An unusual cause of bruising

FACTOR VIII INHIBITOR EVALUATION

2. What is the most likely underlying condition associated with this patient’s factor VIII inhibitor?

• Autoimmune disease
• Malignancy
• A medication
• Unknown (idiopathic)

Acquired hemophilia A (AHA) is a rare disorder caused by autoantibodies against factor VIII. Its estimated incidence is about 1 person per million per year.⁴ It usually presents as unexplained bruising or bleeding and is only rarely diagnosed by an incidentally noted prolonged aPTT. The severity of bleeding is variable and can include subcutaneous, soft-tissue, retroperitoneal, gastrointestinal, and intracranial hemorrhage.⁵

AHA is considered idiopathic in more than half of cases. A study based on a European registry⁵ of 501 patients with AHA and a UK study⁶ of 172 patients found no underlying disease in 52% and 65% of patients, respectively. For patients with an identified cause, the most common causes were malignancy (12%⁵ and 15%⁶) and autoimmune disease (12%⁵ and 17%⁶).

Drugs have rarely been associated with factor VIII inhibitors. Such occurrences have been reported with interferon, blood thinners, antibiotics, and psychiatric medications, but no study yet has indicated causation. However, patients with congenital hemophilia A treated with factor VIII preparations have about a 15% chance of developing factor VIII inhibitors. In this setting, inhibitors develop in response to recombinant factor VIII exposure, unlike the autoimmune phenomena seen in AHA.

TREATMENT OF ACQUIRED HEMOPHILIA A

3. What is the most appropriate treatment for AHA?

• Desmopressin and prednisone
• Recombinant porcine factor VIII and prednisone plus cyclophosphamide
• Recombinant factor VIIa and rituximab
• Any of the above

Any of the above regimens can be used. In general, treatment of AHA has two purposes: to stop acute hemorrhage, and to reduce the level of factor VIII inhibitor. No standard treatment guidelines are available; evidence of the effectiveness of different drugs is based largely on data on congenital hemophilia A.³

Acute treatment to stop bleeding

Initial treatment of AHA often focuses on stopping an acute hemorrhage by either raising circulating levels of factor VIII or bypassing it in the coagulation cascade.

Desmopressin can temporarily raise factor VIII levels, but it is often ineffective in AHA unless the patient has very low inhibitor titers.³

Factor VIII concentrate (human or recombinant porcine factor VIII) may be effective in patients with low inhibitor titers (< 5 BU). Higher doses are often required than those used in congenital hemophilia A. Factor VIII concentrate is usually combined with immunosuppressive treatment to lower the factor VIII inhibitor level (described below).³

If these methods are ineffective or the patient has high inhibitor titers (> 5 BU), activated prothrombin complex concentrates, known as FEIBA (factor eight inhibitor bypassing activity), or recombinant factor VIIa is available. These agents bypass factor VIII in the clotting cascade.

Immunosuppression to reduce factor VIII inhibitor

Immunosuppressive agents are the mainstay of AHA treatment to lower the inhibitor level.

Regimens vary. A 2003 meta-analysis⁴ including 249 patients found that prednisone alone resulted in complete response in about 30% of patients, and the addition of cyclophosphamide increased the response rate to 60% to 100%. High-dose intravenous immunoglobulin led to conflicting results. Conclusions were limited by the variability of dosing and duration in treatment regimens among the 20 different studies included.

An analysis of 331 patients in the European Acquired Hemophilia Registry (EACH2)⁷ found that steroids alone produced remission in 48% of patients, while steroids combined with cyclophosphamide raised the rate to 70%. Rituximab-based regimens were successful in 59% but required twice as long to achieve remission as steroid or cyclophosphamide-based regimens. No benefit was noted from intravenous immunoglobulin.

Risks of disease and treatment

AHA is associated with significant risk of morbidity and death related to bleeding, complications of treatment, and underlying disease.

In EACH2, 16 of the 331 patients died of bleeding, 16 died of causes related to immunosuppression, and 45 died of causes related to the underlying condition.⁵ In the UK registry of 172 patients, 13 patients died of bleeding, and 12 died of sepsis related to immunosuppression.⁶

The factor VIII level and inhibitor titer are not necessarily useful in stratifying bleeding risk, as severe and fatal bleeding can occur at variable levels and patients remain at risk of bleeding as long as the inhibitor persists.^6,7