The Interplay of the Angiotensin Receptor Blockers and Hematological Abnormalities: Insights and Implications
DOI:
https://doi.org/10.55519/JAMC-04-12507Keywords:
angiotensin receptor blocker, hematological abnormalities, anemiaAbstract
Antihypertensive medications known as angiotensin receptor blockers (ARBs) have become increasingly popular for treating conditions beyond hypertension. The reason for this widespread use is mainly due to their renoprotective and cardioprotective properties in patients with congestive heart failure and diabetes mellitus. There have been conflicting studies on the relationship between ARBs and hematological abnormalities. Using the supplied search terms, we carried out a thorough search for relevant papers written in English and published before July 2023. All of the studies that met the selection criteria were searched for on PubMed, Cochrane Library, and Google Scholar. Based on the examined data from the searched literatures, it has been demonstrated that angiotensin II is essential for stimulation of erythropoiesis and inhibition of it by drugs such as ARBs can lower hematocrit levels, leading to anemia. Accordingly, dose reduction or stopping administration of ARBs could be a choice for correction of anemia. However, such decision is based on the clinical situation and the requirements for other management options.
References
References
Brugts JJ, Boersma E, Chonchol M, Deckers JW, Bertrand M, Remme WJ, et al. The cardioprotective effects of the angiotensin-converting enzyme inhibitor perindopril in patients with stable coronary artery disease are not modified by mild to moderate renal insufficiency: insights from the EUROPA trial. J Am Coll Cardiol. 2007 Nov;50(22):2148-55.
Mahmood IH, Abed MN, Merkhan MM. Effects of blocking of angiotensin system on the prevalenceof metabolic syndrome in type 2 diabetic patients. Pakistan J Med Sci. 2012 Nov 1;29(1):140-3.
Marusic-Vrsalovic M, Dominis M, Jaksic B, Kusec R. Angiotensin I-converting enzyme is expressed by erythropoietic cells of normal and myeloproliferative bone marrow. Br J Haematol. 2003 Nov;123(3):539-41.
Marathias K, Agroyannis B, Mavromoustakos T, Matsoukas J, Vlahakos D. Hematocrit-lowering effect following inactivation of renin-angiotensin system with angiotensin converting enzyme inhibitors and angiotensin receptor blockers. Curr Top Med Chem. 2004 Mar;4(4):483-6.
Cheungpasitporn W, Thongprayoon C, Chiasakul T, Korpaisarn S, Erickson SB. Renin-angiotensin system inhibitors linked to anemia: a systematic review and meta-analysis. QJM. 2015 Nov;108(11):879-84.
Plata R, Cornejo A, Arratia C, Anabaya A, Perna A, Dimitrov BD, et al. Angiotensin-converting-enzyme inhibition therapy in altitude polycythaemia: A prospective randomised trial. Lancet. 2002 Feb;359(9307):663-6.
Winkelmayer WC, Kewalramani R, Rutstein M, Gabardi S, Vonvisger T, Chandraker A. Pharmacoepidemiology of anemia in kidney transplant recipients. J Am Soc Nephrol. 2004 May;15(5):1347-52.
Inoue A, Babazono T, Iwamoto Y. Effects of the Renin-Angiotensin system blockade on hemoglobin levels in type 2 diabetic patients with chronic kidney disease. Am J Hypertens. 2008 Mar;21(3):317-22.
Fountain JH, Lappin SL. Physiology, Renin Angiotensin System. StatPearls. 2022 Jun;
Tetzner A, Gebolys K, Meinert C, Klein S, Uhlich A, Trebicka J, et al. G-Protein-Coupled Receptor MrgD Is a Receptor for Angiotensin-(1-7) Involving Adenylyl Cyclase, cAMP, and Phosphokinase A. Hypertension. 2016 Jul;68(1):185-94.
Patel VB, Zhong JC, Grant MB, Oudit GY. Role of the ACE2/angiotensin 1-7 axis of the renin-angiotensin system in heart failure. Circ Res. 2016;118(8):1313-26.
Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, et al. UltraRapid Communication A Novel Angiotensin-Converting Enzyme - Related to Angiotensin 1-9. Circ Res. 2000;87:1-9.
Zhuo JL, Li XC. New insights and perspectives on intrarenal renin-angiotensin system: Focus on intracrine/intracellular angiotensin II. Peptides. 2011 Jul;32(7):1551-65.
Villapol S, Saavedra JM. Neuroprotective Effects of Angiotensin Receptor Blockers. Am J Hypertens. 2015 Mar;28(3):289-99.
Alnori H, Alassaf FA, Alfahad M, Qazzaz ME, Jasim M, Abed MN. Vitamin D and Immunoglobulin E Status in Allergic Rhinitis Patients Compared to Healthy People. J Med Life. 2020;13(4):463-8.
Yosypiv I V. Renin-angiotensin system in mammalian kidney development. Pediatr Nephrol. 2021 Mar 18;36(3):479-89.
Bagby SP, Lebard LS, Luo Z, Ogden BE, Corless C, Mcpherson ED, et al. ANG II AT 1 and AT 2 receptors in developing kidney of normal microswine. Am J Physiol Ren Physiol. 2002;283:755-64.
Norwood VF, Craig MR, Harris JM, Gomez RA. Differential expression of angiotensin II receptors during early renal morphogenesis. Am J Physiol. 1997;272(2 Pt 2).
Schrankl J, Fuchs M, Broeker K, Daniel C, Kurtz A, Wagner C. Localization of angiotensin II type 1 receptor gene expression in rodent and human kidneys. Am J Physiol - Ren Physiol. 2021 Apr;320(4):F644-53.
Li XC, Zhuo JL. Recent Updates on the Proximal Tubule Renin-Angiotensin System in Angiotensin II-Dependent Hypertension. Curr Hypertens Rep. 2016 Aug;18(8):63.
Pei N, Mao Y, Wan P, Chen X, Li A, Chen H, et al. Angiotensin II type 2 receptor promotes apoptosis and inhibits angiogenesis in bladder cancer. J Exp Clin Cancer Res. 2017 Jun;36(1).
la Sierra A. Angiotensin receptor blockers in hypertension and cardiovascular diseases. Cardiovasc Hematol Agents Med Chem. 2006 Jul;4(1):67-73.
Steckelings UM, Artuc M, Wollschläger T, Wiehstutz S, Henz BM. Angiotensin-converting enzyme inhibitors as inducers of adverse cutaneous reactions. Acta Derm Venereol. 2001;81(5).
Raimondo D Di, Tuttolomondo A, Buttà C, Miceli S, Licata G, Pinto A. Effects of ACE-Inhibitors and Angiotensin Receptor Blockers on Inflammation. 2012;4385-413.
Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M, et al. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARγ-modulating activity. Hypertension. 2004;43(5):993-1002.
Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: a randomized trial. Jama. 2008;300(8):924-32.
Silveira KD, Coelho FM, Vieira AT, Barroso LC, Queiroz CM, Costa V V., et al. Mechanisms of the anti-inflammatory actions of the angiotensin type1 receptor antagonist losartan in experimental models of arthritis. Peptides. 2013;46:53-63.
Mrug M, Stopka T, Julian BA, Prchal JF, Prchal JT. Angiotensin II stimulates proliferation of normal early erythroid progenitors. J Clin Invest. 1997 Nov;100(9):2310.
Kato H, Ishida J, Imagawa S, Saito T, Suzuki N, Matsuoka T, et al. Enhanced erythropoiesis mediated by activation of the renin-angiotensin system via angiotensin II type 1a receptor. FASEB J. 2005 Dec;19(14):2023-5.
Doan TN, Gletsu N, Cole J, Bernstein KE. Genetic manipulation of the renin-angiotensin system. Curr Opin Nephrol Hypertens. 2001;10(4):483-91.
Naito M, Kawashima A, Akiba T, Takanashi M, Nihei H. Effects of an angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitors on burst forming units-erythroid in chronic hemodialysis patients. Am J Nephrol. 2003;23(5):287-93.
Jelkmann W. Regulation of erythropoietin production. J Physiol. 2011 Mar;589(Pt 6):1251.
Nakamoto H, Kanno Y, Okada H, Suzuki H. Erythropoietin resistance in patients on continuous ambulatory peritoneal dialysis. Adv Perit Dial. 2004 Jan;20:111-6.
Hu X, li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther 2021 61. 2021 Nov;6(1):1-33.
Yasuoka Y, Izumi Y, Fukuyama T, Inoue H, Oshima T, Yamazaki T, et al. Effects of Angiotensin II on Erythropoietin Production in the Kidney and Liver. Molecules. 2021 Sep;26(17).
Iriyama T, Wang W, Parchim NF, Song A, Blackwell SC, Sibai BM, et al. Hypoxia-independent upregulation of placental hypoxia inducible factor-1α gene expression contributes to the pathogenesis of preeclampsia. Hypertension. 2015 Jun;65(6):1307-15.
An JN, Hwang JH, Lee JP, Chin HJ, Kim S, Kim DK, et al. The Decrement of Hemoglobin Concentration with Angiotensin II Receptor Blocker Treatment Is Correlated with the Reduction of Albuminuria in Non-Diabetic Hypertensive Patients: Post-Hoc Analysis of ESPECIAL Trial. PLoS One. 2015 Jun;10(6):e0128632.
Singer CE, Vasile CM, Popescu M, Popescu AIS, Marginean IC, Iacob GA, et al. Role of Iron Deficiency in Heart Failure-Clinical and Treatment Approach: An Overview. Diagnostics (Basel, Switzerland). 2023 Jan;13(2):304.
Westenbrink BD, Visser FW, Voors AA, Smilde TDJ, Lipsic E, Navis G, et al. Anaemia in chronic heart failure is not only related to impaired renal perfusion and blunted erythropoietin production, but to fluid retention as well. Eur Heart J. 2007 Jan;28(2):166-71.
JENSEN JD, EISKJÆR H, BAGGER JP, PEDERSEN EB. Elevated level of erythropoietin in congestive heart failure relationship to renal perfusion and plasma renin. J Intern Med. 1993;233(2):125-30.
Kato H, Ishida J, Matsusaka T, Ishimaru T, Tanimoto K, Sugiyama F, et al. Erythropoiesis and Blood Pressure Are Regulated via AT1 Receptor by Distinctive Pathways. PLoS One. 2015 Jun;10(6).
Gossmann J, Burkhardt R, Harder S, Lenz T, Sedlmeyer A, Klinkhardt U, et al. Angiotensin II infusion increases plasma erythropoietin levels via an angiotensin II type 1 receptor-dependent pathway. Kidney Int. 2001;60(1):83-6.
Ishizaka N, Saito K, Noiri E, Sata M, Ikeda H, Ohno A, et al. Administration of ANG II induces iron deposition and upregulation of TGF-beta1 mRNA in the rat liver. Am J Physiol Regul Integr Comp Physiol. 2005 Apr;288(4).
Tajima S, Tsuchiya K, Horinouchi Y, Ishizawa K, Ikeda Y, Kihira Y, et al. Effect of angiotensin II on iron-transporting protein expression and subsequent intracellular labile iron concentration in human glomerular endothelial cells. Hypertens Res. 2010;33(7):713-21.
Tajima S, Ikeda Y, Enomoto H, Imao M, Horinouchi Y, Izawa-Ishizawa Y, et al. Angiotensin II alters the expression of duodenal iron transporters, hepatic hepcidin, and body iron distribution in mice. Eur J Nutr. 2015 Aug;54(5):709-19.
Rodgers KE, Xiong S, Steer R, diZerega GS. Effect of angiotensin II on hematopoietic progenitor cell proliferation. Stem Cells. 2000 Jul;18(4):287-94.
Shen XZ, Bernstein KE. The peptide network regulated by angiotensin converting enzyme (ACE) in hematopoiesis. Cell Cycle. 2011 May;10(9):1363.
Cao DY, Saito S, Veiras LC, Okwan-Duodu D, Bernstein EA, Giani JF, et al. Role of angiotensin-converting enzyme in myeloid cell immune responses. Cell Mol Biol Lett. 2020 May;25(1):1-12.
Kim S, Zingler M, Harrison JK, Scott EW, Cogle CR, Luo D, et al. Angiotensin II Regulation of Proliferation, Differentiation and Engraftment of Hematopoietic Stem Cells. Hypertension. 2016 Mar;67(3):574.
Lo  Pez-Farre A, Sa  Nchez De Miguel L, Ân MM, Jime Ânez A, Lopez-Bloya A, Go  Mez J, et al. Angiotensin II AT1 receptor antagonists and platelet activation. Nephrol Dial Transplant. 2001;16:45-9.
Montezano AC, Nguyen Dinh Cat A, Rios FJ, Touyz RM. Angiotensin II and vascular injury. Curr Hypertens Rep. 2014;16(6).
Ahmed GM, Abed MN, Alassaf FA. An overview of the effects of sodium-glucose co-transporter-2 inhibitors on hematological parameters in diabetic patients. Iraqi J Pharm. 2023;20(1):65-71.
Alicic RZ, Neumiller JJ, Johnson EJ, Dieter B, Tuttle KR. Sodium-Glucose Cotransporter 2 Inhibition and Diabetic Kidney Disease. Diabetes. 2019 Feb;68(2):248-57.
Shinozaki K, Ayajiki K, Nishio Y, Sugaya T, Kashiwagi A, Okamura T. Evidence for a causal role of the renin-angiotensin system in vascular dysfunction associated with insulin resistance. Hypertens (Dallas, Tex 1979). 2004;43(2):255-62.
Underwood PC, Adler GK. The Renin Angiotensin Aldosterone System and Insulin Resistance in Humans. Curr Hypertens Rep. 2013 Feb;15(1):59.
Alassaf FA, Jasim MHM, Alfahad M, Qazzaz ME, Abed MN, Thanoon IA. Effects of bee propolis on FBG, HbA1c and insulin resistance in healthy volunteers. Diabetes. 2020;17:18.
Peti-Peterdi J, Kang JJ, Toma I. Activation of the renal renin-angiotensin system in diabetes-new concepts. Nephrol Dial Transplant. 2008 Oct;23(10):3047.
Vlahakos D V., Marathias KP, Madias NE. The role of the renin-angiotensin system in the regulation of erythropoiesis. Am J Kidney Dis. 2010 Sep;56(3):558-65.
Iriyama T, Wang W, Parchim NF, Song A, Blackwell SC, Sibai BM, et al. Hypoxia-independent upregulation of placental hypoxia inducible factor-1α gene expression contributes to the pathogenesis of preeclampsia. Hypertens (Dallas, Tex 1979). 2015 Jun;65(6):1307-15.
Cole J, Ertoy D, Lin H, Sutliff RL, Ezan E, Guyene TT, et al. Lack of angiotensin II-facilitated erythropoiesis causes anemia in angiotensin-converting enzyme-deficient mice. J Clin Invest. 2000;106(11):1391-8.
Raptis AE, Bacharaki D, Mazioti M, Marathias KP, Markakis KP, Raptis SA, et al. Anemia due to coadministration of renin-angiotensin-system inhibitors and PPARγ agonists in uncomplicated diabetic patients. Exp Clin Endocrinol Diabetes. 2012;120(7):416-9.
Alzoubi B, Kharel A, Machhi R, Aziz F, Swanson KJ, Parajuli S. Post-transplant erythrocytosis after kidney transplantation: A review. World J Transplant. 2021 Jun;11(6):220.
Vlahakos D V., Marathias KP, Kosmas EN. Losartan reduces hematocrit in patients with chronic obstructive pulmonary disease and secondary erythrocytosis. Ann Intern Med. 2001 Mar;134(5):426-7.
Dunlay SM, Weston SA, Redfield MM, Killian JM, Roger VL. Anemia and heart failure: a community study. Am J Med. 2008 Aug;121(8):726-32.
Kamper AL, Nielsen OJ. Effect of enalapril on haemoglobin and serum erythropoietin in patients with chronic nephropathy. Scand J Clin Lab Invest. 1990;50(6):611-8.
Witte KKA, Desilva R, Chattopadhyay S, Ghosh J, Cleland JGF, Clark AL. Are hematinic deficiencies the cause of anemia in chronic heart failure? Am Heart J. 2004 May;147(5):924-30.
Nanas JN, Matsouka C, Karageorgopoulos D, Leonti A, Tsolakis E, Drakos SG, et al. Etiology of anemia in patients with advanced heart failure. J Am Coll Cardiol. 2006 Dec;48(12):2485-9.
Macdougall IC, Cooper AC. Hyporesponsiveness to erythropoietic therapy due to chronic inflammation. Eur J Clin Invest. 2005;35 Suppl 3(3):32-5.
Iversen PO, Woldbaek PR, Tønnessen T, Christensen G. Decreased hematopoiesis in bone marrow of mice with congestive heart failure. Am J Physiol Regul Integr Comp Physiol. 2002;282(1).
Jankowska EA, Malyszko J, Ardehali H, Koc-Zorawska E, Banasiak W, Von Haehling S, et al. Iron status in patients with chronic heart failure. Eur Heart J. 2013 Mar;34(11):827-34.
Chiang CK, Tanaka T, Inagi R, Fujita T, Nangaku M. Indoxyl sulfate, a representative uremic toxin, suppresses erythropoietin production in a HIF-dependent manner. Lab Invest. 2011 Nov;91(11):1564-71.
Huang JY, Hsu CW, Yang CW, Hung CC, Huang WH. Role of anuria in the relationship between indoxyl sulfate and anemia in peritoneal dialysis patients. Ther Clin Risk Manag. 2016 Nov;12:1797-803.
Bataille S, Pelletier M, Sallée M, Berland Y, McKay N, Duval A, et al. Indole 3-acetic acid, indoxyl sulfate and paracresyl-sulfate do not influence anemia parameters in hemodialysis patients. BMC Nephrol. 2017 Jul;18(1).
Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of 12 065 patients with new-onset heart failure. Circulation. 2003 Jan;107(2):223-5.
Anand IS, Kuskowski MA, Rector TS, Florea VG, Glazer RD, Hester A, et al. Anemia and change in hemoglobin over time related to mortality and morbidity in patients with chronic heart failure: results from Val-HeFT. Circulation. 2005 Aug;112(8):1121-7.
Go AS, Yang J, Ackerson LM, Lepper K, Robbins S, Massie BM, et al. Hemoglobin level, chronic kidney disease, and the risks of death and hospitalization in adults with chronic heart failure: the Anemia in Chronic Heart Failure: Outcomes and Resource Utilization (ANCHOR) Study. Circulation. 2006 Jun;113(23):2713-23.
Mozaffarian D, Nye R, Levy WC. Anemia predicts mortality in severe heart failure: The prospective randomized amlodipine survival evaluation (PRAISE). J Am Coll Cardiol. 2003 Jun;41(11):1933-9.
Sîrbu O, Floria M, Dascalita P, Stoica A, Adascalitei P, Sorodoc V, et al. Anemia in heart failure - from guidelines to controversies and challenges. Anatol J Cardiol. 2018 Jul;20(1):52.
Azizi M, Junot C, Ezan E, Ménard J. Angiotensin I-converting enzyme and metabolism of the haematological peptide N-acetyl-seryl-aspartyl-lysyl-proline. Clin Exp Pharmacol Physiol. 2001;28(12):1066-9.
Vlahakos D V., Marathias KP, Agroyannis B, Madias NE. Posttransplant erythrocytosis. Kidney Int. 2003 Apr;63(4):1187-94.
Salzberg DJ, Karadsheh FF, Haririan A, Reddivari V, Weir MR. Specific management of anemia and hypertension in renal transplant recipients: influence of renin-angiotensin system blockade. Am J Nephrol. 2014 Feb;39(1):1-7.
Vlahakos D V., Tsioufis C, Manolis A, Filippatos G, Marathias KP, Papademetriou V, et al. Inhibition of the renin-angiotensin system in the cardiorenal syndrome with anaemia: a double-edged sword. J Hypertens. 2019 Nov;37(11):2145-53.
Drüeke TB, Locatelli F, Clyne N, Eckardt K-U, Macdougall IC, Tsakiris D, et al. Normalization of Hemoglobin Level in Patients with Chronic Kidney Disease and Anemia. n engl j med. 2006;20(16):2071-84.
Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013 Mar;368(13):1210-9.
Jankowska EA, Tkaczyszyn M, Suchocki T, Drozd M, von Haehling S, Doehner W, et al. Effects of intravenous iron therapy in iron-deficient patients with systolic heart failure: a meta-analysis of randomized controlled trials. Eur J Heart Fail. 2016 Jul;18(7):786-95.
JT W, JD W, PK W, JK S, KM S, MV R, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015 Nov;373(22):2103-16.
Cheung AK, Rahman M, Reboussin DM, Craven TE, Greene T, Kimmel PL, et al. Effects of Intensive BP Control in CKD. J Am Soc Nephrol. 2017 Sep;28(9):2812-23.
Vardeny O, Claggett B, Packer M, Zile MR, Rouleau J, Swedberg K, et al. Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial. Eur J Heart Fail. 2016 Oct;18(10):1228-34.
Yamada S, Inaba M. Potassium Metabolism and Management in Patients with CKD. Nutrients. 2021;13(6).
Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000 Mar;160(5).
Burnier M. Renin-Angiotensin System Blockade in Advanced Kidney Disease: Stop or Continue? Kidney Med. 2020 May;2(3):231.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2024 Ghada M. Ahmed, Fawaz A. Alassaf, Mohammed N. Abed
This work is licensed under a Creative Commons Attribution-NoDerivatives 4.0 International License.
Journal of Ayub Medical College, Abbottabad is an OPEN ACCESS JOURNAL which means that all content is FREELY available without charge to all users whether registered with the journal or not. The work published by J Ayub Med Coll Abbottabad is licensed and distributed under the creative commons License CC BY ND Attribution-NoDerivs. Material printed in this journal is OPEN to access, and are FREE for use in academic and research work with proper citation. J Ayub Med Coll Abbottabad accepts only original material for publication with the understanding that except for abstracts, no part of the data has been published or will be submitted for publication elsewhere before appearing in J Ayub Med Coll Abbottabad. The Editorial Board of J Ayub Med Coll Abbottabad makes every effort to ensure the accuracy and authenticity of material printed in J Ayub Med Coll Abbottabad. However, conclusions and statements expressed are views of the authors and do not reflect the opinion/policy of J Ayub Med Coll Abbottabad or the Editorial Board.
USERS are allowed to read, download, copy, distribute, print, search, or link to the full texts of the articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author. This is in accordance with the BOAI definition of open access.
AUTHORS retain the rights of free downloading/unlimited e-print of full text and sharing/disseminating the article without any restriction, by any means including twitter, scholarly collaboration networks such as ResearchGate, Academia.eu, and social media sites such as Twitter, LinkedIn, Google Scholar and any other professional or academic networking site.
