# Serum Kallistatin Levels are Associated with the Pathogenesis of Sickle Cell Disease

## Authors

- Serdar Dogan ([ORCID](https://orcid.org/0000-0001-6854-2197)) — Department of Medical Biochemistry, Hatay Mustafa Kemal University, Faculty of Medicine, Hatay, Turkey
- Hamza Malik Okuyan ([ORCID](https://orcid.org/0000-0001-7616-3330)) — Department of Physiotherapy and Rehabilitation, Biomedical Engineering, Sakarya University, Sakarya, Turkey
- Gul Ilhan ([ORCID](https://orcid.org/0000-0003-1616-6358)) — Department of Hematology, Hatay Mustafa Kemal University, Faculty of Medicine, Hatay, Turkey

## Article information

- **Journal:** The Ulutas Medical Journal (Ulutas Med J), ISSN 2149-388X
- **Issue:** Volume 7, Issue 4 (2021), pages 220–227
- **Article type:** Original Article
- **Published online:** 2021-12-26
- **DOI:** [10.5455/umj.20211101020302](https://doi.org/10.5455/umj.20211101020302)
- **Licence:** [CC BY-NC 4.0](https://creativecommons.org/licenses/by-nc/4.0/)
- **Article page:** https://www.ulutasmedicaljournal.com/?mno=137221
- **PDF:** https://www.ulutasmedicaljournal.com/pdf/137221.pdf

## Abstract

Introduction: Sickle cell disease (SCD) is a prevalent monogenic hemoglobin disorder that presents a global burden with life-threatening complications. More studies are needed to understand the complex pathophysiology that causes multi-organ damage and develop effective approaches that ameliorate the clinical complications of patients with SCD. In the present study, we aimed to explore the relationship of Kallistatin with VEGF-A and TNF-α in patients with SCD. Materials and methods: Thirty patients with SCD and 28 age- and sex-matched healthy subjects were included in the study. Serum Kallistatin, VEGF-A and TNF-α levels were measured by Enzyme-Linked Absorbent Assay (ELISA) and biochemical parameters were analyzed with routine techniques. Results: The levels of Kallistatin, VEGF-A, leukocyte, AST, ALT, total bilirubin, direct bilirubin, LDH, and CRP were significantly higher in the patient group than in the control group whereas RBC and hemoglobin levels were significantly lower in patients than healthy individuals. Kallistatin levels were positively correlated with AST, total bilirubin, direct bilirubin, LDH, CRP, VEGF-A. VEGF-A levels were positively correlated with WBC, ALT, total bilirubin, while VEGF-A negatively correlated with RBC and hemoglobin. The areas under the receiver operating characteristic for Kallistatin and VEGF-A were 0.8536 and 0.7488, respectively. Conclusion: We report for the first time that Kallistatin could be a novel marker associated with the pathogenesis of SCD.

## Keywords

Kallistatin; VEGF-A; Sickle Cell Disease; Angiogenesis

## How to cite

Dogan S, Okuyan HM, Ilhan G. Serum Kallistatin Levels are Associated with the Pathogenesis of Sickle Cell Disease. Ulutas Med J. 2021;7(4):220-227. doi:10.5455/umj.20211101020302

## References

1. Lu M, Rab MA, Shevkoplyas SS, Sheehan VA. Blood rheology biomarkers in sickle cell disease. Experimental biology and medicine. 2020;245(2):155-65 https://doi.org/10.1177/1535370219900494
2. Kato GJ, Piel FB, Reid CD, Gaston MH, Ohene-Frempong K, Krishnamurti L, et al. Sickle cell disease. Nature reviews Disease primers. 2018;4:18010 https://doi.org/10.1038/nrdp.2018.10
3. Stuart MJ, Nagel RL. Sickle-cell disease. Lancet. 2004;364 (9442):1343-60 https://doi.org/10.1016/s0140-6736(04)17192-4
4. Conran N, Belcher JD. Inflammation in sickle cell disease. Clinical hemorheology and microcirculation. 2018;68 (2-3): 263-99 https://doi.org/10.3233/ch-189012
5. Antwi-Boasiako C, Frimpong E, Gyan B, Kyei-Baafour E, Sey F, Dzudzor B, et al. Elevated Proangiogenic Markers are Associated with Vascular Complications within Ghanaian Sickle Cell Disease Patients. Medical sciences. 2018;6(3) https://doi.org/10.3390/medsci6030053
6. Chao J, Li P, Chao L. Kallistatin: double-edged role in angiogenesis, apoptosis and oxidative stress. Biological chemistry. 2017;398(12):1309-17 https://doi.org/10.1515/hsz-2017-0180
7. Chao J, Bledsoe G, Chao L. Protective Role of Kallistatin in Vascular and Organ Injury. Hypertension. 2016;68(3):533-41 https://doi.org/10.1161/hypertensionaha.116.07861
8. Al-Habboubi HH, Mahdi N, Abu-Hijleh TM, Abu-Hijleh FM, Sater MS, Almawi WY. The relation of vascular endothelial growth factor (VEGF) gene polymorphisms on VEGF levels and the risk of vasoocclusive crisis in sickle cell disease. European journal of haematology. 2012;89(5):403-9 https://doi.org/10.1111/ejh.12003
9. Niu X, Nouraie M, Campbell A, Rana S, Minniti CP, Sable C, et al. Angiogenic and inflammatory markers of cardiopulmonary changes in children and adolescents with sickle cell disease. PloS one. 2009;4(11):e7956 https://doi.org/10.1371/journal.pone.0007956
10. Mohan JS, Lip PL, Blann AD, Bareford D, Lip GY. The angiopoietin/Tie-2 system in proliferative sickle retinopathy: relation to vascular endothelial growth factor, its soluble receptor Flt-1 and von Willebrand factor, and to the effects of laser treatment. The British journal of ophthalmology. 2005;89(7):815-9 https://doi.org/10.1136/bjo.2004.058164
11. Gurkan E, Tanriverdi K, Baslamisli F. Clinical relevance of vascular endothelial growth factor levels in sickle cell disease. Annals of hematology. 2005;84(2):71-5 https://doi.org/10.1007/s00277-004-0935-y
12. Duits AJ, Rodriguez T, Schnog JJ, Group CS. Serum levels of angiogenic factors indicate a pro-angiogenic state in adults with sickle cell disease. British journal of haematology. 2006;134(1):116-9 https://doi.org/10.1111/j.1365-2141.2006.06103.x
13. Jenkins AJ, McBride JD, Januszewski AS, Karschimkus CS, Zhang B, O'Neal DN, et al. Increased serum kallistatin levels in type 1 diabetes patients with vascular complications. Journal of angiogenesis research. 2010;2:19 227 77 Kallistatin Levels at the Pathogenesis of SCD Doğan et al. https://doi.org/10.1186/2040-2384-2-19
14. McBride JD, Jenkins AJ, Liu X, Zhang B, Lee K, Berry WL, et al. Elevated circulation levels of an antiangiogenic SERPIN in patients with diabetic microvascular complications impair wound healing through suppression of Wnt signaling. The Journal of investigative dermatology. 2014;134(6):1725-34 https://doi.org/10.1038/jid.2014.40
15. Gateva A, Assyov Y, Velikova T, Kamenov Z. Increased kallistatin levels in patients with obesity and prediabetes compared to normal glucose tolerance. Endocrine research. 2017;42(2):163-8 https://doi.org/10.1080/07435800.2017.1286671
16. Wang CR, Chen SY, Shiau AL, Wu CL, Jou IM, Chao L, et al. Upregulation of kallistatin expression in rheumatoid joints. The Journal of rheumatology. 2007;34(11):2171-6
17. Umemura T, Higashi Y. Endothelial progenitor cells: therapeutic target for cardiovascular diseases. Journal of pharmacological sciences. 2008;108(1):1-6 https://doi.org/10.1254/jphs.08r01cp
18. van Beem RT, Nur E, Zwaginga JJ, Landburg PP, van Beers EJ, Duits AJ, et al. Elevated endothelial progenitor cells during painful sickle cell crisis. Experimental hematology. 2009;37(9): 1054-9 https://doi.org/10.1016/j.exphem.2009.06.003
19. Anjum F, Lazar J, Zein J, Jamaleddine G, Demetis S, Wadgaonkar R. Characterization of altered patterns of endothelial progenitor cells in sickle cell disease related pulmonary arterial hypertension. Pulmonary circulation. 2012;2(1):54-60 https://doi.org/10.4103/2045-8932.94834
20. Rodrigo M, Mendelsohn L, Bereal-Williams C, Hunter L, Dalby CK, McGowan V, 2nd, et al. Circulating endothelial progenitor cells in adults with sickle cell disease. Pulmonary circulation. 2013;3(2):448-9 https://doi.org/10.4103/2045-8932.114784
21. Shen B, Smith RS, Jr., Hsu YT, Chao L, Chao J. Kruppel-like factor 4 is a novel mediator of Kallistatin in inhibiting endothelial inflammation via increased endothelial nitric-oxide synthase expression. The Journal of biological chemistry. 2009;284(51):35471-8 https://doi.org/10.1074/jbc.m109.046813
22. Gao L, Li P, Zhang J, Hagiwara M, Shen B, Bledsoe G, et al. Novel role of kallistatin in vascular repair by promoting mobility, viability, and function of endothelial progenitor cells. Journal of the American Heart Association. 2014;3(5):e001194 https://doi.org/10.1161/jaha.114.001194
23. Meher S, Patel S, Das K, Dehury S, Jit BP, Maske MM, et al. Association of plasma homocysteine level with vaso-occlusive crisis in sickle cell anemia patients of Odisha, India. Annals of hematology. 2019;98(10): 2257-65 https://doi.org/10.1007/s00277-019-03776-x
24. Iwalokun BA, Iwalokun SO, Hodonu SO, Aina OA, Omilabu S. A study on the association between parvovirus B19 infection, serum tumour necrosis factor and C-reactive protein levels among Nigerian patients with sickle cell anaemia. Singapore medical journal. 2012;53(11):726-31 https://doi.org/10.1186/1471-2326-11-2
25. Keikhaei B, Mohseni AR, Norouzirad R, Alinejadi M, Ghanbari S, Shiravi F, et al. Altered levels of pro-inflammatory cytokines in sickle cell disease patients during vaso-occlusive crises and the steady state condition. European cytokine network. 2013;24(1):45-52 https://doi.org/10.1684/ecn.2013.0328
26. Toledo SLO, Guedes JVM, Alpoim PN, Rios DRA, Pinheiro MB. Sickle cell disease: Hemostatic and inflammatory changes, and their interrelation. Clinica chimica acta; international journal of clinical chemistry. 2019;493:129-37 https://doi.org/10.1016/j.cca.2019.02.026
27. Cruz PR, Lira RP, Pereira Filho SA, Souza BB, Mitsuushi FN, Menaa F, et al. Increased circulating PEDF and low sICAM-1 are associated with sickle cell retinopathy. Blood cells, molecules & diseases. 2015;54(1):33-7 https://doi.org/10.1016/j.bcmd.2014.08.003
28. Pathare A, Al Kindi S, Alnaqdy AA, Daar S, Knox-Macaulay H, Dennison D. Cytokine profile of sickle cell disease in Oman. American journal of hematology. 2004;77(4):323-8 https://doi.org/10.1002/ajh.20196
29. Alagbe AE, Olaniyi JA, Aworanti OW. Adult Sickle Cell Anaemia Patients in Bone Pain Crisis have Elevated Pro-Inflammatory Cytokines. Mediterranean journal of hematology and infectious diseases. 2018;10(1):e2018017 https://doi.org/10.4084/mjhid.2018.017
30. Qari MH, Dier U, Mousa SA. Biomarkers of inflammation, growth factor, and coagulation activation in patients with sickle cell disease. Clinical and applied thrombosis/ hemostasis: official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2012;18(2):195- https://doi.org/10.1177/1076029611420992
31. Bandeira IC, Rocha LB, Barbosa MC, Elias DB, Querioz JA, Freitas MV, et al. Chronic inflammatory state in sickle cell anemia patients is associated with HBB(*)S haplotype. Cytokine. 2014;65(2):217-21 https://doi.org/10.1016/j.cyto.2013.10.009