The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin.

Jordan, Robert E.; Oosta, G M; Gardner, W.T.; Rosenberg, R D

doi:10.1016/s0021-9258(19)70431-1

Cited by 313 publications

(39 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…5,6 Differently from ex vivo, both thrombin 20 and plasmin 21 are tightly controlled in vivo by inhibitors such as AT and a 2 -antiplasmin, resulting in short-lived protease activity. Moreover, thrombin inactivation in vivo is enhanced by vessel wall-associated heparan sulfates 22 that strongly amplify AT activity. 22 In ex vivo assays, inhibition of thrombin by AT is inefficient in the absence of heparin 23 and there is no clearance involved.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, thrombin inactivation in vivo is enhanced by vessel wall-associated heparan sulfates 22 that strongly amplify AT activity. 22 In ex vivo assays, inhibition of thrombin by AT is inefficient in the absence of heparin 23 and there is no clearance involved. In contrast, TAT 24 and PAP 21 complexes are rapidly formed and cleared in vivo within minutes, affecting the availability of the enzymes to act on complement proteins.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

In vivo–generated thrombin and plasmin do not activate the complement system in baboons

Keshari

Silasi‐Mansat

Lupu

et al. 2017

Blood

View full text Add to dashboard Cite

Sepsis concurrently activates both coagulation and complement systems. Although complement activation by bacteria is well documented, work in mice and in vitro suggests that coagulation proteases can directly cleave complement proteins. We aimed to determine whether generation of coagulation proteases in vivo can activate the complement cascade in 2 highly coagulopathic models. We compared temporal changes in activation biomarkers of coagulation (thrombin-antithrombin [TAT]), fibrinolysis (plasmin-antiplasmin [PAP]), and complement (C3b, C5a, C5b-9) in baboons infused with factor Xa (FXa) and phospholipids (FXa/phosphatidylcholine-phosphatidylserine [PCPS]) vs LD100 We found that, albeit with different timing, both FXa/PCPS and infusion led to robust thrombin and plasmin generation. Conversely, only challenge activated the complement system, reaching a maximum at 2 hours postchallenge during the peaks of lipopolysaccharide and bacteremia but not of TAT and PAP. Despite inducing a strong burst of thrombin and plasmin, FXa/PCPS infusion did not produce measurable levels of complement activation in vivo. Similarly, ex vivo incubation of baboon serum with thrombin, plasmin, or FXa did not show noticeable complement cleavage unless supraphysiologic amounts of enzymes were used. Our results suggest that in vivo-generated thrombin and plasmin do not directly activate the complement in nonhuman primates.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

In vivo–generated thrombin and plasmin do not activate the complement system in baboons

Keshari

Silasi‐Mansat

Lupu

et al. 2017

Blood

View full text Add to dashboard Cite

show abstract

“…Furthermore, the magnitude of antithrombin cofactor activity would reflect net antithrombin binding capacity of endothelium equilibrated physiologically with the full complement of plasma heparin binding proteins. We reasoned first that factor Xa, which binds neither to thrombomodulin (Esmon & Owen, 1981) nor (with significant affinity) to heparin (Jordan et al, 1980;Owen & Owen, 1990), might act as a reliable bulkphase reactant. Second, if vascular heparin binds antithrombin with an affinity near that of isolated heparin (Nordenman & Bjork, 1978), a perfused microvascular bed should retain endogenous antithrombin with sufficient affinity (i.e., retention time) to enable its measurement.…”

Section: Discussionmentioning

confidence: 99%

Endogenous antithrombin associated with microvascular endothelium. Quantitative analysis in perfused rat hearts

Felsch¹,

Owen²

1994

Biochemistry

View full text Add to dashboard Cite

A recirculating Langendorff heart preparation is used to characterize the endogenous antithrombin associated reversibly with murine vascular endothelium. Rat hearts are perfused clear of blood and then recirculated with a physiological salt solution. Addition of heparin educes antithrombin activity continuously into the perfusate during 6 min of recirculation. This process contrasts with a more rapid equilibration of the system as assessed by displacement of [125I]thrombin with hirudin or with a heparin-antithrombin mixture. Perfusion of washed hearts with [125I]factor Xa, which evidences no significant binding to the coronary endothelium, identifies a minor fraction of the endogenous antithrombin that reacts immediately with factor Xa, i.e., at a rate indicative of heparin enhancement. This rapid-reacting antithrombin is not reproducibly detected with [125I]thrombin, which binds preferentially to thrombomodulin in this system. The amount of antithrombin reacting rapidly with factor Xa is too low to detect as a burst of antithrombin activity eluted into the perfusate when the hearts are perfused with heparin. It is concluded that the murine myocardial microvasculature harbors at least two pools of antithrombin, the minor of which is in an activated configuration characteristic of association with heparin. The major pool is in a more slowly accessible compartment or configuration.

show abstract

“…The anticoagulant effect of heparins is in part mediated by a unique pentasaccharide sequence binding with high affinity to antithrombin [ 27 ]. This induces a conformational change in its reactive center leading to an up to 1000-fold enhanced inactivation rate of thrombin and activated coagulation factor X (FXa) by antithrombin [ 28 ]. For therapeutic purposes, three forms of heparins are available: (i) UFH, (ii) LMWH and (iii) synthetic ultra (U)LMWH, the latter corresponding to just five to ten saccharide molecules [ 29 ] ( Table 1 and Figure 1 A).…”

Section: Biology Biochemistry and Clinical Applicationmentioning

confidence: 99%

Heparin and Derivatives for Advanced Cell Therapies

Laner-Plamberger

Oeller

Rohde

et al. 2021

IJMS

View full text Add to dashboard Cite

Heparin and its derivatives are saving thousands of human lives annually, by successfully preventing and treating thromboembolic events. Although the mode of action during anticoagulation is well studied, their influence on cell behavior is not fully understood as is the risk of bleeding and other side effects. New applications in regenerative medicine have evolved supporting production of cell-based therapeutics or as a substrate for creating functionalized matrices in biotechnology. The currently resurgent interest in heparins is related to the expected combined anti-inflammatory, anti-thrombotic and anti-viral action against COVID-19. Based on a concise summary of key biochemical and clinical data, this review summarizes the impact for manufacturing and application of cell therapeutics and highlights the need for discriminating the different heparins.

show abstract

The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin.

Cited by 313 publications

References 15 publications

In vivo–generated thrombin and plasmin do not activate the complement system in baboons

In vivo–generated thrombin and plasmin do not activate the complement system in baboons

Endogenous antithrombin associated with microvascular endothelium. Quantitative analysis in perfused rat hearts

Heparin and Derivatives for Advanced Cell Therapies

Contact Info

Product

Resources

About