scholarly journals Technology-based approaches toward a better understanding of neuro-coagulation in brain homeostasis

2021 ◽  
Author(s):  
Ben M. Maoz ◽  
Maria Asplund ◽  
Nicola Maggio ◽  
Andreas Vlachos
Keyword(s):  
Coagulation Factor ◽  
Epileptic Seizures ◽  
Coagulation Factors ◽  
Protease Activated Receptors ◽  
Blood Coagulation Factors ◽  
Neural Excitability ◽  
Brain Functions ◽  
Brain Interface ◽  
The Brain ◽  
Brain Homeostasis

AbstractBlood coagulation factors can enter the brain under pathological conditions that affect the blood–brain interface. Besides their contribution to pathological brain states, such as neural hyperexcitability, neurodegeneration, and scar formation, coagulation factors have been linked to several physiological brain functions. It is for example well established that the coagulation factor thrombin modulates synaptic plasticity; it affects neural excitability and induces epileptic seizures via activation of protease-activated receptors in the brain. However, major limitations of current experimental and clinical approaches have prevented us from obtaining a profound mechanistic understanding of “neuro-coagulation” in health and disease. Here, we present how novel human relevant models, i.e., Organ-on-Chips equipped with advanced sensors, can help overcoming some of the limitations in the field, thus providing a perspective toward a better understanding of neuro-coagulation in brain homeostasis.

EXPRESSION IN ONTOGENESIS OF HUMAN BLOOD COAGULATION FACTORS

1987 ◽  
Author(s):  
H J Hassan ◽  
A Leonardi ◽  
C Chelucci ◽  
R Guerriero ◽  
P M Mannucci ◽  
...  
Keyword(s):  
Blood Coagulation ◽  
Protein C ◽  
Antithrombin Iii ◽  
Liver Homogenate ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Adult Liver ◽  
Blood Coagulation Factors ◽  
Guanidine Isothiocyanate

We have analyzed the expression of several blood coagulation factors (IX, VIII, X, fibrinogen chains) and inhibitors (antithrombin III, protein C) in human embryonic and fetal livers, obtained from legal abortions at 6-11 week post-conception. The age was established by morphologic staging and particularly crown-rump lenght measurement.Total cellular RNA was isolated from partially purified hepatocytes or total liver homogenate using the guanidine isothiocyanate method. Poly(A)+ RNA was selected by oligodT cellulose chromatography. The size and the number of the embryonic and fetal transcripts are equivalent to those observed in adult liver, as evaluated by Northern blot analysis of total or poly(A)+ RNA hybridized to human cDNA probes.The level of coagulation factor transcripts in embryonic and fetal liver was evaluated by dot hybridization of total RNA (0.5-10 ug), as compared to RNA extracted from normal adult liver biopsies. The expression of blood coagulation factors in embryos is generally reduced for all factors, but at a different degree. In 5-11 wk liver, the level of factor IX is 5-10% of that observed in adults, while fibrinogen, protein C, antithrombin III RNA level rises from 25 to 50% and factor X is expressed at a level comparable to that observed in adult liver.We conclude that during these stages of development blood coagulation factors are expressed according to three different time, curves, possibly due to the effect of different types of regulatory mechanisms.

scholarly journals Thrombin Inhibition Reduces the Expression of Brain Inflammation Markers upon Systemic LPS Treatment

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Efrat Shavit Stein ◽  
Marina Ben Shimon ◽  
Avital Artan Furman ◽  
Valery Golderman ◽  
Joab Chapman ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Specific Inhibitor ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Brain Inflammation ◽  
Coagulation Activity ◽  
Microglia Cell ◽  
The Brain

Systemic inflammation and brain pathologies are known to be linked. In the periphery, the inflammation and coagulation systems are simultaneously activated upon diseases and infections. Whether this well-established interrelation also counts for neuroinflammation and coagulation factor expression in the brain is still an open question. Our aim was to study whether the interrelationship between coagulation and inflammation factors may occur in the brain in the setting of systemic inflammation. The results indicate that systemic injections of lipopolysaccharide (LPS) upregulate the expression of both inflammatory and coagulation factors in the brain. The activity of the central coagulation factor thrombin was tested by a fluorescent method and found to be significantly elevated in the hippocampus following systemic LPS injection (0.5 ± 0.15 mU/mg versus 0.2 ± 0.03 mU/mg in the control). A panel of coagulation factors and effectors (such as thrombin, FX, PAR1, EPCR, and PC) was tested in the hippocampus, isolated microglia, and N9 microglia cell by Western blot and real-time PCR and found to be modulated by LPS. One central finding is a significant increase in FX expression level following LPS induction both in vivo in the hippocampus and in vitro in N9 microglia cell line (5.5 ± 0.6- and 2.3 ± 0.1-fold of increase, resp.). Surprisingly, inhibition of thrombin activity (by a specific inhibitor NAPAP) immediately after LPS injection results in a reduction of both the inflammatory (TNFα, CXL9, and CCL1; p<0.006) and coagulation responses (FX and PAR1; p<0.004) in the brain. We believe that these results may have a profound clinical impact as they might indicate that reducing coagulation activity in the setting of neurological diseases involving neuroinflammation may improve disease outcome and survival.

scholarly journals Macrophage protease-activated receptor 2 regulates fetal liver erythropoiesis in mice

2020 ◽  
Vol 4 (22) ◽  
pp. 5810-5824
Author(s):  
Mona Saffarzadeh ◽  
Kristin Grunz ◽  
T. Son Nguyen ◽  
Young K. Lee ◽  
Maki Kitano ◽  
...  
Keyword(s):  
Messenger Rna ◽  
Fetal Liver ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Protease Activated Receptors ◽  
Inflammatory Stress ◽  
Erythroblastic Island ◽  
Liver Macrophage ◽  
Deficient Mice

Abstract Deficiencies in many coagulation factors and protease-activated receptors (PARs) affect embryonic development. We describe a defect in definitive erythropoiesis in PAR2-deficient mice. Embryonic PAR2 deficiency increases embryonic death associated with variably severe anemia in comparison with PAR2-expressing embryos. PAR2-deficient fetal livers display reduced macrophage densities, erythroblastic island areas, and messenger RNA expression levels of markers for erythropoiesis and macrophages. Coagulation factor synthesis in the liver coincides with expanding fetal liver hematopoiesis during midgestation, and embryonic factor VII (FVII) deficiency impairs liver macrophage development. Cleavage-insensitive PAR2-mutant mice recapitulate the hematopoiesis defect of PAR2-deficient embryos, and macrophage-expressed PAR2 directly supports erythroblastic island function and the differentiation of red blood cells in the fetal liver. Conditional deletion of PAR2 in macrophages impairs erythropoiesis, as well as increases inflammatory stress, as evidenced by upregulation of interferon-regulated hepcidin antimicrobial peptide. In contrast, postnatal macrophage PAR2 deficiency does not have any effect on steady-state Kupffer cells, bone marrow macrophage numbers, or erythropoiesis, but erythropoiesis in macrophages from PAR2-deficient mice is impaired following hemolysis. These data identify a novel function for macrophage PAR2 signaling in adapting to rapid increases in blood demand during gestational development and postnatal erythropoiesis under stress conditions.

Thrombin and Activated Coagulation Factor X Stimulate the Release of Cytokines and Fibronectin from Nasal Polyp Fibroblasts via Protease-Activated Receptors

2017 ◽  
Vol 31 (1) ◽  
pp. e13-e18 ◽  
Author(s):  
Shino Shimizu ◽  
Ichiro Tojima ◽  
Kumiko Takezawa ◽  
Koji Matsumoto ◽  
Hideaki Kouzaki ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Nasal Polyp ◽  
Messenger Rna ◽  
Transforming Growth Factor ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor X ◽  
Tgf Beta ◽  
Protease Activated Receptors ◽  
Mrna And Protein Expression

Background Nasal epithelial cells and infiltrating eosinophils express tissue factor, and high thrombin activity and excess fibrin deposition are found in nasal secretion and in nasal polyp from patients with chronic rhinosinusitis with nasal polyp (CRSwNP). Activated coagulation factors play important roles not only in thrombosis but also in inflammation through interaction with protease-activated receptors (PAR). However, little is known about the effects of activated coagulation factors on the release of cytokines and extracellular matrix from nasal polyp fibroblasts (NPF). Purpose The purpose of this study was to analyze the expression of PARs, which are receptors for activated coagulation factors, on NPFs and to determine the roles of thrombin and activated coagulation factor X (FXa) in the release of cytokines and fibronectin from NPFs. Methods NPFs were obtained from patients with CRSwNP, and the messenger RNA (mRNA) and protein expression of PARs in these NPFs were examined. We then investigated whether thrombin or FXa stimulates the release of transforming growth factor (TGF) beta 1, fibronectin, eotaxin-1, interleukin (IL) 6, or IL-8 from cultured NPFs. The effects of PAR agonists on the release of cytokines and fibronectin were also examined. Results NPFs expressed the mRNA and proteins of all four PARs: PAR-1, PAR-2, PAR-3, and PAR-4. Both thrombin and FXa significantly stimulated the release of TGF beta 1, fibronectin, eotaxin-1, IL-6, and IL-8 from cultured NPFs. PAR-1 and PAR-2 agonists stimulated the secretion of TGF beta 1, fibronectin, eotaxin-1, IL-6, and IL-8. PAR-3 agonist stimulated the release of TGF beta 1, fibronectin, and eotaxin-1. PAR-4 agonist did not induce the release of these molecules. Conclusion NPFs play important roles in the pathophysiology of CRSwNP such as in nasal polyp formation and inflammatory cell infiltration by releasing cytokines and extracellular matrix proteins. Activated coagulation factors, thrombin and FXa, stimulate the release of these cytokines and fibronectin from NPFs via PARs.

scholarly journals A clinical case of the successful use of recombinant activated VII coagulation factor in a newborn with sepsis

2020 ◽  
Vol 7 (3) ◽  
pp. 132-137
Author(s):  
I. G. Trukhanova ◽  
L. V. Krugova ◽  
Yu. G. Kutyreva
Keyword(s):  
Clinical Case ◽  
High Titer ◽  
Intensive Therapy ◽  
Active Form ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Fibrin Clot ◽  
Blood Coagulation Factors ◽  
Important Place

Recently, in the intensive care of acquired coagulopathies in children and newborns, synthetic coagulation factors have occupied an important place, with recombinant VII activated coagulation factor (rFVIIa) being used more often. It initiates hemostasis at the site of vascular damage, forms a complex with tissue factor, and ensures maximum platelet activation. The resulting complex stimulates the transition of blood coagulation factors IX and X to the active form IXa and Xa, then factor Xa leads to increased synthesis thrombin and the formation of a stable fibrin clot. Initially, rFVIIa was developed and used to treat bleeding and surgery in patients with hereditary or acquired hemophilia and a high titer of an inhibitor to coagulation factors VIII or IX. Currently, indications for its use have expanded significantly and it is effective in intensive therapy of other acquired coagulopathy, including the occurrence of coagulopathy due to sepsis. This article presents a clinical case of the successful use of rFVIIa in a newborn with sepsis and hemocogulation disorders. The description of each case is important for the accumulation of experience and the development of further algorithms for the treatment of newborns with sepsis, accompanied by impaired hemocoagulation, since there is currently no single effective management strategy for such patients.

scholarly journals The Procoagulant Snake Venom Serine Protease Potentially Having a Dual, Blood Coagulation Factor V and X-Activating Activity

Toxins ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 358 ◽  
Author(s):  
Zorica Latinović ◽  
Adrijana Leonardi ◽  
Cho Yeow Koh ◽  
R. Manjunatha Kini ◽  
Alenka Trampuš Bakija ◽  
...  
Keyword(s):  
Serine Protease ◽  
Blood Coagulation ◽  
Snake Venom ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Point Of View ◽  
Factor V ◽  
Blood Coagulation Factors ◽  
Prothrombinase Complex ◽  
Blood Coagulation Factor V

A procoagulant snake venom serine protease was isolated from the venom of the nose-horned viper (Vipera ammodytes ammodytes). This 34 kDa glycoprotein, termed VaaSP-VX, possesses five kDa N-linked carbohydrates. Amino acid sequencing showed VaaSP-VX to be a chymotrypsin-like serine protease. Structurally, it is highly homologous to VaaSP-6 from the same venom and to nikobin from the venom of Vipera nikolskii, neither of which have known functions. VaaSP-VX does not affect platelets. The specific proteolysis of blood coagulation factors X and V by VaaSP-VX suggests that its blood-coagulation-inducing effect is due to its ability to activate these two blood coagulation factors, which following activation, combine to form the prothrombinase complex. VaaSP-VX may thus represent the first example of a serine protease with such a dual activity, which makes it a highly suitable candidate to replace diluted Russell’s viper venom in lupus anticoagulant testing, thus achieving greater reliability of the analysis. As a blood-coagulation-promoting substance that is resistant to serpin inhibition, VaaSP-VX is also interesting from the therapeutic point of view for treating patients suffering from hemophilia.

Abnormal Properties and Behaviors of Antithrombin III Found in a Thrombophilic Patient: Defective Biological Functions and Dissimilar Antigenic Determinants

1986 ◽  
Vol 56 (02) ◽  
pp. 165-171 ◽  
Author(s):  
Hideki Murayama ◽  
Michio Matsuda
Keyword(s):  
Blood Coagulation ◽  
Antithrombin Iii ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Chain Structure ◽  
Antigenic Determinants ◽  
Factor X ◽  
Single Chain ◽  
Blood Coagulation Factors ◽  
Genetically Determined

SummaryAbnormal properties of antithrombin III have been found in a 55-year-old male who has been thrombophilic over the last seven years. They are characterized by 1) defective inhibition of thrombin and activated blood coagulation factor X, 2) reduced affinity to heparin and 3) partial immunological identity with the normal molecule. The antithrombin III molecule, however, preserves a single-chain structure and an apparently identical molecular weight with that of the normal molecule. It is, thus, very unlikely that the impaired functions of antithrombin III in the patient’s plasma are induced by possible proteolytic modifications of the molecule by thrombin or other related activated blood coagulation factors.Since no other members of his immediate family have been found to be affected, the abnormality may be acquired rather than genetically determined, although further investigation is necessary for the elucidation of the abnormality of the molecule.

scholarly journals ROTATION THROMBOELASTOMETRY FOR THE DIAGNOSIS OF FACTOR DEFICIENCY AND MANAGEMENT OF THE HEMOSTATIC THERAPY IN PATIENTS WITH INHERITED COAGULATION DISORDERS

2019 ◽  
Vol 64 (3) ◽  
pp. 297-316
Author(s):  
G. M. Galstyan ◽  
O. A. Polevodova ◽  
E. V. Yakovleva ◽  
A. E. Shchekina
Keyword(s):  
Blood Coagulation ◽  
Plasma Sample ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Blood Coagulation Factors ◽  
Congenital Deficiency ◽  
Factor Deficiency ◽  
Coagulation Factor Deficiency ◽  
Hemostatic Therapy ◽  
Fvii Deficiency

Introduction. Rotation thromboelastometry (ROTEM) is a method for studying haemostasis at the place of providing care, which allows identification of disorders on the basis of extrinsic and / or intrinsic coagulation pathways.Aim. To study the possibility of using ROTEM for diagnosing the deficiency of individual blood coagulation factors, as well as for monitoring the efficacy and safety of haemostatic therapy in such coagulopathies.Materials and methods. The study included 9 patients with a congenital deficiency in various coagulation factors. The authors performed ROTEM, as well as coagulological tests to determine activated partial thromboplastin time, Quick’s value, fibrinogen and the plasma activity of coagulation factors FV, FVII, FVIII, FIX, FXI and FXII. In order to exclude the effects of heparin or hyperfibrinogenaemia, HEPTEM and / or FIBTEM were conducted. In order to identify the deficiency of individual coagulation factors, the authors used standard plasma samples and plasma deficient in one of the coagulation factors. The citrated blood under study was mixed with standard plasma and that deficient in one of the studied factors in a 2:1 ratio for subsequent repetition of the EXTEM and / or INTEM tests. Coagulation factor deficiency was confirmed by a change in the CT parameter.Results. Isolated prolongation of EXTEM CT was detected in the setting of FVII deficiency; while INTEM CT prolongation occurred under the deficiency of FVIII, FIX, FXI, FXII, with simultaneous EXTEM and INTEM CT prolongation being observed in the context of FVII deficiency. The test of a mixture of citrated blood and standard plasma revealed shortened EXTEM CT in the setting of FVII deficiency and shortened INTEM CT under the deficiency of FVIII, FIX, FXI, FXII, with the shortening of both EXTEM and INTEM CT being detected in the setting of FV deficiency. In a sample containing a mixture of whole blood and plasma deficient in the studied factor, CT remained prolonged or increased. Clinical examples of using ROTEM for diagnosing coagulation factor deficiency are presented.Conclusion. The normalisation of ROTEM parameters in a standard plasma sample along with the preservation of hypocoagulation in a factor-deficient plasma sample confirms the coagulation factor deficiency. ROTEM provides the possibility of monitoring the efficacy of haemostatic therapy for congenital deficiencies in individual blood coagulation factors. 

scholarly journals HDL biodistribution and brain receptors in zebrafish, using HDLs as vectors for targeting endothelial cells and neural progenitors

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nora Cassam Sulliman ◽  
Batoul Ghaddar ◽  
Laura Gence ◽  
Jessica Patche ◽  
Sepand Rastegar ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Brain Plasticity ◽  
High Density Lipoproteins ◽  
Data Sets ◽  
Sequencing Data ◽  
Brain Functions ◽  
Ventricular Cells ◽  
The Brain ◽  
Brain Homeostasis

AbstractHigh density lipoproteins (HDLs) display pleiotropic functions such as anti-inflammatory, antioxidant, anti-protease, and anti-apoptotic properties. These effects are mediated by four main receptors: SCARB1 (SR-BI), ABCA1, ABCG1, and CD36. Recently, HDLs have emerged for their potential involvement in brain functions, considering their epidemiological links with cognition, depression, and brain plasticity. However, their role in the brain is not well understood. Given that the zebrafish is a well-recognized model for studying brain plasticity, metabolic disorders, and apolipoproteins, it could represent a good model for investigating the role of HDLs in brain homeostasis. By analyzing RNA sequencing data sets and performing in situ hybridization, we demonstrated the wide expression of scarb1, abca1a, abca1b, abcg1, and cd36 in the brain of adult zebrafish. Scarb1 gene expression was detected in neural stem cells (NSCs), suggesting a possible role of HDLs in NSC activity. Accordingly, intracerebroventricular injection of HDLs leads to their uptake by NSCs without modulating their proliferation. Next, we studied the biodistribution of HDLs in the zebrafish body. In homeostatic conditions, intraperitoneal injection of HDLs led to their accumulation in the liver, kidneys, and cerebral endothelial cells in zebrafish, similar to that observed in mice. After telencephalic injury, HDLs were diffused within the damaged parenchyma and were taken up by ventricular cells, including NSCs. However, they failed to modulate the recruitment of microglia cells at the injury site and the injury-induced proliferation of NSCs. In conclusion, our results clearly show a functional HDL uptake process involving several receptors that may impact brain homeostasis and suggest the use of HDLs as delivery vectors to target NSCs for drug delivery to boost their neurogenic activity.

Complexity Measures of Brain Electrophysiological Activity

2010 ◽  
Vol 24 (2) ◽  
pp. 131-135 ◽  
Author(s):  
Włodzimierz Klonowski ◽  
Pawel Stepien ◽  
Robert Stepien
Keyword(s):  
Brain Activity ◽  
Deterministic Chaos ◽  
Epileptic Seizures ◽  
Eeg Signal ◽  
Eeg Signals ◽  
Complexity Measures ◽  
Electrophysiological Activity ◽  
Signal Complexity ◽  
Physiological Sleep ◽  
The Brain

Over 20 years ago, Watt and Hameroff (1987 ) suggested that consciousness may be described as a manifestation of deterministic chaos in the brain/mind. To analyze EEG-signal complexity, we used Higuchi’s fractal dimension in time domain and symbolic analysis methods. Our results of analysis of EEG-signals under anesthesia, during physiological sleep, and during epileptic seizures lead to a conclusion similar to that of Watt and Hameroff: Brain activity, measured by complexity of the EEG-signal, diminishes (becomes less chaotic) when consciousness is being “switched off”. So, consciousness may be described as a manifestation of deterministic chaos in the brain/mind.

Sign in / Sign up

Export Citation Format

Share Document