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Atherogenic Lipoproteins Support Assembly of the Prothrombinase
Complex and Thrombin Generation: Modulation by Oxidation and Vitamin
E
Simin Rota,
Nicola A. McWilliam,
Trevor P. Baglin, and
Christopher
D. Byrne
From the University Department of Clinical Biochemistry and the
Department of Haematology, Addenbrooke's Hospital, Cambridge, UK.
The importance of lipoproteins in the etiology of atherosclerosis is
well established. Evidence is now accumulating to implicate thrombin in
the pathogenesis of atherosclerosis. We have investigated whether
atherogenic lipoproteins can support thrombin generation. In the
absence of platelets or endothelial cells, both very low-density lipoprotein (VLDL) and oxidized low-density lipoprotein (LDL) support
assembly of the prothrombinase complex and generation of thrombin.
Thrombin generation (per µg of apolipoprotein) supported by VLDL was
19.4-fold greater than that supported by high-density lipoprotein
(HDL), P < .00001, and 11.7-fold greater than that supported by LDL, P < .00001. Oxidation of LDL increased
lipoprotein-supported thrombin generation 12-fold compared to
unmodified LDL, P < .0001. We have shown that the
phenomenon of lipoprotein-supported thrombin generation is mediated
predominantly by specific phospholipids and is enhanced by oxidation of
these phospholipids. The addition of vitamin E ( -tocopherol)
markedly reduced the increase in thrombin generation observed after
oxidation of LDL (822 ± 57 v 138 ± 47 nmol/L;
P < .0001). These effects suggest that lipoproteins
are important in the production of thrombin and that vitamin E may confer protection from the detrimental effects of lipoprotein oxidation
by limiting thrombin formation. These results suggest that atherogenic
lipoproteins are linked to the development of atherosclerosis in part
by their capacity to support thrombin generation.
Blood, Vol. 91 No. 2 (January 15), 1998:
pp. 508-515
© 1998 by The American Society of Hematology.
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