Acquired Hemophilia

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 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.^{[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]}

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, 12]}
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
• Sjögren syndrome
• Autoimmune hemolytic anemia
• Goodpasture syndrome
• Myasthenia gravis
• Graves disease
• Autoimmune hypothyroidism

Allergic drug reactions may include the following:

• Penicillin and its derivatives
• Sulfamides
• Phenytoin
• Chloramphenicol
• Methyldopa
• Depot thioxanthene
• Interferon alfa
• Fludarabine
• Bacille Calmette-Guérin (BCG) vaccination

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, 10, 13, 14, 15]} (Open Table in a new window)
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)

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.^[10]
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, 12, 4]}
Acquired hemophilia has no known genetic inheritance pattern and is seen equally in men and women.^[7] It occurs in all racial groups.

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, 11]}
In general, the prognosis of patients with acquired hemophilia depends on the patient’s response to immunosuppression.^{[1, 22, 10]}
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).^{[22, 10]} 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 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.
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.^[10] 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]

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.^[10]
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]