Effects of VLDL and remnant particles on platelets.
Abstract
There is a considerable body of evidence supporting an association between hypertriglyceridaemia, a hypercoagulable state and atherothrombosis. A disorder of triglyceride metabolism is a key feature of the metabolic syndrome that increases risk of both ischaemic heart disease and type 2 diabetes approximately 3-fold. An increasing prevalence of obesity and metabolic syndrome is likely to contribute markedly to the prevalent ischaemic heart in the foreseeable future, and therefore it is crucial to understand mechanisms linking hypertriglyceridaemia and a hypercoagulable state. Activation of platelets and the coagulation cascade are intertwined. VLDL and remnant lipoprotein concentrations are often increased with the metabolic syndrome. These lipoproteins have the capacity to activate platelets and the coagulation pathway, and to support the assembly of the prothrombinase complex. VLDL also upregulates expression of the plasminogen activator inhibitor-1 gene and plasminogen activator inhibitor-1 antigen and activity, a process accompanied by platelet aggregation and clot formation. The surface membrane of activated platelets also supports the assembly and activity of the prothrombinase complex, resulting in further thrombin generation and amplification of the coagulation cascade. Fibrinolysis is also less efficient when thrombin is generated. Thrombin induces thrombin activatable fibrinolysis inhibitor. Thrombin activatable fibrinolysis inhibitor is a carboxypeptidase that cleaves the carboxylic lysine residues on fibrin, thereby abolishing the critical binding site for tPA-plasminogen decreasing plasmin formation. Thus the evidence is supportive of dysregulated coagulation, and impaired fibrinolysis with a predisposition to atherothrombosis, in conditions such as the metabolic syndrome, in which there are increased concentrations of VLDL and remnant lipoproteins. The purpose of this review is to describe the current evidence supporting a procoagulant state induced by VLDL and remnant lipoproteins. The role of these lipoprotein classes in (1) platelet activation; (2) the intrinsic coagulation cascade, and (3) clot formation and fibrinolysis is discussed.
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In vitro studies have implicated these lipids (and in some experiments lipolysis of triglyceride) in inflammation, expression of adhesion molecules, and promotion of coagulation.
“In vitro studies have implicated these lipids (and in some experiments lipolysis of triglyceride) in inflammation (147), expression of adhesion molecules (148), and promotion of coagulation (149).”
From Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline (2012) · cites this paper as [149]
TRL remnants contribute to a prothrombotic phenotype by promoting platelet activation and aggregation and modulating endothelial and systemic hemostatic responses.
“In addition, TRL remnants contribute to a prothrombotic phenotype within the vascular wall by promoting platelet activation and aggregation, and by modulating both endothelial and systemic hemostatic responses [29–32].”
From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [31]
Triacylglycerols have been linked to nephropathy through VLDL induction of PAI-1 with upregulated coagulation and intra-renal microthrombi.
“and through VLDL induction of plasminogen activating inhibitor-1 (PAI-1) with upregulated coagulation and intra-renal microthrombi [33].”
Cites
Cardiovascular Morbidity and Mortality Associated With the Metabolic Syndrome
Isomaa, B., Almgren, P., Tuomi, T., Forsén, B., Lahti, K., Nissén, M., Taskinen, M.-R., & Groop, L. (2001) · Diabetes Care · doi:10.2337/diacare.24.4.683 · Cited by 4,760 · see citing works
Hokanson, J. E., & Austin, M. A. (1996) · Journal of Cardiovascular Risk · doi:10.1097/00043798-199604000-00014 · Cited by 1,706 · see citing works
Plasminogen-Activator Inhibitor Type 1 and Coronary Artery Disease
Kohler, H. P., & Grant, P. J. (2000) · New England Journal of Medicine · doi:10.1056/nejm200006153422406 · Cited by 805 · see citing works
Ford, E. S. (2004) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2003.12.022 · Cited by 501 · see citing works
Broze, G. J., Warren, L., Novotny, W., et al. (1988) · Blood · doi:10.1182/blood.v71.2.335.335 · Cited by 481 · see citing works
Evidence that triglycerides are an independent coronary heart disease risk factor
Cullen, P. (2000) · The American Journal of Cardiology · doi:10.1016/s0002-9149(00)01127-9 · Cited by 462 · see citing works
Sobel, B. E., Woodcock‐Mitchell, J., Schneider, D. J., Holt, R. E., Marutsuka, K., & Gold, H. K. (1998) · Circulation · doi:10.1161/01.cir.97.22.2213 · Cited by 270 · see citing works
Eriksson, P., Nilsson, L., Karpe, F., & Hamsten, A. (1998) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/01.atv.18.1.20 · Cited by 187 · see citing works
Pandolfi, A., Cetrullo, D., Polishuck, R. S., Alberta, M. M., Calafiore, A., Pellegrini, G., Vitacolonna, E., Capani, F., & Consoli, A. (2001) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/hq0801.093667 · Cited by 156 · see citing works
Juhan-Vague, I., Alessi, M., & Vague, P. (1996) · Annals of Medicine · doi:10.3109/07853899608999095 · Cited by 142 · see citing works
Effect of plasminogen activator inhibitor–1 in diabetes mellitus and cardiovascular disease
Lyon, C. J., & Hsueh, W. A. (2003) · The American Journal of Medicine · doi:10.1016/j.amjmed.2003.08.014 · Cited by 131 · see citing works
Chomiki, N., Henry, M., Alessi, M., Anfosso, F. J., & Juhan-Vague, I. (1994) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1648809 · Cited by 108 · see citing works
Cardiolipin is a normal component of human plasma lipoproteins
Deguchi, H., Fernández, J. A., Hackeng, T. M., Banka, C. L., & Griffin, J. H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1743 · Cited by 105 · see citing works
Rota, S., McWilliam, N. A., Baglin, T. P., & Byrne, C. D. (1998) · Blood · doi:10.1182/blood.v91.2.508 · Cited by 103 · see citing works
Self-citationPlasma Lipoproteins Support Prothrombinase and Other Procoagulant Enzymatic Complexes
Moyer, M. P., Tracy, R. P., Tracy, P. B., Veer, C. V. ′., Sparks, C. E., & Mann, K. G. (1998) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.18.3.458 · Cited by 102 · see citing works
Mitropoulos, K. A., Miller, G. J., Watts, G. F., & Durrington, P. N. (1992) · Atherosclerosis · doi:10.1016/0021-9150(92)90015-9 · Cited by 96 · see citing works
Risk of Coronary Heart Disease and Activation of Factor XII in Middle-Aged Men
Miller, G. J., ESNOUF, M. P., Burgess, A. I., Cooper, J. A., & Mitchell, J. P. (1997) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.17.10.2103 · Cited by 95 · see citing works
Insulin resistance syndrome: interaction with coagulation and fibrinolysis
Köhler, H.-P. (2002) · Swiss Medical Weekly · doi:10.4414/smw.2002.09856 · Cited by 94 · see citing works
Kohler, H. P., Carter, A., Stickland, M. H., & Grant, P. J. (1998) · Thrombosis and Haemostasis · doi:10.1055/s-0037-1614210 · Cited by 86 · see citing works
Zito, F., Drummond, F., Bujac, S. R., ESNOUF, M. P., Morrissey, J. H., Humphries, S. E., & Miller, G. J. (2000) · Circulation · doi:10.1161/01.cir.102.17.2058 · Cited by 82 · see citing works
Characterization of the Effect of Plasma Lipoproteins on Platelet Function in vitro
Aviram, M., & Brook, J. G. (2009) · Haemostasis · doi:10.1159/000214820 · Cited by 67 · see citing works
Platelet function, coagulopathy, and impaired fibrinolysis in diabetes
Sobel, B. E., & Schneider, D. J. (2004) · Cardiology Clinics · doi:10.1016/j.ccl.2004.06.009 · Cited by 65 · see citing works
Iwai, N., Shimoike, H., Nakamura, Y., Tamaki, S., & Kinoshita, M. (1998) · Atherosclerosis · doi:10.1016/s0021-9150(97)00191-3 · Cited by 63 · see citing works
Saniabadi, A. R., Umemura, K., Shimoyama, M., Adachi, M., Nakano, M., & Nakashima, M. (1997) · Thrombosis and Haemostasis · doi:10.1055/s-0038-1656092 · Cited by 62 · see citing works
A Novel Role for CD36 in VLDL-Enhanced Platelet Activation
Englyst, N. A., Taube, J. M., Aitman, T. J., Baglin, T. P., & Byrne, C. D. (2003) · Diabetes · doi:10.2337/diabetes.52.5.1248 · Cited by 59 · see citing works
Self-citationThe influence of lipoproteins on blood platelets
Surya, I. I., & Akkerman, J. N. (1993) · American Heart Journal · doi:10.1016/0002-8703(93)90096-r · Cited by 55 · see citing works
Hypofibrinolysis in the insulin resistance syndrome: implication in cardiovascular diseases
Mavri, A., Alessi, M., & Juhan-Vague, I. (2004) · Journal of Internal Medicine · doi:10.1046/j.1365-2796.2003.01288.x · Cited by 52 · see citing works
Pathophysiology of triglyceride-rich lipoproteins in atherothrombosis: Clinical aspects
Hodis, H. N., Mack, W. J., Krauss, R. M., & Alaupovic, P. (1999) · Clinical Cardiology · doi:10.1002/clc.4960221404 · Cited by 43 · see citing works
Pedreño, J., Hurt‐Camejo, E., Wiklund, O., et al. (2000) · Metabolism · doi:10.1053/meta.2000.6742 · Cited by 40 · see citing works
Yamazaki, M., Uchiyama, S., Xiong, Y., Nakano, T., Nakamura, T., & Iwata, M. (2004) · Thrombosis Research · doi:10.1016/j.thromres.2004.08.029 · Cited by 30 · see citing works
Vitamin K-Dependent Proteins Bind to Very Low-Density Lipoproteins
Bradley, W. A., & Gianturco, S. H. (1988) · Seminars in Thrombosis and Hemostasis · doi:10.1055/s-2007-1002786 · Cited by 27 · see citing works
Klein, S., Spannagl, M., & Engelmann, B. (2001) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvb.21.10.1695 · Cited by 22 · see citing works
Ishii, K., Oguchi, S., Murata, M., et al. (2000) · PubMed · Cited by 22 · see citing works
Saniabadi, A. R., Umemura, K., Suzuki, Y., Kondo, K., Ikeda, Y., Adachi, M., & Nakashima, M. (1998) · Life Sciences · doi:10.1016/s0024-3205(98)00368-3 · Cited by 10 · see citing works
Flagged first, then by citations
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Sorted by citations
Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline
Berglund, L., Brunzell, J. D., Goldberg, A. C., Goldberg, I. J., Sacks, F., Murad, M. H., & Stalenhoef, A. F. H. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-3213 · Cited by 887 · see citing works
“(148), and promotion of coagulation (149).”
Sandesara, P. B., Virani, S. S., Fazio, S., & Shapiro, M. D. (2019) · Endocrine Reviews · doi:10.1210/er.2018-00184 · Cited by 626 · see citing works
NAFLD as a driver of chronic kidney disease
Byrne, C. D., & Targher, G. (2020) · Journal of Hepatology · doi:10.1016/j.jhep.2020.01.013 · Cited by 449 · see citing works
on behalf of the FIELD Study investigators, Davis, T. M. E., Ting, R., Best, J. D., Donoghoe, M. W., Drury, P. L., Sullivan, D. R., Jenkins, A. J., O’Connell, R. L., Whiting, M. J., et al. (2011) · Diabetologia · doi:10.1007/s00125-010-1951-1 · Cited by 371 · see citing works
Triglyceride-rich lipoproteins as a causal factor for cardiovascular disease
Toth, P. (2016) · Vascular Health and Risk Management · doi:10.2147/vhrm.s104369 · Cited by 237 · see citing works
Targeting triglycerides for cardiovascular risk reduction
Maiorca, C., Tramontano, D., Di Costanzo, A., & D’Erasmo, L. (2026) · Internal and Emergency Medicine · doi:10.1007/s11739-026-04383-1
- Authors
- Olufadi, R., & Byrne, C. D.
- Affiliations
- Southampton General Hospital (GB)
- Venue
- Pathophysiology of Haemostasis and Thrombosis
- Publisher
- S. Karger AG
- Published
- 2006
- Volume
- 35
- Issue
- 3-4
- Pages
- 281-291
- ISSN
- 1424-8832 (ISSN-L)
- 1424-8840
- OpenAlex
- W2069898248
- Cited by
- 111
- References
- 34
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 11 · 2023: 12 · 2022: 10 · 2021: 9 · 2020: 7 · 2019: 2 · 2018: 6 · 2017: 3 · 2016: 7 · 2015: 2 · 2014: 3 · 2013: 1 · 2012: 3
- FWCI
- 2.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pathophysiology of Haemostasis and Thrombosis (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Blood properties and coagulation
- Keywords
- VLDL, remnant lipoproteins, platelet activation, hypertriglyceridemia, metabolic syndrome, hypercoagulability, atherothrombosis, prothrombinase complex, plasminogen activator inhibitor-1, fibrinolysis, thrombin, thrombin-activatable fibrinolysis inhibitor, thrombus formation
- MeSH terms
- Blood Coagulation, Blood Platelets, Cholesterol, Factor V, Fibrinolysis, Humans, Lipoproteins, Models, Biological, Thrombosis, Triglycerides, Cholesterol, VLDL, Signal Transduction, Platelet Activation, Factor Xa, Plasminogen Activator Inhibitor 1
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