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Measurement of Factor V Activity in Human Plasma Using a Microplate Coagulation Assay
Published on: September 9, 2012
Importance of Coagulation Factors as Critical Components of Premature Cardiovascular Disease in Familial
Uffe Ravnskov1, Michel de Lorgeril2, Malcolm Kendrick3
1Independent Researcher, Magle Stora Kyrkogata 9, 22350 Lund, Sweden.
Insights
Familial hypercholesterolemia (FH) may not be caused by high LDL cholesterol. Increased thrombogenic factors, like higher factor VIII and fibrinogen, appear to be key drivers of premature cardiovascular events in FH patients.
Area of Science:
- Cardiovascular Science
- Genetics
- Biochemistry
Background:
- Familial hypercholesterolemia (FH) is a genetic disorder characterized by extremely high levels of low-density-lipoprotein cholesterol (LDL-C).
- Traditionally, elevated LDL-C has been implicated as the primary cause of atherosclerosis, cardiovascular disease, and ischemic stroke in FH patients.
- However, existing evidence presents inconsistencies with established causality criteria, prompting a re-evaluation of FH pathogenesis.
Purpose of the Study:
- To critically examine the causal link between elevated LDL-C and cardiovascular outcomes in familial hypercholesterolemia.
- To investigate alternative risk factors contributing to premature cardiovascular mortality in FH.
- To review existing literature for evidence supporting thrombogenic factors as primary drivers of cardiovascular events in FH.
Main Methods:
- Systematic review of observational and experimental studies on familial hypercholesterolemia.
- Analysis of data correlating LDL-C levels with atherosclerosis severity and lifespan in FH cohorts.
- Comparative analysis of biomarkers, including lipoprotein (a) (Lp(a)), factor VIII, and fibrinogen, in FH individuals with differing lifespans and cardiovascular outcomes.
Main Results:
- Studies show no consistent association between LDL-C levels and the degree of atherosclerosis or coronary artery calcium (CAC) in FH.
- The average lifespan of individuals with FH is comparable to the general population, and no cholesterol-lowering trials in FH have shown positive outcomes.
- Prematurely deceased FH individuals exhibit higher levels of Lp(a), factor VIII, and/or fibrinogen, with no significant difference in LDL-C compared to those with normal lifespans.
Conclusions:
- High LDL-C is unlikely to be the sole or primary cause of premature cardiovascular mortality in familial hypercholesterolemia.
- Individuals with FH may inherit other significant risk factors beyond elevated LDL-C.
- Increased coagulation factors represent a common, potentially primary, risk factor for adverse cardiovascular events in FH, with other factors also possibly involved.
Abstract:
For almost a century, familial hypercholesterolemia (FH) has been considered a serious disease, causing atherosclerosis, cardiovascular disease, and ischemic stroke. Closely related to this is the widespread acceptance that its cause is greatly increased low-density-lipoprotein cholesterol (LDL-C). However, numerous observations and experiments in this field are in conflict with Bradford Hill's criteria for causality. For instance, those with FH demonstrate no association between LDL-C and the degree of atherosclerosis; coronary artery calcium (CAC) shows no or an inverse association with LDL-C, and on average, the life span of those with FH is about the same as the surrounding population. Furthermore, no controlled, randomized cholesterol-lowering trial restricted to those with FH has demonstrated a positive outcome. On the other hand, a number of studies suggest that increased thrombogenic factors-either procoagulant or those that lead to high platelet reactivity-may be the primary risk factors in FH. Those individuals who die prematurely have either higher lipoprotein (a) (Lp(a)), higher factor VIII and/or higher fibrinogen compared with those with a normal lifespan, whereas their LDL-C does not differ. Conclusions: Many observational and experimental studies have demonstrated that high LDL-C cannot be the cause of premature cardiovascular mortality among people with FH. The number who die early is also much smaller than expected. Apparently, some individuals with FH may have inherited other, more important risk factors than a high LDL-C. In accordance with this, our review has shown that increased coagulation factors are the commonest cause, but there may be other ones as well.
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