The initial clinical manifestation in patients affected by familial hypercholesterolemia may be the occurrence of acute coronary syndrome (ACS) (Table 1). ACS refers to a group of disorders characterized by decreased blood flow, including ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina. Current literature suggests that the prevalence of FH among individuals who require in-patient care for ACS was about 10 times higher compared with the general population [24]. In a cohort of 105 individuals with very-early-onset coronary artery diseases (<35 years old), the occurrence of FH pathogenic mutations (including LDLR, APOB, PCSK9, APOE, STAP1, LIPA, LDLRAP1, ABCG5/8) was 38.1% [25].

In a clinical trial that was conducted in the United States and involved 1,697,513 ACS hospital admissions, the authors of the study found that participants with FH were younger, had less concomitant conditions and were more likely to experience in-hospital cardiac problems than those without FH. Moreover, they frequently presented with STEMI and have a higher incidence of recurrent ACS [26].

In the YOUNG-MI registry, nearly 1 out of 10 patients with myocardial infarction at young age were affected by FH. Many of them had elevated LDLc at one year despite high-intensity statin therapy after discharge [27].

A cohort of 320 individuals who had survived their first STEMI ≤ 35 years of age revealed that one out of five patients had clinical heterozygous FH, who, despite their use of statins, showed a high recurrence of cardiac events [28].

Moreover, even among individuals who are taking high-intensity lipid-lowering medication, the risk of long-term death is twice as high in FH patients as it is in controls [29].

The Dutch Lipid Clinic Network method is advised by the International Familial Hypercholesterolemia Foundation and the National Lipid Association in the USA to detect FH patients early in order to prevent premature ACS [30,31].

Hence, it becomes clear that an early diagnosis is necessary and new therapeutic targets need to be found.

In addition to blood levels of LDL cholesterol, other inherited variables may contribute to cardiovascular risk in people with FH, such as coagulation factors and Lp(a) (Table 2). It was found that maternal FH may influence coagulation and fibrinolytic factors in offspring independently of the children’s FH status [32]. Increased coagulation factors are associated with premature cardiovascular diseases in patients affected by FH [21]. The platelets aggregation ability of these people seems to be enhanced compared to those without FH [33]. In research that included 164 patients with FH and 160 control patients, mean platelet volume (MPV) was higher in individuals with FH and was independently correlated with total cholesterol level [34]. It has been shown that larger platelets are more reactive and more prone to adhesion and that MPV may predict CVD and outcomes in patients with coronary artery disease (CAD) [35]. Another important parameter is factor VII (FVII), that has a key role in coagulation cascade. In a study consisting of 421 people, authors demonstrated that subjects affected by FH with a lack functional LDLR had increased levels of FVII suggesting that the LDLR might have a suppressing role on this glycoprotein blood levels [36]. Additionally, LDLR locus single nucleotide polymorphisms were linked to CAD, independent of lipid profile and consistent with FVII levels. The LDLR locus may have pleiotropic influences on either plasma lipid or coagulation factor levels, which in turn may modulate the risk of CVD [37].

Besides, based on current literature, lowering lipids drug are suspected to be related to coagulation cascade. Statins seem to have a pleiotropic effect through thrombotic factors [38], meanwhile PCSK9 may play an interesting role in the process of thrombogenesis. It was observed that PCSK9 knockout mice have reduced platelet activity and developed less agonist-induced arterial thrombosis compared to the animal control group. Otherwise, elevated blood levels of PCSK9 in humans are associated with an increased platelet reactivity [39]. The breakdown of this blood clotting factor is facilitated by LDLR [40] and PCSK9 inhibitor decreased plasma levels/activity of fibrinogen and plasminogen activator inhibitor 1 [41]. As a result, PCSK9 raises FVII. To conclude, the coagulation factors may play a critical role in FH [42]; however, their mechanisms are still unclear.

Lp(a) is a macromolecular complex made up of one LDL-particle molecule covalently bound to an apoB-100 containing polymorphic glycoprotein molecule apo(a) [43]. Apo(a) is characterized by a triple loop-like structure called “Kringle”, similar to other coagulation factors such as plasminogen (PLG) or prothrombin. Lp(a) blocks the plasmin formation competing with PLG for the binding sites on endothelial cells [44]. This process leads to a delay in fibrinolysis, which means an increased ratio of thrombosis [45]. Despite its role in venous thromboembolism, Lp(a) is linked to an increased incidence of CVD and in particular coronary heart disease [46,47]. Lp(a) is also an independent risk factor for premature cardiovascular events in the general population due to a pro-atherosclerotic effect of ApoB-100. Its blood concentration is significantly influenced by sex, gender, lifestyle and chronic diseases and it seems that hyperlipoproteinemia (a) enhances the occurrence of atherosclerotic cardiovascular diseases in FH [48]. Alonso et al. studied a population of over than 2000 patients, which includes individuals with or without FH, and it has been shown that FH patients, especially those with history of CVD, had elevated Lp(a) plasma levels. A significant high plasma levels of Lp(a) has been related to null and defective mutations of LDLR. Indeed, the Lp(a) could be considered an independent predictor of cardiovascular disease [49]. Furthermore, higher blood levels of Lp(a) in individuals affected by FH are linked to an elevated occurrence of Lp(a) variants and the risk of CVD is increased twofold when both conditions coexist [50]. Hyperlipoproteinemia(a) has been proven to be a predictor of premature atherosclerotic cardiovascular disease in a cohort of patients affected by FH [51]. Furthermore, the measured blood levels of LDLc consist of aggregating LDL and Lp(a) particles. The cholesterol content of Lp(a) constitutes up to 30–45%; therefore, it is necessary to correct LDLc in order to determine the proportion of Lp(a). A study including more than 500,000 individuals discovered that LDLc was no longer a risk factor for incident cardiovascular disease if the correction of LDLc was implemented [52]. Additionally, high blood levels of Lp(a) lead to elevated risk of myocardial infarction [53]; therefore, a routinely testing of Lp(a) may identify individuals who will develop more premature cardiovascular events [54].