AUTHOR AND EDITOR INFORMATION

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• MEDICATION
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INTRODUCTION

Section 2 of 11  

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• Introduction
• CLINICAL
• DIFFERENTIALS
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• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

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 Autoantibody inhibitors against factor II, factor V, factor VII, factor IX, factor X, factor XI, factor XIII, and von Willebrand 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 because of its rarity and because the patient does not have the usual precedent personal or family history of bleeding episodes seen in congenital hemophilia.¹ Moreover, the clinical signs and symptoms of acquired hemophilia differ from those of hereditary hemophilia. Its severity at clinical presentation can also make managing acquired hemophilia challenging.

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 autoantibodies is less common, and the presence of autoantibodies against other clotting factors (II, V, VII, X, XI, XIII, and von Willebrand factor) 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 von Willebrand factor protein, while anti-A2 and anti-A3 antibodies impede the binding of FVIII to activated factors X and IX of the intrinsic pathway factor X 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 result in some level of residual FVIII, which can be detected in the laboratory but does not seem to convey useful clinical efficacy.^{8, 9}

Frequency

United States

• 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 FVIII is unknown, although it is significantly lower than that reported with acquired hemophilia A.

International

• 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.¹⁰
• There is no known association between an increased susceptibility to develop acquired autoantibodies to coagulation factors and ethnicity.

Mortality/Morbidity

• Due to its frequent confusion with other life-threatening conditions (eg, disseminated intravascular coagulation) and its occurrence in a typically 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, 11}

Race

• Acquired hemophilia occurs in all racial groups.

Sex

• Acquired hemophilia has no known genetic inheritance pattern and is seen equally in men and women.⁷

Age

• The vast majority cases of acquired hemophilia occur in older adults. The median age at presentation is between 60 and 67 years.^{7, 12, 4}
• 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}

CLINICAL

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• CLINICAL
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History

• Unlike patients with hereditary hemophilia, patients with acquired hemophilia do not have a personal or family history of bleeding episodes (see Media file 1).¹
• About half the cases are associated with other conditions, such as pregnancy, autoimmune disease, and cancer.^{1, 12} The other cases are often idiopathic.

Physical

• The clinical picture of acquired hemophilia differs from that of hereditary hemophilia.
• • Intra-articular bleeding episodes, which are typical in congenital 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. Media file 2 shows the percentage of patients who experienced various types of bleeding in a cohort of patients with acquired hemophilia (N = 172).¹⁰
  • 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 and urological 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 following attempts to insert intravenous lines.
• Prolonged postpartum bleeding, excessive bleeding following trauma or surgery, and, occasionally, cerebral hemorrhage may also occur.¹

Causes

Acquired hemophilia results from the development of autoantibodies (mostly of the IgG₁ and IgG₄ subclasses) directed against clotting factors.^{2, 8, 4} Numerous conditions have been associated with acquired inhibitors to FVIII (see the list below). These include pregnancy, autoimmune disorders, inflammatory bowel disease, dermatologic disorders, respiratory diseases, diabetes, acute hepatitis B and hepatitis C infection, and malignancies (both solid tumors and hematologic malignancies).¹

Rarely, FVIII autoantibodies arise as idiosyncratic reactions to medications such as penicillin, sulfonamides, phenytoin, methyldopa, chloramphenicol, interferon alpha, and others (see the list of associated conditions below). However, approximately 50% of cases of acquired hemophilia A occur in patients who lack relevant concomitant diseases; these cases are idiopathic in nature.^{1, 12} Table 1 illustrates the frequency of underlying diagnoses in 3 cohort studies of patients with acquired hemophilia A.^{13, 14, 10} Disorders believed to be associated with inhibitors to coagulation factors other than FVIII are shown in Table 2.

Conditions associated with acquired hemophilia A 

(Information adapted from Franchini M, Gandini G, Di Paolantonio T, Mariani G. Acquired hemophilia A: a concise review. Am J Hematol. Sep 2005;80(1):55-63. Used with permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons, Inc.)¹ 

• Idiopathic
• Pregnancy
• Autoimmune disorders 
• • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Multiple sclerosis
  • Temporal arteritis
  • Sjögren syndrome
  • Autoimmune hemolytic anemia
  • Goodpasture syndrome
  • Myasthenia gravis
  • Graves disease
  • Autoimmune hypothyroidism
• Inflammatory bowel disease 
• • Ulcerative colitis
• Dermatologic disorders
• • Psoriasis
  • Pemphigus
• Respiratory diseases
• • Asthma
  • Chronic obstructive pulmonary disease
• Allergic drug reactions
• • Penicillin and its derivatives
  • Sulfamides
  • Phenytoin
  • Chloramphenicol
  • Methyldopa
  • Depot thioxanthene
  • Interferon-alfa
  • Fludarabine
  • Bacille Calmette-Guérin (BCG) vaccination
• 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  
• • Chronic lymphocytic leukemia
  • Non-Hodgkin lymphoma
  • Multiple myeloma
  • Waldenstrom macroglobulinemia
  • Myelodysplastic syndrome
  • Myelofibrosis
  • Erythroleukemia

Table 2. Acquired Factor Inhibitor-Associated Bleeding Disorders Other Than FVIII^{4, 16}

*FFP = fresh frozen plasma

^†APCC = activated prothrombin complex concentrate

‡VWF = von Willebrand factor

DIFFERENTIALS

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Other Problems to Be Considered

Lupus anticoagulant
von Willebrand disease
Disseminated intravascular coagulation
Dysfibrinogenemia
Heparin administration
Congenital hemophilia

WORKUP

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Lab Studies

An isolated prolongation of the activated partial thromboplastin time (aPTT) that is not corrected when the patient's plasma is incubated with equal volumes of normal plasma in a mixing study is a key component of the diagnosis of acquired hemophilia (see Media file 3).^{1, 4}

• Because the action of the inhibitor is often delayed, incubation for 2 hours is required before the correction study is initiated.¹⁷
• Bleeding times, prothrombin times, and platelet counts are normal.
• Reduced factor VIII levels and evidence of a factor VIII inhibitor are critical to the diagnosis of acquired hemophilia A. Although acquired hemophilia A is a rare condition, FVIII inhibitors in very low concentrations and not typically detected in coagulation assays are often detected in healthy individuals with normal FVIII levels and no bleeding symptoms or history.¹⁷ One study reported that a FVIII-neutralizing antibody was in 17% of healthy blood donors, usually in multiparous females.¹⁸
• Acquired hemophilia can occasionally be confused with disseminated intravascular coagulation because of a prolonged aPTT; however, the prolonged prothrombin time and low fibrinogen, elevated fibrin degradation products and D-dimers, and thrombocytopenia⁷ should distinguish between the 2 bleeding conditions quite readily.  Consequently, the presence of an isolated prolonged aPTT is a particularly important characteristic of acquired hemophilia.
• Isolated prolongation of the aPTT may occur for a variety of reasons. For example, decreases in factors VIII, IX, XI, XII, high molecular weight kininogen or prekallikrein, or the presence of anticoagulants, such as lupus anticoagulant or clotting factor inhibitors, may also cause isolated prolongation of aPTT.² The clinician must determine whether the isolated aPTT results from the presence of a lupus anticoagulant or a circulating inhibitor or reflects a true quantitative deficiency of coagulation factor activity in plasma.⁴
• Because the most common cause of isolated prolonged aPTT is lupus anticoagulant,¹⁹ it is essential to consider the presence of a lupus anticoagulant in patients with prolonged aPTT (see Media file 3).
• • The presence of lupus anticoagulant is suggested when aPTT values during the mixing study are similar at time 0 and after incubation at 37 degrees Centigrade.⁸ Lupus anticoagulant can then be confirmed by specific tests, such as the dilute Russell viper venom time and the kaolin clotting time.^{20, 21, 8}
  • However, finding lupus anticoagulant in patients with acquired inhibitors may occur but is uncommon in most situations.¹⁷
• The presence of heparin also must be excluded (see Media file 3).⁸
• • Heparin may be identified by conducting a clinical history and medication sheets and the presence of heparin as a contaminant confounding coagulation assays can be determined specifically by treating the plasma to remove heparin using a heparin-absorbing resin or heparin-cleaving enzyme prior to assay.²
  • The presence of heparin is suggested by a prolonged thrombin time in association with a normal reptilase time.⁸
• The levels of other intrinsic pathway factors (eg, factors IX, XI, and XII) may be reduced in patients with acquired hemophilia A.^{17, 12} Therefore, it is important to repeat factor assays using increasing dilutions of patient plasma to establish the specificity of the inhibitor (see Media file 3).²² Once detected, the acquired inhibitor should be quantified to project the severity of the disorder and the risk of hemorrhagic complications. A specific inhibitor can be confirmed and quantified using specific assays of the factor and the inhibitor.^{23, 8}
• • The methods used for quantifying factor VIII inhibitors are the Bethesda assay and the Nijmegen modification of the Bethesda assay.
  • One Bethesda unit (BU) is the quantity of inhibitor that inactivates 50% of factor VIII in normal plasma after incubation at 37ºC for 2 hours.
  • Both the Bethesda assay and the Nijmegen modification may underestimate the potency of the inhibitor due to its nonlinear complex reaction kinetics.²² As a result of its kinetic profile, the recovery and half-life of exogenous FVIII may be considerably reduced, even in patients with low inhibitor titers.¹⁴
• Searching for inhibitors for porcine FVIII concentrate is not recommended because the porcine FVIII formulation is not currently available.⁸ Clinical studies are being planned to examine the safety and efficacy of recombinant porcine FVIII concentrates in autoantibody inhibitors in acquired hemophilia A. According to a December 2007 abstract from the American Society of Hematology, recombinant porcine FVIII concentrate is being used in a phase 2 trial in patients with hemophilia A and alloantibodies.²⁴

Imaging Studies

• MRI, CT scan, and ultrasound may be needed to localize, quantify, and serially monitor the location and response of bleeding.
• Other imaging tests can be used as needed to diagnose associated diseases.

Other Tests

Testing patients with pregnancy-associated acquired hemophilia for autoimmune disorders such as lupus and rheumatoid arthritis is recommended because the presence of an autoimmune disorder may require a change in therapeutic approach.²²

TREATMENT

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Medical Care

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. 

Treatment of bleeding

Mild bleeding symptoms

• A recent 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.¹⁰
• Consequently, whether or not 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.

Moderate or severe bleeding, FVIII titer less than 5 BU

• Due to the variable kinetics of acquired antibodies, the required dose of FVIII concentrates can only be predicted roughly from the inhibitor titer.
• Some clinicians double or triple the dose of FVIII that should be given to patients with congenital hemophilia of the same weight.^{22, 26}
• A dose of FVIII 200 IU/kg IV bolus every 8-12 hours has been recommended.²⁷
• There are no published studies on the use of human FVIII in acquired hemophilia to guide its dosing.¹⁷

• In healthy individuals, IV infusion of desmopressin (0.3 mcg/kg) may result in a 2- to 3-fold temporary increase in FVIII and von Willebrand factor plasma levels.²²
• However, in most patients with acquired FVIII inhibitors, desmopressin treatment alone will not provide hemostasis.⁷

Moderate to severe bleeding, FVIII titer 5 BU or greater

Recombinant factor VIIa

• Recommended dosing is 90-120 mg/kg every 2-3 hours IV bolus until bleeding is stopped.⁷
• If no response is seen after 2 doses, 120-270 mg/kg every 2.5-3 hours IV bolus should be administered.²⁷
• Minor bleeding episodes are usually treated with 2 or 3 doses, but several days of treatment may be required for major bleeding episodes.²²
• Patients who do not respond within 24 hours are unlikely to respond if rFVIIa treatment is continued.²⁹

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.²⁹ 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).³⁰

rFVIIa is well tolerated and has few side effects.²² Advantages include the following:

• 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.
• Reports of arterial and venous thrombosis with the use of rVIIa have been published.^{7, 31} Treatment with rFVIIa concentrate was associated with venous thromboembolism in a review of data from the Food and Drug Administration's (FDA's) Adverse Event Reporting System (AERS).³² However, most reported thromboembolic events followed the use of rFVIIa for off-label indications and not for people with hemophilia with inhibitors. The thrombogenicity of any agent used to treat bleeding may be of particular concern in older individuals.

Activated prothrombin complex concentrate

• The recommended dose for anti-inhibitor coagulant complex is 50-100 IU/kg/d every 8-12 hours IV bolus.²⁷ Doses 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 (with a median number of 10 doses).³³ Concerns regarding the risk of thrombotic side 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.¹⁷ However, if doses of APCC do not exceed the manufacturers' recommendations, thrombotic side effects are infrequent.¹⁷

Immunoadsorption/plasmapheresis

Eradication of the inhibitor

• About 25% of patients will achieve spontaneous remission without immunosuppression.³⁹
• 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.¹⁰

Steroids/cytotoxic therapy

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 may not show response for months.¹² Because relapse may occur when immunosuppression is stopped or reduced, the premature discontinuation of therapy should be avoided.⁷  

• The usual dose is 375 mg/m² each week for 4 weeks. Most responses are seen within 2 weeks.⁷

Cyclosporine

Immunoglobulin

Immune tolerance induction

Treatment for other types of acquired inhibitors

Surgical Care

Surgical management may be required to help some patients with acquired hemophilia survive acute life-threatening bleeding episodes.⁴⁸ Techniques that may help stop these hemorrhages are classified as mechanical, thermal, or chemical.⁴⁸

• 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.⁴⁸
• 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.⁴⁸
• Some chemical agents possess hygroscopic properties that increase their bulk and aid in plugging disrupted blood vessels.⁴⁸ Certain chemical agents, such as micronized collagen, may also minimize blood loss by serving as hemostatic agents.⁴⁸

Consultations

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.^{17, 7}

Activity

• 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.

MEDICATION

Section 7 of 11  

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• Introduction
• CLINICAL
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• MISCELLANEOUS
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• References

Drug Category: Antihemophilic agent; blood product or recombinant DNA derivative

Recombinant products are recommended to manage bleeding in acquired hemophilia.

Drug Category: Antihemophilic agent, hemostatic agent, vasopressin analog, synthetic­

This agent is used to control bleeding in mild acquired hemophilia.

Drug Category: Antihemophilic agents

These 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.

Drug Category: Corticosteroids

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They also modify the body’s immune response to diverse stimuli.