https://orcid.org/0000-0001-6193-4585
This review series focuses on the structure, composition, and formation of hemostatic plugs and thrombotic occlusions. Blood circulates as a fluid which is primed to form a solid when exposed to certain surfaces. This process is tightly regulated, to promote normal hemostasis when needed, yet avoid the development of a thrombus upon an intact vascular surface. We start this journey with a structural overview of thrombotic occlusions, followed by reviews on 3 key contributors to thrombus formation and stabilization, platelets, factor (F)XIII, and the contact system, and end with a discussion of novel strategies to promote hemostasis and healing without causing unwanted thrombosis.
This review series includes the following articles.
John W. Weisel and Rustem I. Litvinov, “Exploring the thrombus niche: lessons learned and potential therapeutic opportunities”
Frauke Swieringa, Johan W. M. Heemskerk, and Alice Assinger, “Platelet activation and signaling in thrombus formation”
James P. Luyendyk, Matthew J. Flick, and Alisa S. Wolberg, “Factor XIII: driving (cross-)links in hemostasis, thrombosis, and disease”
Jonas Emsley, Yujie Ma, and Joost C. M. Meijers, “Structure and interactions of the proteins from the contact system”
Luke J. Tucker, Krista Hilmas, and Ashley C. Brown, “Structure-based design of therapeutics to control hemostasis”
The review by Weisel and Litvinov provides a mechanistic overview of the components that form a thrombus, primarily consisting of platelets, erythrocytes, and fibrin, but also incorporating neutrophils, monocytes, von Willebrand factor, microvesicles, and a variety of plasma proteins. They describe how the compositions of thrombi differ depending on location within the vasculature, whether clots develop in the venous or arterial circulation, as well as structural changes that occur over time, addressing the evolution of a thrombotic occlusion within a coronary artery developing over time in the context of an acute myocardial infarction. Potential therapeutic interventions could target any of the constituents of a thrombotic occlusion, and optimal therapies will likely differ depending on location of the thrombus within the vasculature, as well as time from initial development of a new clot.
This introduction to clot structure is followed by an article by Swieringa et al that focuses specifically on the contribution of platelet activation and signaling mechanisms to arterial thrombosis and bleeding. They describe how platelet signaling proteins and pathways, including vesicle trafficking, transcription, and intercellular communications, all contribute to the formation of a hemostatic plug. Platelets contribute by surface adhesion, initiation of shape change, activation mediated by transmembrane integrins, formation of cellular aggregates, secretion of granules, and expression of procoagulant activity. Murine studies in combination with the identification of human genes linked to platelet-related bleeding disorders have led to the identification of hundreds of genes that are involved in these processes. The identification of the genes behind these mechanisms identifies new targets for novel therapies.
Luyendyk et al follow this review with an elegant discussion of FXIII, a key contributor to clot stabilization that is essential for normal hemostasis and thereby has an impact on the course of thrombosis formation. Activated FXIII(a) is a transglutaminase that crosslinks and stabilizes fibrin, protecting a developing hemostatic plug from mechanical disruption and biochemical dissolution, and FXIII deficiency is associated with hemorrhagic manifestations. Conversely, when a clot develops within intact vasculature, FXIII(a) can modulate the thrombotic process, resulting in an alteration of the risk for embolization to occur. The authors also discuss how FXIII may contribute to other disorders, including liver disease and colitis.
We next explore the contributions of the contact system, consisting of FXII, FXI, prekallikrein, and high molecular weight kininogen (HMWK), to clot formation. The contact system links the intrinsic pathway of coagulation, through the activation of FIX by FXIa, with inflammation, by the cleavage of HMWK to generate bradykinin. Emsley et al describe the 3-dimensional structures of these molecules and reveal how they interact with one another as well as with endothelial cells, platelets, and other components of a hemostatic plug. The complex interplay between these 4 plasma proteins as well as different cell surfaces regulates systemic activation and the resulting hemostatic and/or inflammatory consequences. Therapies targeting specific components of the contact system are in development as antithrombotic agents, targeting FXI, as well as for the treatment of angioedema, targeting FXII and prekallikrein.
We close this review series with an article by Tucker et al that builds on the previous articles to explore structure-based therapeutic strategies that can be used to promote and enhance hemostasis. Hemostatic materials are broadly categorized as topical hemostatic agents, that are applied directly to a wound, or systemic hemostatic agents, administered IV. Examples of topical materials include gauze, hydrogels, glues, and powders, each of which can be modified depending on specific applications. Targeted biomaterials in development for systemic use include clot-interfacing polymers, such as PolySTAT, a polymer that mimics the effect of FXIII, and high molecular weight polyphosphates that accelerate FXII activation. Platelet-mimetic materials are nano- or micronscaled particles that can be conjugated with compounds that target platelets and/or hemostatic proteins to a wound site. Many of these materials are being developed with a focus on providing therapeutic options for patients in a prehospital setting, by improvements in storage requirements, portability, stability, cost, and patient safety.
This review series explores the complex structure of hemostatic plugs and thrombotic occlusions. By using the information gained from structural studies of thrombi in addition to detailed analyses of the individual constituents of the clot, we will continue to develop new diagnostic and therapeutic tools to enhance normal hemostasis while preventing and treating unwanted thrombosis. And, like Arcimboldo’s paintings of the Four Seasons, we can appreciate the complexity associated with formation of a blood clot!
