Effectiveness of recombinant desulphatohirudin in reducing restenosis after balloon angioplasty of atherosclerotic femoral arteries in rabbits.

Abstract

Rabbits receiving r-hirudin at the time of experimental balloon angioplasty had significantly less restenosis by angiography and by quantitative histopathology than rabbits receiving heparin.

Retroviral vector-mediated expression of hirudin by human vascular endothelial cells: implications for the design of retroviral vectors expressing biologically active proteins

“…Direct thrombin inhibition inhibits thrombosis and decreases vascular lesion formation in animal models. [8][9][10]28 Thrombin inhibition potentiates thrombolysis and improves vessel patency in humans. 29,30 To develop further the therapeutic potential of direct thrombin inhibition, we have sought to generate viral vectors that can overexpress hirudin from vascular cells.…”

“…Although differences in the promoters used in these two vector systems preclude firm conclusions, the superior performance of the adenoviral vector is likely due to the ability of this vector to transfer multiple transgene copies to target cells, 46 whereas our current protocols for retroviral gene transfer achieve delivery of only approximately one transgene copy per cell. 47 This limitation of retroviral gene transfer might be overcome by use of newer generation retroviral vectors, which can be concentrated to higher titers and can effect delivery of multiple transgene copies per cell (up to [10][11][12][13][14][15][16][17][18][19][20] even in the absence of antibiotic selection, (Ref. 48, and Dr D Ory, personal communication).…”

“…Recent studies, perfor- med in several animal model systems, have demonstrated that systemically administered hirudin can prevent thrombosis and neointimal proliferation after arterial injury. [7][8][9][10] Systemically administered hirudin has also been used in humans as an adjunct to thrombolytic therapy and coronary angioplasty. Although some shortterm benefits of hirudin infusion have been reported, systemic hirudin administration has failed to prevent restenosis and has been associated in some settings with unacceptable bleeding complications.…”

Characterization of a functional thrombin receptor. Issues and opportunities.

“…In particular, whether thrombin plays a significant role in inflammatory or proliferative responses to vascular injury remains to be tested. A recent study using recombinant hirudin does suggest a role for thrombin in mediating restenosis after angioplasty in one animal model (21). It is hoped that the characterization of the platelet thrombin receptor will permit the development of thrombin receptor blockers to directly address the importance of thrombin-induced cell activation in vivo.…”

Local gene transfer of tissue factor pathway inhibitor regulates intimal hyperplasia in atherosclerotic arteries

“…In healthy vessels, TF is present in the adventitia and in the deep tunica media (9,10) but increases in the vascular intima and media after arterial injury (11) and in atherosclerotic states, where TF accumulates especially in lipid-laden plaques (10,12,13). In animal models of vascular injury, systemic administration of the inhibitor of TF (TF pathway inhibitor, or TFPI) (14)(15)(16), or of inhibitors of factor Xa (17) or thrombin (18), has suggested a role for the TF pathway of blood coagulation and thrombosis in the pathogenesis of postinjury intimal hyperplasia. However, these studies have not distinguished between the local influence of TF inhibition in the injured vessel wall and the systemic anticoagulant effects achieved with i.v.…”