Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors
The purpose of antithrombotic therapy is the prevention of thrombus formation and/or its extension with a minimum risk of bleeding. The inhibition of a variety of proteolytic processes, particularly those of the coagulation cascade, has been reported as a property of plant protease inhibitors. The r...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2019-04-01
|
| Series: | Platelets |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/09537104.2018.1428738 |
| _version_ | 1797684269414350848 |
|---|---|
| author | Bruno R Salu Silvana Cristina Pando Marlon V De Brito André Fernando Medina Frank Odei-Addo Carminita Frost Ryno Naude Misako U Sampaio Jonas Emsley Francisco Humberto A. Maffei Maria Luiza V Oliva |
| author_facet | Bruno R Salu Silvana Cristina Pando Marlon V De Brito André Fernando Medina Frank Odei-Addo Carminita Frost Ryno Naude Misako U Sampaio Jonas Emsley Francisco Humberto A. Maffei Maria Luiza V Oliva |
| author_sort | Bruno R Salu |
| collection | DOAJ |
| description | The purpose of antithrombotic therapy is the prevention of thrombus formation and/or its extension with a minimum risk of bleeding. The inhibition of a variety of proteolytic processes, particularly those of the coagulation cascade, has been reported as a property of plant protease inhibitors. The role of trypsin inhibitors (TIs) from Delonix regia (Dr) and Acacia schweinfurthii (As), members of the Kunitz family of protease inhibitors, was investigated on blood coagulation, platelet aggregation, and thrombus formation. Different from Acacia schweinfurthii trypsin inhibitor (AsTI), Delonix regia trypsin inhibitor (DrTI) is a potent inhibitor of FXIa with a Kiapp of 1.3 × 10–9 M. In vitro, both inhibitors at 100 µg corresponding to the concentrations of 21 μM and 15.4 μM of DrTI and AsTI, respectively, increased approximately 2.0 times the activated partial thromboplastin time (aPTT) in human plasma compared to the control, likely due to the inhibition of human plasma kallikrein (huPK) or activated factor XI (FXIa), in the case of DrTI. Investigating in vivo models of arterial thrombus formation and bleeding time, DrTI and AsTI, 1.3 µM and 0.96 µM, respectively, prolonged approximately 50% the time for total carotid artery occlusion in mice compared to the control. In contrast to heparin, the bleeding time in mice treated with the two inhibitors did not differ from that of the control group. DrTI and AsTI inhibited 49.3% and 63.8%, respectively, ex vivo murine platelet aggregation induced by adenosine diphosphate (ADP), indicating that these protein inhibitors prevent arterial thrombus formation possibly by interfering with the plasma kallikrein (PK) proteolytic action on the intrinsic coagulation pathway and its ability to enhance the platelet aggregation activity on the intravascular compartment leading to the improvement of a thrombus. |
| first_indexed | 2024-03-12T00:27:05Z |
| format | Article |
| id | doaj.art-703b2a2100744a4f9df64ad47a8936c0 |
| institution | Directory Open Access Journal |
| issn | 0953-7104 1369-1635 |
| language | English |
| last_indexed | 2024-03-12T00:27:05Z |
| publishDate | 2019-04-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Platelets |
| spelling | doaj.art-703b2a2100744a4f9df64ad47a8936c02023-09-15T10:31:59ZengTaylor & Francis GroupPlatelets0953-71041369-16352019-04-0130330531310.1080/09537104.2018.14287381428738Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitorsBruno R Salu0Silvana Cristina Pando1Marlon V De Brito2André Fernando Medina3Frank Odei-Addo4Carminita Frost5Ryno Naude6Misako U Sampaio7Jonas Emsley8Francisco Humberto A. Maffei9Maria Luiza V Oliva10Federal University of São PauloFederal University of São PauloFederal University of São PauloFederal University of São PauloNelson Mandela UniversityNelson Mandela UniversityNelson Mandela UniversityFederal University of São PauloUniversity of NottinghamSão Paulo State UniversityFederal University of São PauloThe purpose of antithrombotic therapy is the prevention of thrombus formation and/or its extension with a minimum risk of bleeding. The inhibition of a variety of proteolytic processes, particularly those of the coagulation cascade, has been reported as a property of plant protease inhibitors. The role of trypsin inhibitors (TIs) from Delonix regia (Dr) and Acacia schweinfurthii (As), members of the Kunitz family of protease inhibitors, was investigated on blood coagulation, platelet aggregation, and thrombus formation. Different from Acacia schweinfurthii trypsin inhibitor (AsTI), Delonix regia trypsin inhibitor (DrTI) is a potent inhibitor of FXIa with a Kiapp of 1.3 × 10–9 M. In vitro, both inhibitors at 100 µg corresponding to the concentrations of 21 μM and 15.4 μM of DrTI and AsTI, respectively, increased approximately 2.0 times the activated partial thromboplastin time (aPTT) in human plasma compared to the control, likely due to the inhibition of human plasma kallikrein (huPK) or activated factor XI (FXIa), in the case of DrTI. Investigating in vivo models of arterial thrombus formation and bleeding time, DrTI and AsTI, 1.3 µM and 0.96 µM, respectively, prolonged approximately 50% the time for total carotid artery occlusion in mice compared to the control. In contrast to heparin, the bleeding time in mice treated with the two inhibitors did not differ from that of the control group. DrTI and AsTI inhibited 49.3% and 63.8%, respectively, ex vivo murine platelet aggregation induced by adenosine diphosphate (ADP), indicating that these protein inhibitors prevent arterial thrombus formation possibly by interfering with the plasma kallikrein (PK) proteolytic action on the intrinsic coagulation pathway and its ability to enhance the platelet aggregation activity on the intravascular compartment leading to the improvement of a thrombus.http://dx.doi.org/10.1080/09537104.2018.1428738blood coagulationfactor xiakallikreinkunitz inhibitorsplateletsthrombosis |
| spellingShingle | Bruno R Salu Silvana Cristina Pando Marlon V De Brito André Fernando Medina Frank Odei-Addo Carminita Frost Ryno Naude Misako U Sampaio Jonas Emsley Francisco Humberto A. Maffei Maria Luiza V Oliva Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors Platelets blood coagulation factor xia kallikrein kunitz inhibitors platelets thrombosis |
| title | Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors |
| title_full | Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors |
| title_fullStr | Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors |
| title_full_unstemmed | Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors |
| title_short | Improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors |
| title_sort | improving the understanding of plasma kallikrein contribution to arterial thrombus formation using two plant protease inhibitors |
| topic | blood coagulation factor xia kallikrein kunitz inhibitors platelets thrombosis |
| url | http://dx.doi.org/10.1080/09537104.2018.1428738 |
| work_keys_str_mv | AT brunorsalu improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors AT silvanacristinapando improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors AT marlonvdebrito improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors AT andrefernandomedina improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors AT frankodeiaddo improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors AT carminitafrost improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors AT rynonaude improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors AT misakousampaio improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors AT jonasemsley improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors AT franciscohumbertoamaffei improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors AT marialuizavoliva improvingtheunderstandingofplasmakallikreincontributiontoarterialthrombusformationusingtwoplantproteaseinhibitors |