scholarly journals Transferrin plays a central role to maintain coagulation balance by interacting with clotting factors

2019 ◽  
Author(s):  
Xiaopeng Tang ◽  
Zhiye Zhang ◽  
Mingqian Fang ◽  
Yajun Han ◽  
Sheng Wang ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Mouse Models ◽  
Antithrombin Iii ◽  
Fine Tuning ◽  
Coagulation Cascade ◽  
Molar Ratio ◽  
Clotting Factor ◽  
Clotting Factors ◽  
Normal Plasma ◽  
At Iii

SummaryCoagulation balance is maintained through fine-tuning interactions among clotting factors. Physiological concentrations of clotting factors are huge difference. Especially, coagulation proteases’ concentration (pM to nM) is much lower than their natural inactivator antithrombin III (AT-III, ∼3 μM). Here we show that transferrin (normal plasma concentration ∼40 μM) interacts with fibrinogen, thrombin, FXIIa and AT-III with different affinity to maintain coagulation balance. Normally, transferrin is sequestered by binding with fibrinogen (normal plasma concentration ∼10 μM) with a molar ratio of 4:1. In atherosclerosis, abnormally up-regulated transferrin interacts with and potentiates thrombin/FXIIa and blocks AT-III’s inactivation on coagulation proteases by binding to AT-III, and thus induces hypercoagulability. In mouse models, transferrin-overexpression aggravated atherosclerosis while transferrin-knockdown, anti-transferrin antibody or designed peptides interfering transferrin-thrombin/FXIIa interactions alleviated it. Collectively, these findings identify transferrin as a clotting factor and an adjuster for maintaining coagulation balance and modify the coagulation cascade.

scholarly journals Transferrin plays a central role in coagulation balance by interacting with clotting factors

Cell Research ◽  
2019 ◽  
Vol 30 (2) ◽  
pp. 119-132 ◽  
Author(s):  
Xiaopeng Tang ◽  
Zhiye Zhang ◽  
Mingqian Fang ◽  
Yajun Han ◽  
Gan Wang ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Mouse Model ◽  
Coagulation Cascade ◽  
Molar Ratio ◽  
Clotting Factors ◽  
Normal Plasma ◽  
Factor Xiia ◽  
Inactivation Effect ◽  
Shrna Knockdown

AbstractCoagulation balance is maintained through fine-tuned interactions among clotting factors, whose physiological concentrations vary substantially. In particular, the concentrations of coagulation proteases (pM to nM) are much lower than their natural inactivator antithrombin (AT, ~ 3 μM), suggesting the existence of other coordinators. In the current study, we found that transferrin (normal plasma concentration ~40 μM) interacts with fibrinogen, thrombin, factor XIIa (FXIIa), and AT with different affinity to maintain coagulation balance. Normally, transferrin is sequestered by binding with fibrinogen (normal plasma concentration ~10 μM) at a molar ratio of 4:1. In atherosclerosis, abnormally up-regulated transferrin interacts with and potentiates thrombin/FXIIa and blocks AT’s inactivation effect on coagulation proteases by binding to AT, thus inducing hypercoagulability. In the mouse model, transferrin overexpression aggravated atherosclerosis, whereas transferrin inhibition via shRNA knockdown or treatment with anti-transferrin antibody or designed peptides interfering with transferrin-thrombin/FXIIa interactions alleviated atherosclerosis. Collectively, these findings identify that transferrin is an important clotting regulator and an adjuster in the maintenance of coagulation balance and modifies the coagulation cascade.

The Effects Of Heparin On The Activation Of Factor X And Prothrombin In Antithrombin III-Depleted Plasma

1981 ◽  
Author(s):  
F Ofosu ◽  
A Cerskus ◽  
J Hirsh ◽  
M A Blajchman
Keyword(s):  
Antithrombin Iii ◽  
Factor Xa ◽  
Clotting Factor ◽  
Factor X ◽  
Independent Action ◽  
Clotting Factors ◽  
Factor Ixa ◽  
Normal Plasma ◽  
High Concentrations ◽  
Independent Effects

The predominant mode of the anticoagulant action of heparin is considered to be the enhancement of the rate of inactivation, by antithrombin-III, of several activated clotting factors. Recent evidence, however, suggests that heparin can reversibly inhibit the activation of prothrombin and factor X even in the absence of anti- thrombin-III. This antithrombin-III-independent action of heparin has been demonstrated only in purified clotting factor systems. In order to determine the significance of the antithrombin-III-independent effects of heparin in plasma, the effects of heparin on the activation of factor X and prothrombin were studied in antithrombin-III- depleted plasma produced by affinity chromatography of normal plasma on heparin-Sepharose. Heparin partially inhibited the activation of factor X and prothrombin on the addition of either factor IXa or factor Xa in anti- thrombin-III-depleted plasma. This inhibition was demonstrable only when high concentrations (1 or 10 units/ ml) of heparin were used. In contrast, when as little as 1% antithrombin-III was added to antithrombin-III-depleted plasma containing 1.0 u of heparin per ml of plasma, no factor X or prothrombin activation could be demonstrated. Thus, it appears that in comparison with the magnitude of the antithrombin-III-dependent effect, the contribution of the antithrombin-III-independent anticoagulant effect of heparin on the activation of factor X and prothrombin in normal plasma is limited.

TWO-SIDE IMMUNOASSAYS OF ENZYME-INHIBITOR COMPLEXES FOR THE DIAGNOSIS OF THROMBOPHILIC STATES

1987 ◽  
Author(s):  
H Bleyl
Keyword(s):  
Heart Surgery ◽  
Enzyme Inhibitor ◽  
Open Heart Surgery ◽  
Coagulation Cascade ◽  
Clotting Factors ◽  
Inhibitor Complex ◽  
At Iii ◽  
Complex Measurement ◽  
Sandwich Assays ◽  
Time Of Admission

The diagnosis of prethrombotic states requires methods which detect products of intravasal activation of the coagulation cascade.Two-side immunoassays for antithrombin complexes with clotting factors were developed (IXi-AT, Xi-AT, IIi- AT). These sandwich assays permit the diagnosis of hypercoagulability in the presence or absence of heparin. The biological half live time of the thrombin-antithrombin-complex was found to be about 15 min. Healthy young men 20-25 years old (n=30) have a thrombin-antithrombin-complex concentration of 0.4 ± 0.2 mU/ml thrombin equivalent (S 2238). Patients with acute myocardial infarction (n=40) showed at the time of admission to the hospital up to 10-fold (n=14), up to 100-fold (n=13) more than 100-fold (n=13) elevated thrombin-antithrombin-complex concentrations. Patients with gastrointestinal cancer showed sometime excessive elevated enzyme-inhibitor complexes.No correlation was found between thromboplastine time (Quick) and complex concentration in patients under anticoagulant therapy with dicumarole. In patients under dialysis as well as in patients under open heart surgery with extracorporal circulation, the biocompatibility can be monitored by inhibitor complex measurement.

In vitro effects of human neutrophil cathepsin G on thrombin generation: Both acceleration and decreased potential

2010 ◽  
Vol 104 (09) ◽  
pp. 514-522 ◽  
Author(s):  
Thomas Lecompte ◽  
Agnès Tournier ◽  
Lise Morlon ◽  
Monique Marchand-Arvier ◽  
Claude Vigneron ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Thrombin Generation ◽  
Time Course ◽  
Anticoagulant Activity ◽  
Cathepsin G ◽  
Coagulation Cascade ◽  
Clotting Factor ◽  
Factor V ◽  
Clotting Factors

SummaryCathepsin G (Cath G), a serine-protease found in neutrophils, has been reported to have effects that could either facilitate or impede coagulation. Thrombin generation (CAT method) was chosen to study its overall effect on the process, at a plasma concentration (240 nM) observed after neutrophil activation. Coagulation was triggered by tissue factor in the presence of platelets or phospholipid vesicles. To help identify potential targets of Cath G, plasma depleted of clotting factors or of inhibitors was used. Cath G induced a puzzling combination of two diverging effects of varying intensities depending on the phospholipid surface provided: accelerating the process under the three conditions (shortened clotting time by up to 30%), and impeding the process during the same thrombin generation time-course since thrombin peak and ETP (total thrombin potential) were decreased, up to 45% and 12%, respectively, suggestive of deficient prothrombinase. This is consistent with Cath G working on at least two targets in the coagulation cascade. Our data indicate that coagulation acceleration can be attributed neither to platelet activation and nor to activation of a clotting factor. When TFPI (tissue factor pathway inhibitor) was absent, no effect on lag time was observed and the anticoagulant activity of TFPI was decreased in the presence of Cath G. Consistent with the literature and the hypothesis of deficient prothrombinase, experiments using Russel’s Viper Venom indicate that the anticoagulant effect can be attributed to a deleterious effect on factor V. The clinical relevance of these findings deserves to be studied.

Crossed Immunoelectrofocusing Of Antithrombin III In Healthy And In Congenital And Acquired Deficiency

1981 ◽  
Author(s):  
G Leone ◽  
V M Valori ◽  
G Traisci ◽  
B Bizzi
Keyword(s):  
Isoelectric Focusing ◽  
Hepatic Cirrhosis ◽  
Antithrombin Iii ◽  
Congenital Defect ◽  
Plasma Pool ◽  
Normal Plasma ◽  
Isoelectric Points ◽  
At Iii ◽  
Two Peaks ◽  
Normal Pool Plasma

Isoelectrofocusing was carried out in LKB Multiphor apparatus with pH 4-6.5 carrier ampholites using poly- acrilamide gels. Specimens of human purified antithrombin, normal plasma pool, plasma with congenital and acquired AT- III deficiency were isoelectric focused. Purified Antithrombin showed two peaks. The isoelectric points of these antithrombin peaks were 4.6 and 4.9. Next the poly- acrilamide gel slabs were placed on glass plates coated with agarose containing 4% anti human antithrombin antibody; crossed electrophoresis was then carried out. Normal pool plasma exhibits two peaks, which correspond to the isoelectric focusing position of the purified AT-III. Plasmas of two families with congenital AT-III deficiency exhibit only one peak at pH lower. On the contrary plasmas of patients with acquired AT-III deficiency (hepatic cirrhosis, asparaginase therapy) exhibit two peaks. Considering that microheterogeneity is fundamentally due to a difference in glycosylation (Borsodi and Nerasimhan, Brit. J. Haemat. 1978, 39,121) it is possible to hypothesize a defect in glycosylation in congenital defect.

A Method for the Quantitative Determination of the Antithrombin III (AT III) a Citivity in Plasma and Serum Using the Complex Formation with Heparin

1975 ◽  
Author(s):  
H. E. Karges ◽  
N. Heimburger ◽  
C. Loechelt
Keyword(s):  
Plasma Concentration ◽  
Antithrombin Iii ◽  
Ph Value ◽  
Immunological Methods ◽  
Good Reproducibility ◽  
High Dilution ◽  
At Iii ◽  
The Mean ◽  
Native Plasma

A prerequisite of most AT III assays is the defibrination of the samples. Defibrination of plasma, however, is generally associated with a loss of AT III. This especially true of heat defibrination. Furthermore, according to our experience, most of the functional determinations don’t correlate well with the immunological ones, and don’t provide reproducible results. Therefore, it was the aim of our investigations to establish a method which omits the defibrination and yields reproducible results.The method reported is based on the identity of AT III and heparin cofactor antithrombin II (AT II) respectively. AT III is converted by heparin from a progressive into an immediate inhibitor, allowing a plasma dilution of 1:50. Due to this high dilution, the defibrination step can be omitted and AT III determined in native plasma. To transform AT III completely into its heparin complex, 5 USP units heparin are used. α2-macro-globulin up to 400% of normal plasma concentration does not influence the assay. When determinations are performed at a certain pH value, good reproducibility is obtained. The mean error of determinations of the same sample does not exeed 4%. Maximal deviations were in the range of 5 to 10%. The results of functional determinations are compared with those obtained by two immunological methods. Deviations scarcely exeed the limits of methodical errors.

Antithrombin III in shock and disseminated intravascular coagulation

1998 ◽  
Vol 79 (1) ◽  
pp. 44-48
Author(s):  
H. A. Vinazzer
Keyword(s):  
Septic Shock ◽  
Antithrombin Iii ◽  
Repeated Administration ◽  
Consumption Coagulopathy ◽  
Clotting Factors ◽  
Heparin Group ◽  
Duration Of Symptoms ◽  
Intravascular Coagulation ◽  
Average Survival ◽  
At Iii

Antithrombin III (AT III) is the physiological inhibitor of a series of activated clotting factors. Its diminution increases the tendency of thromboembolism. In cases of acute DIC, AT III binds to thrombin and to other activated factors in circulation. Thereby both partners of the reaction become inactive. When by this mechanism the available biologic activity of AT III diminishes below about 50% of normal any further inactivation of active clotting enzymes is greatly inhibited. In such cases, the mechanism of DIC decompensates and the full symptoms of consumption coagulopathy develop. It was, therefore, obvious to attempt a substitution with concentrates of AT III in such cases. In different randomized trials it could be shown which effect AT III concentrates had on the outcome of Die. In these tests it could be clearly shown that repeated administration of AT HI concentrates in a dose that keeps AT III activity constantly around 100% had the following advantages over therapy with heparin. The duration of symptoms of DIC could be considerably shortened from an average of 120 h in the heparin group to 40 h in the AT HI substitution group. Furthermore, in most severe cases of acute consumption coagulopathy due to septic shock, the death rate could be considerably and highly significantly diminished in the patients who received AT III. Similar results were also found by different authors who were able to demonstrate that the average survival rate in patients with septic shock increased from 20% to over 70% when AT III was substituted. Key Words: Antithrombin IIIHeparinDiffuse intravascular coagulation.

Hypercoagulability In Acute Esophageal Variceal Bleeding

1981 ◽  
Author(s):  
E Hiller ◽  
F Hegemann ◽  
H Riess
Keyword(s):  
Gel Filtration ◽  
Fresh Frozen Plasma ◽  
Clotting Factor ◽  
Intensive Care Treatment ◽  
Clotting Factors ◽  
Esophageal Variceal ◽  
Esophageal Variceal Bleeding ◽  
At Iii ◽  
Fresh Frozen ◽  
Clotting Factor Concentrates

In 15 patients with acute esophageal bleeding selected parameters of hypercoagulability were determined at frequent intervals during intensive care treatment. Estimation of soluble fibrin monomer complexes (SFMC) by gel filtration of plasma samples which were purified by ß-alanine precipitation allowed the determination of the relative amount of SFMC (percentage of SFMC in relation to the total fibrinogen content in plasma). Antithrombin III (AT III) activity was determined photometrically using the chromogenic substance S-2238 and immunologically by one dimensional immunelectrophoresis. Fibrin split products (FSP) were estimated by the staphylococcal clumping test.Increased levels of SFMC were observed in 10 out of 15 patients on admission. A further increase was noted in most patients in whom bleeding persisted and who needed replacement therapy with blood components. Substitution with prothrombin complex concentrates induced acute DIC in two patients with levels of SFMC up to 24 %. AT III was decreased to levels of 30-50 % in 8 patients during the acute illness. A discrepancy between the functional and immunological AT III value was noted in some instances but more often both values were very low.High levels of SFMC in addition to levels of AT III of less than 50 % reflect a serious state of hypercoagulability with a very poor prognosis for the patients. Clotting factor concentrates may be especially thrombogenic in these patients with impaired clearing activity. Fresh frozen plasma and AT III concentrates provide an appropriate source of the most important clotting factors.

Immunchemical Investigation on Antithrombin III/AT-III/in Presence of Heparin

1979 ◽  
Author(s):  
D. Bánuergyi ◽  
G. Sas
Keyword(s):  
Affinity Chromatography ◽  
Antithrombin Iii ◽  
Original Method ◽  
Normal Plasma ◽  
At Iii ◽  
Different Sources

Various components of AT-III car, be differentiated by crossed ioununo-eleetrophoresis in the presence of heparin as we described previously / Sas et al. 1975 /. The migration of heparin is discontinuous in this original method, i.e. at the end of the electrophoresis the plate does not contain heparin at all. This fact rises the possibility pf the artefactual nature of these AT-III components. To exclude this effect we introduced a modification using double plates incorporated with heparin. The second plate was used as a heparin “reservoir”. By this modification we obtained constant heparin flow in the course of electrophoresis. We found four different AT-III components in normal plasma comparing with three AT-III eomportints of the original method.Investigating heparins originated from different sources we found a higher mobility of AT-III in the pnsenee of mucous heparin than that of lung heparin. This observation corresponds well with the results obtamed by heparin-agarose affinity chromatography.

Further Investigations on Antithrombin III in the Plasmas of Patients with the Abnormality of ‘Antithrombin III Budapest’

1975 ◽  
Vol 33 (03) ◽  
pp. 564-572 ◽  
Author(s):  
Géza Sas ◽  
Duncan S Pepper ◽  
John D Cash
Keyword(s):  
Electrophoretic Mobility ◽  
Antithrombin Iii ◽  
Gel Filtration ◽  
Molecular Size ◽  
High Concentration ◽  
Abnormal Protein ◽  
Crossed Immunoelectrophoresis ◽  
Normal Plasma ◽  
At Iii ◽  
Cofactor Activity

SummaryAntithrombin III (AT-III) was studied in a thrombophilic family with an abnormal AT-III molecule (antithrombin III Budapest) using a modified crossed Immunoelectrophoresis technique, gel filtration, ‘rocket’ Immunoelectrophoresis and a heparin cofactor assay.When plain agarose was applied in the first phase of the crossed Immunoelectrophoresis, the normal and the pathological AT-III revealed identical electrophoretic mobility. However, when heparin was mixed with agarose in the first phase of electrophoresis, the propositus’ plasma displayed a different AT-III pattern from normal plasma. His plasma contained the first component of the normal plasma (Immune Antithrombin III1, IAT-III1) in a concentration of only 5% of normal, and a protein in high concentration which although immunoreactive to AT-III antisera, had an electrophoretic mobility similar (but not identical) to that of IAT-III2. This ab-normal protein had no heparin cofactor activity and a molecular size greater than normal plasma AT-III. Unlike normal AT-III, the addition of heparin did not change the molecular size of the pathologic AT-III molecule significantly.The abnormal protein was present in lower concentrations in the patient’s children and at the time of study they had no clinical or laboratory evidence of intravascular coagulation.

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