Article
Multidisciplinary Sciences
Katherine J. Kearney, Juliet Butler, Olga M. Posada, Clare Wilson, Samantha Heal, Majid Ali, Lewis Hardy, Josefin Ahnstrom, David Gailani, Richard Foster, Emma Hethershaw, Colin Longstaff, Helen Philippou
Summary: PKa can not only activate the coagulation cascade by acting on FXII, but also directly activate FIX to promote thrombin generation and fibrin formation. High-affinity binding interactions between PKa and FIX have been demonstrated under physiological conditions, suggesting a potential significant role of PKa in the absence of FXII or FXI.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Hematology
Zu-Lin Chen, Pradeep K. Singh, Katharina Horn, Marissa R. Calvano, Shigeru Kaneki, Keith R. McCrae, Sidney Strickland, Erin H. Norris
Summary: A dysregulated plasma contact system is involved in various pathological conditions. 3E8 anti-HK antibody blocks HK cleavage and bradykinin generation in human and mouse plasma, and inhibits contact system-induced bradykinin generation. It also inhibits the activation of factor XI, prekallikrein, and FXII, providing a novel strategy to treat contact system dysregulation-related diseases.
Article
Hematology
Magdolna Nagy, Alejandro Pallares Robles, Mayken Visser, Thomas Koeck, Vincent ten Cate, Arina J. ten Cate-Hoek, Stephan Schwers, Stefan Heitmeier, Hugo ten Cate, Philipp S. Wild, Henri M. H. Spronk
Summary: This study found that FXIa levels were elevated in patients with acute VTE and were associated with recurrent VTE, suggesting a significant risk contribution of FXI activation to VTE. The findings support the use of FXIa inhibition in the setting of acute VTE.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Multidisciplinary Sciences
Romy M. W. de Laat-Kremers, Marisa Ninivaggi, Iris van Moort, Moniek de Maat, Bas de Laat
Summary: Factor (F) VIII deficiency in haemophilia A patients leads to reduced thrombin generation and a severe imbalance between procoagulant and anticoagulant processes, increasing the risk of bleeding. Targeting the anticoagulant pathway, such as with thrombin inhibitor antithrombin (AT), could restore the haemostatic balance, but individual variations in response to AT reduction suggest a need for personalized treatment. In silico simulations showed that lowering AT levels dose-dependently restored thrombin generation, indicating the potential future use of modeling thrombin dynamics in managing patients undergoing AT targeting therapy.
SCIENTIFIC REPORTS
(2021)
Article
Cardiac & Cardiovascular Systems
Antonio Greco, Claudio Laudani, Marco Spagnolo, Federica Agnello, Denise Cristiana Faro, Simone Finocchiaro, Marco Legnazzi, Maria Sara Mauro, Placido Maria Mazzone, Giovanni Occhipinti, Carla Rochira, Lorenzo Scalia, Davide Capodanno
Summary: Therapeutic anticoagulation is used to prevent or treat blood clots, but it can increase the risk of bleeding. Inhibitors of Factor XI (FXI) show promise in reducing the adverse events of anticoagulation. Large-scale phase 3 clinical trials are needed to confirm the role of FXI inhibitors and determine their clinical indications.
Article
Biochemistry & Molecular Biology
Shigeyuki Tsutsui, Asuka Yoshimura, Yoshiharu Iwakuma, Osamu Nakamura
Summary: In this study, genomic sequences encoding proteins with APDs and SPD were identified in cartilaginous and bony fishes. Internal amino acid sequences in these proteins were mapped onto possible PK/fXI-like sequences. It was found that the PK/fXI-like gene originated from hepatocyte growth factor and was acquired in a common ancestor of jawed fish. Synteny analysis supported chromosomal translocation and gene duplication as the mechanisms for the presence of PK/fXI-like genes in different fish species.
JOURNAL OF MOLECULAR EVOLUTION
(2023)
Article
Multidisciplinary Sciences
Yang Cao, Yuchen Wang, Zhenqi Zhou, Calvin Pan, Ling Jiang, Zhiqiang Zhou, Yonghong Meng, Sarada Charugundla, Tao Li, Hooman Allayee, Marcus M. Seldin, Aldons J. Lusis
Summary: Tissue-tissue communication through endocrine factors is crucial for physiological homeostasis. A study on mice showed that coagulation factor XI (FXI), a protein derived from the liver, protects against diastolic dysfunction, a key trait of heart failure with preserved ejection fraction. FXI was found to activate the BMP-SMAD1/5 pathway in the heart and inhibit genes associated with inflammation and fibrosis, by cleaving and activating extracellular matrix-associated BMP7. This study reveals a protective role of FXI in heart injury that is separate from its role in blood coagulation.
Article
Hematology
Yuri Hayakawa, Shogo Tamura, Nobuaki Suzuki, Koya Odaira, Mahiru Tokoro, Fumika Kawashima, Fumihiko Hayakawa, Akira Takagi, Akira Katsumi, Atsuo Suzuki, Shuichi Okamoto, Takeshi Kanematsu, Tadashi Matsushita, Tetsuhito Kojima
Summary: A novel homozygous frameshift mutation in F11 was identified, resulting in a unique C-terminal structure in FXI and reduced extracellular secretion. Subsequent analysis revealed that a threonine at position 622 was essential for secretion, engaging in the formation of an alpha-helix motif. This study demonstrates the impact of the C-terminal structure, especially the alpha-helix motif, on FXI secretion.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2021)
Review
Hematology
James C. Fredenburgh, Jeffrey I. Weitz
Summary: Oral anticoagulants are widely used for preventing and treating thrombosis. Direct oral anticoagulants (DOACs) such as dabigatran and apixaban have replaced traditional anticoagulants. New DOACs like asundexian and milvexian, targeting FXIa, offer potential advantages over existing ones.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Medicine, General & Internal
Lindsey A. George, Paul E. Monahan, M. Elaine Eyster, Spencer K. Sullivan, Margaret Ragni, Stacy E. Croteau, John E. J. Rasko, Michael Recht, Benjamin J. Samelson-Jones, Amy MacDougall, Kristen Jaworski, Robert Noble, Marla Curran, Klaudia Kuranda, Federico Mingozzi, Tiffany Chang, Kathleen Z. Reape, Xavier M. Anguela, Katherine A. High
Summary: A gene therapy trial using an AAV vector (SPK-8011) for factor VIII expression in 18 men with hemophilia A showed sustained expression in most participants, leading to reduced bleeding events and discontinuation of prophylaxis.
NEW ENGLAND JOURNAL OF MEDICINE
(2021)
Article
Biochemical Research Methods
Sreekant Damodara, Jaskirat Arora, Dhruva J. Dwivedi, Patricia C. Liaw, Alison E. Fox-Robichaud, P. Ravi Selvaganapathy
Summary: This study developed a low-cost, single-step method for detecting protein C in blood plasma and demonstrated its potential application in sepsis prognosis.
Article
Cell Biology
Stephanie E. Reitsma, Jiaqing Pang, Vikram Raghunathan, Joseph J. Shatzel, Christina U. Lorentz, Erik Tucker, Andras Gruber, David Gailani, Owen J. T. McCarty, Cristina Puy
Summary: The interaction between FXIa and platelets may play a role in modulating thrombosis, with platelets found to enhance FXIa activity and promote coagulation while also inhibiting FXI activation.
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
(2021)
Review
Hematology
Karsten Engseth Kluge, Ingebjorg Seljeflot, Harald Arnesen, Torstein Jensen, Sigrun Halvorsen, Ragnhild Helseth
Summary: In this review, observational and experimental studies on factors XI and XII as potential targets for anticoagulant therapy are discussed. Low concentrations of FXI are found to be protective against ischemic stroke and venous thrombosis, indicating its potential as a target for antithrombotic therapy. The potential of targeting FXII for preventing thrombosis is still unclear, with conflicting results from different studies.
THROMBOSIS RESEARCH
(2022)
Article
Hematology
Chan Li, Awital Bar Barroeta, Szu Shen Wong, Hyo Jung Kim, Monika Pathak, Ingrid Dreveny, Joost C. M. Meijers, Jonas Emsley
Summary: The structure of the complex formed between HK and PK apple domains was determined, revealing different conformations and interactions compared to the FXI-HK complex.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Ruiqi Yin, Vishal Patel, Rida A. Malik, James C. Fredenburgh, Jeffrey I. Weitz
Summary: Polyphosphate (polyP) serves as a template to promote feedback activation of factor XI by thrombin. This study determines the contribution of thrombin exosites 1 and 2 to polyP-induced potentiation of FXI activation. The results show that polyP accelerates FXI activation by thrombin and exosite 2 ligands attenuate this activation.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Rick H. van Gorp, Ingrid Dijkgraaf, Vanessa Broker, Matthias Bauwens, Peter Leenders, Danyel Jennen, Marc R. Dweck, Jan Bucerius, Jacco J. Briede, Joanne van Ryn, Vincent Brandenburg, Felix Mottaghy, Henri M. H. Spronk, Chris P. Reutelingsperger, Leon J. Schurgers
Summary: Short-term treatment with warfarin promotes the formation of atherosclerotic plaques, while long-term use increases calcification activity in plaques. Dabigatran significantly reduces plaque progression compared to warfarin. Warfarin and thrombin increase VSMC oxidative stress and extracellular vesicle release, which can be prevented by dabigatran.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2021)
Article
Hematology
Tom W. van de Berg, Anne-Marije M. Hulshof, Magdolna Nagy, Rene van Oerle, Jan-Willem Sels, Bas van Bussel, Hugo ten Cate, Yvonne Henskens, Henri M. H. Spronk
Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection is associated with a prothrombotic phenotype, making thrombosis an important factor in the prognosis and outcome of COVID-19. This study validated global coagulation assays for COVID-19 patients with high fibrinogen levels and heparin use, showing that thrombin generation assay was sensitive in heparin spiked plasma and tPA-ROTEM was effective in measuring coagulant changes by high fibrinogen and heparins without clear fibrinolytic effect.
THROMBOSIS RESEARCH
(2021)
Article
Hematology
S. H. E. van der Beelen, S. M. Agten, D. P. L. Suylen, K. Wichapong, J. Hrdinova, B. M. E. Mees, H. M. H. Spronk, T. M. Hackeng
Summary: A new method for quantifying FXIa in plasma was developed using a unique multivalent catch-and-release system, showing promising potential for clinical applications.
THROMBOSIS RESEARCH
(2021)
Article
Hematology
Marina Panova-Noeva, Bianca Wagner, Markus Nagler, Thomas Koeck, Vincent Ten Cate, Lisa Eggebrecht, Jurgen H. Prochaska, Imke Meyer, Christoph Gerdes, Henri M. Spronk, Karl J. Lackner, Hugo Ten Cate, Kirsten Leineweber, Stefan Heitmeier, Stavros Konstantinides, Philipp S. Wild
Summary: This study found significant differences in platelet function between different phenotypes of VTE, with distinct platelet reactivity and platelet-dependent thrombin generation between pulmonary embolism-related phenotypes and isolated deep vein thrombosis.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Hematology
Sophie C. Dolleman, Stijn M. Agten, Henri M. H. Spronk, Tilman M. Hackeng, Mettine H. A. Bos, Henri H. Versteeg, Anton Jan van Zonneveld, Hetty C. de Boer
Summary: This study investigated the potential effects of different DOACs on vascular integrity. The results showed that the anti-FXa DOAC rivaroxaban preserved endothelial barrier function, while the anti-thrombin DOAC dabigatran failed to protect endothelial integrity over time. However, the loss of barrier function caused by dabigatran could be prevented by a mimicking peptide that blocks thrombin's exosite-I.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Cardiac & Cardiovascular Systems
Steven P. Grover, Taylor Coughlin, Salma M. Fleifil, Jens J. N. Posma, Henri H. M. Spronk, Stefan Heitmeier, A. Phillip Owens, Nigel Mackman
Summary: Contrary to the hypothesis, the combination of aspirin and rivaroxaban did not show a greater reduction of atherosclerosis in Ldlr(-/-) mice compared to using each agent alone. However, all treatment groups (aspirin, rivaroxaban, and combination) reduced macrophage content and apoptosis in the lesions compared to control group. The expression of a small number of proteins in the aorta and plasma was altered in mice treated with aspirin and/or rivaroxaban.
Review
Medicine, General & Internal
Sierk Dauwerse, Hugo ten Cate, Henri M. H. Spronk, Magdolna Nagy
Summary: Hemostasis is a finely tuned process with dysregulation potentially leading to bleeding or thrombotic complications. COVID-19 patients often have a hypercoagulable state and require hospitalization, with ROTEM being considered a promising tool to predict outcomes in these patients.
Article
Medicine, Research & Experimental
Magdalena L. Bochenek, Rajinikanth Gogiraju, Stefanie Grossmann, Janina Krug, Jennifer Orth, Sabine Reyda, George S. Georgiadis, Henri M. Spronk, Stavros Konstantinides, Thomas Muenzel, John H. Griffin, Philipp Wild, Christine Espinola-Klein, Wolfram Ruf, Katrin Schaefer
Summary: The signaling between endothelial protein C receptor and protease activated receptor 1 plays a crucial role in ischemic reperfusion and neovascularization. This study highlights the connection between coagulation signaling, endothelial nitric oxide bioavailability, and angiogenesis.
Review
Chemistry, Medicinal
Magdolna Nagy, Paola E. J. van der Meijden, Julia Glunz, Leon Schurgers, Esther Lutgens, Hugo ten Cate, Stefan Heitmeier, Henri M. H. Spronk
Summary: This review focuses on the important factors of atherosclerosis contributing to the pathophysiology of peripheral arterial disease (PAD). The role of thrombo-inflammation and hypercoagulability in vascular diseases, including PAD, is discussed. The current antithrombotic treatments and potential new targets for the development of new treatments are also examined.
Article
Hematology
Katherine J. Kearney, Henri M. H. Spronk, Jonas Emsley, Nigel S. Key, Helen Philippou
Summary: It was previously believed that plasma kallikrein (PKa) only functioned to activate factor XII (FXII) in the coagulation cascade. However, recent studies have revealed a new pathway where PKa can directly activate factor IX (FIX). These studies identified the binding of FIX/FIXa with PK/PKa, the PKa-induced thrombin generation and clot formation independent of FXI, and the increased formation of FIXa:AT complexes due to PKa activity. The existence of both a canonical (FXIa-dependent) and non-canonical (PKa-dependent) pathway of FIX activation is suggested.
SEMINARS IN THROMBOSIS AND HEMOSTASIS
(2023)
Article
Medicine, General & Internal
Loes H. Willems, Lotte M. C. Jacobs, Laszlo A. Groh, Hugo ten Cate, Henri M. H. Spronk, Boden Wilson-Storey, Gerjon Hannink, Sander M. J. van Kuijk, Chahinda Ghossein-Doha, Magdi Nagy, Dick H. J. Thijssen, Andre S. van Petersen, Michiel C. Warle
Summary: COVID-19 affects the cardiovascular system, leading to sustained microvascular dysfunction, systemic inflammation, and coagulation activation. 18 months after infection, macrovascular dysfunction does not increase, but endothelial cell activation, inflammation, and coagulation activation still persist.
JOURNAL OF CLINICAL MEDICINE
(2023)
Review
Cardiac & Cardiovascular Systems
Constance C. F. M. J. Baaten, Magdolna Nagy, Wolfgang Bergmeier, Henri M. H. Spronk, Paola E. J. van der Meijden
Summary: Coronary atherosclerosis is the leading cause of heart disease in developed countries and is a chronic inflammatory process. The composition and location of atherosclerotic plaques determine the phenotype of the lesion, and plaque rupture or erosion can lead to acute clinical events. The contribution of platelets to thrombus formation differs depending on the plaque phenotype.
EUROPEAN HEART JOURNAL
(2023)
Article
Hematology
Sanne L. N. Brouns, Bibian M. E. Tullemans, Cristiana Bulato, Gina Perrella, Elena Campello, Luca Spiezia, Johanna P. van Geffen, Marijke J. E. Kuijpers, Rene van Oerle, Henri M. H. Spronk, Paola E. J. van der Meijden, Paolo Simioni, Johan W. M. Heemskerk
Summary: This study assessed the role of platelets in thrombus and fibrin formation in patients with protein C or protein S deficiency under high-shear flow conditions. The results showed that these patients had impaired platelet activation, thrombus phenotype, and fibrin formation, but unchanged platelet adhesion. The defect may be caused by negative platelet priming.
RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Hematology
Elisa D'Alessandro, Billy Scaf, Rene van Oerle, Frans A. van Nieuwenhoven, Arne van Hunnik, Sander Verheule, Ulrich Schotten, Hugo ten Cate, Henri M. H. Spronk
Summary: This study presents the customization of the CAT assay for goats, with both the GBP and RVV-X methods triggering TG in goat plasma effectively. The RVV-X method appeared to better distinguish changes in TG curves due to increases in clotting potential as well as to FXa inhibition by rivaroxaban in goat plasma.
RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
(2021)
Article
Hematology
Loes H. Willems, Magdolna Nagy, Hugo Ten Cate, Henri M. H. Spronk, Lotte M. C. Jacobs, Josephine Kranendonk, Maaike van Leeuwen, Danielle Meijer, Saskia Middeldorp, Laszlo A. Groh, Michiel C. Warle
Summary: The ChAdOx1 vaccination leads to an inflammatory response with increased levels of IL6, but no activation of the blood coagulation system was observed 1-2 days following vaccination.
RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
(2021)