The Impact of the First Exposure to Different Blood Products on the Prevalence and Natural History of Hepatitis C Virus Infection in Von Willebrand Disease (VWD): Results from a Large Cohort Study Comparing VWD and Hemophilia Patients.

Background: Hepatitis C virus (HCV) infection is a major cause of morbidity and mortality in patients with inherited bleeding disorders who received clotting factors concentrates before the introduction of viral inactivation procedures in the mid 1980s. Severity of hepatitis C has been largely associated to male gender, long duration of infection, high prevalence of genotype 1, high levels of viremia and multiple inocula with HCV. Compared to hemophiliacs (HEM), patients with von Willebrand disease (VWD) have been less extensively exposed to large-pool concentrates because they usually have a less severe bleeding diathesis and bleedings could be often controlled in the past by desmopressin (DDAVP) or cryoprecipitates prepared by national blood banks.

Aims and Study design: To assess the prevalence and natural history of HCV infection in VWD, 358 patients (VWD types 1=41%; 2=53%;3=6%) regularly followed up at the Angelo Bianchi Bonomi Hemophilia Thrombosis Center of Milan have been surveyed since 1998 in this six-year cohort study. Blood borne viral markers have been controlled yearly in all transfused patients and liver function tests have been monitored in all HCV infected cases at least every six months. To explore the impact of different blood products on HCV infection, the 358 VWD were also compared with 397 HEM (mild =27%, moderate = 9%, severe = 64%) similarly followed up at the same Center, taking into account the type of blood components or FVIII concentrates to which individual patients of both populations were first exposed.

Methods: The comparison between VWD and HEM data were performed by univariate analysis (t-test). Multivariate unconditional logistic regression was used to analyze the association between HCV genotypes and VWD/HEM status: maximum likelihood estimates of odds ratios and 95% confidence intervals were also calculated.

Results: Data obtained in VWD/HEM are as follows: A) Blood transfusions: 1) transfused patients= 39/95%; 2) First exposures to: whole blood or plasma=58/9%; cryoprecipitate=22/4%; large-pool FVIII concentrates=20/87%. B) Blood borne infections: 1) anti-HIV=1.4/23%; 2) anti-HCV=43/96%; 3) HCV-RNA negative=19/20%; 4) HCV genotype distribution: 1a=17/38%; 1b=32/30%; 2=26/16%; 3=21/14%; 4=4/2%. Even though genotype distribution was clearly different in VWD, only the risk to be infected by HCV type 1a was significantly reduced (OR=0.36; 95% CI 0.15–0.84). However, no difference was found in the exposure to large-pool concentrates between VWD and HEM with HCV type 1a infection (57 versus 67%, p-value=0.3). C) Natural history of HCV infection: 1) Male gender=41/99%; 2) Median age at infection=24/7 years with ranges = 10-69/5-68; 3) Serum ALT activity persistently or intermittently high= 67/79% (p-value=0.06) in cases with positive HCV-RNA; 4) Cirrhosis and HCC= 4/9% (p-value=0.4) of patients, respectively.

Conclusions: VWD Italian patients showed a sporadic risk of infection with HIV and a lower prevalence of HCV. HCV genotypes distribution seems to reflect the source of blood products and can influence the natural history of HCV in VWD, as shown by the relatively lower incidence of liver abnormalities.