Investigation of a Thromboxane A ₂ Receptor–Based Vaccine for Managing Thrombogenesis

Abstract

BackgroundDespite the well‐established role for the thromboxane A2 receptor (TPR) in the development of thrombotic disorders, none of the antagonists developed to date has been approved for clinical use. To this end, we have previously shown that an antibody targeted against TPR's ligand‐binding domain inhibits platelet activation and thrombus formation, without exerting any effects on hemostasis. Thus, the goal of the present studies is to design a novel TPR‐based vaccine, demonstrate its ability to trigger an immune response, and characterize its antiplatelet and antithrombotic activity.Methods and ResultsWe used a mouse keyhole limpet hemocyanin/peptide‐based vaccination approach rationalized over the TPR ligand‐binding domain (ie, the C‐terminus of the second extracellular loop). The biological activity of this vaccine was assessed in the context of platelets and thrombotic diseases, and using a host of in vitro and in vivo platelet function experiments. Our results revealed that the TPR C‐terminus of the second extracellular loop vaccine, in mice: (1) triggered an immune response, which resulted in the development of a C‐terminus of the second extracellular loop antibody; (2) did not affect expression of major platelet integrins (eg, glycoprotein IIb‐IIIa); (3) selectively inhibited TPR‐mediated platelet aggregation, platelet‐leukocyte aggregation, integrin glycoprotein IIb‐IIIa activation, as well as dense and α granule release; (4) significantly prolonged thrombus formation; and (5) did so without impairing physiological hemostasis.ConclusionsCollectively, our findings shed light on TPR's structural biological features, and demonstrate that the C‐terminus of the second extracellular loop domain may define a new therapeutic target and a TPR vaccine‐based approach that should have therapeutic applications.

The JUUL E-Cigarette Elevates the Risk of Thrombosis and Potentiates Platelet Activation

“…Washed platelets were prepared as described previously. 25 , 28 Blood was drawn from mice as described earlier, and it was mixed with phosphate-buffered saline (pH 7.4), incubated with PGI 2 (10 ng/mL; 5 minutes), to ensure there is no platelet activation. Platelets underwent centrifugation (10 minutes, RT; at 237 g ).…”

TxA 2 Receptor‐Based Vaccination: A Novel Potential Therapeutic Approach to Limit Thrombosis

“…Taken together, the work from Alshbool et al4 is an important step toward the development of a potential vaccine against TPR. The vaccine would potentially provide complete inhibition of platelet TPR.…”

“…In this issue of the Journal of the American Heart Association (JAHA) , Alshbool et al4 reported excellent in vivo results for a peptide‐based vaccine against TPR. Platelet TPR, a G‐protein–coupled receptor, is clinically important because it mediates platelet activation and aggregation through TxA 2 binding 5.…”

“…Alshbool et al4 used a novel approach to inhibit TPR. They showed interesting results from a study testing a vaccine against platelet TPR.…”

Pathophysiological role of prostanoids in coagulation of the portal venous system in liver cirrhosis

“…Importantly, COX-2 and TXAS are induced by various inflammatory stimuli, resulting in a close relationship between inflammation and regulation of the vascular tone and platelet function[5]. Hence, increased production and activity of TXA 2 is known to contribute to the pathogenesis of diverse thrombotic arterial diseases, such as stroke or coronary heart disease[6,7]. However, little is known about the role of TXA 2 in the portal vein and thrombosis in the portal compartment.…”