Direct platelet effect of low molecular weight dextran in small calibre PTFE grafts.

The thrombogenicity of synthetic vascular grafts is a major factor in occlusion of grafts when they are used to bypass small calibre arteries. In this paper, the effect of low molecular weight dextran (LMWD, Dextran-40) on graft surface-platelet interaction was studied using Indium-III-oxine labelled platelets. It was found that LMWD significantly reduced platelet deposition onto graft surfaces (P less than 0.001). Dextran had a direct antiplatelet effect independent of plasma volume expansion as dextran-soaked grafts significantly reduced platelet deposition when compared to systemic dextran administration (P less than 0.001). We therefore conclude that LMWD has a direct antiplatelet effect which is beneficial in reducing platelet deposition on synthetic PTFE grafts which may improve the early patency of such grafts.     

Effect of defibrinogenation on the early patency rate of experimental small calibre arterial grafts

The effect of defibrinogenation with Arvin was studied in a new animal model of early thrombosis of a 3 mm diameter polytetrafluoroethylene (PTFE) graft with a poor run-off. Fifteen control animals were compared with fourteen animals treated with subcutaneous Arvin 20 units kg-1 body weight day-1, starting 2 days before surgery and continuing for 2 days postoperatively. The peroperative fibrinogen level in the controls was 2.8 +/- 0.9 gl-1 compared with 0.4 +/- 0.3 gl-1 in the treated group. There was no significant difference in the peroperative or postoperative platelet count or haematocrit value between the two groups. Plasma viscosity and whole blood viscosity (at a low shear rate of 0.7s-1) were significantly less during and after surgery in the defibrinogenated group. The degree of defibrinogenation in these animals produced no problems with haemostasis during surgery or in the postoperative period. The cumulative patency rates of the controls at 24 h, 48 h, and 4 days were 43 per cent, 28 per cent and 28 per cent compared with 86 per cent (P less than 0.05), 73 per cent (P less than 0.05) and 73 per cent (P less than 0.05) respectively in the defibrinogenated group. In this model of a narrow PTFE graft with a poor run-off, defibrinogenation was a safe and effective method of improving early patency of small calibre arterial grafts.     

Forskolin inhibits platelet deposition in small diameter polytetrafluoroethylene grafts

Synthetic vascular grafts have a thrombogenic surface which probably is an important factor in graft failure. Systemic pharmacologic intervention has been used but is associated with side effects. In this communication we describe the results of a new therapeutic principle of applying forskolin, a powerful cyclic adenosine monophosphate stimulator (cAMP), to the inner surface of a synthetic graft material, polytetrafluoroethylene. Evaluation was done with Indium-111-oxine labelled platelets and histopathology. It was found that forskolin significantly lowers the platelet deposition onto the treated graft surface compared to controls.     

The effect of preformed confluent endothelial cell monolayers on the patency and thrombogenicity of small calibre vascular grafts

Endothelial cell seeding has been proposed as a method to improve the patency rates in small calibre prosthetic vascular grafts. The seeding methods used at present leave much of the graft luminal surface devoid of endothelial cells and thus still significantly thrombogenic. We have developed a method to preform confluent endothelial cell monolayers, on the grafts prior to implantation, and this study investigates the effect of these monolayers on the early thrombogenicity and patency of polytetrafluoroethylene (PTFE) grafts. Small diameter PTFE grafts were seeded with canine endothelial cells obtained from the external jugular vein. Each of five dogs then received a graft seeded with its own cells and a contralateral, non-seeded control graft. At 1 and 10 weeks after graft implantation graft thrombogenicity was assessed by the use of Indium labelled platelets. The thrombogenicity index (TI) of each graft was determined from counts of gamma activity recorded over a period of 7 days. Grafts were subsequently removed at 12 weeks. At 1 week the mean TI for the seeded grafts was 0.123 (SD 0.019) and that for the controls 0.183 (SD 0.017) (p = 0.005). At 10 weeks only the seeded grafts could be assessed because all of the control grafts had occluded. At this point in time the seeded grafts had a mean TI of 0.159 (SD 0.011) (p = 0.047 vs. seeded at 1 week). By the time of removal at 12 weeks, all control grafts were occluded but only one of the seeded grafts had occluded (p = 0.025). In conclusion, the use of preformed, confluent endothelial cell monolayers for seeding prosthetic grafts significantly reduces the early graft thrombogenicity and improves graft patency. It does not, however, completely halt the increase in thrombogenicity which occurs during the early post-implantation period.     

Does dextran 40 reduce early graft thrombogenicity? An experimental investigation on patency and platelet deposition on prosthetic graft materials in sheep.

The mechanism by which dextran 40 reduces early graft thrombogenicity has not been fully elucidated. Dextran improves haemaodynamics, reduces platelet aggregation, alters fibrin formation and enhances thrombus lysis. In this experimental investigation on sheep using a low flow model, the thrombogenicity of various grafts was studied when either a dextran or saline infusion was given. Bilateral carotid interposition grafts with expanded polytetrafluorethylene (ePTFE) on one side and dacron on the other (random allocation) were inserted in 12 sheep. The sheep were randomly divided into two groups, one given a dextran infusion and the other saline. A tendency for improved graft patency was seen in the dextran 40 treated animals (P less than 0.05 at 3 h). However, platelet accumulation did not differ markedly between the dextran 40 and saline treated groups. On the other hand there was a clear reduction of platelet accumulation on ePTFE grafts compared to dacron grafts (P less than 0.01). A large part of the radioactivity measured from the dacron graft was located within the graft wall. Further studies to clarify the mechanism of action of dextran are needed.     

In vivo h-VEGF165 gene transfer improves early endothelialisation and patency in synthetic vascular grafts.

OBJECTIVES: Small-diameter synthetic vascular graft performance is inferior to autologous vein grafts. This study tested the hypotheses that local in vivo administration of plasmids encoding for human vascular endothelial growth factor (VEGF), or co-administration of plasmids encoding for human vascular endothelial growth factor/plasmids encoding for fibroblast growth factor-2 in the tissues surrounding a porous synthetic vascular graft would enhance graft endothelialisation and, consecutively, graft patency. METHODS: First, optimal gene for small-diameter synthetic graft endothelialisation was studied in rat abdominal aorta model (n=132): plasmids encoding for human vascular endothelial growth factor; co-administration of plasmids encoding for human vascular endothelial growth factor/plasmids encoding for fibroblast growth factor-2; or control plasmids were injected around 60 microm ePTFE graft. Second, optimal small-diameter synthetic graft design for endothelialisation was explored in rabbit abdominal aorta model (n=90). Various ePTFE grafts or pre-clotted polyester grafts were used with/without plasmids encoding for human vascular endothelial growth factor. Third, clinically used medium-size synthetic grafts were investigated with/without plasmids encoding for human vascular endothelial growth factor in dog carotid (n=20) and femoral arteries (n=15). Endothelialisation was assessed in midgraft area with scanning electron microscopy. RESULTS: In rats, plasmids encoding for human vascular endothelial growth factor enhanced endothelialisation; whereas co-administration of plasmids encoding for human vascular endothelial growth factor/plasmids encoding for fibroblast growth factor-2 had worst outcome at 1 week (NS), 2 weeks (P=0.01) and 4 weeks (P=0.02). In rabbits, pre-clotted polyester grafts had a trend for faster endothelialisation than ePTFE grafts (P=0.08); whereas plasmids encoding for human vascular endothelial growth factor enhanced endothelialisation compared to controls at 2 weeks (P=0.06), however, the effect reversed at 4 weeks (P=0.03). In dogs, synthetic graft patency was improved by plasmids encoding for human vascular endothelial growth factor in femoral position (P=0.103); whereas all carotid grafts were patent at 6 weeks. CONCLUSIONS: Thus, these data suggested that endothelialisation was fastest in pre-clotted polyester grafts; and that local application of plasmids encoding for human vascular endothelial growth factor had a potential to improve early endothelialisation and patency in synthetic vascular grafts.     

Favorable balance of prostacyclin and thromboxane A2 improves early patency of human in situ vein grafts

Graft thrombosis soon after reconstruction remains a major obstacle to the use of reversed vein grafts in infrapopliteal reconstruction. Our clinical experience with in situ vein grafts corroborates Leather's results by demonstrating an overall graft patency of 95% below the knee at 1 year and 94% in the infrapopliteal group. It has been postulated that this improved early patency rate of in situ vein grafts is the result of more optimal preservation of the endothelium of the vein graft. To investigate this hypothesis, human saphenous veins were handled by an in situ and a reversed technique. The intact vein segments were then tested for luminal production of prostacyclin and thromboxane A₂ and fixed for scanning electron microscopic analysis of the surface morphology. This study demonstrated that endothelial cell prostacyclin release is enhanced in human in situ vein segments but not in reversed vein segments. In addition, luminal production of thromboxane A₂ is significantly greater in the reversed than in the in situ vein segments. These findings are associated with marked endothelial structural damage in the reversed veins and minimal endothelial disruption in the situ veins. Therefore the ratio of the antiaggregatory vasodilator prostacyclin to the proaggregatory vasoconstrictor thromboxane A₂ is significantly more favorable for the in situ vein segment than for the reversed vein segment. The observed excellent early patency of the situ vein grafts in our poor-risk patient population may in part be the result of this favorable balance of prostacyclin and thromboxane A₂ and the more optimally preserved endothelial morphology. (J VASC SURG 1984;1:149-59.)     

Improved patency in reversed femoral-infrapopliteal autogenous vein grafts by early detection and treatment of the failing graft

One hundred two femoral-infrapopliteal bypasses, in which reversed autogenous saphenous vein grafts were used, were performed from January 1978 to July 1984, in 94 patients with severe claudication (14%) or threatened limb loss (86%). Follow-up examinations at 3-month intervals during the first 18 months and at 6-month intervals thereafter were performed to document the return of ischemic symptoms or loss of peripheral pulses. Ankle pressure index and pulse volume recordings were also measured. A decrease in ankle pressure index equal to or greater than 0.2 or a pulse volume recording decrease of 5 mm or more with or without confirmatory symptoms were indications for repeat arteriography. Twenty-two primary graft or anastomotic stenoses were discovered in 19 grafts during follow-up. Seventy-eight percent of these lesions were treated primarily by percutaneous transluminal angioplasty and the remainder were treated by short proximal interposition grafts or patch graft angioplasty. Twenty-five grafts occluded during follow-up and all of these were considered to have failed for purpose of life-table analysis. Stenotic lesions, which were corrected before occlusion, were listed as continuously patent under secondary patency and as failed under primary patency life-table analysis. The secondary graft patency rate was 70% at 5 years, which was significantly higher (p less than 0.01) than the primary patency rate (47%), which was obtained without intervention. This 23% differential represents graft salvage achieved by careful surveillance and is reflected not only by improved patency but also by high limb salvage rates (86%) observed at 5 years.     

The validity of canine platelet aggregometry in predicting vascular graft patency

Several laboratories have found canine platelet aggregometry predictive of thrombotic potential in vascular grafts. Adenosine diphosphate (ADP) is a frequently used agonist, often at unspecified or differing concentrations. This study was designed to evaluate the predictive value of ADP-induced platelet aggregometry and the validity of the methodology. Platelet aggregometry in response to 2 x 10(-5) M ADP was assayed in 70 dogs. Twenty-six percent were aggregators, 51% were non-aggregators, and 20% were indeterminant. All dogs were then treated with aspirin and dipyridamole. Vascular prostheses were implanted bilaterally (aorto-iliac) and anti-platelet therapy continued for two weeks. Dose-response to ADP was studied at three concentrations in 20 dogs. At 2 x 10(-5) 1/20 aggregated, at 4 x 10(-5) 3/19 aggregated and at 2 x 10(-4) 15/20 aggregated. Time between samples and study was evaluated in 11 dogs, with 2/11 changing from non-aggregator to aggregator at two or three hours. Daily reproducibility was studied in 70 dogs, 14 of which changed aggregation status between days. Patency was 58/68 (85%) for non-aggregators, 23/34 (68%) for aggregators (p = 0.038). Platelet aggregometry has significant predictive value for graft patency but methodology must be specified and standardized.     

Skeletonized harvesting improves the early-term and mid-term perfect patency of a radial artery graft

Objective A radial artery (RA) graft is frequently used for coronary artery bypass grafting (CABG), but little information exists regarding the early- and mid-term patency associated with the harvesting procedure. The objective of this study is to compare the early- and midterm patency of the RA graft obtained using non-skeletonized and skeletonized harvesting. Methods Altogether, 131 patients and 159 anastomoses were studied. In 85 patients the RA was harvested non-skeletonized (group A: procedures between September 2000 and November 2002), whereas in 46 patients the RA was harvested skeletonized (group B: procedures between November 2002 and April 2004). Angiography results were analyzed before discharge [A: postoperative day (POD) 14.7 ± 2.9, 75 patients, 90 anastomoses; B: POD 13.7 ± 1.9, 38 patients, 47 anastomoses], and after 1 year (A: POD 386.8 ± 149.3, 44 patients, 51 anastomoses; B: POD 267.1 ± 148.7, 11 patients, 13 anastomoses). Results There was no difference in patency between the two groups (group A vs group B, 96.7% vs 100%, P = not significant [NS], in the early-term, 96.2% vs 100%, P = NS, in the mid-term). However, the perfect patency rates for groups A and B were 86.7% and 98.1%, respectively, in the early-term (P = 0.034) and 77.5% and 100%, respectively, in the mid-term (P = 0.048). The location and severity of the target vessel did not influence the angiographic results. Conclusion The early- and mid-term patency of RA grafts was excellent, and skeletonized harvesting improved the perfect patency rates at both time points.     

Polytetrafluoroethylene (PTFE) grafts for haemodialysis: patency and complications compared with those of saphenous vein grafts.

A comparison has been made between polytetrafluoroethylene (PTFE) and saphenous vein as graft material for the construction of arteriovenous fistulas for use in haemodialysis. Fifty patients with PTFE grafts have been examined and compared with 70 patients with saphenous vein grafts. At eighteen months the accumulative patency rate was 69.8% for PTFE grafts and 68.9% for saphenous grafts. Although the PTFE grafts were similar in terms of patency, their complication rate was higher. The infection rate and distal ischaemia rate for PTFE grafts were double those of the vein grafts. Two patients developed median and ulnar nerve paralysis respectively shortly after implantation of PTFE grafts. Because of this it is recommended that their use be restricted to the lower limb. Despite a higher incidence of complications, PTFE grafts are a satisfactory substitute if a suitable saphenous vein is not available.     

The effect of distal anastomotic site on PTFE graft patency in lower extremity bypass

The site of distal anastomosis of polytetrafluorethylene (PTFE) lower extremity bypass grafts may significantly affect results. We examined patency in 144 cases; 45 femoro-popliteal above knee (AK), 55 femoro-popliteal below the knee (BK) and 44 femoro-distal (D) PTFE bypasses, the groups being comparable with regard to other risk factors studied. Cumulative graft patency at 3 years was 71.3% for AK, 36.7% for BK, 16.4% for D and overall 35%. The site of distal anastomosis is an important determinant, of PTFE lower extremity bypass patency. We have abandoned the use of PTFE for BK and D, but feel that AK PTFE is a suitable alternative to autogenous reversed saphenous vein.     

Effect of desmopressin on vein graft patency in a microvascular model

Desmopressin acetate decreases blood loss after cardiac surgery by activating platelets. We studied whether this effect was detrimental to small-caliber vein grafts in rats. Thirty minutes before femoral artery grafting with 0.75-mm-diameter reverse autogenous saphenous vein grafts, 20 rats received desmopressin acetate intravenously at 1.0 micrograms/kg over 10 minutes, and 20 control rats received normal saline intravenously over 10 minutes. In each group, 10 rats received a 6-mm-long graft and 10 an 18-mm-long graft. Graft patency was evaluated at 20 minutes, 24 hours, and 30 days. Intimal thickening was assessed by light and scanning electron microscopy. At 30 days, 9 short grafts and 8 long grafts in the desmopressin-treated group were patent, whereas only 8 short control grafts and only 6 long control grafts were patent. Intimal thickening and platelet deposition were the same in both groups. These data show no detrimental effects of desmopressin acetate on saphenous vein graft patency.     

Silyl-heparin bonding improves the patency and in vivo thromboresistance of carbon-coated polytetrafluoroethylene vascular grafts

OBJECTIVES: Our purpose was to improve the performance of carbon-coated expanded polytetrafluoroethylene vascular grafts by bonding the grafts with silyl-heparin, a biologically active heparin analog, using polyethylene glycol as a cross-linking agent.Material and method Silyl-heparin-bonded carbon-coated expanded polytetrafluoroethylene vascular grafts (Bard Peripheral Vascular, Tempe, Ariz), were evaluated for patency and platelet deposition 2 hours, 7 days, and 30 days after graft implantation in a canine bilateral aortoiliac artery model. Platelet deposition was determined by injection of autologous, (111)Indium-radiolabeled platelets, followed by a 2-hour circulation period prior to graft explantation. Histologic studies were performed on a 2-mm longitudinal strip of each graft (7-day and 30-day groups). Heparin activity of the explanted silyl-heparin grafts was determined by using an antithrombin-III based thrombin binding assay. RESULTS: Overall chronic graft patency (7-day and 30-day groups) was 100% for the silyl-heparin bonded (16/16) grafts versus 68.75% for control (11/16) grafts (P =.043). Acute 2-hour graft patency was 100% for the silyl-heparin bonded (6/6) grafts versus 83.3% for control (5/6) grafts. Radiolabeled platelet deposition studies revealed a significantly lower amount of platelets deposited on the silyl-heparin grafts as compared with control grafts in the 30-day group (13.8 +/- 7.18 vs 28.4 +/- 9.73, CPM per cm2 per million platelets, mean +/- SD, P =.0451, Wilcoxon rank sum test). In the 2-hour group of dogs, a trend towards a lower deposition of platelets on the silyl-heparin grafts was observed. There was no significant difference in platelet deposition between the two grafts in the 7-day group. Histologic studies revealed a significant reduction in intraluminal graft thrombus present on the silyl-heparin grafts as compared with control grafts in the 30-day group of animals. In contrast, there was no difference in amount of graft thrombus present on both graft types in the 7-day group of dogs. Pre-implant heparin activity on the silyl-heparin bonded grafts was 2.0 IU/cm(2) (international units[IU]/cm(2)). Heparin activity remained present on the silyl-heparin grafts after explantation at all 3 time points (2 hours: above upper limit of assay, upper limit = 0.57, n = 6; 7 days: 0.106 +/- 0.015, n = 5; 30 days: 0.007 +/- 0.001, n = 5; mean +/- SD, IU/cm(2)). CONCLUSION: Silyl-heparin bonding onto carbon-coated expanded polytetrafluoroethylene vascular grafts resulted in (1) improved graft patency, (2) increased in vivo graft thromboresistance, and (3) a significant reduction in intraluminal graft thrombus. This graft may prove to be useful in the clinical setting.     

Combined arachidonic acid and ADP platelet inhibition maximizes patency of small-diameter vascular grafts

Arachidonic acid (AA) and adenosine diphosphate (ADP) are potent stimuli of platelet aggregation. Each agonist may act through separate platelet pathways. In order to evaluate inhibition of ADP and AA on platelet aggregation, we studied the effect of ticlopidine (TC) and aspirin (ASA) alone and in combination on plasma thromboxane levels, platelet deposition, and patency of small-diameter vascular grafts in a canine model. Thirty-four mongrel dogs were classified as thrombosis prone (TP) or thrombosis resistant (TR) on the basis of in vitro platelet aggregation to AA. Four groups were studied: group I, control; group II, TC (100 mg/kg/day); group III, ASA (3 mg/kg/day); and group IV, TC/ASA (same doses). PTFE grafts were implanted bilaterally in the carotid and femoral arteries Ticlopidine inhibited in vitro platelet aggregation to both ADP and AA but had no significant effect on plasma thromboxane (Tx) B2 production. Aspirin inhibited AA-induced platelet aggregation and significantly decreased TxB2 production. Aspirin inhibited AA-induced platelet aggregation and significantly decreased TxB2 levels in both TP and TR animals (p less than 0.01). Although TC and ASA significantly inhibited platelet deposition and improved 1-month patency in both TP and TR animals, maximal patency was achieved in the group in which TC and ASA were combined. We conclude that platelet ADP and AA pathways are important determinants of the thrombogenic potential in vascular graft performance in dogs and that combined inhibition of both pathways achieves maximal vascular graft patency.     

Effect of a selective thromboxane synthase inhibitor on arterial graft patency and platelet deposition in dogs

This study examined the effect of selective thromboxane synthase inhibition and nonselective cyclooxygenase inhibition on vascular graft patency and indium 111-labeled platelet deposition in 35 mongrel dogs undergoing carotid artery replacement with 4 mm X 4 cm polytetrafluoroethylene (PTFE) (one side) and Dacron (opposite side) end-to-end grafts. Aspirin-dipyridamole therapy improved one-week graft patency, from 46% in untreated dogs to 93% in treated dogs. Thromboxane synthase inhibition (U-63557A) improved graft patency in these dogs to 81%. Both drug treatments reduced platelet deposition on Dacron and PTFE grafts by 48% to 68% compared with control dogs. Dacron grafts accumulated significantly more platelets than PTFE grafts but had comparable patency rates. Low-dose aspirin therapy had no significant effect on either graft patency or platelet deposition. All treatment groups showed a 60% to 76% reduction in serum thromboxane B2, but only thromboxane synthase inhibitor treatment increased plasma 6-keto-prostaglandin F1 alpha by 100%. Selective thromboxane synthase inhibition improved small-caliber prosthetic graft patency to the same extent as did conventional cyclooxygenase inhibition in this preliminary study.     

Bilateral ankle skin temperature as a predictor of early vascular graft patency

The efficacy of postoperative bilateral ankle skin temperature as a predictor of early graft patency was prospectively evaluated in 138 consecutive cases of femoropopliteal bypass surgery. The difference between ipsilateral and contralateral ankle temperature (hourly registrations) was significantly greater in the patients with patent graft on postoperative day 1 than in those with an occluded graft. In measurements 8 h postoperatively, highest sensitivity (84 per cent) and specificity (93 per cent) of the test were obtained when the difference was +0.4 degrees C. The overall accuracy of prediction with this simple method was 89 per cent.