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Volume 35, Issue 1, March 2024



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Mediterr J Rheumatol 2022;33(4):478-9
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Low Folate Levels are Associated with Strokes and Less Venous Thromboses in Primary Antiphospholipid Syndrome
Jozélio Freire Carvalho1, Yehuda Shoenfeld2,3,4
Authors Information
  1. Institute for Health Sciences from Federal University of Bahia, Salvador, BA, Brazil
  2. Zabludowicz Research Centre for Autoimmune Diseases, Sheba Medical Centre, Tel Hashomer, Israel
Abstract
This paper has no abstract.

Cite this article as: Carvalho JF, Shoenfeld Y. Low Folate Levels are Associated with Strokes and Less Venous Thromboses in Primary Antiphospholipid Syndrome. Mediterr J Rheumatol 2022;33(4):478-9.

Article Submitted: 4 Dec 2021; Article Accepted: 20 Jan 2022; Available Online: 23 Nov 2022

https://doi.org/10.31138/mjr.33.4.478

This work is licensed under a Creative Commons Attribution 4.0 International License.

©2022 The Author(s).

Keywords: antiphospholipid syndrome, thrombophilia, folic acid, vitamin, stroke
Full Text

To the editor,

Antiphospholipid syndrome (APS) is associated with venous and/or arterial thromboses, recurrent miscarriages, and/or thrombocytopenia.1 In addition, it is known that some patients may develop cardiovascular events linked to traditional and non-traditional risk factors.2 Low folate levels have been associated with comorbidities, including strokes.3 However, we were unable to find any previous study which has evaluated the clinical and laboratory associations of FL in primary APS patients. Therefore, it would be reasonable to evaluate if serum folate levels (SFL) might be connected to clinical (strokes) or laboratory features of APS, independently of homocysteine and vitamin B12 levels.

A sample of 23 primary APS (pAPS) was studied to verify clinical and serological differences between individuals with normal and low SFL. Twenty-three pAPS females (Sidney criteria)4 were enrolled for this cross-sectional analysis, which excluded individuals with associated connective tissue disease and using folate supplementation. Data were assessed by a chart review and clinical examinations. IgG and IgM anticardiolipin antibodies (ACL) were tested at least twice using ELISA (Inova Diagnostics, Inc., San Diego, USA). In addition, lupus anticoagulant (LAC) was determined according to the international guidelines.5 Serum folate levels were measured in a Beckman-Coulter DxI 800 chemiluminescent immunoassay, and normal levels were considered above 6.8 ng/mL.6

In this sample, 4/23 (17.4%) have had low SFL (group 1), and 19/23 (82.6%) did not (group 2). Median SFL between the groups were significantly different (4.85 [3.5-5.8 ng/mL] vs. 12.1 [7.4-20 ng/mL], p=0.0003). Group 1 patients were older (50 [42-52 years] vs. 40 [21-54 years], p=0.04), had more Sneddon’s syndrome (75% vs. 21%, p=0.04), strokes (75% vs. 26.3$, p=0.05), livedo reticularis (75% vs. 21%, p=0.02), acute myocardial infarction (25% vs. 0, p=0.01), family history of coronary diseases (50% vs. 5.2%, p=0.03), and currently were under low molecular weight heparin (75% vs. 26.3%, p=0.03) in comparison with group 2. On the other hand, group 1 had less venous thromboses event (0 vs. 47.3%, p=0.01), and consumed less glucocorticoid (0 vs. 58%, p=0.017) than group 2. No other variable was significantly different between groups 1 and 2, including homocysteine and vitamin B12 levels (p> 0.05).  We proceeded a logistic regression analysis, and the independent variables associated with low folate levels were stroke (p=0.03), and less venous thrombosis (p=0.02).

The present study found for the first time a positive association of low folate levels with strokes, and a negative association with venous thromboses in patients with pAPS. Previous studies of the literature have shown a positive link between low folate levels and stroke in hypertensive patients.3 The risk of first ischemic stroke was significantly higher in hypertensive patients with low levels of both folate and B1, and the authors suggesting a folic acid supplementation for this risk population. Furthermore, a meta-analysis with 55,764 subjects studied concluded that folic acid supplementation may prevent stroke.7 It is logical to think that low folate can induce hyper-homocysteine, although we did not find this typical association in the present study. One hypothesis is that low folate creates an inflammatory environment due to low methylation. It is well known that folic acid has a direct antioxidant, antithrombotic, and endothelium-protective effects and has a significant role in DNA synthesis or repair.8 Ultimately might induce endothelial damage, and a patient may become prone to stroke.

This study has the great advantage of including pAPS patients exclusively, excluding other connective tissue diseases, avoiding the consequences of associated diseases. However, a limitation of the present study is the relatively low number of participants, and it might bring type 1 errors in the interpretation of the results.

In conclusion, 17% of the PAPS patients had low folate levels. Serum folate levels in pAPS is linked to stroke and less venous events. In patients with folate levels below the normal range, we recommend supplementing folic acid for these APS subjects.

 

FUNDING SOURCES

None.

CONFLICT OF INTEREST


The authors declare no conflict of interest.


ETHICAL STATEMENT

The authors declare that they followed the World Medical Association Declaration of Helsinki in this study. Informed consent was obtained from all participants to participate in this study and for this publication.

 

ACKNOWLEDGMENTS

We are thankful to Sergio Dias Ribeiro for the English revision of the manuscript.

References
  1. de Carvalho JF, Levy RA, Shoenfeld Y. Antiphospholipid syndrome and antibodies. J Immunol Res 2014;2014:942869.
  2. Mazidi M, Katsiki N, Mikhailidis DP, Banach M; Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group. Associations of serum uric acid with total and cause-specific mortality: Findings from individuals and pooling prospective studies. Atherosclerosis 2020 Mar;296:49-58.
  3. Qin X, Spence JD, Li J, Zhang Y, Li Y, Sun N, et al. Interaction of serum vitamin B12 and folate with MTHFR genotypes on risk of ischemic stroke. Neurology 2020 Mar 17;94(11):e1126-e1136.
  4. Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006 Feb;4(2):295-306. 
  5. 5.Wisløff F, Jacobsen EM, Liestøl S. Laboratory diagnosis of the antiphospholipid syndrome. Thromb Res 2002;108:263-71.
  6. Ma Y, Peng D, Liu C, Huang C, Luo J. Serum high concentrations of homocysteine and low levels of folic acid and vitamin B12 are significantly correlated with the categories of coronary artery diseases. BMC Cardiovasc Disord 2017 Jan 21;17(1):37.
  7. Huo Y, Qin X, Wang J, Sun N, Zeng Q, Xu X, et al. Efficacy of folic acid supplementation in stroke prevention: new insight from a meta-analysis. Int J Clin Pract 2012 Jun;66(6):544-51.
  8. Verhaar MC, Stroes E, Rabelink TJ. Folates and cardiovascular disease. Arterioscler Thromb Vasc Biol 2002;22:6-13.