antiplatelet therapy: a clinician-oriented and practical approach. Hosp Pract (Minneap). 2011;39:41–54
        130. Imberti D, Barillari G, Biasioli C, Bianchi M, Contino L, Duce R, D’Incà M, Gnani MC, Mari E, Ageno W. Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage. Blood Transfus. 2011;9:148–55
        131. Lorenz R, Kienast J, Otto U, Kiehl M, Schreiter D, Haertel S, Barthels M. Successful emergency reversal of phenprocoumon anticoagulation with prothrombin complex concentrate: a prospective clinical study. Blood Coagul Fibrinolysis. 2007;18:565–70
        132. Demeyere R, Gillardin S, Arnout J, Strengers PF. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. 2010;99:251–60
        133. Baker RI, Coughlin PB, Gallus AS, Harper PL, Salem HH, Wood EMWarfarin Reversal Consensus Group. . Warfarin reversal: consensus guidelines, on behalf of the Australasian Society of Thrombosis and Haemostasis. Med J Aust. 2004;181:492–7
        134. Steiner T, Kaste M, Katse M, Forsting M, Mendelow D, Kwiecinski H, Szikora I, Juvela S, Marchel A, Chapot R, Cognard C, Unterberg A, Hacke WEuropean Stroke Initiative Writing Committee. Writing Committee for the EUSI Executive Committee. . Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee. Cerebrovasc Dis. 2006;22:294–316
        135. Morgenstern LB, Hemphill JC 3rd, Anderson C, Becker K, Broderick JP, Connolly ES Jr, Greenberg SM, Huang JN, MacDonald RL, Messé SR, Mitchell PH, Selim M, Tamargo RJAmerican Heart Association Stroke Council and Council on Cardiovascular Nursing. . Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2010;41:2108–29
        136. Pernod G, Godiér A, Gozalo C, Tremey B, Sié PFrench National Authority for Health. . French clinical practice guidelines on the management of patients on vitamin K antagonists in at-risk situations (overdose, risk of bleeding, and active bleeding). Thromb Res. 2010;126:e167–74
        137. Baglin TP, Keeling DM, Watson HG. Guidelines on oral anticoagulation (warfarin): third edition--2005 update. Br J Haematol. 2011;132:277–85
        138. Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schuünemann HJAmerican College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. . Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:7S–47S
        139. Beshay JE, Morgan H, Madden C, Yu W, Sarode R. Emergency reversal of anticoagulation and antiplatelet therapies in neurosurgical patients. J Neurosurg. 2010;112:307–18
        140. Bershad EM, Suarez JI. Prothrombin complex concentrates for oral anticoagulant therapy-related intracranial hemorrhage: a review of the literature. Neurocrit Care. 2010;12:403–13
        141. Marietta M, Pedrazzi P, Luppi M. Three- or four-factor pro thrombin complex concentrate for emergency anticoagulation reversal: what are we really looking for? Blood Transfus. 2011;9:469
        142. Hellstern P. Production and composition of prothrombin complex concentrates: correlation between composition and therapeutic efficiency. Thromb Res. 1999;95:S7–12
        143. Warkentin TE, Crowther MA. Reversing anticoagulants both old and new. Can J Anaesth. 2002;49:S11–25
        144. . FEIBA NF (anti-inhibitor coagulant complex). 2010 Available at: Accessed December 7, 2011
        145. Wójcik C, Schymik ML, Cure EG. Activated prothrombin complex concentrate factor VIII inhibitor bypassing activity (FEIBA) for the reversal of warfarin-induced coagulopathy. Int J Emerg Med. 2009;2:217–25
        146. Bobbitt L, Merriman E, Raynes J, Henderson R, Blacklock H, Chunilal S. PROTHROMBINEX(®)-VF (PTX-VF) usage for reversal of coagulopathy: prospective evaluation of thrombogenic risk. Thromb Res. 2011;128:577–82
        147. Grottke O, Braunschweig T, Spronk HM, Esch S, Rieg AD, van Oerle R, ten Cate H, Fitzner C, Tolba R, Rossaint R. Increasing concentrations of prothrombin complex concentrate induce disseminated intravascular coagulation in a pig model of coagulopathy with blunt liver injury. Blood. 2011;118:1943–51
        148. Lusher JM. Thrombogenicity associated with factor IX complex concentrates. Semin Hematol. 1991;28:3–5
        149. Köhler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res. 1999;95:S13–7
        150. Sørensen B, Spahn DR, Innerhofer P, Spannagl M, Rossaint R. Clinical review: Prothrombin complex concentrates–evaluation of safety and thrombogenicity. Crit Care. 2011;15:201
        151. Riess HB, Meier-Hellmann A, Motsch J, Elias M, Kursten FW, Dempfle CE. Prothrombin complex concentrate (Octaplex) in patients requiring immediate reversal of oral anticoagulation. Thromb Res. 2007;121:9–16
        152. Pabinger I, Tiede A, Kalina U, Knaub S, Germann R, Ostermann HBeriplex P/N Anticoagulation Reversal Study Group. . Impact of infusion speed on the safety and effectiveness of prothrombin complex concentrate: a prospective clinical trial of emergency anticoagulation reversal. Ann Hematol. 2010;89:309–16
        153. Franchini M, Lippi G. Prothrombin complex concentrates: an update. Blood Transfus. 2010;8:149–54
        154. Khorsand N, Veeger NJ, Muller M, Overdiek JW, Huisman W, van Hest RM, Meijer K. Fixed versus variable dose of prothrombin complex concentrate for counteracting vitamin K antagonist therapy. Transfus Med. 2011;21:116–23
        155. Ratnoff OD. Some complications of the therapy of classic hemophilia. J Lab Clin Med. 1984;103:653–9
        156. Heger A, Svae TE, Neisser-Svae A, Jordan S, Behizad M, Römisch J. Biochemical quality of the pharmaceutically licensed plasma OctaplasLG after implementation of a novel prion protein (PrPSc) removal technology and reduction of the solvent/detergent (S/D) process time. Vox Sang. 2009;97:219–25
        157. Custer B, Agapova M, Martinez RH. The cost-effectiveness of pathogen reduction technology as assessed using a multiple risk reduction model. Transfusion. 2010;50:2461–73
        158. Toner RW, Pizzi L, Leas B, Ballas SK, Quigley A, Goldfarb NI. Costs to hospitals of acquiring and processing blood in the US: a survey of hospital-based blood banks and transfusion services. Appl Health Econ Health Policy. 2011;9:29–37
        159. Medcalf RL. Fibrinolysis, inflammation, and regulation of the plasminogen activating system. J Thromb Haemost. 2007;5 Suppl 1:132–42
        160. Stassen JM, Arnout J, Deckmyn H. The hemostatic system. Curr Med Chem. 2004;11:2245–60
        161. Lasne D, Jude B, Susen S. From normal to pathological hemostasis. Can J Anaesth. 2006;53:S2–11
        162. Lucas MA, Fretto LJ, McKee PA. The binding of human plasminogen to fibrin and fibrinogen. J Biol Chem. 1983;258:4249–56
        163. Levy JH. Efficacy and safety of aprotinin in cardiac surgery. Orthopedics. 2004;27:s659–62
        164. Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussières JS, Côté D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius RBART Investigators. . A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008;358:2319–31
        165. Greilich PE, Jessen ME, Satyanarayana N, Whitten CW, Nuttall GA, Beckham JM, Wall MH, Butterworth JF. The effect of epsilon-aminocaproic acid and aprotinin on fibrinolysis and blood loss in patients undergoing primary, isolated coronary artery bypass surgery: a randomized, double-blind, placebo-controlled, noninferiority trial. Anesth Analg. 2009;109:15–24
        166. Roberts I, Shakur H, Afolabi A, Brohi K, Coats T, Dewan Y, Gando S, Guyatt G, Hunt BJ, Morales C, Perel P, Prieto-Merino D, Woolley TCRASH-2 collaborators. . The importance of early treatment with tranexamic acid in bleeding trauma patients: an exploratory analysis of the CRASH-2 randomised controlled trial. Lancet. 2011;377:1096–101, 1101.e1–2
        167. Crescenti A, Borghi G, Bignami E, Bertarelli G, Landoni G, Casiraghi GM, Briganti A, Montorsi F, Rigatti P, Zangrillo A. Intraoperative use of tranexamic acid to reduce transfusion rate in patients undergoing radical retropubic prostatectomy: double blind, randomised, placebo controlled trial. BMJ. 2011;343:d5701
        168. Zufferey PJ, Miquet M, Quenet S, Martin P, Adam P, Albaladejo P, Mismetti P, Molliex Stranexamic acid in hip-fracture surgery (THIF) study. . Tranexamic acid in hip fracture surgery: a randomized controlled trial. Br J Anaesth. 2010;104:23–30
        169. Morrison JJ, Dubose JJ, Rasmussen TE, Midwinter MJ. Military Application of Tranexamic Acid in Trauma Emergency Resuscitation (MATTERs) Study. Arch Surg. 2012;147:113–9
        170. The WOMAN Trial. . Tranexamic acid for the treatment of postpartum haemorrhage: an international randomised, double blind, placebo controlled trial. Available at: Accessed April 9, 2012
        171. Adler Ma SC, Brindle W, Burton G, Gallacher S, Hong FC, Manelius I, Smith A, Ho W, Alston RP, Bhattacharya K. Tranexamic acid is associated with less blood transfusion in off-pump coronary artery bypass graft surgery: a systematic review and meta-analysis. J Cardiothorac Vasc Anesth. 2011;25:26–35
        172. Henry DA, Carless PA, Moxey AJ, O’Connell D, Stokes BJ, Fergusson DA, Ker K. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev. 2011:CD001886
        173. Ngaage DL, Bland JM. Lessons from aprotinin: is the routine use and inconsistent dosing of tranexamic acid prudent? Meta-analysis of randomised and large matched observational studies. Eur J Cardiothorac Surg. 2010;37:1375–83
        174. . Health Canada decision on Trasylol (aprotinin). Available at: Accessed March 6, 2012
        175. . European Medicines Agency. European Medicines Agency recommends lifting suspension of aprotinin. Available at: Accessed February 17, 2012
        176. . Desmopressin acetate injection. 2009 Irvine, CA Teva Parenteral Medicines, Inc Pamphlet
        177. Kaufmann JE, Vischer UM. Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP). J Thromb Haemost. 2003;1:682–9
        178. Crescenzi G, Landoni G, Biondi-Zoccai G, Pappalardo F, Nuzzi M, Bignami E, Fochi O, Maj G, Calabrò MG, Ranucci M, Zangrillo A. Desmopressin reduces transfusion needs after surgery: a meta-analysis of randomized clinical trials. Anesthesiology. 2008;109:1063–76
        179. Ozier Y, Bellamy L. Pharmacological agents: antifibrinolytics and desmopressin. Best Pract Res Clin Anaesthesiol. 2010;24:107–19
        180. Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, Song HK, Clough ER, Shore-Lesserson LJ, Goodnough LT, Mazer CD, Shander A, Stafford-Smith M, Waters J, Baker RA, Dickinson TA, FitzGerald DJ, Likosky DS, Shann KGSociety of Thoracic Surgeons Blood Conservation Guideline Task Force. Society of Cardiovascular Anesthesiologists Special Task Force on Blood Transfusion. International Consortium for Evidence Based Perfusion. . 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91:944–82
        181. . RiaSTAP, fibrinogen concentrate (human) for intravenous use (January 3, 2010). 2010 King of Prussia, PA CSL Behring LLC Pamphlet
        182. Rahe-Meyer N, Pichlmaier M, Haverich A, Solomon C, Winterhalter M, Piepenbrock S, Tanaka KA. Bleeding management with fibrinogen concentrate targeting a high-normal plasma fibrinogen level: a pilot study. Br J Anaesth. 2009;102:785–92
        183. Solomon C, Schöchl H, Hanke A, Calatzis A, Hagl C, Tanaka K, Rahe-Meyer N. Haemostatic therapy in coronary artery bypass graft patients with decreased platelet function: comparison of fibrinogen concentrate with allogeneic blood products. Scand J Clin Lab Invest. 2012;72:121–8
        184. Kozek-Langenecker S, Sorensen B, Hess JR, Spahn DR. Clinical effectiveness of fresh frozen plasma compared with fibrinogen concentrate: a systematic review. Crit Care. 2011;15:R239
        185. Meyer MA, Ostrowski SR, Windeløv NA, Johansson PI. Fibrinogen concentrates for bleeding trauma patients: what is the evidence? Vox Sang. 2011;101:185–90
        186. Warmuth M, Mad P, Wild C. Systematic review of the efficacy and safety of fibrinogen concentrate substitution in adults. Acta Anaesthesiol Scand. 2012;56:539–48
        187. Bell SF, Rayment R, Collins PW, Collis RE. The use of fibrinogen concentrate to correct hypofibrinogenaemia rapidly during obstetric haemorrhage. Int J Obstet Anesth. 2010;19:218–23
        188. Glover NJ, Collis RE, Collins P. Fibrinogen concentrate use during major obstetric haemorrhage. Anaesthesia. 2010;65:1229–30
        189. Gödje O, Gallmeier U, Schelian M, Grünewald M, Mair H. Coagulation factor XIII reduces postoperative bleeding after coronary surgery with extracorporeal circulation. Thorac Cardiovasc Surg. 2006;54:26–33
        190. Korte WC, Szadkowski C, Gähler A, Gabi K, Kownacki E, Eder M, Degiacomi P, Zoller N, Devay J, Lange J, Schnider T. Factor XIII substitution in surgical cancer patients at high risk for intraoperative bleeding. Anesthesiology. 2009;110:239–45
        191. . Multi-national study investigating the effect and safety of rFXIII on transfusion needs in patients undergoing heart surgery. Available at: Accessed on November 13, 2012
        192. Carless PA, Anthony DM, Henry DA. Systematic review of the use of fibrin sealant to minimize perioperative allogeneic blood transfusion. Br J Surg. 2002;89:695–703
        193. Wong J, Abrishami A, El Beheiry H, Mahomed NN, Roderick Davey J, Gandhi R, Syed KA, Muhammad Ovais Hasan S, De Silva Y, Chung F. Topical application of tranexamic acid reduces postoperative blood loss in total knee arthroplasty: a randomized, controlled trial. J Bone Joint Surg Am. 2010;92:2503–13
        194. Abrishami A, Chung F, Wong J. Topical application of antifibrinolytic drugs for on-pump cardiac surgery: a systematic review and meta-analysis. Can J Anaesth. 2009;56:202–12
        195. Isgro F, Stanisch O, Kiessling AH, Gürler S, Hellstern P, Saggau W. Topical application of aprotinin in cardiac surgery. Perfusion. 2002;17:347–51
        196. Emilia M, Luca S, Francesca B, Luca B, Paolo S, Giuseppe F, Gianbattista B, Carmela M, Luigi M, Mauro L. Topical hemostatic agents in surgical practice. Transfus Apher Sci. 2011;45:305–11
        197. Spotnitz WD, Burks S. Hemostats, sealants, and adhesives: components of the surgical toolbox. Transfusion. 2008;48:1502–16
        198. Spotnitz WD, Burks S. State-of-the-art review: Hemostats, sealants, and adhesives II: Update as well as how and when to use the components of the surgical toolbox. Clin Appl Thromb Hemost. 2010;16:497–514
        199. Achneck HE, Sileshi B, Jamiolkowski RM, Albala DM, Shapiro ML, Lawson JH. A comprehensive review of topical hemostatic agents: efficacy and recommendations for use. Ann Surg. 2010;251:217–28
        200. Barnard J, Millner R. A review of topical hemostatic agents for use in cardiac surgery. Ann Thorac Surg. 2009;88:1377–83
        201. Spotnitz WD. Fibrin sealant: past, present, and future: a brief review. World J Surg. 2010;34:632–4
        202. Nasso G, Piancone F, Bonifazi R, Romano V, Visicchio G, De Filippo CM, Impiombato B, Fiore F, Bartolomucci F, Alessandrini F, Speziale G. Prospective, randomized clinical trial of the FloSeal matrix sealant in cardiac surgery. Ann Thorac Surg. 2009;88:1520–6
        203. Figueras J, Llado L, Miro M, Ramos E, Torras J, Fabregat J, Serrano T. Application of fibrin glue sealant after hepatectomy does not seem justified: results of a randomized study in 300 patients. Ann Surg. 2007;245:536–42
        204. Katkhouda N. Application of fibrin glue after hepatectomy might still be justified. Ann Surg. 2008;247:399–400
        205. Carless PA, Henry DA, Anthony DM. Fibrin sealant use for minimising peri-operative allogeneic blood transfusion. Cochrane Database Syst Rev. 2003:CD004171
        206. Carless PA, Henry DA, Anthony DM. Fibrin sealant use for minimising peri-operative allogeneic blood transfusion. Cochrane Database Syst Rev. 2009:CD004171
        207. Croxtall JD, Scott LJ. Recombinant human thrombin: in surgical hemostasis. BioDrugs. 2009;23:333–8
        208. Kessler CM, Ortel TL. Recent developments in topical thrombins. Thromb Haemost. 2009;102:15–24
        209. Ballard JL, Weaver FA, Singla NK, Chapman WC, Alexander WA. Safety and immunogenicity observations pooled from eight clinical trials of recombinant human thrombin. J Am Coll Surg. 2010;210:199–204
        210. Groenewold MD, Gribnau AJ, Ubbink DT. Topical haemostatic agents for skin wounds: a systematic review. BMC Surg. 2011;11:15
        211. Gasparini G, Papaleo P, Pola P, Cerciello S, Pola E, Fabbriciani C. Local infusion of norepinephrine reduces blood losses and need of transfusion in total knee arthroplasty. Int Orthop. 2006;30:253–6
        212. Hersh EV, Giannakopoulos H. Beta-adrenergic blocking agents and dental vasoconstrictors. Dent Clin North Am. 2010;54:687–96
        213. Higgins TS, Hwang PH, Kingdom TT, Orlandi RR, Stammberger H, Han JK. Systematic review of topical vasoconstrictors in endoscopic sinus surgery. Laryngoscope. 2011;121:422–32
        214. Moore PA, Hersh EV. Local anesthetics: pharmacology and toxicity. Dent Clin North Am. 2010;54:587–99
        215. Poon MC. Use of recombinant factor VIIa in hereditary bleeding disorders. Curr Opin Hematol. 2001;8:312–8
        216. 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;154:516–22
        217. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner TRecombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. . Recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777–85
        218. Mayer SA, Brun NC, Begtrup K, Broderick J, Davis S, Diringer MN, Skolnick BE, Steiner TFAST Trial Investigators. . Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage. N Engl J Med. 2008;358:2127–37
        219. Gill R, Herbertson M, Vuylsteke A, Olsen PS, von Heymann C, Mythen M, Sellke F, Booth F, Schmidt TA. Safety and efficacy of recombinant activated factor VII: a randomized placebo-controlled trial in the setting of bleeding after cardiac surgery. Circulation. 2009;120:21–7
        220. Goodnough LT, Lublin DM, Zhang L, Despotis G, Eby C. Transfusion medicine service policies for recombinant factor VIIa administration. Transfusion. 2004;44:1325–31
        221. Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R, Sundaram V, McMahon D, Olkin I, McDonald KM, Owens DK, Stafford RS. Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications. Ann Intern Med. 2011;154:529–40
        222. Warkentin TE, Margetts P, Connolly SJ, Lamy A, Ricci C, Eikelboom JW. Recombinant factor VIIa (rFVIIa) and hemodialysis to manage massive dabigatran-associated postcardiac surgery bleeding. Blood. 2012;119:2172–4
        223. Freeman WD, Brott TG, Barrett KM, Castillo PR, Deen HG Jr, Czervionke LF, Meschia JF. Recombinant factor VIIa for rapid reversal of warfarin anticoagulation in acute intracranial hemorrhage. Mayo Clin Proc. 2004;79:1495–500
        224. Ilyas C, Beyer GM, Dutton RP, Scalea TM, Hess JR. Recombinant factor VIIa for warfarin-associated intracranial bleeding. J Clin Anesth. 2008;20:276–9
        225. Robinson MT, Rabinstein AA, Meschia JF, Freeman WD. Safety of recombinant activated factor VII in patients with warfarin-associated hemorrhages of the central nervous system. Stroke. 2010;41:1459–63
        226. Deveras RA, Kessler CM. Reversal of warfarin-induced excessive anticoagulation with recombinant human factor VIIa concentrate. Ann Intern Med. 2002;137:884–8
        227. Rosovsky RP, Crowther MA. What is the evidence for the off-label use of recombinant factor VIIa (rFVIIa) in the acute reversal of warfarin? ASH evidence-based review 2008. Hematology Am Soc Hematol Educ Program. 2008::36–8
        228. Tanaka KA, Szlam F, Dickneite G, Levy JH. Effects of prothrombin complex concentrate and recombinant activated factor VII on vitamin K antagonist induced anticoagulation. Thromb Res. 2008;122:117–23
        229. Skolnick BE, Mathews DR, Khutoryansky NM, Pusateri AE, Carr ME. Exploratory study on the reversal of warfarin with rFVIIa in healthy subjects. Blood. 2010;116:693–701
        230. Logan AC, Goodnough LT. Recombinant factor VIIa: an assessment of evidence regarding its efficacy and safety in the off-label setting. Hematology Am Soc Hematol Educ Program. 2010;2010:153–9
        231. O’Connell KA, Wood JJ, Wise RP, Lozier JN, Braun MM. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA. 2006;295:293–8
        232. Thomas GO, Dutton RP, Hemlock B, Stein DM, Hyder M, Shere-Wolfe R, Hess JR, Scalea TM. Thromboembolic complications associated with factor VIIa administration. J Trauma. 2007;62:564–9
        233. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363:1791–800
        234. Madjdpour C, Dettori N, Frascarolo P, Burki M, Boll M, Fisch A, Bombeli T, Spahn DR. Molecular weight of hydroxyethyl starch: is there an effect on blood coagulation and pharmacokinetics? Br J Anaesth. 2005;94:569–76
        235. Istaphanous GK, Wheeler DS, Lisco SJ, Shander A. Red blood cell transfusion in critically ill children: a narrative review. Pediatr Crit Care Med. 2011;12:174–83
        236. Kocian R, Spahn DR. Haemoglobin, oxygen carriers and perioperative organ perfusion. Best Pract Res Clin Anaesthesiol. 2008;22:63–80
        237. Van Meter KW. A systematic review of the application of hyperbaric oxygen in the treatment of severe anemia: an evidence-based approach. Undersea Hyperb Med. 2005;32:61–83
        238. Shander A, Goodnough LT. Why an alternative to blood transfusion? Crit Care Clin. 2009;25:261–77
        239. Goodnough LT, Shander A. Evolution in alternatives to blood transfusion. Hematol J. 2003;4:87–91
        240. Castro CI, Briceno JC. Perfluorocarbon-based oxygen carriers: review of products and trials. Artif Organs. 2010;34:622–34
        241. Scott MG, Kucik DF, Goodnough LT, Monk TG. Blood substitutes: evolution and future applications. Clin Chem. 1997;43:1724–31
        242. Hai CM. Systems biology of HBOC-induced vasoconstriction. Curr Drug Discov Technol. 2011;;15:1449–61
        243. Inayat MS, Bernard AC, Gallicchio VS, Garvy BA, Elford HL, Oakley OR. Oxygen carriers: a selected review. Transfus Apher Sci. 2006;34:25–32
        244. Chen JY, Scerbo M, Kramer G. A review of blood substitutes: examining the history, clinical trial results, and ethics of hemoglobin-based oxygen carriers. Clinics (Sao Paulo). 2009;64:803–13
        245. Sloan EP, Koenigsberg M, Gens D, Cipolle M, Runge J, Mallory MN, Rodman G Jr. Diaspirin cross-linked hemoglobin (DCLHb) in the treatment of severe traumatic hemorrhagic shock: a randomized controlled efficacy trial. JAMA. 1999;282:1857–64
        246. Kerner T, Ahlers O, Veit S, Riou B, Saunders M, Pison UEuropean DCLHb Trauma Study Group. . DCL-Hb for trauma patients with severe hemorrhagic shock: the European “On-Scene” multicenter study. Intensive Care Med. 2003;29:378–85
        247. Sloan EP, Koenigsberg MD, Philbin NB, Gao WDCLHb Traumatic Hemorrhagic Shock Study Group. European HOST Investigators. . Diaspirin cross-linked hemoglobin infusion did not influence base deficit and lactic acid levels in two clinical trials of traumatic hemorrhagic shock patient resuscitation. J Trauma. 2010;68:1158–71
        248. Jahr JS, Mackenzie C, Pearce LB, Pitman A, Greenburg AG. HBOC-201 as an alternative to blood transfusion: efficacy and safety evaluation in a multicenter phase III trial in elective orthopedic surgery. J Trauma. 2008;64:1484–97
        249. Mackenzie CF, Moon-Massat PF, Shander A, Javidroozi M, Greenburg AG. When blood is not an option: factors affecting survival after the use of a hemoglobin-based oxygen carrier in 54 patients with life-threatening anemia. Anesth Analg. 2010;110:685–93
        250. Rempf C, Standl T, Schenke K, Chammas K, Gottschalk A, Burmeister MA, Gottschalk A. Administration of bovine polymerized haemoglobin before and during coronary occlusion reduces infarct size in rabbits. Br J Anaesth. 2009;103:496–504
        251. Rice J, Philbin N, Light R, Arnaud F, Steinbach T, McGwin G, Collier S, Malkevich N, Moon-Massatt P, Rentko V, Pearce LB, Ahlers S, McCarron R, Handrigan M, Freilich D. The effects of decreasing low-molecular weight hemoglobin components of hemoglobin-based oxygen carriers in swine with hemorrhagic shock. J Trauma. 2008;64:1240–57
        252. Wehausen CE, Kirby R, Rudloff E. Evaluation of the effects of bovine hemoglobin glutamer-200 on systolic arterial blood pressure in hypotensive cats: 44 cases (1997-2008). J Am Vet Med Assoc. 2011;238:909–14
        253. Moore EE, Moore FA, Fabian TC, Bernard AC, Fulda GJ, Hoyt DB, Duane TM, Weireter LJ, Gomez GA, Cipolle MD, Rodman GH, Malangoni MA, Hides GA, Omert LA, Gould SAPolyHeme Study Group. . Human polymerized hemoglobin for the treatment of hemorrhagic shock when blood is unavailable: the USA multicenter trial. J Am Coll Surg. 2009;208:1–13
        254. Bernard AC, Moore EE, Moore FA, Hides GA, Guthrie BJ, Omert LA, Gould SA, Rodman GH JrPolyHeme Study Group. . Postinjury resuscitation with human polymerized hemoglobin prolongs early survival: a post hoc analysis. J Trauma. 2011;70:S34–7
        255. Kipnis K, King NM, Nelson RM. An open letter to institutional review boards considering Northfield Laboratories’ PolyHeme® trial. Am J Bioeth. 2010;10:5–8
        256. Kipnis K, King NM, Nelson RM. Trials and errors: barriers to oversight of research conducted under the emergency research consent waiver. IRB. 2006;28:16–9
        257. Grassley C. Americans should not be on a game show in U.S. emergency rooms and ambulances. Am J Bioeth. 2010;10:9–10
        258. Natanson C, Kern SJ, Lurie P, Banks SM, Wolfe SM. Cell-free hemoglobin-based blood substitutes and risk of myocardial infarction and death: a meta-analysis. JAMA. 2008;299:2304–12
        259. Greenburg AG, Light WR, Dubé GP. Reconstructing hemoglobin-based oxygen carriers. Transfusion. 2010;50:2764–7
        260. Shander A, Javidroozi M, Thompson G. Hemoglobin-based blood substitutes and risk of myocardial infarction and death. JAMA. 2008;300:1296–7
        261. Donahue LL, Shapira I, Shander A, Kolitz J, Allen S, Greenburg G. Management of acute anemia in a Jehovah’s Witness patient with acute lymphoblastic leukemia with polymerized bovine hemoglobin-based oxygen carrier: a case report and review of literature. Transfusion. 2010;50:1561–7
        262. Olofsson CI, Górecki AZ, Dirksen R, Kofranek I, Majewski JA, Mazurkiewicz T, Jahoda D, Fagrell B, Keipert PE, Hardiman YJ, Levy HStudy 6084 Clinical Investigators. . Evaluation of MP4OX for prevention of perioperative hypotension in patients undergoing primary hip arthroplasty with spinal anesthesia: a randomized, double-blind, multicenter study. Anesthesiology. 2011;114:1048–63
        263. van der Linden P, Gazdzik TS, Jahoda D, Heylen RJ, Skowronski JC, Pellar D, Kofranek I, Górecki AZ, Fagrell B, Keipert PE, Hardiman YJ, Levy H6090 Study Investigators. . A double-blind, randomized, multicenter study of MP4OX for treatment of perioperative hypotension in patients undergoing primary hip arthroplasty under spinal anesthesia. Anesth Analg. 2011;112:759–73
        264. Brook RH. Two years and counting: how will the effects of the Affordable Care Act be monitored? JAMA. 2012;307:41–2
        265. Stiggelbout AM, Van der Weijden T, De Wit MP, Frosch D, Légaré F, Montori VM, Trevena L, Elwyn G. Shared decision making: really putting patients at the centre of healthcare. BMJ. 2012;344:e256
        266. Goodnough LT, Shuck JM. Risks, options, and informed consent for blood transfusion in elective surgery. Am J Surg. 1990;159:602–9
        © 2013 International Anesthesia Research Society