The K23 candidate (Sylvia T. Singer, MD) is a Pediatric Hematologist with a specific interest in the genetic blood disease thalassemia. The purpose of this proposal is to foster her scientific development so she may become an independent clinical investigator. The comprehensive thalassemia center at CHRCO will provide the applicant with the ideal setting in which to investigate the clinical, biochemical and cellular mechanisms leading to pulmonary hypertension (PHT) in thalassemia and investigate the effect of specific anticoagulant treatment. PHT is increasingly recognized as cause for significant morbidity and mortality in thalassemia patients. However, the prevalence in non-selected thalassemia patients, the clinical risk factors and mechanism of its development are not fully understood, resulting in sub-optimal screening and inadequate treatment. Hypercoagulability has been known to occur in thalassemia and thought to play a major role in the pathogenesis of PHT.
The specific aims of this proposal are: (1) To determine the factors responsible for the development of PHT and identify associated coagulation and inflammatory markers. (2) To determine if commonly applied treatment with an anti-coagulant (coumadin) or a platelet-inhibitor (aspirin), beneficially affect these physiological markers. As no controlled studies have been done for treatment of this complication, this information is fundamental prior to initiation of randomized controlled clinical trials for PHT in thalassemia. Dr. Singer has demonstrated that platelet activation and thrombin generation are associated with PHT and that they can result in endothelial and inflammatory changes; hence specific anti-platelet or anti-thrombin agents may be a new and specific intervention which could prevent or improve PHT in thalassemia patients, in future studies. Successful completion of the research outlined in this proposal will substantially increase our knowledge of the pathogenesis of PHT and on the potential utility of specific therapeutic agents, which could improve life expectancy and quality of life for these patients.
| Singer, Sylvia T; Kuypers, Frans; Fineman, Jeffery et al. (2014) Elevated tricuspid regurgitant jet velocity in subgroups of thalassemia patients: insight into pathophysiology and the effect of splenectomy. Ann Hematol 93:1139-48 |
