Thrombin Generation and Activity During Coronary Angioplasty: Influence of Angiographic Lesion Morphology.

OBJECTIVE: To investigate the relationships between coronary atherosclerotic plaque injury, lesion morphology, and activation of the coagulation cascade. BACKGROUND: Balloon angioplasty of coronary lesions may result in intracoronary thrombin generation and activity. It is unknown whether the angiographic morphology of the lesion prior to intervention, an indicator of the presence of thrombus in the lesion, is a determinant of the degree of coagulation cascade activation. METHODS AND RESULTS: Biochemical markers of thrombin generation (prothrombin fragment F1+2) and thrombin activity (fibrinopeptide A; FPA) were measured in coronary blood before, 1 and 10 minutes after percutaneous transluminal coronary angioplasty (PTCA) in 24 patients with an angiographically complex lesion morphology and 24 patients with an angiographically simple lesion morphology. Using previously defined criteria, 18 of the 48 patients (38%) demonstrated a significant rise in coronary plasma F1+2; 8 of these 18 (44%) had simple and 10 of 18 (55%) had complex angiographic lesion morphologies (p=NS). With respect to thrombin activity, 15 of the 48 patients (31%) demonstrated a significant rise in coronary plasma FPA; 7 of these 15 patients (47%) had a simple lesion morphology and 8 (53%) had a complex morphology (p=NS). When analyzed as a group, patients with complex lesion morphologies demonstrated a small elevation in coronary plasma levels of FPA 10 minutes post-PTCA (median 3.2 ng/ml, 95% CI 2.4Ð5.8 ng/ml) in comparison to the levels measured proximal to the lesion pre-PTCA (median 2.1 ng/ml, 95% CI 1.6Ð3.5 ng/ml; p=0.05). In contrast, in the group of patients with simple lesion morphologies, the plasma FPA levels proximal to the lesion pre-PTCA (median 2.1 ng/ml, 95% CI 1.5 to 3.9 ng/ml) were similar to those measured 10 minutes after the procedure (median 2.0 ng/ml, 95% CI 1.5 to 6.3 ng/ml; p=NS). CONCLUSIONS: In comparison to patients with angiographically complex lesions, patients with angiographically simple lesions demonstrate a similar incidence (~33%) of elevated coronary plasma thrombin generation (F1+2) and activity (FPA) after PTCA. As a group, patients with angiographically complex lesions (irregular borders, overhanging edges, filling defects) demonstrate a slightly greater increase in thrombin activity in comparison to patients with simple lesion morphologies. Percutaneous coronary interventions of lesions with a wide variety of angiographic morphologies are prone to result in activation of the coagulation cascade.

Thrombosis in ischemic heart disease.

Thrombus formation on a fissured or disrupted atherosclerotic plaque is the main pathogenetic mechanism for the acute coronary syndromes of myocardial infarction and unstable angina. Myocardial infarction results from an acute total occlusion of the artery, while unstable angina is secondary in most cases to mural thrombus formation. Thrombus formation has also been implicated in chronic atherosclerotic disease progression and in restenosis following coronary angioplasty. Therapeutic measures to treat thrombus rely on the ability of drugs to either prevent thrombus extension, dissolve its fibrin component, or prevent further platelet aggregation. Other measures rely on the ability of intracoronary techniques to open coronary arteries. The primary prevention of intracoronary thrombus formation is evolving. Measures to stabilize plaques or to reduce hypercoagulability are being tested or have been tested in recent trials.

Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis.

The metabolism of infused 111In-labeled phospholipid liposomes was examined in Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack low density lipoprotein (LDL) receptors, and in normal control rabbits. The half-times (t1/2) for clearance of 111In and excess phospholipid from plasma were 20.8 +/- 0.9 hr and 20.3 +/- 4.6 hr in WHHL and 20.0 +/- 0.8 hr and 19.6 +/- 2.2 hr in the normal rabbits (means +/- SEM; n = 4). By 6 hr postinfusion, the plasma concentration of unesterified cholesterol increased by 2.2 +/- 0.23 mmol/liter in WHHL and 2.1 +/- 0.04 mmol/liter in normal rabbits, presumably reflecting mobilization of tissue stores. Disappearance of excess plasma cholesterol was greater than 90% complete in both groups of rabbits by 70 hr postinfusion. By quantitative gamma camera imaging, hepatic trapping of 111In-labeled liposomes over time was indistinguishable between the two groups. At autopsy, the liver was the major organ of clearance, acquiring 22.0% +/- 1.7% (WHHL) and 16.8% +/- 1.0% (normal of total 111In. Aortic uptake of 111In was less than 0.02%. Thus, mobilization of cholesterol and hepatic uptake of phospholipid liposomes do not require LDL receptors. Because phospholipid infusions produce rapid substantial regression of atherosclerosis in genetically normal animals, our results suggest that phospholipid liposomes or triglyceride phospholipid emulsions (e.g., Intralipid) might reduce atherosclerosis in WHHL rabbits and in humans with familial hypercholesterolemia.