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HHT for the hematologist
monary and cerebral AVMs that may increase their bleed- ing risk.
Clinical trials and future directions
There are several ongoing clinical trials studying new therapies for HHT (Online Supplementary Table S1). HHT is relatively unique in the family of rare bleeding disor- ders in that several off-the-shelf therapeutics, such as bevacizumab, and the immunomodulatory agents (IMiDs) currently being used are rational targeted thera- pies that may be highly effective. The majority of studies are currently investigating the use of bevacizumab via dif- ferent routes of administration (submucosal, topical or intravenous). In a murine model of HHT, four anti-angio- genic agents were studied for their impact on AVM for- mation.73 Sorafenib (a dual Raf kinase/VEGF receptor inhibitor with additional tyrosine kinase targets) and a pazopanib analog (pazopanib is a multi-target tyrosine kinase inhibitor with anti-VEGF receptor properties) were beneficial in improving anemia from bleeding from the GI tract more than from mucocutaneous lesions in the upper aerodigestive tract. A phase II study is being conducted to examine the efficacy of increasing doses of pazopanib, from 50 mg to 400 mg daily, in reducing epistaxis and improving anemia.
Tacrolimus, a calcineurin inhibitor used principally as an immunosuppressive therapy, may have a therapeutic role in HHT. Ruiz et al. identified tacrolimus as an activator of the ALK1-SMAD1/5/8 pathway, improving defects caused by ALK1 loss.74 Their data in human embryonic vascular endothelial cells demonstrated that tacrolimus activated
ALK1 HHT mutants unresponsive to BMP9, and inhibited Akt and p38 stimulation by VEGF (normally a major driver of angiogenesis). In a mouse model of HHT, hypervascu- larization and AVMs were reduced in number by treat- ment with tacrolimus. Tacrolimus may, therefore, repre- sent yet another off-the-shelf pharmacological option of potential therapeutic benefit in HHT patients.
Lastly, the aforementioned IMiDs are promising. In com- parison with thalidomide and lenalidomide, pomalidomide may be a superior potential therapeutic option due to its efficacy and reduced toxicity (such as less peripheral neu- ropathy and cytopenias). Interim results from a phase I study of pomalidomide in HHT patients have been report- ed in which its use was associated with reduced bleeding outcomes in a small cohort of patients.75 Larger studies are needed to better evaluate the efficacy of this and other IMiDs in the management of bleeding in HHT.
Future directions in HHT may look to evaluate other antiangiogenic agents and other targets of the vascular endothelium. In patients with Heyde syndrome, acquired VWF syndrome occurs due to the loss of large molecular multimers of VWF from high shear stress.76 The reduced level of VWF observed in a small case series of patients with HHT36 raises the question of whether VWF replace- ment may reduce bleeding, as patients with ineffective or low VWF cannot effectively clot. Better understanding of the role of acquired VWF deficiency in the pathogenesis of angiodysplasia in Heyde syndrome may prove useful in the development of novel HHT therapies.
In conclusion, HHT is a rare but poorly recognized genetic bleeding disorder that demands greater attention in order to develop targeted and rational management strategies that are both safe and cost-effective.
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