Acquired Hemophilia A

Disease Overview

Summary

Acquired hemophilia A (AHA) is a rare autoimmune bleeding disorder. Unlike inherited bleeding disorders, it occurs in people who have no personal or family history of clotting (coagulation) problems.

Autoimmune disorders occur when the immune system mistakenly attacks the body’s own healthy cells or tissues. In AHA, the immune system makes antibodies (known as inhibitors) that attack clotting factor VIII, a protein that is essential for normal blood clotting. Clotting factors work together to stop bleeding when a blood vessel is injured. When factor VIII is blocked or destroyed, the blood cannot clot properly.

As a result, people with AHA can develop unexpected and uncontrolled bleeding, which may occur spontaneously (without an obvious cause), after surgery, or following injury or trauma. Bleeding most often affects the skin, muscles and soft tissues, but it can also occur internally. Common symptoms include nosebleeds (epistaxis), bruising throughout the body, solid swellings caused by pooled blood (hematomas), blood in the urine (hematuria), and bleeding from the gastrointestinal (GI) urinary tract (urogenital bleeding).

In severe cases, AHA can cause life-threatening bleeding. In about half of affected individuals, an underlying medical condition or triggering factor can be identified. In the remaining 50% of cases, no clear cause is found; these cases are described as idiopathic.

Introduction

Acquired hemophilia A (AHA) is different from inherited hemophilia, which is caused by genetic changes (variants) in the genes that affect clotting factor production. The most common inherited form, hemophilia A (classic hemophilia), is caused by a deficiency or dysfunction of factor VIII and is usually inherited in an X-linked pattern, meaning it mostly affects males, though females can also be affected.

Although both inherited hemophilia A and acquired hemophilia A (AHA) involve problems with the same clotting factor (factor VIII), the bleeding patterns are quite different. People with inherited hemophilia A typically experience frequent bleeding into the joints, while this type of bleeding is uncommon in AHA. The exact reason for these differences is not fully understood.

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Synonyms

Acquired factor VIII deficiency
Acquired F8 deficiency
AHA

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Signs & Symptoms

The signs and symptoms of acquired hemophilia A (AHA) occur because the blood cannot clot properly. Clotting is the process by which blood thickens and forms a plug to stop bleeding of a wound after an injury. This process depends on clotting factors, including factor VIII, which work together in a precise sequence.

Most people with AHA require medical treatment to control bleeding. The severity of bleeding varies, but more than 1/3 of affected people experience multiple bleeding episodes.

Common signs and symptoms may include:

Bleeding under the skin (subcutaneous bleeding, ecchymoses), which appears as large or unexplained bruises is the most common symptom

Muscle bleeding (hematomas), the second most common symptom

Gastrointestinal (GI) bleeding such as dark, tar-colored stools (melena)

Blood in the urine (hematuria)

Retroperitoneal bleeding, a serious spontaneous bleed into the space behind the abdominal lining, leading to severe pain, shock, and potential nerve damage (such as femoral neuropathy). This type of bleeding is especially dangerous because the blood collects internally, where it can’t be seen.

Bleeding inside the skull (intracranial hemorrhage), which is rare, but can be fatal

Unlike inherited/congenital hemophilia A, bleeding into the joints (hemarthrosis) is uncommon in AHA.

Bleeding often occurs without an obvious trigger (spontaneously). Bleeding episodes are often severe and can become life-threatening. Delayed diagnosis and the presence of other medical conditions can worsen outcomes. Bleeding into soft tissues can progress rapidly and may lead to compartment syndrome, a painful and potentially serious condition caused by increased pressure within muscles that can damage nerves and blood vessels, most often in the arms and legs, with damage due to compression of these structures.

Affected Individuals are also at risk of excessive bleeding during surgery or after even minor injuries. In women, heavy genital bleeding may occur during pregnancy or after childbirth, particularly in the postpartum period.

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Causes

Acquired hemophilia A (AHA) is an autoimmune disorder. It occurs when the immune system produces antibodies that mistakenly attack clotting factor VIII.

Normally, the immune system produces antibodies to defend the body against infections and other foreign substances. 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 the body’s own tissues, they are called autoantibodies. Researchers believe that a triggering event (such as an infection or underlying disorder) may induce the immune system to produce autoantibodies. In AHA, these autoantibodies are referred to as inhibitors because they block (inhibit) the normal function of factor VIII.

Hemostasis is the body’s natural process for stopping bleeding. When a blood vessel is injured, the body quickly recognizes the damage and starts a series of steps to prevent too much blood loss. When there is an injury, substances at the injury site signal that clotting is needed. Next, small blood cells called platelets gather and stick together to form an initial plug. Finally, a chain reaction known as the coagulation cascade occurs, in which clotting proteins work together to strengthen the clot and seal the injury. For example, factor VIII and factor IX work together to support clot formation, and problems with either of these factors can lead to bleeding disorders such as hemophilia. Factor X and factor II (prothrombin) help produce thrombin, an enzyme that plays a key role in clot formation. Thrombin converts fibrinogen (factor I) into fibrin, which forms the strong mesh-like material that holds the clot together. When factor VIII is blocked, this process is disrupted, leading to abnormal bleeding.

AHA is predominantly a disease of older adults. In about 50% of the affected people, no underlying disorder or triggering event can be identified (idiopathic form). The remaining 50% have coexisting disorders or conditions. AHA may be associated with:

Lupus

Rheumatoid arthritis

Multiple sclerosis

Sjogren syndrome

Temporal arteritis

Inflammatory bowel disease or ulcerative colitis

Infections

Diabetes

Hepatitis

Respiratory or skin (dermatological) diseases

Blood (hematological) cancers or certain solid tumors

AHA has also been associated with certain medication (such as penicillin or interferon) and to pregnancy, most often developing after birth in the post-partum period.

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Affected populations

Acquired hemophilia A (AHA) is very rare in the USA, with an estimated annual incidence of about 1.5 to 1.78 people per million people. In the United Kingdom, the disorder is estimated to affect 1.4 people per 1,000,000/year. However, because AHA can be misdiagnosed or go unrecognized, the true frequency may be higher.

Individuals of any age can be affected, but AHA is extremely rare in children. 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. AHA affects individuals of all ethnic groups and has been reported worldwide. AHA develops in individuals with no previous history of bleeding disorder.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of AHA. Comparing these conditions can help doctors make the correct diagnosis.

Inherited (or sometimes called congenital) hemophilia refers to a group of genetic bleeding disorders present from birth. The most common types are hemophilia A (factor VIII deficiency) and hemophilia B (factor IX deficiency), both of which are inherited in an X-linked pattern and primarily affect males. Unlike AHA, inherited hemophilia usually appears in childhood and often runs in families.

Von Willebrand disease (VWD) is an inherited bleeding disorder caused by problems with von Willebrand factor, a protein that helps platelets stick to damaged blood vessels and helps stabilize factor VIII. VWD often causes milder bleeding and may not be diagnosed until adulthood. Unlike AHA, it is not caused by antibodies and does not involve sudden onset severe bleeding later in life.

Acquired hemophilia B: an exceptionally rare, acquired type of hemophilia due to deficiency of the factor IX. Symptoms include abnormal, uncontrolled bleeding that can occur spontaneously, during surgery, or after an injury. Like AHA, it is acquired rather than inherited.

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Diagnosis

Acquired hemophilia A (AHA) should be suspected in anyone who develops new, unexplained bleeding, especially older adults or women during or after pregnancy. Bleeding may involve the skin, muscles, or soft tissues, and can be severe or life-threatening.

Diagnosis is supported by blood clotting tests showing an isolated prolongation of the activated partial thromboplastin time (aPTT). This means the blood takes longer than normal to clot through one specific clotting pathway. Another clotting test, the prothrombin time (PT), is typically normal in AHA.

Clinical Testing and Work-Up:

Initial laboratory testing includes aPTT and PT, which measure how long it takes blood to clot through different clotting pathways. In AHA, only the aPTT is prolonged.

Other causes of prolonged aPTT must be ruled out, including lupus anticoagulant, heparin (blood thinner) exposure, and certain medications.

A mixing study is then performed by combining the plasma of the affected person with normal plasma. If the clotting time returns to normal, this suggests a clotting factor deficiency. If it does not correct, it indicates the presence of an inhibitor, meaning an antibody is blocking the clotting factor.

Once an inhibitor is confirmed, additional tests are performed. Factor VIII activity testing shows how much functional factor VIII is present. An inhibitor titer (measured in Bethesda units) shows how strongly the antibody interferes with factor VIII. These tests confirm the diagnosis of AHA and help guide treatment decisions.

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Standard Therapies

Treatment
Because acquired hemophilia A (AHA) is a rare disorder, most treatment recommendations are based on observational studies, patient registries, case series, and clinical experience rather than large, randomized clinical trials. Few studies directly compare the effectiveness of specific therapies.

Treatment of AHA has two primary goals – to control active bleeding and to eliminate the antibody (inhibitor) that interferes with normal blood clotting.

Bleeding in AHA can occur suddenly and may be severe or life-threatening. For this reason, treatment should begin promptly after diagnosis and should be managed by physicians experienced in bleeding disorders. The treatment plan is individualized, considering the severity and location of bleeding, overall health of the individual, risk factors of the individual, and their response to therapy.

International guidelines recommend treating clinically significant bleeding regardless of factor VIII level or inhibitor titer, as laboratory values alone do not reliably predict bleeding risk.

Control of bleeding:

The preferred first-line treatments for bleeding episodes are medications known as bypassing agents. These drugs promote clot formation without relying on factor VIII, which is inhibited in AHA. Bypassing agents include:

Recombinant activated factor VII (rFVIIa), such as NovoSeven® RT and Sevenfact®

- NovoSeven® RT is a laboratory-produced form of activated clotting factor VII. It is not made from human blood or plasma, reducing the risk of infection. NovoSeven® RT is generally well tolerated, and serious clotting complications are uncommon when used according to recommended guidelines. It is approved by the U.S. Food and Drug Administration (FDA) for the treatment of bleeding in individuals with acquired hemophilia A.

- Sevenfact® is another recombinant activated factor VII product. It was approved by the FDA in 2020 for the treatment and control of bleeding in adults and adolescents aged 12 years and older with hemophilia A or B who have inhibitors. Although it is not specifically approved for acquired hemophilia A, limited clinical experience supports its use in this condition. Its mechanism of action is similar to other factor VII products and allows clot formation without dependence on factor VIII.

Activated prothrombin complex concentrate (aPCC, FEIBA®)

- Activated prothrombin complex concentrate (aPCC) is a plasma-derived medication that contains a mixture of activated clotting factors that bypass the need for factor VIII. The product undergoes viral inactivation during manufacturing to reduce infection risk. Serious clotting complications are uncommon when used at recommended doses. In the United States, FEIBA® is the only available aPCC product.

Both recombinant factor VII products and aPCC are effective treatments, although no single therapy works for all individuals. The choice of treatment depends on the severity and site (location) of bleeding, patient-specific risk factors, and prior response to treatment.

Another approved treatment option for AHA is recombinant porcine factor VIII (rpFVIII, Obizur®). Because this medication is less likely to be neutralized by the patient’s antibodies, it can raise measurable factor VIII levels. Because factor VIII levels can be directly measured during treatment, doctors can closely monitor response to therapy. For these reasons, rpFVIII is being used more frequently in clinical practice.

For certain types of bleeding, particularly localized bleeding episodes, additional supportive treatments may be helpful, including fibrin glue or antifibrinolytic medications.

Treatments designed to raise factor VIII levels directly, such as human factor VIII concentrates or desmopressin (DDAVP), are generally less effective in AHA because inhibitors are present. These options may be considered only in selected situations, such as when inhibitor levels are very low and other therapies are unavailable.

Elimination of the inhibitor:

In addition to controlling bleeding, treatment focuses on removing the antibody that causes AHA through immunosuppressive therapy. As long as the inhibitor remains present, the risk of bleeding-related complications remains high. For this reason, immunosuppressive treatment is usually started soon after diagnosis unless there is a clear reason to delay it.

Corticosteroids, either alone or in combination with cyclophosphamide, are commonly used as first-line immunosuppressive therapy. Many people experience improvement and eventual remission over several months.

If first-line therapy is ineffective or cannot be tolerated, rituximab may be used. Rituximab is an immunosuppressive medication that targets B cells, the immune cells responsible for producing antibodies against factor VIII.
- Rituximab is most commonly used in patients who do not respond to first-line immunosuppressive therapy or who cannot tolerate corticosteroids or cyclophosphamide. However, in some cases, such as very low factor VIII levels or high inhibitor titers, clinicians may consider using rituximab earlier in the treatment course.. Decisions regarding its use are individualized, taking into account disease severity, patient age, underlying medical conditions, and potential risks. Ongoing research continues to evaluate the optimal timing, combinations, and long-term safety of rituximab in AHA.

Although spontaneous remission can occur, especially in pregnancy-related cases, close follow-up is essential. Relapse may occur after immunosuppressive therapy is reduced or stopped. Because immunosuppressive treatments increase the risk of infections and other side effects, especially in older adults, careful monitoring throughout therapy is required. Long-term immunosuppression is generally avoided due to these risks.

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 (put back in the body), along with the patient’s original blood cells.

The modified Bonn-Malmö Protocol (MBMP) combines immunoadsorption (blood filtering treatment to remove inhibitors that block factor VIII) with FVIII replacement and immunosuppression and can achieve rapid and safe control of acute bleeding. It is used more commonly in some European centers. Availability varies by region and treatment center.

Ongoing care and monitoring:

In addition to physical examination and laboratory tests, imaging studies may be required to detect or monitor bleeding, especially when bleeding is internal or difficult to see. Imaging techniques used may include ultrasound, computed tomography (CT) scans, or MRI (magnetic resonance imaging) can be particularly helpful for detecting deep muscle bleeding, internal bleeding, or bleeding that is not easily apparent on physical examination.

Imaging may also be used during follow-up to confirm that bleeding has resolved and to guide decisions about ongoing or additional treatment. The choice of imaging method depends on the location of bleeding, the patient’s symptoms, and overall clinical condition.

Until the inhibitor has been eradicated, people with acquired hemophilia A (AHA) are generally advised to avoid activities that have a higher risk of injury.

Decisions regarding specific therapies should be made collaboratively by the healthcare team and the patient (and family, when appropriate), with careful discussion of potential benefits, risks, side effects, long-term considerations, and patient preferences.

Patients with AHA will benefit from referral to a specialized 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.

The National Bleeding Disorders Foundation has updated information about all FDA-approved therapies to treat bleeding disorders.

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Clinical Trials and Studies

AHA is more frequently encountered by an internal medicine physician (internist) or emergency room doctor who is most often the first to evaluate the patient. It is likely that AHA 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 AHA.

For most, AHA is highly treatable, especially when recognized early. Both bleeding-control (hemostatic) and immunosuppressive treatments carry risks and require close monitoring to ensure safety.

Current research priorities focus on developing safer immunosuppressive strategies that effectively eliminate inhibitors while reducing treatment-related side effects and improving long-term outcomes.

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: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

JOURNAL ARTICLES
Tiede A, Hofbauer CJ, Werwitzke S, et al. Anti-factor VIII IgA as a potential marker of poor prognosis in acquired hemophilia A: results from the GTH-AH 01/2010 Study. Blood. 2016;127:2289-2297. https://www.ncbi.nlm.nih.gov/pubmed/26912467

Kruse-Jarres R, St-Louis J, Greist A, et al. Efficacy and safety of OBI-1, an antihaemophilic factor VIII (recombinant), porcine sequence, in subjects with acquired haemophilia A. Haemophilia. 2015;21:162-170. https://www.ncbi.nlm.nih.gov/pubmed/25623166

Tiede A, Klamroth R, Scharf RE, et al. Prognostic factors for remission of and survival in acquired hemophilia A (AHA): Results from the GTH-AH 01/2010 study. Blood. 2015;125:1091-1097. https://www.ncbi.nlm.nih.gov/pubmed/25525118

Borg JY, Guillet B, Le Cam-Duchez V, Goudemand J, Levesque H, Group SS. Outcome of acquired haemophilia in France: the prospective SACHA (Surveillance des Auto antiCorps au cours de l’Hemophilie Acquise) registry. Haemophilia. 2013;19:564-570. https://www.ncbi.nlm.nih.gov/pubmed/23574453

Seita I AK, Higasa S, Sawada A, Kuwahara M, Shima M. . Treatment of acute bleeding episodes in acquired haemophilia with recombinant activated factor VII (rFVIIa): analysis from 10-year Japanese post-marketing surveillance. J Thromb Haemost. 2013;11:119.

Baudo F, Collins P, Huth-Kuhne A, et al. Management of bleeding in acquired hemophilia A: Results from the European Acquired Haemophilia (EACH2) registry. Blood. 2012;120:39-46. https://www.ncbi.nlm.nih.gov/pubmed/22618709

Collins P, Baudo F, Knoebl P, et al. Immunosuppression for acquired hemophilia A: results from the European Acquired Haemophilia Registry (EACH2). Blood. 2012;120:47-55. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390961/

Kempton CL, Abshire TC, Deveras RA, et al. Pharmacokinetics and safety of OBI-1, a recombinant B domain-deleted porcine factor VIII, in subjects with haemophilia A. Haemophilia. 2012;18:798-804. https://www.ncbi.nlm.nih.gov/pubmed/22512291

Knoebl P, Marco P, Baudo F, et al. Demographic and clinical data in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry. J Thromb Haemost. 2012;[Epub ahead of print]. https://www.ncbi.nlm.nih.gov/pubmed/22321904

Baudo F, Caimi T, de Cataldo F. Diagnosis and treatment of acquired haemophilia. Haemophilia. 2010;16:102-106. https://www.ncbi.nlm.nih.gov/pubmed/20536992

Kelesidis T, Raphael J, Blanchard E, Parameswaran R. Acquired hemophilia as the cause of life-threatening hemorrhage in a 94-year-old man: a case report. J Med Case Reports. 2010:4:231. https://www.ncbi.nlm.nih.gov/pubmed/20670435

Huth-Kunhe A, Baudo F, Collins P, et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica. 2009;94:566-575. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2663620/?tool=pubmed

Franchini M, Lippi G. Acquired factor VIII inhibitors. Blood. 2008;112:250-255. https://bloodjournal.hematologylibrary.org/content/112/2/250.full

Ma AD, Carrizosa D. Acquired factor VIII inhibitors: pathophysiology and treatment. Hematology Am Soc Hematol Educ Program. 2006:432-437. https://www.ncbi.nlm.nih.gov/pubmed/17124095

Maillard H, Launay D, Hachulla E, Goudemand J, Lambert M, Morell-Dubois S, et al. Rituximab in postpartum-related acquired hemophilia. Am J Med. 2006 Jan. 119(1):86-8.

Aggarwal A, Grewal R, Green RJ, Boggio L, Green D, Weksler BB, et al. Rituximab for autoimmune haemophilia: a proposed treatment algorithm. Haemophilia. 2005 Jan. 11(1):13-9.

Franchini M, Gandini G, di Paolantonio T, Mariani G. Acquired hemophilia A: a concise review. Am J Hematol. 2005;80:55-63. https://onlinelibrary.wiley.com/doi/10.1002/ajh.20390/pdf

Franchini M, Girelli D, Olivieri O, et al. Clinical heterogeneity of acquired hemophilia A: a description of 4 cases. Haematologica. 2005;90:e46-e49. https://www.haematologica.org/content/90/3/ECR16.long

Freedman J, Garvey MB. Immunoadsorption of factor VIII inhibitors. Curr Opin Hematol. 2004;11:327-333. https://www.ncbi.nlm.nih.gov/pubmed/15666656

Kain S, Copeland TS, Leahy MF. Treatment of refractory autoimmune (acquired) haemophilia with anti-CD20 (rituximab). Br J Haematol. 2002 Nov. 119(2):578.

Wiestner A, Cho HJ, Asch AS, Michelis MA, Zeller JA, Peerschke EI, et al. Rituximab in the treatment of acquired factor VIII inhibitors. Blood. 2002 Nov 1. 100(9):3426-8.

Yu D, Xue F, Liu X, et al. Acquired hemophilia A: a single-center study of 165 patients. Res Pract Thromb Haemost. 2024;8(1):102318. Published 2024 Jan 17. doi:10.1016/j.rpth.2024.102318

INTERNET
Grethlein SJ. Acquired Hemophilia Treatment & Management. Medscape. Last update January 10, 2020. https://emedicine.medscape.com/article/211186-treatment. Accessed April 26, 2021.

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Programs & Resources

RareCare^® Assistance Programs

Hemophilia Emergency Relief

Temporarily Waitlisting

Phone: 203-514-7192 Email: [email protected] Fax: 475-204-3597

Related Rare Diseases: Acquired Hemophilia A, Hemophilia A, Hemophilia B, ...

Resource(s): EmergRelief_Hemophilia (2), EmergRelief_Hemophilia-SPANISH (2)

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MedicAlert Assistance Program

NORD and MedicAlert Foundation have teamed up on a new program to provide protection to rare disease patients in emergency situations.

Learn more https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Rare Disease Educational Support Program

Ensuring that patients and caregivers are armed with the tools they need to live their best lives while managing their rare condition is a vital part of NORD’s mission.

Learn more https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/