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Intensive Care Med (2011) 37:12401249 DOI 10.

1007/s00134-011-2258-5

REVIEW

Aryeh Shander Christopher E. Walsh Caroline Cromwell

Acquired hemophilia: a rare but life-threatening potential cause of bleeding in the intensive care unit

Abstract Objective: There are a number of potential etiologies of severe bleeding encountered in the intensive care unit. Although rare, acquired hemophilia is one such etiology that often presents with major bleeding requiring intensive care. Despite the introduction of effective treatments, the reported mortality rate of patients with acquired hemophilia ranges from 6 to 8% and is in part attributable to sequential delays in diagnosis and appropriate treatment. The purpose of this review is to familiarize the intensive care specialist with this underrecognized cause of bleeding, with an emphasis on diagnosis and treatment. Methods: As the objective of this A. Shander ()) Department of Anesthesiology and Critical article was to provide a concise overview of the diagnosis and management Care Medicine, Englewood Hospital and of acquired hemophilia, a directed Medical Center, 350 Engle Street, Englewood, NJ 07631, USA search of English-language literature e-mail: aryeh.shander@ehmc.com was undertaken using the PubMed database, targeting such topics as the C. E. Walsh C. Cromwell differential diagnosis of bleeding in the Division of Hematology and Medical intensive care unit and the epidemiolOncology, Department of Medicine, ogy, diagnosis, and treatment of Mount Sinai School of Medicine, acquired hemophilia. Clinical study New York, NY, USA
Received: 14 January 2011 Accepted: 9 May 2011 Published online: 31 May 2011 Copyright jointly held by Springer and ESICM 2011

ndings pertaining to the efcacy of specic treatments for acquired hemophilia were summarized. Results and conclusion: Recognition of acquired hemophilia presents a clinical challenge, given the rarity of this condition, a general lack of familiarity with acquired hemophilia, and the potential for confusion with other more common causes of bleeding in the intensive care unit. Nevertheless, there are sentinel clinical and laboratory ndings that should raise suspicion of this diagnosis. The treatment of acquired hemophilia is a multi-step, physiologically focused process aimed at controlling both active and recurrent bleeding. Therefore, prompt diagnosis is central to prognosis. Consultation with a hematologist may facilitate efcient diagnosis and management. Keywords Blood coagulation disorders Hemophilia A Antibodies, neutralizing

Introduction
There are numerous potential causes of bleeding in the critically ill patient, which are summarized in Table 1 and discussed in greater detail elsewhere [16]. Acquired hemophilia (AH) is a condition in which inhibiting antibodies develop against coagulation factors, most often

factor VIII, leading to signicant bleeding episodes that carry high morbidity and mortality. The majority (66.5%) of patients with AH will present with a major bleeding event [7], making them likely candidates for admission to the intensive care unit (ICU). Severe bleeding occurs in up to 90% of patients with AH [8], and the mortality rate attributable to bleeding episodes is substantial, ranging

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Table 1 Potential etiologies of bleeding in the intensive care unit [1, 2, 5459] Inherited Inherited platelet disorders Primarily impact platelet function Congenital hemophilia von Willebrand disease Acquired thrombocytopenia Defective production, increased consumption or destruction, or sequestration of platelets Immune mediated Acquired abnormalities of platelet function Common causes include uremia, liver failure, myeloma, myeloproliferative disorders, CPB, and medications, of which only antiplatelet medications (e.g., aspirin, clopidogrel) and b-lactam antibiotics (penicillins [ cephalosporins) cause clinical bleeding Reduced production of coagulation factors Liver dysfunction Vitamin K deciency May arise in patients receiving TPN without supplemental vitamin K or in patients receiving broad-spectrum antibiotics Dilution of coagulation factors Massive transfusion, particularly if unbalanced (e.g., transfusion of PRBCs without FFP) Consumption of coagulation factors (e.g., DIC) Acquired hemophilia Acquired von Willebrand syndrome von Willebrand factor depletion secondary to thrombocytosis (e.g., in myeloproliferative disorders or essential thrombocythemia) Complex of von Willebrand factor with specic or nonspecic autoantibodies (e.g., in lymphoproliferative conditions) Presumptive proteolysis of large von Willebrand factor multimers distorted by shear stresses in uncorrected aortic stenosis Trauma Coagulopathy is present in 2535% of trauma patients at admission Preoperative uid resuscitation (hemodilution) Administration of hetastarch for volume expansion is an independent risk factor for coagulopathy Massive preoperative transfusion Pre-existing antiplatelet or anticoagulant therapy Pre-existing liver or renal dysfunction Tissue injury Massive intraoperative or postoperative hemorrhage Massive intraoperative or postoperative transfusion Cardiopulmonary bypass for complex cardiac surgery Therapeutic heparinization Failure to reverse or manage preoperative treatment with antiplatelet or anticoagulant agents

Acquired

Surgical Preoperative factors

Intraoperative and/or postoperative factors

CPB Cardiopulmonary bypass, DIC disseminated intravascular coagulation, FFP fresh frozen plasma, PRBCs packed red blood cells, TPN total parenteral nutrition

from 6 to 8% even after the advent of effective treatments [9, 10]. The severity of the clinical presentation, along with the rarity of AH, makes it a challenging condition to diagnose and treat. However, prompt diagnosis is a primary determinant of prognosis in these patients [11] because they will not respond to customary management algorithms for severe hemorrhage and in fact need specic treatments aimed at removing inhibitors and/or bypassing neutralized coagulation factors. The undiagnosed presence of this condition may also complicate the execution of lifesaving invasive or surgical procedures in the critically ill patient. Accordingly, intensivists must have a high index of suspicion when it comes to diagnosing this condition in their coagulopathic patients.

This review will highlight the epidemiology, clinical presentation, diagnosis, and management of AH in critically ill patients.

Epidemiology and clinical presentation of acquired hemophilia


Although the incidence of AH in the general population ranges from 1 to 4 cases per million per year [8], the incidence increases with age (6.0 per million per year among those aged 6585 years and 16.6 per million per year among those over the age of 85 years) [12]. In fact,

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The usual clinical presentation of AH is one of recentonset or acute bleeding in a patient without a personal or family history of bleeding diatheses [15]. Bleeding may be spontaneous or, quite often, secondary to a trivial injury or minor invasive procedure (e.g., intramuscular injection or venous catheter placement) [16]. In approximately 25% of cases, bleeding occurs in the setting of a surgical procedure [7]. Common bleeding sites in AH are different from those commonly observed in the setting of congenital hemophilia. More than 80% of patients with AH will experience hemorrhages affecting the skin (Fig. 1), muscles or other soft tissues, or mucous membranes of the nares or gastrointestinal or genitourinary tracts, but hemarthrosis, a common manifestation of congenital hemophilia, is rare in the setting of AH [13, 17]. Retropharyngeal and retroperitoneal bleeding may also occur [14, 18, 19]. Intracranial hemorrhage is a rare but potentially catastrophic manifestation of AH [7, 20]. In addition to the hemorrhage itself, other serious complications of AH-related bleeding may occur. For example, retropharyngeal hemorrhage may threaten airway patency, and intramuscular bleeding may produce a Fig. 1 Photograph depicting extensive subcutaneous ecchymosis in compartment syndrome with neurovascular compromise a patient with acquired hemophilia. Adapted from Collins et al. [17] [7, 18, 19].
(copyright Collins et al.; licensee BioMed Central Ltd)

the median age at diagnosis ranges from 55 to 78 years [7], making AH a disease of primarily the elderly, a factor that contributes to the high morbidity and mortality of this condition. Both genders are equally affected, except in younger age groups, where its association with pregnancy makes AH more common in females [7]. Etiologically, AH is associated with a number of underlying conditions, including autoimmune disorders and malignancies (more often solid tumors than lymphoproliferative malignancies), as well as some medications, including penicillin, sulfonamides, phenytoin, methyldopa, and interferon alpha [7, 13]. However, in approximately 50% of cases, AH is idiopathic [13, 14].

Diagnosing acquired hemophilia


Recent and/or acute onset of bleeding in a patient without a family or personal history of bleeding should raise suspicion of AH, particularly if the patient is elderly or postpartum [15]. The early laboratory diagnosis of AH is characterized by the singular prolongation of activated partial thromboplastin time (aPTT) with a normal prothrombin time (PT) and platelet count [13, 14, 21], ndings that will automatically rule out other common causes of bleeding in the ICU (Table 2). Because this may be the only laboratory clue to the presence of acquired

Table 2 Typical diagnostic laboratory ndings for coagulation disorders affecting intensive care unit patients [2, 23, 24, 60, 61] Condition DICa Liver failure Vitamin K deciency Acquired hemophilia Heparin effect Abnormal platelet function Platelet count Decreased Low/normal Normal Normal Normal Normal aPTT Prolonged Prolonged Normal/prolongedb Prolonged Prolonged Normal PT Prolonged Prolonged Prolonged Normal Normal Normal Fibrinogen Decreasedc Low/normald Normal Normal Normal Normal Fibrin degradation D-dimer products Positive Negative Negative Negative Negative Negative Positive Negative Negative Negative Negative Negative Thrombin time Prolonged Prolonged Normal Normal Prolonged Normal

aPTT Activated partial thromboplastin time; PT prothrombin time c May be normal, reecting increased production of brinogen in a Schistocytes will also be seen on peripheral blood smear the face of accelerated consumption b In mild vitamin K deciency, only PT will be prolonged, given d Fibrinogen may be elevated in the setting of end-stage liver that the production of factor VII is especially dependent on vitamin disease, although functional abnormalities of brinogen may K; however, in more severe deciencies, both PT and aPTT will coexist become prolonged, as more vitamin Kdependent factors are affected

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hemophilia, even a minimally prolonged aPTT should be thoroughly investigated in patients who otherwise t the clinical description for this condition, especially if they are actively bleeding. Delays in doing so may postpone the initiation of effective treatments or lead to interventions that put the patient at greater risk, such as surgery without appropriate perioperative hemostatic coverage. Other causes of an isolated prolonged aPTT can usually be ruled out based on clinical presentation or additional laboratory testing. From a clinical standpoint, AH and acquired or congenital von Willebrand disease are the only conditions associated with an isolated prolonged aPTT that manifest with a bleeding phenotype, whereas other non-iatrogenic conditions that cause a prolonged aPTT typically present with no symptoms [factor XII (Hageman factor) and prekallikrein deciencies] or thrombosis (lupus anticoagulant) [22, 23]. Acquired hemophilia may be differentiated from von Willebrand disease on the basis of family history, which is often present in the congenital form of the latter given an autosomal dominant pattern of inheritance, and bleeding site, since von Willebrand disease is characterized by mucous membrane bleeding [24]. A laboratory test known as a mixing study can determine whether a prolonged aPTT is the result of a deciency in an intrinsic pathway factor (i.e., factors VIII, IX, XI, and XII) or von Willebrand factor (VWF), or the presence of an inhibitor. In this study, which can easily be performed in any laboratory [12], plasma from an affected patient is incubated with an equal volume of normal plasma, resulting in normalization of the aPTT if there is a factor or VWF deciency but only partial or no correction when a factor-directed inhibitor or lupus anticoagulant is present. In the case of a factor VIIIdirected inhibitor, however, a mixing study may yield misleading results if not performed under proper conditions. Factor VIII inhibitors are time- and temperaturedependent, and the action of these inhibitors is often delayed [14, 15, 25]. Therefore, assessment of the aPTT immediately after mixing and after an incubation period of 2 h is recommended; a more prolonged aPTT after 12 h versus the immediate mix is suggestive of a factor VIII inhibitor [12, 15, 25]. Acquired hemophilia is essentially conrmed by the additional documentation of reduced factor VIII activity (typically to 015% of normal values), along with quantication of the factor VIII inhibitor by the Bethesda assay [26]. This assay measures residual factor VIII activity following serial dilutions of the patients plasma with normal plasma [27]. The inhibitor titer in Bethesda units (BUs) is equivalent to the inverse of the dilution that produces 50% inactivation of factor VIII activity [27]. Measurement of the inhibitor titer will provide the point of reference upon which initial management of AH is usually based. Early consultation with a hematologist will facilitate efcient diagnosis and management of the patient with

active AH-related bleeding. In cases where the laboratory has limited experience performing the tests needed to conrm the diagnosis of AH (e.g., mixing study, factor assays), the hematologist may be a valuable resource to the laboratory, ensuring that the tests are performed correctly and promptly. Most important, he or she can provide invaluable guidance regarding treatment, particularly for the unstable or deteriorating patient when conrmatory laboratory results are pending.

Management of acquired hemophilia in the ICU


In the symptomatic patient with AH, there are two primary goals of treatment: early restoration of hemostasis and eradication of the inhibitor. Restoration of hemostasis is achieved by increasing circulating levels of factor VIII or by bypassing the factor at which inhibitors are directed within the clotting cascade. The inhibitor titer is used as a guide to determine which of these strategies should be employed; however, because of the complex, nonlinear kinetics of the autoantibodies seen in AH, the titer does not always reect the potency of the inhibitor [15]. Therefore, the severity of hemorrhage should serve as the primary basis upon which treatment decisions are made. In the actively bleeding patient in whom a diagnosis of AH is suspected but not yet conrmed by advanced laboratory testing (e.g., factor levels or inhibitor titer), consideration should be given to initiating hemostatic treatmentin this case, a bypassing agentin the setting of life- or limb-threatening bleeds, hemodynamic instability, or symptomatic anemia, particularly if the hemoglobin level has fallen below 7 g/dL. Determining the efcacy of any given treatment is difcult because in studies of AH, patients often receive a number of therapies at once or in rapid sequence [28]. Systematic evaluation of treatments for AH is further hampered by the rarity of this diagnosis. Consequently, the management of AH is largely based on the application of similar treatments in the setting of congenital hemophilia with inhibitors or on AH-centered studies limited by small sample sizes or retrospective study design. In light of the lack of evidence guiding the management of these patients, international consensus guidelines have recently been developed for this purpose based on collective clinical experience [15].

Restoration of hemostasis in patients with low inhibitor titers For a low inhibitor titer (\5 BU/mL) and minor bleeding, strategies to increase the circulating levels of factor VIII

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Table 3 Dosing of treatments for acquired hemophilia with active bleeding [8, 9, 15, 16, 21, 32] Dosing treatments Restoration of hemostasis Treatments that increase circulating levels of factor VIII Human factor VIII concentratesa Desmopressin Bypassing agents rFVIIa pd-aPCC Dosing regimen

40 IU/kg IV plus 20 IU/kg IV for each BU of inhibitor 0.3 lg/kg IV/SC 7090 lg/kgd IV every 23 h until response is observed 50100 U/kg every 612 h until response is observed (maximum of 200 U/kg/day) Mucous membrane bleed: 50 U/kg every 6 h; increase to 100 U/kg every 6 h for persistent bleeding Serious soft tissue or other severe bleed: 100 U/kg every 12 h 12 mg/kg/day PO 12 mg/kg/day PO 200300 mg/day 375 mg/m2

Elimination and suppression of inhibitor First-line agents Prednisone Cyclophosphamideb Second-line agents Cyclosporin Ab Rituximabc

BU Bethesda unit; IV intravenous; pd-aPCC plasma-derived acti- c Rituximab is added as a salvage therapy in patients not vated prothrombin complex concentrate; PO per os (by mouth); responding to standard immunosuppressive regimens d rFVIIa, recombinant activated factor VII; SC subcutaneous Most of the evidence regarding efcacy of rFVIIa is based on a a Recommended human factor VIII concentrates dosing varies mean/median dose of 90 lg/kg from source to source. There are no clinical studies to guide dosing of this product b Cyclophosphamide is often used in combination with steroids, as part of a second-line regimen. Cyclosporin A may be used alone or in combination with steroids

are generally employed. Fresh frozen plasma (FFP) and cryoprecipitate are usually ineffective for this purpose because they contain only small amounts of factor VIII, which are quickly neutralized by the inhibitor [26]. The large volumes of FFP that would be required to overwhelm the inhibitor may lead to uid overload and cardiac failure in the susceptible critically ill patient [29]. The primary strategy to increase circulating factor VIII levels is the administration of high doses of human factor VIII concentrate (Table 3) [8]. It should be noted that the recommended dosing algorithms for human factor VIII, which are based on the inhibitor titer, are only rough estimates because inhibitor kinetics will vary from patient to patient [16]. Furthermore, there are no published studies to guide the dosing of human factor VIII for this purpose [25]. Because the half-life of administered human factor VIII cannot be reliably predicted in patients with AH, serial measurement of plasma factor VIII levels is critical to the proper adjustment of therapy [16]. In general, plasma factor VIII levels of 3050% will correlate with successful hemostasis [27]. Desmopressin may also be used alone or in combination with factor VIII in the setting of a low inhibitor titer in AH (Table 3). As an analogue of vasopressin, desmopressin induces the release of VWF from the vascular endothelium and increases circulating levels of factor VIII [30]. Intravenous infusion at a dose of 0.3 lg/kg increases plasma levels of factor

VIII by two- to threefold in normal individuals [16]. However, due to tachyphylaxis, desmopressin is only effective for 34 consecutive days [21]. Patients with AH and very low inhibitor titers (\3 BU/mL) may have sufcient endogenous stores of factor VIII to overcome their inhibitor burden following treatment with desmopressin, but in the majority of patients with AH, desmopressin alone will be unable to achieve hemostasis [27]. Restoration of hemostasis in patients with high inhibitor titers For high inhibitor titers ([5 BU/mL) or active severe bleeding regardless of inhibitor titer, bypassing agents are the primary treatment of choice [13, 15]. In cases where a bypassing agent is not available, FVIII restoration strategies are recommended as an initial measure to control bleeding [15]. As their categorical name suggests, bypassing agents effect hemostasis by circumventing the role of the factor at which inhibitors are directed within the coagulation cascade. There are currently two commercially available bypassing agents: recombinant activated factor VII [rFVIIa (NovoSeven); Novo Nordisk A/S, Bagsvaerd, Denmark] and plasmaderived activated (or puried) prothrombin complex concentrate {pd-aPCC [factor eight inhibitor bypassing

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agent (FEIBA)]; Baxter Healthcare Corp, Westlake events was signicantly higher among patients who received rFVIIa (5.5%) versus placebo (3.2%; Village, CA}. P = 0.003), with the highest rates observed among patients exceeding 65 years of age [34]. The overall rates of venous thromboembolic events were similar between Recombinant activated factor VII the rFVIIa and placebo groups. The incidence of arterial Recombinant activated factor VII is the only recombinant thromboembolic events increased with increasing rFVIIa bypassing agent. This molecule binds to the surface of dosing (\80 vs. 80120 vs. [120 lg/kg) in the subset of activated platelets, replacing the absent factor IXa/VIIIa patients presenting with CNS bleeding in this analysis complex to generate factor Xa, which then augments local [34]. In contrast, a retrospective review of data from the thrombin generation [31]. In addition to being used for Hemophilia and Thrombosis Research Society Registry the treatment of acute bleeding episodes in AH, rFVIIa found that there were no thromboembolic complications is also indicated for the prevention of bleeding during in 25 patients with congenital hemophilia and inhibitors surgical interventions or invasive procedures in this patient who received one or more rFVIIa doses of 250 lg/kg or more for a total of 172 bleeding episodes [35]. population [32]. Hemostasis can be expected with an rFVIIa dosage of up to 90 lg/kg administered intravenously every 23 h (Table 3) [32]. This was the median dosage used in a Plasma-derived activated prothrombin complex small, multicenter compassionate-use study (N = 38) in concentrate which rFVIIa was used primarily as a second-line treatment for AH-related bleeding episodes, following Plasma-derived aPCC, a plasma-derived concentrate nonresponse to blood products for a median of 4 days [9]. composed of both activated and nonactivated clotting Response to rFVIIa was judged as good (i.e., effec- factors, is another commercially available bypassing tive), partial, or poor. The efcacy of rFVIIa as a agent used for the management of AH-related bleeding rst-line agent for 14 bleeding episodes was judged as episodes [36]. This concentrate is composed of clotting good in 100% of cases at 8 and 24 h post-treatment ini- factors II, IX, and X, mainly in nonactivated forms, and tiation. Of 60 bleeding episodes treated with rFVIIa as a factor VII, mainly in an activated form [37]. This product salvage therapy, the response at 24 h posttreatment ini- is indicated for the control of spontaneous bleeding epitiation was good in 75%, partial in 17%, and poor in 8% sodes or to cover surgical interventions in patients with [9]. The results of this study suggest that rFVIIa is more hemophilia A and hemophilia B with inhibitors [37]. effective when used as rst-line therapy rather than as Although it is not formally indicated for the treatment of salvage therapy, an observation that was echoed in a spontaneous hemorrhages in the setting of AH, pd-aPCC retrospective review of data from compassionate and has been used for this purpose [36]. A dose ranging from emergency use programs, the Hemophilia and Thrombo- 50 to 100 U/kg is recommended, depending primarily on sis Research Society (HTRS) Registry, and independent the anatomic site of bleeding (Table 3) [37]. In all cases, a published reports, encompassing a total of 182 bleeding daily dosing of 200 U/kg should not be exceeded [37]. A retrospective analysis incorporating patients with episodes for which rFVIIa was used [33]. This review found that rFVIIa was overall effective (meaning effec- AH who received pd-aPCC for bleeding episodes in a tive or partially effective in controlling the index bleed) in total of three tertiary medical centers (N = 34) found that 95% of bleeding episodes for which it was used as a rst- a complete response was achieved in 86% of patients line therapy compared with 6783% of bleeding episodes [38]. Only patients who received pd-aPCC as rst-line for which it was used as salvage therapy, depending on therapy were included in this analysis; patients who received factor VIII prior to pd-aPCC for the same the data set examined [33]. The most common adverse reactions observed in bleeding episode were also included. There were no clinical studies for all approved indications of rFVIIa reported thromboembolic events in this analysis [38]. One were pyrexia, hemorrhage, injection site reaction, patient experienced an increase in D-dimers, although this arthralgia, headache, hypertension, hypotension, nausea, patient, who had ulcerative colitis, had undergone emervomiting, pain, edema, and rash [32]. The cumulative gency colectomy to control severe gastrointestinal incidence of thrombotic events with a possible or proba- hemorrhage, so it was not known whether the increased ble relationship to rFVIIa in clinical trials of patients with D-dimers were an effect of the surgical intervention or AH was 4% [32]. In a systematic analysis of randomized, treatment with pd-aPCC [38]. Nevertheless, concerns placebo-controlled studies evaluating rFVIIa for off-label about potential thrombotic adverse events (including indications, including liver disease, trauma, spontaneous myocardial infarction) in the setting of treatment with central nervous system (CNS) bleeding, and postoperative aPCCs have been raised, particularly in patients with AH, bleeding in patients without acquired or congenital who are often elderly or postpartum, or who may have an hemophilia, the overall rate of arterial thromboembolic associated condition (e.g., a malignancy) that may

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predispose them to thrombosis at baseline [25, 36]. Over a 10-year postmarket surveillance period (19901999), the incidence of thromboembolic events was 4.05 per 100,000 infusions; half of these events occurred in patients who received pd-aPCC doses exceeding the upper limit of recommended dosing [39]. In addition to the risk for thrombosis, other reported adverse events identied during the use of pd-aPCC include injection site pain, anaphylactic reaction, hypersensitivity, urticaria, decreased blood pressure, and hypoaesthesia [37]. In a randomized, open-label, noninferiority study of patients with congenital hemophilia, rFVIIa and pd-aPCC were found to have equivalent efcacy 6 h after treatment initiation, which was the primary study endpoint [40]. However, there were apparent aws in the study design and data collection, including a lack of statistical power for the primary endpoint and a high rate of patient discontinuation. In addition, a substantial proportion of patients rated one treatment effective and the other ineffective at most time points within the study, including 6 h after treatment initiation [40]. No studies that directly compare the efcacy and safety of rFVIIa and pd-aPCC specically in patients with AH have been performed to date. Given the limited evidence pertaining to the comparative efcacy and safety of these agents, the treating clinician may consider other factors when deciding which bypassing agent to use in any given patient. These may include treatment availability or cost, as well as clinically relevant variables, such as the location and severity of bleeding and the existence of any comorbidities [27]. One theoretical advantage of rFVIIa is its recombinant derivation, which eliminates the risk of transmitting human pathogens [27]. In contrast, pd-aPCC is derived from human plasma and thus carries a risk of transmitting infectious agents [37]; however, in addition to the general rigorous screening of human blood product donors, pdaPCC is vapor heated and nanoltered in an effort to inactivate and remove viruses [37], and there have been no documented cases of transmission of human immunodeciency virus or hepatitis A, B, or C attributed to coagulation factor replacement products (including aPCCs) licensed in the USA since the mid-1980s [41]. Plasma-derived aPCC may induce allergic reactions, including severe anaphylactoid reactions, as well as an anamnestic rise in inhibitor titers [37], which may hinder the achievement of adequate coagulation [41]. Because rFVIIa is a recombinant product free of human plasmaderived FVIII, allergic and anamnestic responses are not a concern. A new room temperature formulation of rFVIIa (rFVIIa-RT) may be particularly convenient in the unpredictable ICU environment; reconstituted rFVIIa-RT can be used up to 3 h after mixing when either stored at room temperature or refrigerated [32]. Clinical experience with these agents has shown that individual efcacy is highly variable from patient to patient and that neither is

universally effective [42]. Therefore, these agents have been used sequentially and even in combination [4345]. That said, the combination of these agents has not been systematically evaluated and should therefore be approached with caution, particularly given the additive risk of thrombotic events. The use of the antibrinolytic agents aminocaproic acid and tranexamic acid for AH-related bleeding is controversial [15], given the sparse anecdotal data pertaining to their use. These agents have been successfully used both alone and in combination with other treatments for AH [15, 46] and may be especially useful for mucous membrane bleeding [15, 26]. Antibrinolytic agents are contraindicated in the setting of hematuria as expected clot formation may lead to urinary tract obstruction [26]. Severe bradycardia has been described in two elderly patients in whom aminocaproic acid was used for major AH-related bleeding [46, 47]. In one patient, the development of complete heart block was temporally associated with aminocaproic acid infusion; however, a rst-degree atrioventricular block and left anterior fascicular block were noted on the patients baseline electrocardiogram at admission [46]. Thrombotic complications are a theoretical concern when combining antibrinolytic agents with bypassing agents. For this reason, the prescribing information for pd-aPCC recommends against the administration of antibrinolytics within 12 h of pd-aPCC [15, 37], despite reports of simultaneous pdaPCC and antibrinolytics use without complications [37]. Eradication of inhibitor Interventions to eliminate inhibitors in the actively bleeding patient with AH may necessarily be part of the immediate treatment strategy, particularly when bleeding is severe and inhibitor titers are high. Extracorporeal techniques, such as plasmapheresis and immunoadsorption, are employed for the rapid elimination of inhibitor [8, 48]. It should be noted that these techniques result in only temporary inhibitor removal [8] to facilitate successful factor VIII replacement; long-term eradication of inhibitor may require concomitant or sequential initiation of immunosuppressive therapy [16]. An important advantage of immunoadsorption over plasma-exchange techniques is the lack of simultaneous removal of coagulation factors during the former procedure [28], the occurrence of which might augment bleeding risk. The specialized equipment and expertise required for these techniques limit their application to primarily specialized centers [7]. As previously indicated, immunosuppressive therapy may be undertaken for the purpose of long-term suppression of inhibitor formation in AH. Although spontaneous clearance of the inhibitor occurs in up to one-third of patients, it cannot be reliably predicted which patients will experience spontaneous remission [21].

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Furthermore, the risk of recurrent bleeding is high in patients with persistent inhibitors, as is the risk of mortality; in a meta-analysis of prognostic factors in AH, 42% of patients who failed to achieve complete remission (CR) died [16]. Accordingly, some have recommended initiation of immunosuppressive therapy as soon as the diagnosis of AH is made [15, 21]. Immunosuppressive agents used for long-term inhibitor suppression include corticosteroids and cytotoxic drugs, such as cyclophosphamide, cyclosporin A, azathioprine, 6-mercaptopurine, and vincristine [8, 13]. Standard rst-line therapy consists of prednisone at a dose of 12 mg/kg/day for 36 weeks, with or without oral cyclophosphamide (12 mg/kg/day; Table 3) [13, 21]. However, the results of a prospective randomized study suggested that cyclophosphamide should only be added in AH patients who are steroid-resistant [49]. Rituximab, an anti-CD20 monoclonal antibody that has been shown to be highly effective as a salvage immunosuppressive strategy [21], is currently considered a second-line treatment, as is cyclosporin A (Table 3) [50]. Immune tolerance therapy (ITT), in which factor VIII is administered in combination with immunosuppressive agents and, occasionally, immunoadsorption, has been shown to be effective in congenital hemophilia with inhibitors, but the documented experience in AH is limited to a few small case series describing the successful use of various ITT regimens, including a modied BonnMalmo Protocol consisting of immunoadsorption, factor VIII concentrates, intravenous immunoglobulin, and immunosuppression [28, 51, 52]. As a result, ITT is currently only recommended in cases of life-threatening hemorrhage attributable to AH [15]. Given the potential for recurrence, long-term followup of patients who achieve CR is recommended [53]. Patients must also be followed for potential adverse effects of long-term immunosuppression, infection being the primary complication.

Conclusion
Acquired hemophilia is a rare but serious potential cause of bleeding in critically ill patients that carries a high risk of morbidity and mortality. The diagnosis of this condition is hampered by its rarity, along with a general lack of familiarity with AH. Nevertheless, rapid diagnosis is a prerequisite to initiating denitive therapy, because AH will not respond to typical interventions aimed at controlling hemorrhage. The diagnosis of AH should be considered in the actively bleeding patient with no personal or family history of bleeding diatheses, particularly if the patient is elderly or postpartum. The presence of an isolated prolonged aPTT in an actively bleeding patient who ts this description is virtually pathognomonic of AH; partial or no correction of aPTT in a mixing study and documentation of low factor VIII levels and factordirected antibodies will conrm the diagnosis. Treatment should consist of measures that both restore hemostasis and eliminate inhibitor. Restoration of hemostasis is addressed by the administration of treatments that will either increase circulating levels of factor VIII or bypass the role of the neutralized factor within the coagulation cascade. Eradication of inhibitor will not only reduce the likelihood of recurrent bleeding but may also be integral to the immediate management of active bleeding in the setting of high inhibitor titers. Consultation with a hematologist should be considered for this rare and complex condition, particularly given the fact that the patient with AH will require ongoing follow-up upon leaving the ICU.
Acknowledgments Writing support was provided by Lara Primak, MD, of ETHOS Health Communications, Newtown, Pennsylvania, with nancial assistance from Novo Nordisk, Inc., in compliance with international guidelines for Good Publication Practice.

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