Vascular procedures that thermo-coagulate collagen reduce local platelet deposition and thrombus formation: laser and laser-thermal versus balloon angioplasty.

BACKGROUND AND OBJECTIVE: Exposure of the arterial wall matrix to blood leads to platelet deposition resulting in thrombosis. Because heat alters tissue matrix we proposed that heating reduces platelet deposition. STUDY DESIGN/MATERIALS AND METHODS: Sixty arterial homografts (15 dogs) were mounted in an arterio-venous "shunt." Interventions included balloon angioplasty (BA), direct laser (LA), laser-thermal (LTA), and combined LTABA. 111Indium-labeled platelets were circulated, radio activity measured, and homografts processed for histology. RESULTS: Radioactivity count (mean+/- SE) at BA sites (13,853+/-3,192 cpm/cm(2)) was greater than LA (7,038+/-981), LTA (5,294 +/-1,145), LTABA (6,176+/-1,571), and control (1,826+/-339), P<0.05. Electron microscopy showed fewer platelets at LA, LTA, and control than BA sites. BA spread the collagen on the arterial lumen while heat gelled collagen and confined it to the arterial media. CONCLUSIONS: Heating the artery and gelling collagen during LA, LTA, or LTABA significantly reduced thrombogenicity.

Local antithrombotic therapy using a novel porous balloon catheter.

The efficacy of local treatment of thrombosis with low-dose antithrombotic drugs (heparin: 30 U/kg, or argatroban: 0.02 mg/kg) was investigated using a novel porous balloon catheter. This novel balloon catheter can deliver drug into arterial walls without causing vascular trauma. Thrombus formation was significantly inhibited in balloon-injured and locally-treated iliac arteries compared with control balloon-injured arteries in 12 dogs. In the systemic high-dose delivery group (ten times as high as the low dose), thrombus formation in injured arteries was significantly less than that of controls in 7 dogs. Low-dose systemic delivery was not effective at inhibiting this thrombus formation. Thus, local treatment with an antithrombotic drug using this novel porous balloon catheter can prevent thrombosis without influencing systemic coagulability.

Local delivery of antithrombotic drug prevents restenosis after balloon angioplasty in atherosclerotic rabbit artery.

We investigated the ability of various antithrombotic drugs, delivered locally, to prevent restenosis after angioplasty in hypercholesterolemic rabbits. After dilating atherosclerotic iliac stenoses by balloon angioplasty, a low dose of heparin or a new antithrombotic drug, such as low molecular weight heparin (fragmin), argatroban, or batroxobin, was delivered locally using the balloon double-occlusion technique. In 1 group, high-dose heparin was administered intravenously. Animals that received no drugs served as a control group. After angioplasty, the stenotic segment was dilated and the mean percentage luminal stenosis fell from 89% to 9% in the group that received locally delivered heparin, from 88% to 7% in the group that received locally delivered argatroban, from 87% to 11% in the group that received locally delivered fragmin, from 88% to 15% in the group that received locally delivered batroxobin, from 82% to 18% in the group that received i.v. heparin (p < 0.0001 compared with before angioplasty in each case), and from 84% to 17% in the control group (p < 0.005 compared with before angioplasty). Twenty-eight days after angioplasty, the percentage luminal stenosis remained at 14% in the group that received locally delivered argatroban, 15% in the group that received locally delivered fragmin, and 28% in the group that received locally delivered batroxobin, whereas it increased to 45% in the group that received i.v. heparin, 30% in the group that received locally delivered heparin and 72% in the control group (p < 0.05 compared with after angioplasty in each case). Thus, local delivery low doses of new antithrombotic drugs prevents restenosis after angioplasty without affecting systemic coagulability; heparin, whether administered locally or intravenously, was less effective than the new drugs in preventing restenosis.

Induction of thrombolysis and prevention of thrombus formation by local drug delivery with a double-occlusion balloon catheter.

The efficacy of the local delivery of an antithrombotic drug in preventing thrombosis and enabling thrombolysis was investigated in 29 dogs. An antithrombotic drug (heparin, 25 U/kg), or an antithrombin (argatroban, 0.05 mg/kg) was infused into injured canine iliac arteries, using a double-occlusion balloon catheter, and the preventive effect of the drug was evaluated. Local delivery of low-dose tissue-type plasminogen activator (t-PA; Tisokinase, 50,000 U; Kowa, Nagoya and Asahi Chemical Industries, Fuji, Japan) into thrombosed canine iliac arteries, using the same catheter, or intravenous infusion of low-dose or high-dose t-PA (30,000 U/kg) was also performed. Angiographically, stenotic thrombosis was 2% by local delivery of argatroban and 7% by local delivery of heparin (P < 0.01 vs each control; 47% and 51% respectively). Thrombotic stenosis, as observed by angiography, decreased from 91% to 9% after local delivery of t-PA, and from 94% to 52% in controls. Local delivery of t-PA effectively reduced the thrombus size (P < 0.01 vs control). After systemic intravenous delivery of low-dose t-PA, no reduction of residual thrombotic stenosis, was observed. Reduction of residual thrombotic stenosis after intravenous delivery of high-dose t-PA, was similar to that achieved by local delivery of the drug. Angioscopy demonstrated a similar trend. High-dose drug delivery reduced systemic coagulability. Local delivery of an antithrombotic drug, using a double-occlusion balloon catheter, effectively prevented thrombus formation, and local delivery of t-PA induced thrombolysis without exerting a significant influence on coagulability.

Local treatment with an antithrombotic drug reduces thrombus size in coronary and peripheral thrombosed arteries.

Since the treatment of thrombotic disease by antithrombotic drugs may be associated with bleeding complications, a local delivery technique for administration of the drug may be useful. The efficacy of low-dose local delivery of an antithrombotic drug on thrombosis was investigated in 73 dogs. The antithrombotic drug (heparin, 25 U/kg, antithrombin: argatroban, 0.05 mg/kg, or defibrinogenating agent: batroxobin, 0.05 U/kg) was infused locally to a 1-h-old thrombus, and no drug was given in controls. The effect of the local delivery on the thrombus was evaluated. Low- and high-dose systemic drug delivery was also evaluated. The mean reduction in thrombotic coronary stenosis observed by angiography was 30.3% with argatroban, 22% with heparin, and 20.8% with batroxobin (P < 0.005 vs controls). Systemic delivery of low-dose heparin or argatroban did not induce any change in thrombus size. With high-dose systemic drug delivery (heparin 250 U/kg, argatroban 0.5 mg/kg), the mean reduction of thrombotic stenosis was 15.2% with heparin and 32.8% with argatroban (P < 0.005 vs controls). In the iliac arterial thrombosis, after local delivery of the drugs, the mean reduction of thrombotic stenosis observed by angiography was 24.4% in the argatroban group, and 19.2% in the heparin group (P < 0.05 vs controls, respectively). With high-dose systemic heparin delivery, the mean reduction of the thrombotic stenosis was 13.2% (P < 0.01 vs control). Angioscopy also demonstrated a similar trend. The high-dose drug delivery reduced systemic coagulability. Thus, local delivery of an antithrombotic agent can reduce the thrombus size in the coronary and iliac arteries without having any significant influence on coagulability.

Loss of vasoreactivity by laser thermal energy or argon laser irradiation.

Vasoreactivity of laser-treated vessels was investigated in two different experimental conditions. The canine left circumflex coronary artery (LCx) was lased under perfusion with Krebs-bicarbonate buffer by means of a thermal laser (hot-tip probe, HT) at 7 W for 6 seconds and an argon laser beam through a 300 microns optical fiber at 3 W (tip power) for 1 second at 12 spots. A nontreated segment of the LCx served as a control. Two 3-mm long segments were obtained from the treated segment: one to measure the results of potassium (K) induced contraction, and another 3, 4 diaminopyridine (DAP; K channel inhibitor) induced contraction. In 11 instances, coronary angiography of the perfused artery showed less than 50% stenosis after laser treatment. The segments were then mounted isometrically with 1 g tension in Krebs-bicarbonate buffer. Contraction was induced either with 30 mM KCI or 10(-2) M DAP and expressed as developed tension (gram; g). KCI induced vasocontraction of 4.15 +/- 0.93 g in the control, 0.33 +/- 0.71 g in laser irradiated segments (P < 0.0001 vs control), and 0.02 +/- 0.06 g in thermally-treated segments (P < 0.0001 vs control). DAP induced vasocontraction of 5.21 +/- 1.32 g in the control, 0.39 +/- 0.83 g in laser irradiated segments (P < 0.0001 vs control), and 0.07 +/- 0.13 g in thermally treated segments (P < 0.001 vs control). In 4 instances, more than 50% stenosis remained and additional balloon dilatation reduced the stenosis to less than 50%. The lesions also showed reduced vasoreactivity. In vivo thermal angioplasty resulted in reduced vasoreactivity compared to control in 4 anesthetized dogs. Thus, laser and thermal angioplasty reduced vasoreactivity induced by either KCI or 3, 4 DAP. Neither acetylcholine at 10(-6) M nor papaverine at 10(-4) M was able to induce relaxation of treated segments. In conclusion, 1) the lased coronary artery loses its vasoreactivity to either a constrictive or relaxing agent, 2) although stenosis may be produced by laser energy, additional balloon dilatation can reduce residual stenosis, and 3) laser thermal or argon laser angioplasty may prevent severe coronary spasm.