Significant progress was achieved in the search of a thrombin receptor antagonist as a novel antithrombotic treatment since the thrombin receptor (protease-activated receptor-1, PAR-1) was cloned 20 years ago. Previou...Significant progress was achieved in the search of a thrombin receptor antagonist as a novel antithrombotic treatment since the thrombin receptor (protease-activated receptor-1, PAR-1) was cloned 20 years ago. Previous works have shown that it is possible to develop potent thrombin receptor antagonists to compete effectively with the receptor’s internal “tethered” ligand to block platelet activation. Vorapaxar (SCH 530348) from Schering-Plough (now Merck) and atopaxar (E5555) from Eisai have been advanced to human clinical trials. Recently, the pivotal phase III clinical trial results for vorapaxar were published. In this article we review these results plus the phase II results from atopaxar. Several newly described thrombin receptor antagonists from the literature will also be discussed. The phase III results from vorapaxar demonstrated that a thrombin receptor antagonist can achieve efficacy in addition to current standard- of-care in treating atherothrombotic patients, especially those with previous myocardial infarction (MI). However, the increased moderate and severe bleeding, especially intracranial bleeding, point to the limitations of current thrombin receptor antagonists. Future thrombin receptor antagonists that can improve on the efficacy and bleeding profile of current ones should have a promising place in meeting the unmet medical need in treating atherothrombotic patients using current standard therapy.展开更多
The neuro-glial interface extends far beyond mechanical support alone and includes interactions through coagulation cascade proteins. Here, we systematically review the evidence indicating that synaptic and node of Ra...The neuro-glial interface extends far beyond mechanical support alone and includes interactions through coagulation cascade proteins. Here, we systematically review the evidence indicating that synaptic and node of Ranvier glia cell components modulate synaptic transmission and axonal conduction by a coagulation cascade protein system, leading us to propose the concept of the neuro-glial coagulonome. In the peripheral nervous system, the main thrombin receptor protease activated receptor 1 (PAR1) is located on the Schwann microvilli at the node of Ranvier and at the neuromuscular junction. PAR1 activation effects can be both neuroprotective or harmful, depending on thrombin activity levels. Low physiological levels of thrombin induce neuroprotective effects in the Schwann cells which are mediated by the endothelial protein C receptor. High levels of thrombin induce conduction deficits, as found in experimental autoimmune neuritis, the animal model for Guillaine-Barre syndrome. In the central nervous system, PAR1 is located on the peri-synaptic astrocyte end-feet. Its activation by high thrombin levels is involved in the pathology of primary inflammatory brain diseases such as multiple sclerosis, as well as in other central nervous system insults, including trauma, neoplasms, epilepsy and vascular injury. Following activation of PAR1 by high thrombin levels the seizure threshold is lowered. On the other hand, PAR1 activation by lower levels of thrombin in the central nervous system protects against a future ischemic insult. This review presents the known structure and function of the neuro-glial coagulonome, focusing on coagulation, thrombin and PAR1 in a pathway which may be either physiological (neuroprotective) or detrimental in peripheral nervous system and central nervous system diseases. Understanding the neuro-glial coagulonome may open opportunities for novel pharmacological interventions in neurological diseases.展开更多
Objective：To investigate the effects of Salvia Miltiorrhiza Liguspyragine Hydrochloride and Glucose Injection（参芎葡萄糖注射液,SLGI） on the expression of platelet membrane receptors proteinase-activated receptor-1...Objective：To investigate the effects of Salvia Miltiorrhiza Liguspyragine Hydrochloride and Glucose Injection（参芎葡萄糖注射液,SLGI） on the expression of platelet membrane receptors proteinase-activated receptor-1（PAR1） and proteinase-activated receptor-4（PAR4） in end-stage renal disease（ESRD） patients on chronic haemodialysis（HD）.Methods：Eighty-six ESRD patients on HD（treated group） were treated with SLGI,7 days as one therapeutic course,for two successive courses.The previous therapies were unchanged.Flow cytometry was used to assess the expression of platelet PAR1 and PAR4 in the patients,and turbidity method was used to determine the platelet maximum aggregation rate（MAR）.Meanwhile,renal function was measured.The final data were compared with those before treatment and with those in the normal control group（54 healthy subjects）.Results：Compared with the normal control group,the expressions of PAR1 and PAR4 and platelet MAR in ESRD patients on HD was significantly higher before treatment（P=0.001,P=0.006, and P=0.008）;after treatment with SLGI,the above indices in patients were remarkably decreased（P=0.036 and P=0.046）,except PAR4（P=0.067）,but still higher than those in the normal control group,however,it was not statistically significant.Conclusions：（1） The overexpression of PAR1 and PAR4 might lead to increased platelet aggregation and this could be one of the reasons for the thrombotic events in ESRD patients on HD.（2） SLGI was able to down-regulate the expression of PAR1 in ESRD patients on HD,improve platelet function,and regulate platelet activation.展开更多
To investigate the role of platelet membrane glycoprotein （GP） Ib/Ⅸ/Ⅴ complex and its subunit GP Ibα in patients with hemorrhagic thrombopathy （HT）, the expressions of GP Ib/Ⅸ/Ⅴ complex and GP Ibα,defined as...To investigate the role of platelet membrane glycoprotein （GP） Ib/Ⅸ/Ⅴ complex and its subunit GP Ibα in patients with hemorrhagic thrombopathy （HT）, the expressions of GP Ib/Ⅸ/Ⅴ complex and GP Ibα,defined as mean fluorescence intensity （MFI）, were assessed by flow cytometry. The maximum aggregation of platelet was determined by turbidity method. These indicators were compared among 68 HT patients with the presenting complaint of hemorrhage, 33 well-controlled HT patients and 32 normal healthy subjects. The results showed that the MFI of GP Ib/Ⅸ /Ⅴ complex and GP Ibα was markedly lower in HT patients with current hemorrhage than that in the healthy subjects, with difference being statistically significant （P〈0.05）. There was no significant difference in the expressions of GP Ib/ Ⅸ/ Ⅴ complex and GP Ibα between well-controlled HT patients and normal healthy subjects （P〉0.05）. It was concluded that the expression of GP Ib/Ⅸ /Ⅴ complex, the receptor of thrombin and von Willebrand factor, was down-regulated in HT patients with current hemorrhage, which might result in the dysfunction of platelet aggregation and recurrence of HT.展开更多
Background Vorapaxar reduces cardiovascular death, myocardial infarction （MI）, or stroke in patients with previous MI while increasing bleeding. Patients with diabetes mellitus （DM） are at high risk of recurrent t...Background Vorapaxar reduces cardiovascular death, myocardial infarction （MI）, or stroke in patients with previous MI while increasing bleeding. Patients with diabetes mellitus （DM） are at high risk of recurrent thrombotic events despite standard therapy and may derive particular benefit from antithrombotic therapies. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50 trial was a randomized, double-blind, placebo-controlled trial of vorapaxar in patients with stable atherosclerosis.展开更多
Hippocampal neurons were treated by thrombin and thrombin receptor activatingpeptides (TRAP). Cell survival rate was decreased in a dose-dependent manner by MTT assay. Thenumbers of apoptotic cell and apoptotic rate o...Hippocampal neurons were treated by thrombin and thrombin receptor activatingpeptides (TRAP). Cell survival rate was decreased in a dose-dependent manner by MTT assay. Thenumbers of apoptotic cell and apoptotic rate of hippocampal neurons treated bydifferentconcentrations of thrombin were increased in a dose-dependent manner by terminal deoxynucleotidyltransferase (TdT) mediated dUTP-biotin nick end-labeling (TUNED method and Flow Cytometry. When theconcentration of thrombin is 40 U/mL, TUNEL positive cells and apoptotic rate of hippocampal neuronsreached peak value, were 27. 3 +- 4. 0 and (29. 333 +- 4. 633 ) % , respectively.Immunocytochemistry assay show that Bcl-2 protein expression was down- regulated and Bax proteinexpression was up-regulated with the concentration of thrombin increased. TRAP can mimic the effectof thrombin to induce apoptosis on hippocampal neurons. These data demonstrated that thrombininduced hippocampal neuron apoptosis in a dose-dependent manner through activatingprotease-acti-vated protein-1 (PAR-1). The change in expression of Bcl-2 and Bax was related withthe effect of high concentration thrombin induced apoptosis on hippocampal neurons.展开更多
文摘Significant progress was achieved in the search of a thrombin receptor antagonist as a novel antithrombotic treatment since the thrombin receptor (protease-activated receptor-1, PAR-1) was cloned 20 years ago. Previous works have shown that it is possible to develop potent thrombin receptor antagonists to compete effectively with the receptor’s internal “tethered” ligand to block platelet activation. Vorapaxar (SCH 530348) from Schering-Plough (now Merck) and atopaxar (E5555) from Eisai have been advanced to human clinical trials. Recently, the pivotal phase III clinical trial results for vorapaxar were published. In this article we review these results plus the phase II results from atopaxar. Several newly described thrombin receptor antagonists from the literature will also be discussed. The phase III results from vorapaxar demonstrated that a thrombin receptor antagonist can achieve efficacy in addition to current standard- of-care in treating atherothrombotic patients, especially those with previous myocardial infarction (MI). However, the increased moderate and severe bleeding, especially intracranial bleeding, point to the limitations of current thrombin receptor antagonists. Future thrombin receptor antagonists that can improve on the efficacy and bleeding profile of current ones should have a promising place in meeting the unmet medical need in treating atherothrombotic patients using current standard therapy.
文摘The neuro-glial interface extends far beyond mechanical support alone and includes interactions through coagulation cascade proteins. Here, we systematically review the evidence indicating that synaptic and node of Ranvier glia cell components modulate synaptic transmission and axonal conduction by a coagulation cascade protein system, leading us to propose the concept of the neuro-glial coagulonome. In the peripheral nervous system, the main thrombin receptor protease activated receptor 1 (PAR1) is located on the Schwann microvilli at the node of Ranvier and at the neuromuscular junction. PAR1 activation effects can be both neuroprotective or harmful, depending on thrombin activity levels. Low physiological levels of thrombin induce neuroprotective effects in the Schwann cells which are mediated by the endothelial protein C receptor. High levels of thrombin induce conduction deficits, as found in experimental autoimmune neuritis, the animal model for Guillaine-Barre syndrome. In the central nervous system, PAR1 is located on the peri-synaptic astrocyte end-feet. Its activation by high thrombin levels is involved in the pathology of primary inflammatory brain diseases such as multiple sclerosis, as well as in other central nervous system insults, including trauma, neoplasms, epilepsy and vascular injury. Following activation of PAR1 by high thrombin levels the seizure threshold is lowered. On the other hand, PAR1 activation by lower levels of thrombin in the central nervous system protects against a future ischemic insult. This review presents the known structure and function of the neuro-glial coagulonome, focusing on coagulation, thrombin and PAR1 in a pathway which may be either physiological (neuroprotective) or detrimental in peripheral nervous system and central nervous system diseases. Understanding the neuro-glial coagulonome may open opportunities for novel pharmacological interventions in neurological diseases.
基金Supported by the National Natural Science Foundation of China (No.30572441)
文摘Objective：To investigate the effects of Salvia Miltiorrhiza Liguspyragine Hydrochloride and Glucose Injection（参芎葡萄糖注射液,SLGI） on the expression of platelet membrane receptors proteinase-activated receptor-1（PAR1） and proteinase-activated receptor-4（PAR4） in end-stage renal disease（ESRD） patients on chronic haemodialysis（HD）.Methods：Eighty-six ESRD patients on HD（treated group） were treated with SLGI,7 days as one therapeutic course,for two successive courses.The previous therapies were unchanged.Flow cytometry was used to assess the expression of platelet PAR1 and PAR4 in the patients,and turbidity method was used to determine the platelet maximum aggregation rate（MAR）.Meanwhile,renal function was measured.The final data were compared with those before treatment and with those in the normal control group（54 healthy subjects）.Results：Compared with the normal control group,the expressions of PAR1 and PAR4 and platelet MAR in ESRD patients on HD was significantly higher before treatment（P=0.001,P=0.006, and P=0.008）;after treatment with SLGI,the above indices in patients were remarkably decreased（P=0.036 and P=0.046）,except PAR4（P=0.067）,but still higher than those in the normal control group,however,it was not statistically significant.Conclusions：（1） The overexpression of PAR1 and PAR4 might lead to increased platelet aggregation and this could be one of the reasons for the thrombotic events in ESRD patients on HD.（2） SLGI was able to down-regulate the expression of PAR1 in ESRD patients on HD,improve platelet function,and regulate platelet activation.
基金supported by a grant from the National Natural Science Foundation of China (No. 30572441).
文摘To investigate the role of platelet membrane glycoprotein （GP） Ib/Ⅸ/Ⅴ complex and its subunit GP Ibα in patients with hemorrhagic thrombopathy （HT）, the expressions of GP Ib/Ⅸ/Ⅴ complex and GP Ibα,defined as mean fluorescence intensity （MFI）, were assessed by flow cytometry. The maximum aggregation of platelet was determined by turbidity method. These indicators were compared among 68 HT patients with the presenting complaint of hemorrhage, 33 well-controlled HT patients and 32 normal healthy subjects. The results showed that the MFI of GP Ib/Ⅸ /Ⅴ complex and GP Ibα was markedly lower in HT patients with current hemorrhage than that in the healthy subjects, with difference being statistically significant （P〈0.05）. There was no significant difference in the expressions of GP Ib/ Ⅸ/ Ⅴ complex and GP Ibα between well-controlled HT patients and normal healthy subjects （P〉0.05）. It was concluded that the expression of GP Ib/Ⅸ /Ⅴ complex, the receptor of thrombin and von Willebrand factor, was down-regulated in HT patients with current hemorrhage, which might result in the dysfunction of platelet aggregation and recurrence of HT.
文摘Background Vorapaxar reduces cardiovascular death, myocardial infarction （MI）, or stroke in patients with previous MI while increasing bleeding. Patients with diabetes mellitus （DM） are at high risk of recurrent thrombotic events despite standard therapy and may derive particular benefit from antithrombotic therapies. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50 trial was a randomized, double-blind, placebo-controlled trial of vorapaxar in patients with stable atherosclerosis.
文摘Hippocampal neurons were treated by thrombin and thrombin receptor activatingpeptides (TRAP). Cell survival rate was decreased in a dose-dependent manner by MTT assay. Thenumbers of apoptotic cell and apoptotic rate of hippocampal neurons treated bydifferentconcentrations of thrombin were increased in a dose-dependent manner by terminal deoxynucleotidyltransferase (TdT) mediated dUTP-biotin nick end-labeling (TUNED method and Flow Cytometry. When theconcentration of thrombin is 40 U/mL, TUNEL positive cells and apoptotic rate of hippocampal neuronsreached peak value, were 27. 3 +- 4. 0 and (29. 333 +- 4. 633 ) % , respectively.Immunocytochemistry assay show that Bcl-2 protein expression was down- regulated and Bax proteinexpression was up-regulated with the concentration of thrombin increased. TRAP can mimic the effectof thrombin to induce apoptosis on hippocampal neurons. These data demonstrated that thrombininduced hippocampal neuron apoptosis in a dose-dependent manner through activatingprotease-acti-vated protein-1 (PAR-1). The change in expression of Bcl-2 and Bax was related withthe effect of high concentration thrombin induced apoptosis on hippocampal neurons.
