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Mechanisms and Therapeutics of Platelet Thrombus Formation
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Mechanisms and Therapeutics of Platelet Thrombus Formation

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (25 September 2019) | Viewed by 25267

Special Issue Editor

Prof. Dr. Denise Jackson

E-Mail Website
Guest Editor
Discipline Leader and Program Leader of Laboratory Medicine, BP147 Program Co-ordinator, Head of Thrombosis and Vascular Diseases Laboratory, School of Health and Biomedical Sciences, RMIT University, PO Box 71, Bundoora, Victoria 3083, Australia
Interests: thrombosis; platelet biology; mouse models; human platelets; anti-platelet therapy; biochemistry; atherosclerosis; vascular biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Platelets are normally free flowing in a blood vessel. However, in the event of vessel injury or disease such as atherosclerotic plaques, platelets will initially tether, via exposed extracellular matrix ligands with respective platelet receptors, then adhesive events occur, followed by activation through signaling events. These inside out signaling events lead to the conversion of the major platelet integrin alphaIIbbeta3 from a resting to an activated state, where it will bind its natural ligands, including fibrinogen, to create stable platelet aggregates. The numerous steps involved in platelet thrombus formation are regulated by different receptors, ligands, signaling molecules, rheological biomechanical forces, and soluble agonist dependent mechanisms. These events regulate not only thrombus growth and stability but also the propagation of blood clots formed. In addition, papers that evaluate new technologies or new therapeutics that modulate thrombus formation will be also be considered.

Prof. Dr. Denise Jackson
Guest Editor

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Keywords

  • platelet adhesion
  • platelet aggregation
  • tissue factor bearing microparticles
  • thrombus growth
  • thrombus stability
  • platelet tethering
  • platelet activation
  • propagation of thrombus formation
  • rheological biomechanical platelet aggregation
  • soluble agonist dependent mechanisms

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Related Special Issue

Published Papers (6 papers)

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Research

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17 pages, 3282 KiB  
Article
Suppression of Human Platelet Activation via Integrin αIIbβ3 Outside-In Independent Signal and Reduction of the Mortality in Pulmonary Thrombosis by Auraptene
by Chih-Wei Hsia, Cheng-Lin Tsai, Joen-Rong Sheu, Wan-Jung Lu, Chih-Hsuan Hsia, Marappan Velusamy, Thanasekaran Jayakumar and Jiun-Yi Li
Int. J. Mol. Sci. 2019, 20(22), 5585; https://doi.org/10.3390/ijms20225585 - 8 Nov 2019
Cited by 10 | Viewed by 3013
Abstract
Auraptene is the most abundant coumarin derivative from plants. The pharmacological value of this compound has been well demonstrated, especially in the prevention of cancer and neurodegenerative diseases. Platelet activation is a major factor contributing to arterial thrombosis. Thus, this study evaluated the [...] Read more.
Auraptene is the most abundant coumarin derivative from plants. The pharmacological value of this compound has been well demonstrated, especially in the prevention of cancer and neurodegenerative diseases. Platelet activation is a major factor contributing to arterial thrombosis. Thus, this study evaluated the influence of auraptene in platelet aggregation and thrombotic formation. Auraptene inhibited platelet aggregation in human platelets stimulated with collagen only. However, auraptene was not effective in inhibiting platelet aggregation stimulated with thrombin, arachidonic acid, and U46619. Auraptene also repressed ATP release, [Ca2+]i mobilization, and P-selectin expression. Moreover, it markedly blocked PAC-1 binding to integrin αIIbβ3. However, it had no influence on properties related to integrin αIIbβ3-mediated outside-in signaling, such as the adhesion number, spreading area of platelets, and fibrin clot retraction. Auraptene inhibited the phosphorylation of Lyn-Fyn-Syk, phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), Akt, and mitogen-activated protein kinases (MAPKs; extracellular-signal-regulated kinase (ERK1/2), and c-Jun N-terminal kinase (JNK1/2), but not p38 MAPK). Neither SQ22536, an adenylate cyclase inhibitor, nor ODQ, a guanylate cyclase inhibitor, reversed the auraptene-mediated inhibition of platelet aggregation. Auraptene reduced mortality caused by adenosine diphosphate (ADP)-induced pulmonary thromboembolism. In conclusion, this study provides definite evidence that auraptene signifies a potential therapeutic agent for preventing thromboembolic disorders. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutics of Platelet Thrombus Formation)
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14 pages, 3547 KiB  
Article
Dasatinib Inhibits Procoagulant and Clot Retracting Activities of Human Platelets
by Ildikó Beke Debreceni, Gabriella Mezei, Péter Batár, Árpád Illés and János Kappelmayer
Int. J. Mol. Sci. 2019, 20(21), 5430; https://doi.org/10.3390/ijms20215430 - 31 Oct 2019
Cited by 15 | Viewed by 3133
Abstract
Tyrosine kinase inhibitors (TKI) such as the BCR-ABL inhibitor dasatinib and nilotinib are highly effective therapies for chronic myeloid leukemia (CML). However, several lines of evidence suggest that dasatinib can induce bleeding which may be due to impaired collagen-induced platelet adhesion, aggregation, and [...] Read more.
Tyrosine kinase inhibitors (TKI) such as the BCR-ABL inhibitor dasatinib and nilotinib are highly effective therapies for chronic myeloid leukemia (CML). However, several lines of evidence suggest that dasatinib can induce bleeding which may be due to impaired collagen-induced platelet adhesion, aggregation, and secretion. Sarcoma family kinases (SFK) play central role in the GPVI-induced signaling pathway. We aimed to investigate whether and how dasatinib can modulate SFK-mediated platelet procoagulant activity in a purified system and in dasatinib/nilotinib treated CML patients. In platelet rich plasmas of healthy volunteers, dasatinib dose-dependently reduced convulxin-induced phosphatidylserine exposure and attenuated thrombin formation. Similarly to these changes, integrin activation and clot retraction were also significantly inhibited by 100 nM dasatinib. Platelets isolated from dasatinib treated patients showed a significantly lower phosphatidylserine expression upon convulxin activation compared to premedication levels. In these samples, thrombin generation was significantly slower, and the quantity of formed thrombin was less compared to the trough sample. Western blot analyses showed decreased phosphorylation levels of the C-terminal tail and the activation loop of SFKs upon dasatinib administration. Taken together, these results suggest that dasatinib inhibits the formation of procoagulant platelets via the GPVI receptor by inhibiting phosphorylation of SFKs. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutics of Platelet Thrombus Formation)
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10 pages, 3532 KiB  
Article
Novel Stenotic Microchannels to Study Thrombus Formation in Shear Gradients: Influence of Shear Forces and Human Platelet-Related Factors
by Mathew Lui, Elizabeth E. Gardiner, Jane F. Arthur, Isaac Pinar, Woei Ming Lee, Kris Ryan, Josie Carberry and Robert K. Andrews
Int. J. Mol. Sci. 2019, 20(12), 2967; https://doi.org/10.3390/ijms20122967 - 18 Jun 2019
Cited by 17 | Viewed by 3784
Abstract
Thrombus formation in hemostasis or thrombotic disease is initiated by the rapid adhesion, activation, and aggregation of circulating platelets in flowing blood. At arterial or pathological shear rates, for example due to vascular stenosis or circulatory support devices, platelets may be exposed to [...] Read more.
Thrombus formation in hemostasis or thrombotic disease is initiated by the rapid adhesion, activation, and aggregation of circulating platelets in flowing blood. At arterial or pathological shear rates, for example due to vascular stenosis or circulatory support devices, platelets may be exposed to highly pulsatile blood flow, while even under constant flow platelets are exposed to pulsation due to thrombus growth or changes in vessel geometry. The aim of this study is to investigate platelet thrombus formation dynamics within flow conditions consisting of either constant or variable shear. Human platelets in anticoagulated whole blood were exposed ex vivo to collagen type I-coated microchannels subjected to constant shear in straight channels or variable shear gradients using different stenosis geometries (50%, 70%, and 90% by area). Base wall shears between 1800 and 6600 s−1, and peak wall shears of 3700 to 29,000 s−1 within stenoses were investigated, representing arterial-pathological shear conditions. Computational flow-field simulations and stenosis platelet thrombi total volume, average volume, and surface coverage were analysed. Interestingly, shear gradients dramatically changed platelet thrombi formation compared to constant base shear alone. Such shear gradients extended the range of shear at which thrombi were formed, that is, platelets became hyperthrombotic within shear gradients. Furthermore, individual healthy donors displayed quantifiable differences in extent/formation of thrombi within shear gradients, with implications for future development and testing of antiplatelet agents. In conclusion, here, we demonstrate a specific contribution of blood flow shear gradients to thrombus formation, and provide a novel platform for platelet functional testing under shear conditions. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutics of Platelet Thrombus Formation)
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17 pages, 4760 KiB  
Article
Esculetin, a Coumarin Derivative, Prevents Thrombosis: Inhibitory Signaling on PLCγ2–PKC–AKT Activation in Human Platelets
by Chih-Wei Hsia, Kao-Chang Lin, Tzu-Yin Lee, Chih-Hsuan Hsia, Duen-Suey Chou, Thanasekaran Jayakumar, Marappan Velusamy, Chao-Chien Chang and Joen-Rong Sheu
Int. J. Mol. Sci. 2019, 20(11), 2731; https://doi.org/10.3390/ijms20112731 - 3 Jun 2019
Cited by 30 | Viewed by 4798
Abstract
Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and cardiovascular disorders (CVDs). Platelet activation plays a major role in CVDs. Thus, disrupting platelet activation represents an attractive therapeutic target. We examined the effect of esculetin in [...] Read more.
Esculetin, a bioactive 6,7-dihydroxy derivative of coumarin, possesses pharmacological activities against obesity, diabetes, renal failure, and cardiovascular disorders (CVDs). Platelet activation plays a major role in CVDs. Thus, disrupting platelet activation represents an attractive therapeutic target. We examined the effect of esculetin in human platelet activation and experimental mouse models. At 10–80 μM, esculetin inhibited collagen- and arachidonic acid-induced platelet aggregation in washed human platelets. However, it had no effects on other agonists such as thrombin and U46619. Esculetin inhibited adenosine triphosphate release, P-selectin expression, hydroxyl radical (OH·) formation, Akt activation, and phospholipase C (PLC)γ2/protein kinase C (PKC) phosphorylation, but did not diminish mitogen-activated protein kinase phosphorylation in collagen-activated human platelets. Platelet function analysis indicated that esculetin substantially prolonged the closure time of whole blood. In experimental mice, esculetin significantly increased the occlusion time in thrombotic platelet plug formation and reduced mortality associated with acute pulmonary thromboembolism. However, it did not prolong the bleeding time. This study demonstrates that esculetin inhibits human platelet activation via hindering the PLCγ2–PKC cascade, hydroxyl radical formation, Akt activation, and ultimately suppressing platelet activation. Therefore, esculetin may act as an essential therapeutic agent for preventing thromboembolic diseases. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutics of Platelet Thrombus Formation)
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Graphical abstract

16 pages, 4990 KiB  
Article
Sphingosine-1-phosphate in Endothelial Cell Recellularization Improves Patency and Endothelialization of Decellularized Vascular Grafts In Vivo
by Kai Hsia, Chih-Hsun Lin, Hsin-Yu Lee, Wei-Min Chen, Chao-Ling Yao, Chien-Chin Chen, Hsu Ma, Shyh-Jen Wang and Jen-Her Lu
Int. J. Mol. Sci. 2019, 20(7), 1641; https://doi.org/10.3390/ijms20071641 - 2 Apr 2019
Cited by 18 | Viewed by 3844
Abstract
Background: S1P has been shown to improve the endothelialization of decellularized vascular grafts in vitro. Here, we evaluated the potential of tissue-engineered vascular grafts (TEVGs) constructed by ECs and S1P on decellularized vascular scaffolds in a rat model. Methods: Rat aorta was decellularized [...] Read more.
Background: S1P has been shown to improve the endothelialization of decellularized vascular grafts in vitro. Here, we evaluated the potential of tissue-engineered vascular grafts (TEVGs) constructed by ECs and S1P on decellularized vascular scaffolds in a rat model. Methods: Rat aorta was decellularized mainly by 0.1% SDS and characterized by histology. Rat ECs, were seeded onto decellularized scaffolds, and the viability of the ECs was evaluated by biochemical assays. Then, we investigated the in vivo patency rate and endothelialization for five groups of decellularized vascular grafts (each n = 6) in a rat abdominal aorta model for 14 days. The five groups included (1) rat allogenic aorta (RAA); (2) decellularized RAA (DRAA); (3) DRAA with S1P (DRAA/S1P); (4) DRAA with EC recellularization (DRAA/EC); and (5) DRAA with S1P and EC recellularization (DRAA/EC/S1P). Results: In vitro, ECs were identified by the uptake of Dil-Ac-LDL. S1P enhanced the expression of syndecan-1 on ECs and supported the proliferation of ECs on decellularized vascular grafts. In vivo, RAA and DRAA/EC/S1P both had 100% patency without thrombus formation within 14 days. Better endothelialization, more wall structure maintenance and less inflammation were noted in the DRAA/EC/S1P group. In contrast, there was thrombus formation in the DRAA, DRAA/S1P and DRAA/EC groups. Conclusion: S1P could inhibit thrombus formation to improve the patency rate of EC-covered decellularized vascular grafts in vivo and may play an important role in the construction of TEVGs. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutics of Platelet Thrombus Formation)
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Review

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13 pages, 991 KiB  
Review
Using PAR4 Inhibition as an Anti-Thrombotic Approach: Why, How, and When?
by Simeng Li, Volga Tarlac and Justin R. Hamilton
Int. J. Mol. Sci. 2019, 20(22), 5629; https://doi.org/10.3390/ijms20225629 - 11 Nov 2019
Cited by 26 | Viewed by 6126
Abstract
Protease-activated receptors (PARs) are a family of four GPCRs with a variety of cellular functions, yet the only advanced clinical endeavours to target these receptors for therapeutic gain to date relates to the impairment of platelet function for anti-thrombotic therapy. The only approved [...] Read more.
Protease-activated receptors (PARs) are a family of four GPCRs with a variety of cellular functions, yet the only advanced clinical endeavours to target these receptors for therapeutic gain to date relates to the impairment of platelet function for anti-thrombotic therapy. The only approved PAR antagonist is the PAR1 inhibitor, vorapaxar—the sole anti-platelet drug against a new target approved in the past 20 years. However, there are two PARs on human platelets, PAR1 and PAR4, and more recent efforts have focused on the development of the first PAR4 antagonists, with first-in-class agents recently beginning clinical trial. Here, we review the rationale for this approach, outline the various modes of PAR4 inhibition, and speculate on the specific therapeutic potential of targeting PAR4 for the prevention of thrombotic conditions. Full article
(This article belongs to the Special Issue Mechanisms and Therapeutics of Platelet Thrombus Formation)
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