SummaryAcquired hemophilia 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 acquired hemophilia, 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. Acquired hemophilia can potentially cause severe, life-threatening bleeding complications in severe cases. In approximately 50% of cases, there is an identifiable underlying clinical condition; in the other 50% no cause is known (idiopathic).
IntroductionAcquired hemophilia 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 fully affects males only. It is caused by deficiency or inactivation of factor VIII, the same clotting factor that is affected in most cases of acquired hemophilia. 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 acquired hemophilia result from excessive or prolonged bleeding, often into the muscles, skin soft tissue and mucous membranes. Bleeding often occurs without cause (spontaneously). Unlike classic hemophilia, bleeding into the joints is rare. Bleeding episodes are often severe and can become life-threatening. In some cases, delayed diagnosis and the presence of additional medical issues are often contributing factors to the overall severity of acquired hemophilia.
Affected individuals may display bruising anywhere on the body due to bleeding into the skin. Bruising can occur spontaneously. Large, purple discoloration can extend over a significant area of the body such as an entire limb or the chest or abdomen. Bruising may result from internal bleeding from small blood vessels, which can cause a large purple rash (purpura). Discoloration of the skin due to bleeding underneath the skin (ecchymoses) may also occur.
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. Compartmental syndrome can result in muscle and nerve damage due to compression of these structures or lack of blood flow to the muscle compartment.
Affected individuals may also experience frequent nose bleeds, gastrointestinal bleeding (black, tarry stools – melena) or genitourinary bleeding (blood in the urine), Hematomas, which are solid swellings of congealed blood, may form in the space behind the lining of the abdomen (retroperitoneal space).
Individuals with acquired hemophilia are also at risk of excessive bleeding during surgery or following trauma, even trivial. Genital heavy bleeding in pregnant women with acquired hemophilia may occur especially after childbirth (postpartum period). In rare cases, affected individuals have developed bleeding on the brain (cerebral hemorrhage).
Acquired hemophilia 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 acquired hemophilia are also termed inhibitors because they inhibit the function of the affected clotting factor.
In approximately 50% of individuals with acquired hemophilia no underlying disorder or triggering event can be identified (idiopathic). Idiopathic acquired hemophilia is most common in the elderly. The remaining 50% have some form of coexisting disorder or condition that is believed to trigger the abnormal immune system response. A wide and varied number of conditions have been associated with the development of acquired hemophilia including various autoimmune disorders such as lupus, rheumatoid arthritis, multiple sclerosis, Sjogren syndrome, and temporal arteritis; inflammatory bowel disease or ulcerative colitis; infections; diabetes; hepatitis; and certain respiratory or dermatological diseases.
In addition, acquired hemophilia can occur due to cancer, especially blood (hematological) cancer or certain solid tumors, or as an allergic drug reaction to such drugs as penicillin or interferon. In some women, acquired hemophilia occurs as a complication after pregnancy (postpartum acquired hemophilia).
The symptoms of acquired hemophilia develop because the blood cannot clot properly. Clotting factors, such as factor VIII, are specialized proteins that are essential for the blood to clot properly. Clotting is the process by which blood clumps together to plug the site of a wound to stop bleeding. Individuals with acquired hemophilia bleed because they have difficulty stopping the flow of blood from a wound. This may be referred to as prolonged bleeding or a prolonged bleeding episode. Acquired hemophilia can be mild, moderate or severe.
Acquired hemophilia affects males and females in equal numbers. 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, cases of acquired hemophilia 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 acquired hemophilia is extremely rare in children. The incidence increases with age and most cases affect elderly individuals (between 60-80 years of age). A small increase in incidence occurs in pregnant woman between the ages of 20-40. Acquired hemophilia affects individuals of all ethnic groups and has been reported worldwide. Acquired hemophilia develops in individuals with no previous history of a bleeding disorder. 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.
Obtaining a diagnosis of acquired hemophilia, can be difficult due to the rarity of the disorder and because most affected individuals do not have a personal or family history of bleeding disorders. A diagnosis is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of laboratory tests.
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 acquired hemophilia 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) have to also be performed.
aPTT mixing tests, carried out by mixing patient’s plasma with normal plasma, can further confirm a diagnosis of acquired hemophilia. 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. In individuals with acquired hemophilia this will demonstrate factor VIII deficiency and can ascertain the severity (titer count) as well.
Because acquired hemophilia 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 for acquired hemophilia is highly individualized.
The specific therapeutic procedures and interventions for individuals with acquired hemophilia will vary, depending upon numerous factors including the specific symptoms present; the natural course of the disorder including underlying cause (if known); an individual’s 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 reported in individuals with acquired hemophilia; 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 cases of acquired hemophilia that undergo spontaneous resolution is unknown.
Individuals with a known underlying condition, e.g. autoimmune disease, should receive therapy for that condition. Often, treatment of the underlying condition resolves acquired hemophilia.
In the remaining cases, treatment is symptomatic and supportive and is aimed at controlling bleeding episodes and eradicating the inhibitors that cause the disorder.
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 AHA 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, at present 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 acquired hemophilia. 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 the pharmaceutical company Novo Nordisk. For more information, contact:
Novo Nordisk Inc.
100 College Road West
Princeton, NJ 08540
NovoSeven® RT Coagulation Factor VIIa (Recombinant)
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 Baxter Healthcare Corporation. For more information, contact:
Baxter Healthcare Corporation
One Baxter Parkway
Deerfield, IL 60015
(800) 551-0478 Canada
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 the past, infusion with factor VIII derived from pig’s blood (porcine factor VIII) was used to treat some individuals with acquired hemophilia. Porcine factor VIII is similar enough to human factor VIII to treat bleeding episodes, but different enough to be less susceptible to inactivation by inhibitors. Although porcine factor VIII was effective in treating individuals with acquired hemophilia, the product is no longer widely available. Researchers are working on developing a genetically engineered (recombinant) version of porcine factor VIII.
In addition to treating active bleeding episodes, individuals with acquired hemophilia; undergo therapy to eradicate the inhibitors that cause the disorder. Such therapy may begin immediately after a diagnosis of acquired hemophilia is made. This therapy requires the administration of drugs that suppress the immune system (immunosuppressive agents).
Individuals may initially receive therapy with corticosteroids, such as prednisone. Some individuals may also require adjunct therapy with another drug, most often cyclophosphamide. In some individuals, inhibitors may be completely wiped out by this therapy. 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.
Relapse of acquired hemophilia 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 acquired hemophilia are encouraged to avoid activities that have a significant risk of trauma until after inhibitor eradication.
Individuals with acquired hemophilia 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 therapist, social worker and genetic counselor) experienced at treating individuals with hemophilia.
Researchers have been studying the drug rituximab, as a potential therapy for individuals with acquired hemophilia. This drug attacks the autoantibodies that cause acquired hemophilia. 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 result in eradicating inhibitors. Some researchers have proposed rituximab as a second-line therapy for eradicating inhibitors in individuals with acquired hemophilia 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 acquired hemophilia.
High-dose intravenous immunoglobulin has been used to eradicate inhibitors in individuals with acquired hemophilia. 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 in individuals with acquired hemophilia.
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 individuals 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. Immunoabsorption is a similar procedure, but unlike plasmapheresis can specifically target the autoantibodies (inhibitors) that cause acquired hemophilia. After the inhibitors are removed, the plasma (now rid of the inhibitors) is returned to the patient. Generally, immunoabsorption is associated with fewer side effects than plasmapheresis.
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
For information about clinical trials sponsored by private sources, in the main, contact:
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