Role of tissue factor in ischemic reperfusion injury: iv) the effect of tissue factor pathway inhibitor on the survival rate in vivo

L-selectin on leukocyte surfaces mediates cell rolling on endothelium. L-selectin blockade with antibodies attenuated ischemic-reperfusion injury (IRI) in heart and skeletal muscle, but its role in renal IRI is unknown. We evaluated the role of L-selectin in renal IRI using L-selectin-deficient mice. Neutrophil migration to chemically inflamed peritoneum was reduced by 47% (P < 0.01) in L-selectin-deficient mice. Ischemia was induced by bilateral renal pedicle clamping for 30 min. Control and L-selectin groups had similar elevations of serum creatinine (1.8 +/- 0.3 vs. 1.7 +/- 0.2 mg/dl) and blood urea nitrogen (111 +/- 17 vs. 128 +/- 12 mg/dl) 24 h postischemia. Pathological assessment showed comparable degrees of tubular necrosis at 24 h. The postischemic increase in peritubular neutrophils per 10 high-power field was similar in control and L-selectin-deficient groups at 4 (28 +/- 10 vs. 22 +/- 5), 12 (245 +/- 80 vs. 236 +/- 78), and 24 h (130 +/- 12 vs. 156 +/- 18). These data argue against a significant role for L-selectin in renal IRI. Patho-physiological roles of L-selectin in vivo appear to be more complex than in vitro data would suggest.

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Adenovirus-mediated Gene Transfer of Recombinant Tissue Factor Pathway Inhibitor in Vitro and in Vivo

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(97)84333-1 ◽

1998 ◽

Vol 31 (2) ◽

pp. 145A

Author(s):

P Zoldhelyi

Keyword(s):

Gene Transfer ◽

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Tissue Factor Pathway

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Factor Xa Enhances the Binding of Tissue Factor Pathway Inhibitor to Acidic Phospholipids

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650369 ◽

1996 ◽

Vol 75 (05) ◽

pp. 796-800 ◽

Cited By ~ 10

Author(s):

Sanne Valentin ◽

Inger Schousboe

Keyword(s):

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Factor Xa ◽

Microtitre Plate ◽

C Terminus ◽

Microtitre Plate Assay ◽

Kunitz Domain ◽

Tissue Factor Pathway ◽

Acidic Phospholipids

SummaryIn the present study, the interaction between tissue factor pathway inhibitor (TFPI) and phospholipids has been characterized using a microtitre plate assay. TFPI was shown to bind calcium-independently to an acidic phospholipid surface composed of phosphatidylserine, but not a surface composed of the neutral phosphatidylcholine. The interaction was demonstrated to be dependent on the presence of the TFPI C-terminus. The presence of heparin (1 U/ml, unfractionated) was able to significantly reduce the binding of TFPI to phospholipid. The interaction of TFPI with phosphatidylserine was significantly decreased in the presence of calcium, but this was counteracted, and even enhanced, following complex formation of TFPI with factor Xa prior to incubation with the phospholipid surface. Moreover, a TFPI variant, not containing the third Kunitz domain and the C-terminus, was unable to bind to phospholipid. However, following the formation of a TFPI/factor Xa-complex this TFPI variant was capable of interacting with the phospholipid surface. This indicates that the role of factor Xa as a TFPI cofactor, at least in part, is to mediate the binding of TFPI to the phospholipid surface.

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Effect of Depolymerized Holothurian Glycosaminoglycan (DHG) on Tissue Factor Pathway Inhibitor: In Vitro and In Vivo Studies

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657643 ◽

1997 ◽

Vol 78 (02) ◽

pp. 864-870 ◽

Cited By ~ 9

Author(s):

Hideki Nagase ◽

Kei-ichi Enjyoji ◽

Yu-ichi Kamikubo ◽

Keiko T Kitazato ◽

Kenji Kitazato ◽

...

Keyword(s):

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Factor Xa ◽

Free Form ◽

Initial Reaction ◽

Extrinsic Pathway ◽

Factor Xa Inhibition ◽

Tissue Factor Pathway

SummaryDepolymerized holothurian glycosaminoglycan (DHG) is a glycosaminoglycan extracted from the sea cucumber Stichopus japonicusSelenka. In previous studies, we demonstrated that DHG has antithrombotic and anticoagulant activities that are distinguishable from those of heparin and dermatan sulfate. In the present study, we examined the effect of DHG on the tissue factor pathway inhibitor (TFPI), which inhibits the initial reaction of the tissue factor (TF)-mediated coagulation pathway. We first examined the effect of DHG on factor Xa inhibition by TFPI and the inhibition of TF-factor Vila by TFPI-factor Xa in in vitro experiments using human purified proteins. DHG increased the rate of factor Xa inhibition by TFPI, which was abolished either with a synthetic C-terminal peptide or with a synthetic K3 domain peptide of TFPI. In contrast, DHG reduced the rate of TF-factor Vila inhibition by TFPI-factor Xa. Therefore, the effect of DHG on in vitroactivity of TFPI appears to be contradictory. We then examined the effect of DHG on TFPI in cynomolgus monkeys and compared it with that of unfractionated heparin. DHG induced an increase in the circulating level of free-form TFPI in plasma about 20-fold when administered i.v. at 1 mg/kg. The prothrombin time (PT) in monkey plasma after DHG administration was longer than that estimated from the plasma concentrations of DHG. Therefore, free-form TFPI released by DHG seems to play an additive role in the anticoagulant mechanisms of DHG through the extrinsic pathway in vivo. From the results shown in the present work and in previous studies, we conclude that DHG shows anticoagulant activity at various stages of coagulation reactions, i.e., by inhibiting the initial reaction of the extrinsic pathway, by inhibiting the intrinsic Xase, and by inhibiting thrombin.

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