B-Thalassemia - Call for Restoration of Normal Vitamin E Status

Short Communication

Ann Hematol Oncol. 2022; 9(1): 1390.

β-Thalassemia - Call for Restoration of Normal Vitamin E Status

Wilairat P¹, Auparakkitanon S² and Wilairat P³*

1Department of Chemistry, Faculty of Science, Mahidol University, Bangkok, Thailand

2Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

3Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, Thailand

*Corresponding author: Wilairat P, Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400 Thailand

Received: February 23, 2022; Accepted: March 12, 2022; Published: March 19, 2022

Keywords

F2-Isoprostane; Hypercoagulopathy; Oxidative stress; Vitamin E Supplementation; β-Thalassemia

Short Communication

A recent review of β-thalassemia pathophysiology discussed several drugs (old and new) for treating anemia and concomitant iron overload [1], but an obvious consequence of the presence of unmatched a-hemoglobin (Hb) in β-thalassemia red blood cells (β-thal RBCs) is systemic oxidative stress, first noted by reduced plasma vitamin E (vit E) levels and increased sensitivity of β-thal RBCs to H2O2-induced lysis in β-thalassemia subjects [2]. This led to numerous clinical trials in β-thal subjects of vitamin E supplementation (alone or combined with other anti-oxidants, e.g., N-acetyl cysteine), ranging from 300 mg/day for 15 days to 600 mg/day for nine months, which produced improvements in β-thal RBC parameters of oxidant damage but not in Hb levels, dampening this “quick fix” approach [3]. This is not surprising given recent understandings of the complex changes to erythrocyte plasma membrane (including intracellular membranes of erythroid progenitor cells) caused by bound unmatched a-Hb and consequent heme-dependent oxidative damage to both membrane lipids and proteins, affording an explanation for ineffective erythropoiesis (due to apoptosis/autophagy) and premature eryptosis [4]. Although the exact mechanisms by which aged RBCs are removed by the body reticuloendothelial system remain unclear, in the case of β-thal RBCs, oxidative damage to plasma membrane proteins is accepted as the primary etiology.

Nevertheless, a new appraisal for restoration of normal vitamin E status in β-thal patients is warranted. With availability of fluorescentlabelled Annexin V to detect presence of cell surface phosphatidylserine (PS), it was realized that PS on surface of circulating β-thal RBCs is responsible (in part) to the hypercoagulable state, platelet activation, thrombosis and pulmonary hypertension observed in β-thal subjects [1,4]. A limited number of clinical trials of vit E supplement (alone or together with N-acetylcysteine) on small cohorts of β-thal subjects showed improvement in parameters related to oxidative stress and hypercoagulopathy (Table 1). However, it is worth noting that upon cessation of vitamin E supplementation, all measured parameters (including plasma vit E) returned to pre-treatment levels within three months (in studies that carried out these experiments).

Table 1: Effects of vitamin E supplementation on hypercoagulation and oxidative stress status of β-thalassemia subjects.





  

    
Reference

    
Subject/Treatment

    
Result

  

  

    
Kasemsant et al. 1996 [8]

    
NSPLZ and SPLZ β-thalassemia (β-thal)/Hb    E (n = 7 each group). Vitamin (vit) E 485 U/day for 3 months.

    
    
      
  • Pre-supplement    parameters, median (range): NSPLZ and SPLZ β-thal/Hb E plasma vit E = 0.61    (0.52-1.66) and 0.60 (0.16-0.81) mg/L respectively; prothrombinase activity =    0.60 (0.41-0.72) and 0.81 (0.48-1.70) thrombin unit/108 cells.
    • 
      
  • Post-supplement    parameters, median (range): NSPLZ and SPLZ β-thal/Hb E plasma vit E = 14.21    (10.53-22.38) and 12.40 (5.04-23.80) mg/L respectively; prothrombinase    activity = 0.33 (0.30-0.38) and 0.48 (0.38-0.65) thrombin unit/108 cells.
    • 
    

  

  

    
Unchern et al. 2003 [9]

    
NSPLZ (n = 16) and SPLZ (n = 9)    β-thal/Hb E. Vit E 525 U/day for 3 months.

    
    
      
  • Pre-supplement    parameters, median (range): NSPLZ and SPLZ β-thal/Hb E: plasma vit E = 34.9    (8.1-53.2) and 33.4 (5.4-45.0) mg/L respectively; platelet aggregation (induced    by 2 μM ADP) = 48 (19-64) and 56 (37-64)% light transmission respectively.
    • 
      
  • Post-supplement    parameters, median (range): NSPLZ and SPLZ β-thal/Hb E plasma vit E = 127    (66-353) and 174 (111-238) mg/L respectively; platelet aggregation (induced    by 2 μM ADP) = 51 (8-67) and 44 (18-57)% light transmission respectively.
    • 
    

  

  

    
Yanpanitch et al. 2015 [10]

    
NSPLZ β-thal/Hb E (n = 19). Vit    E 400 U + N-acetylcysteine 200 mg/day for 12 months.

    
    
      
  • Pre-supplement    parameters, mean ± SD: Red blood cell MDAa = 1,487 ± 138 nmol/g Hb;    procoagulation status: PF3-like activityb, RBC PSc and    platelet PSc = A405 nm1.24 ± 0.10, 5.41 ± 1.03% and    0.61 ± 0.15%, respectively; platelet activation status: CD62 expressiond    and PAC1 expressione = 16.9 ± 3.1 and 4.6 ± 1.1% respectively.
    • 
      
  • Post-supplement    parameters, mean ± SD: Red blood cell MDAa = 698 ± 24 nmol/g Hb;    procoagulation status: PF3-like activityb, RBC PSc and    platelet PSc = A405 nm 0.67 ± 0.06, 1.73 ± 0.71% and    0.24 ± 0.04%, respectively; platelet activation status: CD62 expressiond    and PAC1 expressione = 12.3 ± 3.3 and 2.7 ± 1.0% respectively.
    • 
    

  

  

    
Haghpanah et al. [11]

    
NSPLZ (n = 20) and SPLZ (n = 20)    β-thal (n = 26). Vit E 10 U/kg/day (maximum dose of 400 IU) for 3 months.

    
    
      
  • Pre-supplement    parameters, mean ± SD:
    • 
    

      
TOSf = 0.83 ± 0.20 μmol H2O2    Eqv./L;

        TACg = 3.25 ± 0.68 mmol Eqv./L

      
    
        
  • Post-supplement    parameters, mean ± SD: TOSf = 0.74 ± 0.07 μmol H2O2    Eqv./L; TACg = 2.98 ± 0.20 mmol Eqv./L.
    • 
      

  










Table 1: Effects of vitamin E supplementation on hypercoagulation and oxidative stress status of β-thalassemia subjects.

Although the clinical significance of these studies of vit E supplementation on the hypercoagulation status of β-thal patients may be questioned, it surely cannot be beneficial to the general health of a person to be under a state of constant hypovitaminosis E, regardless of current debates on whether vit E, in addition to its canonical function as a lipophilic antioxidant, might also have nonantioxidant properties, such as a direct regulator of gene expression or indirectly through modulation of metabolic pathways [5]. The ability to measure in urine, using gas or liquid chromatography-mass spectrometry, F2-isoprostanes, the biomarker of systemic oxidative stress provides a convenient non-invasive method for quantifying this stress condition [6,7] and a ready means to assess the efficacy of vit E supplementation (with or without other antioxidants) in alleviating oxidative stress in β-thal individuals.

Taken altogether, we advocate vitamin E supplementation of β-thalassemia subjects at a minimal level that restores plasma vitamin E level to the accepted normal level designated by the subject’s country FDA together with determination of attenuation in systemic oxidative stress. This simple, available and non-toxic supplement should be beneficial to the overall health of the global β-thal population in particular those who live in regions with limited access to other relatively more expensive pharmacological interventions.

References

  1. Taher AT, Musallam KM, Cappellini MD. β-Thalassemias. N Engl J Med. 2021; 384: 727-743.
  2. Editorial. Vitamin E and red cells. Br Med J. 1974; 2: 625-626.
  3. Fibach E, Rachmilewitz EA. The role of antioxidants and iron chelators in the treatment of oxidative stress in thalassemia. Ann N Y Acad Sci. 2010; 1202: 10-16.
  4. Rund D, Rachmilewitz E. β-Thalassemia. N Engl J Med. 2005; 353: 1135- 1146.
  5. Blaner WS, Shmarakov IO, Traber MG. Vitamin A and vitamin E: Will the real antioxidant please stand up? Annu Rev Nutr. 2021; 41: 105-131.
  6. Matayatsuk C, Lee CYJ, Kalpravidh RW, Sirankapracha P, Wilairat P, Fucharoen S, et al. Elevated F2-isoprostanes in thalassemic patients. Free Radic Biol Med. 2007; 43: 1649-1655. https://doi.org/10.1016/j. freeradbiomed.2007.08.026.
  7. Halliwell B, Lee CYJ. Using isoprostanes as biomarkers of oxidative stress: some rarely considered issues. Antioxid Redox Signal. 2010; 13: 145-156.
  8. Kasemsant S, Wilairat P. Vitamin E supplementation restores PS inner leaflet location of β-thalassemia rbc. Packer L, Traber MG, Xin W, editors. In: Proceedings of the international symposium on natural antioxidants: molecular mechanisms and health effects. AOCS Press. 1996: 162-166.
  9. Unchern S, Laoharuangpanya N, Phumala N, Sipankapracha P, Pootrakul P, Fucharoen S, et al. The effects of vitamin E on platelet activity in β-thalassaemia patients. Br J Haematol. 2003; 123: 738-744.
  10. Yanpanitch O, Hatairaktham S, Charoensakdi R, Panichkul N, Fucharoen S, Srichairatanakool S, et al. Treatment of β-thalassemia/hemoglobin E with antioxidant cocktails results in decreased oxidative stress, increased hemoglobin concentration, and improvement of the hypercoagulable state. Oxid Med Cell Longev. 2015; 2015: 537954.
  11. Haghpanah S, Cohan N, Bordbar M, Bazrafshan A, Karimi M, Zareifar S, et al. Effects of three months of treatment with vitamin E and N-acetyl cysteine on the oxidative balance in patients with transfusion-dependent β-thalassemia. Ann Hematol. 2021; 100: 635-644.

Citation: Wilairat P, Auparakkitanon S and Wilairat P. β-Thalassemia - Call for Restoration of Normal Vitamin E Status. Ann Hematol Oncol. 2022; 9(1): 1390.