A low molecular weight platelet inhibitor of factor XIa: purification, characterization, and possible role in blood coagulation

Biochemistry ◽  
1992 ◽  
Vol 31 (6) ◽  
pp. 1685-1694 ◽  
Author(s):  
Anne L. Cronlund ◽  
Peter N. Walsh
Keyword(s):  
Molecular Weight ◽  
Blood Coagulation ◽  
Low Molecular Weight ◽  
Platelet Inhibitor ◽  
Factor Xia

Surface Independent Factor XI Activation by Thrombin in the Presence of High Molecular Weight Kininogen

1994 ◽  
Vol 72 (03) ◽  
pp. 397-402 ◽  
Author(s):  
Peter A Kr von dem Borne ◽  
Stefan J Koppelman ◽  
Bonno N Bouma ◽  
Joost C M Meijers
Keyword(s):  
Molecular Weight ◽  
Blood Coagulation ◽  
High Molecular Weight ◽  
Dextran Sulfate ◽  
Factor Xa ◽  
Factor X ◽  
High Molecular Weight Kininogen ◽  
Factor Xi ◽  
Factor Xia

SummaryA deficiency of one of the proteins of the contact system of blood coagulation does not result in a bleeding disorder. For this reason activation of blood coagulation via this system is believed to be an in vitro artefact. However, patients deficient in factor XI do suffer from variable bleeding abnormalities. Recently, an alternative pathway for factor XI activation has been described. Factor XI was found to be activated by thrombin in the presence of dextran sulfate as a surface. However, high molecular weight kininogen (HK), to which factor XI is bound in plasma, and fibrinogen were shown to block this activation suggesting it to be an in vitro phenomenon. We investigated the thrombin-mediated factor XI activation using an amplified detection system consisting of factors IX, VIII and X, which was shown to be very sensitive for factor XIa activity. This assay is approximately 4 to 5 orders of magnitude more sensitive than the normal factor XIa activity assay using a chromogenic substrate. With this assay we found that factor XI activation by thrombin could take place in the absence of dextran sulfate. The initial activation rate was approximately 0.3 pM/min (using 25 nM factor XI and 10 nM thrombin). The presence of dextran sulfate enhanced this rate about 8500-fold. A very rapid and complete factor X activation was observed in the presence of dextran sulfate. Although only minute amounts of factor XIa were formed in the absence of dextran sulfate, significant activation of factor X was detected in the amplification assay within a few minutes. HK inhibited the activation of factor XI by thrombin strongly in the presence, yet only slightly in the absence of dextran sulfate (26 and 1.2 times, respectively). Despite the strong inhibition of HK on the activation of factor XI by thrombin in the presence of dextran sulfate, HK had only a minor effect on the factor Xa generation.We conclude that activation of factor XI by thrombin can take place regardless of the presence of a surface or HK. This activation might therefore be physiologically relevant. The inhibitory effect of HK on the thrombin-mediated factor XI activation is largely dextran sulfate dependent. Due to the amplification in the intrinsic system, trace amounts of factor XIa might generate physiological sufficient amounts of factor Xa for an adequate haemostatic response.

Effects of a low molecular weight starch (ELOHES) on blood coagulation, comparison with albumin in hip surgery

1992 ◽  
Vol 65 ◽  
pp. S177
Author(s):  
P. Toulon ◽  
N. Vassiliev ◽  
V. Guigonis ◽  
N. Rosencher ◽  
Ch. Conseiller
Keyword(s):  
Molecular Weight ◽  
Blood Coagulation ◽  
Hip Surgery ◽  
Low Molecular Weight

scholarly journals The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kallikrein by antithrombin

1981 ◽  
Vol 193 (2) ◽  
pp. 395-400 ◽  
Author(s):  
E Holmer ◽  
K Kurachi ◽  
G Söderström
Keyword(s):  
Molecular Weight ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Clotting Factors ◽  
Factor Ixa ◽  
Molecular Weight Dependence ◽  
Factor Xiia ◽  
Factor Xia ◽  
Heparin Fractions ◽  
Inhibition Of Thrombin

Heparin fractions of different molecular weight and with high affinity for antithrombin were studied with respect to their ability to potentiate the inhibition of activated clotting factors by antithrombin. Inhibition of thrombin, Factor IXa and Factor XIa showed similarities in the dependence on the molecular weight of heparin and was found to decrease with decreasing molecular weight. Inactivation of Factor Xa, Factor XIIa and kallikrein was, however, less dependent on the size of the polysaccharide and, to a great extent, was potentiated even by low-molecular-weight heparin fractions that had virtually no effect on the inhibition of thrombin, Factor IXa and Factor XIa.

scholarly journals RGD-hirudin-based low molecular weight peptide prevents blood coagulation via subcutaneous injection

2020 ◽  
Vol 41 (6) ◽  
pp. 753-762
Author(s):  
Ya-ran Li ◽  
Yi-nong Huang ◽  
Bing Zhao ◽  
Meng-fang Wu ◽  
Tian-yu Li ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Blood Coagulation ◽  
Subcutaneous Injection ◽  
Low Molecular Weight

Influence of Low Molecular Weight Heparin and Low Molecular Weight Dextran Sulfate on the Inhibition of Coagulation Factor XIa by Serpins

1998 ◽  
Vol 80 (07) ◽  
pp. 82-86 ◽  
Author(s):  
Thomas Mauron ◽  
Bernhard Lämmle ◽  
Walter Wuillemin
Keyword(s):  
Molecular Weight ◽  
Rate Constant ◽  
Dextran Sulfate ◽  
Coagulation Factor ◽  
Order Rate Constant ◽  
Second Order ◽  
Low Molecular Weight ◽  
C1 Inhibitor ◽  
Order Rate ◽  
Factor Xia

SummaryWe investigated the influence of low molecular weight dextran sulfate (LMWdxs) and low molecular weight heparins (LMWH: dalteparin, enoxaparin and nadroparin) on the inhibition of FXIa by C1-inhibitor, α1-antitrypsin, α2-antiplasmin and antithrombin in a purified system and in plasma.The second order rate constant for inactivation of FXIa by C1-inhibitor, α1-antitrypsin, α2-antiplasmin, and antithrombin was 1.23, 0.056, 0.33 and 0.59 × 103 M–1 s–1, respectively.LMWdxs and LMWH dose-dependently increased the second order rate constant of the inactivation of FXIa by C1-inhibitor up to 39-fold. The second order rate constant of the inactivation of FXIa by anti-thrombin was increased up to 6-fold by LMWH, whereas LMWdxs had no effect. In plasma, FXIa was inactivated to about 50% by C1-inhibitor, while the other serpins contributed together to the remaining 50% of plasma’s inhibitory capacity towards FXIa. In the presence of LMWdxs or LMWH, FXIa was inactivated in plasma to more than 90% by C1-inhibitor. LMWH at maximal therapeutic plasma levels enhanced the contribution of antithrombin to the inactivation of FXIa in plasma up to 5-fold.In conclusion, we found that the tested low molecular weight glycosaminoglycans dalteparin, enoxaparin and nadroparin and LMWdxs stimulate inactivation of FXIa by C1-inhibitor in a system using purified proteins as well as in plasma. Furthermore, LMWH but not LMWdxs slightly enhanced FXIa inhibition by antithrombin.

scholarly journals Effect of High- and Low-molecular-weight Low-substituted Hydroxyethyl Starch on Blood Coagulation during Acute Normovolemic Hemodilution in Pigs

2006 ◽  
Vol 105 (6) ◽  
pp. 1228-1237 ◽  
Author(s):  
Caroline Thyes ◽  
Caveh Madjdpour ◽  
Philippe Frascarolo ◽  
Thierry Buclin ◽  
Marco Bürki ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Blood Coagulation ◽  
Plasma Concentrations ◽  
Hemoglobin Concentration ◽  
Low Molecular Weight ◽  
Acute Normovolemic Hemodilution ◽  
Regression Parameters ◽  
Angle Alpha ◽  
Normovolemic Hemodilution

Background Hydroxyethyl starches (HES) with lower impact on blood coagulation but longer intravascular persistence are of clinical interest. The current study aimed to investigate in vivo the isolated effect of molecular weight on blood coagulation during progressive acute normovolemic hemodilution. Methods Twenty-four pigs were normovolemically hemodiluted up to a total exchange of 50 ml . kg . body weight of HES 650/0.42 or HES 130/0.42. Serial blood sampling was performed to measure HES plasma concentration and to assess blood coagulation. Concentration-effect relations were analyzed by linear regression, followed by the Student t test on regression parameters. Results Blood coagulation was increasingly compromised toward hypocoagulability by acute normovolemic hemodilution with both treatments (P < 0.01). Significantly greater impact on activated partial thromboplastin time (P = 0.04) and significantly stronger decrease of maximal amplitude (P = 0.04), angle alpha (P = 0.02), and coagulation index (P = 0.02) was seen after acute normovolemic hemodilution with HES 650/0.42 as compared with HES 130/0.42. Except for factor VIII (P = 0.04), no significant differences between both treatments were observed when relating antihemostatic effects to HES plasma concentrations (P > 0.05). A significantly lesser decrease of hemoglobin concentration has been found with HES 650/0.42 as compared with HES 130/0.42 (P < 0.01) in relation to HES plasma concentrations. Conclusion High-molecular-weight HES (650/0.42) shows a moderately greater antihemostatic effect than low-molecular-weight HES (130/0.42) during acute normovolemic hemodilution. However, similar effects on hemostasis were observed with both treatments when observed antihemostatic effects were related to measured HES plasma concentrations. In addition, HES 650/0.42 may have a lower efficacy in immediately restoring plasma volume.

Anti Factor Xa Activity In Plasma Following Oral, Pulmonary, Subcutaneous And Intravenous Administration Of Cd5000 Low Molecular Weight Heparin And Commercial Heparin To Rats, Rabbits And Dogs

1981 ◽  
Author(s):  
L I Harrison ◽  
C R Kehe ◽  
R E Ober
Keyword(s):  
Molecular Weight ◽  
Oral Administration ◽  
Blood Coagulation ◽  
Intravenous Administration ◽  
Plasma Levels ◽  
Low Molecular Weight Heparin ◽  
Factor Xa ◽  
Low Molecular Weight ◽  
Dog Plasma ◽  
Antifactor Xa

CD5000 heparin (LMWH) is a low molecular weight heparin fraction, ave. mol wt. ∼ 5100. Plasma levels of antiFactor Xa activity (XaA) after iv, pulmonary, sc and oral administration of LMWH and commercial heparin (CH) were examined in rats, rabbits and dogs. Overall, LMWH maintained higher levels of XaA in plasma than did a similar mg dose of CH. When the heparins were given iv, plasma XaA after LMWH had a t1/2 ∼ 2X as long as that after CH. When similar mg doses were given sc, the average plasma XaA following LMWH was significantly higher than that following CH during 0-6 hrs postdose. When equal USP unit doses (four times as much LMWH on a mg basis) were administered into the lungs of dogs, LMWH showed plasma XaA significantly higher than after CH. LMWH also showed higher plasma XaA on oral administration of equal USP unit doses in rats, but the fraction of the dose absorbed and the plasma levels were low. About 4X as much LMWH on a mg basis as CH had to be given to achieve similar APTT values in dog plasma. LMWH may have significant therapeutic advantages in man if pharmacokinetic differences and different blood coagulation effects of the various mol wt. heparins described here in animals also occur in man. Studies in humans are planned.

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