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  • Hypothesis
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Anemia: A Potential Source of Bias in Clinical Trials of Angiogenesis Inhibitors: A Hypothesis

  • Reza Rastmanesh1,2,3,* 
 Author information  Cite
Exploratory Research and Hypothesis in Medicine   2023;8(4):388-393

doi: 10.14218/ERHM.2023.00013

Abstract

Although anemia may cause angiogenesis and neovascularization, especially in ocular situations, neither published nonrandomized clinical trials nor registered clinical trials have reported the anemia status as inclusion or exclusion criteria in their design. Increases in the circulating levels of erythropoietin and vascular endothelial growth factor are proportional to the levels of tissue hypoxia, which are influenced by hematocrit. Erythropoietin is a potent retinal angiogenic factor that is independent of endothelial growth factor and is capable of stimulating ischemia-induced retinal angiogenesis. We suggest that clinical trials investigating anti-vascular endothelial growth factor treatment for retinal neovascularization should measure appropriate variables such as serum erythropoietin, vascular endothelial growth factor, hemoglobin, and hematocrit to yield preliminary data for future trials of angiogenesis inhibitors. Ignoring the anemia status, serum erythropoietin, and/or vascular endothelial growth factor levels could create clinical uncertainty and subtle statistical bias in both systematic reviews and nonrandomized clinical trials that aim to evaluate the efficiency of angiogenesis inhibitors in several medical situations, including but not limited to ocular alterations, rheumatoid arthritis, and many types of cancer, just to mention a few. Implications of this type of bias could be involved in other disease situations in which angiogenesis inhibitors are used for medication, such as different carcinomas as well as metastases. In this hypothesis paper, we suggest that clinical trials of angiogenesis inhibitors should measure appropriate variables such as serum erythropoietin, hemoglobin, and hematocrit and match their participants by anemia and its severity to avoid a game-changing bias in their data analysis.

Keywords

Anemia, Bias, Clinical trials, Neovascularization, Angiogenesis inhibitor

Introduction

Anemia and angiogenesis

Anemia is among the most common hematological manifestations of cancer, and it is estimated that almost 40–64% of patients treated for malignancies are affected by anemia. From a pathophysiological point of view, cancer-related anemia may be categorized into four broad but overlapping classes: hypoproliferative anemia comprising the common anemia of inflammation/chronic disease, miscellaneous etiologies, hemolytic anemia, and anemias with uncertain etiologies. A positive connection is seen between tumor hypoxia and anemia. Hypoxemic situations enhance tumor growth and thereby resistance to medication through stimulating angiogenesis.1 Erythropoietin (EPO) is considered as a hormone, a cytokine, and a growth factor. Its major function is regulation of erythropoiesis. EPO contributes to angiogenesis and neovascularization in the angiogenic switch of a tumor2 and vascular endothelial growth factor (VEGF), which is a key dynamic molecule of angiogenesis.3 The development and application of anti-angiogenesis agents, specifically those targeting vascular VEGF, have become integral components of neovascularization therapies and anticancer regimens for many tumor types.

Anemia and angiogenesis inhibitors

The potential of angiogenesis inhibitors or angiogenesis-modulating agents as therapies for human diseases, namely eye diseases like retinal neovascularization and corneal neovascularization, has increased dramatically over the past 20 years due to newly emerged clinically available agents. Most of the recently published articles benefit from elegant and sophisticated methodology.4 However, although anemia is causally related to angiogenesis and neovascularization,5 especially in ocular situations,6 neither the published nonrandomized clinical trials nor the registered nonrandomized clinical trials have reported the anemia status as inclusion or exclusion criteria in their design. The main methodological issue here is whether the iron-deficiency status in enrolled patients confounds the efficacy of angiogenesis inhibitors, since a low hemoglobin level is associated with increased serum levels of vascular endothelial growth factor (VEGF) and it has been suggested that anemia might increase the progression of angiogenesis.7 Increases in the circulating levels of EPO are proportional to the levels of tissue hypoxia, which are influenced by hematocrit.8 In addition, there have been several reports that anemic patients have elevated levels of VEGF, which is a marker of tissue hypoxia.9 Moreover, it has been shown recently that the anemia of newborns induces EPO expression in the developing mouse retina.10

EPO and VEGF are independently associated with proliferative diabetic retinopathy (PDR), and EPO is more strongly associated with PDR than VEGF. EPO is a potent retinal angiogenic factor independent of VEGF and is capable of stimulating ischemia-induced retinal angiogenesis in PDR.11 Additionally, the EPO-independent EPO-receptor signaling pathway has been demonstrated to play a potential role in cell proliferation and angiogenesis in human pterygium.12 Furthermore, the gene expression levels of EPO and VEGF are upregulated in the murine ischemic retina, and the blockade of EPO inhibits retinal neovascularization in vivo and endothelial-cell proliferation in the vitreous of patients with PDR in vitro.13

Hypothesis

Through alteration of the endogenous EPO and VEGF levels, different types of anemia create a bias in trials of angiogenesis inhibitors. Interestingly, the results from an animal model of cancer showed that the antitumor efficacy of bevacizumab (a well-known anti-VEGF agent) was compromised in an anemic situation. Surprisingly, anti-vascular endothelial growth factor receptor (anti-VEGFR)-2, at the effective dose for normalization of systemic tissues and organs, did not show a significant antitumor effect in that cancer model. This was possibly because the plasma levels of EPO were significantly elevated in VEGF tumor-bearing mice. Also, VEGF-induced anemia was reversed by anti-VEGFR-2 but not by anti-VEGFR-1.14

These results may pertain to angiogenesis inhibitors and retinal neovascularization; in the human retina, VEGFR-1 neutralization decreased pigment epithelium-derived factor mRNA and protein expression, whereas anti-VEGFR-2 antibody had no effect.15 It should be kept in mind that a critical balance between VEGF and pigment epithelium-derived factor is important to prevent the development of retinal neovascularization.

Evaluation of hypothesis

If these findings can be extrapolated to human patients suffering from retinal neovascularization, a loss of anti-VEGF agent efficacy in patients suffering from iron deficiency or elevated plasma EPO levels might be involved. There is indirect evidence from human16 and direct evidence from animal14,17 studies that support our idea; for example, in patients with pre-existing higher EPO levels, the efficacy of anti-VEGF treatment was lower than that of patients with lower EPO levels.18 In addition, in an animal model of musculocutaneous tissue ischemia, flaps treated with EPO and bevacizumab did not show any change in tissue necrosis when compared with animals receiving EPO only,19 supporting a possible counteraction between EPO and anti-VEGF agents. It might be argued that the interaction between locally administered exogenous anti-VEGF and endogenous intravitreal EPO and/or VEGF levels is complex. It should be kept in mind that there is a direct correlation between serum EPO and intravitreal EPO levels,20 as well as between intravitreal EPO and intravitreal VEGF levels.20 Very recently, it was found that the plasma VEGF level could predict the response in non-small cell lung cancer patients treated with bevacizumab.21 Interestingly, systemic dosing of squalamine lactate, an anti-VEGF agent, has yielded promising results in animal models as well as in humans.22

Furthermore, there is strong evidence that changes in endogenous VEGF are related to the therapeutic effect of anti-VEGF agents.23,24 There are several reports of the high efficacy of systemic steroid treatment for retinal neovascularization, possibly through suppression of intravitreal VEGF. Overall, the results of these studies spark the hypothesis that the correlation between systemic and intravitreal EPO or VEGF levels is more plastic than previously anticipated. An anemic situation might have implications in anti-VEGF dose calculation as well. Such patients suffering from retinal neovascularization may need higher doses of anti-VEGF agents, while administering the same doses to nonanemic patients may increase the side effects of anti-VEGF agents. Further support for our claim comes from findings indicating increased anemia in exudative age-related macular degeneration.25

Effects of different types of anemia and supplements on angiogenic/tumorigenic situations

It is noteworthy that different types of anemia and nutrient deficiencies leading to or contributing to anemia may have differential effects on the VEFG and EPO levels or their expression, and thereby on angiogenesis. Both severe and moderate iron deficiency5–7,26 as well as vitamin B12 deficiency27–33 lead to higher VEGF levels and angiogenesis, while the opposite is true in the case of folate deficiency anemia.34–42 Other vitamins have their own mechanism for the regulation of angiogenesis.43 Recently, Pedrosa and Lemes have reported a significantly enhanced gene expression of VEGF and HIF-1α in patients with zinc deficiency and sickle cell anemia, and they showed an inverse dose-response association with hydroxyurea therapy.44 Previously, higher serum VEGF levels in beta-thalassemia,45–48 hemolytic anemia,49–52 idiopathic aplastic anemia53–55 and anemia of chronic disease56–58 have been well established. Etiologically, it is conceivable that different mechanisms are behind different types of anemia. Obviously, the interactions among the severity/types of anemia, nutrient reserves of the body, and the duration of the study/intervention can create an intricate and chaotic pattern, which is difficult to control by usual statistical methods.

There are many examples where the type of anemia and/or the type of nutrient supplementation can alter or modulate the process of tumorigenesis/angiogenesis as well as the therapy. For instance, some people take iron supplements without a medical indication. In a recent randomized controlled trial, it was shown that among comparable patients participating in age-related macular degeneration treatment trials, the use of iron supplements in participants undergoing bevacizumab treatment was correlated with retinal/subretinal hemorrhage in a dose-response fashion.59 Ample literature exists on the deterioration and/or amelioration of tumorigenesis/angiogenesis following (un)indicated iron, folate, and vitamin B12 supplementation for different angiogenic/tumorigenic situations31,60–71Figure 1 shows a simplified diagram of the mechanisms by which different types of anemia may create a bias in studies of angiogenesis inhibitors.

A simplified diagram of mechanisms by which different types of anemia may create a bias in studies of angiogenesis inhibitors.
Fig. 1  A simplified diagram of mechanisms by which different types of anemia may create a bias in studies of angiogenesis inhibitors.

HIF-1, hypoxia-inducible factor 1; HIF-1α, hypoxia-inducible factor 1 alpha.

Discussion

Ignoring the anemia status, serum EPO levels, and/or VEGF levels are likely examples of sources of bias in nonrandomized clinical trials that aim to evaluate the efficiency of angiogenesis inhibitors, especially in eye diseases. It might be argued that in clinical trials that randomly assign treatment or standard care to the study participants, the major advantage is that the treated and the untreated subjects are similar in many aspects because of the power of randomization, provided that a sufficient number of participants are enrolled (adequate power). It might also be argued that randomization is unlikely to lead to bias. However, a simple search of clinical trials registered in the National Institutes of Health database reveals that in almost half of the registered clinical trials, the design of the study is nonrandomized and uncontrolled.

Future directions

We would like to urge that all clinical trials on anti-VEGF agents include the patient anemia status in their design. Obviously, the VEGF levels depend on the duration of anemia (chronic vs. acute), the definition of anemia, and the metabolic demand of the patients. Thus, it would be more important to measure the VEGF levels to meet the discussed problem more appropriately. To sufficiently randomize patients, data concerning the incidence of elevated EPO levels are necessary to plan a sufficient sample size. If researchers find it difficult to randomly allocate patients to the study arms or to balance the number of anemic/nonanemic patients in the study arms, like most other clinical trials, they can adjust the anemia status, preferably as the serum EPO level, as a potential confounder in the placebo and intervention groups when doing statistics, using proper statistical treatments.

One could argue that besides anemia, we should include genetic analysis, history of smoking, and food frequency questionnaires to measure anti-angiogenic food components into clinical trials. The point is that one should be able to estimate the size of the effect that these factors have based on scientific data prior to the planning of trials and to adjust the power calculation accordingly. The goal is to evenly distribute these factors between the treatment arm(s) and control arm(s) of a randomized controlled trial. So, if it is not possible to correct for all of these factors, the concept of randomization comes into play. Due to the high impact of confounding factors in clinical trials investigating angiogenesis inhibitors, the results of nonrandomized clinical trials might lead to a major bias in reviews and guideline protocols. On the other hand, in randomized clinical trials, the power of the study has to be so strong that all of these confounding factors can be equally distributed between the groups.

Conclusions

We suggest that the significance of systematic reviews could be enhanced by including all factors and giving an estimation of the effect size of the affected group. This could positively impact the design of contemporary clinical trials. Implications of this kind of bias could be involved in other disease situations in which angiogenesis inhibitors/promotors are used for medication, such as different carcinomas as well as metastases. Implications of this kind of bias also could be involved both in situations of higher endogenous EPO production and exogenous EPO administration, just to mention a few examples.

Abbreviations

Anti-VEGFR: 

anti-vascular endothelial growth factor receptor

EPO: 

erythropoietin

PDR: 

proliferative diabetic retinopathy

VEGF: 

vascular endothelial growth factor

Declarations

Acknowledgement

None.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest

The author declares no conflict of interest.

References

  1. Gaspar BL, Sharma P, Das R. Anemia in malignancies: pathogenetic and diagnostic considerations. Hematology 2015;20(1):18-25 View Article PubMed/NCBI
  2. Annese T, Tamma R, Ruggieri S, Ribatti D. Erythropoietin in tumor angiogenesis. Exp Cell Res 2019;374(2):266-273 View Article PubMed/NCBI
  3. Goswami AG, Basu S, Huda F, Pant J, Ghosh Kar A, et al. An appraisal of vascular endothelial growth factor (VEGF): the dynamic molecule of wound healing and its current clinical applications. Growth Factors 2022;40(3-4):73-88 View Article PubMed/NCBI
  4. Tanioka H, Shimada K, Tsuji A, Kochi M, Kim HM, Takahashi T, et al. Phase II Study of S-1 and Irinotecan Plus Bevacizumab as Second-line Treatment for Patients With Metastatic Colorectal Cancer Resistant to the Fluoropyrimidine-oxaliplatin-cetuximab Regimen. Anticancer Res 2022;42(5):2675-2681 View Article PubMed/NCBI
  5. Zohora F, Bidad K, Pourpak Z, Moin M. Biological and immunological aspects of iron deficiency anemia in cancer development: A narrative review. Nutr Cancer 2018;70(4):546-556 View Article PubMed/NCBI
  6. Rastmanesh R. Possibility of enhanced risk of retinal neovascularization in repeated blood donors: blood donation and retinal alteration. Int J Gen Med 2011;4:647-656 View Article PubMed/NCBI
  7. Kang HS, Shin AY, Yeo CD, Park CK, Kim JS, Kim JW, et al. Clinical significance of anemia as a prognostic factor in non-small cell lung cancer carcinoma with activating epidermal growth factor receptor mutations. J Thorac Dis 2020;12(5):1895-1902 View Article PubMed/NCBI
  8. Chang X, Li Q, Tang H. Use of preoperative erythropoietin therapy to facilitate autologous blood donation in orthopedic surgery: A meta-analysis. Medicine (Baltimore) 2020;99(2):e18577 View Article PubMed/NCBI
  9. Howarth C, Banerjee J, Eaton S, Aladangady N. Biomarkers of gut injury in neonates - where are we in predicting necrotising enterocolitis?. Front Pediatr 2022;10:1048322 View Article PubMed/NCBI
  10. Scheerer N, Dünker N, Imagawa S, Yamamoto M, Suzuki N, Fandrey J. The anemia of the newborn induces erythropoietin expression in the developing mouse retina. Am J Physiol Regul Integr Comp Physiol 2010;299(1):R111-118 View Article PubMed/NCBI
  11. Loukovaara S, Sandholm J, Aalto K, Liukkonen J, Jalkanen S, Yegutkin GG. Deregulation of ocular nucleotide homeostasis in patients with diabetic retinopathy. J Mol Med (Berl) 2017;95(2):193-204 View Article PubMed/NCBI
  12. Kase S, Kitaichi N, Furudate N, Yoshida K, Ohno S. Increased expression of mucinous glycoprotein KL-6 in human pterygium. Br J Ophthalmol 2006;90(9):1208-1209 View Article PubMed/NCBI
  13. Watanabe D, Suzuma K, Matsui S, Kurimoto M, Kiryu J, Kita M, et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N Engl J Med 2005;353(8):782-792 View Article PubMed/NCBI
  14. Farzam P, Johansson J, Mireles M, Jiménez-Valerio G, Martínez-Lozano M, Choe R, et al. Pre-clinical longitudinal monitoring of hemodynamic response to anti-vascular chemotherapy by hybrid diffuse optics. Biomed Opt Express 2017;8(5):2563-2582 View Article PubMed/NCBI
  15. Bhattarai N, Hytti M, Reinisalo M, Kaarniranta K, Mysore Y, Kauppinen A. Hydroquinone predisposes for retinal pigment epithelial (RPE) cell degeneration in inflammatory conditions. Immunol Res 2022;70(5):678-687 View Article PubMed/NCBI
  16. Vroling L, Lind JS, de Haas RR, Verheul HM, van Hinsbergh VW, Broxterman HJ, et al. CD133+ circulating haematopoietic progenitor cells predict for response to sorafenib plus erlotinib in non-small cell lung cancer patients. Br J Cancer 2010;102(2):268-275 View Article PubMed/NCBI
  17. Xue Y, Religa P, Cao R, Hansen AJ, Lucchini F, Jones B, et al. Anti-VEGF agents confer survival advantages to tumor-bearing mice by improving cancer-associated systemic syndrome. Proc Natl Acad Sci USA 2008;105(47):18513-18518 View Article PubMed/NCBI
  18. Rezaeian F, Wettstein R, Egger JF, Sandmann F, Rücker M, Tobalem M, et al. Erythropoietin-induced upregulation of endothelial nitric oxide synthase but not vascular endothelial growth factor prevents musculocutaneous tissue from ischemic damage. Lab Invest 2010;90(1):40-51 View Article PubMed/NCBI
  19. Wang B, Zhang X, Chen H, Koh A, Zhao C, Chen Y. A Review of Intraocular Biomolecules in Retinal Vein Occlusion: Toward Potential Biomarkers for Companion Diagnostics. Front Pharmacol 2022;13:859951 View Article PubMed/NCBI
  20. Stahl A, Buchwald A, Martin G, Junker B, Chen J, Hansen LL, et al. Vitreal levels of erythropoietin are increased in patients with retinal vein occlusion and correlate with vitreal VEGF and the extent of macular edema. Retina 2010;30(9):1524-1529 View Article PubMed/NCBI
  21. Li B, Jiang C, Xu Y, Fan X, Yang L, Zou B, et al. Genome-wide DNA methylation signature predict clinical benefit of bevacizumab in non-small cell lung cancer. BMC Cancer 2022;22(1):828 View Article PubMed/NCBI
  22. Mammari N, Salles E, Beaussart A, El-Kirat-Chatel S, Varbanov M. Squalamine and its aminosterol derivatives: Overview of biological effects and mechanisms of action of compounds with multiple therapeutic applications. Microorganisms 2022;10(6):1205 View Article PubMed/NCBI
  23. Bockhorn M, Goralski M, Prokofiev D, Dammann P, Grünewald P, Trippler M, et al. VEGF is important for early liver regeneration after partial hepatectomy. J Surg Res 2007;138(2):291-299 View Article PubMed/NCBI
  24. Tsuchihashi S, Ke B, Kaldas F, Flynn E, Busuttil RW, Briscoe DM, et al. Vascular endothelial growth factor antagonist modulates leukocyte trafficking and protects mouse livers against ischemia/reperfusion injury. Am J Pathol 2006;168(2):695-705 View Article PubMed/NCBI
  25. Naito Y, Tsujino T, Matsumoto M, Sakoda T, Ohyanagi M, Masuyama T. Adaptive response of the heart to long-term anemia induced by iron deficiency. Am J Physiol Heart Circ Physiol 2009;296(3):H585-593 View Article PubMed/NCBI
  26. Devi S, Mukhopadhyay A, Dwarkanath P, Thomas T, Crasta J, Thomas A, et al. Combined vitamin B-12 and balanced protein-energy supplementation affect homocysteine remethylation in the methionine cycle in pregnant south Indian women of low vitamin B-12 status. J Nutr 2017;147(6):1094-1103 View Article PubMed/NCBI
  27. Lewerenz J, Gocht A, Hoeger PH, von den Driesch P, Eckert B, Lamszus K, et al. Multiple vascular abnormalities and a paradoxical combination of vitamin B12 deficiency and thrombocytosis in a case with POEMS syndrome. J Neurol 2003;250(12):1488-1491 View Article PubMed/NCBI
  28. Mani C, Kochhar P, Ravikumar G, Dwarkanath P, Sheela CN, George S, et al. Placental expression of ENG, VEGF, and FLT: Gender-specific associations with maternal vitamin B12 status. Eur J Clin Nutr 2020;74(1):176-182 View Article PubMed/NCBI
  29. Rathod R, Khaire A, Kale A, Joshi S. A combined supplementation of vitamin B12 and n-3 polyunsaturated fatty acids across two generations improves nerve growth factor and vascular endothelial growth factor levels in the rat hippocampus. Neuroscience 2016;339:376-384 View Article PubMed/NCBI
  30. Rathod RS, Khaire AA, Kale AA, Joshi SR. Maternal omega-3 fatty acid supplementation to a vitamin B12 deficient diet normalizes angiogenic markers in the pup brain at birth. Int J Dev Neurosci 2015;43:43-49 View Article PubMed/NCBI
  31. Reddy SS, Prabhakar YK, Kumar CU, Reddy PY, Reddy GB. Effect of vitamin B12 supplementation on retinal lesions in diabetic rats. Mol Vis 2020;26:311-325 PubMed/NCBI
  32. Vacca A, Ria R, Ribatti D, Semeraro F, Djonov V, Di Raimondo F, et al. A paracrine loop in the vascular endothelial growth factor pathway triggers tumor angiogenesis and growth in multiple myeloma. Haematologica 2003;88(2):176-185 PubMed/NCBI
  33. Bendardaf R, Sharif-Askari FS, Sharif-Askari NS, Syrjänen K, Pyrhönen S. Patients with hMLH1 or/and hMSH2-deficient Metastatic Colorectal Cancer Are Associated with Reduced Levels of Vascular Endothelial Growth Factor-1 Expression and Higher Response Rate to Irinotecan-based Regimen. Anticancer Res 2018;38(11):6399-6404 View Article PubMed/NCBI
  34. Davis CK, Nampoothiri SS, Rajanikant GK. Folic Acid Exerts Post-Ischemic Neuroprotection In Vitro Through HIF-1α Stabilization. Mol Neurobiol 2018;55(11):8328-8345 View Article PubMed/NCBI
  35. Hyodo T, Ito Y, Hosono K, Uematsu S, Akira S, Majima M, et al. The role of mPGES-1 in promoting granulation tissue angiogenesis through regulatory T-cell accumulation. In Vivo 2022;36(5):2061-2073 View Article PubMed/NCBI
  36. Iloki-Assanga S, McCarty MF. Nutraceutical targeting of placental synthesis of soluble Fms-like tyrosine Kinase- 1 (sFlt-1) as strategy for preventing and controlling pre-eclampsia. Curr Pharm Des 2018;24(20):2255-2263 View Article PubMed/NCBI
  37. Li Y, Gao R, Liu X, Chen X, Liao X, Geng Y, et al. Folate Deficiency could restrain decidual angiogenesis in pregnant mice. Nutrients 2015;7(8):6425-6445 View Article PubMed/NCBI
  38. Mathur RS, Mathur SP. In vitro downregulation of growth factors by insulin-like growth factor binding protein-3 in cervical cancer. Gynecol Onco 2003;91(2):410-415 View Article PubMed/NCBI
  39. Tuska RM, Helm SM, Graf CF, James C, Kong G, Stiemsma LT, et al. Surfeit folic acid, protein, and exercise modify oncogenic inflammatory biomarkers and fecal microbiota. Front Nutr 2023;9:1060212 View Article PubMed/NCBI
  40. Westin SN, Herzog TJ, Coleman RL. Investigational agents in development for the treatment of ovarian cancer. Invest New Drugs 2013;31(1):213-229 View Article PubMed/NCBI
  41. Yin J, Yi J, Yang C, Xu B, Lin J, Hu H, et al. Weiqi Decoction attenuated chronic atrophic gastritis with precancerous lesion through regulating microcirculation disturbance and HIF-1α signaling pathway. Evid Based Complement Alternat Med 2019;2019:2651037 View Article PubMed/NCBI
  42. Saghiri MA, Asatourian A, Ershadifar S, Moghadam MM, Sheibani N. Vitamins and regulation of angiogenesis: [A, B1, B2, B3, B6, B9, B12, C, D, E, K]. J Func Foods 2017;38:180-196
  43. Pedrosa AM, Lemes RPG. Gene expression of HIF-1α and VEGF in response to hypoxia in sickle cell anaemia: Influence of hydroxycarbamide. Br J Haematol 2020;190(1):e39-e42 View Article PubMed/NCBI
  44. Åström M, Hahn-Strömberg V, Zetterberg E, Vedin I, Merup M, Palmblad J. X-linked thrombocytopenia with thalassemia displays bone marrow reticulin fibrosis and enhanced angiogenesis: comparisons with primary myelofibrosis. Am J Hematol 2015;90(3):E44-48 View Article PubMed/NCBI
  45. Fahmey SS, Naguib HF, Abdelshafy SS, Alashry RE. Vascular endothelial growth factor in children with thalassemia major. Mediterr J Hematol Infect Dis 2013;5(1):e2013044 View Article PubMed/NCBI
  46. Olgar S, Kara A, Hicyilmaz H, Balta N, Canatan D. Evaluation of angiogenesis with vascular endothelial growth factor in patients with thalassemia major. Pediatr Int 2010;52(2):247-251 View Article PubMed/NCBI
  47. Tantawy AAG, Adly AAM, Ismail EAR, Youssef OI, Ali ME. Soluble fms-like tyrosine kinase 1 as a link between angiogenesis and endothelial dysfunction in pediatric patients with β-thalassemia intermedia. Clin Appl Thromb Hemost 2017;23(8):943-950 View Article PubMed/NCBI
  48. Carlucci S, Stabile G, Catagini S, Borghi C, Scutiero G, Morano D, et al. Fetal disseminated intravascular coagulopathy, hydrops and massive umbilical vein thrombosis consequence of a rare placental condition: multifocal chorangiomatosis. J Matern Fetal Neonatal Med 2022;35(20):4009-4013 View Article PubMed/NCBI
  49. Négrier S, Pérol D, Bahleda R, Hollebecque A, Chatelut E, Boyle H, et al. Phase I dose-escalation study of pazopanib combined with bevacizumab in patients with metastatic renal cell carcinoma or other advanced tumors. BMC Cancer 2017;17(1):547 View Article PubMed/NCBI
  50. Pellé G, Shweke N, Duong Van Huyen JP, Tricot L, Hessaïne S, Frémeaux-Bacchi V, et al. Systemic and kidney toxicity of intraocular administration of vascular endothelial growth factor inhibitors. Am J Kidney Dis 2011;57(5):756-759 View Article PubMed/NCBI
  51. Yonem O, Arslan S, Sokmensuer C, Salmanzade S. Can angiogenesis be a target of treatment for ribavirin associated hemolytic anemia?. Hepatogastroenterology 2010;57(99-100):562-566 PubMed/NCBI
  52. Deng S, Zeng Y, Wu L, Hu Z, Shen J, Shen Y, et al. The regulatory roles of VEGF-Notch signaling pathway on aplastic anemia with kidney deficiency and blood stasis. J Cell Biochem 2019;120(2):2078-2089 View Article PubMed/NCBI
  53. Gupta P, Khurana N, Singh T, Gupta D, Dhingra KK. Bone marrow angiogenesis in aplastic anemia—a study of CD 34 and VEGF expression in bone marrow biopsies. Hematology 2009;14(1):16-21 View Article PubMed/NCBI
  54. Li JP, Zheng CL, Han ZC. Abnormal immunity and stem/progenitor cells in acquired aplastic anemia. Crit Rev Oncol Hematol 2010;75(2):79-93 View Article PubMed/NCBI
  55. Čubranić A, Dobrila-Dintinjana R, Redžović A, Dintinjana M, Petranović D, Golčić M. Endogenous erythropoietin and erythropoietin receptors in colorectal cancer; can we answer the questions?. Med Hypotheses 2016;96:16-19 View Article PubMed/NCBI
  56. Besarab A, Hemmerich S. Management of Anemia: A Comprehensive Guide for Clinicians. New York: Springer; 2018, 43-80 View Article
  57. Muchnik E, Kaplan J. HIF prolyl hydroxylase inhibitors for anemia. Expert Opin Investig Drugs 2011;20(5):645-656 View Article PubMed/NCBI
  58. Song D, Ying GS, Dunaief JL, Bhuyan R, Li Y, Maguire MG, et al. Association between oral iron supplementation and retinal or subretinal hemorrhage in the comparison of age-related macular degeneration treatment trials. Retina 2019;39(10):1965-1972 View Article PubMed/NCBI
  59. Abri Aghdam K, Soltan Sanjari M, Ghasemi Falavarjani K. Erythropoietin in ophthalmology: A literature review. J Curr Ophthalmol 2016;28(1):5-11 View Article PubMed/NCBI
  60. Blazovics A. Small molecules in cancer therapy: Cytotoxics and molecularly targeted agents. Curr Signal Transd Therapy 2011;6(1):2-19
  61. Cartron PF, Hervouet E, Debien E, Olivier C, Pouliquen D, Menanteau J, et al. Folate supplementation limits the tumourigenesis in rodent models of gliomagenesis. Eur J Cancer 2012;48(15):2431-2441 View Article PubMed/NCBI
  62. Chai SM, Mathur R, Ong SG. Retinal vasculopathy in Fanconi anemia. Ophthalmic Surg Lasers Imaging 2009;40(5):498-500 View Article PubMed/NCBI
  63. Ciappio ED, Liu Z, Brooks RS, Mason JB, Bronson RT, Crott JW. Maternal B vitamin supplementation from preconception through weaning suppresses intestinal tumorigenesis in Apc1638N mouse offspring. Gut 2011;60(12):1695-1702 View Article PubMed/NCBI
  64. Gerald D, Berra E, Frapart YM, Chan DA, Giaccia AJ, Mansuy D, et al. JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 2004;118(6):781-794 View Article PubMed/NCBI
  65. Kim YI. Role of folate in colon cancer development and progression. J Nutr 2003;133(11):3731S-3739S View Article PubMed/NCBI
  66. Pascual M, Bohle B, Alonso S, Mayol X, Salvans S, Grande L, et al. Preoperative administration of erythropoietin stimulates tumor recurrence after surgical excision of colon cancer in mice by a vascular endothelial growth factor-independent mechanism. J Surg Res 2013;183(1):270-277 View Article PubMed/NCBI
  67. Rahat B, Mahajan A, Bagga R, Hamid A, Kaur J. Epigenetic modifications at DMRs of placental genes are subjected to variations in normal gestation, pathological conditions and folate supplementation. Sci Rep 2017;7:40774 View Article PubMed/NCBI
  68. Sasaki K, Duan J, Murohara T, Ikeda H, Shintani S, Shimada T, et al. Rescue of hypercholesterolemia-related impairment of angiogenesis by oral folate supplementation. J Am Coll Cardiol 2003;42(2):364-72 View Article PubMed/NCBI
  69. Souza E, Cho KH, Harris ST, Flindt NR, Watt RK, Pai AB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: a paradigm shift for treatment of anemia in chronic kidney disease?. Expert Opin Investig Drugs 2020;29(8):831-844 View Article PubMed/NCBI
  70. Suk KK, Dunbar JA, Liu A, Daher NS, Leng CK, Leng JK, et al. Human recombinant erythropoietin and the incidence of retinopathy of prematurity: a multiple regression model. J AAPOS 2008;12(3):233-238 View Article PubMed/NCBI
  71. van Patot MC, Gassmann M. Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2α. High Alt Med Biol 2011;12(2):157-167 View Article PubMed/NCBI
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  • Exploratory Research and Hypothesis in Medicine
  • pISSN 2993-5113
  • eISSN 2472-0712

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Anemia: A Potential Source of Bias in Clinical Trials of Angiogenesis Inhibitors: A Hypothesis

Reza Rastmanesh
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