Thrombin also promotes secondary fibrin-reinforcement of the platelet plug. Platelet activation in turn degranulates and releases factor V and fibrinogen, potentiating the coagulation cascade. So, in reality, the process of platelet plugging and coagulation are occurring simultaneously rather than sequentially, with each inducing the other to form the final fibrin-crosslinked thrombus. Components (consequences)
GPIIb/IIIa activation
Collagen-mediated GPVI signalling increases the platelet production of thromboxane A2 (TXA2) and decreases the production of prostacyclin. This occurs by altering the metabolic flux of platelets eicosanoid synthesis pathway, which involves enzymes phospholipase A2, cyclo-oxygenase 1, and thromboxane-A synthase. Platelets secrete thromboxane A2, which acts on the platelets own thromboxane receptors on the platelet surface (hence the so-called "out-in" mechanism), and those of other platelets. These receptors trigger intraplatelet signaling, which converts GPIIb/IIIa receptors to their active form to initiate aggregation. Granule secretion
Platelets contain dense granules, lambda granules and alpha granules. Activated platelets secrete the contents of these granules through their canalicular systems to the exterior. Simplistically, bound and activated platelets degranulate to release platelet chemotactic agents to attract more platelets to the site of endothelial injury.
In a 2016 report using both mouse models and a limited human clinical trial ROCK2 inhibition with belumosudil targeted both the immunologic and fibrotic components of cGvHD and reversed the symptoms of the disease.In October 2017, belumosudil was granted orphan drug status in the United States for treatment of patients with cGvHD.Efficacy of belumosudil was evaluated in clinical trial NCT03640481, a randomized, open-label, multicenter dose-ranging trial that included 65 patients with chronic GVHD who were treated with belumosudil 200 mg taken orally once daily.On 16 July 2021, the U.S. Food and Drug Administration (FDA) approved belumosudil for adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. Research
IPF is a progressive fibrotic disease where the lining of the lungs become thickened and scarred. Increased ROCK activity has been found in the lungs of humans and animals with IPF. Treatment with belumosudil reduced lung fibrosis in a bleomycin mouse model study.Psoriasis is an inflammatory skin condition where patients experiences eruptions and remissions of thickened, erythematous, and scaly patches of skin. Down-regulation of pro-inflammatory responses was observed with KD025 treatment in Phase 2 clinical studies in patients with moderate to severe psoriasis. References
External links
"Belumosudil". Drug Information Portal. U.S. National Library of Medicine.