scholarly journals COVID‐19‐associated coagulopathy—Hypothesis: Are children protected due to enhanced thrombin inhibition by higher α 2 ‐Macroglobulin macroglobulin (α2‐M)?

2020 ◽  
Vol 18 (9) ◽  
pp. 2416-2418 ◽  
Author(s):  
Wolfgang Schramm ◽  
Rainer Seitz ◽  
Lutz Gürtler
Keyword(s):  
Thrombin Inhibition

Further Studies on the Mechanisms for the Antithrombotic Effects of Sulfated Polysaccharides in Rabbits

1988 ◽  
Vol 60 (02) ◽  
pp. 188-192 ◽  
Author(s):  
F A Ofosu ◽  
F Fernandez ◽  
N Anvari ◽  
C Caranobe ◽  
F Dol ◽  
...  
Keyword(s):  
Antithrombin Iii ◽  
Ex Vivo ◽  
Thrombus Formation ◽  
Minimum Weight ◽  
Sulfated Polysaccharides ◽  
Pentosan Polysulfate ◽  
Heparin Cofactor Ii ◽  
Thrombin Inhibition ◽  
The Relationship ◽  
Prothrombin Activation

SummaryA recent study (Fernandez et al., Thromb. Haemostas. 1987; 57: 286-93) demonstrated that when rabbits were injected with the minimum weight of a variety of glycosaminoglycans required to inhibit tissue factor-induced thrombus formation by —80%, exogenous thrombin was inactivated —twice as fast in the post-treatment plasmas as the pre-treatment plasmas. In this study, we investigated the relationship between inhibition of thrombus formation and the extent of thrombin inhibition ex vivo. We also investigated the relationship between inhibition of thrombus formation and inhibition of prothrombin activation ex vivo. Four sulfated polysaccharides (SPS) which influence coagulation in a variety of ways were used in this study. Unfractionated heparin and the fraction of heparin with high affinity to antithrombin III potentiate the antiproteinase activity of antithrombin III. Pentosan polysulfate potentiates the activity of heparin cofactor II. At less than 10 pg/ml of plasma, all three SPS also inhibit intrinsic prothrombin activation. The fourth agent, dermatan sulfate, potentiates the activity of heparin cofactor II but fails to inhibit intrinsic prothrombin activation even at concentrations which exceed 60 pg/ml of plasma. Inhibition of thrombus formation by each sulfated polysaccharides was linearly related to the extent of thrombin inhibition achieved ex vivo. These observations confirm the utility of catalysis of thrombin inhibition as an index for assessing antithrombotic potential of glycosaminoglycans and other sulfated polysaccharides in rabbits. With the exception of pentosan polysulfate, there was no clear relationship between inhibition of thrombus formation and inhibition of prothrombin activation ex vivo.

The Venous Antithrombotic Profile of Naroparcil in the Rabbit

1994 ◽  
Vol 72 (06) ◽  
pp. 874-879 ◽  
Author(s):  
Jean Millet ◽  
Jocelyne Theveniaux ◽  
Neil L Brown
Keyword(s):  
Oral Administration ◽  
Bleeding Time ◽  
Dermatan Sulfate ◽  
Factor Xa ◽  
Bleeding Risk ◽  
Thrombin Time ◽  
Heparin Cofactor Ii ◽  
Antithrombotic Activity ◽  
Thrombin Inhibition ◽  
Maximal Reduction

SummaryThe venous antithrombotic profile of naroparcil or (4-[4-cyanoben-zoyl]-phenyl)-1.5-dithio-β-D-xylopyranoside was investigated in the rabbit following single i. v. and oral administration. Naroparcil attenuated thrombus development in a Wessler stasis model of venous thrombosis (jugular vein) employing bovine factor Xa as a thrombogenic stimulus giving ED50 values of 21.9 mg/kg and 36.0 mg/kg after respectively i. v. and oral administration. Venous antithrombotic activity was maximal 2-3 h after i. v. administration and 4-8 h after oral administration. Four hours after the oral administration of maximal antithrombotic (Wessler model, factor Xa) doses (100 and 400 mg/kg), naroparcil had no significant effect on bleeding time. In platelet poor plasma obtained from animals treated 4 h previously with various doses (25 to 400 mg/kg) of naroparcil, there was no detectable anti-factor Xa nor antithrombin activity. Similarly, naroparcil had no effect on APTT nor on thrombin time. A sensitized thrombin time (to about 35 s) was modestly but significantly increased following oral administration of the compound at 400 mg/kg. However, thrombin generation by the intrinsic pathway was reduced in a dose-related manner, maximal reduction being 65% at 400 mg/kg. The same doses of naroparcil enhanced the formation of thrombin/heparin cofactor II complexes at the expense of thrombin/antithrombin III complexes in plasma incubated with (125I)-human a-thrombin and induced the appearance of dermatan sulfate-like material in the plasma of treated rabbits, as measured by a heparin cofactor II-mediated thrombin inhibition assay. The results suggest that naroparcil could have a safe venous antithrombotic profile following oral administration (antithrombotic effect compared to bleeding risk). It is probable that part of the mechanism of action of the β-D-xyloside, naroparcil, is due to the induction of chondroitin sulfate-like glycosaminoglycan biosynthesis, this material being detectable in the plasma.

Reactivity of a Hereditary Abnormal Antithrombin III Fraction in the Inhibition of Thrombin and Factor Xa

1980 ◽  
Vol 44 (02) ◽  
pp. 092-095 ◽  
Author(s):  
T H Tran ◽  
C Bondeli ◽  
G A Marbet ◽  
F Duckert
Keyword(s):  
Antithrombin Iii ◽  
Factor Xa ◽  
Heparin Binding ◽  
Thrombin Inhibition ◽  
Superficial Thrombophlebitis ◽  
Heparin Concentration ◽  
Heparin Binding Site ◽  
At Iii ◽  
The Difference ◽  
Inhibition Of Thrombin

SummaryTwo different AT-III fractions were purified from the plasma of a patient with recurrent superficial thrombophlebitis. The abnormal AT-III fraction (A-AT) was compared to the normal AT-III fraction (N-AT) in the inhibition of thrombin and factor Xa. Without heparin, both inactivate proteases in a similar manner and at the same rate. However, at low heparin concentration the thrombin inhibition proceeds more slowly with A-AT than with N-AT. At high heparin concentration the difference between A-AT and N-AT becomes very small. The inhibition of factor Xa follows a similar pattern. It is suggested that the heparin binding site of A-AT differs from that of N-AT resulting in a decreased heparin cofactor activity.

Thrombin Inhibition and Thrombin Generation by Cultured Aortic Endothelial and Smooth Muscle Cells from Minipig

1982 ◽  
Vol 48 (01) ◽  
pp. 101-103 ◽  
Author(s):  
B Kirchhof ◽  
J Grünwald
Keyword(s):  
Endothelial Cells ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vessel Wall ◽  
Thrombin Generation ◽  
Muscle Cells ◽  
Thrombin Inhibition ◽  
Generating Capacity ◽  
Wall Interaction ◽  
Cells Cultured

SummaryEndothelial and smooth muscle cells cultured from minipig aorta were examined for their inhibitory activity on thrombin and for their thrombin generating capacity.Endothelial cells showed both a thrombin inhibition and an activation of prothrombin in the presence of Ca++, which was enhanced in the presence of phospholipids. Smooth muscle cells showed an activation of prothrombin but at a lower rate. Both coagulation and amidolytic micro-assays were suitable for studying the thrombin-vessel wall interaction.

On the Reliability of the Use of Heparin Immobilized on Agarose for the Study of the Interactions among Heparin, Thrombin and Antithrombin

1982 ◽  
Vol 48 (01) ◽  
pp. 084-086
Author(s):  
Wayne W Fish ◽  
Ingemar Björk
Keyword(s):  
Experimental Approach ◽  
Antithrombin Iii ◽  
Chromogenic Substrate ◽  
Experimental Protocol ◽  
Appreciable Difference ◽  
Thrombin Inhibition ◽  
Highly Sensitive ◽  
Inhibition Of Thrombin

SummaryThe extent of inhibition of thrombin was re-examined as a consequence of the sequence of addition of thrombin and antithrombin III to a column of heparin immobilized on agarose. With the use of pure enzyme, pure inhibitor, and a highly sensitive chromogenic substrate, no appreciable difference in the extent of thrombin inhibition was observed between the two sequences of addition. These observations, together with a demonstrated sensitivity of the method to variations in experimental protocol, challenge the conclusions reached in an earlier work (Hatton and Regoeczi, Thromb. Res. 1977; 10:645) which utilized this experimental approach but which employed larger quantities of reactants and a less sensitive substrate.

A Collaborative Study Designed to Establish the 4th International Standard for Heparin

1984 ◽  
Vol 52 (02) ◽  
pp. 148-153 ◽  
Author(s):  
D P Thomas ◽  
A D Curtis ◽  
T W Barrowcliffe
Keyword(s):  
Collaborative Study ◽  
International Standard ◽  
Thrombin Inhibition ◽  
Freeze Dried ◽  
Assay Methods ◽  
The Mean ◽  
International Collaborative ◽  
International Collaborative Study

SummaryAn international collaborative study, in which 22 laboratories participated, was carried out to establish a replacement for the International Standard for Heparin. A total of 248 assays were analyzed, including APTT, thrombin inhibition and anti-Xa assays, as well as pharmacopoeial assays. Overall, there was less than 5% difference in the mean potency estimates of the candidate preparations, by all assay methods. The freeze-dried preparation 82/502 demonstrated the closest parallelism by bioassay to the existing standard and was established by WHO as the 4th International Standard for Heparin, with an assigned unitage of 1780 i.u. per ampoule.

Evaluating Thrombin Inhibition in Alzheimer’s Disease (The BEACON Trial): Protocol for a Pilot Study (Preprint)

2019 ◽  
Author(s):  
Cláudia Yang Santos ◽  
Christine Getter ◽  
John Stoukides ◽  
Brian Ott ◽  
Stephen Salloway ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pilot Study ◽  
Cognitive Performance ◽  
Thrombin Inhibitor ◽  
Placebo Control ◽  
Open Label ◽  
Double Blind ◽  
Thrombin Inhibition ◽  
Approved Drugs

BACKGROUND The precise mechanisms whereby cardiovascular risk factors increase the risk of Alzheimer’s disease (AD) have not been delineated. We reported that microvessels isolated from AD brains overexpress a diverse array of neurotoxic and inflammatory proteins, which is consistent with the process of vascular activation. In pre-clinical studies using AD animal models we showed that a vascular activation inhibitor reduced vascular-derived neuroinflammation and improved cognitive performance. Thrombin is a key mediator of cerebrovascular activation in AD. OBJECTIVE This study aims to investigate the safety and potential efficacy of the direct thrombin inhibitor dabigatran, in patients with mild cognitive impairment (MCI) or mild AD to decrease vascular-derived neuroinflammation and improve cognitive performance. METHODS Participants will be enrolled then evaluated quarterly throughout the 24-month study. This is a 24-month randomized-control, double-blind, placebo-controlled, multicenter, delayed-start, pilot study evaluating thrombin inhibition in people with biomarker-confirmed MCI probably due to AD or mild AD. 40 - 60 participants will be recruited between 50 - 85 years old. In the initial 9-months of study, either dabigatran or placebo will be orally administered to patients at a dose of 150 mg per day. After 9 months of the placebo-control (Phase I), the placebo arm will cross-over to an active, open-label (Phase II) where all patients will be treated with a 150 mg daily dose of dabigatran orally for an additional 12 months. A 3-month non-treatment follow-up period will assess duration of effects. RESULTS Beginning in July 2019, and concluding in August 2022, this study is expected to publish final results in January 2023. CONCLUSIONS BEACON is a first-in-kind randomized clinical trial targeting thrombin activation in AD therapeutics. This trial will stimulate translational investigations of an FDA-approved drugs in a newly defined therapeutic areas. CLINICALTRIAL Clinicaltrials.gov NCT03752294

Thrombin Inhibition by Novel Benzamidine Derivatives:  A Free-Energy Perturbation Study

2002 ◽  
Vol 45 (23) ◽  
pp. 4995-5004 ◽  
Author(s):  
Cristiano Ruch Werneck Guimarães ◽  
Ricardo Bicca de Alencastro
Keyword(s):  
Free Energy ◽  
Free Energy Perturbation ◽  
Thrombin Inhibition ◽  
Energy Perturbation

scholarly journals Substitution of arginine for Leu444 in the reactive site of heparin cofactor II enhances the rate of thrombin inhibition.

1990 ◽  
Vol 265 (10) ◽  
pp. 5623-5628 ◽  
Author(s):  
V M Derechin ◽  
M A Blinder ◽  
D M Tollefsen
Keyword(s):  
Reactive Site ◽  
Heparin Cofactor Ii ◽  
Thrombin Inhibition
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