SURGICAL SPECIALITIES

Received: October 22^nd 2014

Accepted: March 6^th 2015

The cord blood bank at the Instituto Mexicano del Seguro Social

Karina Peñaflor-Juárez,^a Sonia Marilyn Guillén-Chan,^a Yanín Romero-Juárez, Fernando Luna-Bautista,^a Elizabeth Franco-Gutiérrez,^a Jesús Salvador Arellano-Ocampo,^a Rocío Ibáñez-Sánchez,^a María de Lourdes Domínguez-Contreras,^a Angel Guerra-Márquez^a

^aBanco Central de Sangre, Hospital de Especialidades, Centro Médico Nacional La Raza, Instituto Mexicano del Seguro Social, Distrito Federal, México

Communication with: Angel Guerra-Márquez

Telephone: (55) 5724 5900, extensión 24203

Email: angel.guerra@imss.gob.mx

Background: Hematopoietic stem cells have been used for over 50 years in the treatment of diverse diseases. Umbilical cord blood (UCB) has proved to be a viable source of hematopoietic stem cells for transplantation purposes. The aim was to report the contribution of the umbilical cord blood bank over the past 9 years, in the treatment of various diseases.

Methods: Since 2005 the number of units of blood from the umbilical cord and their use for transplantation in diverse disease were analyzed. A selection of volunteer pregnant women in labor was performed. Umbilical cord blood was obtained from them, which underwent processing, cryopreservation and validation, as well as compatibility test before using for transplantation.

Results: Ten thousand and ninety nine candidates to donation were assessed, from whom 2481 unit of UCB were collected. Of these, 893 unit were processed and cryopreserved for transplantation. In 65 % of cases there was histocompatibility between the cord cell and the receptors. Transplantation was done in 87 patients, 67 % had hematologic neoplasias, who have received 140 units of UCB in 102 transplants. This Bank of UCB ranks second in the world in productivity according to the rate of utility of units in transplantation (3.3 %).

Conclusions: Our bank of UCB has been able to develop a cell line (hematopoietic stem cells) with international quality standards and has been beneficial for patients served by our institution with need of a transplant mainly in hemato-oncologic patients.

Keywords: Cord blood banking, Transplantation, Hematopoietic stem cells.

Hematopoietic stem cells (HSC) have been used in transplants to treat a number of diseases, primarily hematologic, for over 50 years.¹ The original source to obtain it was bone marrow and subsequently mobilized peripheral blood. Since the 80’s of the last century it has been seen that cord blood is a rich source of HSC and could be an alternative to bone marrow.² The first successful transplant using umbilical cord blood was performed by Elianne Gluckman in Paris in 1988.³ Unlike HSC from bone marrow or mobilized peripheral blood, HSC collection from umbilical cord blood has no risk for the donor and it gives therapeutic use to a product that is considered a biological waste. Cord blood banks (CBB), both public and private, have been established worldwide. The first public CBB was established in 1993 by Rubinstein in New York.⁴

HSC from cord blood has advantages over those obtained from bone marrow or mobilized peripheral blood: they are less alloreactive, so full compatibility with the receiver is not required; they have a lower risk of transmission of infectious agents; and they are immediately available for clinical use.⁵

Allogeneic transplant of HSC is the treatment of choice for a great variety of hematologic diseases, immunodeficiency, and innate errors of metabolism, but it requires having a donor compatible with the recipient, ideally in their immediate family. Only 25-30% of patients have a related matched donor, so the CCB have become a viable alternative to supply compatible units.

Epidemiological reports of the IMSS insured population show that acute leukemia ranks first or second in morbidity and mortality in the pediatric population. Particularly in patients with high-risk leukemia, HSC transplantation is a viable therapeutic alternative when they have a compatible donor in their family. For those who do not have a related matched donor there is need for an unrelated donor of mobilized peripheral blood or umbilical cord blood, so the project of developing an institutional CBB was established in 2002.

CBB institutional headquarters was assigned to the Central Blood Bank of Centro Médico Nacional La Raza as the Institute's largest and most productive blood bank; it gathers 14.16% of the blood that is collected at IMSS and 5.5% of that of the country, and also because it has a physical area in its new building opened in 2002. The integration program included, apart from the designation of a physical area, defining processes, implementing a Quality Management System, and the selection and training of personnel and equipment. The aim of this paper is to present the experience of the CBB at Instituto Mexicano del Seguro Social 9 years after its creation.

Methods

This study was conducted at the Banco de Sangre of the Centro Médico Nacional La Raza during the period from 2005 to July 2014. It describes the following:

• Donor selection and collection of umbilical cord blood: the potential donors are evaluated in the obstetrics area of the Hospital de Ginecoobstetricia 3-A. The minimum selection criteria include: age 18-40 years, pregnancy of normal development, and maximum fourth pregnancy. A specific medical history is applied that includes history of genetic and infectious risk in both mother and father of the child, and sexual risk history of the couple. If they comply with the selection criteria, the mother is asked to sign the informed consent letter and answer the confidential self-exclusion questionnaire (which will then be applied after the delivery or caesarean), and blood samples are taken for validation studies (Table I). There is also a perinatal medical history in which selection criteria of the newborn are evaluated: weight greater than 2,500 grams, APGAR score of 8 or higher, no evidence of birth defects or acute fetal distress. The cord blood is taken in utero immediately postpartum. The umbilical cord is carefully cleaned with an antiseptic solution to minimize the risk of microbial contamination, the umbilical vein is punctured with a needle attached to a collection bag with a capacity of 150 ml, containing 25 ml of anticoagulant CPD solution (citrate, phosphate, dextrose), and the blood is drained by gravity. The collection bag is labeled with the identification data of the mother, placed inside a sealed plastic bag, and transported to the CBB in containers previously validated to maintain a temperature between 6-25 degrees Celsius. 



Table I Evaluation of umbilical cord blood units.Tests carried out on maternal and umbilical cord samples to determine their availability for transplantation
Maternal samples	Umbilical cord blood units
Typing of blood group ABO and Rh(D)	Typing of blood group ABO and Rh(D)
Infectious serology (Hepatitis B, Hepatitis C, Human immunodeficiency virus, Treponemal antibodies, Trypanosoma cruziantibodies1	Infectious serology (Hepatitis B, Hepatitis C, Human immunodeficiency virus, Treponemal antibodies, Trypanosoma cruzi antibodies, Cytomegalovirus viral load2)
Complete blood cytometry	Complete blood cytometry
Determination of irregular antibodies	Determination of CD34+ cells3
	Clonogenic culture4
	Microbiological culture (aerobic, anaerobic, fungi, mycobacteria)
	HLA typing5
	Cell viability6
1Using chemiluminescence and determination of viral nucleic acid (VNA) 2Using chemiluminescence, VNA, and PCR 3Using flow cytometry 4In semi-solid medium 5Using molecular biology: locus A and B medium resolution, locus DRB1 high resolution 6Using trypan blue exclusion method



• Processing, cryopreservation, and validation of units: once in the CBB, the collected units are tested for quality to select those that will be processed. The criteria are: volume equal to or greater than 80 ml, total nucleated cell (TNC) count equal to or greater than 8 x 108, and negative maternal infectious serology. The selected units are processed in automated equipment that removes plasma and erythrocytes, while concentrating the buffy coat. Samples are taken pre-cryopreservation for validation (Table I) and units undergo a gradual freezing process, after addition of a cryoprotectant solution of dimethyl sulfoxide (DMSO)/dextran in automated equipment that, at the end of the gradual freezing, stores the units in cryogenic conditions (196 ° Celsius below zero), waiting to be validated and made available for transplant. 
• Search requests for compatible units and transplanted units: the units kept in cryopreservation undergo HLA typing in locus A, B (low to medium resolution) and DRB1 (high resolution). Transplant centers send search requests for compatible units with the clinical data of patients and their HLA type. A computer program searches for umbilical cord blood units HLA-compatible with patients, a report is made to the transplant center, and they wait to request the unit for transplant.
• Publications, accreditation, and international registration: the institution’s bank is the second public bank established in our country. The experience gained in its implementation, process development, quality management system, and operation has resulted in a number of national and international publications. Since 2009 it is part of The World Marrow Donor Association (WMDA), a Netherlands-based organization that concentrates the productivity of 160 public banks in the world.

Results

From February 2005 to July 2014 10,099 potential donors were evaluated, 24.56% completed the donation, and 36% of the collected units were cryopreserved (Table II). Of all potential donors only 893 units (8.84%) were cryopreserved, which means that to have one unit of cord blood available for transplant, it is necessary to assess just over twelve potential donors and also to collect three units of umbilical cord blood in order to have one available for transplant.

From February 2005 to July 2014, 689 search requests for HLA-compatible units were received from eight institutional transplant centers. Positive response (at least one compatible unit) was given in 65% of cases, with variations according to geographic region: 81% response for transplant centers located in Puebla and Mexico City, and only 59% for Monterrey and Torreon. 140 umbilical cord blood units have been transplanted in 87 patients with a total of 102 transplants. Transplant centers of the Institute that have transplanted cord blood units are shown in Table III, and the conditions for which they have been used in Table IV. Significantly, two-thirds of the units have been used to transplant patients with hematologic malignancies, and of these 75% were acute lymphoblastic leukemia (ALL).   

Three articles have been published in national journals^6-8 and two in international publications,^9,10 as well as being worthy of an editorial because of the paper published in the journal Transfusion in 2008.¹¹ In 2011 a global overview was published of the organization and operation of CBB programs in a select group of developing countries (according to the Human Development Index of the United Nations) with emerging economies, representing regions designated by the World Health Organization. Mexico was selected as representative of the region of the Americas, together with Brazil,¹² mention being made of the Institution’s CBB.

In December 2006 the ISO-9001-2000 certification was obtained and in December 2012 the ISO-9001-2008 system was updated and remains valid. 

By 2012, the institution’s CBB ranked second in the world in productivity, considering the utilization rate of transplant units (3.342%), surpassed only by the consortium of Japanese umbilical cord blood banks (3.908%)¹³ (Table V).

Discussion

The CBB of the Instituto Mexicano del Seguro Social has developed a (hematopoietic stem) cell line with international quality standards, and their experience is comparable to that reported by other banks qualified as world-class.^14-18 This has been possible thanks the implementation of a Quality Management System in the CBB, the validation process prior to its implementation, the focus on quality rather than quantity, the monitoring of indicators, continuous improvement, and the experience and productivity of institutional transplant centers.

The CBB can be considered as a mature organization that has benefitted patients in need of a transplant. However, the future of CBB is in the development of new cell lines that can be used therapeutically: dendritic cells, mesenchymal cells, and platelet factors. This type of cells, in addition to the HSC, appear to have a significant impact on the treatment of various disorders, in therapeutic modalities known as cell therapy and regenerative medicine,¹⁹ without its usefulness in clinical practice currently having been fully demonstrated. However, we must consider the evolution of CBB as biotechnology entities.

Conclusions

The CBB of the Instituto Mexicano del Seguro Social has developed a (hematopoietic stem) cell line with international quality standards that has been used in patients in need of transplant.

References

1. Starzl TE. History of Clinical Transplantation. World J Surg 2000;24(7):759-82.
2. Broxmeyer HE, Douglas GW, Hangoc G, et al. Human umbilical cord blood as a potencial source of transplantable hematopoietic stem/progenitor cells. Proc Natl Acad Sci USA 1989;86:3828-32.
3. Gluckman E, Broxmeyer HE, Auerbach AD et al. Hematopoietic reconstitution in a patient with Fanconi´s anemia by means of umbilical-cord blood from an HLA-identical sibling. N Eng J Med 1989; 321:1174-78.
4. Rubinstein P, Dobrila L, Richard E, Rosenfield RE, Adamson JW, Migliaccio G, Migliaccio AR, Taylor PE, Stevens CE. Processing and cryopreservation of placental/umbilical cord blood for unrelated bone marrow reconstitution. Proc Natl Acad Sci USA 1995;92:10119-22.
5. Gluckman EG, Rocha V, Chastang C. Use of Cord Blood for Banking and Transplant. The Oncologist 1997;2:340-3.
6. Novelo-Garza BA, Benítez-Arvizu G, Cortés-Márquez S, Sánchez-Cañas JA, Franco-Gutiérrez E. ¿Es importante el volumen en la recolección de sangre de cordón umbilical?. Rev Med Inst Mex Seguro Soc 2006;44(Supl 2):107-10.
7. Benítez-Arvizu G, Martínez S, Guerra A, Luna F, Romero Y, Novelo-Garza BA. Dos técnicas para reducir el volumen de sangre obtenida de cordón umbilical. Rev Med Inst Mex Seguro Soc 2010;48(4):443-6.
8. Benítez-Arvizu G, Ibarra-Pichardo Y, Guerra-Márquez A, Malagón-Martínez A. Una cosecha adecuada de células nucleadas totales en sangre de cordón umbilical. ¿Qué valorar? Rev Mex Med Tran 2013;6(1):7-11.
9. Novelo-Garza B, Limón-Flores A, Guerra-Márquez A, Bautista-Luna F, Juan-Shum L et al. Establishing a cord blood banking and transplantation program in Mexico: a single institution experience. Transfusion 2008;48:228-36.
10. Guerra-Márquez A, Novelo-Garza B, Malagón-Martínez A, Limón-Flores A, Luna-Bautista F et al. Cord blood banking and transplantation at the Mexican Institute of Social Security: the first 5 years. Transfusion 2011;51:328-32.
11. Boo M. Public cord blood banking may play an important role in the emergence of unrelated transplant in developing countries. Transfusion 2008;48; 207-8.
12. Sniecinski I. Cord Blood Banking in Developing Countries. En: Broxmeyer HE ed. Cord Blood: Biology, Transplantation, Banking, and Regulation. Bethesda, MD: AABB Press, 2011. p. 647-62.
13. World Marrow Donor Association. Unrelated Cord Blood Banks/Registries Annual Report 2012. 14th ed. Leiden, Netherlands. World Marrow Donor Association, 2013.
14. Donaldson C, Buchanan R, Webster J, et al. Development of a district Cord Blood Bank: a model for cord blood banking in the National Health Service. Bone Marrow Transplant 2000;25:899-905.
15. Armitage S, Warwick R, Fehily D, et al. Cord blood banking in London: the first 1000 collections. Bone Marrow Transplant 1999;24:139-45.
16. Lauber S, Latta M, Klüter H, et al. The Mannheim Cord Blood Bank: Experiences and Perspectives for the Future. Transfus Med Hemother 2010;37: 90-7.
17. Liu J, He J, Chen S, et al. Cord Blood Banking and Transplantation in China: A Ten Years Experience of a Single Public Bank. Transfus Med Hemother 2012; 39:23-7.
18. Viswanathan C, Kabra P, Nazareth V, et al. India´s first public cord blood repository – looking back and moving forward. Indian J Hematol Transfus 2009;25(3):111-7.
19. Mironov V, Visconti RP, Markwald RR. What is regenerative medicine? The emergence of applied stem cell and development biology. Expert Opin Biol Ther 2004;4(6):773-81.