**5. Vitamin D and thrombosis**

highest prevalence [28]. Defined by the IDF criteria, the prevalence of MetS among 71 Brazilian PAPS patients was 33.8% [27]. Comparable prevalences of MetS were recorded among 58 Mexican PAPS patients, using NCEP ATP III (34.5%) or IDF definitions (37.9%), while it was only 17.2% when WHO definition was applied [3]. It has been hypothesized that these cases, identified by WHO definition, were insulin resistant and with more severe forms of MetS [3, 29]. However, in investigation conducted by Medina et al., prevalence of MetS among PAPS patients was higher than in corresponding general population (17.2% vs. 13.6%) when WHO definition was used [3]. Same as in general population without APS [20, 21, 23], among PAPS patients agreement between WHO and NCEP ATP III definitions of MetS was low (κ value 0.394), moderate between WHO and IDF definitions (κ value 0.427), while only between NCEP

Regarding individual components of MetS, atherogenic dyslipidaemia was most prevalent among Mexican PAPS patients, being present in approximately half of them [3]. Significantly higher mean triglyceride levels and significantly lower mean HDL levels were previously reported among PAPS patients in comparison with controls [30–33]. Some specific autoanti‐ bodies could influence lipoprotein levels and effects in these patients. These antibodies may interfere with paraoxonase (PON) activity of HDL and, indirectly, beta‐2‐glycoprotein I (beta‐ 2‐GPI) [32, 33], thus promoting LDL oxidation. Relationships between lipid profile, certain anti‐lipoprotein antibodies, inflammatory markers and clinical manifestations of PAPS were meticulously investigated [31–33], but on relatively small number of patients and with inconsistent results. Delgado Aves et al. have not demonstrated any correlation between the observed decrease in PON activity and either aPL nor antibodies against HDL (anti‐HDL) in PAPS patients [33]. However, pro‐inflammatory and prothrombotic roles were proposed for anti‐HDL, being present in higher titre among asymptomatic persistently aPL positive subjects, as well as in PAPS patients with thrombotic events, when compared with patients with inherited thrombophilia and healthy controls [32]. It has been also hypothesized that hypertriglyceridemia could be the result of decreased degradation as a consequence of an inhibition of lipoprotein lipase (LPL) by aPL [3]. Currently, there are only scarce data on prevalence of antibodies against LPL (anti‐LPL) in PAPS patients, speaking against their

Different authors have observed similar prevalences of hypertension among PAPS patients (22.4 and 26.3%) [3, 31], not differing significantly from that in controls (20%). Nevertheless, among PAPS patients, hypertension was significantly more frequent in those with arterial thrombosis, with which it was independently associated [31]. It is interesting that in spite of highly prevalent insulin resistance (32.8%), hyperglycaemic disorders were present in only 5%

**4.2. Metabolic syndrome in patients with antiphospholipid syndrome associated with**

The literature data on coexistence of MetS and numerous rheumatic diseases (i.e. systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, ankylosing spondylitis, osteoarthritis, gout) are fairly extensive [1, 34–42]. The prevalence of MetS among patients with

ATP III and IDF definitions agreement was good (κ value 0.851) [3].

existence and influence [31].

188 A Critical Evaluation of Vitamin D - Clinical Overview

of PAPS patients [3].

**autoimmune rheumatic diseases.**

Prothrombotic state is one of the well‐known characteristics of both antiphospholipid and metabolic syndrome. It has rather complex pathogenesis in which VitD status has an important role affecting primarily immune‐mediated thrombosis. Indirect proofs for this relationship are as follows: (a) existence of nuclear VitD receptors in vascular smooth muscle cells, endothelial cells, cardiomyocytes, platelets, as well as in most types of the immune cells [47–51], and (b) expression of cytochrome P450 enzyme, CYP27B1 activity by the same cell types, enabling local synthesis of biologically active form of VitD, 1,25(OH)2D [52].

There is substantial experimental data indicating that VitD plays significant role in mainte‐ nance of physiological balance between thrombosis and haemostasis [47]. It has been demon‐ strated that VitD exerts following actions:


Net result of numerous effects of this vitamin on different haemostatic factors is its antith‐ rombotic role. Prothrombotic state that exists in VitD receptor knockout animal models proves the importance of these extra‐skeletal effects of VitD as well as the observation that all of them are VitD receptor‐mediated [47, 56].

However, there are still relatively few indirect and even less direct clinical evidences for the association between VitD status and thrombotic events in humans. First of them came from the epidemiological studies in which have been observed that cardiovascular morbidity and mortality depended on season of the year and latitude [47, 57, 58]. Seasonal variations were also demonstrated for tissue plasminogen activator (tPA) antigen, fibrinogen, D‐dimer and von Willebrand factor (vWF) concentrations in 6538 British subjects without significant cardiovascular disorders, aged 45 years [59]. In this population, negative correlation between VitD level and tPA, fibrinogen and D‐dimer concentrations was observed indicating that at least some of the seasonal variations of these thrombotic markers could be attributed to the VitD status. More direct proof for the association between VitD status and thrombosis came from the research conducted in huge population of 18 791 subjects from general population of Copenhagen [60]. Authors have observed that every quartile of a decrease in VitD concentra‐ tions was accompanied by an increase in risk of venous thromboembolism (VTE), resulting in a 37% increased VTE risk between subjects with the VitD concentrations, in the lowest quartile and those in highest quartile.

Recent publication which retested the seasonality of different cardiovascular events in regard to VitD levels, in the Scottish Heart Health Extended Cohort (SHHEC), brings a dose of confusion in previously proposed relations. Namely, it failed to prove that seasonal appearance of cardiovascular events resembled seasonal variations in serum VitD concentrations nor that these events expressed more pronounced seasonality in those with lower VitD concentrations, compared with those with its higher concentrations [61]. But, during follow‐up, significant correlations were observed between lower baseline concentrations of VitD and subsequent incident cardiovascular morbidity and incident cardiovascular and all‐cause mortality [61].

Results of recent trials assessing the effects of VitD supplementation on the risk of throm‐ boembolism were inconclusive [62–64]. In the Multiple Environmental and Genetic Assess‐ ment (MEGA) case‐control study which included 2506 patients with venous thrombosis, thrombotic risk was 37% lower in those supplemented with various vitamins including VitD [62]. However, in a large cohort of postmenopausal women (n=36282) from the Women's Health Initiative, daily supplementation with calcium and VitD failed to reduce the overall risk of thromboembolism [63]. Even when high doses (300,000 IU) of VitD were given intra‐ muscularly, in a small group of patients with proven deep vein thrombosis and pulmonary embolism, observed reduction in plasma concentrations of P‐selectin and high‐sensitive C‐ reactive protein (hs‐CRP) did not reached statistical significance [64]. Additional information could be expected from the ongoing Vitamin D and OmegA‐3 Trial (VITAL) and that is why the results of this investigation are eagerly awaited [65].
