There is one clinical trial.
The investigators will study digoxin to inhibit the hypoxic response in congenital erythrocytosis due to germ line mutations that result in up-regulated hypoxia sensing. These forms of congenital erythrocytosis, characterized by augmented levels of hypoxia inducible factor (HIF)-1 and HIF-2, are due to mutations of VHL (von Hippel Lindau), EGLN1 (encoding prolyl hydroxylase 2 [PHD2]) and EPAS1 (endothelial PAS domain-containing protein 1) (encoding HIF-2α). In addition to a high hematocrit, patients have thrombotic complications and early mortality that are not improved by phlebotomy therapy. There is no effective therapy. Digoxin, long used to treat congestive heart failure, is a potent inhibitor of the master hypoxia-inducible transcription factor, HIF-1. The study hypothesis is that pharmacologic doses and levels of digoxin will decrease hemoglobin and hematocrit, decrease need for phlebotomy, decrease the propensity to thrombosis and decrease pulmonary pressure in patients with erythrocytosis due to up-regulated hypoxic responses. The clinical trial consists of 24 weeks of digoxin therapy in patients with hypoxic response-related erythrocytosis. The complete blood count, safety, symptoms of headache and lack of energy, echocardiogram, physical performance, and plasma products and blood cell expression of HIF-1-regulated genes are the outcome variables.
Chuvash erythrocytosis (CE), endemic in the Chuvash Republic of Russia and the Italian island of Ischia, is due to homozygosity for a missense mutation of VHL (VHL c.598C>T; VHL R200W). --- R200W ---
VHL R200W impairs interactions of VHL with HIF-α subunits, reducing their ubiquitin-mediated destruction. --- R200W ---
Aim 3. In a corollary study, determine if in vivo achievable digoxin concentrations abrogate in vitro erythroid progenitor EPO hypersensitivity of mutations other than VHL R200W, and if HIF-2α inhibitors (already in clinical trials) abrogate erythroid progenitor EPO hypersensitivity alone or in combination with digoxin. --- R200W ---
Description: Change of 1.5 g/dL or moreMeasure: Hemoglobin concentration Time: 24 weeks
Description: Change in log Epo concentration of 15% or moreMeasure: Serum EPO concentration Time: 24 weeks
Description: Change compared to baselineMeasure: Plasma concentration of PAI-1 (plasminogen activator inhibitor 1) Time: 24 weeks
Description: Change compared to baselineMeasure: Granulocyte mRNA (messenger ribonucleic acid) expression of F3 as determined by RT-PCR (reverse transcription polymerase chain reaction) Time: 24 weeks
Description: Change compared to baselineMeasure: Tricuspid regurgitation velocity determine by echocardiogram Time: 24 weeks