Practice Essentials
Acquired hemophilia is a rare but potentially life-threatening bleeding disorder caused by the development of autoantibodies (inhibitors) directed against plasma coagulation factors, most frequently factor VIII (FVIII). [1] Acquired hemophilia can arise in the context of a variety of disorders, including autoimmune diseases and malignancies, or be due to medications, but approximately half of cases are idiopathic. Most cases occur in elderly persons, but acquired hemophilia is also seen in pregnancy and post partum, and in children. [2]
Signs and symptoms
Patients with acquired hemophilia may have no bleeding, mild bleeds, or life-threatening bleeds. [3] Most patients present with hemorrhage into the skin, muscles, or soft tissues and mucous membranes. Intra-articular bleeding episodes are uncommon. Life-threatening bleeds often involve the colon or small intestine.
Diagnosis
Laboratory study results in acquired hemophilia are as follows:
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The activated partial thromboplastin time (aPTT) typically shows a prolongation that is not reversed on a correction study
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The bleeding time, prothrombin time (PT), and platelet count are normal
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Reduced FVIII levels and evidence of an FVIII inhibitor are critical to the diagnosis of acquired hemophilia A
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Other factor levels should be determined to establish inhibitor specificity
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Once the acquired inhibitor is detected, quantification of the level may may be useful in selecting hemostatic therapy in patients who require it
Testing to exclude lupus anticoagulant (eg, dilute Russell viper venom time and the kaolin clotting time) is indicated if aPTT values during the mixing study are similar at time 0 and after incubation at 37°C. Special testing is done if patients are already on heparin, to exclude its effect on PTT values.
Management
Therapeutic options in acquired hemophilia include the following:
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Treatment of the underlying disorder or discontinuation of an offending drug may eliminate or assist in the eradication of the inhibitor
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Clinically relevant bleeding can be treated with recombinant FVIII porcine sequence (rpFVIII), if the baseline anti-porcine FVIII inhibitor titer is ≤ 20 BU; recombinant activated factor VII (rFVIIa); or activated prothrombin complex concentrate (APCC). The choice is determined by the agents' availability and cost, and—for rpFVIII—baseline anti-porcine FVIII inhibitor titer and ability to monitor rpFVIII.
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If the patient has a low FVIII inhibitor level (< 5 BU) and other options are not available, human FVIII concentrates may be used to control bleeding; however, no dosing guides are available and massive doses may be required.
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Hemostatic prophylaxis is indicated for patients at high risk of bleeding and for invasive procedures (both minor and major); if possible, invasive procedures should be delayed until the inhibitor has been eradicated. Prophylaxis can be with rpFVIII, rFVIIa, APCC, or emicizumab (off label).
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Eradication of the inhibitor with immunosuppression should be initiated as soon as the diagnosis of acquired hemophilia is established.
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First-line therapy for inhibitor eradication is with corticosteroids alone or combined with rituximab or cyclophosphamide.
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Salvage therapy with cyclosporine is particularly effective in patients with underlying systemic lupus erythematosus.
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, 4] Autoantibodies against other factor proteins have also been reported. [1] 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:
Pathophysiology
Acquired hemophilia is a spontaneous autoimmune disorder in which patients with previously normal hemostasis develop autoantibodies against clotting factors, most frequently FVIII. [5] 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 factors—factors II (FII), V (FV), VII (FVII), X (FX), XI (FXI), and XIII (FXIII), as well as von Willebrand factor (vWF)—is extremely rare. [5, 6, 7]
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. [6, 8, 9]
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. [10]
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. [11] 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. [11, 12]
Etiology
Acquired hemophilia results from the development of autoantibodies (mostly of immunoglobulin G [IgG] subclasses 1 and 4) directed against clotting factors. [6, 7, 11] Numerous conditions have been associated with acquired inhibitors to FVIII. Rarely, FVIII autoantibodies arise as idiosyncratic reactions to medications. However, approximately 50% of cases are idiopathic, arising in the absence of relevant concomitant diseases or medication use. [1, 13]
The following conditions may be associated with acquired hemophilia A [1] :
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Autoimmune disorders
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Inflammatory bowel disease, ulcerative colitis
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Dermatologic disorders (eg, psoriasis, pemphigus)
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Respiratory diseases (eg, asthma, chronic obstructive pulmonary disease)
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Allergic drug reactions
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Hematologic malignancies
Autoimmune disorders may include the following:
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Autoimmune hemolytic anemia
Allergic drug reactions may occur from the following [14, 15] :
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Clopidogrel
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Alemtuzumab
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Omalizumab
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Penicillin and its derivatives
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Sulfamides
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Phenytoin
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Chloramphenicol
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Methyldopa
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Depot thioxanthene
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Interferon alfa
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Fludarabine
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Bacille Calmette-Guérin (BCG) vaccination
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Desvenlafaxine [16]
Hematologic malignancies may include the following:
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Chronic lymphocytic leukemia
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Non-Hodgkin lymphoma
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Multiple myeloma
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Waldenström macroglobulinemia
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Myelodysplastic syndrome
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Myelofibrosis
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Erythroleukemia
Underlying diagnoses in 3 cohort studies of acquired hemophilia A are listed in Table 1, below. [17, 18, 19]
Table 1. Underlying Diagnoses in Patients with Acquired Hemophilia A. (Open Table in a new window)
Disease Association |
Green 1981 (N = 215), % |
Morrison 1993 (N = 65), % |
Collins 2007 (N = 172), % |
Idiopathic |
46.1 |
55.0* |
63.3 |
Collagen, vascular, and other autoimmune diseases |
18.0 |
17.0 |
16.7 |
Malignancy |
6.7 |
12.0 |
14.7 |
Skin diseases |
4.5 |
2.0 |
3.3 |
Possible drug reaction |
5.6 |
3.0 |
NR |
Pregnancy |
7.3 |
11.0 |
2.0 |
Other |
11.8 |
NR |
NR |
*In this trial, idiopathic and other were combined. NR—not reported. |
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Disorders believed to be associated with inhibitors to coagulation factors other than FVIII are shown in Table 2, below. [7, 20]
Table 2. Acquired Bleeding Disorders Associated With Inhibitors of Factors Other Than FVIII (Open Table in a new window)
Coagulation Factor Inhibited |
Most Commonly Associated Disorders |
Treatment |
V |
Lymphoproliferative disorders, adenocarcinoma, tuberculosis, aminoglycosides, topical thrombin |
FFP, rFVIIa |
IX |
Systemic lupus erythematosus, acute rheumatic fever, hepatitis, collagen vascular diseases, multiple sclerosis, postprostatectomy, and postpartum |
FIX concentrates, APCCs, rFVIIa, corticosteroids |
XI |
Autoimmune diseases, prostate carcinoma, chronic lymphocytic leukemia, chlorpromazine |
FFP, FXI concentrates, rFVIIa, tranexamic acid, fibrin glue |
XIII |
Idiopathic, isoniazid, penicillin |
FXIII concentrate, FFP, stored plasma, cryoprecipitate |
VWF‡ |
Autoimmune disorders, monoclonal gammopathies, lymphoproliferative diseases, epidermoid malignancies, hypothyroidism, myeloproliferative disorders, and certain medications |
Desmopressin, infusion of FVIII that contains vWF, IVIG, plasma exchange |
II |
Topical thrombin, idiopathic, autoimmune diseases, procainamide |
APCC, FFP |
VII |
Bronchogenic carcinoma, idiopathic |
FIX concentrates, APCC, FVIII concentrates, rFVIIa, fibrin glue, tranexamic acid |
X |
Amyloidosis, carcinoma, acute nonlymphocytic leukemia, acute respiratory infections, fungicide exposure, idiopathic |
APCC, tranexamic acid, fibrin glue, FFP |
APCC—activated prothrombin complex concentrate; FFP—fresh frozen plasma; IVIG—intravenous immunoglobulin; vWF—von Willebrand factor. |
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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. [17]
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, 7] The vast majority cases of acquired hemophilia occur in older adults. The median age at presentation is from 60 to 67 years. [7, 10, 13]
Acquired hemophilia has no known genetic inheritance pattern and is seen equally in men and women. [10] 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. [10] 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. [10] Other manifestations include prolonged postpartum bleeding, excessive bleeding following surgery or trauma, and, occasionally, cerebral hemorrhage. [1, 21]
In general, the prognosis of patients with acquired hemophilia depends on the patient’s response to immunosuppression. [1, 17, 22]
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). [17, 22] 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 after delivery or stopping the drug responsible. [1] In contrast, patients with associated autoimmune disorders usually have high-titer 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. [22] 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.
In the United Kingdom, 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. [17] 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. [23]
Tiede et al studied neutralizing autoantibodies against FVIII in acquired hemophilia and found that anti-FVIII IgA autoantibodies are predictors of poor outcome. Partial remission rates were similar in patients with and without anti-FVIII IgA autoantibodies, but IgA-positive patients had a higher risk of recurrence. Consequently, IgA-positive patients were less likely to achieve complete remission (adjusted hazard ratio [ahR] 0.35, 95% confidence interval [CI] 0.18-0.68, p< 0.01) and had a higher risk of death (aHR 2.62, 95% CI 1.11-6.22, p< 0.05). [24]
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. [17]
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. [22]
-
Acquired Hemophilia. Clinical presentation of acquired hemophilia.
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Acquired Hemophilia. 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.
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Acquired Hemophilia. Workup for acquired hemophilia.
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Acquired Hemophilia. Management of bleeding in acquired hemophilia.
Tables
Disease Association |
Green 1981 (N = 215), % |
Morrison 1993 (N = 65), % |
Collins 2007 (N = 172), % |
Idiopathic |
46.1 |
55.0* |
63.3 |
Collagen, vascular, and other autoimmune diseases |
18.0 |
17.0 |
16.7 |
Malignancy |
6.7 |
12.0 |
14.7 |
Skin diseases |
4.5 |
2.0 |
3.3 |
Possible drug reaction |
5.6 |
3.0 |
NR |
Pregnancy |
7.3 |
11.0 |
2.0 |
Other |
11.8 |
NR |
NR |
*In this trial, idiopathic and other were combined. NR—not reported. |
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Coagulation Factor Inhibited |
Most Commonly Associated Disorders |
Treatment |
V |
Lymphoproliferative disorders, adenocarcinoma, tuberculosis, aminoglycosides, topical thrombin |
FFP, rFVIIa |
IX |
Systemic lupus erythematosus, acute rheumatic fever, hepatitis, collagen vascular diseases, multiple sclerosis, postprostatectomy, and postpartum |
FIX concentrates, APCCs, rFVIIa, corticosteroids |
XI |
Autoimmune diseases, prostate carcinoma, chronic lymphocytic leukemia, chlorpromazine |
FFP, FXI concentrates, rFVIIa, tranexamic acid, fibrin glue |
XIII |
Idiopathic, isoniazid, penicillin |
FXIII concentrate, FFP, stored plasma, cryoprecipitate |
VWF‡ |
Autoimmune disorders, monoclonal gammopathies, lymphoproliferative diseases, epidermoid malignancies, hypothyroidism, myeloproliferative disorders, and certain medications |
Desmopressin, infusion of FVIII that contains vWF, IVIG, plasma exchange |
II |
Topical thrombin, idiopathic, autoimmune diseases, procainamide |
APCC, FFP |
VII |
Bronchogenic carcinoma, idiopathic |
FIX concentrates, APCC, FVIII concentrates, rFVIIa, fibrin glue, tranexamic acid |
X |
Amyloidosis, carcinoma, acute nonlymphocytic leukemia, acute respiratory infections, fungicide exposure, idiopathic |
APCC, tranexamic acid, fibrin glue, FFP |
APCC—activated prothrombin complex concentrate; FFP—fresh frozen plasma; IVIG—intravenous immunoglobulin; vWF—von Willebrand factor. |
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