Altered Plasma Antigen Levels of Tissue Factor Pathway Inhibitor During Open-Heart Surgery

Sun, Ling; Utoh, Junichi; Kunitomo, Ryuji; Tsurusaki, Shigeyuki; Tagami, Hirofumi; Hirata, Tomomi; Moriyama, Shuji; Kitamura, Nobuo

doi:10.1007/s005950050027

Cited by 13 publications

(7 citation statements)

References 30 publications

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“…The original knowledge that the released TFPI is not associated with lipoproteins was obtained by experiments with UFH. 5,13,25,26 As recently reported by Sun et al, 27 the changes in the total plasma TFPI antigen level depended significantly on the level of free TFPI antigen after administration of UFH (r = 0.96, P <0.0001). In contrast to this, in a comparison of the release of total and free TFPI by the LMWH bemiparin, 28 the %-free TFPI ranged between 43.1 and 70.3% in dependence on the applied bemiparin dose.…”

Section: Figuresupporting

confidence: 59%

Molecular Weight-Dependent Influence of Heparin on the Form of Tissue Factor Pathway Inhibitor Circulating in Plasma

Alban

2001

Semin Thromb Hemost

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The increase of circulating tissue factor pathway inhibitor (TFPI) in plasma by heparins is thought to contribute to their overall antithrombotic activity. In a clinical study in healthy volunteers, we recently found that the specific potency of a heparin to mobilize TFPI from the vessel wall increases with its molecular weight (MW). The released TFPI originally is not associated with lipoproteins, but it is not known whether it remains free circulating in plasma. A further question is whether the MW of heparin influences not only the release of TFPI but also its potential association with lipoproteins. In the present study, the release of free TFPI was compared with the release of total TFPI after application of four heparins with different MWs. Only the TFPI released by unfractionated heparin (UFH) circulated completely as free TFPI. With decreasing heparin MW, the percentage of released free TFPI on released total TFPI decreased to 57%. As a consequence, the longer the heparin chains are, the better they are at preventing the binding of the released, originally free, TFPI to plasma lipoproteins. Because only free TFPI is known to exhibit anticoagulant activity, the activity of released TFPI is better the higher the MW of the applied heparin is. In conclusion, in addition to the potency of heparin to mobilize TFPI, there is its influence on the circulating form, and thus the anticoagulant activity of the released TFPI depends on its MW.

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Section: Figuresupporting

confidence: 59%

Molecular Weight-Dependent Influence of Heparin on the Form of Tissue Factor Pathway Inhibitor Circulating in Plasma

Alban

2001

Semin Thromb Hemost

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“…The presence of the 38 kDa fragment is probably not a result of heparin and protamine alone, as previous authors have observed that protamine rapidly and completely reverses the effect of unfractionated heparin on plasma TFPI activity [13]. Our findings are consistent with the findings of Sun et al [30], who demonstrated a persistent elevation of free TFPI following CPB, and suggest that TFPI undergoes proteolytic degradation during CPB. Plasma TFPI may play an important role in heparinmediated suppression of coagulation activity during CPB.…”

Section: Discussionsupporting

confidence: 92%

Disposition of tissue factor pathway inhibitor during cardiopulmonary bypass

Donahue

Gailani

Mast

2006

Journal of Thrombosis and Haemostasis

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Summary. Background: The tissue factor (TF) factor (F) VIIa complex activates coagulation FIX and FX to initiate coagulation, and also cleaves protease activated receptors (PARs) to initiate inflammatory processes in vascular cells. Tissue factor pathway inhibitor (TFPI) is the only specific inhibitor of the TF-FVIIa complex, regulating both its procoagulant and pro-inflammatory properties. Upon heparin infusion during cardiopulmonary bypass (CPB), a heparin releasable pool of endothelial associated TFPI circulates in plasma. Following protamine neutralization of heparin, the plasma TFPI level decreases, but does not return completely to baseline, suggesting that during CPB a fraction of the plasma TFPI becomes heparin-independent. We have investigated the structural and functional properties of plasma TFPI during CPB to further characterize how TFPI is altered during this procedure. Methods: We enrolled 17 patients undergoing firsttime cardiac surgery involving CPB. Plasma samples were obtained at baseline, 5 min and 1 h after start of CPB (receiving heparin), 10 min after protamine administration (off CPB) and 24 h following surgery. Samples were analyzed for full-length and free (non-lipoprotein bound) TFPI antigen by enzymelinked immunosorbent assay (ELISA) and for TFPI anticoagulant activity using an amidolytic assay. Western blot analysis was used to identify TFPI species of varying molecular weights in three additional patients. Dunnett's test for post hoc comparisons was used for statistical analysis. Results: The ELISA and Western blot data indicated that an increase in fulllength TFPI accounted for most of the heparin releasable TFPI. Following heparin neutralization with protamine, the fulllength TFPI antigen returned to baseline levels while the free TFPI antigen and the total plasma TFPI activity remained elevated. This was associated with the appearance of a new 38 kDa form of plasma TFPI identified by Western blot analysis. The 38 kDa form of TFPI did not react with an antibody directed against the C-terminal region of TFPI indicating it has undergone proteolysis within this region. All TFPI measurements returned to baseline 24 h following CPB. Conclusions: During CPB the full-length form of TFPI is the predominant form in plasma because of its prompt release from the endothelial surface following heparin administration. Upon heparin neutralization with protamine, full-length TFPI redistributes back to the endothelial surface. However, a new 38 kDa TFPI fragment is generated during CPB and remains circulating in plasma, indicating that TFPI undergoes proteolytic degradation during CPB. This degradation may result in a decrease in endothelium-associated TFPI immediately post-CPB, and may contribute to the procoagulant and proinflammatory state that often complicates CPB.

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“…Preheparinization of the donor efficaciously increased total plasma TFPI levels by a factor of 8.0 when compared to the nonheparinized blood. It has been documented that total plasma TFPI levels strongly correlate with the levels of free plasma TFPI during CPB . This heparin‐induced TFPI elevation completely counterbalanced the production of both TAT and F 1+2 boosted by rTF.…”

Section: Discussionmentioning

confidence: 92%

“…TFPI directly inhibits TF/VIIa complex and activated factor X (Xa). Previous studies have demonstrated that heparin administration causes endothelial release of TFPI, which increases serum concentrations by twofold to tenfold within minutes . It has been postulated that heparin suppresses the TF‐dependent coagulation pathway during CPB by releasing TFPI.…”

mentioning

confidence: 99%

Early Heparin Administration Attenuates Tissue Factor-Mediated Thrombin Generation During Simulated Cardiopulmonary Bypass

et al. 2013

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Altered Plasma Antigen Levels of Tissue Factor Pathway Inhibitor During Open-Heart Surgery

Cited by 13 publications

References 30 publications

Molecular Weight-Dependent Influence of Heparin on the Form of Tissue Factor Pathway Inhibitor Circulating in Plasma

Molecular Weight-Dependent Influence of Heparin on the Form of Tissue Factor Pathway Inhibitor Circulating in Plasma

Disposition of tissue factor pathway inhibitor during cardiopulmonary bypass

Early Heparin Administration Attenuates Tissue Factor-Mediated Thrombin Generation During Simulated Cardiopulmonary Bypass

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