A Case of Acquired Hemophilia Post Treatment with Recombinant Human Activated Protein C (rh APC).

A 87-year old male without a diagnosis of hemophilia presented to the ER with a large shoulder hematoma, developing after a minor fall. Activated partial thromboplastin time (aPTT) was 79.4 sec, not correcting on mixing studies.

Factor assays showed a factor VIII of 11.9 %, factor IX of 74.7 %, factor XI of 82.2 % and factor XII of 65.5 %. Anticardiolipin IgG, IgM antibodies and lupus anticoagulant were negative.

Factor VIII inhibitor was found and initially measured at 14 Bethesda Unit (BU). A diagnosis of Acquired Hemophilia was made and the patient was treated with recombinant factor VII (rVIIa) and factor VII concentrates, FFP, PRBC transfusions and steroids.

The patient had 4 bleeding episodes during hospitalization. First episode was not treated because of the lack of correct diagnosis. However, rVIIa was administered for all bleeding episodes and prior to surgical procedures like tracheostomy.

Interestingly, despite immunosupression with steroids, the inhibitor titer did not decrease, rather it displayed a greater variation in the BU values ranging from 14 to 67.

The patient bled unpredictably at different titers of inhibitor, without any concordance between the bleeding or the aPTT or the BU value. Finally,he succumbed to uncontrolled bleeding from the tracheostomy site and expired on operating table on day 30 of his fateful admission.

This is a unique case of Acquired Hemophilia as 8 months ago this patient had received rhAPC, also known as Drotrecogin Alfa Activated (DAA) for severe sepsis with APACHE score of 25.

DAA has a newly established therapeutic role in the inhibitor of factors Va and VIIIa, limiting the thrombotic effect and thus the mortality of sepsis. However, cost-effectiveness and safety of DAA remain somewhat controversial.

Despite its recent entry into the medical armamentarium of our fight against sepsis, there exist several references in the published literature about the need of a confirmatory prospective trial about its role even in patients with a high APACHE score. Although neutralizing antibody against APC have not been detected in any patient and there are no published reports about DAA induced antibodies to factor VIII, it remains a viable hypothesis nonetheless.

Unknown mechanisms such as exposure of new epitopes of factor VIII degraded by rhAPC could precipitate factor VIII antibodies. Further, the unpredictable titer of factor VIII inhibitor may be secondary to the unique mode of antibody formation in this instance.