Sickle cell disease (SCD) is a hematological disorder caused by a single nucleotide mutation in the ?-globin gene of hemoglobin (Hb). Under hypoxic conditions, sickle Hb tetramers polymerize which results in sickling of red blood cells, leading to hemolytic anemia and vaso-occlusion. This leads to a complex vascular pathophysiology associated with oxidative stress, ischemia/reperfusion, endothelial cell activation, inflammation and activation of coagulation1. We have recently demonstrated that tissue factor (TF), the primary initiator of the extrinsic coagulation pathway, contributes to coagulation activation, endothelial cell activation and inflammation in the two mouse models of SCD2. TF and the downstream coagulation proteases factor VIIa (FVIIa), FXa, and thrombin, can contribute to the inflammatory response by activating protease activated receptors (PARs). Thrombin and other proteases activate PAR-1, whereas TF:FVIIa and FXa activate PAR-2. In addition to systemic inflammation and neutrophil activation, PAR-2 signaling is associated with pulmonary hypertension (PH), a common clinical complication in SCD patients. PH in SCD has been linked to pulmonary vasoconstriction, mediated by hemolysis and NO depletion3. An alternative hypothesis that thrombosis may contribute to the development of PH has recently been proposed4-6. Interestingly, FXa7, PAR-28,9 and IL-610,11 have been linked to that pathogenesis of PH in rodent models. Therefore, I will test the hypothesis that FXa mediates both thrombosis and PAR-2 dependent inflammation, which contribute to PH in SCD. My proposal is divided into two aims.
In Aim 1, I will assess the effects of PAR-2 deficiency or pharmacologic inhibition of PAR-2 on the development of PH in sickle cell mice.
In Aim 2 I will use the clinically approved FXa inhibitor rivaroxaban to determine the effect of long-term FXa inhibition on coagulation, inflammation and PH in sickle cell mice. These results will be compared to those obtained from mice treated with the thrombin inhibitor dabigatran. These studies will increase our understanding of the etiology of PH in SCD, and provide insight into therapeutic targets that could be used to reduce inflammation, coagulation, and PH in patients.

Public Health Relevance

Over 300,000 children are born with SCD every year12. Treatment options are limited to hydroxyurea therapy and bone marrow transplantation, and clinical complications severely limit the lifespan of SCD patients. Increased understanding of the pathways that contribute to end-organ pathology will enable the scientific and medical communities to identify therapeutic targets and treatment strategies to manage this complex disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Colombini-Hatch, Sandra
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University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
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Sparkenbaugh, Erica M; Chantrathammachart, Pichika; Chandarajoti, Kasemsiri et al. (2016) Thrombin-independent contribution of tissue factor to inflammation and cardiac hypertrophy in a mouse model of sickle cell disease. Blood 127:1371-3
Sparkenbaugh, Erica M; Chantrathammachart, Pichika; Wang, Shaobin et al. (2015) Excess of heme induces tissue factor-dependent activation of coagulation in mice. Haematologica 100:308-14
Antoniak, Silvio; Sparkenbaugh, Erica; Pawlinski, Rafal (2014) Tissue factor, protease activated receptors and pathologic heart remodelling. Thromb Haemost 112:893-900