NORD gratefully acknowledges Francesco Baudo, MD, Hematology Department, Ospedale Niguarda, Milan, Italy, for assistance in the preparation of this report.
Acquired hemophilia (AH) is a rare autoimmune disorder characterized by bleeding that occurs in patients with a personal and family history negative for hemorrhages. Autoimmune disorders occur when the body's immune system mistakenly attacks healthy cells or tissue. In AH, the body produces antibodies (known as inhibitors) that attack clotting factors, most often factor VIII. Clotting factors are specialized proteins required for the blood to clot normally. Consequently, affected individuals develop complications associated with abnormal, uncontrolled bleeding into the muscles, skin and soft tissue and during surgery or following trauma. Specific symptoms can include nosebleeds (epistaxis), bruising throughout the body, solid swellings of congealed blood (hematomas), blood in the urine (hematuria) and gastrointestinal or urogenital bleeding. AH can potentially cause severe, life-threatening bleeding complications in severe cases. In approximately 50% of patients, there is an identifiable underlying clinical condition; in the other 50% no cause is known (idiopathic).
AH is different from congenital hemophilia, a group of rare genetic disorders caused by congenital deficiency of certain clotting factors. The main form of hemophilia is hemophilia A (classic hemophilia), which is an X-linked disorder that mostly affects males but can also affect females. It is caused by deficiency or inactivation of factor VIII, the same clotting factor that is affected in most individuals of AH. Although both disorders involve deficiency of the same clotting factor, the bleeding pattern is quite different. The reason the bleeding patterns differ between these disorders is not fully understood.
The symptoms of AH develop because the blood cannot clot properly. Clotting is the process by which blood clumps together to plug the site of a wound. Clotting factors, such as factor VIII, are specialized proteins that are essential for the blood to clot properly.
Although about 1/3 of patients do not require therapy to control bleeds, bleeding severity varies and more than 1/3 of patients had multiple bleeding episodes. Subcutaneous bleeding (ecchymoses) is the most common manifestation of AH followed by muscle bleeding (hematoma), gastrointestinal (melena), genitourinary (hematuria), and retroperitoneal. Intracranial hemorrhage is rare, but can be fatal. In contrast to congenital hemophilia A, joint bleeding is infrequent.
Bleeding often occurs without cause (spontaneously).Bleeding episodes are often severe and can become life-threatening. In some patients, delayed diagnosis and the presence of additional medical issues are often contributing factors to its overall severity Bleeding into the soft tissues can progress rapidly, potentially causing compartmental syndrome, a potentially serious, painful condition characterized by increased pressure on muscles, nerves and blood vessels most often within the arms and legs with damage due to compression of these structures.
Affected Individuals are also at risk of excessive bleeding during surgery or following trauma, even trivial. Genital heavy bleeding in pregnant women may occur especially after childbirth (postpartum period).
AH is an autoimmune disorder. It occurs when the immune system produces antibodies that mistakenly attack healthy tissue, specifically specialized proteins known as clotting factors, most often clotting factor VIII.
The immune system normally responds to a foreign substance by producing specialized proteins called antibodies. Antibodies work by destroying foreign substances directly or by coating them with a substance that marks them for destruction by white blood cells. When antibodies target healthy tissue they may be referred to as autoantibodies. Researchers believe that a triggering event (such as an infection or underlying disorder) may induce the immune system to produce autoantibodies. Autoantibodies in AH are termed inhibitors because they inhibit the function of the affected clotting factor.
AH is predominantly a disease of the elderly. In approximately 50% of the patients, no underlying disorder or triggering event can be identified (idiopathic form). The remaining 50% have coexisting disorders or conditions including autoimmune disorders such as lupus, rheumatoid arthritis, multiple sclerosis, Sjogren syndrome, and temporal arteritis; inflammatory bowel disease or ulcerative colitis; infections; diabetes; hepatitis; respiratory or dermatological diseases; blood (hematological) cancer or certain solid tumors or association with drugs such as penicillin or interferon. Association with pregnancy is reported mainly in the post-partum period.
AH develops in individuals with no previous history of bleeding disorder with approximately equal numbers of males and females affected. In the United States, the disorder is estimated to affect approximately .2-1 individuals per 1,000,000/year in the general population. In the United Kingdom, the disorder is estimated to affect 1.4 per 1,000,000/year. However, affected individuals may go undiagnosed or misdiagnosed, making it difficult to determine the disorder’s true frequency in the general population.
Individuals of any age can be affected, although AH is extremely rare in children. The incidence increases with age and mostly affects elderly individuals (between 60-80 years of age). A small increase in incidence occurs in pregnant woman between the ages of 20-40. AH affects individuals of all ethnic groups and has been reported worldwide. The majority of cases involve deficiency of factor VIII (acquired hemophilia A). A handful of cases have been described that involve deficiency of factor IX (acquired hemophilia B). Although rare, acquired hemophilia involving other clotting factors has also been reported.
AH should be suspected by the clinical picture and confirmed by an abnormal coagulation test. A diagnosis should be considered in patients with a recent onset of abnormal bleeding and an isolated prolongation of the activated partial thromboplastin time (aPTT), especially the elderly and peri- and post-partum women.
Clinical Testing and Work-Up
Routine first line coagulation tests include activated partial thromboplastin time (aPTT) and prothrombin time (PT). The two tests measure coagulation time of plasma, triggered by two different tissue factors (in aPTT partial thromboplastin). aPTT is sensitive mainly to FVIII, FIX, FXI and XII, whereas PT is sensitive to coagulation proteins synthesized by the liver (FII, FVII, FIX so called “prothrombin complex” with synthesis depending on vitamin K).
Individuals with AH have an isolated prolonged aPTT, with normal PT. Tests to rule out other causes of isolated prolonged aPTT such as non-specific inhibitors (e.g., lupus anticoagulant) or heparin therapy are also performed.
aPTT mixing tests, carried out by mixing patient’s plasma with normal plasma, can further confirm the diagnosis. A mixing study differentiates genetic factor deficiencies from factor inhibitors. A sample of blood is taken and mixed with blood from a control subject. In individuals with a factor deficiency the normal plasma restores the test value to normal; in individuals with a factor inhibitor it does not.
Once a factor inhibitor is established, an assay will be done to measure the activity of coagulation factors (in the majority of cases FVIII) and the titer of the inhibitor. In individuals with AHA, this will demonstrate factor VIII deficiency and can ascertain the severity (titer count) as well.
Because AH is a rare disorder, most therapies used to treat affected individuals are based upon anecdotal reports or small cases series. There are few studies comparing the efficacy of specific treatments against one another. Consequently, treatment is highly individualized.
The specific therapeutic procedures and interventions will vary, depending upon numerous factors including the specific symptoms present; the natural course of the disorder including underlying cause (if known); age and overall health (e.g., concomitant disease), tolerance of certain medications or procedures, and personal preference; and other factors. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks including possible side effects and long-term effects; patient preference; and other appropriate factors.
Spontaneous remission has been reported; in general, it may occur in postpartum cases (within a few months of delivery) and, in the cases secondary to an allergic drug reaction, usually within a few months of stopping the offending medication. Spontaneous remission can also occur in other affected individuals such as those who have low titer inhibitors. The exact percentage of patients that undergo spontaneous resolution is unknown.
The management of AH focuses on the following goals: controlling and preventing bleeding (if present or significant), eradication of the inhibitor, and treatment of the underlying disease (if applicable).
Controlling Bleeding Episodes
Bleeding may be very severe and may have a sudden onset. Therefore, prompt hemostatic control is mandatory in order to reduce morbidity and mortality. The International Recommendations state that anti-hemorrhagic treatment should be started in patients with severe bleeding in which a diagnosis of AH is confirmed, irrespective of inhibitor titer and factor VIII activity. Two approaches are available: the use of bypassing agents (concentrates of factors that bypass the acquired deficiency) or strategies to increase FVIII levels. The choice between these two options is based on the site and the severity of bleeding and the characteristics of each individual patient. Since hemostatic agents do not have a predictable effect, treatment of bleeding should be supervised by an expert in this field and proper laboratory tests, imaging techniques and a skillful clinical evaluation are necessary to confirm hemostatic control and bleeding resolution. Fibrin glue or antifibrinolytic agents may be useful in the control of local bleeding.
Bypassing agents are the recommended first-line therapy due to their rapid action and high level of effectiveness. The dosage is largely based on experience with the management of patients with FVIII inhibitors in congenital hemophilia and is generally based on the clinical assessment.
The bypassing agents presently available are recombinant activated factor VII (rFVIIa or NovoSeven® RT) or activated prothrombin complex concentrate (aPCC or FEIBA®). Neither of these therapies is effective in all individuals.
NovoSeven® RT is a genetically engineered (recombinant) version of factor VII. Because it is artificially created in a lab, it does not contain human blood or plasma and consequently, there is no risk of blood-borne viruses or other such pathogens. NovoSeven has been well-tolerated and associated with few side effects. Risk of thrombotic adverse effects (thrombosis) is below 1% for individuals with AH. NovoSeven has been approved by the Food and Drug Administration (FDA) for use as a bypassing agent for the treatment of individuals with acquired hemophilia. NovoSeven® RT is manufactured by Novo Nordisk. For more information, contact:
Novo Nordisk Inc.
aPCC is a plasma-derived, anti-inhibitor complex that contains various activated clotting factors. These factors allow the drug to bypass certain steps in the formation of blood clots (including the steps that require factor VIII). aPCC is treated to inactivate any potential viruses or similar pathogens and adverse thrombotic events are rare. The only form of aPCC currently available in the United States is FEIBA®, which is available from Baxalta, now part of Shire. For more information, contact:
Therapeutic modalities that allow an increase of FVIII, such as infusion of FVIII concentrate or DDAVP, that induces release of FVIII by the endothelial cells, are usually considered inadequate unless the inhibitor titer is very low (i.e. < 5 Bethesda units [BU]) and bypassing agents are not available. In 2014 The US FDA approved Obizur [Antihemophilic Factor (Recombinant), Porcine Sequence] for the treatment of bleeding episodes in adults with acquired hemophilia A (acquired Factor VIII [FVIII] deficiency). Obizur is manufactured by Baxalta, now part of Shire. For more information contact: Baxalta http://www.obizur.com/
Although in some cases inhibitor can disappear spontaneously as long as the inhibitor is present, bleeding related morbidity and mortality is significant. Therefore, therapy to eradicate the inhibitor (iimunosuppression therapy) in adults is recommended to start immediately after the diagnosis of AH unless clearly contraindicated. Recommendations are largely derived from observation made in registries that have collected real life data.
In general, corticosteroids alone or associated with cyclophosphamide are the first line therapy. No clear difference in long term survival was observed in these two modalities. However, individuals respond differently to immunosuppressive drugs and what is effective in one individual may be ineffective in another. A variety of additional immunosuppressive agents have been used to treat acquired hemophilia including cyclosporine A, azathioprine, vincristine, mycophenolate mofetil, and 2-chlorodeoxyadenosine.
Criteria for the response to treatment have not been established; nevertheless, high inhibitor titer and low FVIII level seem to predict the response to therapy.
Relapse of AH can occur in individuals who achieve remission once immunosuppressive therapy is stopped or if the dose is reduced. Because of associated side effects, long-term immunosuppressive therapy is not recommended.
Individuals with AH are encouraged to avoid activities that have a significant risk of trauma until after inhibitor eradication.
Patients with AH will benefit from referral to a federally-funded hemophilia treatment center. These specialized centers can provide comprehensive care for individuals with hemophilia and related disorders including the development of specific treatment plans, monitoring and follow-up of affected individuals, and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapists, social workers and genetic counselors) experienced at treating individuals with hemophilia.
Researchers have been studying the drug rituximab, as a potential therapy for individuals with AH. This drug attacks the autoantibodies that cause the disease. Rituximab is classified as a monoclonal antibody or biologic therapy – medications that act like antibodies, but are artificially created in a lab. Initially, rituximab has demonstrated promising results in eradicating inhibitors. Some researchers have proposed rituximab as a second-line therapy for eradicating inhibitors in individuals who do not respond to corticosteroid/cyclophosphamide therapy or as a first-line therapy in individuals who cannot tolerate corticosteroid/cyclophosphamide therapy. More research is necessary to determine the long-term safety and effectiveness of rituximab for the treatment of AH.
High-dose intravenous immunoglobulin has been used to eradicate inhibitors in AH. However, most reports in the medical literature detail disappointing results. Some researchers believe that this therapy best holds promise as an adjunct treatment to other drugs or procedures that eradicate inhibitors.
Some individuals who have high titers of inhibitors and severe bleeding may undergo a procedure called plasmapheresis or immunoabsorption. These procedures are usually reserved for patients who have not responded to other treatment options and are experiencing life-threatening bleeding episodes. Plasmapheresis involves removing unwanted substances from the blood. Blood is removed from the patient and the solid blood cells are separated from the liquid plasma. The patient’s plasma is then replaced with donor human plasma or albumin, which is re-transfused, along with the patient’s original blood cells. The modified Bonn-Malmö Protocol (MBMP) combines immunoadsorption on columns that specifically link immunoglobulins (FVIII inhibitor) with FVIII replacement and immunosuppression and can achieve rapid and safe control of acute bleeding. It is mainly implemented in Europe since immunoadsorption columns are not available in the US.
Complications of immunosuppressive therapy (IST)
IST increases risk for infection in the already elderly, fragile population. Neutropenia (decrease of white blood cells) and sepsis are frequently reported and contributed to death. Other well-recognized complications of steroid therapy have been reported including raised blood sugar levels, gastrointestinal ulcers, muscle disorders, and psychiatric disorders (3%).
Conclusions: Research and Other Needs
AH is more frequently encountered by the internist or emergency room doctor who is most often the first to evaluate the patient. It is likely that AH is underdiagnosed and misdiagnosed in real-world clinical practice, suggesting the need to raise awareness of this disease among healthcare practitioners and to encourage referral to specialists in the management of AH. For most, AH is eminently treatable, with clear benefits from prompt recognition and appropriate management. Both hemostatic and immune therapy imposes considerable risks and requires close monitoring to ensure safety. The highest priority in AH research is to develop safer immunosuppressive regimens that improve survival by better balancing inhibitor eradication with the side effects of treatment.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: pr[email protected]
For information about clinical trials sponsored by private sources, in the main, contact:
For information about clinical trials conducted in Europe, contact:
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