Iron Mediated Vascular Disease in Sickle Cell Anemia Patients

NCT01239901 | Completed DMC

• 1 other identifier: 1RC1HL099412-01
• Study Type: observational
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this research study is to determine the frequency and severity of iron overload in patients with Sickle Cell Anemia and its relationship to blood vessel function. The investigators hypothesize that intermittent transfusions that these patients receive during hospitalizations produces significant iron overload and impairs blood vessel relaxation.

Conditions

Sickle Cell Disease

Keywords

sickle cell disease; sickle cell anemia; sickled cells; blood vessel; iron overload

Outcome Measures

Primary Outcomes (1)

• Liver iron concentration (LIC), pancreas R2*, and kidney R2*, measured by MRI

  Liver iron concentration (LIC) will be used as a surrogate for total body iron, pancreatic iron represents a surrogate for extravascular iron deposition, and renal iron as a surrogate for chronic intravascular hemolysis. In addition, labile plasma iron will be measured in blood plasma.

  15 min MRI done completed during one time study visit

Secondary Outcomes (1)

• Vascular function.

  Scheduled during one time study visit

Eligibility Criteria

• Age: 13 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Our large and well-established sickle cell Center has strong ties to the SCD community in a large metropolitan area (Los Angeles), placing us in an ideal position to rapidly accrue sufficient subjects to study the prevalence of iron overload and determine the relation between directly measured iron loading, vascular responsiveness and clinically relevant biomarkers of vascular function.

You may qualify if:

• Age \> 13 years
• Documented diagnosis of sickle cell anemia (SS, SC, Sß0, Sß+)
• Transfused no more than 8 times in a year.

You may not qualify if:

• Cardiac pacemaker, implantable neurostimulator or other MRI incompatible device.
• History of extreme claustrophobia in MRI machine or other reason for inability to do MRI without sedation.
• Inability to be positioned on the MRI table for sufficient time to complete the MRI exams.
• Any medical or psychological condition that, in the opinion of the local investigator, would make it unsafe or ill-advised for the subject to participate.
• Currently not receiving chronic transfusion therapy, defined as greater than 8 transfusions per year.

Sponsors & Collaborators

• Children's Hospital Los Angeles: lead

Study Sites (1)

Children's Hospital Los Angeles

Los Angeles, California, 90027, United States

Location

Related Publications (25)

• Ballas SK. Iron overload is a determinant of morbidity and mortality in adult patients with sickle cell disease. Semin Hematol. 2001 Jan;38(1 Suppl 1):30-6. doi: 10.1016/s0037-1963(01)90058-7.

  PMID: 11206959 BACKGROUND

• Cheung YF, Chan GC, Ha SY. Effect of deferasirox (ICL670) on arterial function in patients with beta-thalassaemia major. Br J Haematol. 2008 May;141(5):728-33. doi: 10.1111/j.1365-2141.2008.07092.x. Epub 2008 Mar 3.

  PMID: 18318756 BACKGROUND

• Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, Romeo MA, Forni GL, Gamberini MR, Ghilardi R, Piga A, Cnaan A. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica. 2004 Oct;89(10):1187-93.

  PMID: 15477202 BACKGROUND

• Pakbaz Z, Fischer R, Fung E, Nielsen P, Harmatz P, Vichinsky E. Serum ferritin underestimates liver iron concentration in transfusion independent thalassemia patients as compared to regularly transfused thalassemia and sickle cell patients. Pediatr Blood Cancer. 2007 Sep;49(3):329-32. doi: 10.1002/pbc.21275.

  PMID: 17554789 BACKGROUND

• Schein A, Enriquez C, Coates TD, Wood JC. Magnetic resonance detection of kidney iron deposition in sickle cell disease: a marker of chronic hemolysis. J Magn Reson Imaging. 2008 Sep;28(3):698-704. doi: 10.1002/jmri.21490.

  PMID: 18777554 BACKGROUND

• Wood JC, Enriquez C, Ghugre N, Tyzka JM, Carson S, Nelson MD, Coates TD. MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood. 2005 Aug 15;106(4):1460-5. doi: 10.1182/blood-2004-10-3982. Epub 2005 Apr 28.

  PMID: 15860670 BACKGROUND

• Wood JC, Enriquez C, Ghugre N, Otto-Duessel M, Aguilar M, Nelson MD, Moats R, Coates TD. Physiology and pathophysiology of iron cardiomyopathy in thalassemia. Ann N Y Acad Sci. 2005;1054:386-95. doi: 10.1196/annals.1345.047.

  PMID: 16339687 BACKGROUND

• Ganz T. Molecular control of iron transport. J Am Soc Nephrol. 2007 Feb;18(2):394-400. doi: 10.1681/ASN.2006070802. Epub 2007 Jan 17.

  PMID: 17229910 BACKGROUND

• Oudit GY, Trivieri MG, Khaper N, Liu PP, Backx PH. Role of L-type Ca2+ channels in iron transport and iron-overload cardiomyopathy. J Mol Med (Berl). 2006 May;84(5):349-64. doi: 10.1007/s00109-005-0029-x. Epub 2006 Apr 8.

  PMID: 16604332 BACKGROUND

• Walter PB, Fung EB, Killilea DW, Jiang Q, Hudes M, Madden J, Porter J, Evans P, Vichinsky E, Harmatz P. Oxidative stress and inflammation in iron-overloaded patients with beta-thalassaemia or sickle cell disease. Br J Haematol. 2006 Oct;135(2):254-63. doi: 10.1111/j.1365-2141.2006.06277.x.

  PMID: 17010049 BACKGROUND

• Kato GJ, Gladwin MT. Evolution of novel small-molecule therapeutics targeting sickle cell vasculopathy. JAMA. 2008 Dec 10;300(22):2638-46. doi: 10.1001/jama.2008.598.

  PMID: 19066384 BACKGROUND

• Vanhoutte PM, Shimokawa H, Tang EH, Feletou M. Endothelial dysfunction and vascular disease. Acta Physiol (Oxf). 2009 Jun;196(2):193-222. doi: 10.1111/j.1748-1716.2009.01964.x. Epub 2009 Feb 10.

  PMID: 19220204 BACKGROUND

• Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, Hazen SL, Vichinsky EP, Morris SM Jr, Gladwin MT. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. JAMA. 2005 Jul 6;294(1):81-90. doi: 10.1001/jama.294.1.81.

  PMID: 15998894 BACKGROUND

• Werner ER, Gorren AC, Heller R, Werner-Felmayer G, Mayer B. Tetrahydrobiopterin and nitric oxide: mechanistic and pharmacological aspects. Exp Biol Med (Maywood). 2003 Dec;228(11):1291-302. doi: 10.1177/153537020322801108.

  PMID: 14681545 BACKGROUND

• Valenti L, Fracanzani AL, Dongiovanni P, Bugianesi E, Marchesini G, Manzini P, Vanni E, Fargion S. Iron depletion by phlebotomy improves insulin resistance in patients with nonalcoholic fatty liver disease and hyperferritinemia: evidence from a case-control study. Am J Gastroenterol. 2007 Jun;102(6):1251-8. doi: 10.1111/j.1572-0241.2007.01192.x. Epub 2007 Mar 27.

  PMID: 17391316 BACKGROUND

• Tanner MA, Galanello R, Dessi C, Smith GC, Westwood MA, Agus A, Roughton M, Assomull R, Nair SV, Walker JM, Pennell DJ. A randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance. Circulation. 2007 Apr 10;115(14):1876-84. doi: 10.1161/CIRCULATIONAHA.106.648790. Epub 2007 Mar 19.

  PMID: 17372174 BACKGROUND

• Castro O, Haddy TB. Improved survival of iron-deficient patients with sickle erythrocytes. N Engl J Med. 1983 Mar 3;308(9):527. No abstract available.

  PMID: 6823275 BACKGROUND

• Gladwin MT, Sachdev V, Jison ML, Shizukuda Y, Plehn JF, Minter K, Brown B, Coles WA, Nichols JS, Ernst I, Hunter LA, Blackwelder WC, Schechter AN, Rodgers GP, Castro O, Ognibene FP. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. N Engl J Med. 2004 Feb 26;350(9):886-95. doi: 10.1056/NEJMoa035477.

  PMID: 14985486 BACKGROUND

• de Montalembert M, Aggoun Y, Niakate A, Szezepanski I, Bonnet D. Endothelial-dependent vasodilation is impaired in children with sickle cell disease. Haematologica. 2007 Dec;92(12):1709-10. doi: 10.3324/haematol.11253.

  PMID: 18055999 BACKGROUND

• Belhassen L, Pelle G, Sediame S, Bachir D, Carville C, Bucherer C, Lacombe C, Galacteros F, Adnot S. Endothelial dysfunction in patients with sickle cell disease is related to selective impairment of shear stress-mediated vasodilation. Blood. 2001 Mar 15;97(6):1584-9. doi: 10.1182/blood.v97.6.1584.

  PMID: 11238095 BACKGROUND

• Takeda M, Yamashita T, Shinohara M, Sasaki N, Takaya T, Nakajima K, Inoue N, Masano T, Tawa H, Satomi-Kobayashi S, Toh R, Sugiyama D, Nishimura K, Yokoyama M, Hirata K, Kawashima S. Plasma tetrahydrobiopterin/dihydrobiopterin ratio: a possible marker of endothelial dysfunction. Circ J. 2009 May;73(5):955-62. doi: 10.1253/circj.cj-08-0850. Epub 2009 Mar 18.

  PMID: 19293532 BACKGROUND

• Gonzalez J, Wood JC, Dorey FJ, Wren TA, Gilsanz V. Reproducibility of carotid intima-media thickness measurements in young adults. Radiology. 2008 May;247(2):465-71. doi: 10.1148/radiol.2472070691. Epub 2008 Mar 18.

  PMID: 18349312 BACKGROUND

• Cheung YF, Chow PC, Chan GC, Ha SY. Carotid intima-media thickness is increased and related to arterial stiffening in patients with beta-thalassaemia major. Br J Haematol. 2006 Dec;135(5):732-4. doi: 10.1111/j.1365-2141.2006.06349.x.

  PMID: 17107355 BACKGROUND

• Kato GJ, McGowan V, Machado RF, Little JA, Taylor J 6th, Morris CR, Nichols JS, Wang X, Poljakovic M, Morris SM Jr, Gladwin MT. Lactate dehydrogenase as a biomarker of hemolysis-associated nitric oxide resistance, priapism, leg ulceration, pulmonary hypertension, and death in patients with sickle cell disease. Blood. 2006 Mar 15;107(6):2279-85. doi: 10.1182/blood-2005-06-2373. Epub 2005 Nov 15.

  PMID: 16291595 BACKGROUND

• Morris CR, Suh JH, Hagar W, Larkin S, Bland DA, Steinberg MH, Vichinsky EP, Shigenaga M, Ames B, Kuypers FA, Klings ES. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood. 2008 Jan 1;111(1):402-10. doi: 10.1182/blood-2007-04-081703. Epub 2007 Sep 11.

  PMID: 17848621 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Red Blood Cells (RBCs), Peripheral Blood Mononuclear Cells (PBMCs), Plasma, Serum, and Urine

MeSH Terms

Conditions

Anemia, Sickle Cell; Iron Overload

Condition Hierarchy (Ancestors)

Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Anemia; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemoglobinopathies; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Iron Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Study Officials

• John C Wood, MD, PhD

  Children's Hospital Los Angeles

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Pediatrics - Division of Cardiology

Study Record Dates

• First Submitted: November 12, 2010
• First Posted: November 15, 2010
• Study Start: December 1, 2009
• Primary Completion: October 1, 2018
• Study Completion: October 1, 2018
• Last Updated: January 10, 2019

Record last verified: 2019-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)