To the best of our knowledge, our study is one of the first studies that addressed the influence of vitamin D status on warfarin maintenance dose requirements. Based on the results of our survey, there was a significant but weakly positive correlation between WSI and 25-hydroxyvitamin D serum levels. Our results showed that compared to the patients with vitamin D deficiency, the patients with sufficient vitamin D state had a higher mean WSI value, indicating that patients with sufficient vitamin D state require lower warfarin doses to maintain their INR in the therapeutic range. Our data suggests that, in addition to other traditional factors, vitamin D status may influence sensitivity to warfarin and maintenance dose requirements. This should be considered when determining warfarin dosing.
The exact molecular mechanism by which vitamin D exerts its anticoagulant effects has not been fully elucidated. Nevertheless, vitamin D, through regulatory effects on coagulation factors, endothelium homeostasis, and inflammatory pathways, exerts a protective role against the occurrence of thrombosis [
26]. Both in vitro and in vivo experiments demonstrated that vitamin D and other VDR ligands up-regulate the expression of thrombomodulin, and down-regulate the expression of tissue factor (TF) [
15,
17,
27‐
29]. TF is the high-affinity receptor and cofactor for factor VII/VIIa that plays a primary role in initiating the coagulation cascade [
30]. On the other hand, thrombomodulin is an anticoagulant glycoprotein involved in promoting the activation of the anticoagulant protein C pathway [
31]. Apart from this, vitamin D has been shown to reduce the production of pro-inflammatory cytokines that can induce a pro-thrombotic state by increasing the production of TF on the endothelium and suppressing the synthesis of the anticoagulant protein C [
32‐
34]. The protective effect of VDR on endothelial cells has also been identified [
35‐
37]. It has been observed that vitamin D therapy, through activation of VDR, improves endothelial function and thereby suppresses thrombogenicity in patients with vitamin D deficiency or insufficiency [
38].
Accumulative data from the clinical reports are increasingly reporting a strong negative relationship between serum levels of 25-hydroxyvitamin D and the development of venous thromboembolism, suggesting inadequate vitamin D levels may increase the risk of venous thromboembolism [
39‐
42]. Consistent with this evidence, several epidemiological studies have highlighted a seasonal pattern for the occurrence of thrombotic events, as the risk of thrombotic events is greater in the winter months compared to the summer months, which is thought to be related to the seasonal variation in vitamin D status [
43‐
45]. In support of this hypothesis, the results of a prospective study on a cohort of 40,000 southern Swedish women after 11 years follow-up indicated that women with a habit of more active sun exposure were at a 30% lower risk of thromboembolism events than those who did not [
46]. This evidence suggests that treating vitamin D deficiency or insufficiency can reduce the risk of venous thromboembolism events [
14,
47]. Hejazi and colleagues in a pilot randomized control clinical trial on subjects with a diagnosis of deep vein thrombosis or pulmonary embolism who had vitamin D deficiency showed that compared to placebo treatment, subjects receiving oral vitamin D3 supplementation required significantly lower doses of warfarin to achieve a therapeutic INR. They concluded that treating vitamin D deficiency could enhance the anticoagulant effects of warfarin [
21]. Consistent with these findings, in 2006, Beer and colleagues, in a randomized controlled clinical study on 250 men suffering from prostate cancer, showed that in comparison to the placebo, administration of a weekly high dose of calcitriol, as an active form of vitamin D3, could reduce thromboembolic events in such patients. They postulated that this benefit might be related to calcitriol’s antithrombotic effects [
18]. Similarly, Moscarelli et al. also reported that combined therapy with calcitriol, angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme inhibitors (ACEIs) could reduce the rate of venous thromboembolism in renal transplant recipients [
48]. However, some inconsistent data have also been reported. Blondon and coworkers, in a randomized, double-blind, placebo-controlled trial where the participants were followed for an average period of 7 years, found that supplementation with calcium (1000 mg) plus vitamin D (400 IU) does not influence the overall risk of venous thrombotic events in postmenopausal women. The authors speculated that a higher dose of vitamin D might be required to see the antithrombotic effects of vitamin D supplementation in the general population [
49]. However, in a supplemental analysis, they detected a modest thrombotic risk reduction for idiopathic thrombotic events among women with low 25-hydroxyvitamin D concentrations at baseline, which suggests subjects with severe vitamin D deficiency may benefit from vitamin D supplementation [
49]. In support of this hypothesis, Blondon et al., in their recent study, showed that supplementation with a high dose of vitamin D for 3 months in subjects with severe vitamin D deficiency could decrease a prothrombotic profile [
20]. However, some other studies evaluating the impact of vitamin D supplementation on coagulation and fibrinolysis parameters have generated conflicting data. A study conducted by Jorde et al. on obese or overweight subjects who had high serum vitamin D levels at baseline (a mean serum 25-hydroxyvitamin D level of 61.8 nmol/l), 1-year high-dose treatment of vitamin D (40,000 IU weekly) did not affect the fibrinolytic and thrombin generation parameters [
50]. In a prospective cohort study of patients with vitamin D deficiency (25-hydroxyvitamin D serum levels of < 25 nmol/l) with and without hyperparathyroidism, the coagulation or fibrinolysis parameters did not change after 2 months of vitamin D treatment (900,000 IU in 2 months) [
51]. Interestingly, in another study, Saliba and colleagues showed that vitamin D supplementation at a dose of 2000 IU daily for 90 days in healthy participants with serum 25-hydroxyvitamin D < 50 nmol/l levels could have prothrombotic effects [
52]. Several factors, including the selected participants, having or not having comorbidities such as cardiovascular diseases and hyperparathyroidism, and methods of assaying fibrinolytic and thrombin generation parameters may be possible explanations for these conflicting data. However, the current data in the literature suggests that subjects with vitamin D deficiency might benefit more from the anticoagulant actions of vitamin D supplementation [
14]. More studies are needed to elucidate which population may benefit from the anticoagulation actions of vitamin D supplementation.
Despite the novelty of our findings, there are some limitations in the present research. The main limitation of this study is that it was a retrospective single-center investigation with a relatively small number of participants. Further, unassessed confounding factors, such as diet and genotype that could affect the warfarin dose requirement, may affect the results in a way not anticipated. Additionally, due to financial constriction, we did not assess the relationship between vitamin D status and coagulation and fibrinolysis parameters. Thus, these findings should be interpreted with caution, and future studies are needed to better assess the relationship between vitamin D status and warfarin maintenance dose requirements.