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S R Hanson

Publications and source records attributed to S R Hanson.

140 records · Page 8Linked to original sources
PubMed1981

Prevention of acquired transient defect in platelet plug formation by infused prostacyclin.

Cardiopulmonary bypass in baboons produced transient severe platelet dysfunction (bleeding times prolonged to 27.8 +/- 1.4 min compared with 3.9 +/- 0.7 baseline) that was associated with a parallel release of platelet alpha-granule proteins into plasma (platelet factor 4 and beta-thromboglobulin levels of 28.8 +/- 9.3 and 20.0 +/- 1.8 ng/ml, respectively) and their clearance into urine with a reciprocal depletion from circulating platelets. In contrast, platelet-dense granules did not undergo significant release. The bleeding times normalized rapidly following bypass (8.5 +/- 1.4 min at 1 hr). The infusion of prostacyclin (PGI2) into the bubble oxygenator during bypass (40--80 ng/kg/min) prevented the prolongation in bleeding time (p less than 0.01 compared with untreated control values) but did not block the release of alpha-granule proteins. Dosages outside this range were associated with prolonged bleeding times. These results show that transient platelet dysfunction occurring during cardiopulmonary bypass represents activation of platelets independent of alpha or dense granule release and is blocked by potent short-acting inhibition of platelet function using PGI2 infused into the oxygenator apparatus at optimal therapeutic doses.

Animals↗
PubMed1979

Experimental arterial thromboembolism in baboons. Mechanism, quantitation, and pharmacologic prevention.

A quantitative primate model of arterial thromboembolism has been characterized with respect to mechanism and usefulness in evaluating modifying variables. The model involved the kinetic measurements of (51)Cr-platelets and (125)I-fibrinogen consumption by femoral arteriovenous cannulae in chaired baboons. Cannula platelet consumption correlated directly with exposed cannular area for irradiated Silastic and polyurethane (correlation coefficients of 0.940 and 0.901, respectively; P < 0.001) and remained steady state for months. Nonirradiated Silastic was only minimally reactive with platelets. Despite increased rates of platelet consumption circulating fibrinogen was not measurably destroyed by any of the cannulae tested. Cannula platelet consumption was independent of cannula flow rate, platelet count, heparin anti-coagulation, and ancrod defibrinogenation.(111)In-platelet imaging of irradiated Silastic cannulae demonstrated luminal accumulation and subsequent embolization of irregular platelet masses. When irradiated Silastic cannulae were inserted as extension segments in the renal arteries of four animals the glomerular vessels became progressively occluded with nonfibrin-containing platelet thromboemboli. Nonirradiated Silastic cannulae in control arteries produced no significant vascular occlusion. Because the survival of platelets from animals with consumptive cannulae was not shortened in normal recipient animals we concluded that platelets were either irreversibly removed through thromboembolic consumption or unaffected in their viability. Oral administration of dipyridamole and sulfinpyrazone decreased cannula platelet consumption in a dose-dependent manner with complete interruption at 20 and 250 mumol/kg body wt per d (in three divided doses), respectively, whereas oral acetylsalicylic acid (10-330 mumol/kg per d) had no measurable effect on cannula platelet consumption. We conclude that this primate model simulates arterial thrombotic processes in man and that this model is suitable for the in vivo evaluation of biomaterials and of drugs that modify platelet behavior.

Animals↗
PubMedDate not supplied

The kinetics of baboon fibrinogen adsorption to polymers: in vitro and in vivo studies.

Fibrinogen adsorption on polymers from blood may mediate or potentiate thrombosis because of its involvement in both the intrinsic clotting system and the formation of platelet aggregates. While the kinetics of fibrinogen adsorption from plasma in vitro have previously been found to be very different on polar and nonpolar surfaces [T. A Horbett, "The kinetics of adsorption of plasma proteins to a series of hydrophilic-hydrophobic copolymers," ACS Org. Coat. Plas. Chem. 40, 642-646 (1979)] the significance of this difference with respect to thrombogenesis in vivo has not been clarified. In this study, the kinetics of deposition of baboon 125I fibrinogen from plasma in vitro or from blood in vivo on a series of polymers was measured. The polymers chosen for this study had previously been found to have a large range in surface polarity and reactivity in the in vivo baboon shunt model. The kinetics of fibrinogen adsorption in vitro were observed to be of three types, depending on the polymer: high initial adsorption decreasing to a lower steady state value; constant throughout the time course; low initial adsorption rising steadily to a plateau value. In vivo, fibrinogen deposition kinetics were of two types: low, constant deposition throughout the time course, independent of heparinization; low deposition initially followed by a second phase of greatly increased deposition (probably as fibrin) which was prevented or greatly decreased by heparinizing the animals. Polymers for which fibrinogen adsorption increased to a plateau in vitro were found to have a heparin inhibitable second phase of enhanced in vivo fibrinogen deposition. These polymers also have been found in previous studies to enhance the rate of platelet destruction when used as in vivo shunts on baboons. Conversely, most polymers with high initial in vitro fibrinogen adsorption followed by a decrease had low fibrinogen deposition behavior in vivo and were also minimally destructive of platelets. The adsorption kinetics of fibrinogen to polymers from blood in vivo and in vitro and the consumption of platelets in vivo induced by the polymers all vary with polymer polarity. More polar polymers had in vitro fibrinogen kinetics characterized by a rise to a plateau, in vivo fibrinogen deposition characterized by a second stage of great increase inhibitable by heparin, and enhanced platelet consumption. The correlation of three separate indicators of surface thrombogenicity with surface polarity suggests that more polar materials may be more thrombogenic because of an influence on the way in which fibrinogen interacts with these surfaces.

Adsorption↗
PubMedDate not supplied

A novel method for efficient drug delivery.

Local delivery of anti-thrombotic and anti-restenotic drugs is desired to achieve high concentrations of agents which may be rapidly degraded systemically or which exhibit very short half-lives in vivo. In this article, the operating characteristics of a novel local drug delivery method are described and its effectiveness demonstrated computationally and experimentally. Computational models used a finite volume method to determine the concentration field. Optical dye density measurements of Evans blue in saline were performed in an in vitro steady flow system. Modeling parameters were kept in the physiologic range. Experimental flow visualization studies demonstrated high concentrations of infusate near the vessel wall. Computational studies predicted high, clinically significant drug concentrations along the wall downstream of the infusion device. When the radial infusion velocity is large (infusion flow rate, Qinf>0.5% of the main flow rate, Q), the wall concentration of the infused drug remains high, e.g., levels are greater than 80% of the infusate concentration 5 cm downstream of the infusion device. At lower infusion rates (Qinf<0.001Q), the drug concentration at the wall decreases exponentially with axial distance to less than 25% of the infusate concentration 5 cm downstream of the infusion device, although therapeutic drug levels are still readily maintained. The near wall drug concentration is a function of flow conditions, infusion rate, and the drug diffusivity. Good agreement was obtained between computational and experimental concentration measurements. Flow simulation and experimental results indicate that the technique can effectively sustain high local drug concentrations for inhibition of thrombosis and vascular lesion formation.

Antithrombins↗
PubMedDate not supplied

Inhibition of thrombus formation in vivo by novel antiplatelet agent.

The antithrombotic and antihemostatic effects of the novel antiplatelet compound, alpha, alpha'-bis[3-(N,N-diethylcarbamoyl)piperidino]-p-xylene dihydrobromide (GT-12), were investigated in a baboon model of platelet-dependent thrombosis under high flow conditions. In this model, segments of collagen-coated tubing and Dacron vascular graft were placed as thrombus-inducing extension devices in exteriorized femoral arteriovenous shunts. The deposition of 111In-labeled platelets was measured for each thrombogenic segment throughout 1 hour by using gamma camera imaging. In addition, the 125I-fibrin retained in the forming thrombus was measured. Intravenous infusion of GT-12 (100 mumol/kg, 63.3 mg/kg) over a 15-minute period before the insertion of the test segments prolonged the bleeding time from a baseline value of 4.4 +/- 0.4 min to 7.6 +/- 1.0 min (p = 0.036) and inhibited platelet aggregation ex vivo induced by adenosine diphosphate (ED50 4.7 +/- 0.9 to 10.3 +/- 2.2 microM; p less than 0.02) and collagen (ED50 2.0 +/- 0.4 to 8.0 +/- 2.4 micrograms/ml; p less than 0.05). Deposition of platelets and fibrin was decreased in concert by 30% (p less than 0.05) for vascular grafts and possibly collagen segments at the end of the 60-minute observation period. We conclude that GT-12 is antithrombotic for Dacron graft-induced thrombus formation in vivo.

Adenosine Diphosphate↗
PubMedDate not supplied

Analysis of indium-111 platelet kinetics and imaging in patients with aortic grafts and abdominal aortic aneurysms.

To quantitatively characterize processes of platelet thrombus formation in vivo, the kinetics and incorporation into thrombus of autologous In-111-labeled platelets were compared in six patients with aortic aneurysms and in seven patients with prosthetic aortic grafts. Although platelet survival was comparably shortened in both patient groups (mean, 5.8 days), the maximum radioactivity (percentage of whole body radioactivity) as determined by gamma camera imaging was higher in the aneurysms than in the grafts (3.3% +/- 1.6% vs. 1.6% +/- 1.1%, p = 0.05). Maximum In-111 uptake was also attained more quickly in the aneurysm patients (2.3 +/- 0.8 days vs. 3.5 +/- 1.3 days; p = 0.07). The experimental platelet kinetic and imaging data were subsequently evaluated by compartmental analysis to estimate both normal and disease-related components of platelet destruction. This analysis indicated that deposited platelet radioactivity had a longer residence time on grafts (2.9 +/- 1.7 days vs. 1.4 +/- 0.9 days, p = 0.07) but accumulated at a faster rate in aneurysms (5.0% +/- 3.4% per day vs. 1.4% +/- 0.9% per day, p = 0.02). As determined by imaging, only a proportion of increased platelet destruction was specifically due to the aneurysms (55% +/- 38%) or grafts (17% +/- 11%, p = 0.03). This result indicates additional components of platelet destruction unrelated to graft and aneurysm thrombus formation which, in some graft patients, may reflect a greater severity of vascular disease or other mechanisms causing a preferential shortening of platelet survival. Thus, the analytical approach described may be a useful one for discriminating components of in vivo platelet utilization including platelet removal due to normal hemostatic and senescent mechanisms, localized thrombus formation, and more generalized vascular disease.

Adult↗
PubMedDate not supplied

Platelet interactions with Dacron vascular grafts. A model of acute thrombosis in baboons.

We have developed a model of acute Dacron graft thrombosis in baboons in order to assess platelet alterations secondary to arterial thrombus formation. In this model, thrombus formation was initiated by Dacron vascular grafts inserted as extension segments into chronic arteriovenous Silastic shunts. Following platelet labeling with 111In-oxine, platelet deposition was measured for 1 hour following blood contact under arterial flow conditions using a scintillation camera. Graft platelet activity rapidly increased 40- to 50-fold, plateauing by 1 hour. All grafts produced equivalent reductions in circulating platelet count and blood 111In-platelet radioactivity, demonstrating that the labeled cells were functionally equivalent to the total platelet population. After graft placement, the remaining platelets survived normally. Acute platelet deposition was equivalent on grafts placed 1, 24, 48, and 72 hours following injection of the labeled cells, indicating that a variable delay between platelet labeling and graft imaging was without detectable consequence. Platelet destruction by the graft produced a tenfold increase in plasma levels of platelet factor 4 (PF4) and beta-thromboglobulin (beta TG) but did not modify either the alpha-granule (PF4, beta TG) or dense granule (ADP, ATP) contents of circulating platelets.

Animals↗
PubMedDate not supplied

Iliac artery mural thrombus formation. Effect of antiplatelet therapy on 111In-platelet deposition in baboons.

To measure the rate, extent, and time course of arterial mural thrombus formation in vivo and to assess the effects of antiplatelet therapy in that setting, we have studied autologous 111In-platelet deposition induced by experimental iliac artery aneurysms in baboons. Scintillation camera imaging analyses were performed at 1, 24, 48, and 72 hours after implantation of the device. Correction for tissue attenuation was determined by using a small, comparably located 111In source implanted at the time of surgery. In five animals, 111In-platelet activity accumulated progressively after device implantation, reaching a maximum after the third day. Repeat image analysis carried out 2 weeks after the surgical procedure also showed progressive accumulation of 111In-platelets over 3 days but at markedly reduced amounts as compared with the initial study. In five additional animals, treatment with a combination of aspirin and dipyridamole begun 1 hour after surgical implantation reduced 111In-platelet deposition to negligible levels by the third day. Although platelet survival time was shortened and platelet turnover was reciprocally increased in all operated animals, platelet survival and turnover were not affected by antiplatelet therapy. We conclude that, in contrast to platelet survival and turnover measurements, 111In-platelet imaging is a reliable and sensitive method for localizing and quantifying focal arterial thrombi and for assessing the effects of antiplatelet therapy.

Animals↗
PubMedDate not supplied

Experimental acute thrombotic stroke in baboons.

To study the effects of antithrombotic therapy in experimental stroke, we have characterized a baboon model of acute cerebrovascular thrombosis. In this model an inflatable silastic balloon cuff has been implanted by transorbital approach around the right middle cerebral artery (MCA), proximal to the take-off of the lenticulostriate arteries (LSA). Inflation of the balloon for 3 hours in six animals produced a stereotypic sustained stroke syndrome characterized by contralateral hemiparesis. An infarction volume of 3.2 +/- 1.5 cm3 in the ipsilateral corpus striatum was documented by computerized tomographic (CT) scanning at 10 days following stroke induction and 3.9 +/- 1.9 cm3 (n = 4) at 14 days by morphometric neuropathologic determinations of brain specimens fixed in situ by pressure-perfusion with 10% buffered formalin. Immediate pressure-perfusion fixation following deflation of the balloon was performed in 16 additional animals given Evans blue dye intravenously prior to the 3 hour MCA balloon occlusion. Light microscopy and transmission electron microscopy consistently confirmed the presence of thrombotic material occluding microcirculatory branches of the right LSA in the region of Evans blue stain, but not those of the contralateral corpus striatum. When autologous 111In-platelets were infused intravenously in four animals from the above group prior to the transient 3 hour occlusion of the right MCA, gamma scintillation camera imaging of each perfused-fixed whole brain demonstrated the presence of a single residual focus of 111In-platelet activity involving only the Evans blue-stained right corpus striatum. Focal right hemispheric activity was equivalent to 0.55 +/- 0.49 ml of whole blood, and the occlusion score derived from histologic examination of the microcirculation of the Evans blue-stained corpus striatum averaged 34.8 +/- 2.8. Similar 111In-platelet imaging and histologic scoring experiments carried out in four animals pretreated with the antithrombotic combination heparin and ticlopidine showed marked reduction of both 111In-platelet activity (0.01 +/- 0.03 ml vs. 0.55 +/- 0.49 ml; p less than 0.01) and thrombotic occlusion of the microcirculation (10.8 +/- 7.4 units vs. 34.8 +/- 2.8 units; p less than 0.01) in the right corpus striatum following 3 hours of MCA occlusion. In separate control experiments 111In-labeled autologous platelets were infused after the 3 hour period of right MCA occlusion and subsequent balloon deflation in two animals; no focus of 111In-platelet activity was demonstrated in fixed whole brain.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMedDate not supplied

Factors influencing acute thrombus formation on carotid artery vascular grafts.

Scintillation camera imaging of 111Indium-labeled platelets has been used to measure acute thrombus formation on modified expanded Teflon (ePTFE) vascular grafts (Gore-Tex, 4.0 mm i.d. x 3-5 cm in length, W. L. Gore and Associates, Inc., Flagstaff, AZ) placed in the carotid arteries of normal baboons. Platelet deposition plateaued over 2 hr postoperatively and occurred primarily at the graft-vessel anastomoses. A positive correlation was found between the circulating platelet count in individual animals and the extent of early platelet thrombus deposition. Unmodified ePTFE grafts accumulated 4.6 +/- 1.2 x 10(9) platelets per graft, or 2.3 +/- 0.71 x 10(9) platelets per anastomosis. Acutely, platelet accumulation was reduced versus control graft results by coating the graft lumenal surfaces with a smooth layer of silicone rubber polymer (0.60 +/- 0.19 x 10(9) platelets per anastomosis; P less than 0.02) but not by coating the grafts using a plasma polymer based on methane, which did not modify graft texture (8.2 +/- 1.7 x 10(9) platelets per graft; P greater than 0.10). The benefit of the silicone rubber coating persisted for at least 48 hr. However, longer term patency was not preserved because 10 of 12 grafts placed had failed within 1 to 2 months.

Anastomosis, Surgical↗