Arterial Thrombosis Formation Research Articles

Effect of anticoagulation and inhibition of platelet aggregation on arterial versus venous microvascular thrombosis.

On the basis of clinical empirical observations and classic theory of platelet aggregation, microvascular surgeons have held that platelet aggregation is more responsible for arterial thrombosis and fibrin clot formation is more responsible for venous thrombosis. This theory was tested in two models of thrombosis, one created in arteries and the other in veins, using systemic antithrombotic agents. The models were pair matched in rats, creating a crush-avulsion injury to the femoral artery on one leg and a crushing injury to the femoral vein on the contralateral leg. There were four treatment groups (n = 15 per group): systemic heparin, aspirin and dipyridamole, both sets of agents, and dual controls (vehicle treated). One-day patency rates in the controls were 13.4% and 0% for the arterial and venous models, respectively. Heparin treatment caused an increase in arterial patency to 73.3% but had no effect on venous patency (6.7%). Aspirin and dipyridamole had a modest effect on venous patency (40%) but had no effect on arterial patency (6.7%). Administration of both sets of agents led to 100% and 86.7% patency in the arterial and venous models, respectively. Patency rates were maintained at the 7-day evaluation in the arteries; in contrast, all thrombosed veins were found to be patent 7 days postoperatively (100% patency in all groups). These findings are in contrast to classic thinking about microvascular thrombosis, but this reverse effect may be unique to the rat. The high rate of recanalization in thrombosed veins indicates a need for caution in performing experimental studies of patency in rat veins.

Electrical injury in the femoral artery of rabbits as a model for arterial thrombosis: a pilot study.

Electrical stimulation was delivered to the femoral artery of 20 rabbits to examine whether endothelial injury results in a consistent formation of arterial thrombosis. The arterial patency was monitored throughout the experiment by flowmeter and was visualized by femoral angiography in 5/20 cases. The arterial segments remained totally occluded in 7/20 (35%), partially occluded in 9/20 (45%), and patent in 4/20 (20%) rabbits following stimulation with 200 microA anodal current for 180 minutes. The average time of electrical stimulation needed to achieve total occlusion (n = 7) was 110 +/- 49 minutes. Alternating occlusion and recanalization of the artery (cyclic flow variation) was observed in 12 rabbits, with total occlusion ensuing in 6/12 cases. Intravenous administration of recombinant tissue-type plasminogen activator (20 micrograms/kg/min for sixty minutes) resulted in femoral reflow and subsequent reocclusion in 2/5 cases. Histopathologic examination disclosed arterial thrombi composed of platelets, fibrin, and red blood cells. Thus, according to these data this technique was found to induce arterial thrombosis following electrical stimulation of the rabbit femoral artery but was inconsistent regarding the arterial patency.

Thromboxane antagonism in experimental canine carotid artery thrombosis.

The two objectives of this study were to assess the potential of BAY U 3405 to prevent arterial thrombosis in response to vessel wall injury and to determine the ability of BAY U 3405 to prevent thrombotic reocclusion after thrombolysis with anisoylated plasminogen streptokinase activator complex. Dogs were instrumented with a carotid flow probe, stimulating electrode, and a stenosis. Current (150 microA) was applied to the intimal surface of the right carotid artery, and time to occlusive thrombus formation was noted. BAY U 3405 was administered, and the procedure for thrombus formation was repeated for the left carotid artery. BAY U 3405 administration prevented occlusive arterial thrombosis formation. Ex vivo platelet aggregation was inhibited, bleeding time increased, and thrombus weight reduced after BAY U 3405 treatment. In a second group, thrombi were formed initially in both carotid arteries, BAY U 3405 was administered as before, and anisoylated plasminogen streptokinase activator complex was infused in the right carotid artery proximal to the occlusive thrombus. BAY U 3405 did not alter the incidence of rethrombosis compared with the lytic agent alone. BAY U 3405 prevented primary arterial thrombosis, corresponding to inhibition of platelet aggregation, and increased bleeding times. BAY U 3405, however, did not prevent rethrombosis after successful thrombolysis with anisoylated plasminogen streptokinase activator complex, despite the fact that platelet reactivity was inhibited. The data are consistent with the concept that the residual thrombus represents a more effective thrombogenic stimulus as compared with arterial wall injury alone and that the mechanisms associated with primary versus secondary thrombus formation may require separate therapeutic approaches.

Prevention of the formation of arterial thrombi using different antiplatelet drugs: Experimental study in dogs

We have induced the formation of arterial thrombosis in dogs by means of an intima lesion produced by continuous current. The platelets were labeled with 111-In-oxine. Groups of 7 mongrel dogs received treatment for 7 days prior to the trial: Group I, control; Group II, 5 mg/kg body weight/day acetylsalicylic acid; Group III, 20 mg/kg body wt/day acetylsalicylic acid; Group IV, 15 mg/kg body wt/day triflusal + 5 mg/kg body wt/day dipyridamole; Group V, 15 mg/kg body wt/day triflusal; and Group VI, 5 mg/kg body wt/day acetylsalicylic acid + 5 mg/kg body wt/day dipyridamole. The only effective treatment for arterial thrombosis prevention was that employed in Group II (p < 0.05).

Potentiation of the inhibitory effect of a thromboxane A 2 antagonist (L-640,035) on arterial thrombosis formation in rabbit by the angiotensin converting enzyme inhibitor enalapril

The angiotensin converting enzyme inhibitor enalapril (0.5 mg/kg i.v.) potentiated significantly the inhibitor effect of the thromboxane A 2 antagonist L-640,035 (1 mg/kg i.v.) on electrically induced platelet accumulation in the rabbit in vivo. Enalapril had no effect upon platelet accumulation when given alone. The hypotensive effects of enalapril did not account for the potentiation because a combination of hexamethonium (5 mg/kg i.v.) and hydralazine (1 mg/kg i.v.), which decreased blood pressure similarly to enalapril, did not augment the effect of L-640,035. Determination by radioimmunoassay of plasma levels of immunoreactive 6-keto-PGF 1α, suggested that increases in PGI 2 levels after combined administration of enalapril and L-640,035 could explain the observed potentiation.

Electrochemical properties of platelets: clinical and pharmacological applications.

Although it has been accepted that platelets take part in hemostasis and in arterial thrombosis formation, the physiochemical mechanisms of platelet adhesion and aggregation have still been clearly determined.

Antibodies to Blood Coagulation Factors

The coagulation protease cascade plays the central requisite role in initiation of arterial atherothrombosis. However, the relative participation of the extrinsic as compared to the intrinsic pathway is incompletely resolved. We have investigated in vivo the relative importance of the extrinsic and intrinsic pathways to define which is more essential to atherothrombosis and therefore the preferable prophylactic therapeutic target. We further addressed which type of plaque associated macrophage population is associated with the thrombotic propensity of atherosclerotic plaques.Both photochemical injury and ferric chloride vascular injury models demonstrated arterial thrombosis formation in ApoE deficient mice. We found that direct interference with the extrinsic pathway, but not the intrinsic pathway, markedly diminished the rate of thrombus formation and occlusion of atherosclerotic carotid arteries following experimental challenge. To explore which plaque macrophage subtype may participate in plaque thrombosis in regard to expression tissue factor pathway inhibitor (TFPI), bone marrow derived macrophages of both M and GM phenotypes expressed tissue factor (TF), but the level of TFPI was much greater in M- type macrophages, which exhibited diminished thrombogenic activity, compared to type GM-macrophages.Our works support the hypothesis that the TF-initiated and direct extrinsic pathway provides the more significant contribution to arterial plaque thrombogenesis. Activation of the TF driven extrinsic pathway can be influenced by differing colony-stimulating factor influenced macrophage TFPI-1 expression. These results advance our understanding of atherothrombosis and identify potential therapeutic targets associated with the extrinsic pathway and with macrophages populating arterial atherosclerotic plaques.

Isolation of a chemical trigger for thrombosis

‘Labile aggregation-stimulating substance’ (‘LASS’) is a lipid which may be a chemical trigger for the platelet thrombus formation of arterial thrombosis. It potently induces aggregation of human blood platelets and incubation mixtures containing LASS are lethal when injected intravenously in mice; death is associated with intravascular platelet aggregation. LASS is enzymatically synthesized from arachidonate (the precursor for biosynthesis of PGs E 2 and F 2α) in platelet microsomal preparations. This synthesis is blocked by aspirin, a known inhibitor of platelet aggregation and experimentally induced arterial thrombosis. LASS has properties which cannot be distinguished from those of a recently isolated endoperoxide intermediate of prostaglandin synthesis. Thus, molecular oxygen is required for its formation and it is inactivated by stannous chloride. Furthermore, its net biosynthetic production is increased by p-mercuribenzoate or N-ethylmaleimide and it is an acid lipid, having a similar polarity to the endoperoxide. Using rapid thin layer chromatographic techniques at low temperature, LASS was isolated as a single zone on silica gel, whether or not this was impregnated with silver nitrate; it had a mobility between that of arachidonate and PGE 2. Material in TLC zones containing LASS also produced contractions of isolated rabbit aorta.