Risk of Hypertension in Hemophilia Patients with a History of Inhibitors
Authors: Ter-Zakarian Anna , Barnes Richard , Kruse-Jarres Rebecca , Quon Doris , Jackson Shannon , Sun Linda , von Drygalski Annette 
Published: February 2021

Hemophilia is an X-linked bleeding disorder characterized by deficiencies of Factor VIII or IX. Hypertension in persons with hemophilia (PWH) appears to be more prevalent compared to the general population. A major complication of hemophilia remains the development of neutralizing antibodies (inhibitors) against infused clotting factor. It tends to occur within the first 50 exposure days and therefore mostly in children with severe hemophilia. Since inhibitor development is associated with high mortality and morbidity, their eradication with high dose clotting factor concentrates is critical and successful in the majority of patients. Recently a cohort study showed a positive association between presence of inhibitors in elderly patients and cardiovascular disease, although a small number of patients with inhibitors were included in that study (Sood SL, Blood Advances 2018). To date, the link between a history of inhibitors and hypertension has not been established. The primary purpose of our study was to evaluate the relationship between hypertension in PWH and a history of inhibitors, with the additional goals of investigating the association between hypertension and hemophilia type and viral status.
In a retrospective review, clinical records were extracted for PWH aged 18 to 79 between 2003 and 2014 from four Hemophilia Treatment Centers in North America: Los Angeles Orthopaedic Hospital, University of California San Diego, Tulane University and University of British Columbia. We extracted demographic information on age and ethnicity, weight, height, hemophilia type and severity, inhibitor history, Hepatitis C (HCV; by serology) and Human Immunodeficiency Virus (HIV) status or reported history thereof and medication history. Primary outcomes were prevalence of hypertension stratified by inhibitor status, hemophilia type, and presence of viral coinfection. Blood pressure measurements were taken for the three clinic visits closest to the evaluation date.
We fitted generalized additive models with a non-parametric spline function for age. The outcomes were hypertension (with a binary logit), systolic blood pressure (SBP) and diastolic BP (DBP). The models were adjusted for logBMI, type of hemophilia, severity, race/ethnicity, HCV and HIV. We plotted standardized curves generated by the models to compare trends in each outcome.
A total of 691 PWH were included. Forty-four (6%) had a history of inhibitors, 533 had hemophilia type A (77%) and 157 had hemophilia type B (23%). HCV was positive in 419 patients (61%) and HIV in 128 patients (19%).
There was no difference in the risk of hypertension between patients with or without a history of inhibitors. SBPs and DBSs were only analyzed for patients not on anti-hypertensives, and were not associated with a history of inhibitors (Fig. 1A). However, risk of hypertension was considerably higher among patients with Hemophilia B compared to patients with Hemophilia A (Fig. 1B). Hemophilia B patients were more likely to be categorized as hypertensive because both SBPs and DBPs were higher, especially in patients between 40 and 60 years of age. Finally, risk of hypertension was higher among those coinfected with both HCV and HIV (Fig. 1C).
This large-scale study found no evidence that inhibitor history influenced the risk for hypertension or elevated BPs in PWH. Interestingly, Hemophilia B was associated with a higher risk of hypertension and higher BPs, similar to prior studies showing Hemophilia B had 1.87-fold higher odds of hypertension compared to Hemophilia A (von Drygalski A, Hypertension, 2013). Inhibitor development in Hemophilia B is very rare, which provides additional support that factors other than inhibitors play a role. Finally, our study showed coinfection with HIV and HCV was associated with higher hypertension risk, adding clarity to inconsistent findings on the association between hypertension and blood transmitted viral diseases in PWH.
While there was no evidence that patients with a history of inhibitors have a higher risk of hypertension, our observations add to the continued efforts to elucidate the etiology of the hypertension in hemophilia and confirm that patients with Hemophilia B and/or viral infections may be at higher risk. These findings continue to inform medical care and also pave the way for additional studies to address physiological factors inherent to hemostasis and vascular pathology.

Disclosures
Kruse-Jarres: NovoNordisk: Other; CSLBehring and Genentech/Roche: Research Funding; Biomarin, Chugai, CSLBehring, and Genentech/Roche: Consultancy. Quon:Orthopaedic Institute for Children: Current Employment; Bayer: Honoraria; Shire/Takeda: Speakers Bureau; Genentech, Inc./F. Hoffmann-La Roche Ltd: Honoraria, Speakers Bureau; Octapharma: Honoraria; Novo Nordisk: Honoraria, Speakers Bureau; Bioverativ/Sanofi: Honoraria, Speakers Bureau; Biomarin: Honoraria, Speakers Bureau. Jackson:Octapharma, Takeda, Bayer, Roche and Pfizer: Honoraria; Bayer: Research Funding; Sanofi: Research Funding. von Drygalski:Hematherix Inc: Membership on an entity's Board of Directors or advisory committees, Other: Cofounder; superFVa; Joint Activity and Damage Examination (JADE) Ultrasound measurement tool: Patents & Royalties; Biomarin, Bioverativ/Sanofi-Genzyme, Novo Nordisk, Pfizer, Uniqure, Takeda: Consultancy.