Cyclophosphamide Treatment for Acquired Factor VIII Inhibitor in a Patient with AIDS-Associated Progressive Multifocal Leukoencephalopathy

Abstract

Acquired hemophilia A (AHA) is a severe bleeding disorder with high mortality rates resulting from the development of autoantibodies to factor VIII (FVIII). Patients typically present with hemorrhages in the skin, subcutaneous tissues, and muscles, which are frequently severe. They can also develop life-threatening retroperitoneal hematomas and compartment syndromes. We describe the case of a man with a long history of AIDS complicated by progressive multifocal leukoencephalopathy (PML), who developed AHA while on stable antiretroviral therapy and then presented with new onset bleeding and hypotension. We treated our patient with incrementally increasing doses of cyclophosphamide resulting in resolution of coagulopathy. We review the medical literature for additional cases of HIV-associated AHA and discuss the challenges in the care of our patient, since the immunosuppression needed to eradicate the FVIII inhibitor had the potential to cause recrudescence of his PML.

Introduction

Acquired hemophilia A (AHA) is a potentially life-threatening bleeding disorder resulting from the development of autoantibodies to factor VIII (FVIII). While these are the most common autoantibodies that affect clotting factor activity, the reported disease incidence is only 1.3 to 1.5 cases per million population per year, which may be an underestimate, given the diagnostic challenges. ^1,2 Patients typically present with hemorrhages in the skin, subcutaneous tissues, and muscles as well as mucosal bleeds. ^3,4 The hemorrhages are frequently severe and can be accompanied by life-threatening retroperitoneal hematomas and compartment syndromes. Joint bleeds, a characteristic feature of classical congenital hemophilia, are rare. Lack of personal or family history of bleeding, compounded by the severity and rarity of the condition, presents many diagnostic and management challenges for the clinician. ⁵ The goals of treatment involve control of bleeding followed by elimination of the inhibitor. ^{6 –8} The backbone of treatment consists of immunosuppressive therapies, of which the main ones are glucocorticoids, cyclophosphamide, and rituximab either as single agents or in varying combinations. Response to treatment is variable and the overall prognosis heterogeneous with mortality rates estimated at between 8% and 22%. ⁹

The most common diseases associated with AHA are autoimmune conditions (16%), malignancies (12%), pregnancy (8%), and exposure to various drugs (5%-10%). ^{7,10 –14} Fifty percent of cases are idiopathic, occurring most frequently in older adults. ^{7,10 –14} The association between AHA and HIV infection is largely anecdotal, with only a handful of case reports describing patients with HIV infection and FVIII inhibitors either in the backdrop of hepatitis C virus (HCV) co-infection, preexisting hemophilia, or in the context of highly active antiretroviral treatment (HAART) and immune reconstitution inflammatory syndrome (IRIS). ^{15 –19} We describe the case of a man with a history of AIDS complicated by progressive multifocal leukoencephalopathy (PML), who presented with new onset bleeding and an abnormal laboratory coagulation profile. We briefly review the literature of other cases of HIV-associated AHA and discuss the care of our patient while acknowledging concerns that the immunosuppression needed to eradicate the FVIII inhibitor could also exacerbate his underlying neurological condition.

Case Report

A 49-year-old man with a history of advanced AIDS was transferred from a skilled nursing facility (SNF) to the emergency department in October 2013, with low-grade fever, hypotension, and a large spontaneous bruise on the right arm. He had no prior history of abnormal bleeding or bruising, no family history suggestive of a bleeding disorder, and a coagulation profile in 2009 that was within normal limits. The patient was diagnosed with HIV-1 infection in 2006 when he presented with pneumocystis jiroveci pneumonia, a nadir CD4 count of 25 cells/mm³, and an HIV viral load of greater than 100 000 copies/mL. Over the next 2 years, he was poorly adherent to HAART. In 2008, he sought attention at our institution for short-term memory deficits and visual disturbances. A retinal examination was unremarkable, cerebrospinal fluid analysis showed 390 000 copies/mL of Jakob-Creutzfeldt (JC) virus, and magnetic resonance imaging of the brain showed white matter changes characteristic of PML (Figure 1). The patient began salvage HAART consisting of raltegravir, tenofovir (TDF)/emtricitabine, and lopinavir/ritonavir (LPV/r) and was transferred to an SNF. The patient currently resides in the SNF due to his inability to care for himself because of neurologic sequelae of PML, including blindness, severe short-term memory deficits, emotional liability, and tonic–clonic seizures. His neurologic deficits remained stable, and his CD4 count (190 cells/μL) and HIV viral load (<40 copies/mL) improved. In April 2013, his HAART regimen was switched to elvitegravir, cobicistat, TDF, and emtricitabine (STRIBILD; Gilead, Foster City, California) because of lipodystrophy and chronic low-grade diarrhea. The patient’s other medications were unchanged and included citalopram, levetiracetam, quetiapine, loratadine, mirtazapine, and trimethoprim/sulfamethoxazole. The patient’s physical examination was notable for orthostatic hypotension, tachycardia, and a large tense hematoma over the right arm, gingival oozing, and iatrogenic ecchymosis at the sites of needle puncture. His initial laboratory studies included a normal white blood count and platelet count but the hemoglobin level of 7 g/dL. Coagulation studies included a normal prothrombin time (PT) international normalized ratio of 1.1 and a normal thrombin time of 15 seconds, but the partial thromboplastin time (PTT) was prolonged at 92 seconds (upper limit of normal, 35.5 seconds). The patient was hospitalized, and over the ensuing days the patient developed additional massive bruises over the left arm and legs. Hematology consultation was obtained and further workup showed that a PTT mixing study with normal plasma failed to correct his coagulopathy and that he had an undetectable plasma FVIII activity (normal, >50%-200% of laboratory control) and a FVIII inhibitor level of 11 Bethesda units (BU) (upper limit of normal, 0.8). He also had a strongly positive lupus anticoagulant in the absence of other antiphospholipid antibodies and normal complement levels, and negative studies for antineutrophil cytoplasmic antibody, antinuclear antibody, antiproteinase 3, and antimyeloperoxidase. A serum electrophoresis did not reveal a monoclonal band. Incidentally, the patient was also diagnosed with adrenal insufficiency that was possibly the cause of his hypotension, and this corrected once he was started on hydrocortisone supplementation at a dose of 10 mg daily. Computerized tomographic imaging did not demonstrate any bleeding in the adrenals.

Figure 1.

Brain magnetic resonance image (MRI). Axial T1-weighted fluid-attenuated inversion recovery (FLAIR) image demonstrates abnormal signal intensity with patchy contrast enhancement involving the gray and white matter of the right temporal and occipital lobes and posterior and medial aspects of the left temporal lobe.

The patient’s hematomas were effectively managed by the nursing staff, with compression wraps and close monitoring for compartment syndrome. He received 4 units of packed red blood cells and cyclophosphamide at an initial oral dose of 50 mg/d. Each week his oral chemotherapy was titrated upward as 25 mg increments. The PTT peaked at 113 seconds, 10 days after beginning cyclophosphamide, and FVIII inhibitor level peaked at 47 BU 6 weeks after presentation. During this initial treatment period, his FVIII activity remained undetectable and he continued to bruise easily and had episodic guaiac-positive stool. Two months after beginning oral chemotherapy, and while he was receiving 175 mg of cyclophosphamide daily, the BU inhibitor value began to fall. By the third month of treatment, the patient had a detectable FVIII level and a normal PTT (Figure 2). Over the ensuing several months, his care team reduced his cyclophosphamide as 25 mg decrements and then discontinued after a consistently normal coagulation profile. The patient tolerated this treatment well, with no nausea or vomiting, no problematic hematuria, and no cytopenias.

Figure 2.

Trends in factor VIII activity and inhibitor titers. Factor VIII activity is expressed as a percentage of normal and inhibitor titers expressed in Bethesda units. Patient was treated with cyclophosphamide from October 15, 2013, through March 18, 2014.

Discussion

Patients with an acquired FVIII inhibitor typically seek medical attention (as our patient did) for marked bruising, rapidly expanding hematomas, gastrointestinal bleeding, and hematuria. Unlike inherited forms of hemophilia, hemarthrosis is less common. Laboratory assessment shows a prolonged PTT and a normal PT. It is important to recognize that an isolated prolongation in the PTT can be due to a number of causes, such as deficiencies or inhibitors of factors VIII, IX, or XI; von Willebrand disease (vWD), and the presence of antiphospholipid antibodies and heparin use. In a PTT mixing study, laboratory technicians combine patient plasma with pooled normal plasma, and the PTT is measured after a 2-hour incubation. Correction of the PTT suggests a factor deficiency or vWD, whereas a persistently abnormal PTT is indicative of the presence of an inhibitor. The Bethesda assay is particularly valuable and serves 2 purposes, that is, it secures the diagnosis of an acquired FVIII inhibitor and provides a measure of the titer. ²⁰ FVIII autoantibodies are usually polyclonal immunoglobulin (Ig) G belonging to IgG1 and IgG4 subclasses, although monoclonal IgA or IgM antibodies have been rarely described and mostly found in association with malignancies. The antibodies bind to the highly antigenic C2 and A2 domains on FVIII, resulting in impaired procoagulant activity. ²¹ Some human leukocyte antigen (HLA) class II alleles and single-nucleotide polymorphisms of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) are seen more frequently in AHA. This implies that CD4 T-helper lymphocytes may have a central role in the pathogenesis through regulation of humoral immunity. ²²

Only a small number of case reports have described an association between the presence of FVIII inhibitors and HIV infection. ¹⁷ Some occurred in patients with a history of congenital hemophilia A who after factor replacement therapy acquired alloantibodies to FVII. ²² A handful of patients coinfected with HIV and with HCV have been diagnosed with AHA. This occurred either while they were receiving interferon-based treatment for HCV or seemingly spontaneously and absent specific HCV treatment. ^19,23 Acquired hemophilia A has also been reported as a possible manifestation of IRIS. ^16,18,19,23 Both B-and T-cell immune dysregulation may predispose the development of autoantibodies and autoimmune diseases in this group. The autoimmune diseases described in HIV/AIDS include systemic lupus erythematosus, antiphospholipid syndrome, vasculitis, primary biliary cirrhosis, polymyositis, Graves disease, and idiopathic thrombocytopenic purpura, among others. In addition, an array of autoantibodies has been reported including anti-cardiolipin, anti-DNA, anti–small nuclear ribonucleoproteins (snRNPs), anti-thyroglobulin, anti-thyroid peroxidase, anti-myosin, and anti-erythropoietin antibodies. ¹⁵

Reactions associated with drug hypersensitivity may herald the onset of AHA. Suspected medications include antibiotics (penicillin, sulfonamides, and chloramphenicol), anticonvulsants (phenytoin), antihypertensive agents (methyldopa), and immunomodulatory agents (bacillus Calmette-Guérin vaccination, interferon, and fludarabine). ²⁰ These antibodies often disappear following cessation of the offending drug and the prognosis in these cases is favorable. In our patient, AHA manifested about 6 months after starting a new drug regimen consisting of elvitegravir, cobicistat, TDF, and emtricitabine, and therefore, it is conceivable that he developed a reaction to either the elvitegravir or the cobicistat that were both new to him. However, there are no reported cases of AHA in association with these drugs thus far and the inhibitor has not recurred post-oral cyclophosphamide even though these antiretroviral drugs remain and without changes is dose for the past 12 months.

The treatment goals for AHA are similar to the treatment goals for congenital hemophilia. Specifically, they revolve around efforts to control bleeding and eventually eradicate the antibody. However, unlike congenital hemophilia, there are no randomized trials on the treatment options for patients with AHA. Initial efforts to control bleeding are usually predicated by the severity of the bleeding and the titer of the inhibitor. Despite best efforts and very expensive therapies, bleeding-related mortality is considerable and ranges between 15% and 30%. ⁶

Patients with mild bleeding are treated with desmopressin acetate (DDAVP) or high-dose human FVIII concentrates. Those with substantial bleeding and high inhibitor levels require more aggressive interventions such as administration of activated prothrombin complex concentrate Factor 8 inhibitor bypassing activity (FEIBA). ⁴ For those patients who fail to respond and for whom bleeding remains problematic, human recombinant factor VIIa (rfVIIa) may be efficacious as a salvage therapy in as many as 80% of patients. ^5,24,25 While there are no randomized trials comparing FEIBA and rVIIa effectiveness, results from an uncontrolled European registry of 501 patients with acquired FVIII deficiency suggest that the 2 agents have similar efficacy. ²⁴ The choice between FEIBA and rfVIIa is dictated most often by local experience and cost considerations.

Elimination of the FVIII inhibitor requires the use of immunosuppressive modalities. There are no convincing data from randomized trials to show that one immunosuppressive regimen is better than the other or if the choice of regimen should be based upon the inhibitor titer or FVIII level. In a retrospective analysis of the outcomes of various immunosuppression regimens in 331 patients enrolled in the European Acquired Hemophilia Registry, complete remissions (ie, undetectable inhibitor levels, FVIII levels >70 International units/mL, and immunosuppression stopped) were noted in 48%, 70%, and 59% of those treated with glucocorticoids alone, glucocorticoids plus cyclophosphamide, and glucocorticoids plus rituximab, respectively. ⁷ The Ig administration did not improve the outcome. Second-line therapy was successful in approximately 60% of cases that failed first-line therapy, and the outcome was not affected by the choice of first-line therapy. Anecdotally, patients who do not respond to conventional immunosuppressive therapies may benefit from the use of cyclosporine or cladarabine, rituximab, as well as extracorporeal plasmapheresis with an immunoadsorption column to absorb the autoantibody.

Progressive multifocal leukoencephalopathy is a demyelinating disease of the central nervous system that occurs almost exclusively in immunosuppressed individuals, such as patients with AIDS, hematological malignancies, autoimmune diseases, patients undergoing organ transplantation, and patients with HIV infection, accounting for almost 85% of the total cases. ²⁶ The disease is characterized by widespread lesions due to oligodendrocytes infection caused by human papovavirus named JC virus. Progressive multifocal leukoencephalopathy has also been reported in patients receiving immune therapy with monoclonal antibodies (eg, rituximab) and other immunosuppressants, including prednisone, cyclophosphamide, methotrexate, and cyclosporine. The estimated risk of rituximab inducing PML is 1 event per 25 000 patients and the case fatality rate is 90%. ²⁷

In the pre-HAART era, the prognosis for patients with PML was dismal, with death occurring in approximately 95% of patients within 4 to 6 months after diagnosis. With the widespread adoption of HAART, the incidence of PML decreased substantially, and several case series have shown prolonged survival. Given our patient’s history of PML, we sought a treatment that would minimize adverse events and the risk of JC viral reactivation. We sought to minimize morbidity associated with our intervention by prescribing cyclophosphamide cautiously and in incremental doses while we closely monitored neurological function as well as the development of cytopenias and hematuria. We believe that the treatment did not exacerbate his underlying neurologic condition likely because our patient had been on stable HAART with suppressed viremia for a number of years. In summary, immunosuppression with cyclophosphamide was well tolerated in the context of stable HAART and resulted in the resolution of AHA without recrudescence of HIV replication or PML.