HAEMAGGLUTINATION TECHNIQUES TO EVALUATE SPECIFIC SAFETY OF HUMAN INTRAVENOUS IMMUNOGLOBULINS

The safety issues of human intravenous immunoglobulin preparations are particularly important in modern pharmacotherapy for immunodeficiencies, hematologic and neurologic diseases, like as at transplant centers. Upon massive infusions of these media some complications are detected that are associated with spontaneous activation of complement system accompanied by production of anaphylatoxins, as well as activation of kallikrein/kinin, plasmin, and blood coagulation systems, changed blood rheology, initiation of intravascular hemolysis. For distinct groups of patients, these complications may be due to presence of some anti-erythrocyte antibodies (e.g., anti-A and anti-B haemagglutinins, anti-D antibodies) in the intravenous human immunoglobulin preparations. In the present review article, we show development of current quality standards for human intravenous immunoglobulins based on determination of antibody contents. Antibodies to erythrocytes represent a special safety index aiming to minimize risk of possible adverse effects connected with transfusions of human blood preparations. Different haemagglutination tests were compared to assess contents of anti-A, anti-B haemagglutinins and anti-D antibodies for specific safety of human intravenous immunoglobulins. Analysis of haemagglutination techniques for evaluation of human intravenous immunoglobulin preparations revealed their relative advantages and disadvantages. Various modifications of the methods are discussed, thus allowing to optimize process of quality control for these preparations based on detection of haemagglutinins and anti-D antibodies. We demonstrate a necessity to adjust regulations and to improve evaluation techniques for haemagglutinin determination in human immunoglobulin preparations at amounts of 100 mg/ml of protein. Special features of Russian national quality standards for human immunoglobulin preparations are considered with respect to assessment of haemagglutinins and anti-D contents. One may conclude that haemagglutination methods present the most informative and economically substantiated approach when assessing specific safety of human intravenous immunoglobulins by measuring contents of anti-A, anti-B haemagglutinins, and anti-D antibodies.

1. Жибурт Е.Б. Трансфузиология: учебник. СПб.: Питер, 2002. 736 с. [Zhiburt E.B. Transfusion Medicine: a textbook]. St. Petersburg: Peter, 2002. 736 p.

2. Жибурт Е.Б., Караваев А.В., Мадзаев С.Р., Губанова М.Н. Особенности национального определения антител к эритроцитам // Вестник Росздравнадзора, 2012. № 4. С. 61-63. [Zhiburt E.B., Karavaev A.V., Mazaev S.R., Gubanov M.N. Features of national definition of antibodies to red blood cells. Vestnik Roszdravnadzora = Journal of Healthcare, 2012, nо. 4, рр. 61-63. (In Russ.)]

3. Иммуноглобулин человека нормальный для внутривенного введения: ФС.3.3.2.0008.15 // Государственная фармакопея Российской Федерации. XIII издание [Электронный ресурс]. [Normal human immunoglobulin for intravenous injection: PA.3.3.2.0008.15. State Pharmacopoeia of the Russian Federation. XIII edition. (In Russ.)] URL: http://193.232.7.120/feml/clinical_ref/pharmacopoeia_3/HTML/#1244

4. Испытание на анти-D антитела в лекарственных препаратах иммуноглобулинов человека: ОФС.1.8.2.0004.15 // Государственная фармакопея Российской Федерации. XIII издание. [Электронный ресурс]. [Test for anti-D antibodies in medicinal preparations of human immunoglobulin: GPA.1.8.2.0004.15. State Pharmacopoeia of the Russian Federation. XIII edition. (In Russ.)] URL: http://193.232.7.120/feml/clinical_ref/pharmacopoeia_2/HTML/#924

5. Определение анти-А и анти-В гемагглютининов в лекарственных препаратах иммуноглобулинов человека: ОФС.1.8.2.0005.15 // Государственная фармакопея Российской Федерации. XIII издание. [Электронный ресурс]. [Determination of anti-A and anti-haemagglutinin in medicinal preparations of human immunoglobulin: GPA.1.8.2.0005.15. State Pharmacopoeia of the Russian Federation. XIII edition. (In Russ.)]URL: http://193.232.7.120/feml/clinical_ref/pharmacopoeia_2/HTML/#928

6. Bellac C.L., Polatti D., Hottiger T., Girard P., Sanger M., Gilgen M. Anti-A and anti-B haemagglutinin levels in intravenous immunoglobulins: Are they on the rise? A comparison of four different analysis methods and six products. Biologicals, 2014, Vol. 42, pp. 57-64.

7. Berard R., Wittemore B., Scuccimarri R. Hemilytic anemia following intravenous immunoglobulin therapy in patients treated for Kawasaki disease: a report of 4 cases. Pediatric Rheumatology, 2012, Vol. 10, no. 1, p. 10.

8. Branch D.R. Anti-A and anti-B: what are they and where do they come from? Transfusion, 2015, Vol. 55, pp. S75-S79.

9. Darling L., Puget S. Haemolysis And IVIG: Why This Side Effect Increases And How To Prewents it in Dysimmune Neuropathies? Meeting Abstracts, p.131. URL:http://static1.squarespace.com/static/53e0d272e4b0ea4fa48a8d40/t/5583e600e4b0b30480059c63/1434707456553/2015+PNS+Program+11June2015.pdf

10. Daw Z., Padmore R., Neurath D., Cober N., Tokessy M., Desjardins D., Olberg B., Tinmouth A., Giulivi A. Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: a case series analysis. Transfusion, 2008, Vol. 48, pp. 1598-1601.

11. European Pharmacopoeia [Электронный ресурс]: EDQM. 8th Ed. Доступ по подписке. URL: http://online6.edqm.eu/ep801/#

12. Hekker A.C., Klomp-Magnee W., Krijnen H.W., van Loghem J.J.Jr. A Papain Slide Test for Rh Mass Typing. Vox Sang, 1957, Vol. 2, pp. 128-133.

13. Jolles S., Sewell W.A.C., Misbah S.A. Clinical uses of intravenous immunoglobulin. Clinical and Experimental Immunology, 2005, Vol. 142, pp. 1-11.

14. Jordan S., Hsi R., Abumuhor I., Klapper E., Vo A. Assessment of Anti-A and Anti-B Antibody Titers in Different IVIG Preparations: Correlation with Risk for Hemolysis [abstract]. Am J. Transplant., 2013, Vol. 13, Suppl. 5.

15. Kahwaji J., Barker E., Pepkowitz S., Klapper E., Villicana R., Peng., Chang R., Jordan S.C., Vo A.A. Acute hemolysis after high-dose intravenous immunoglobulin therapy in highly HLA sensitized patient. Clin. J. Am. Soc. Nephrol., 2009, Vol.4, no. 12, pp.1993-1997.

16. Kimber M.C. PPTA Publishes Qualitative Analyses of IVIG-Associated Hemolysis Case Series. Fall 2015. The Source, pp. 27-28.

17. Moscow J.A., Casper A.J., Kodis C., Fricke W.A. Positive direct antiglobulin test results after intravenous immune globulin administration. Transfusion, 1987, Vol. 27, pp. 248-249.

18. Nguyen T.P., Biliciler S., Wahed A., Sheikh K. Occurrence of hemolytic anemia in patients with GBS treated with high-dose IVIg. Neurol. Neuroimmunol. Neuroinflamm., 2014, Vol. 1, p. 50.

19. NIBSC. Red cell immunohaematology. URL: http://www.nibsc.org/science_and_research/biotherapeutics/red_cell_immunohaematology.aspx

20. NIBSC. Therapeutic immunoglobulins. URL: http://www.nibsc.org/science_and_research/biotherapeutics/large_volume_parenteral_medicines/therapeutic_immunoglobulins.aspx

21. Niosi Ph., Lundberg J., McCullough, Park B.H., Biggar D.W. Blood-Group Antibodies in Human Immune Serum Globulin [letter]. The New England Jornal of Medicine, 1971, pp. 1435-1436.

22. Oberman H.A., Beck M.L. Red blood cell sensitization due to unexpected Rh antibodies in immune serum globulin. Transfusion, 1971, Vol. 11, pp. 382-384.

23. Padmore R. Possible mechanisms dor intravenous immunoglobulin-assotiated hemolysis: clues obtained from review of clinical case reports. Transfusion, 2015, Vol. 55, pp. S59-S64.

24. Pisani G., Wirz M., Gentili G. Anti-D testing in intravenous immunoglobulins: shouldn’t it be considered? [Letter]. Vox. Sang, 1996, Vol. 71, p. 132.

25. Siani B., Willimann K., Wymann S., Marques A.A., Widmer E. Isoagglutinin reduction in human immunoglobulin products by donor screening. Biol. Ther., 2014, Vol. 4, no, 1-2, pp. 15-26.

26. Steiner E.A., Butch S.H., Carey J.L., Oberman H.A. Passive anti-D from intravenous immune serum globulin [Letter]. Transfusion, 1983, Vol. 23, p. 363.

27. Thorpe S.J. Specifications for anti-A and anti-B in intravenous immunoglobulin: history and rationale. Transfusion, 2015, Vol. 55, pp. S80-S85.

28. Thorpe S. J., Fox B.J., Dolman C.D., Thorpe R. Anti-A and anti-B activity in batches of different intravenous immunoglobulin products determined using a direct haemagglutination method. Biologicals, 2005, Vol. 33, pp. 111-116.

29. Thorpe S.J., Fox B., Sharp G., Heath A.B., Behr-Gross M.-E., Terao E., Virata-Theimer M.L., Yu M.W. International collaborative study to evaluate candidate reference reagents to standardize haemagglutination testing for anti-A and anti-B in normal intravenous immunoglobulin products. Vox Sang, 2009, Vol. 97, pp. 160-168.

30. Turner C.E., Тhorpe S., Brasher M. Anti–Rh D Activity of Commercial Intravenous Immunoglobulin Preparations. Vox Sang, 1999, Vol. 76, pp. 55-58.

31. Wilson J.R., Bhoopalam N., Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Mucle and Nerve, 1997, Vol. 20, pp.1142-1145.