scholarly journals Host-Parasite Relationships in Porcine Ascariosis: Anticoagulant Potential of the Third Larval Stage of Ascaris suum as a Possible Survival Mechanism

Animals ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 804
Author(s):  
Alicia Diosdado ◽  
Fernando Simón ◽  
Rodrigo Morchón ◽  
Javier González-Miguel
Keyword(s):  
Ascaris Suum ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Helminth Parasites ◽  
Factor X ◽  
Larval Stages ◽  
Third Stage ◽  
Migration Strategies ◽  
Host Parasite ◽  
First Time

In order to evade the response of their hosts, helminth parasites have evolved precise and highly regulated mechanisms, including migration strategies of the larval stages. In regard to porcine ascariosis caused by Ascaris suum, its infective third-stage larvae (AsL3) undergo a complex migratory route through the bloodstream of their host before establishing in the small intestine to reach maturation. Despite the benefits attributed to this migration, blood clots formation could compromise larvae survival. The aim of this work was to study the interaction between the cuticle and excretory/secretory antigens of AsL3 and the host coagulation cascade. Larvae were obtained after incubating and hatching A. suum eggs, after which the antigenic extracts were produced. Their ability to disrupt the coagulation cascade was studied using anticoagulation and chromogenic assays, and techniques based on electrophoresis. The obtained results showed that both antigenic extracts possessed anticoagulant potential, being able to inhibit the intrinsic, extrinsic and/or common pathways of the blood coagulation cascade as well as the activated factor X. Moreover, three A. suum serpin proteins were identified as candidates to inhibit this host coagulation factor. To the best of our knowledge, this study shows, for the first time, the anticoagulant potential of the infective larvae of A. suum, which could be used by the parasite as a mechanism to facilitate its invasion and survival in the host.

scholarly journals Recognition Pattern of the Fasciola hepatica Excretome/Secretome during the Course of an Experimental Infection in Sheep by 2D Immunoproteomics

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 725
Author(s):  
David Becerro-Recio ◽  
Javier González-Miguel ◽  
Alberto Ucero ◽  
Javier Sotillo ◽  
Álvaro Martínez-Moreno ◽  
...  
Keyword(s):  
Experimental Infection ◽  
Fasciola Hepatica ◽  
Cathepsin L ◽  
Helminth Parasites ◽  
Glutathione S Transferase ◽  
Serum Samples ◽  
Secretory Products ◽  
Immunogenic Proteins ◽  
Host Parasite ◽  
First Time

Excretory/secretory products released by helminth parasites have been widely studied for their diagnostic utility, immunomodulatory properties, as well as for their use as vaccines. Due to their location at the host/parasite interface, the characterization of parasite secretions is important to unravel the molecular interactions governing the relationships between helminth parasites and their hosts. In this study, the excretory/secretory products from adult worms of the trematode Fasciola hepatica (FhES) were employed in a combination of two-dimensional electrophoresis, immunoblot and mass spectrometry, to analyze the immune response elicited in sheep during the course of an experimental infection. Ten different immunogenic proteins from FhES recognized by serum samples from infected sheep at 4, 8, and/or 12 weeks post-infection were identified. Among these, different isoforms of cathepsin L and B, peroxiredoxin, calmodulin, or glutathione S-transferase were recognized from the beginning to the end of the experimental infection, suggesting their potential role as immunomodulatory antigens. Furthermore, four FhES proteins (C2H2-type domain-containing protein, ferritin, superoxide dismutase, and globin-3) were identified for the first time as non-immunogenic proteins. These results may help to further understand host/parasite relationships in fasciolosis, and to identify potential diagnostic molecules and drug target candidates of F. hepatica.

scholarly journals Exosites expedite blood coagulation

2020 ◽  
Vol 295 (45) ◽  
pp. 15208-15209
Author(s):  
Maria Luiza Vilela Oliva ◽  
Ingrid Dreveny ◽  
Jonas Emsley
Keyword(s):  
Active Site ◽  
Serine Proteases ◽  
Critical Role ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Coagulation Cascade ◽  
Factor X ◽  
Inhibitor Development ◽  
Prothrombinase Complex ◽  
Factor X Activation

A careful balance between active-site and exosite contributions is critically important for the specificity of many proteases, but this balance is not yet defined for some of the serine proteases that serve as coagulation factors. Basavaraj and Krishnaswamy have closed an important gap in our knowledge of coagulation factor X activation by the intrinsic Xase complex by showing that exosite binding plays a critical role in this process, which they describe as a “dock and lock.” This finding not only significantly enhances our understanding of this step in the coagulation cascade and highlights parallels with the prothrombinase complex, but will also provide a novel rationale for inhibitor development in the future.

Regulation of human coagulation factor X gene expression by GATA-4 and the Sp family of transcription factors

Blood ◽  
2001 ◽  
Vol 97 (4) ◽  
pp. 946-951 ◽  
Author(s):  
Hsiao-Ling Hung ◽  
Eleanor S. Pollak ◽  
Rama D. Kudaravalli ◽  
Valder Arruda ◽  
Kirk Chu ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Protein Binding ◽  
Promoter Activity ◽  
Critical Role ◽  
Coagulation Factor ◽  
Proximal Promoter ◽  
Coagulation Cascade ◽  
Clotting Factor ◽  
Factor X ◽  
Specific Expression

Abstract Serine protease factor Xa plays a critical role in the coagulation cascade. Zymogen factor X is synthesized and modified in the liver. To understand the mechanisms governing the liver-specific expression of factor X, the proximal promoter of human factor X was previously characterized. Two crucial cis elements at −73 and −128 and their cognate binding proteins, HNF-4 and NF-Y, respectively, were identified. In this report, studies are extended to 3 additionalcis elements within the factor X promoter. Using gel mobility shift assays, the liver-enriched protein GATA-4 was identified as the protein binding to the GATA element at −96. GATA-4 transactivates the factor X promoter 28-fold in transient transfection experiments. It was also determined that the Sp family of transcription factors binds 2 DNase I–footprinted sites at −165 and −195. Disruption of Sp protein binding at either site reduces the promoter activity by half. Simultaneous disruption of both sites reduces the promoter activity 8-fold. This is the first report indicating the involvement of GATA-4 in the regulation of clotting factor expression. These observations provide novel insight into mechanisms by which the vitamin K–dependent coagulation factors are regulated.

scholarly journals Bridging the Missing Link with Emicizumab: A Bispecific Antibody for Treatment of Hemophilia A

2020 ◽  
Vol 120 (10) ◽  
pp. 1357-1370
Author(s):  
Georg Gelbenegger ◽  
Christian Schoergenhofer ◽  
Paul Knoebl ◽  
Bernd Jilma
Keyword(s):  
Clinical Trials ◽  
Hemophilia A ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Factor X ◽  
Current Standard ◽  
Bleeding Events ◽  
Recombinant Activated Factor Vii

AbstractHemophilia A, characterized by absent or ineffective coagulation factor VIII (FVIII), is a serious bleeding disorder that entails severe and potentially life-threatening bleeding events. Current standard therapy still involves replacement of FVIII, but is often complicated by the occurrence of neutralizing alloantibodies (inhibitors). Management of patients with inhibitors is challenging and necessitates immune tolerance induction for inhibitor eradication and the use of bypassing agents (activated prothrombin complex concentrates or recombinant activated factor VII), which are expensive and not always effective. Emicizumab is the first humanized bispecific monoclonal therapeutic antibody designed to replace the hemostatic function of activated FVIII by bridging activated factor IX and factor X (FX) to activate FX and allow the coagulation cascade to continue. In the majority of hemophilic patients with and without inhibitors, emicizumab reduced the annualized bleeding rate to almost zero in several clinical trials and demonstrated a good safety profile. However, the concurrent use of emicizumab and activated prothrombin complex concentrate imposes a high risk of thrombotic microangiopathy and thromboembolic events on patients and should be avoided. Yet, the management of breakthrough bleeds and surgery remains challenging with only limited evidence-based recommendations being available. This review summarizes published clinical trials and preliminary reports of emicizumab and discusses the clinical implications of emicizumab in treatment of hemophilia A.

Extra-mammalian larval stages of Elaphostrongylus alces (Nematoda: Protostrongylidae), a parasite of moose (Alces alces) in Fennoscandia

1998 ◽  
Vol 76 (1) ◽  
pp. 33-38 ◽  
Author(s):  
Murray W Lankester ◽  
Ing-Marie C Olsson ◽  
Margareta Stéen ◽  
Alvin A Gajadhar
Keyword(s):  
Long Range ◽  
Alces Alces ◽  
The Other ◽  
Intermediate Hosts ◽  
Larval Stages ◽  
Third Stage ◽  
The Mean ◽  
First Time

Dimensions and illustrations of the first-, second-, and third-stage larvae of Elaphostrongylus alces are presented for the first time. First-stage larvae were 417 ± 16 µm long (mean ± SD) (range 377-445 µm) and similar in size to those of E. cervi (420 ± 13 µm long; range 392-445 µm) and E. rangiferi, the other recognized members of the genus. The mean length of third-stage E. alces larvae (714 ± 23 µm long; range 675-756 µm) recovered from gastropod intermediate hosts was significantly less than that of E. cervi (831 ± 78 µm long; range 669-954 µm) and E. rangiferi, providing further evidence of the distinct status of E. alces, a recently described species from moose in Fennoscandia.

scholarly journals Functional assembly of intrinsic coagulation proteases on monocytes and platelets. Comparison between cofactor activities induced by thrombin and factor Xa.

1992 ◽  
Vol 176 (1) ◽  
pp. 27-35 ◽  
Author(s):  
M P McGee ◽  
L C Li ◽  
M Hensler
Keyword(s):  
Factor Viii ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Factor X ◽  
Regulatory Pathways ◽  
Factor Ixa ◽  
Factor Viiia ◽  
Human Factor Viii

Generation of coagulation factor Xa by the intrinsic pathway protease complex is essential for normal activation of the coagulation cascade in vivo. Monocytes and platelets provide membrane sites for assembly of components of this protease complex, factors IXa and VIII. Under biologically relevant conditions, expression of functional activity by this complex is associated with activation of factor VIII to VIIIa. In the present studies, autocatalytic regulatory pathways operating on monocyte and platelet membranes were investigated by comparing the cofactor function of thrombin-activated factor VIII to that of factor Xa-activated factor VIII. Reciprocal functional titrations with purified human factor VIII and factor IXa were performed at fixed concentrations of human monocytes, CaCl2, factor X, and either factor IXa or factor VIII. Factor VIII was preactivated with either thrombin or factor Xa, and reactions were initiated by addition of factor X. Rates of factor X activation were measured using chromogenic substrate specific for factor Xa. The K1/2 values, i.e., concentration of factor VIIIa at which rates were half maximal, were 0.96 nM with thrombin-activated factor VIII and 1.1 nM with factor Xa-activated factor VIII. These values are close to factor VIII concentration in plasma. The Vsat, i.e., rates at saturating concentrations of factor VIII, were 33.3 and 13.6 nM factor Xa/min, respectively. The K1/2 and Vsat values obtained in titrations with factor IXa were not significantly different from those obtained with factor VIII. In titrations with factor X, the values of Michaelis-Menten coefficients (Km) were 31.7 nM with thrombin-activated factor VIII, and 14.2 nM with factor Xa-activated factor VIII. Maximal rates were 23.4 and 4.9 nM factor Xa/min, respectively. The apparent catalytic efficiency was similar with either form of factor VIIIa. Kinetic profiles obtained with platelets as a source of membrane were comparable to those obtained with monocytes. These kinetic profiles are consistent with a 1:1 stoichiometry for the functional interaction between cofactor and enzyme on the surface of monocytes and platelets. Taken together, these results indicate that autocatalytic pathways connecting the extrinsic, intrinsic, and common coagulation pathways can operate efficiently on the monocyte membrane.

scholarly journals Anticoagulant activity of direct factor Xa inhibitors as a tool to ensure the effectiveness and safety of drugs intake

Kardiologiia ◽  
2019 ◽  
Vol 59 (11S) ◽  
pp. 28-35 ◽  
Author(s):  
T. V. Vavilova
Keyword(s):  
Clinical Presentation ◽  
Anticoagulant Activity ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Factor X ◽  
Direct Factor Xa Inhibitors ◽  
Thematic Review ◽  
Generation Test

The thematic review presents modern solutions using oral anticoagulants with a focus on direct coagulation factor X inhibitors. It contains information about the pharmacodynamics and pharmacokinetics of apixaban and rivaroxaban against the background of different drug intake regimens - twice and once per day. There are shown studies of concentration dynamics and the corresponding functional response, measured using the integral method - the thrombin generation test, which is widely used in scientific research to describe hemostatic processes based on an objective quantitative assessment of the thrombin formation – a key coagulation cascade serine protease. The logical relationship between the pharmacodynamics of anticoagulant action and the clinical presentation of the effectiveness and safety of drugs is traced. The review provides links to actual literature and current clinical guidelines.

scholarly journals Analysis of 180 genetic variants in a new interactive FX variant database reveals novel insights into FX deficiency

TH Open ◽  
2021 ◽  
Author(s):  
Victoria Anne Harris ◽  
Weining Lin ◽  
Stephen J Perkins
Keyword(s):  
Genetic Variants ◽  
Case Reports ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Type I ◽  
Type Ii ◽  
Factor X ◽  
Coagulation Proteins ◽  
Set Up ◽  
Variant Database

Coagulation Factor X (FX), often termed Stuart-Prower Factor, is a plasma glycoprotein composed of the γ-carboxyglutamic acid (Gla) domain, two epidermal growth factor domains (EGF-1, EGF-2) and the serine protease (SP) domain. FX plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss. Genetic variants in FX disrupt coagulation and lead to FX or Stuart-Prower Factor deficiency. To better understand the relationship between FX deficiency and disease severity, an interactive FX variant database has been set up at https://www.factorx-db.org, based on earlier websites for the Factor XI and IX coagulation proteins. To date (April 2021), we report 427 case reports on FX deficiency corresponding to 180 distinct F10 genetic variants. Of these, 149 are point variants (of which 128 are missense), 22 are deletions, three are insertions and six are polymorphisms. FX variants are phenotypically classified as being Type I or Type II. Type I variants involve the simultaneous reduction of FX coagulant activity (FX:C) and FX antigen levels (FX:Ag), whereas Type II variants involve a reduction in FX:C with normal FX:Ag plasma levels. Both types of variants were distributed throughout the FXa protein structure. Analyses based on residue surface accessibilities showed the most damaging variants to occur at residues with low accessibilities. The interactive FX web database provides a novel easy-to-use resource for clinicians and scientists to improve the understanding of FX deficiency. Guidelines are provided for clinicians who wish to use the database for diagnostic purposes.

Region of Factor IXa Protease Domain that Interacts with Factor VIIIa: Analysis of Select Hemophilia B Mutants

1999 ◽  
Vol 82 (08) ◽  
pp. 218-225 ◽  
Author(s):  
S. Paul Bajaj
Keyword(s):  
X Chromosome ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Factor X ◽  
Homologous Proteins ◽  
Dependent Protein ◽  
Factor Ix Deficiency

IntroductionThe identification of coagulation factor IX as a substance required for blood coagulation was first established by Pavlovsky, who reported that a mixture of blood from two hemophiliacs clotted normally.1 Based on this discovery and subsequent observations,2 hemophilia was divided into two conditions-hemophilia A or factor VIII deficiency, the most prevalent condition, and hemophilia B or factor IX deficiency, a less common condition. Since then, much has been learned about the molecular and structural biology of factor IX. It is a vitamin K-dependent protein that participates in the middle phase of the intrinsic as well as the extrinsic coagulation cascade.3 The gene for factor IX consists of eight exons and seven introns, is approximately 34 kb long, and located on the long arm of the X-chromosome at band Xq27.1.4,5 The positions of the introns in the factor IX gene are essentially identical to those of the other three homologous proteins, namely, factor VII, factor X, and protein C;3 the genes for the latter three proteins, however, are not located on the X-chromosome.

scholarly journals The helminth community ofGeophagus proximus(Perciformes: Cichlidae) from a tributary of the Paraná River, Ilha Solteira Reservoir, São Paulo State, Brazil

2012 ◽  
Vol 87 (2) ◽  
pp. 203-211 ◽  
Author(s):  
A.C. Zago ◽  
L. Franceschini ◽  
M.C. Zocoller-Seno ◽  
R. Veríssimo-Silveira ◽  
A.A.D. Maia ◽  
...  
Keyword(s):  
Sao Paulo ◽  
Paraná River ◽  
Helminth Parasites ◽  
São Paulo ◽  
Larval Stages ◽  
Parana River ◽  
Paulo State ◽  
Host Sex ◽  
São Paulo State ◽  
First Time

AbstractThis study aimed to evaluate the helminth parasites ofGeophagus proximusfrom the São José dos Dourados River, a tributary of Paraná River, Ilha Solteira Reservoir, São Paulo State, Brazil. From May 2006 to May 2007, 116G. proximusspecimens were examined and seven different taxa of helminth were collected and identified: proteocephalidean plerocercoids (Cestoda); metacercariae ofAustrodiplostomumcompactum, Clinostomum heluansandClinostomumsp. (Trematoda); andRaphidascaris(Sprentascaris)hypostomi, and larvae ofRaphidascarissp. andContracaecumsp. (Nematoda). All parasites presented the typical aggregated pattern of distribution, as well as the presence of a high number of larval stages, an absence of influence of the host sex and seasonality upon community parameters, as well as a correlation between species richness and host body weight. Moreover, with the exception ofA. compactummetacercariae, all helminths found in this study are reported for the first time inG. proximus.

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