Effect of anticoagulants on fibrin clot structure: a comparison between vitamin K antagonists and factor Xa inhibitors

Background Abnormal clot structure has been identified in patients with thrombotic disorders. Anticoagulant therapy offers clear benefits for thrombosis prevention and treatment by reducing blood clot formation and size; nevertheless, there are limited data on the effects of different anticoagulants, where clotting is initiated with different triggers, on clot structure. Objectives Our aim was to investigate the effects of vitamin K antagonists and factor Xa inhibitors on clot structure. Methods Clots from pooled plasma spiked with rivaroxaban, apixaban, or enoxaparin, as well as plasma from patients on warfarin, were compared to plasma without anticoagulation. The kinetic profile of polymerizing clots was obtained by turbidity, fiber density was determined by confocal microscopy, clot pore size was investigated by permeation, and fiber size was analyzed using scanning electron microscopy. Clotting agonist was either tissue factor or thrombin. Results Following clotting with tissue factor, all anticoagulated clots had a significantly increased lag time, with the exception of enoxaparin. Rivaroxaban additionally led to significantly less dense and more permeable clots, with thicker fibers. In contrast, turbidity analysis following initiation with thrombin showed few effects of anticoagulation, with only enoxaparin leading to a prolonged lag time. Enoxaparin clots made with thrombin were less dense and more permeable. Conclusion Our results show that anticoagulants modulate clot structure particularly when induced by tissue factor, most likely due to reduction of thrombin generation. We propose that the effects of different anticoagulants could be assessed with a global clot structure measurement such as permeation or turbidity, providing information on clot phenotype

The interaction between fibrinogen and zymogen FXIII-A₂B₂ is mediated by fibrinogen residues γ390-396 and the FXIII-B subunits

Coagulation transglutaminase factor XIII (FXIII) exists in circulation as heterotetrameric proenzyme FXIII-A2B2. Effectively all FXIII-A2B2 circulates bound to fibrinogen, and excess FXIII-B2 circulates in plasma. The motifs that mediate interaction of FXIII-A2B2 with fibrinogen have been elusive. We recently detected reduced binding of FXIII-A2B2 to murine fibrinogen that has γ-chain residues 390-396 mutated to alanines (Fibγ390-396A). Here, we evaluated binding features using human components, including recombinant fibrinogen variants, FXIII-A2B2, and isolated FXIII-A2 and -B2 homodimers. FXIII-A2B2 coprecipitated with wild-type (γA/γA), alternatively-spliced (γ′/γ′), and αC-truncated (Aα251) fibrinogens, whereas coprecipitation with human Fibγ390-396A was reduced by 75% (P < .0001). Surface plasmon resonance showed γA/γA, γ′/γ′, and Aα251 fibrinogens bound FXIII-A2B2 with high affinity (nanomolar); however, Fibγ390-396A did not bind FXIII-A2B2. These data indicate fibrinogen residues γ390-396 comprise the major binding motif for FXIII-A2B2. Compared with γA/γA clots, FXIII-A2B2 activation peptide release was 2.7-fold slower in Fibγ390-396A clots (P < .02). Conversely, activation of recombinant FXIII-A2 (lacking FXIII-B2) was similar in γA/γA and Fibγ390-396A clots, suggesting fibrinogen residues γ390-396 accelerate FXIII-A2B2 activation in a FXIII-B2–dependent mechanism. Recombinant FXIII-B2 bound γA/γA, γ′/γ′, and Aα251 with similar affinities as FXIII-A2B2, but did not bind or coprecipitate with Fibγ390-396A. FXIII-B2 also coprecipitated with fibrinogen from FXIII-A–deficient mouse and human plasmas. Collectively, these data indicate that FXIII-A2B2 binds fibrinogen residues γ390-396 via the B subunits, and that excess plasma FXIII-B2 is not free, but rather circulates bound to fibrinogen. These findings provide insight into assembly of the fibrinogen/FXIII-A2B2 complex in both physiologic and therapeutic situations

Fermat-linked relations for the Boubaker polynomial sequences via Riordan matrices analysis

The Boubaker polynomials are investigated in this paper. Using Riordan matrices analysis, a sequence of relations outlining the relations with Chebyshev and Fermat polynomials have been obtained. The obtained expressions are a meaningful supply to recent applied physics studies using the Boubaker polynomials expansion scheme (BPES).Comment: 12 pages, LaTe

Proteolytic and nonproteolytic activation mechanisms result in conformationally and functionally different forms of coagulation factor XIII A

Factor XIIIA (FXIIIA) is a transglutaminase that cross‐links intra‐ and extracellular protein substrates. FXIIIA is expressed as an inactive zymogen, and during blood coagulation, it is activated by removal of an activation peptide by the protease thrombin. No such proteolytic FXIIIA activation is known to occur in other tissues or the intracellular form of FXIIIA. For those locations, FXIIIA is assumed instead to undergo activation by Ca2+ ions. Previously, we demonstrated a monomeric state for active FXIIIA. Current analytical ultracentrifugation and kinetic experiments revealed that thrombin‐activated FXIIIA has a higher conformational flexibility and a stronger affinity toward glutamine substrate than does nonproteolytically activated FXIIIA. The proteolytic activation of FXIIIA was further investigated in a context of fibrin clotting. In a series of fibrin cross‐linking assays and scanning electron microscopy studies of plasma clots, the activation rates of FXIIIA V34X variants were correlated with the extent of fibrin cross‐linking and incorporation of nonfibrous protein into the clot. Overall, the results suggest conformational and functional differences between active FXIIIA forms, thus expanding the understanding of FXIIIA function. Those differences may serve as a basis for developing therapeutic strategies to target FXIIIA in different physiological environments

Reversibility in Chemical Reactions

open access bookIn this chapter we give an overview of techniques for the modelling and reasoning about reversibility of systems, including outof- causal-order reversibility, as it appears in chemical reactions. We consider the autoprotolysis of water reaction, and model it with the Calculus of Covalent Bonding, the Bonding Calculus, and Reversing Petri Nets. This exercise demonstrates that the formalisms, developed for expressing advanced forms of reversibility, are able to model autoprotolysis of water very accurately. Characteristics and expressiveness of the three formalisms are discussed and illustrated

Submesothelial deposition of carbon nanoparticles after toner exposition: Case report

Inhalation of carbon nanoparticles (CNP) from toner dust has been shown to have impact on the respiratory health of persons exposed. Office printers are known emitters of CNP. We report about a female open office worker who developed weight loss and diarrhoea. Laparoscopy done for suspected endometriosis surprisingly revealed black spots within the peritoneum. Submesothelial aggregates of CNP with a diameter of 31-67 nm were found by scanning and transmission electron microscopy in these tissue specimens. Colon biopsies showed inflammatory bowel disease with typically signs of Crohn disease, but no dust deposits. Transport of CNP via lymphatic and blood vessels after inhalation in the lungs has to be assumed. In this case respiratory symptoms were not reported, therefore no lung function tests were done. We have shown that workers with toner dust exposure from laser printers can develop submesothelial deposition of CNP in the peritoneum. Impact of toner dust exposure on the respiratory health of office workers, as suspected in other studies, has to be evaluated further

Synthesis and biological evaluation of cyclobutane-based β3 integrin antagonists: A novel approach to targeting integrins for cancer therapy

YesThe Arg-Gly-Asp (RGD)-binding family of integrin receptors, and notably the β3 subfamily, are key to multiple physiological processes involved in tissue development, cancer proliferation, and metastatic dissemination. While there is compelling preclinical evidence that both αvβ3 and αIIbβ3 are important anticancer targets, most integrin antagonists developed to target the β3 integrins are highly selective for αvβ3 or αIIbβ3. We report the design, synthesis, and biological evaluation of a new structural class of ligand-mimetic β3 integrin antagonist. These new antagonists combine a high activity against αvβ3 with a moderate affinity for αIIbβ3, providing the first evidence for a new approach to integrin targeting in cancer.This work was supported by the EPSRC (RCUK Academic Fellowship and Grant EP/H002626/1 to H.M.S.) and Prostate Cancer UK (Pilot Grant PA10-01). F.O.F.O.A-S.. was funded by the Public Authority for Applied Education and Training, Kuwait (PhD studentship)

Rehabilitation at the Time of Pandemic: Patient Journey Recommendations

Purpose: The World Health Organization (WHO) declared severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a pandemic in March 2020, causing almost 3.5 million coronavirus disease (COVID-19) related deaths worldwide. The COVID-19 pandemic has imposed a significant burden on healthcare systems, economies, and social systems in many countries around the world. The access and delivery of rehabilitation care were severely disrupted, and patients have faced several challenges during the COVID-19 outbreak. These challenges include addressing new functional impairments faced by survivors of COVID-19 and infection prevention to avoid the virus spread to healthcare workers and other patients not infected with COVID-19. In this scoping review, we aim to develop rehabilitation recommendations during the COVID-19 pandemic across the continuum of rehabilitation care. Materials and Methods: Established frameworks were used to guide the scoping review methodology. Medline, Embase, Pubmed, CINAHL databases from inception to August 1, 2020, and prominent rehabilitation organizations’ websites were searched. Study Selection: We included articles and reports if they were focused on rehabilitation recommendations for COVID-19 survivors or the general population at the time of the COVID-19 pandemic. Data Extraction: Two of our team members used the pre-tested data extraction form to extract data from included full-text articles. The strength and the quality of the extracted recommendations were evaluated by two reviewers using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach. Results: We retrieved 6,468 citations, of which 2,086 were eligible after removing duplicates. We excluded 1,980 citations based on the title and the abstract. Of the screened full-text articles, we included 106 studies. We present recommendations based on the patient journey at the time of the pandemic. We assessed the evidence to be of overall fair quality and strong for the recommendations. Conclusion: We have combined the latest research results and accumulated expert opinions on rehabilitation to develop acute and post-acute rehabilitation recommendations in response to the global COVID-19 pandemic. Further updates are warranted in order to incorporate the emerging evidence into rehabilitation guidelines