Occlusive arterial thrombosis in cynomolgus monkeys with varying plasma concentrations of lipoprotein(a).

Abstract

Lipoprotein(a) (Lp[a]) is a newly recognized risk factor for the development of coronary heart disease and stroke in human beings; however, the mechanisms by which Lp(a) increases the risk of coronary heart disease remain unclear. The purpose of this study was to examine the effects of Lp(a) on the occurrence of occlusive arterial thrombosis. Occlusive arterial thrombus formation was examined in 18 cynomolgus monkeys with high plasma Lp(a) concentrations (> 35 mg/dL, n = 6), intermediate Lp(a) concentrations (20-25 mg/dL, n = 6), and low Lp(a) concentrations (< 12 mg/dL, n = 6). A Goldblatt clamp was positioned around the left common carotid artery to produce a stenotic segment, and the artery was pinch-injured with needle holders. A 20-MHz Doppler velocity crystal, placed distal to the stenosis/injury site, was used to detect cyclic flow reductions (indicative of transient thrombosis) or permanent cessation of flow velocity (indicative of more stable occlusive thrombosis). All monkeys with high Lp(a) concentrations developed permanent cessation of flow, whereas only one of six arteries from low-Lp(a) monkeys developed permanent cessation of flow (p < 0.05). Arteries from monkeys with intermediate Lp(a) concentrations developed pronounced cyclic reductions of flow but did not progress to permanent cessation of flow. There were no differences in plasma von Willebrand factor activity among the three groups. Immunohistochemical analysis of the damaged arterial segments indicated incorporation of Lp(a) into the adventitia, media, and intima of arteries from monkeys with low and high plasma Lp(a) concentrations, as well as the presence of an occlusive thrombus in arteries that developed permanent cessation of flow.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral Contraceptives and Hormone Replacement Therapy Do Not Increase the Incidence of Arterial Thrombosis in a Nonhuman Primate Model

“…Two parameters that have previously been shown to be important in this injury/stenosis model are vWF and Lp(a). 33,34 In this model, the absence of vWF prevents arterial thrombosis, whereas high levels of Lp(a) have been shown to be associated with an increase in arterial thrombosis. 34 In this study, neither the plasma concentrations of vWF nor those of Lp(a) were associated with occlusive arterial thrombosis.…”

“…33,34 In this model, the absence of vWF prevents arterial thrombosis, whereas high levels of Lp(a) have been shown to be associated with an increase in arterial thrombosis. 34 In this study, neither the plasma concentrations of vWF nor those of Lp(a) were associated with occlusive arterial thrombosis. In the previous studies, vWF was absent, whereas in this study, even the lowest levels would be sufficient to support arterial thrombosis.…”

“…49 The technique, developed originally in dogs, has been used in other species, including monkeys. 34,50 Although this model does not require the presence of atherosclerotic plaque and does not directly mimic what happens during plaque rupture, it, like other injury thrombosis models, causes intimal injury and exposes subintimal components to circulating blood in a setting of altered blood flow.…”

Structural basis for the pathophysiology of lipoprotein(a) in the athero-thrombotic process

“…Scarce evidence has been obtained from a few experimental studies. Occlusive arterial thrombosis with incorporation of Lp(a) into damaged arterial segments was observed in cynomolgous monkeys with high plasma Lp(a) levels (38). Biemond et al (39) studied the effect of a recombinant form of apo(a) on endogenous and t-PAmediated lysis in an in vivo model of experimental thrombosis; endogenous thrombolysis but not t-PA-induced lysis was significantly reduced in the presence of apo(a).…”

Hypertriglyceridemic VLDL Downregulates Tissue Plasminogen Activator Gene Transcription Through cis -Repressive Region(s) in the Tissue Plasminogen Activator Promoter in Cultured Human Endothelial Cells

“…4,5 Therefore, it is conceivable that perturbation of the expression or activity of Ն1 of these fibrinolytic proteins may alter the hemostatic balance on the EC surface, thus promoting early initiation of fibrin deposition, atherogenesis, CAD, and eventual MI. 1 Several atherogenic lipoproteins may cause such a perturbation; eg, Lp(a), 6 oxidized LDL, 7,8 and acetylated LDL 9 increase PAI-1 levels and decrease tPA expression in cultured human ECs. 8,10 In addition, abnormal triglyceride-rich lipoproteins, including VLDL (hypertriglyceridemic VLDL [HTG-VLDL]), have been shown to increase PAI levels 11,12 and decrease surface localized plasmin generation.…”