Foreign body sarcoma: effects of foreign DNA, beta-carotene and paprika applied to the implant surface.

Sarcoma arises extremely rarely on foreign bodies in man, but is aggressive and often lethal. A coating for implants which would further reduce the risk in man is desirable. The incidence in mice is much greater, and responds to chemical treatment of the implant surface. Coating with histones increases tumour yield. Accordingly, related substances, foreign DNA, DNase and a mixture of the two, were tested for anticancer activity by application to 25 mm nitrocellulose filters in groups of 30-45 BALB/c mice, in comparison with untreated filters. Other substances reported to influence neoplasia, paprika, beta-carotene, rhodamine and tuftsin; and substances expected to be neutral, oxyprenolol, liquid paraffin, iodine, and adenosine diphosphate were similarly tested against concurrent untreated controls for comparison. Bovine DNA (p = 0.01) and DNA/DNase mixture (p = 0.04) and DNase fomented tumour growth by 55, 45 and 59% respectively. Paprika and beta-carotene did so by 70% (p = 0.05). The other substances were inert. None were candidates for an anti-sarcoma coating.

Some effects of prophylactic aspirins and heparins on concurrent arterial and venous thrombosis in the same animal.

The antithrombotic effect of unfractionated heparin, a low-molecular weight heparin, oral acetylsalicylic acid, intravenous lysine-aspirin and oral soluble aspirin was measured on platinum wire simultaneously in artery and vein, in groups of 12-20 rats with concurrent untreated controls. Subcutaneous low molecular weight heparin reduced mean thrombus weight by 26% in the artery only. Venous thrombosis was reduced 56% by oral soluble acetylsalicylic acid and 27% by oral aspirin. Other reductions did not reach statistical significance. While thrombus deposition was induced by both 2-cm (upper site) and 1-cm (lower site) wires, the results obtained on the 2-cm wires in the upper vein and artery were more reliable [corrected].

The reliability of thrombotic tendency measured by intravascular wires in the rat.

The objective was to determine if the amount of thrombus on two adjacent wires in an artery or in a vein was similar, and whether an upstream wire affected thrombosis on the downstream wire. Two 2 cm platinum wires were placed at adjoining sites in the abdominal vena cava and a further 2 in the abdominal aorta in 26 male and 24 female rats. In the artery, mean thrombus weight on the aortic downstream wire, set where the vessel is narrow, was significantly (p < 0.001) less than on the upstream wire, but the two correlated fairly well correlation coefficient (r = 0.608). In the vein, mean thrombus weight deposited in 1 hour was comparable on the pairs of wires both in males (r = 0.819) and females (r = 0.805). The mean downstream thrombus was slightly (10%) heavier than the upstream one both in males and females, a possible effect of vessel diameter, or of an activation by the upstream wire of thrombosis on the downstream one. An experiment to clarify that issue showed mean downstream venous thrombus to be again heavier than mean up-stream in both sexes (22 males, 30 females), and heavier than in controls in which no upstream wire was inserted. The platinum wire venous model seems to measure individual thrombotic response in a reasonably reproducible way in the rat. Upstream venous wire appears to activate thrombosis downstream from it by some 10%.

Quantitation of the thrombotic effects in artery and vein of the increase in coagulation factors during normal pregnancy in the rat.

Coagulation factors increase and fibrinolysin activity decreases in pregnant women. While the nett change in thrombotic tendency is unmeasured, venous thromboembolism increases five-fold in this group. We measured thrombus formation in vein and artery on standard platinum wires in 45 near-term pregnant rats, 19 pregnant for the first time and 26 for the second time, and in 33 never-pregnant controls. No significant increase in arterial thrombus occurred in the pregnant rats. Venous thrombus, however, increased by 65% in rats pregnant for the first time and 176% in those pregnant for the second time, compared to never-pregnant animals. Their mean increase in coagulation factors VIII, X, V, VII and II varied from 165 to 268%. Factor VIII level (r = 0.59, p < 0.05) correlated with venous thrombosis level, but the rarity of spontaneous thrombosis did not permit the limits of risk to be determined. Factors VII, X and V showed little correlation with thrombus weight (r = < 0.16) and Factor II an insignificant one. Monitoring factor VIII levels in pregnant women might help identify a group at risk of thromboembolism and establish a threshold for prophylactic intervention.

Effect of film size on production of foreign body sarcoma by perforated film implants.

Sarcoma may arise on unabsorbable foreign bodies in rodents and more rarely in man. Perforations of the implant reduce its carcinogenicity so that nitrocellulose filters of pore size 0.45 micron have failed to induce tumour. We examined whether increase of surface area would restore carcinogenesis to film with such pore size. Nitrocellulose filters of 25 mm diameter and pore size 0.45 micron were implanted singly, in pairs and in trios subcutaneously in 3 respective groups of BALB/c mice (total 97) and observed for sarcomagenesis for 100 weeks. No tumour arose on the singles (surface area 0.98 mm2), while 7 arose on the paired (1.96 mm2) at a mean of 54 weeks and 16 on the trios (2.95 mm2) at a mean of 46 weeks (differences significant at p > 0.01). A sufficiency of surface area restores carcinogenicity to perforated foreign surfaces in mice. Surface area is dominant over film perforation size in film sarcomagenesis.

The quantitative reduction by acute-dose warfarin of venous thrombosis in normal and hyperthrombotic rats.

Warfarin was tested for its relative ability to reduce thrombosis in two series of rats. In one series both the warfarin and control animals were made hyperthrombotic by an infusion of ellagic acid just before thrombosis was measured. In the second series (termed normothrombotic) no thrombotic stimulant was given. In all, 179 test and 109 control animals were used. Warfarin was given in varying doses to the test animals. Ellagic acid was administered as a single standard dose. At operation, two test animals and one control of similar weight were operated on concurrently. Thrombosis was measured by the weight of thrombus occurring on a standard 2 cm intravenous platinum wire in one hour. In optimum dose, warfarin reduced thrombus formation by 74% in the unstimulated series and by 83% in the hyperthrombotic one, when the mean factor II levels were 18% and 19% respectively. The residual thrombus under warfarin treatment was, however, greater in the hyperthrombotic than in the unstimulated animals at all levels of factor II. Best correlation of thrombus weight was with factor II in unstimulated animals.

Effect of aspirin-dipyridamole and heparin and their combination on venous thrombosis in hypercoagulable or thrombotic animals.

Epsilon-amino-caproic acid (EACA) induces a clinically-useful anti-haemorrhagic, mildly thrombotic state while ellagic acid (EA) induces a severe hypercoagulable one. Reversal of these states may on occasion be necessary. The effectiveness of the antiplatelet drugs, aspirin and dipyridamole (ASA/D), in reducing thrombus weight was studied in normocoagulable animals and animals made hypercoagulable with EACA (333mg/kg) or EA (1.2mg/kg). Heparin (114iu/kg) was tested in the EACA group, both alone and in combination with ASA/D. Thrombogenicity was measured by weight formed on intravenous platinum wire in one hour. In normocoagulable animals, ASA/D reduced thrombus by 32%. Ellagic acid trebled mean thrombus weight and ASA/D reduced this by 49%, but did not restore normality. EACA increased mean thrombosis by one sixth. Treatment with heparin reduced this by 48% to a level well below that of untreated animals. Addition of a single dose of aspirin/dipyridamole to the heparin regime, reduced thrombosis by a further 31%, reaching to 21% of control thrombus. The results were statistically significant. Kaolin-activated blood clotting time was shortened by EA, but EACA had little effect on it, while ASA/D slightly and heparin markedly lengthened it.