ACQUIRED HEMOFILIA

Background
Acquired hemophilia is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies directed against plasma coagulation factors, most frequently factor VIII (FVIII).[1] Autoantibodies against other factor proteins have also been reported.[2] Because inhibitors to FVIII are the most frequently observed in clinical practice, this article focuses on the etiology and management of FVIII autoantibody inhibitors, or acquired hemophilia A. Diagnosis of acquired hemophilia can be difficult, both because the condition is rare and because the patient does not have the usual personal or family history of bleeding episodes, such as is seen in congenital hemophilia.[1] Moreover, the clinical signs and symptoms of acquired hemophilia differ from those of hereditary hemophilia. The severity of acquired hemophilia at clinical presentation can also make its management challenging. Treatment strategies for acquired hemophilia have 2 major objectives. During acute bleeding episodes, effective control of bleeding manifestations is the primary objective. However, the ultimate therapeutic goal is to eliminate the inhibitor and cure the disease. Please see the following for more information:

Hemophilia A Hemophilia B Hemophilia C

Pathophysiology
Acquired hemophilia is a spontaneous autoimmune disorder in which patients with previously normal hemostasis develop autoantibodies against clotting factors, most frequently FVIII.[3] The development of autoantibodies against FVIII leads to FVIII deficiency, which results in insufficient generation of thrombin by factor IXa and the factor VIIIa complex through the intrinsic pathway of the coagulation cascade. The development of factor IX (FIX) autoantibodies is less common, and the presence of autoantibodies against other clotting factorsfactors II (FII), V (FV), VII (FVII), X (FX), XI (FXI), and XIII (FXIII), as well as von Willebrand factor (vWF)is extremely rare.[3, 2, 4] The most common epitopes for autoantibody binding to FVIII appear to occur between amino acids 454-509 and 593 in the A2 domain on the heavy chain of FVIII, between 1804 and 1819 in the A3 domain on the heavy chain, and between 2181 and 2243 in the C2 domain on the light chain.[2, 5, 6] Anti-C2 antibodies inhibit the binding of FVIII to phospholipids and may also interfere with the binding of FVIII to vWF protein, whereas anti-A2 and anti-A3 antibodies impede the binding of FVIII to activated FX and FIX of the intrinsic pathway FX activation complex.[7]

Although both alloantibody inhibitors in patients with hereditary hemophilia and autoantibodies in patients with acquired hemophilia appear to recognize the same epitopes on each domain, the inactivation of FVIII resulting from these interactions differs.[8] For example, alloantibodies totally inactivate FVIII activity according to type 1 kinetics, and this total inactivation is not dependent on the titer/concentration of circulating antibody. In contrast, autoantibodies typically exhibit more complex type II kinetics, undergoing an initial rapid inactivation followed by a slower inactivation curve and resulting in some level of residual FVIII, which can be detected in the laboratory but does not seem to convey useful clinical efficacy.[8, 9]

Etiology
Acquired hemophilia results from the development of autoantibodies (mostly of immunoglobulin G [IgG] subclasses 1 and 4) directed against clotting factors.[2, 8, 4] Numerous conditions have been associated with acquired inhibitors to FVIII. Rarely, FVIII autoantibodies arise as idiosyncratic reactions to medications. However, approximately 50% of cases occur in patients who lack relevant concomitant diseases; these cases are idiopathic.
[1, 10]

The following conditions may be associated with acquired hemophilia A[1] :

Idiopathic Pregnancy Autoimmune disorders Inflammatory bowel disease, ulcerative colitis Dermatologic disorders (eg, psoriasis, pemphigus) Respiratory diseases (eg, asthma, chronic obstructive pulmonary disease) Allergic drug reactions Diabetes Acute hepatitis B infection Acute hepatitis C infection Malignancies-solid tumors (prostate, lung, colon, pancreas, stomach, bile duct, head and neck, cervix, breast, melanoma, kidney) Hematologic malignancies

Autoimmune disorders may include the following:

Rheumatoid arthritis Systemic lupus erythematosus Multiple sclerosis Temporal arteritis Sjgren syndrome Autoimmune hemolytic anemia Goodpasture syndrome Myasthenia gravis Graves disease Autoimmune hypothyroidism

Allergic drug reactions may occur from the following:

Penicillin and its derivatives Sulfamides Phenytoin Chloramphenicol Methyldopa Depot thioxanthene Interferon alfa Fludarabine Bacille Calmette-Gurin (BCG) vaccination Desvenlafaxine[11]

Hematologic malignancies may include the following:

Chronic lymphocytic leukemia Non-Hodgkin lymphoma Multiple myeloma Waldenstrom macroglobulinemia Myelodysplastic syndrome Myelofibrosis Erythroleukemia

Table 1 below illustrates the frequency of underlying diagnoses in 3 cohort studies of patients with acquired hemophilia A.[9, 12, 13, 14, 15] (Open Table in a new window) Disease Association Green 1981 (N = Morrison 1993 (N = Collins 2007 (N = 215), % 65), % 172), % 46.1 55.0* 63.3 18.0 17.0 16.7 12.0 2.0 3.0 11.0 NR 14.7 3.3 NR 2.0 NR

Idiopathic Collagen, vascular, and other autoimmune diseases Malignancy 6.7 Skin diseases 4.5 Possible drug reaction 5.6 Pregnancy 7.3 Other 11.8 *In this trial, idiopathic and other were combined.

NRnot reported.

Disorders believed to be associated with inhibitors to coagulation factors other than FVIII are shown in the table below.[4, 16]

Table 2. Acquired Bleeding Disorders Associated With Inhibitors of Factors Other Than FVIII (Open Table in a new window) Coagulation Factor Inhibited V IX Most Commonly Associated Disorders Lymphoproliferative disorders, adenocarcinoma, tuberculosis, aminoglycosides, topical thrombin Systemic lupus erythematosus, acute rheumatic fever, hepatitis, collagen vascular diseases, multiple sclerosis, postprostatectomy, and postpartum Autoimmune diseases, prostate carcinoma, chronic lymphocytic leukemia, chlorpromazine Idiopathic, isoniazid, penicillin Autoimmune disorders, monoclonal gammopathies, lymphoproliferative diseases, epidermoid malignancies, hypothyroidism, myeloproliferative disorders, and certain medications Topical thrombin, idiopathic, autoimmune diseases, procainamide Bronchogenic carcinoma, idiopathic Treatment FFP, rFVIIa FIX concentrates, APCCs, rFVIIa, corticosteroids FFP, FXI concentrates, rFVIIa, tranexamic acid, fibrin glue FXIII concentrate, FFP, stored plasma, cryoprecipitate Desmopressin, infusion of FVIII that contains vWF, IVIG, plasma exchange APCC, FFP

XI XIII VWF

II VII

FIX concentrates, APCC, FVIII concentrates, rFVIIa, fibrin glue, tranexamic acid X Amyloidosis, carcinoma, acute nonlymphocytic APCC, tranexamic acid, leukemia, acute respiratory infections, fungicide fibrin glue, FFP exposure, idiopathic APCCactivated prothrombin complex concentrate; FFPfresh frozen plasma; IVIG intravenous immunoglobulin; vWFvon Willebrand factor.

Epidemiology
United States statistics
The incidence of acquired hemophilia A has been estimated to be 0.2-1.0 case per 1 million persons per year, but this figure may underestimate the true incidence of the disorder, given the difficulty in making the diagnosis.[1] In addition, some patients with acquired hemophilia and low titers of inhibitors may not be diagnosed unless they undergo surgery or trauma, which also may lead to an underestimation of the incidence of the disease.[1] The incidence of acquired inhibitors to clotting factors other than factor VIII (FVIII) is unknown, although it is significantly lower than that reported with acquired hemophilia A.

International statistics
Acquired hemophilia has a worldwide distribution. In the United Kingdom, the incidence of acquired hemophilia has been reported to be 1.48 per million persons per year.[12] There is no known association between an increased susceptibility to develop acquired autoantibodies to coagulation factors and ethnicity.

Age-, sex-, and race-related demographics

The age distribution of acquired hemophilia is typically biphasic. There is a small peak in incidence in women aged 20-30 years, and a major peak in males aged 60-80 years.[1, 4] The vast majority cases of acquired hemophilia occur in older adults. The median age at presentation is between 60 and 67 years.[7, 10, 4] Acquired hemophilia has no known genetic inheritance pattern and is seen equally in men and women.[7] It occurs in all racial groups.

Prognosis
Because it is frequently confused with other life-threatening conditions (eg, disseminated intravascular coagulation) and typically occurs in an elderly population, acquired hemophilia can lead to severe morbidity and even mortality before it is correctly diagnosed.[7] Estimates of the mortality associated with acquired hemophilia range from 7.9% to 22%, with most hemorrhagic deaths occurring within a few weeks of presentation.[1] More than 80% of patients with FVIII autoantibodies hemorrhage into the skin, muscles, or soft tissues and mucous membranes. Muscle bleeding episodes can be severe and can lead to compartment syndrome and tissue death.[7] Other manifestations include prolonged postpartum bleeding, excessive bleeding following surgery or trauma, and, occasionally, cerebral hemorrhage.[1, 17] In general, the prognosis of patients with acquired hemophilia depends on the patients response to immunosuppression.[1, 18, 12] A meta-analysis of 249 patients with acquired hemophilia found that 3 factors had an independent impact on overall survival and disease-free survival: related conditions (malignancy vs postpartum), complete remission status, and age at diagnosis (< 65 y vs 65 y).[18, 12] Survival was greatest in patients with postpartum inhibitors, in those who achieved complete remission, and in those who were younger than 65 years. In some patients, such as those with postpartum or drug-induced inhibitors, the inhibitors may disappear spontaneously within a few months of delivery or after the discontinuance of drug therapy.[1] In contrast, patients with associated autoimmune disorders usually have hightiter inhibitors that seldom resolve spontaneously or with monotherapy with steroids.[1] Patients with underlying malignancies may have a worse prognosis than patients without a malignancy.[18] Fifty percent to 70% of patients with underlying malignancies achieve complete eradication of the inhibitor.[1] Nonetheless, the inhibitor may not always disappear

despite successful treatment of the tumor. In addition, the reappearance of the inhibitor may not predict the recurrence of the malignancy. Approximately 20% of patients experienced a relapse after immunosuppressive therapy was discontinued. Relapse typically occurred between 1 week and 14 months after therapy was stopped.[12] This finding reinforces the need for long-term follow-up of patients with acquired hemophilia. Most patients who relapse (70%) achieve a second complete remission, although some may need long-term maintenance immunosuppression.[15]

Patient Education
Clinicians should conduct one-on-one discussions of issues with patients and family members. Because of the substantial risk of relapse, patients should be counseled to report signs of bleeding or bruising so that relapse can be detected as early as possible. Early recognition of relapse may minimize the time during which patients are at risk for hemorrhage.[12] Although pregnancy-related inhibitors tend not to recur in subsequent pregnancies in patients who achieve complete remission, women who experience pregnancy-related acquired hemophilia should be counseled about the possibility of recurrence in future pregnancies.[18]

History
Unlike patients with hereditary hemophilia, patients with acquired hemophilia do not have a personal or family history of bleeding episodes (see the image below).[1]

Clinical presentation of acquired hemophilia. About half of the cases are associated with other conditions, such as pregnancy, autoimmune disease, and cancer.[1, 10] The other cases are often idiopathic.

Physical Examination
The clinical picture of acquired hemophilia differs from that of hereditary hemophilia. For instance, intra-articular bleeding episodes, which are typical in congenital factor VIII (FVIII) deficiency complicated by the presence of alloantibodies, are unusual in patients with acquired hemophilia. Instead, hemorrhages into the skin, muscles, or soft tissues and mucous membranes occur in most patients.[1] Bleeding episodes are more frequent and severe in patients with acquired hemophilia than in patients with congenital hemophilia (see the image below).[12]

Sites of bleeding in patients with acquired hemophilia (n = 149). This research was originally published in Blood. Collins PW, Hirsch S, Baglin TP, et al. Acquired hemophilia A in the United Kingdom: a 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors' Organisation. Blood. 2007;109(5):1870-7. American Society of Hematology. The etiology underlying the difference in bleeding symptomatology between acquired and congenital hemophilia is unknown.[7] Typical signs of acquired hemophilia A include overt bleeding, epistaxis, gastrointestinal (GI) and urologic bleeding, and retroperitoneal hematomas.[1, 7, 4] Spontaneous bruising and muscle hematomas are most frequent.[2] If untreated, bleeding into the muscles may progress into a compartment syndrome, with compression of the neurovascular bundles. Subglottic hemorrhage may threaten the airway. Other frequent manifestations of acquired hemophilia include melena, hematuria, and iatrogenic bleeding, particularly after attempts to insert intravenous (IV) lines. Prolonged postpartum bleeding, excessive bleeding after trauma or surgery, and, occasionally, cerebral hemorrhage may also occur.[1]

Complications
Complications may be divided into hemorrhagic and nonhemorrhagic categories. Hemorrhagic complications include epistaxis, GI and urologic bleeding, retroperitoneal hematomas, compartment syndrome, prolonged postpartum bleeding, excessive posttraumatic or postoperative bleeding, subglottic or cerebral hemorrhage, and thrombocytopenia.[1, 2, 18] Adverse thrombotic events may also occur as a result of hemostatic therapy. Hemarthroses are rare. Nonhemorrhagic complications include the adverse effects of immunosuppression, such as infection, sepsis, and neutropenia.[18]

Diagnostic Considerations
Diagnosis of acquired hemophilia can be difficult, both because the condition is rare and because the patient does not have the usual personal or family history of bleeding episodes, such as is seen in congenital hemophilia.[1] Moreover, the clinical signs and symptoms of acquired hemophilia differ from those of hereditary hemophilia. In addition to the differentials (see below), conditions to be considered include the following:

Heparin administration

Lupus anticoagulant

Please see the following for more information:

Hemophilia A Hemophilia B Hemophilia C

Differentials

Congenital hemophilia Disseminated Intravascular Coagulation Dysfibrinogenemia von Willebrand Disease

Approach Considerations
Treatment strategies for acquired hemophilia have 2 major objectives. During acute bleeding episodes, effective control of bleeding manifestations is the primary objective. However, the ultimate therapeutic goal is to eliminate the inhibitor and cure the disease. The treatments used to accomplish these objectives usually depend on the natural history of acquired hemophilia, the clinical presentation of the coagulopathy, and the titer of the inhibitor (expressed in Bethesda units [BU]).[1] Most patients with acquired hemophilia are older and may have many concomitant diseases, and, thus, may require an individualized therapeutic approach.[26] Frequently, treatment of the underlying disorder or the discontinuation of an offending drug may eliminate or assist in the eradication of the inhibitor.[7] Patients with acquired hemophilia A can bleed after negligible or minor trauma, and may even bleed spontaneously. Any physical activity may trigger bleeding in soft tissues. Until inhibitors are eradicated, patients with acquired hemophilia should avoid activities with a significant risk of trauma. Patients who have mild bleeding episodes may not require hemostatic therapy (see the image below). In these patients, immunosuppressive therapy should be initiated as soon as the diagnosis of acquired hemophilia is established, when indicated.[15]

Management of bleeding in acquired hemophilia. A study of practically all patients who presented with acquired hemophilia A in the United Kingdom over a 2-year period reported that the severity of bleeding did not correlate with

FVIII level or inhibitor titer and was not useful in predicting those patients who would have fatal bleeding or those who may not require hemostatic treatment.[12] Consequently, whether patients should receive hemostatic therapy should depend on their bleeding symptoms and not on their FVIII activity or inhibitor levels. However, considering inhibitor levels may be useful in selecting hemostatic therapy in patients who require it. Common treatments used in the management of patients with inhibitors to clotting factors other than factor VIII (FVIII) are listed elsewhere (see Etiology). Please see the following for more information:

Hemophilia A Hemophilia B Hemophilia C

Hemostatic Therapy for Moderate or Severe Bleeding, FVIII < 5 BU

In patients with acquired hemophilia and low levels of inhibitors (< 5 BU), increasing plasma FVIII levels to 30-50% by using agents that increase FVIII concentrations may achieve hemostasis,[7] but this is not predictable a priori, and experience with the patients pattern of bleeding and response to therapies is necessary. Administering infusions of FVIII to patients with low-titer inhibitors may facilitate hemostasis. The dosing requirements for FVIII concentrate are considerably higher in these patients than in patients with congenital hemophilia; occasionally, massive doses are required, and even these massive doses are not always effective.[7, 10] Ultimately, using FVIII concentrates may only delay the need for more effective therapies.[19] Because of the variable kinetics of acquired antibodies, the required dose of FVIII concentrate can be only roughly predicted from the inhibitor titer. Some clinicians double or triple the dose of FVIII that should be given to a congenital hemophilia patient of the same weight.[18, 27] A dose of FVIII 200 IU/kg IV bolus every 8-12 hours has been recommended.[28] There are no published studies guide the dosing of human FVIII in acquired hemophilia.[19] Historically, porcine factor VIII has provided a good effect; however, it is no longer commercially available.[7] Recombinant porcine FVIII concentrates have not been used in acquired hemophilia, although they have been introduced in early clinical trials for the alloantibody hemophilia inhibitor population. Patients with very low inhibitor titers (< 3 BU) and residual FVIII activity may also benefit from treatment with desmopressin (1-deamino-8-D-arginine vasopressin). In healthy individuals, intravenous (IV) infusion of desmopressin (0.3 g/kg) may result in a 2- to 3fold temporary increase in FVIII and von Willebrand factor (vWF) plasma levels.[18] However, in most patients with acquired FVIII inhibitors, desmopressin treatment alone will not provide hemostasis.[7]

Hemostatic Therapy for Moderate to Severe Bleeding, FVIII 5 BU

When the inhibitor titer is high (5 BU), FVIII concentrates and desmopressin cannot overcome the FVIII-inhibiting capacity by increasing FVIII activity and are ineffective.[8, 26] Consequently, patients with severe bleeding and inhibitor titers of 5 BU or higher should receive therapy with an agent that bypasses FVIIInamely, either with recombinant factor VIIa (rFVIIa) or an activated prothrombin complex concentrate (APCC).[7] Considerations such as the location of bleeding, the severity of bleeding, comorbidities, treatment availability, and treatment cost may help clinicians select a hemostatic therapy.[7] Monitoring the efficacy of these agents by means of standard measures of coagulation, such as prothrombin time (PT) or activated partial thromboplastin time (aPTT), is not useful.[7]

Recombinant factor VII

Initially developed for use in patients with congenital hemophilia with alloantibody inhibitors, rVIIa has been successfully used in patients with acquired hemophilia. It binds to the surface of activated platelets, where it supports thrombin generation and bypasses the need for FVIII.[29, 7] Recommended dosing is 90-120 mg/kg IV bolus every 2-3 hours until bleeding is stopped.[7] If no response is seen after 2 doses, 120-270 mg/kg IV bolus every 2.5-3 hours should be administered.[28] Minor bleeding episodes are usually treated with 2 or 3 doses, but several days of treatment may be required for major bleeding episodes.[18] Patients who do not respond within 24 hours are unlikely to respond if rFVIIa treatment is continued.[30] Early studies of rFVIIa as a second-line agent for the treatment of acquired hemophilia showed a complete response rate in 75% of bleeding episodes.[30] A more recent analysis from an Italian registry of acquired hemophilia has demonstrated that rFVIIa controlled bleeding in 90% of the 20 cases in which it was used (in 19 cases as first-line therapy and in 1 case as salvage treatment).[31] rFVIIa is well tolerated and has few adverse effects.[18] One advantage of rVIIa is that it does not have the potential to transmit human pathogens, because it is made from cultured mammalian cells and is free from human pathogens.[7] No anamnestic risk in inhibitors with the use of rFVIIa has been described. Arterial and venous thrombosis have been reported with the use of rVIIa.[7, 32] Treatment with rFVIIa concentrate was associated with venous thromboembolism in a review of data from the Adverse Event Reporting System (AERS) of the US Food and Drug Administration (FDA).[33] However, most reported thromboembolic events followed the use of rFVIIa for offlabel indications, not its use for people with hemophilia with inhibitors. The thrombogenicity of any agent used to treat bleeding may be of particular concern in older individuals. In a comprehensive meta-analysis of 35 randomized clinical trials of rFVIIa use in nonhemophiliacs, those who were treated with high doses of rFVIIa on an off-label basis experienced a substantially higher risk of arterial, but not venous, thromboembolic events. Elderly individuals were particularly susceptible to this adverse event. Neither arterial nor

venous hypercoagulability has been noted in individuals who received rFVIIa to prevent or treat bleeding complications associated with their acquired hemophilia.[34]

Activated prothrombin complex concentrate

APCCs are other FVIII-bypassing agents used to manage bleeding episodes in acquired hemophilia. Currently, the only APCC available in the United States is FEIBA (BaxterImmuno). FEIBA, an anti-inhibitor coagulant complex, is a plasma-derived concentrate containing activated clotting factors that has undergone viral inactivation with dry heat vapor treatment.[7, 30] The recommended dosage for anti-inhibitor coagulant complex is 50-100 IU/kg IV bolus every 8-12 hours.[28] The total dose should not exceed 200 U/Kg within a 24-hour period.[7] Because no assay is available to monitor response to anti-inhibitor coagulant complex, clinicians should use their judgment to determine duration of treatment. A retrospective study of APCC use as first-line therapy in patients with acquired hemophilia has shown an overall complete response rate of 86% with a dosing regimen of 75 U/kg every 8-12 hours (median dose number, 10).[35] Concerns regarding the risk of thrombotic adverse effects (including myocardial infarction) with APCC treatment have been raised, particularly among patients with acquired hemophilia, many of whom are elderly, have a malignancy, or are postpartum.[19] However, if doses of APCC do not exceed the manufacturers recommendations, thrombotic adverse effects are infrequent.[19] It should be noted that large doses of APCCs may trigger an anamnestic rise in inhibitor titer because they may contain some FVIII.[10, 35] Being derived from plasma, APCCs do have the potential to transmit infection; however, there has never been a documented case of transmitted bloodborne virus in congenital or acquired hemophilia.[2]

Combination therapy
Patients who do not respond to rFVIIa or APCC can either receive a combination of the 2 agents or undergo immunoadsorption/plasmapheresis (see below).[28] There is emerging evidence that in individuals with alloantibody-related bleeding who do not respond to either APCC or rFVIIa used alone, the combination of APCC with rVIIa may be useful. This combined approach has not been used systematically in acquired inhibitor patients; however, in off-label settings, it has been associated with high morbidity and mortality from thrombogenesis in adults. If combined therapy with APCC or rFVIIa is administered, clinicians should carefully monitor the patient for hypercoagulable complications.

Immunoadsorption or plasmapheresis
Temporary reduction of the inhibitor titer through extracorporeal removal of the autoantibody should be considered in patients with high inhibitor titers and severe hemorrhages and in those who do not respond to rFVIIa or APCC.[1]

Extracorporeal autoantibody removal can be accomplished by using therapeutic plasmapheresis or specific immunoadsorption of immunoglobulins.[1, 36, 37, 38, 39, 40] Unfortunately, no Sepharose columns are currently available in the United States to accomplish this. Immunoadsorption may be particularly useful when a rapid reduction in the inhibitor titer is required.[19] After plasmapheresis or immunoadsorption, FVIII replacement should be initiated to achieve hemostasis.[7]

Eradication of Inhibitor
Guidelines suggest that as soon as the diagnosis of acquired hemophilia is established, elimination of the inhibitor should be attempted by means of immunosuppression (see the image below).[15] Eradicating the inhibitor is important to restore normal hemostasis and minimize the patients risk of bleeding.[15] Patients who achieve complete remission (eradication of the inhibitor) have been shown to have a better outcome in terms of overall survival than patients who do not achieve complete remission.[18]

Eradication of the inhibitor for acquired hemophilia. In patients with mild hemorrhagic symptoms and low levels of inhibitors, immunosuppressive therapy may not be required to eliminate the inhibitor. About 25% of patients will achieve spontaneous remission without immunosuppression.[41] Drug-induced or pregnancy-associated autoantibodies frequently resolve spontaneously, whereas those associated with underlying autoimmune diseases rarely spontaneously resolve. [1] Because patients remain at risk for fatal bleeding until the inhibitor is eradicated, and there are no clinical laboratory features that identify all high-risk patients, all patients should be immunosuppressed as soon as the diagnosis is made.[12]

Steroids/cytotoxic therapy
First-line therapy for eradicating inhibitors usually includes methylprednisolone at a dose of 1 mg/kg/day (or an equivalent dose of prednisone), which results in the abolition of inhibitors in approximately 60-70% of patients.[15, 18] Adding oral cyclophosphamide 50-150 mg/d can increase the response rate to 70-80%.[15, 18] However, the overall survival and disease-free survival are the same for steroids as for steroids plus cytotoxic agents.[15, 18] Cyclophosphamide has also been administered IV at high intermittent doses. In addition, a nonrandomized study reported no difference between treatment with steroids alone and treatment with steroids plus cytotoxic agents.[12] Other cytotoxic agents that have been used

include azathioprine, vincristine, mycophenolate mofetil, and 2-chlorodeoxyadenosine.[7, 13, 42,

43, 44]

Because alkylating agents may cause infertility, alopecia, myelosuppression, and other adverse effects, prednisolone alone or combined with azathioprine may be preferred for patients with acquired hemophilia associated with pregnancy.[15] Response is typically seen in 3-6 weeks, but some patients may not show response for months.[10] Because relapse may occur when immunosuppression is stopped or reduced, premature discontinuance of therapy should be avoided.[7]

Targeted/biologic therapy
Rituximab, an anti-CD20 monoclonal antibody, has shown promising results in eradicating inhibitors in acquired hemophilia.[7, 45, 46, 47, 48] The usual dose is 375 mg/m2 each week for 4 weeks. Most responses are seen within 2 weeks.[7] The current consensus is that rituximab should be considered in patients who are resistant to first-line therapy or who cannot tolerate standard immunosuppressive therapy.[7] Some authors, however, have proposed that rituximab should be included as first-line therapy in combination with prednisone for patients whose inhibitor titers are higher than 5 but lower than 30 BU and in combination with prednisone and cyclophosphamide for patients whose titers are higher than 30.[47, 7] At present, there are no results from randomized controlled trials to confirm the usefulness of rituximab as a first-line or salvage therapy for acquired hemophilia.

Cyclosporine
Cyclosporine has been used as salvage therapy alone or with prednisolone, but it is particularly effective in patients with underlying systemic lupus erythematosus.[7] Because of cyclosporines toxicities and adverse effects, serum levels should be monitored. Successful treatment with cyclosporine can usually be discontinued after 1 year of therapy.

Intravenous immunoglobulin
Intravenous immunoglobulin (IVIG) may be useful as a second-line therapy for patients who do not initially respond to immunosuppression.[7] However, a large retrospective study showed no benefit when high-dose IVIG was added to prednisolone or cytotoxic agents.[15] Another study reported that adding IVIG to immunosuppressive regimens does not affect rates of complete remission and survival.[12] This should be reserved as first-line treatment for those with low antibody titers.

Immune tolerance induction

Immune tolerance induction regimens involving immunosuppression and immunoadsorption (eg, the modified Bonn-Malm regimen) also have been shown to rapidly eradicate autoantibody inhibitors.[28, 49] In one study, 35 patients with acquired hemophilia and severe bleeding were treated with a combination of cyclophosphamide, prednisolone, large volume immunoadsorption, IVIG, and

FVIII, and treatment appeared to achieve rapid remission in the vast majority of patients.[49] This approach is a potentially useful treatment option for those with severe bleeding.

Surgical Control of Acute Hemorrhage

Surgical management may be required to help some patients with acquired hemophilia survive acute life-threatening bleeding episodes.[50] Techniques that may help stop these hemorrhages are classified as mechanical, thermal, or chemical.[50] Mechanical procedures that close a bleeding point or prevent blood from entering the area of disruption by ligature placement or selective embolization may be useful.[50] Heat (eg, electrocautery) can denature protein and result in coagulation of bleeding tissue, while cryotherapy may cause dehydration and denaturation of lipid molecules and facilitate the cessation of bleeding.[50] Some chemical agents possess hygroscopic properties that increase their bulk and aid in plugging disrupted blood vessels.[50] Certain chemical agents, such as micronized collagen, may also minimize blood loss by serving as hemostatic agents.[50] Anti-inhibitor coagulant complex (FEIBA) has been demonstrated in small studies to provide adequate hemostasis to permit surgery in patients with acquired inhibitors.[51]

Special Treatment Concerns

The advanced age of patients with acquired hemophilia and the presence of comorbid conditions may preclude the most aggressive treatments and necessitate dose reductions (eg, steroids in diabetes), which may lead to a lower response rate and, thus, a decreased survival rate.[1] Immunosuppressive agents are associated with multiple adverse effects, particularly in elderly persons, the age group in which acquired hemophilia is most common.[18] Common adverse effects include cytopenia, alopecia, toxic hepatitis, and severe bacterial infections.[18] In a recent analysis of 172 patients with acquired hemophilia, about half of the cohort experienced morbidity unrelated to bleeding (usually due to the adverse effects of immunosuppression).[12] Nonetheless, patients who receive immunotherapy typically do better than patients who do not.[18] Careful selection and close monitoring of immunosuppressive therapy is critical. Although cyclophosphamide may enhance inhibitor eradication, it is associated with severe adverse effects, especially in elderly persons. In fact, a substantial proportion of patients die as a result of complications associated with this agent, primarily neutropenia-related infections.[18, 12] In patients with acquired hemophilia and an underlying malignancy, the primary malignancy should be treated because it is easier to eradicate the antibody when the tumor is controlled.[18, 52] Moreover, the presence of a malignancy is not a contraindication to the use of immunosuppression to eradicate the antibody, even in cases that do not respond to treatment

of the tumor. However, the decision to initiate immunosuppressive therapy should take into account other factors (eg, patient age, malignancy type, and bleeding severity). Severe bleeding can occur from trivial injuries, intramuscular injections, intra-arterial blood sampling, and invasive procedures, all of which should be prevented.[18] To minimize the risk of bleeding in patients with acquired hemophilia, it is important to avoid situations that may place patients at high risk for bleeding, at least until they are in remission.

Consultations and Further Care

Because acquired hemophilia can be difficult to diagnose and causes significant morbidity and mortality, it may be prudent to refer patients in whom acquired hemophilia is suggested to a center that has laboratory and clinical experience in the disorder, as well as the necessary pharmacy and blood bank support.[19, 7] Hospitalizing patients with internal bleeding or with uncontrollable bleeding is advised. Constant clinical evaluation to ensure adequacy of treatment, pain relief, and other supportive care is necessary. The hematologist must be centrally involved to coordinate care. Because relapse has been reported in approximately 1 in 5 patients after immunosuppressive therapy is discontinued, long-term follow-up of patients with acquired hemophilia is recommended.[12]

Medication Summary
Drugs that disturb platelet function, including aspirin and nonsteroidal anti-inflammatory agents (NSAIDs), and any herbal medications that can precipitate bleeding should be avoided until the inhibitor is eradicated. Medications used to treat acquired hemophilia include antihemophilic agents, corticosteroids, immunosuppressive agents, and monoclonal antibodies (mAbs).

Antihemophilic Agent; Blood Product Or Recombinant Dna Derivative

Class Summary
Recombinant products are recommended to manage bleeding in acquired hemophilia. View full drug information

Antihemophilic factor (Advate, Alphanate, Helixate FS, Hemofil M, HumateP, Koate-DVI, Kogenate FS, Monarc-M, Monoclate-P, Recombinate, ReFacto)

Factor VIII (FVIII) is a protein in normal plasma that is necessary for clot formation and hemostasis. It activates factor X (FX) in conjunction with activated factor IX (FIX); activated FX converts prothrombin to thrombin, which converts fibrinogen to fibrin, which, with factor XIII (FXIII), forms a stable clot. View full drug information

Recombinant factor VIIa (NovoSeven, NiaStase)

Recombinant factor VII (rVIIa) is indicated to treat bleeding episodes in patients with hemophilia A or B and inhibitors. It promotes hemostasis by activating the extrinsic pathway of the coagulation cascade, forming complexes with tissue factor, and promoting activation of FX to factor Xa, FIX to factor IXa, and factor II (FII) to factor IIa. rVIIa is indicated for treatment of bleeding episodes and for prevention of bleeding in surgical interventions or invasive procedures in patients with acquired hemophilia.

Antihemophilic Agent, Hemostatic Agent, Vasopressin Analog, Synthetic

Class Summary
This agent is used to control bleeding in mild acquired hemophilia. View full drug information

Desmopressin (DDAVP, Stimate)

Main effect is enhancement of water reabsorption in the kidney and smooth muscle constriction. Causes dose-dependent increase in plasma FVIII and plasminogen activator.

Antihemophilic Agents
Class Summary
Antihemophilic agents are used for FVIII replacement therapy in patients with acquired hemophilia A. Appropriate monitoring is needed to manage active bleeding and to monitor and manage any allergic reactions that may develop during the infusion. View full drug information

Anti-inhibitor coagulant complex (Feiba VH)

Anti-inhibitor coagulant complex is used in patients with FVIII inhibitors. It can temporarily correct the coagulation defect of patients with inhibitors to FVIII; it is generally used in patients with inhibitor titers of 5 BU/mL or higher. The dose depends on patient weight, hemorrhage severity, inhibitor titer, and in vivo effect. The clinical effect on bleeding is the most important determinant of the dose and frequency of therapy. When inhibitors are present, dosage requirements are extremely variable and are determined by clinical response.

Corticosteroids
Class Summary
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They also modify the bodys immune response to diverse stimuli. View full drug information

Prednisolone (Delta-Cortef, Pediapred, Prelone)

Prednisolone is a delta 1-derivative of the naturally occurring adrenocortical steroids. It suppresses key components of the immune system.

Immunosuppressive Agents
Class Summary
Patients with autoimmune reactions, such as the development of inhibitors, often benefit from immunosuppression. View full drug information

Cyclophosphamide (Neosar, Cytoxan)

Cyclophosphamide is chemically related to nitrogen mustards. It is an alkylating agent; the mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with the growth of normal and neoplastic cells. Cyclophosphamide may also be administered intravenously (IV) at doses up to 750 mg/m2 q3-4wk. View full drug information

Cyclosporine (Neoral, Sandimmune, Gengraf)

Cyclosporine may control autoimmune enteropathy; it functions to downregulate T-cell activation

Monoclonal Antibodies
Class Summary
Rituximab (anti-CD-20) monoclonal antibody binds to pre-B cells and mature B cells. It results in lymphocytotoxic effects to B cells, which should result in reduced autoantibody production. There are a small number of reports suggesting that immunosuppressed individuals receiving rituximab may be susceptible to developing progressive multifocal encephalopathy. Low leukocyte counts may also occur. View full drug information

Rituximab (Rituxan)

Rituximab is a genetically engineered chimeric murine/human mAb directed against the CD20 antigen found on surface of normal and malignant B lymphocytes. It is an immunoglobulin G1 (IgG1) kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences.