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Current Opinion in Hematology
Journal Prestige (SJR): 1.588  Citation Impact (citeScore): 3 Number of Followers: 20  Hybrid journal (It can contain Open Access articles)ISSN (Print) 1065-6251 - ISSN (Online) 1531-7048 Published by LWW Wolters Kluwer  [297 journals]
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- Editorial introduction
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Abstract:
No abstract available
PubDate: Thu, 01 Sep 2022 00:00:00 GMT-
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- Recent advances in factor XII structure and function
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Authors: Shamanaev; Aleksandr; Litvak, Maxim; Gailani, David
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Purpose of review Factor XII (FXII), the precursor of the protease FXIIa, contributes to pathologic processes including angioedema and thrombosis. Here, we review recent work on structure-function relationships for FXII based on studies using recombinant FXII variants.Recent findings FXII is a homolog of pro-hepatocyte growth factor activator (Pro-HGFA). We prepared FXII in which domains are replaced by corresponding parts of Pro-HGA, and tested them in FXII activation and activity assays. In solution, FXII and prekallikrein undergo reciprocal activation to FXIIa and kallikrein. The rate of this process is restricted by the FXII fibronectin type-2 and kringle domains. Pro-HGA replacements for these domains accelerate FXII and prekallikrein activation. When FXII and prekallikrein bind to negatively charged surfaces, reciprocal activation is enhanced. The FXII EGF1 domain is required for surface binding.Summary We propose a model in which FXII is normally maintained in a closed conformation resistant to activation by intramolecular interactions involving the fibronectin type-2 and kringle domains. These interactions are disrupted when FXII binds to a surface through EGF1, enhancing FXII activation and prekallikrein activation by FXIIa. These observations have important implications for understanding the contributions of FXII to disease, and for developing therapies to treat thrombo-inflammatory disorders.
PubDate: Thu, 01 Sep 2022 00:00:00 GMT-
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- Fibrin structure, viscoelasticity and lysis face the interplay of
biorelevant polyions-
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Authors: Komorowicz; Erzsébet; Kolev, Krasimir
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Purpose of review In the past 5 decades, heparins have been widely used as anticoagulants in the prevention and treatment of thrombosis. Subsequent development of heparin variants of various size and charge facilitated the discovery of their multiple biological actions and nonanticoagulant benefits. Platelet-derived or microbial polyphosphates, as well as DNA released in the course of neutrophil extracellular trap-formation are additional polyanions, which can modulate the development and stability of thrombi associated with cancer or inflammation. In this review, we focus on the size-dependent and electric charge-dependent modulatory effects of the three polyanions of different chemical structure.Recent findings The polycationic histones have been recognized as potential biomarkers and therapeutic targets in several diseases related to inflammation and thrombosis. Since combating histones with activated protein C or heparin could cause unwanted bleeding, the quest for nonanticoagulant histone-neutralizing agents is ongoing. Polyanions may neutralize or exaggerate certain histone-mediated effects depending on their electric charge, size and histone effects under investigation. Several prothrombotic effects of polyphosphates and DNA are also size-dependent.Summary The efficiency of future therapeutics targeting prothrombotic polyanions or histones is not a simple matter of electric charge, but may rely on a delicate combination of size, charge and chemical composition.
PubDate: Thu, 01 Sep 2022 00:00:00 GMT-
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- The protein C pathways
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Authors: Leon; Gemma; Rehill, Aisling M.; Preston, Roger J.S.
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Purpose of review To provide an overview of the state-of-the-art in protein C (PC) pathway research.Recent findings The PC pathway is crucial for maintaining hemostasis to prevent venous thromboembolism. This is evident from genetic mutations that result in impaired PC pathway activity and contribute to increased venous thromboembolism risk in affected individuals. In addition to its anticoagulant role, activated PC (APC) also mediates a complex, pleiotropic role in the maintenance of vascular cell health, which it achieves via anti-inflammatory and antiapoptotic cell signaling on endothelial cells. Emerging data have demonstrated that cell signaling by APC, mediated by multiple receptor interactions on different cell types, also confers cytoprotective and anti-inflammatory benefits. Defects in both arms of the PC pathway are associated with increased susceptibility to thrombo-inflammatory disease in various preclinical thrombotic, proinflammatory and neurological disease models. Moreover, recent studies have identified attenuation of anticoagulant PC pathway activity as an exciting therapeutic opportunity to promote hemostasis in patients with inherited or acquired bleeding disorders.Summary In this review, we provide an overview of some recent developments in our understanding of the PC pathways.
PubDate: Thu, 01 Sep 2022 00:00:00 GMT-
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- Complement contributions to COVID-19
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Authors: Conway; Edward M.; Pryzdial, Edward L.G.
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Purpose of review COVID-19 remains a major source of concern, particularly as new variants emerge and with recognition that patients may suffer long-term effects. Mechanisms underlying SARS-CoV-2 mediated organ damage and the associated vascular endotheliopathy remain poorly understood, hindering new drug development. Here, we highlight selected key concepts of how the complement system, a major component of innate immunity that is dysregulated in COVID-19, participates in the thromboinflammatory response and drives the vascular endotheliopathy.Recent findings Recent studies have revealed mechanisms by which complement is activated directly by SARS-CoV-2, and how the system interfaces with other innate thromboinflammatory cellular and proteolytic pathways involving platelets, neutrophils, neutrophil extracellular traps and the coagulation and kallikrein-kinin systems. With this new information, multiple potential sites for therapeutic intervention are being uncovered and evaluated in the clinic.Summary Infections with SARS-CoV-2 cause damage to the lung alveoli and microvascular endothelium via a process referred to as thromboinflammation. Although not alone in being dysregulated, complement is an early player, prominent in promoting the endotheliopathy and consequential organ damage, either directly and/or via the system's complex interplay with other cellular, molecular and biochemical pathways. Delineating these critical interactions is revealing novel and promising strategies for therapeutic intervention.
PubDate: Thu, 01 Sep 2022 00:00:00 GMT-
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- Measurement of tissue factor-positive extracellular vesicles in plasma:
strengths and weaknesses of current methods-
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Authors: Mackman; Nigel; Sachetto, Ana Teresa Azevedo; Hisada, Yohei
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Purpose of review This review evaluates the different methods used to measure levels of tissue factor (TF) in plasma and on extracellular vesicles (EVs). Levels of TF-positive (TF+) EVs in blood are increased in a variety of diseases, such as cancer, sepsis, and viral infection, and are associated with thrombosis. Highly sensitive assays are required to measure the low levels of TF+ EVs in blood.Recent findings TF antigen levels in plasma have been measured using standard ELISAs, SimpleStep ELISA technology, and solid-phase proximity ligation assay. Some studies reported the detection of TF+ EVs in plasma by flow cytometry. In addition, TF+ EVs can be captured onto beads and chips using anti-TF antibodies. Several assays have been developed to measure TF activity in EVs isolated from plasma. Importantly, activity-based assays are more sensitive than antigen-based assays as a single TF/FVIIa complex can generate large amounts of FXa.Summary We recommend isolating EVs from plasma and measuring TF activity using a functional assay in the presence and absence of an anti-TF antibody. We do not recommend using antigen-based assays as these are not sensitive enough to detect the low levels of TF in plasma.
PubDate: Thu, 01 Sep 2022 00:00:00 GMT-
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