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Temple University

1. Bhavaraju, Kamala. MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS.

Degree: PhD, 2010, Temple University

Molecular and Cellular Physiology

Cardiovascular diseases are a major cause of mortality and morbidity in the developed countries. Anti-platelet therapy is a cornerstone treatment for patients with cardiovascular diseases. Patients are routinely managed with a combination therapy consisting of aspirin and clopidogrel. Aspirin inhibits cyclooxygenase 1 (COX 1) a crucial intermediate enzyme involved in thromboxane biosynthesis. Clopidogrel on the other hand antagonizes ADP receptor P2Y12. ADP is a weak platelet agonist stored in platelet dense granules and is released upon platelet activation. ADP activates platelets through two purinergic receptors namely P2Y1 and P2Y12 these receptors couple to Gq and Gi class of G-proteins, respectively. P2Y1 causes calcium mobilization through activation of PLC-β. P2Y12 inhibits adenylyl cyclase, causes activation of Rap1B and Akt. Signaling from both the receptors is required for complete integrin activation, thromboxane generation and Erk activation. Previous studies have shown that P2Y12 potentiates fibrinogen receptor activation, secretion, thrombi stabilization, thrombin generation, platelet leukocyte aggregation formation. ThromboxaneA2 (TXA2) is a potent platelet agonist generated through arachidonic acid metabolism in platelets. TXA2 thus, generated after platelet activation acts as a positive feedback mediator along with ADP. Under physiological conditions, platelet activation leads to thrombin generation through coagulation cascades. Generated thrombin activates PAR receptors and ADP is released from dense granules, which further potentiates thromboxane generation downstream of PARs. Current anti-platelet therapy regimens often include P2Y12 antagonists and aspirin in management of patients with acute coronary syndrome (ACS) and in those undergoing percutaneous coronary intervention (PCI) with stent implantation. However, there still exists a need for improved treatment strategies as not all patients benefit from this dual combination therapy. Reasons include, poor responders either to P2Y12 antagonists or to aspirin, or if aspirin is contraindicated in these patient populations. In the current study we evaluated the role of P2Y12 in thromboxane generation under physiological conditions. We studied serum thromboxane generation in a model system wherein P2Y12 was antagonized or deficient. Using pharmacological approaches we show that dosing mice with 30mg/Kg/body weight clopidogrel or 3mg/Kg/body weight prasugrel decreased serum thromboxane levels when compared to the control mice. Pre-treatment of human blood ex vivo with active metabolites of clopidogrel (R361015) or prasugrel (R138727) also led to reduction in thromboxane levels. We also evaluated serum thromboxane levels in P2Y receptor null mice, serum thromboxane levels in P2Y1 null mice were similar to those in wild type littermates, and were inhibited in P2Y12 null mice. Furthermore, serum thromboxane levels in P2Y12 deficient patients, previously described in France and Japan, were also evaluated and these…

Advisors/Committee Members: Kunapuli, Satya P., Driska, Steven Paul, Eguchi, Satoru, Woulfe, Donna.

Subjects/Keywords: Biology, Physiology; ADP Receptors; Anti-platelet Therapy; G12/13 Pathways; Platelets; Serum Thromboxane; Thrombin

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Bhavaraju, K. (2010). MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,92746

Chicago Manual of Style (16th Edition):

Bhavaraju, Kamala. “MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS.” 2010. Doctoral Dissertation, Temple University. Accessed October 30, 2020. http://digital.library.temple.edu/u?/p245801coll10,92746.

MLA Handbook (7th Edition):

Bhavaraju, Kamala. “MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS.” 2010. Web. 30 Oct 2020.

Vancouver:

Bhavaraju K. MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS. [Internet] [Doctoral dissertation]. Temple University; 2010. [cited 2020 Oct 30]. Available from: http://digital.library.temple.edu/u?/p245801coll10,92746.

Council of Science Editors:

Bhavaraju K. MOLECULAR PHYSIOLOGY OF THROMBOXANE A2 GENERATION IN PLATELETS. [Doctoral Dissertation]. Temple University; 2010. Available from: http://digital.library.temple.edu/u?/p245801coll10,92746

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