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.

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 Factor XIII and Fibrin Clot Properties in Acute Venous Thromboembolism

2021 ◽  
Vol 22 (4) ◽  
pp. 1607
Author(s):  
Michał Ząbczyk ◽  
Joanna Natorska ◽  
Anetta Undas
Keyword(s):  
Venous Thromboembolism ◽  
Factor Xiii ◽  
Active Form ◽  
Coagulation Factor ◽  
Proteome Analysis ◽  
Fibrin Clot ◽  
Subsequent Increase ◽  
Vein Thrombosis ◽  
Acute Pe ◽  
Fxiii Activity

Coagulation factor XIII (FXIII) is converted by thrombin into its active form, FXIIIa, which crosslinks fibrin fibers, rendering clots more stable and resistant to degradation. FXIII affects fibrin clot structure and function leading to a more prothrombotic phenotype with denser networks, characterizing patients at risk of venous thromboembolism (VTE). Mechanisms regulating FXIII activation and its impact on fibrin structure in patients with acute VTE encompassing pulmonary embolism (PE) or deep vein thrombosis (DVT) are poorly elucidated. Reduced circulating FXIII levels in acute PE were reported over 20 years ago. Similar observations indicating decreased FXIII plasma activity and antigen levels have been made in acute PE and DVT with their subsequent increase after several weeks since the index event. Plasma fibrin clot proteome analysis confirms that clot-bound FXIII amounts associated with plasma FXIII activity are decreased in acute VTE. Reduced FXIII activity has been associated with impaired clot permeability and hypofibrinolysis in acute PE. The current review presents available studies on the role of FXIII in the modulation of fibrin clot properties during acute PE or DVT and following these events. Better understanding of FXIII’s involvement in the pathophysiology of acute VTE might help to improve current therapeutic strategies in patients with acute VTE.

scholarly journals Cryo-EM structures of human coagulation factors V and Va

Blood ◽  
2021 ◽  
Author(s):  
Eliza A Ruben ◽  
Michael J Rau ◽  
James Fitzpatrick ◽  
Enrico Di Cera
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Proteolytic Processing ◽  
Coagulation Cascade ◽  
Factor V ◽  
Prothrombinase Complex ◽  
A2 Domain

Coagulation factor V is the precursor of factor Va that, together with factor Xa, Ca2+ and phospholipids, defines the prothrombinase complex and activates prothrombin in the penultimate step of the coagulation cascade. Here we present cryo-EM structures of human factors V and Va at atomic (3.3 Å) and near-atomic (4.4 Å) resolution, respectively. The structure of fV reveals the entire A1-A2-B-A3-C1-C2 assembly but with a surprisingly disordered B domain. The C1 and C2 domains provide a platform for interaction with phospholipid membranes and support the A1 and A3 domains, with the A2 domain sitting on top of them. The B domain is highly dynamic and visible only for short segments connecting to the A2 and A3 domains. The A2 domain reveals all sites of proteolytic processing by thrombin and activated protein C, a partially buried epitope for binding factor Xa and fully exposed epitopes for binding activated protein C and prothrombin. Removal of the B domain and activation to fVa exposes the sites of cleavage by activated protein C at R306 and R506 and produces increased disorder in the A1-A2-A3-C1-C2 assembly, especially in the C-terminal acidic portion of the A2 domain responsible for prothrombin binding. Ordering of this region and full exposure of the factor Xa epitope emerge as a necessary step for the assembly of the prothrombin-prothrombinase complex. These structures offer molecular context for the function of factors V and Va and pioneer the analysis of coagulation factors by cryo-EM.

scholarly journals The anticoagulant mechanism of action of heparin in contact-activated plasma: inhibition of factor X activation

Blood ◽  
1985 ◽  
Vol 65 (5) ◽  
pp. 1226-1231 ◽  
Author(s):  
TB McNeely ◽  
MJ Griffith
Keyword(s):  
Antithrombin Iii ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Factor X ◽  
Clotting Time ◽  
Intrinsic Pathway ◽  
Blood Coagulation Factors ◽  
Factor Ixa ◽  
Factor X Activation

Abstract The effects of heparin on the activation of blood coagulation factors IX and X in contact-activated plasma were determined in the present study. In the presence and absence of 0.5 U/mL heparin, the amounts of factor IX that were cleaved 30 minutes after the addition of calcium and phospholipid to plasma exposed to glass (ie, contact activated) were essentially identical. In the absence of heparin, however, the plasma clotting time was between three and four minutes, while in the presence of heparin, the clotting time was approximately 40 minutes. More factor IXa was inhibited by antithrombin III in the presence of heparin than in its absence, but factor IXa levels sufficient for factor X activation appeared to be present in the heparinized plasma. Neither an increase in factor Xa nor a decrease in factor X was detected, however, in heparinized plasma. We conclude that the step in the intrinsic pathway of coagulation that is inhibited in the presence of heparin is at the level of factor X activation.

Plasmin-Mediated Coagulation Factor Xa Derivative, Xa33/13, Enhances Plasminogen Activation and Fibrin Clot Lysis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1717-1717
Author(s):  
Ed L.G. Pryzdial ◽  
Kimberley Talbot ◽  
Scott C. Meixner
Keyword(s):  
Factor Xa ◽  
Coagulation Factor ◽  
Fibrin Clot ◽  
Clot Formation ◽  
Clot Lysis ◽  
Fragmentation Pattern ◽  
Plasmin Activity ◽  
Anionic Phospholipid ◽  
Western Blots ◽  
Chromogenic Assay

Abstract Previous reports showed that coagulation factor Xa (FXa) treated with the fibrinolysis protease, plasmin, loses procoagulant activity and can accelerate tissue plasminogen activator (tPA). The resulting FXa derivative, Xa33/13, acquires binding sites for plasminogen and was consequently presumed to be the form of FXa involved in generating plasmin. By evaluating the function of purified Xa33/13, the current work addresses the hypothesis that conversion of FXa to Xa33/13 is the basis of enhanced plasmin generation by tPA and that this newly acquired FXa function can also contribute to clot lysis. Using purified proteins in a chromogenic assay, both Xa33/13 and FXa were found to increase the generation of plasmin activity by tPA at least 10-fold. To explain the involvement of FXa reported previously, Western blots demonstrated a correlation between the disappearance of FXa, appearance of Xa33 antigen and enhanced plasmin production. The Western blots also revealed that detection of Xa33 antigen is lost at later time points, which explains the observation that plasmin generation is eventually shut down during the chromogenic assay. Despite fibrin being recognized as the principal accelerator of tPA, at concentrations as low as 10 nM, either Xa33/13 or FXa reduced the lysis time of thrombin-mediated fibrin clot in a turbidity assay. The Xa33/13 or FXa could be added during clot formation before the tPA or after clot formation with the tPA to facilitate a 50–70% reduction in the time required to achieve half maximal lysis at 0.1 μM. The time-dependent formation of Xa33 antigen in plasma that was induced to clot with tissue factor, anionic phospholipid vesicles and Ca2+, demonstrated that the plasmin-mediated fragmentation pattern of purified FXa represents the complex physiological mixture. However, the use of specific inhibitors and immuno-depleted plasma indicated that plasmin is not required for production of Xa33 antigen in plasma. Cumulatively the data presented here support a role for coagulation FXa in fibrinolysis. These diametrically opposing functions derived from the same molecule, may contribute to the balance between coagulation and fibrinolysis, thereby facilitating tolerance for a wide normal physiological range of FX and possibly other coagulation proteins.

scholarly journals Pathways in the activation of human coagulation factor X

1980 ◽  
Vol 185 (3) ◽  
pp. 647-658 ◽  
Author(s):  
K Mertens ◽  
R M Bertina
Keyword(s):  
Heavy Chain ◽  
Active Form ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Terminal Region ◽  
Factor Vii ◽  
Factor X ◽  
Catalytically Active ◽  
A Site ◽  
Polypeptide Chains

Purified human Factor X (apparent mol.wt. 72000), which consists of two polypeptide chains (mol.wt. 55000 and 19000), was activated by both Russell's-viper venom and the purified physiological activators (Factor VII/tissue factor and Factor IXa/Factor VIII). They all convert Factor X to catalytically active Factor Xa (mol.wt. 54000) by cleaving the heavy chain at a site on the N-terminal region. In the presence of Ca2+ and phospholipid, the Factor Xa formed catalyses (a) the cleavage of a small peptide (mol.wt. 4000) from the C-terminal region of the heavy chain of Factor Xa, resulting in a second active form (mol.wt. 50000), and (b) the cleavage of a peptide containing the active-site serine residue (mol.wt. 13000) from the C-terminal region of the heavy chain of Factor X, resulting in an inactivatable component (mol.wt. 59000). A nomenclature for the various products is proposed.

scholarly journals Autoimmune Factor V Deficiency That Took 16 Years to Diagnose due to Pseudodeficiency of Multiple Coagulation Factors

2021 ◽  
Vol 2021 ◽  
pp. 1-5
Author(s):  
Takaaki Kato ◽  
Takaya Hanawa ◽  
Mea Asou ◽  
Tomohiko Asakawa ◽  
Hisashi Sakamaki ◽  
...  
Keyword(s):  
High Titer ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
International Normalized Ratio ◽  
University Hospital ◽  
Coagulation Cascade ◽  
Factor V ◽  
Normal Limits ◽  
Factor V Deficiency ◽  
The Right

A 70-year-old man presented to our hospital with intramuscular hemorrhage in the right thigh. He had exhibited a tendency to bleed for the last 16 years and had visited several medical institutions, but no diagnosis had been made. Since the risk of sudden bleeding was assumed to be high due to his age, we decided to examine him in our department. A coagulation abnormality with prothrombin time-international normalized ratio (PT-INR) of 4.5 and activated partial thromboplastin time (aPTT) of 99.6 seconds was observed, but the platelet count, fibrinogen, and PIVKAII were within normal limits. Coagulation activities of factor V, VII, VIII, IX, X, XI, XII, and XIII were all reduced. Anti-factor VIII and IX antibodies which were measured by the Bethesda method, lupus anti-coagulant (diluted Russell snake venom time method) and anti-cardiolipin antibody were also positive. The results of these tests were comparable to those undertaken 15 years ago when they were scrutinized at the university hospital. We suspected the presence of anti-factor V antibodies because there was a dissociation between the thrombotest values measured and those calculated from the PT-INR. Moreover, cross-mixing test showed an immediate inhibitor pattern. Subsequently, factor V antibodies were confirmed by the immunoblot method and the diagnosis of autoimmune factor V deficiency was made. When factor V, which is downstream of the coagulation cascade, is inhibited, coagulation test using the one-stage clotting method shows a pseudolow value. Therefore, extensive abnormalities of coagulation factor activity and inhibitor assay should be interpreted with caution, and the presence of a high titer of factor V inhibitor should be considered.

scholarly journals Synthesis, Docking, and In Vitro Anticoagulant Activity Assay of Hybrid Derivatives of Pyrrolo[3,2,1-ij]Quinolin-2(1H)-one as New Inhibitors of Factor Xa and Factor XIa

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1889 ◽  
Author(s):  
Nadezhda Novichikhina ◽  
Ivan Ilin ◽  
Anna Tashchilova ◽  
Alexey Sulimov ◽  
Danil Kutov ◽  
...  
Keyword(s):  
Anticoagulant Activity ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Protein Targets ◽  
Ic50 Value ◽  
Anticoagulant Drugs ◽  
Factor Xia ◽  
Derivatives Of

Coagulation factor Xa and factor XIa are proven to be convenient and crucial protein targets for treatment for thrombotic disorders and thereby their inhibitors can serve as effective anticoagulant drugs. In the present work, we focused on the structure–activity relationships of derivatives of pyrrolo[3,2,1-ij]quinolin-2(1H)-one and an evaluation of their activity against factor Xa and factor XIa. For this, docking-guided synthesis of nine compounds based on pyrrolo[3,2,1-ij]quinolin-2(1H)-one was carried out. For the synthesis of new hybrid hydropyrrolo[3,2,1-ij]quinolin-2(1H)-one derivatives, we used convenient structural modification of both the tetrahydro- and dihydroquinoline moiety by varying the substituents at the C6,8,9 positions. In vitro testing revealed that four derivatives were able to inhibit both coagulation factors and three compounds were selective factor XIa inhibitors. An IC50 value of 3.68 μM for was found for the best factor Xa inhibitor and 2 μM for the best factor XIa inhibitor.

The Mechanism of Activation of Human Coagulation Factor X

1979 ◽  
Author(s):  
K. Mertens ◽  
R.M. Bertina
Keyword(s):  
Active Site ◽  
Human Factor ◽  
Polyacrylamide Gel Electrophoresis ◽  
Active Form ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Factor X ◽  
Process Factor ◽  
Molecular Events ◽  
Product Factor

During the coagulation process factor X is converted to a serine protease, factor Xa. The present study concerns the molecular events which occur during the activation of human factor X by Russell’s viper venom and by the purified proteins of the extrinsic and intrinsic activator. Conversion of factor X was detected by amidolytic assays and SDS/polyacrylamide-gel electrophoresis.The results show that all activators convert factor X (MW 72,000) to an active form. In the presence of phospholipid the initially formed factor Xa (MW 54,000) complicates the further sequence of reactions by catalysing a) the conversion of factor Xa to a second active form (MW 50,000), b) the conversion of factor X to an inactive product (MW 59,000) by splitting off a peptide containing the active site serine, and c) the further degradation of the 50,000 and 59,000 components to a smaller component (MW 40,000).Comparison of these data with those reported for bovine factor X suggests that the mechanism of activation of human factor X is more complicated. The inactivation of both factor Xa and factor X by product factor Xa might be considered as important regulatory principles.

scholarly journals Roles of factor Xa beyond coagulation

2021 ◽  
Author(s):  
Wolfram Ruf
Keyword(s):  
Clinical Evidence ◽  
Inflammatory Diseases ◽  
Oral Anticoagulant Therapy ◽  
Macrophage Polarization ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Therapeutic Benefit ◽  
Pathway Activation ◽  
Excessive Activation

AbstractOral anticoagulant therapy has changed by clinical evidence that coagulation factor Xa (FXa) can be safely and effectively targeted for thromboprophylaxis. Because thrombotic and thrombo-inflammatory diseases are frequently caused by excessive activation of the tissue factor (TF) pathway, activation of FX by the TF-FVIIa complex is of central importance for understanding the roles of FXa in thrombosis and hemostasis and functions beyond blood coagulation. Recent data showed that the nascent product FXa associated with TF-FVIIa not only supports hemostatic cofactor VIII activation, but also broadly influences immune reactions in inflammation, cancer, and autoimmunity. These signaling functions of FXa are mediated through protease activated receptor (PAR) cleavage and PAR2 activation occurs in extravascular environments specifically by macrophage synthesized FX. Cell autonomous FXa-PAR2 signaling is a mechanism for tumor-promoting macrophage polarization in the tumor microenvironment and tissue penetrance of oral FXa inhibitors favors the reprogramming of tumor-associated macrophages for non-coagulant therapeutic benefit. It is necessary to decipher the distinct functions of coagulation factors synthesized by the liver for circulation in blood versus those synthesized by extrahepatic immune cells for activity in tissue milieus. This research will lead to a better understanding of the broader roles of FXa as a central regulator of immune and hematopoietic systems.

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