The State of Acquired Hemophilia

Hemophilia is a blood disorder affecting approximately 20,000 males in the United States, with positive tests for approximately one in every 5,000 births, according to the National Hemophilia Foundation. Hemophilia A, typified by a drop in clotting factor VIII, and its rarer cousin, hemophilia B, marked by a deficiency of clotting factor IX, are relatively straightforward to diagnose. These forms of hemophilia are passed down genetically and often are discovered in the first weeks after birth.

In recent years, however, researchers and clinicians have begun to fill in the gaps of knowledge about acquired hemophilia (AH). This type of hemophilia is both far more rare and far more difficult to diagnose since it presents with a different set of symptoms than hemophilia A and B. It typically affects older patients suffering from other disorders, and it occurs in patients without a family history of immunological syndromes. Given the mortality rate of those affected by AH, which ranges between 7 percent and 21 percent, as well as the importance for clinicians to work quickly to relieve its associated bleeding, it is imperative that medical practitioners be able to diagnose AH when symptoms arise and understand the range of therapies available for its treatment.

What Is AH?

AH is a rare blood disorder marked by sudden bleeding in patients without a previous personal or family history of hemophilia. Incidences of acquired hemophilia are believed to occur in up to one case per million persons per year. However, it’s likely that available statistics underestimate the true figure, given that AH can be difficult to diagnose and many cases of AH remain uncounted unless discovered during surgery or testing for other disorders.¹

Almost all known cases of AH are characterized by autoantibodies that either disrupt the functioning of coagulation factor VIII or that clear this clotting factor from the plasma, which results in unpreventable bleeding in AH patients.² Approximately half of AH incidences have been linked to a wide variety of underlying medical conditions, such as collagen, vascular and other autoimmune diseases (different studies put the percentage of cases between 16.7 percent and 18 percent); lymphoproliferative malignancies or solid tumors (between 6.7 percent and 14.7 percent of cases); skin diseases (between 3.3 percent and 4.5 percent of cases); possible drug reactions (between 2.0 percent and 4.5 percent of cases); and pregnancy (between 2.0 percent and 11 percent of cases).³ Other reported factors for AH include diabetes, respiratory diseases such as asthma, acute hepatitis B infection and acute hepatitis C infection.

A 2007 study cited by Medscape suggests that in up to 63.3 percent of cases reported, the occurrence of AH remains without an identifiable source. However, because the occurrence may be a result of adverse drug reactions in patients taking several such medications, the figure for this reported factor might be artificially low. According to the World Federation of Hemophilia, pharmaceuticals implicated in the acquisition of AH include antibiotics such as a penicillin, sulphonamides and ciprofloxacin; immunological drugs such as interferon and fludarabine; psychotropics such as phenytoin, flupentixol and zuclopenthixol; as well as the antiplatelet agent clopidogrel. And, since this list is not exhaustive, clinicians should look to other recently used medications as the source for AH in patients.

Data shows that there is a peak in incidence rates among patients between the ages of 20 and 30, and an even greater number of incidences occurring between 60 and 80 years old. 4 In the 20 to 30 age group, most patients are female, given AH’s link to women going through their first pregnancies⁵ and, by and large, they occur in the three months following delivery. However, deaths from AH have been reported more than one year postpartum.⁴ There are no known genetic components to the disorder, and AH is reported across all racial groups.¹

The prognosis for AH patients ranges from life-threatening losses of blood to mild or no-bleeding tendencies, although it should be emphasized that life-threatening bleeding occurs in 80 percent of patients.⁶ And, according to a 2007 study in the Journal of Thrombosis and Haemostasis, most deaths from AH occur in the first weeks after the appearance of symptoms. Only in recent years have clinicians in the U.S. and Europe attempted to develop recommendations on best practices for responding to AH, and their task has been made difficult since the low numbers of patients involved preclude proper, statistically significant longitudinal studies.

Diagnosing AH

Despite the common threat to the functioning of coagulation factor VIII, there are very different symptoms between AH and the hereditary form of hemophilia A.⁷ Typical symptoms for hemophilia A include blood in the urine or stool, hemorrhaging in the gastrointestinal or urinary tracts, and swelling in the joints. For reasons still not clear, patients with AH display a different set of symptoms, including bleeding into the skin and musculature, haematemesis, haematuria, as well as longerthan-usual postpartum or postoperative bleeding.⁶ Often, the condition is misdiagnosed as other types of acquired bleeding disorders, including disseminated intravascular coagulation.⁷

Commonly, AH patients exhibit an unexplainable and prolonged activated partial thromboplastin time (aPTT), which is an indicator for determining the efficiency of both the contact activation pathway and common coagulation pathways.² For patients with any of the above symptoms, as well as a prolonged aPTT at less than 45 percent mean normal level, clinicians measure the levels of clotting factors VIII, IX, XI and XII, and a low level of clotting factorVIII alone is highly suggestive of the appearance in the blood of an inhibitor related to AH. Other indications of AH are normal prothrombin time assays, template bleeding times, and platelet and leukocyte levels. Tests for the presence of lupus anticoagulant or heparin are often conducted to rule out these factors in a patient’s symptoms. The antibodies in acquired hemophilia directed toward clotting factorVIII are typically polyclonalIgG4 antibodies, although more rarely, they are of the IgM or IgA varieties.

The World Federation of Hemophilia suggests repeating tests after a few days if an inhibitor is not at first revealed. The Bethesda assay, used to measure residual clotting factor VIII after incubating the patient plasma with normal plasma for two hours at 37 degrees Celsius, may be used to determine the quantity of the inhibitor in the patient’s plasma. Making diagnoses more difficult, clotting factor VIII may form a complex with other antibodies, which may create some residual clotting factor VIII activity and, thus, interfere with ascertaining AH’s signature drop in factor VIII. The upshot for clinicians is that AH patients may still exhibit factor VIII baseline levels even as they have high-titer inhibitory antibodies.

Treatment Options

The first objective for the treatment of AH is to control the affected areas of bleeding, while the long-term objective is to remove the inhibitor causing the disorder in the first place. Due to bleeding complications, the World Federation of Hemophilia recommends patients receive care in specialist hemostasis units that have experience in treating the disorder and the requisite blood products for treatment, which must be specific to the needs of each patient. In the U.S., the federal government supports a network of hemophilia care centers. Experts on staff provide not just direct treatment, but also education and support for specialists and AH patients. The Centers for Disease Control and Prevention provides a list of more than 100 centers on its website.

For many patients, especially those cases appearing postpartum or due to drug-induced inhibitors, the AH inhibitors may disappear on their own, and these patients, therefore, require only initial care with follow-up for maintaining their blood supply after the original hemorrhaging. However, older patients with underlying malignancies and other autoimmune disorders experience cases of AH that do not resolve on their own. For these patients, practitioners need to weigh the use of steroids against a range of health factors. Historically, because human factor VIII is likely to face the same assaults as the patients’ own factor VIII, clinicians had widely prescribed the use of porcine factorVIII.It was believed that the similarity to human factor VIII would provide some hemostatic effects, while being different enough to avoid inactivation by the bodies’ production of antibodies. However, results proved inconclusive on its uses.

For the last 30 years, according to the National Hemophilia Foundation, the typical treatment for AH bleeding episodes included the use of activated prothrombin complex concentrates, such as Factor VIII Inhibitor Bypassing Activity (FEIBA), which contains activated factors VII, IX and X. According to the World Federation of Hemophilia, doses of 50 to 100 units are to be provided intravenously in the treatment of AH, although doses exceeding 200 units per kilogram within any 24-hour period carry the risk of venous thromboembolism. FEIBA is no longer approved by the FDA to treat AH.

In 2006, the U.S. Food and Drug Administration (FDA) approved another bypassing agent for the treatment of AH, Novo Nordisk’s NovoSeven, which also is FDA approved for the treatment of bleeding episodes in patients with congenital FVII deficiency and in patients with hemophilia A or B with inhibitors to FVIII or FIX. According to Novo Nordisk’s website, NovoSeven’s intravenous bolus injection, a recombinant activated factor VII, has a half-life of 2.5 hours, which requires more frequent dosing — approximately 90 to 120 micrograms per kilogram given every three hours until the patient’s bleeding is under control.

Sabah Sallah, Novo Nordisk’s executive director in clinical development in hemostatis, says there are several benefits of NovoSeven for treating AH, including a well-established mode of action and safety profile, its effectiveness as a treatment regardless of the magnitude of inhibitor titer or anamnestic response, and its proven efficacy in life-threatening bleeding episodes in patients with AH. Several analyses have “demonstrated a high efficacy of rFVIIa in a very difficult-to-treat setting like AH and without major safety issues,” says Sallah. The World Federation of Hemophilia notes that in a 2006 study of 74 bleeding episodes in 34 patients, 75 percent of the patients demonstrated a good response, with another 17 percent demonstrating at least some partial response. The patients in this study were unable to respond to other blood products, and the World Federation of Hemophilia notes that response rates could be higher in patients who received no prior forms of treatment.

There are several possible side effects of NovoSeven, says Sallah, including deep vein thrombosis, pulmonary embolism, thrombotic stroke and ischemic cardiac episodes. And, because AH patients usually are elderly with other potential concomitant chronic illnesses such as diabetes, ischemic heart disease, hypertension, etc., they require close follow-up and monitoring for thrombotic events. However, these events have been reported in less than 1 percent of all bleeds, so NovoSeven for AH patients demonstrates a positive risk/ benefit profile.

NovoNordisk is currently in Phase 3 clinical trials for the development of a variant of rFVIIa to treat AH.

Prognosis of AH Patients

Survival rates for AH are greatest in patients with postpartum inhibitors, those who are younger than 65 years old and those whose symptoms are drug-induced. According to Medscape Reference, those patients suffering from underlying malignancies face a worse prognosis, with between 50 percent and 70 percent of patients able to eradicate the inhibitor after the onset of AH, and with about 20 percent of patients suffering a relapse between one week and 14 months after the immunosuppressive therapy is stopped. In those patients who have relapsed, approximately 70 percent are able to realize another remission.

Education Key for Patients and Clinicians

Educating patients with AH is important, since its recurrence can lead to severe bleeding after even slight traumas, and minor activities may trigger bleeding in the body’s soft tissues. Patients should report any prolonged or abnormal bleeding and, in the months following treatment, avoid activities that would risk significant trauma to the body. Just as important, frontline clinicians should be made aware of this rare disorder, since part of the reason for its high mortality rate is misdiagnosis for those who contract this rare, yet grave, disease.