Procoagulation Factors in Cardiovascular Complications Among Individuals with Familial Hypercholesterolemia

Familial Hypercholesterolemia (FH) is often considered to be a serious condition, causing Coronary Heart Disease (CHD) and stroke. It is generally accepted that the main cause of CHD and stroke among these people is their high cholesterol levels. However, there are too many contradictions to the theory affirming there is a direct causality between high cholesterol and Cardiovascular Disease (CVD) in these people. For instance, among individuals with FH there is no significant association between cholesterol levels and the severity of CVD. In addition, the life expectancy of individuals with FH is close to that of the population without FH. Finally, no controlled cholesterol-lowering trial in people with FH has demonstrated any significant benefit. On the other hand, studies suggest that procoagulant factors might be a critical risk factor in FH, as in patients without FH. For instance, FH individuals with CVD have high lipoprotein (a), high factor VIII and/or high fibrinogen (whereas their cholesterol does not differ) compared to those without CVD. Thus, many studies suggest that high cholesterol cannot be the cause of CVD mortality among individuals with FH. Some of them have inherited critical risk factors other than a high cholesterol. This review shows that inherited procoagulation factors may be one of the common causes of CVD in FH, not high cholesterol.

Keywords:Familial hypercholesterolemia; Cholesterol; Coagulation; Coronary heart disease; Cardiovascular disease; Lipoprotein (a); Fibrinogen; Factor VIII

Coronary Heart Disease (CHD) and stroke among people with FH is is considered to be caused by their high cholesterol. Some studies have demonstrated that Cardiovascular Disease (CVD) is associated with high cholesterol, but many other studies have shown that the cholesterol hypothesis is not credible [1]. For example, people with low cholesterol have the same degree of risk as people with high cholesterol [2,3]. A further support of this is that the trials testing anti-CETP and anti-PCSK9 drugs did not show a lowering of total or CVD mortality although these drugs lower cholesterol much more than the statins and, in addition, do increase the supposed “good” cholesterol by about 100% [4]. In recent reviews [5,6], we have shown many contradictions to the consensus about FH and CVD. Here, we present a summary of the studies in which it is shown that only a minority of FH-people die prematurely, and that those who die have inherited various procoagulation factors, whereas their cholesterol levels do not differ from those who have a normal life expectancy

The main contradictions

If a high cholesterol is the main cause of CVD, those with the highest values should have a higher risk compared with those with low values. In recent reviews [1-3], we show that several studies in the non-FH population report that those with low cholesterol have the same risk as those with high values. Furthermore, five studies in FH-individuals report that cholesterol levels are not associated with degrees of various markers of risk [7- 11]. It is generally believed that people with FH have a reduced life expectancy. However, this theory has been exclusively based on studies of people with FH and a family history of CVD or who already have clinical manifestations of CVD. This obviously introduces a major bias. In fact, two unbiased studies have shown that people with FH have a life expectancy comparable to the no-FH population. For instance, in the study by the Simon Broome Register group, 526 FH-individuals were followed for about four years [12]. Mortality was higher among those below age 60, but lower among the elderly. In another study, 4688 FH-individuals were followed from 1992 to 2010 [13]. During that time, CVD mortality was higher than in the general population, but total mortality was lower. Before the year 1900, the life expectancy of individuals with FH was as long as in the general population [14]. At that time, infectious diseases were the commonest causes of death. One possible reason why the life of people with FH was just as long as the life of people without FH may be that cholesterol-rich lipoproteins stimulate the immune system, a fact that has been well documented [15]. According to the cholesterol theory, cholesterol should be lowered as much as possible in individuals with FH. However, no cholesterol-lowering trial in FH has demonstrated significant benefit [6]. This is also true among individuals without FH [1-3]. Although it was claimed, for instance in a review of more than 30 statin-trials, that there was a significant benefit from the statin treatment [16], the authors only used data from twelve of the trials. When data from all trials are combined, the benefit is no longer present [1].

As the level of cholesterol in FH varies considerably, it is assumed that those individuals who suffer from CVD have higher cholesterol levels and will die earlier than those with the lowest values. Several studies have shown that age and cholesterol level in FH people with or without CVD did not differ significantly [5, 6]. Many of the participants in these studies were on statin treatment, which may have biased the results. However, five studies selected FH individuals without cholesterol-lowering treatment. Only one of these studies showed that the cholesterol level was higher in individuals with CHD [17-21]. Finally, among previous reviews on FH [5,6], ten randomized, controlled cholesterol-lowering trials that only included FH-individuals were identified. None of them succeeded in lowering CVD or global mortality, nor non-fatal CHD events. In one of them, patients with ileal bypass were compared with usual treatment [22]. Although cholesterol level was much lower in the ileal bypass group, the numbers of fatal and non-fatal events were almost identical in the two groups.

New explanations

Why do some individuals from families with FH suffer from early CHD? One possible answer is that - in addition to other classical risk factors such as smoking, diabetes, deleterious diet and others - they may have inherited other risk factors of CHD. If this is true, some of those with normal cholesterol levels in families with FH should also have a higher risk of CHD compared to the population without FH. This has indeed been shown in a study of a FH-kindred [23]. It has led to identify several other factors among FH individuals that are clearly associated with the risk of CHD. The commonest are inborn or acquired procoagulation factors and/or other thrombogenic factors, such as increased platelet aggregation. In a study of the platelet function in FH-people and non-FH people, the platelet aggregation parameters from those with FH were significantly increased [24]. Plasma fibrinogen and factor VIII levels are higher among FH people with CHD compared with those without CHD, with no difference in the levels of cholesterol [25]. In a study comparing 164 FH subjects with and without CHD (all without cholesterol-lowering treatment) with 160 subjects with “normal” cholesterol levels, the mean platelet volume was significantly higher in the FH subjects [26]. It has been shown that larger platelets are more prone to provoke formation of platelet thrombus [27]. In an analysis of DNA extracted from leukocytes in 2000 FH individuals, polymorphism in the prothrombin gene was strongly associated with CHD risk [21]. In addition, it was reported that polymorphism of the LDL-receptor - the main mechanism of high cholesterol in FH families - is associated with an increased level of coagulation factor VIII which is associated with accelerated coagulation [28].

Lipoprotein (a) [Lp(a)] is a major procoagulant factor and it is quite clear that Lp(a) is a direct cause of CHD in the non-FH population [29-31]. Obviously, Lp(a) may play the same role in FH. In a study of 388 FH individuals, the risk associated with Lp(a) was highly significant whereas the risk associated with cholesterol was non-significant [32]. In a comparison of 54 FH patients with CHD and 61 without CHD, Lp(a) was significantly higher among those with CHD, whereas cholesterol did not differ [33]. The same was found in a study of 782 FH patients with CVD and 1618 without CVD [34], and in a study of 247 FH patients with CHD and 1,713 without [35]. In the latter, cholesterol was even significantly higher among those without CHD.

We are showing that there is clearly little - if any-evidence that high cholesterol is the main cause of CVD in FH. In accordance, no controlled cholesterol-lowering trial in FH individuals has shown that such treatment is beneficial. It is therefore questionable to use cholesterol-lowering treatment in individuals with FH, with or without CVD. Another reason to abstain is that statins have many serious side effects [36-39]. Studies have shown that FHindividuals who suffer from CVD do have the same classical risk factors (smoking, diabetes, hypertension, deleterious diet and others) as people without FH [40]. It is likely that procoagulant factors may contribute to the additional risk associated with FH in certain families. To definitely demonstrate that procoagulation factors explain (at least partly) the risk of CVD in FH individuals, we need double-blind placebo-controlled trials testing whether anticoagulant (or antiplatelet) treatments may prevent CVD complications in FH patients.

1. Ravnskov U, de Lorgeril M, Diamond DM, Hama R, Hamazaki T, et al. (2018) LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature. Exp Rev Clin Pharmacol 11(10): 959-970.
2. Ravnskov U, de Lorgeril M, Diamond DM, Hamazaki T, Hammarskjöld B, et al. (2016) Lack of an association or an inverse association between low-density-lipoprotein cholesterol and mortality in the elderly: a systematic review. BMJ Open 6(6): e010401.
3. Ravnskov U, de Lorgeril M, Diamond DM, Hamazaki T, Hammarskjöld B, et al. (2020) The LDL paradox: higher LDL-cholesterol is associated with greater longevity. Epidemiol Public Health 3(1): 1040-1046.
4. Rabaeus M, de Lorgeril M (2019) A systematic review of clinical trials testing CETP and PCSK9 inhibitors: the cholesterol-heart theory-time for a requiem? J Controversies Biomed Res 5(1): 4-11.
5. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM (2018) Inborn coagulation factors are more important cardiovascular risk factors than high LDL-cholesterol in familial hypercholesterolemia. Med Hypotheses 121: 60-63.
6. Ravnskov U, de Lorgeril M, Kendrick M, Diamond DM (2022) Importance of coagulation factors as critical components of premature cardiovascular disease in familial hypercholesterolemia. Int J Mol Sci 23(16): 9146.
7. Kroon AA, Ajubi N, Asten WN, Stalenhoef AF (1995) The prevalence of peripheral vascular disease in familial hypercholesterolemia. J Intern Med 238(5): 451-459.
8. Hausmann D, Johnson JA, Sudhir K, Mullen WL, Friedrich G, et al. (1996) Angiographically silent atherosclerosis detected by intravascular ultrasound in patients with familial hypercholesterolemia and familial combined hyperlipidemia: correlation with high-density lipoproteins. J Am Coll Cardiol 27(7): 562-570.
9. Miname MH, Bittencourt MS, Moraes SR, Alves RI, Silva PR, et al. (2019) Coronary artery calcium and cardiovascular events in patients with familial hypercholesterolemia receiving standard lipid-lowering therapy. JACC Cardiovasc Imaging 12(9): 1797-1804.
10. Lavrencic A, Kosmina B, Keber I, Videcnik V, Keber D (1996) Carotid intima-media thickness in young patients with familial hypercholesterolemia. Heart 76(4): 321-325.
11. Martinez LR, Miname MH, Bortolotto LA, Chacra AP, Rochitte CE, et al. (2008) No correlation and low agreement of imaging and inflammatory atherosclerosis' markers in familial hypercholesterolemia. Atherosclerosis 200(1): 83-88.
12. (1991) Risk of fatal coronary heart disease in familial hypercholesterolemia. Scientific steering committee on behalf of the Simon Broome register group. BMJ 303(6807): 893-896.
13. Mundal L, Sarancic M, Ose L, Iversen PO, Borgan J, et al. (2014) Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992-2010. J Am Heart Assoc 3(6): e001236.
14. Sijbrands EJ, Westendorp RG, Defesche JC, de Meier PH, Smelt AH, et al. (2001) Mortality over two centuries in large pedigree with familial hypercholesterolemia: family tree mortality study. BMJ 322(7293): 1019-1023.
15. Ravnskov U (2003) High cholesterol may protect against infections and atherosclerosis. QJM 96(12): 927-934.
16. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, et al. (2017) Low-density lipoproteins cause atherosclerotic cardiovascular disease 1 Evidence from genetic, epidemiologic and clinical studies. A consensus statement from the European atherosclerosis society consensus panel. Eur Heart J 38(32): 2459-2472.
17. Yamashita S, Kawamoto T, Ueyama Y, Funahashi T, Hara H, et al. (1987) Relationship between LDL receptor activity and development of coronary heart disease in Japanese cases with heterozygous familial hypercholesterolemia. Artery 15(1): 24-43.
18. Seed M, Hoppichler F, Reaveley D, McCarthy S, Thompson GR, et al. (1990) Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med 322(21): 1494-1499.
19. Hill JS, Hayden MR, Frohlich J, Pritchard PH (1991) Genetic and environmental factors affecting the incidence of coronary heart disease in heterozygous familial hypercholesterolemia. Arterioscl Thromb 11(2): 290-297.
20. Tato F, Keller C, Schuster H, Spengel F, Wolfram GZ, et al. (1993) Relation of lipoprotein(a) to coronary heart disease and duplex sonographic findings of the carotid arteries in heterozygous familial hypercholesterolemia. Atherosclerosis 101(1): 69-77.
21. Jansen ACM, van Aalst-Cohen ES, Tanck MW, Cheng S, Fonmtecha MR, et al. (2005) Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 25(7): 1475-1481.
22. Koivisto P, Miettinen T (1984) Long-term effects of ileal bypass on lipoproteins in patients with familial hypercholesterolaemia. Circulation 70(2): 290-296.
23. Harlan WR, Graham JB, Estes EH (1966) Familial hypercholesterolemia: a genetic and metabolic study. Medicine 45: 77-110.
24. Carvalho AC, Colman RW, Lees RS (1974) Platelet function in hyperlipoproteinemia. N Engl J Med 290(8): 434-438.
25. Sugrue DD, Trayner I, Thompson GR, Vere VJ, Dimeson J, et al. (1985) Coronary artery disease and haemostatic variables in heterozygous familial hypercholesterolemia. Br Heart J 53(3): 265-268.
26. Icli A, Aksoy F, Nar G, Kaymaz H, Alpay MF, et al. (2015) Increased mean platelet volume in familial hypercholesterolemia. Angiology 67(2): 146-150.
27. Boos CJ, Lip GY (2007) Assessment of mean platelet volume in coronary artery disease-what does it mean? Thromb Res 120(1): 11-13.
28. Martinelli N, Girelli D, Lunghi B, Pionotti M, Marchetti G, et al. (2010) Polymorphism at LDLR locus may be associated with coronary artery through modulation of coagulation factor VIII activity and independently from lipid profile. Blood 116(25): 5688-5697.
29. Nordestgaard BG, Langsted A (2016) Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics and biology. J Lipid Res 57(11): 1953-1975.
30. Bucci M, Tana C, Giamberardino MA, Cipollone F (2016) Lp(a) and cardiovascular risk: investigating the hidden side of the moon. Nutr Metab Cardiovasc Dis 26(11): 980-986.
31. Boffa MB, Koschinsky ML (2016) Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res 57(5): 745-757.
32. Holmes DT, Schick BA, Humphries KH, Frohlich J (2005) Lipoprotein(a) is an independent risk factor for cardiovascular disease in heterozygous familial hypercholesterolemia. Clin Chem 51(11): 2067-2073.
33. Seed M, Hoppichler F, Reaveley D, McCarthy S, Thompson GR, et al. (1990) Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med 322(21): 1494-1499.
34. Jansen AC, Aalst-Cohen ES, Tanck MW, Trip MD, Lansberg PJ, et al. (2004) The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolemia: data in 2400 patients. J Intern Med 256(6): 482-490.
35. Alonso R, Andres E, Mata N, Fuentes-Jimenez F, Badimon L, et al. (2014) Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J Am Coll Cardiol 63(19): 1982-1989.
36. Diamond DM, Ravnskov U (2015) How statistical deception created the appearance that statins are safe and effective in primary and secondary prevention of cardiovascular disease. Expert Rev Clin Pharmacol 8(2): 201-210.
37. Tan B, Rosenfeldt F, Ou R, Stough C (2019) Evidence and mechanisms for statin-induced cognitive decline. Expert Rev Clin Pharmacol, pp. 1-10.
38. Roy S, Hyman D, Ayyala S, Bakhshi A, Kim SH, et al. (2020) Cognitive function assessment in patients on moderate- or high-intensity statin therapy. J Clin Med Res 12(4): 255-265.
39. Jurcau A, Simion A (2021) Cognition, statins, and cholesterol in elderly ischemic stroke patients: a neurologist's perspective. Medicina 57: 616-629.
40. Diamond DM, Alabdulgader AA, de Lorgeril M, Harcombe Z, Kendrick M, et al. (2021) Dietary recommendations for familial hypercholesterolemia: an evidence-free zone. BMJ Evid Based Med 26(6): 295-301.