Acquisition of Factor VIII Inhibitor After Acute Hepatitis C Virus Infection

To the Editor:

We report an unusual case of acquired serious factor VIII deficiency due to the development of human factor VIII inhibitor that occured in an elderly female patient 2 months after having had an acute episode of hepatitis C virus (HCV). The case may suggest that the event could be a rare complication after HCV acute infection. An 84-year-old woman suffering from psoriasis, gastritis, and slight glucose intollerance was admitted to our division, in July 1996, because of jaundice and suspected acute hepatitis. The serum transaminase level was elevated (aspartate transaminase [AST] 923 U/L, alanine transferase [ALT] 765 U/L), showing hepatic cytolysis, and the total bilirubin level was 13.9 mg%. An ultrasonographic examination of the liver showed the presence of a sclero-atrophic gallbladder, and biopsy of gastric mucosa, effectuated during gastroscopy, showed a chronic gastritis associated to Helicobacter pylori.

Abnormal ALT serum level (1,776 U/L) persisted during the first 2 weeks, subsiding thereafter gradually. The HCV antibody titer, which was determinated by specific immune absorbent assays, increased from 0.55 to 1.57 optical density (OD) during her 3-week stay at the hospital, after which she was discharged with diagnosis of HCV acute hepatitis. The recombinant immunoblotting assay test showed antibody positivity against C-33 antigen; antinuclear autoantibodies, lupus anticoagulant, and crioglobulins were negative. No bleeding or other signs of coagulopathy were reported at admittance until discharge: prothrombin time (PT) was 81%, partial thromboplastin time (PTT) was 55 seconds, and platelet count was 195,000/μL. Afterwards, the patient was observed at the divisional day hospital without evidence of complications. Two months later, the patient was readmitted with a large, spontaneous left arm hematoma, hematuria, and evidence of poor coagulation. The platelet count was 232,000/μL; PTT was prolonged to 93 seconds, PT was 75%, and only factor VIII, among other prothrombin factors, was found decreased to a level of 0.013 IU/mL (normal range, 0.70 to 1.50 IU/mL). The human factor VIII specific inhibitor was found to be positive (37.7 Bethesda unit [BU]/mL), whereas porcine factor inhibitor was 1.6 BU/mL. To avoid autoimmune response against porcine factor VIII, the patient was treated on activated prothrombin complex concentrate at 75 U/kg and methylprednisolone at 40 mg daily for 3 weeks, reserving treatment with porcine factor VIII concentrate for more severe events or high-risk situations of hemorragia.

No bleedings occurred any further and the patient was referred to a center for coagulation of another hospital.

One month later, because of recurrency of hematuria, she underwent cystoscopic examination and a bladder benign papilloma was removed under coverage of preentive treatment with porcine factor VIII (100 U/Kg) everyday for 2 days. A week later, the patient was discharged.

A month later, the patient died at home after a severe acute bleeding episode of the gastrointestinal tract.

Development of inhibitors against factor VIII or factor IX is a common complication during specific substitutive treatment of hemophilia,1,2 and it is occasionally reported during interferon-α chronic therapy in patients with hemophilia A and chronic HCV hepatitis,3 but its relationship with acute or chronic HCV hepatitis is unknown.

The mechanism responsible for development of inhibitory reactivity against factor VIII in hemophilia A is related to the immunologic restricted specificity of inhibitor antibodies against regions on factor VIII protein; their reaction has been identified on immunoblotting.4 The 44-kD fragment from the heavy chain and the 72-kD fragment from the light chain of factor VIII, either or both, are immunogenic5 and increase antibody response toward them. Our patient did not have a history or signs of bleeding or spontaneous soft tissue hematomas before developing acute C hepatitis, and there has been no evidence of autoantibodies or clinical evidence of autoimmune diseases. This report suggests the possibility that, in this case, acute HCV infection could have induced the development of human factor VIII specific inhibitor.