Extrinsic pathway inhibitor (EPI) released to the blood by heparin is a more powerful coagulation inhibitor than is recombinant EPI

Lindahl, Anne Karin; Abildgaard, Ulrich; Kobæk-Larsen, Morten; Staalesen, Rita; Hammer, Anne Kari Gangnæs; Sandset, Per Morten; Nordfang, Ole; Beck, Thomas C.

doi:10.1016/0049-3848(91)90365-4

Cited by 29 publications

(19 citation statements)

References 16 publications

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“…However, relatively high doses of recombinant EPI were necessary to protect against DIC [89]. This may have been due to a weaker potency of recombinant EPI in inhibiting factor VIIa-TP catalytic activity than that of plasma EPI [63]. Recombinant EPI also effi ciently prevented reocclusion of arteries after thrombolysis in a thrombosis model [90],These studies therefore indicate that re combinant EPI has a potential use in the protection and treatment of several medical conditions.…”

Section: In Vivo Evidence For a Role Of Epi As A Natural Anticoagulantmentioning

confidence: 92%

“…How ever, in plasma deficient in factor XII, a shortening is much more evident [62], These observations show that EPI definitely acts as an inhibitor also when coagulation is trig gered via the intrinsic pathway. The addition of recombinant EPI to normal plasma caused prolongation of global clotting times [63]. The significance of this finding will be discussed below.…”

Section: Effect Of Epi On Plasma Coagulationmentioning

confidence: 99%

“…Thus, recombinant EPI is rela tively potent in the intrinsic pathway, where inhibition of factor Xa alone accounts for the anticoagulant effect. In the extrinsic pathway, postheparin plasma EPI is much more effective [63]. The relatively weak anti thrombotic effect observed by recombinant EPI in thrombosis models should therefore not be interpreted to mean that plasma EPI has the same weak activity.…”

Section: The Postheparin Effectmentioning

confidence: 99%

“…The relatively modest anticoagulant ef fect exerted by recombinant EPI contrasts with the strong anticoagulant effect of post heparin plasma [63], A more detailed com parison of postheparin EPI in plasma, and plasma spiked with recombinant EPI sug gested that a main anticoagulant effect of recombinant EPI may be the inhibition of factor Xa. Thus, recombinant EPI is rela tively potent in the intrinsic pathway, where inhibition of factor Xa alone accounts for the anticoagulant effect.…”

Section: The Postheparin Effectmentioning

confidence: 99%

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Extrinsic Pathway Inhibitor – The Key to Feedback Control of Blood Coagulation Initiated by Tissue Thromboplastin

Sandset¹,

Abildgaard²

1991

Pathophysiol Haemos Thromb

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Extrinsic pathway inhibitor (EPI) is a Kunitz type serine protease inhibitor. EPI is a potent inhibitor of the factor VIIa/thromboplastin (TP) complex in the presence of factor Xa and is also a direct inhibitor of factor Xa. The inhibitory mechanism is complex and is currently thought to involve, in a first step, the formation of a EPI-factor Xa complex, and, in a second step, the formation a quaternary EPI-factor Xa-factor VIIa-TP complex. In the blood vessels, EPI is confined to three different pools. A major pool of EPI is bound to the endothelial surface, and this fraction may be released by heparin. Plasma contains a second, but smaller pool of EPI (≈ 10–50% of the endothelial surface pool) at a concentration of 50–100ng/ml. This pool consists mostly of EPI-lipoprotein complexes and only less than 10% is carrier-free EPI. A third pool of EPI is confined to platelets ( < 10% of the plasma pool). The biological role of these pools has not yet been clarified, but some evidence suggest that the carrier-free EPI is biologically most active. In patients, disseminated intravascular coagulation may continue despite normal or even elevated EPI levels. However, evidence has now been provided to indicate that EPI can inhibit factor VIIa/TP complexes formed in vivo to prevent the effect of limited amounts of TP. Taken together, the present knowledge of EPI indicates that EPI functions as a key inhibitor to feedback control of blood coagulation initiated by TP.

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Section: In Vivo Evidence For a Role Of Epi As A Natural Anticoagulantmentioning

confidence: 92%

Section: Effect Of Epi On Plasma Coagulationmentioning

confidence: 99%

Section: The Postheparin Effectmentioning

confidence: 99%

Section: The Postheparin Effectmentioning

confidence: 99%

See 2 more Smart Citations

Extrinsic Pathway Inhibitor – The Key to Feedback Control of Blood Coagulation Initiated by Tissue Thromboplastin

Sandset¹,

Abildgaard²

1991

Pathophysiol Haemos Thromb

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“…Tris(hydroxymethyl)aminomethane-HCl and ethylenediaminetetraacetic acid (EDTA) were purchased from Sigma-Aldrich Chemie GmbH (Steinheim, Germany). The chromogenic peptides used for FXa and FIIa determination were Suc-Ile-Gly ( ␥ Pip) Gly-Arg-pNa.HCl [Biophen CS-11 (32)] and H-D -Phe-PipArg-pNA ؒ 2HCl (pNAPEP 0238), respectively, both obtained through CoaChrom Diagnostics. Concentrations of pro-and anticoagulant proteins in PPP were determined on a BM/Hitachi 917 from Boehringer Mannheim (Vienna, Austria).…”

Section: Reagents and Devicesmentioning

confidence: 99%

Effects of Nadroparin, Enoxaparin, and Unfractionated Heparin on Endogenous Formation of Factor Xa and IIa and on Thrombelastometry Profiles in Cord versus Adult Blood

Cvirn¹,

Hörl²,

Tafeit³

et al. 2010

Neonatology

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Background: To date, only few pharmacokinetic studies on low-molecular-weight heparins (LMWHs) in neonates exist not allowing to formally assess pharmacodynamics of LMWHs in neonates. Objective: To evaluate the anticoagulant effects of the two LMWHs nadroparin and enoxaparin on endogenous formation of FXa or FIIa in cord versus adult platelet-poor plasma (PPP) and on thrombelastometry profiles in cord versus adult whole blood (WB). Unfractionated heparin (UH) was the reference antithrombotic drug. Methods: The effects of nadroparin, enoxaparin, or UH on endogenous formation of FXa or FIIa was investigated in tissue factor-activated PPP using a subsampling technique and chromogenic substrates. The anticoagulant efficacy of these drugs was also investigated in WB triggered by the physiological relevant activator collagen/endogenous thrombin using thrombelastometry. Results: The major findings are (i) nadroparin is as efficient as enoxaparin concerning inhibition of the endogenous formation of FXa and FIIa, (ii) cord PPP and WB are significantly more susceptible to the addition of LMWHs or UH than adult PPP or WB, and (iii) compared by equivalent anti-FXa activity, the anticoagulant action of UH is markedly higher than that of the LMWHs in PPP and WB of neonatal or adult origin. Conclusions: Administration of LMWHs in neonates has to be performed carefully to avoid bleeding side effects due to their high anticoagulant efficacy in cord PPP and WB.

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Antithrombotic activity of heparin and its derivatives: reliable and other putative mechanisms

Sarret¹

1994

Anticoagulation

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Extrinsic pathway inhibitor (EPI) released to the blood by heparin is a more powerful coagulation inhibitor than is recombinant EPI

Cited by 29 publications

References 16 publications

Extrinsic Pathway Inhibitor – The Key to Feedback Control of Blood Coagulation Initiated by Tissue Thromboplastin

Extrinsic Pathway Inhibitor – The Key to Feedback Control of Blood Coagulation Initiated by Tissue Thromboplastin

Effects of Nadroparin, Enoxaparin, and Unfractionated Heparin on Endogenous Formation of Factor Xa and IIa and on Thrombelastometry Profiles in Cord versus Adult Blood

Antithrombotic activity of heparin and its derivatives: reliable and other putative mechanisms

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