Acquired hemophilia is a rare autoimmune disorder characterized by bleeding that occurs in patients with a personal and family history negative for hemorrhages.
In acquired hemophilia, the body produces antibodies [also known as inhibitors] that attack clotting factors, most often factor VIII.
The affected individuals develop complications associated with abnormal, uncontrolled bleeding into the muscles, skin and soft tissue and during surgery or following trauma.
Autoantibodies against other factors have also been reported.
Acquired hemophilia is a rare disorder.
The incidence of acquired hemophilia A is 0.2-1.5 case per 1 million persons per year,
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. The vast majority cases of acquired hemophilia occur in older adults.
Acquired hemophilia has no known genetic inheritance pattern and is seen equally in men and women across all races.
Pathophysiology of Acquired Hemophilia
The immune system normally responds to a foreign substance by producing specialized proteins called antibodies.
When antibodies target healthy tissue they may be referred to as autoantibodies.
A triggering event such as an infection or underlying disorder may induce the immune system to produce autoantibodies.
Autoantibodies in acquired hemophilia are termed inhibitors because they inhibit the function of the affected clotting factor.
In approximately 50% of the patients, no underlying disorder or triggering event can be identified (idiopathic). The remaining 50% have coexisting conditions [see below]
The development of autoantibodies against factor VIII leads to factor VIII deficiency, which results in insufficient generation of thrombin by factor IXa and the factor VIIIa complex through the intrinsic pathway of the coagulation cascade.
Though less common autoantibodies are known against factor IX , II, V, VII, X, XI, and XIII, as well as von Willebrand factor.
Causes of Acquired Hemophilia
The following conditions may be associated with acquired hemophilia A
- 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 (eg, psoriasis, pemphigus)
- Respiratory diseases (eg, asthma, chronic obstructive pulmonary disease)
- Allergic drug reactions
- Penicillin and its derivatives
- Sulfamides
- Phenytoin
- Chloramphenicol
- Methyldopa
- Depot thioxanthene
- Interferon alfa
- Fludarabine
- BCG vaccination
- Desvenlafaxine
- Diabetes
- Acute hepatitis B infection
- Acute hepatitis C infection
- Malignancies-solid tumors
- Hematologic malignancies
- Chronic lymphocytic leukemia
- Non-Hodgkin lymphoma
- Multiple myeloma
- Waldenstrom macroglobulinemia
- Myelodysplastic syndrome
- Myelofibrosis
- Erythroleukemia
Clinical Presentation of Acquired Hemophila
Patients with acquired hemophilia do not have a history of bleeding episodes [compare with hereditary hemophilia]. There is no family history of the bleeding disorders as well.
Typical signs of acquired hemophilia include
- Overt bleeding
- Epistaxis
- Gastrointestinal bleeding- melena
- Urologic bleeding – hematuria
- Retroperitoneal hematomas.
Spontaneous bruising and muscle hematomas are most frequent.
Subglottic hemorrhage may threaten the airway.
Iatrogenic bleeding, particularly after attempts to insert intravenous lines could be present. Prolonged postpartum bleeding, excessive bleeding after trauma or surgery, and, occasionally, cerebral hemorrhage may also occur.
Intra-articular bleeding episodes are unusual in patients with acquired hemophilia. Instead, hemorrhages into the skin, muscles, or soft tissues and mucous membranes occur in most patients.
Overall, bleeding episodes are more frequent and severe in patients with acquired hemophilia than in patients with congenital hemophilia.
Differential Diagnoses
- Congenital hemophilia
- Disseminated Intravascular Coagulation
- Dysfibrinogenemia
- Von Willebrand Disease
Diagnostic Work Up
Conduct the following
| If normal, conduct aPTT
|
| If altered, consider other diagnosis
| |
| aPTT | If normal, consider other diagnoses
|
| If prolonged – Repeat aPTT after mixing normal plasma
| |
| Repeat aPTT after mixing with normal plasma | If aPTT corrects, do following assay and quantify Factor VII Factor IX Factor X Factor XI |
| If aPTT does not correct · Screening for heparin · Screening for lupus anticoagulant | |
| Screening for heparin and lupus anticoagulant | If either is positive, then that condition is present and should be treated accordingly |
| If both are negative, go for factor VIII assay and quantification of inhibitors if present |
Other tests
MRI, CT and ultrasonography may be indicated to localize, quantify, and serially monitor the location and response of bleeding.
Treatment of Acquired Hemophilia
Spontaneous remission has been reported especially in postpartum cases and the cases secondary to an allergic drug reaction. Spontaneous remission can also occur in individuals who have low titer inhibitors. The exact percentage of patients that undergo spontaneous resolution is unknown.
The management of acquired hemophilia focuses on the following goals
- Controlling and preventing bleeding if present
- Eradication of the inhibitor
- Ttreatment of the underlying disease (if applicable).
Patients who have mild bleeding episodes may not require hemostatic therapy and immunosuppressive therapy should be initiated as soon possible.
Control of Bleeding
Moderate or Severe Bleeding, Inhibitors < 5 BU
Increasign plasma FVIII levels to 30-50% by infusions of FVIII to patients with low-titer inhibitors may facilitate hemostasis. Patients with very low inhibitor titers (<3 BU) and residual FVIII activity may also benefit from treatment with desmopressin.
Moderate or Severe Bleeding, Inhibitors ≥ 5 BU
In these cases factor VIII concentrates and desmopressin are ineffective.
An agent that bypasses factor VIII, like recombinant factor VIIa (rFVIIa) or an activated prothrombin complex concentrate (APCC) should be used.
Neither of these therapies is effective in all individuals.
Patients who do not respond to rFVIIa or APCC can either receive a combination of the 2 agents or undergo immunoadsorption/plasmapheresis.
After plasmapheresis or immunoadsorption [Selectiveremoval of a desiredcompoundfrom a solution or a mixture,using an antibody or antigenthathasbeenbound to a large,insolublemolecule.], FVIII replacement should be initiated to achieve hemostasis.
Eradication of Inhibitor
This is done by of immunosuppression aims to restore normal hemostasis and minimize the patient’s risk of bleeding.
Therapy for eradicating inhibitors usually includes methylprednisolone alone or with cytotoxic agents like cyclophosphamide, azathioprine, vincristine, mycophenolate mofetil, and 2-chlorodeoxyadenosine.
Immunosuppresants are associated with severe side effects.
Investigational Therapies
Rituximab, a monoclonal antibody has demonstrated promising results in eradicating inhibitors.
High-dose intravenous immunoglobulin has been used to eradicate inhibitors in AH. However, most reports have not shown encouraging results.
Surgical Measures for acute hemorrhage may be required in some cases.
These may involve ligature placement, selective embolization electrocautery or cryotherapy.
Treatment of Underlying Disease
Treatment of underlying condition if feasible should be done. For example, underlying tumor should be treated.
Prognosis
Acquired hemophilia can lead to severe morbidity and even mortality before it is correctly diagnosed. In general, the prognosis of patients with acquired hemophilia depends on the patient’s response to immunosuppression.
References
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