Article
Cell Biology
Maan H. Harbi, Christopher W. Smith, Phillip L. R. Nicolson, Steve P. Watson, Mark R. Thomas
Summary: Antiplatelet medications are crucial in treating diseases involving arterial thrombosis, but may cause bleeding and recurrence of thrombotic events. Targeting platelet GPVI and CLEC-2 receptors could offer novel treatment strategies with enhanced antithrombotic efficacy and minimal disruption to hemostasis. Further research into these receptors and their inhibition strategies is needed for effective prevention of platelet recruitment and activation in thrombotic diseases.
Article
Cell Biology
Foteini-Nafsika Damaskinaki, Luis A. Moran, Angel Garcia, Barrie Kellam, Steve P. Watson
Summary: GPVI and CLEC-2 have potential as long-term targets for preventing arterial thrombosis and thrombo-inflammation, but the development of small molecule inhibitors faces challenges in bioavailability and ensuring nanomolar potency.
Article
Hematology
Rainer Kaiser, Raphael Escaig, Jan Kranich, Marie-Louise Hoffknecht, Afra Anjum, Vivien Polewka, Magdalena Mader, Wenbo Hu, Larissa Belz, Christoph Gold, Anna Titova, Michael Lorenz, Kami Pekayvaz, Stefan Kaab, Florian Gaertner, Konstantin Stark, Thomas Brocker, Steffen Massberg, Leo Nicolai
Summary: Impairment of vascular integrity is a characteristic of inflammatory diseases. This study demonstrates the essential role of procoagulant platelets in preventing inflammatory bleeding by promoting coagulation cascade activation. The presence of exposed collagen triggers platelet arrest and subsequent procoagulant activation. The findings highlight the importance of procoagulant platelets in maintaining vascular integrity during inflammation.
Article
Cell Biology
Hilaire Yam Fung Cheung, Luis A. Moran, Albert Sickmann, Johan W. M. Heemskerk, Angel Garcia, Steve P. Watson
Summary: Src tyrosine kinases and spleen tyrosine kinase (Syk) play a role in sustained platelet aggregation under minimal shear following activation of glycoprotein VI (GPVI) and C-type lectin-like receptor-2 (CLEC-2). Aggregation and tyrosine phosphorylation were monitored by light transmission aggregometry (LTA) and fluorescence-labeled antibody. Src contributes to sustained aggregation through a Syk-independent pathway that inhibits outside-in signaling from glycoprotein IIb-IIia (GPIIIb-IIIa) to the cytoskeleton.
Article
Cell Biology
Samantha J. Montague, Pushpa Patel, Eleyna M. Martin, Alexandre Slater, Lourdes Garcia Quintanilla, Gina Perrella, Caroline Kardeby, Magdolna Nagy, Diego Mezzano, Paula M. Mendes, Steve P. Watson
Summary: This article highlights the critical role of charge interactions in the activation of the innate immune system and discusses how platelet glycoprotein receptors can recognize a wide spectrum of ligands through a common mechanism. It also explores the implications of this mechanism in rapid platelet activation and potential opportunities for designing novel antithrombotic agents such as nanoparticles and dendrimers.
Article
Hematology
Lukas J. Weiss, Maria Drayss, Kristina Mott, Sarah Beck, David Unsin, Bastian Just, Christian P. Speer, Christoph Haertel, Oliver Andres, Harald Schulze
Summary: Erythrocytes undergo a switch from fetal to postnatal circulation indicated by hemoglobin chain expression. Perinatal alterations in thrombopoiesis were poorly understood, so this study assessed the ontogenesis of platelet phenotype and function from early prematurity to adulthood. The study found that expression levels of surface receptors for fibrinogen, collagen, vWF, fibronectin, and laminin were reduced in neonates, but correlated with platelet size, indicating normal surface density. GPIIb/IIIa activation showed a continuous increase until adulthood, and platelet subpopulation analysis revealed changes in CD63(+) and PAC-1(+) platelets as age increased.
Article
Pharmacology & Pharmacy
Kakarla Ramakrishna, Neha Singh, Sairam Krishnamurthy
Summary: Diindolylmethane (DIM) is a metabolite of indole-3-carbinol (I3C) that plays a crucial role in inhibiting platelet aggregation and thrombus generation. In silico studies suggest that DIM modulates platelet interaction with glycoproteinVI (GPVI) and purinergic receptor Y-12 (P2Y12) receptors more effectively than I3C. In vitro and in vivo experiments demonstrate that DIM significantly inhibits platelet aggregation, reduces reactive oxygen species (ROS) and thromboxane 2 (TXB2), while increasing cyclic adenosine monophosphate (cAMP) levels and extending time to occlusion (TTO). DIM acts as an antiplatelet aggregation and antithrombotic agent, making it a potential treatment for thrombotic diseases.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2022)
Article
Hematology
Joshua H. Bourne, Christopher W. Smith, Natalie J. Jooss, Ying Di, Helena C. Brown, Samantha J. Montague, Mark R. Thomas, Natalie S. Poulter, Julie Rayes, Steve P. Watson
Summary: C-type lectin-like receptor 2 (CLEC-2) is highly expressed on platelets and plays a critical role in lymphatic development. This study demonstrates that CLEC-2 supports thrombus formation at sites of inflammation without affecting hemostasis. It suggests that CLEC-2 could be a promising therapeutic target for thromboinflammatory disorders.
THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Medicine, Research & Experimental
Chaojun Tang, Lei Wang, Yulan Sheng, Zhong Zheng, Zhanli Xie, Fan Wu, Tao You, Lijie Ren, Lijun Xia, Changgeng Ruan, Li Zhu
Summary: This study demonstrated that disturbed blood flow can induce platelet accumulation in atherosclerosis, with CLEC-2 gene knockout potentially reducing subendothelial accumulation of platelets and monocytes/macrophages, thereby ameliorating plaque formation.
Review
Cell Biology
Eva M. Soriano Jerez, Jonathan M. Gibbins, Craig E. Hughes
Summary: Although current oral antiplatelet therapies benefit many patients, they also deregulate the hemostatic balance and increase the risk of systemic side-effects such as hemorrhage. Recent efforts have been focusing on developing new classes of anti-platelet drugs by targeting primary platelet activation pathways.
Article
Hematology
Bojing Shao, Christopher Hoover, Huiping Shi, Yuji Kondo, Robert H. Lee, Junmei Chen, Xindi Shan, Jianhua Song, J. Michael McDaniel, Meixiang Zhou, Samuel McGee, Karen Vanhoorelbeke, Wolfgang Bergmeier, Jose A. Lopez, James N. George, Lijun Xia
Summary: GPIba-mediated activation of integrin alpha IIb beta 3 plays an important role in the formation of thrombosis in patients with thrombotic thrombocytopenic purpura (TTP).
Article
Biology
Joanne C. Clark, Eleyna M. Martin, Luis A. Moran, Ying Di, Xueqing Wang, Malou Zuidscherwoude, Helena C. Brown, Deirdre M. Kavanagh, Johan Hummert, Johannes A. Eble, Bernhard Nieswandt, David Stegner, Alice Y. Pollitt, Dirk-Peter Herten, Michael G. Tomlinson, Angel Garcia, Steve P. Watson
Summary: Fluorescence correlation spectroscopy was used to investigate the clustering of CLEC-2 induced by crosslinked nanobody ligands. The results showed that the valency of the ligands and the expression levels of CLEC-2 were important factors in determining the activation of CLEC-2. Divalent ligands were found to be partial agonists while tetravalent ligands stimulated platelet aggregation.
COMMUNICATIONS BIOLOGY
(2023)
Review
Hematology
Gina Perrella, Magdolna Nagy, Steve P. Watson, Johan W. M. Heemskerk
Summary: GPVI is a receptor expressed on megakaryocytes and platelets that plays a role in both arterial and venous thrombus formation, as well as in the formation of platelet-leukocyte complexes. It is emerging as a potential therapeutic target for venous thrombosis, pulmonary thromboembolism, and cancer metastasis due to its involvement in venous thrombus formation and thromboinflammation. Circulating soluble GPVI is also being explored as a biomarker for thrombosis-related complications.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2021)
Article
Hematology
Alexey A. Martyanov, Ivan P. Tesakov, Lili A. Khachatryan, Olga I. An, Anna E. Boldova, Anastasia A. Ignatova, Ekaterina M. Koltsova, Julia -Jessica D. Korobkin, Nadezhda A. Podoplelova, Galina S. Svidelskaya, Eugenia Yushkova, Galina A. Novichkova, Johannes A. Eble, Mikhail A. Panteleev, Dmitrii V. Kalinin, Anastasia N. Sveshnikova
Summary: This study aimed to assess platelet functionality in KHE/KMP patients. The results showed that platelet responses induced by CLEC-2 or GPVI activation were impaired in patients, which correlated with the severity of the disease and resolved as the patient recovered.
Review
Immunology
Danyang Meng, Man Luo, Beibei Liu
Summary: CLEC-2, expressed on platelets and immune cells, plays a crucial role in infection and immunity, participating in processes such as thromboinflammation.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Hematology
Alexandra Mazharian, Blandine Maitre, Alicia Bornert, Desline Hennequin, Marc Lourenco-Rodrigues, Mitchell J. Geer, Christopher W. Smith, Silke Heising, Michaela Walter, Florian Montel, Lucy S. K. Walker, Henri de la Salle, Steve P. Watson, Christian Gachet, Yotis A. Senis
Summary: Mice lacking the G6b-B receptor exhibit a range of platelet abnormalities, including macrothrombocytopenia and reduced collagen receptor expression. Treatment with romiplostim, a thrombopoietin mimetic, showed promising results in rescuing platelet counts and function in G6b KO mice. However, inhibitors targeting Syk and Src kinases had limited effects on platelet abnormalities. These findings suggest that romiplostim may be a potential therapeutic option for patients lacking functional G6b-B.
Article
Oncology
Abdullah O. Khan, Antonio Rodriguez-Romera, Jasmeet S. Reyat, Aude-Anais Olijnik, Michela Colombo, Guanlin Wang, Wei Xiong Wen, Nikolaos Sousos, Lauren C. Murphy, Beata Grygielska, Gina Perrella, Christopher B. Mahony, Rebecca E. Ling, Natalina E. Elliott, Christina Simoglou Karali, Andrew P. Stone, Samuel Kemble, Emily A. Cutler, Adele K. Fielding, Adam P. Croft, David Bassett, Gowsihan Poologasundarampillai, Anindita Roy, Sarah Gooding, Julie Rayes, Kellie R. Machlus, Bethan Psaila
Summary: This study presents a human bone marrow organoid that can support the growth and survival of primary cells from patients with myeloid and lymphoid blood cancers. This organoid model allows for mechanistic studies of blood cancers within their microenvironment and serves as an ex vivo tool for prioritizing new therapeutics.
Article
Hematology
Philippe Billiald, Alexandre Slater, Martin Welin, Joanne C. Clark, Stephane Loyau, Martine Pugniere, Isabella G. Jiacomini, Nadia Rose, Kristell Lebozec, Elie Toledano, Deborah Francois, Steve P. Watson, Martine Jandrot-Perrus
Summary: This study shows that glenzocimab, a humanized antibody fragment, blocks the binding of GPVI to vascular collagen and fibrin through steric hindrance and structural change. This finding is significant for the development of new antiplatelet molecules with a low bleeding risk.
Review
Hematology
Jordan D. D. Dimitrov, Lubka T. T. Roumenina, Gina Perrella, Julie Rayes
Summary: Regardless of the cause, hemolytic diseases are associated with thrombosis, inflammation, and immune dysregulation, resulting in organ damage and poor outcomes. Hemolysis not only leads to anemia and loss of the anti-inflammatory functions of red blood cells, but also releases damage-associated molecular patterns, such as ADP, hemoglobin, and heme, which trigger a hyperinflammatory and hypercoagulable state through various receptors and signaling pathways. Extracellular free heme, in particular, can activate platelets, endothelial cells, innate cells, as well as the coagulation and complement cascades, thereby promoting thrombo-inflammatory events. This review discusses the main mechanisms by which hemolysis, especially heme, drives this thrombo-inflammatory environment and explores the impact of hemolysis on the host response to secondary infections.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Article
Hematology
Stephanie Roullet, Norman Luc, Julie Rayes, Jean Solarz, Dante Disharoon, Andrew Ditto, Emily Gahagan, Christa Pawlowski, Thibaud Sefiane, Frederic Adam, Caterina Casari, Olivier D. Christophe, Michael Bruckman, Peter J. Lenting, Anirban Sen Gupta, Cecile Denis
Summary: The lack of innovation in von Willebrand disease (VWD) is due to the complexity and heterogeneity of the disease and a lack of recognition of the impact of bleeding symptoms experienced by patients. This study proposes a new approach using synthetic platelet (SP) nanoparticles for the treatment of VWD-2B and severe VWD. The results show that SP can improve thrombus formation and reduce blood loss in VWD-2B and VWF-KO mice.
Article
Hematology
Asim Cengiz Akbulut, Ryanne A. Arisz, Constance C. F. M. J. Baaten, Gaukhar Baidildinova, Aarazo Barakzie, Rupert Bauersachs, Jur Ten Berg, Wout W. A. van den Broek, H. C. de Boer, Amandine Bonifay, Vanessa Broker, Richard J. Buka, Hugo ten Cate, Arina J. ten Cate-Hoek, S. Cointe, Ciro De Luca, Ilaria De Simone, Rocio Vacik Diaz, Francoise Dignat-George, Kathleen Freson, Giulia Gazzaniga, Eric C. M. van Gorp, Anxhela Habibi, Yvonne M. C. Henskens, Aaron F. J. Iding, Abdullah Khan, Gijsje H. Koenderink, Akhil Konkoth, Romaric Lacroix, Trisha Lahiri, Wilbur Lam, Rachel E. Lamerton, Roberto Lorusso, Qi Luo, Coen Maas, Owen J. T. McCarty, Paola E. J. van der Meijden, Joost C. M. Meijers, Adarsh K. Mohapatra, Neta Nevo, Alejandro Pallares Robles, Philippe Poncelet, Christoph Reinhardt, Wolfram Ruf, Ronald Saraswat, Claudia Schonichen, Roger Schutgens, Paolo Simioni, Stefano Spada, Henri M. H. Spronk, Karlygash Tazhibayeva, Jecko Thachil, Rocio Vacik Diaz, L. Vallier, Alicia Veninga, Peter Verhamme, Chantal Visser, Steve P. Watson, Philip Wenzel, Ruth A. L. Willems, Anne Willers, Pengyu Zhang, Konstantinos Zifkos, Anton Jan van Zonneveld
Summary: The Fourth Maastricht Consensus Conference on Thrombosis covered a wide range of topics, including the role of coagulation proteins in cardiovascular disease, novel mechanisms of thrombosis, strategies to limit bleeding risks, hemostasis in extracorporeal systems, and clinical dilemmas in thrombosis and antithrombotic management. The conference also revisited the coagulopathy associated with COVID-19.
THROMBOSIS AND HAEMOSTASIS
(2023)
Letter
Hematology
Helena C. Brown, Sarah Beck, Stefano Navarro, Ying Di, Eva M. Soriano Jerez, Jana Kaczmarzyk, Steven G. Thomas, Valbona Mirakaj, Steve P. Watson, Bernhard Nieswandt, David Stegner
Article
Biology
Joanne C. Clark, Eleyna M. Martin, Luis A. Moran, Ying Di, Xueqing Wang, Malou Zuidscherwoude, Helena C. Brown, Deirdre M. Kavanagh, Johan Hummert, Johannes A. Eble, Bernhard Nieswandt, David Stegner, Alice Y. Pollitt, Dirk-Peter Herten, Michael G. Tomlinson, Angel Garcia, Steve P. Watson
Summary: Fluorescence correlation spectroscopy was used to investigate the clustering of CLEC-2 induced by crosslinked nanobody ligands. The results showed that the valency of the ligands and the expression levels of CLEC-2 were important factors in determining the activation of CLEC-2. Divalent ligands were found to be partial agonists while tetravalent ligands stimulated platelet aggregation.
COMMUNICATIONS BIOLOGY
(2023)
Article
Hematology
Claudia Schoenichen, Samantha J. Montague, Sanne L. N. Brouns, James J. Burston, Judith M. E. M. Cosemans, Kerstin Jurk, Beate E. Kehrel, Rory R. Koenen, Fionnuala Ni Ainle, Valerie B. O'Donnell, Oliver Soehnlein, Steve P. Watson, Marijke J. E. Kuijpers, Johan W. M. Heemskerk, Magdolna Nagy
Summary: This study reveals the key interaction mechanisms between platelets and neutrophils in arterial thrombus formation. Activated platelet integrin αIIbβ3 plays a role in preventing leukocyte adhesion, while platelet-released substances promote neutrophil activation. These findings provide insights for potential pharmacological intervention.
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
(2023)
Editorial Material
Pharmacology & Pharmacy
Joanne C. Clark, Steve P. Watson, Dylan M. Owen
Summary: This article discusses how a combination of agent-based modelling, advanced microscopy, and structural studies can provide new insights into the regulation of clustering, including spatial considerations, and reveal novel targets for therapeutic intervention.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2023)
Article
Hematology
Foteini-Nafsika Damaskinaki, Natalie J. Jooss, Eleyna M. Martin, Joanne C. Clark, Mark R. Thomas, Natalie S. Poulter, Jonas Emsley, Barrie Kellam, Steve P. Watson, Alexandre Slater
Summary: This study investigates the binding sites of three high-affinity nanobodies, Nb2, Nb21, and Nb35, on the platelet-signaling receptor GPVI. The researchers found that all three nanobodies can bind to the D1 domain of GPVI and inhibit collagen-induced GPVI signaling. They also identified common target residues, Arg46, Tyr47, and Ala57, on GPVI for these nanobodies. Additionally, the study negates the idea that GPVI dimerization induces a conformational change required for ligand binding.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Julia S. Gauer, Cedric Duval, Rui-Gang Xu, Fraser L. Macrae, Helen R. McPherson, Christian Tiede, Darren Tomlinson, Steve P. Watson, Robert A. S. Ariens
Summary: The interaction between GPVI and fibrin significantly affects the formation of procoagulant platelets and the structure of blood clots. Inhibition of GPVI signaling increases clot porosity and impairs clot contractibility to varying degrees.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Caroline Kardeby, Alice Evans, Joana Campos, Afraa Moosa Al-Wahaibi, Christopher W. Smith, Alexandre Slater, Eleyna M. Martin, Sonia Severin, Alexander Brill, Gunnar Pejler, Yi Sun, Steve P. Watson
Summary: English Summary: The study identified PEAR1 as a receptor for heparin and HPGM, and PI3K(3 as a key signaling molecule downstream of PEAR1 in platelets. These findings may provide important insights into the role of PEAR1 in cardiovascular disease.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Fawaz O. Alenazy, Maan H. Harbi, Dean P. Kavanagh, Joshua Price, Paul Brady, Oscar Hargreaves, Paul Harrison, Alexandre Slater, Alok Tiwari, Phillip L. R. Nicolson, Derek L. Connolly, Paulus Kirchhof, Neena Kalia, Martine Jandrot-Perrus, Pierre H. Mangin, Steve P. Watson, Mark R. Thomas
Summary: This study investigated the additional antithrombotic effects of combining glenzocimab, a GPVI inhibitor, with aspirin and ticagrelor. The results showed that glenzocimab enhanced platelet inhibition and reduced atherosclerotic plaque-induced platelet aggregation, adhesion, and activation. Compared to a GPIIb/IIIa inhibitor, glenzocimab exhibited similar antithrombotic effects but with less inhibition of general hemostasis.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Natalie J. Jooss, Christopher W. Smith, Jeremy A. Pike, Richard W. Farndale, Yvonne M. C. Henskens, Steve P. Watson, Johan W. M. Heemskerk, Natalie S. Poulter
Summary: This study utilized labeled anti-GPVI nanobody Nb28 to assess the distribution of GPVI on platelets in whole blood microfluidics. The results supported a relationship between GPVI cluster formation, thrombus size, and PS exposure. Inhibition of GPVI binding disrupted cluster formation, while inhibition of downstream signaling prevented thrombus formation.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
