scholarly journals Role, Laboratory Assessment and Clinical Relevance of Fibrin, Factor XIII and Endogenous Fibrinolysis in Arterial and Venous Thrombosis

2021 ◽  
Vol 22 (3) ◽  
pp. 1472
Author(s):  
Vassilios P. Memtsas ◽  
Deepa R. J. Arachchillage ◽  
Diana A. Gorog
Keyword(s):  
Venous Thrombosis ◽  
Factor Xiii ◽  
Physiological Role ◽  
Coagulation Cascade ◽  
Terminal Phase ◽  
Healthy Individuals ◽  
Peripheral Vascular ◽  
Laboratory Assessment ◽  
Disease States ◽  
Endogenous Fibrinolysis

Diseases such as myocardial infarction, ischaemic stroke, peripheral vascular disease and venous thromboembolism are major contributors to morbidity and mortality. Procoagulant, anticoagulant and fibrinolytic pathways are finely regulated in healthy individuals and dysregulated procoagulant, anticoagulant and fibrinolytic pathways lead to arterial and venous thrombosis. In this review article, we discuss the (patho)physiological role and laboratory assessment of fibrin, factor XIII and endogenous fibrinolysis, which are key players in the terminal phase of the coagulation cascade and fibrinolysis. Finally, we present the most up-to-date evidence for their involvement in various disease states and assessment of cardiovascular risk.

scholarly journals An exploratory assessment of the applicability of direct-to-consumer genetic testing to translational research in Japan

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Masahiro Inoue ◽  
Shota Arichi ◽  
Tsuyoshi Hachiya ◽  
Anna Ohtera ◽  
Seok-Won Kim ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Translational Research ◽  
Drug Target ◽  
Target Genes ◽  
Healthy Individuals ◽  
Alcohol Sensitivity ◽  
Direct To Consumer ◽  
Disease States ◽  
Multiple Phenotypes ◽  
Related Phenotype

Abstract Objective In order to assess the applicability of a direct-to-consumer (DTC) genetic testing to translational research for obtaining new knowledge on relationships between drug target genes and diseases, we examined possibility of these data by associating SNPs and disease related phenotype information collected from healthy individuals. Results A total of 12,598 saliva samples were collected from the customers of commercial service for SNPs analysis and web survey were conducted to collect phenotype information. The collected dataset revealed similarity to the Japanese data but distinguished differences to other populations of all dataset of the 1000 Genomes Project. After confirmation of a well-known relationship between ALDH2 and alcohol-sensitivity, Phenome-Wide Association Study (PheWAS) was performed to find association between pre-selected drug target genes and all the phenotypes. Association was found between GRIN2B and multiple phenotypes related to depression, which is considered reliable based on previous reports on the biological function of GRIN2B protein and its relationship with depression. These results suggest possibility of using SNPs and phenotype information collected from healthy individuals as a translational research tool for drug discovery to find relationship between a gene and a disease if it is possible to extract individuals in pre-disease states by properly designed questionnaire.

The role of monocytes in thrombotic disorders

2009 ◽  
Vol 102 (11) ◽  
pp. 916-924 ◽  
Author(s):  
Gregory Lip ◽  
Eduard Shantsila
Keyword(s):  
Innate Immunity ◽  
Dendritic Cells ◽  
Tissue Factor ◽  
Physiological Role ◽  
Coagulation Cascade ◽  
Pathophysiological Role ◽  
Platelet Aggregates

SummaryAlthough, the main physiological role of monocytes is attributed to innate immunity (that is, phagocytosis) and the development of tissue macrophages and dendritic cells, the pathophysiological role of these goes far behind these (simplistic) limits. Indeed, monocytes constitute a major source of blood tissue factor, a key element of the extrinsic coagulation cascade. Monocytes actively bind to platelets, thus forming very prothrombotic monocyte-platelet aggregates. Additionally, these cells link inflammation and the procoagulant state observed in various prothrombotic conditions. However, monocytes are also crucial for successful thrombus recanalisation. In this article, we review the available data on potential mechanisms that link monocytes with thrombosis-related processes.

scholarly journals Measurement of Midregional Proadrenomedullin in Plasma with an Immunoluminometric Assay

2005 ◽  
Vol 51 (10) ◽  
pp. 1823-1829 ◽  
Author(s):  
Nils G Morgenthaler ◽  
Joachim Struck ◽  
Christine Alonso ◽  
Andreas Bergmann
Keyword(s):  
Cardiovascular Disease ◽  
Room Temperature ◽  
Polyclonal Antibodies ◽  
Reference Interval ◽  
Healthy Individuals ◽  
Disease States ◽  
Significant Difference ◽  
Edta Plasma ◽  
Technical Evaluation ◽  
Reliable Quantification

Abstract Background: Adrenomedullin (ADM) is a potent vasodilatory peptide, and circulating concentrations have been described for several disease states, including dysfunction of the cardiovascular system and sepsis. Reliable quantification has been hampered by the short half-life, the existence of a binding protein, and physical properties. Here we report the technical evaluation of an assay for midregional pro-ADM (MR-proADM) that does not have these problems. Methods: MR-proADM was measured in a sandwich immunoluminometric assay using 2 polyclonal antibodies to amino acids 45–92 of proADM. The reference interval was defined in EDTA plasma of 264 healthy individuals (117 male, 147 female), and increased MR-proADM concentrations were found in 95 patients with sepsis and 54 patients with cardiovascular disease. Results: The assay has an analytical detection limit of 0.08 nmol/L, and the interassay CV was <20% for values >0.12 nmol/L. The assay was linear on dilution with undisturbed recovery of the analyte. EDTA-, heparin-, and citrate-plasma samples were stable (<20% loss of analyte) for at least 3 days at room temperature, 14 days at 4 °C, and 1 year at −20 °C. MR-proADM values followed a gaussian distribution in healthy individuals with a mean (SD) of 0.33 (0.07) nmol/L (range, 0.10–0.64 nmol/L), without significant difference between males or females. The correlation coefficient for MR-proADM vs age was 0.50 (P <0.001). MR-proADM was significantly (P <0.001) increased in patients with cardiovascular disease [median (range), 0.56 (0.08–3.9) nmol/L] and patients with sepsis [3.7 (0.72–25.4) nmol/L]. Conclusions: MR-proADM is stable in plasma of healthy individuals and patients. MR-proADM measurements may be useful for evaluating patients with sepsis, systemic inflammation, or heart failure.

scholarly journals Acceleration of fibrinolysis by the N-terminal peptide of alpha 2- plasmin inhibitor

Blood ◽  
1985 ◽  
Vol 66 (1) ◽  
pp. 157-160 ◽  
Author(s):  
S Kimura ◽  
T Tamaki ◽  
N Aoki
Keyword(s):  
Factor Xiii ◽  
Coagulation Factor ◽  
Cross Linking ◽  
Clot Retraction ◽  
Plasma Clot ◽  
Tissue Plasminogen ◽  
Previous Proposal ◽  
Reverse Relationship ◽  
Plasmin Inhibitor ◽  
Endogenous Fibrinolysis

Abstract When blood plasma containing the NH2-terminal 12-residue peptide (N- peptide) of alpha 2-plasmin inhibitor (alpha 2PI; alpha 2-antiplasmin) was clotted in the presence of calcium ions, the N-peptide and alpha 2PI were cross-linked to fibrin by activated coagulation factor XIII. The amount of N-peptide cross-linked to fibrin was proportional to the concentration of N-peptide present in plasma. On the other hand, the amount of alpha 2PI cross-linked to fibrin was decreased by the presence of N-peptide, and the decrease was in reverse relationship to the increase of cross-linking of N-peptide. Spontaneous fibrinolysis or fibrinolysis induced by tissue plasminogen activator was accelerated by the presence of N-peptide, and the acceleration was dependent on the concentrations of N-peptide and directly proportional to inhibition of alpha 2PI cross-linking exerted by N-peptide. The acceleration was more pronounced when the clot was compacted by platelet-mediated clot retraction or by a squeeze. Fibrinolysis of an alpha 2PI-deficient or a factor XIII-deficient plasma clot was not accelerated by N-peptide. These findings were substantiated in a purified system and support the previous proposal that alpha 2PI is cross-linked to fibrin at the glutamine residue that is next to the NH2-terminus of alpha 2PI, and this factor XIII-mediated cross-linking of alpha 2PI is significant in inhibition of physiologically occurring endogenous fibrinolysis.

scholarly journals Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia

Blood ◽  
2000 ◽  
Vol 96 (7) ◽  
pp. 2479-2486 ◽  
Author(s):  
István Balogh ◽  
Gabriella Szôke ◽  
Levente Kárpáti ◽  
Ulla Wartiovaara ◽  
Éva Katona ◽  
...  
Keyword(s):  
Protective Effect ◽  
Venous Thrombosis ◽  
Factor Xiii ◽  
Coagulation Factor ◽  
Wild Type ◽  
Thrombin Cleavage ◽  
Plasma Factor ◽  
Thrombin Activation ◽  
A Subunit ◽  
The Mean

Abstract Val34Leu polymorphism of the A subunit of coagulation factor XIII (FXIII-A) is located in the activation peptide (AP) just 3 amino acids away from the thrombin cleavage site. This mutation has been associated with a protective effect against occlusive arterial diseases and venous thrombosis; however, its biochemical consequences have not been explored. In the current study it was demonstrated that the intracellular stability and the plasma concentration of FXIII of different Val34Leu genotypes are identical, which suggests that there is no difference in the rate of synthesis and externalization of wild-type and mutant FXIII-A. In contrast, the release of AP by thrombin from the Leu34 allele proceeded significantly faster than from its wild-type Val34 counterpart. By molecular modeling larger interaction energy was calculated between the Leu34 variant and the respective domains of thrombin than between the Val34 variant and thrombin. In agreement with these findings, the activation of mutant plasma FXIII by thrombin was faster and required less thrombin than that of the wild-type variant. Full thrombin activation of purified plasma FXIII of different genotypes, however, resulted in identical specific transglutaminase activities. Similarly, the mean specific FXIII activity in the plasma was the same in the groups with wild-type, heterozygous, and homozygous variants. Faster activation of the Leu34 allele hardly could be associated with its presumed protective effect against venous thrombosis. No such protective effect was observed in a large group of patients with familial thrombophilia.

scholarly journals Noninvasive Assessment of Cardiac Output: Accuracy and Precision of the Closed‐Circuit Acetylene Rebreathing Technique for Cardiac Output Measurement

2020 ◽  
Vol 9 (17) ◽  
Author(s):  
E. Ashley Hardin ◽  
Douglas Stoller ◽  
Justin Lawley ◽  
Erin J. Howden ◽  
Michinari Hieda ◽  
...  
Keyword(s):  
Cardiac Output ◽  
Coefficient Of Variation ◽  
Clinical Disease ◽  
Closed Circuit ◽  
Stress Tests ◽  
Healthy Individuals ◽  
Output Measurement ◽  
Disease States ◽  
Accuracy And Precision ◽  
Rebreathing Method

Background Accurate assessment of cardiac output is critical to the diagnosis and management of various cardiac disease states; however, clinical standards of direct Fick and thermodilution are invasive. Noninvasive alternatives, such as closed‐circuit acetylene (C 2 H 2 ) rebreathing, warrant validation. Methods and Results We analyzed 10 clinical studies and all available cardiopulmonary stress tests performed in our laboratory that included a rebreathing method and direct Fick or thermodilution. Studies included healthy individuals and patients with clinical disease. Simultaneous cardiac output measurements were obtained under normovolemic, hypovolemic, and hypervolemic conditions, along with submaximal and maximal exercise. A total of 3198 measurements in 519 patients were analyzed (mean age, 59 years; 48% women). The C 2 H 2 method was more precise than thermodilution in healthy individuals with half the typical error (TE; 0.34 L/min [ r =0.92] and coefficient of variation, 7.2%) versus thermodilution (TE=0.67 [ r =0.70] and coefficient of variation, 13.2%). In healthy individuals during supine rest and upright exercise, C 2 H 2 correlated well with thermodilution (supine: r =0.84, TE=1.02; exercise: r =0.82, TE=2.36). In patients with clinical disease during supine rest, C 2 H 2 correlated with thermodilution ( r =0.85, TE=1.43). C 2 H 2 was similar to thermodilution and nitrous oxide (N 2 O) rebreathing technique compared with Fick in healthy adults (C 2 H 2 rest: r =0.85, TE=0.84; C 2 H 2 exercise: r =0.87, TE=2.39; thermodilution rest: r =0.72, TE=1.11; thermodilution exercise: r =0.73, TE=2.87; N 2 O rest: r =0.82, TE=0.94; N 2 O exercise: r =0.84, TE=2.18). The accuracy of the C 2 H 2 and N 2 O methods was excellent ( r =0.99, TE=0.58). Conclusions The C 2 H 2 rebreathing method is more precise than, and as accurate as, the thermodilution method in a variety of patients, with accuracy similar to an N 2 O rebreathing method approved by the US Food and Drug Administration.

Antithrombin III and Venous Thrombosis

1979 ◽  
Author(s):  
Duncan P. Thomas
Keyword(s):  
Venous Thrombosis ◽  
Antithrombin Iii ◽  
Physiological Role ◽  
Factor Xa ◽  
Original Description ◽  
Clear Cut ◽  
Naturally Occurring ◽  
At Iii ◽  
General Studies

Increasing interest in the physiological role of inhibitors of coagulation has highlighting the role of antithrombin III (AT III) as the most important naturally occurring inhibitor of venous thrombosis. Since Egeberg’s original description in 1965, it has been recognized that inherited deficiency of AT III is associated with an increased incidence of venous thromboembolism. The role of acquired deficiency of AT III in the pathogenesis of thromboembolism remainsless clear-cut, partly due to methodological differences. While low values have been reported in groups of patients with thromboembolism, estimations of AT III in individual patients are not allways abnormal. In general, studies which have measured protein concentration rather than functional activity, or cl otting assays which measure total antithrombin activity and not specific anti-Factor Xa activity have failed to demonstrate a clear relationship between AT III and thromboembolism. However, in two groups of patients, namely women on oral contraceptives and patients undergoing total hipreplacement, an acquired deficiency of AT III, particularly when measured by anti-Xa clotting assays, correlates highly with postoperative venous thrombosis. Although venous thrombosis may develop in patients despite normal AT III values, an activity below approximately 80% in an anti-Xa clotting assay has been found to be of predictive value in patients subjected to the stress of trauma or surgery.

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