In each of the families studied, we observed particular characteristics. For example, in Family 2, the one with the highest number of patients with LCPD (Figure 1B), there were also members who suffered from osteoarthritis. This pathology has been previously related to LCPD [23], so it would be of interest to continue studying in order to know if, in our population, there could be alterations related to bone development possibly associated with LCPD.
LCPD is a complex disease; the lack of knowledge regarding its etiology is considered the main obstacle to its study. Different etiological factors have been described as the causative agents of LCPD, some of them present in our population, such as socioeconomic deprivation, which is an important factor to consider, since it has been observed that, in the population with lower socioeconomic levels, there is a higher incidence of the disease. The socioeconomic level of our population ranged between middle, lower middle, and lower classes, which can be considered as an environmental factor and could be related to the predisposition to LCPD due to poor nutrition, urbanization and other variables [24,25].
Another factor present in our group of patients is exposure to wood and tobacco smoke, which has been proposed in several studies as an important factor in the appearance of LCPD. According to what has been described, wood or tobacco smoke may be related to alterations in hemostasis by various mechanisms [26-28].
Moreover, in our population, there are disturbances in the distribution of mechanical loads, such as overdue arches and/or the practice of high-impact sports like taekwondo, which could lead to the development of LCPD due to the discrepancy of the forces applied on the hip and femur, as well as venous occlusion [29,30].
A family study was performed with the presence of related patients, so genetically it is proposed that LCPD could be caused by inherited factors. Although no evidence was found that could relate the polymorphisms studied to LCPD, the fact that other genetic alterations could be involved in the development of this disease cannot be ruled out [31,32].
Regarding laboratory studies, all our patients presented high hemoglobin levels, a factor linked to increased blood viscosity and, probably, to subsequent thrombotic events [33-35]. In addition, our results show that there are different hemostatic alterations in every individual analyzed, presenting out-of-range values in one or more parameters.
When patients were compared with controls, significant differences were found in some parameters, such as fibrinogen. It is interesting to note that the circulating amount of fibrinogen, the G455A polymorphism in the β-chain of fibrinogen, and its interaction with exposure to tobacco smoke have been described as risk factors for LCPD [36]. This is an example of how the relationship of environmental, genetic, and metabolic factors may be related to the development of LCPD.
Because the elevated levels of FIX have been established as risk factors for lower limb venous thrombosis, and given that we found higher FIX activity in the patient group, it is presumable that FIX could play a role in the development of LCPD [37].
Homocysteine disturbances have emerged as risk factors for multiple pathological conditions, such as osteoporosis, venous thrombosis, osteonecrosis, and LCPD [38,39], while elevated Hcy levels have been associated with increased oxidative stress in the bone microenvironment. This could lead to increased osteoclast differentiation and activity. Additionally, oxidative stress decreases the viability of nitric oxide through the production of superoxide anions, which would result in decreased bone blood flow and possibly affect angiogenesis. It has been described that osteoblast activity is affected by Hcy concentration [38]. Hcy concentration, on the other hand, can be altered by factors such as diet and lifestyle [39].
The C677T polymorphism is a point mutation in position 677 on the methylenetetrahydrofolate reductase (MTHFR) gene with the substitution of cysteine to thymine nucleotide. This point mutation causes the substitution of alanine to valine in the MTHFR enzyme. The single nucleotide polymorphism of this gene reduces the ability of the MTHFR enzyme to catalyze the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate and leads to the rise of plasma homocysteine levels in the homozygous mutated subjects, while the heterozygous mutated subjects have mildly raised Hcy levels compared to the normal, non-mutated controls [40]. All the patient’s members of the families studied, presented the mutated polymorphism in a homozygous or heterozygous manner.
Based on the study of clotting factors and Hcy in a group of patients with LCPD, we decided to study only familial cases and began with the study of MTHFR. Our findings in this studied population of familial cases with LCPD agrees with previous studies where the same factors have been related to LCPD onset and development. We also observed that some environmental factors specific to each family, together with hemostatic disorders, may be involved in the development of LCPD. In addition, we presume that, since we found familial cases, it is very likely that there is an important contribution of inherited genetic factors. Although with this sample we cannot establish a specific type of inheritance. We intend to continue with the study of different polymorphisms, such as that of MTHFR. To establish if these polymorphisms are related to the LCPD. In this study, we wish to highlight the presence of a multifactorial picture, in which diverse environmental, genetic, and prothrombotic factors are involved in this pathology.