Neointimal Thickening After Severe Coronary Artery Injury Is Limited by Short-term Administration of a Factor Xa Inhibitor

Schwartz, Robert S.; Holder, Daniel; Holmes, David R.; Veinot, John P.; Camrud, Allan R.; Jorgenson, Michael A.; Johnson, Robert G.

doi:10.1161/01.cir.93.8.1542

Cited by 66 publications

(31 citation statements)

References 38 publications

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“…This may account for our previous observation of attenuated neointimal thickening and luminal stenosis in minipigs subjected to similar carotid injury procedures and rTFPI infusions. 15 It is also consistent with data from other experimental studies showing inhibition of neointimal thickening after either direct inhibition of thrombin 6 -8,28 or its generation from tissue factor/factor VIIa 15,29 or Xa 30,31 and with clinical evidence of reduced restenosis in patients treated with antibodies to platelet glycoprotein IIb/IIIa receptors after angioplasty, 32 which appears to inhibit thrombin generation both by decreasing the number of platelets in thrombi that support assembly of prothrombinase and by interfering with platelet activation. 33 Despite variability in the accumulation of radiolabeled platelets and fibrin(ogen) among control animals, it is apparent that both rTFPI and heparin reduced the net accumulation of thrombus over time (Figures 2 and 3).…”

Section: Discussionsupporting

confidence: 89%

Tissue Factor Pathway Inhibitor Attenuates Procoagulant Activity and Upregulation of Tissue Factor at the Site of Balloon-Induced Arterial Injury in Pigs

Pierre¹,

Yang²,

Tamirisa³

et al. 1999

ATVB

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Abstract-Intravenous infusion of recombinant tissue factor pathway inhibitor (rTFPI) for 24 hours decreases neointimal thickening and luminal stenosis 1 month after balloon-induced injury to the carotid arteries in minipigs. This study was designed to determine whether the effect of rTFPI is accounted for by early decreases in procoagulant activity and thrombosis on the injured vessel wall. Vascular injury was induced by balloon hyperinflations in both carotid arteries of anesthetized pigs given no anticoagulant as a control (nϭ16), an intravenous infusion for 24 hours of rTFPI (0.5 mg/kg bolus and 25 g ⅐ kg Ϫ1 ⅐ min Ϫ1 , nϭ14), or an intravenous infusion of unfractionated heparin (100 U ⅐ kg Ϫ1 ⅐ h Ϫ1 , nϭ19). Accumulation of radiolabeled autologous platelets was markedly decreased over 24 hours on injured arteries from animals given rTFPI (0.6ϫ10 6 /cm 2 ) compared with controls (2.5ϫ10 6 /cm 2 , Pϭ0.0004). Deposition of radiolabeled fibrin was also decreased in rTFPI-treated animals (269Ϯ266 g/cm 2 ) compared with controls (2389Ϯ1673 g/cm 2 , Pϭ0.04). Similar effects were observed with heparin. However, factor Xa activity, assayed after 24 hours by incubation of the injured arterial segments with the chromogenic substrate S-2222, was decreased more markedly on arteries from rTFPI-treated animals (0.14Ϯ0.13 OD) than those from heparin-treated animals (0.29Ϯ0.18 OD) compared with controls (0.47Ϯ0.24 OD, Pϭ0.0007). In addition, arteries from rTFPI-treated animals showed a 4-fold lower induction of tissue factor protein compared with controls (Pϭ0.0002). Attenuation of procoagulant activity and tissue factor-mediated thrombin generation in response to injury may account for the promising results with rTFPI in the porcine angioplasty model.

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Section: Discussionsupporting

confidence: 89%

Tissue Factor Pathway Inhibitor Attenuates Procoagulant Activity and Upregulation of Tissue Factor at the Site of Balloon-Induced Arterial Injury in Pigs

Pierre¹,

Yang²,

Tamirisa³

et al. 1999

ATVB

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“…40 However, because direct thrombin inhibition induces only transient attenuation of bound-thrombin activity, 19 inhibition of the tissue factor pathway or the Xa/Va complex may be a more effective strategy for inhibiting neointimal hyperplasia after arterial injury. [41][42][43][44] Our findings are consistent with clinical observations of persistent prothrombin activation in patients with thrombotic complications of coronary artery disease that is not inhibited by heparin or direct thrombin inhibitors. 38,[45][46][47] The persistence of Xa/Va activity after arterial injury also likely contributes to the increases in thrombin activity that occur after discontinuation of thrombin inhibitors or heparin.…”

Section: Significance Of Procoagulant Activity Bound To the Arterial supporting

confidence: 88%

Prolonged Activation of Prothrombin on the Vascular Wall After Arterial Injury

Ghigliotti

Waissbluth

Speidel

et al. 1998

ATVB

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Abstract-This study was designed to characterize the relative roles of bound Xa/Va and thrombin activity in vascular wall procoagulant activity after balloon-induced injury and the extent to which intravenous aspirin and heparin attenuate procoagulant activity associated with the vascular wall. Abdominal aortic injury was induced in rabbits by overinflation and multiple passages of a 4F embolectomy catheter. Rabbits were killed 15 minutes or 4,8,24,48, 72, 96, or 120 hours after injury. Aortic segments were incubated ex vivo to define bound procoagulant activity. Thrombin activity bound to the aorta was detected by 4 hours after injury and was most marked over the first 24 hours, as estimated by increases in concentration of fibrinopeptide A during incubation of segments with recalcified barium-adsorbed plasma or activity against the thrombinsynthetic substrate S-2238. Based on comparison with purified human thrombin incubated under the same conditions, a maximum of 0.04 to 0.1 nmol/L per square centimeter of thrombin activity was associated with the vascular wall during the first 24 hours and remained detectable for 72 hours. In contrast, bound Xa/Va complex activity to injured segments was detected within 15 minutes and induced activation of prothrombin added to recalcified barium-adsorbed plasma incubated with injured segments for 96 hours. Aspirin (15 mg/kg) administered 30 minutes before injury attenuated 111In-platelet deposition at 4 hours by 67%, with an associated decrease in bound Xa/Va and thrombin activity at 15 minutes and 4 hours. However, intravenous heparin did not attenuate bound Xa/Va activity at 15 minutes or thrombin activity at 15 minutes and 4 hours. Platelet-dependent bound Xa/Va activity occurs rapidly after arterial injury and may promote thrombin elaboration for up to 96 hours. Bound thrombin activity and de novo thrombin elaboration on the vascular wall may play an important role in the progression of thrombosis and vascular wall remodeling. (Arterioscler Thromb Vasc Biol. 1998;18:250-257.)

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“…The authors found a trend toward reduced cross-sectional narrowing. The effectiveness of a prolonged inhibition of antithrombotic activity was initially suggested by Schwartz et al 31 in the pig model after metallic stent implantation. The authors demonstrated a decrease in neointimal thickening in coronary arteries after administration of TAP for 5 days.…”

Section: Discussionmentioning

confidence: 95%

Prolonged Thrombin Inhibition Reduces Restenosis After Balloon Angioplasty in Porcine Coronary Arteries

et al. 1998

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Background-Arterial injury after percutaneous transluminal coronary angioplasty (PTCA) triggers acute thrombus formation and thrombin generation. Hirudin, a potent and direct thrombin inhibitor, prevents thrombus formation after arterial injury. Two large clinical trials showed marked reduction in acute clinical events but no long-term benefits in reducing restenosis during short-term administration of thrombin inhibitors. Our hypothesis is that adequate, maintained thrombin inhibition, by inhibiting all the thrombin-dependent mechanisms, will reduce neointima formation after PTCA. Methods and Results-Thirty-six pigs received three different regimens of hirudin: bolus (1 mg/kg), short-term (bolusϩ0.7 mg/kg per day for 2 days), and long-term (bolusϩ0.7 mg/kg per day for 14 days). The results on neointima formation at 4 weeks after coronary angioplasty were compared with the control group (100 IU heparin/kg bolus). Hirudin was continuously administered for 2 weeks through an infusion pump. In vivo thrombin generation was persistently increased up to 2 weeks after angioplasty. Inhibition of thrombin activity for 14 days reduced luminal narrowing by 40% (58Ϯ3% versus 35Ϯ3%; PϽ.001). No differences were observed among the bolus and short-term hirudin groups and the control group. Conclusions-Our results indicate that there is a continued, marked thrombin generation that lasts for at least 2 weeks after PTCA. Administration of r-hirudin for 2 weeks significantly reduces neointima formation after PTCA. This observation, if extrapolated to humans, could explain the lack of effect on restenosis observed in the clinical trials with antithrombin agents despite the clear benefits on reducing acute thrombotic complications after PTCA. Therefore an adequate and prolonged administration of thrombin inhibitors is needed to "passivate" the thrombogenic substrate (disrupted arterial wall) and achieve full benefit of this therapeutic approach. (Circulation. 1998;97:581-588.)

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Neointimal Thickening After Severe Coronary Artery Injury Is Limited by Short-term Administration of a Factor Xa Inhibitor

Cited by 66 publications

References 38 publications

Tissue Factor Pathway Inhibitor Attenuates Procoagulant Activity and Upregulation of Tissue Factor at the Site of Balloon-Induced Arterial Injury in Pigs

Tissue Factor Pathway Inhibitor Attenuates Procoagulant Activity and Upregulation of Tissue Factor at the Site of Balloon-Induced Arterial Injury in Pigs

Prolonged Activation of Prothrombin on the Vascular Wall After Arterial Injury

Prolonged Thrombin Inhibition Reduces Restenosis After Balloon Angioplasty in Porcine Coronary Arteries

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