Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2019; 18: 59-65
Применение концентрата протеина С у детей с приобретенным его дефицитом
https://doi.org/10.24287/1726-1708-2019-18-2-59-65Аннотация
В мировой практике накоплен опыт применения концентрата протеина С, но сведения о применении данного препарата у больных, страдающих от онкогематологических заболеваний, у больных с первичными иммунодефицитами весьма ограничены. Цель исследования: изучение эффективности применения концентрата протеина С у педиатрических пациентов онкологического, гематологического, иммунологического профилей с приобретенной недостаточностью данного фактора. Проанализированы данные историй болезни 12 пациентов, находившихся на стационарном лечении в НМИЦ ДГОИ им. Дмитрия Рогачева в период с 01.01.2012 по 31.12.2018 и получавших терапию концентратом протеина С. В зависимости от наличия или отсутствия тромбозов пациенты были разделены на две группы – в каждой по 6 пациентов. В обеих группах изучали эффективность лечения при однократной и суточной дозах введенного препарата в зависимости от количества введений в сутки, длительности терапии, определяли процент активности протеина С. Медиана разовой дозы концентрата была ниже в группе пациентов с тромбозами – 20 МЕ/кг; у пациентов без тромбозов – 71,4 МЕ/кг (р < 0,0001), при этом разницы в эффективности лечения не было (p = 0,45). При сравнении введенной дозы препарата у детей с неразрешившимся и разрешившимся тромбозами выявлено, что медиана разовой дозы у пациентов с неэффективным лечением была ниже по сравнению с теми, у кого терапия была эффективна, – 8,78 и 71,4 МЕ/кг соответственно (р < 0,0001). Медиана суточной дозы также была ниже в группе с неэффективным лечением – 20 и 71,4 МЕ/кг соответственно (р < 0,005). Применение концентрата протеина С у детей с приобретенным его дефицитом с целью антитромботической профилактики может быть потенциально эффективным, особенно если у пациента на момент введения уже есть тромбоз. Эффективность такой профилактики может зависеть от дозы вводимого концентрата. Для определения адекватной дозы и режима введения препарата у детей требуется проведение проспективных исследований. Данное исследование поддержано Независимым этическим комитетом и утверждено решением Ученого совета НМИЦ ДГОИ.
Список литературы
1. Silvetti S., Crivellari M., Muchetti M., Taddeo D., Franco A., Landoni G., Zangrillo A. Administration of protein C concentrates in patients without congenital deficit: A systematic review of the literature. Signa Vitae 2013; 8: 15–9.
2. Manco-Johnson M.J., Bomgaars L., Palascak J., Shapiro A., Geil J., Fritsch S., et al. Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency. Thromb Haemost 2016; 116: 58–68.
3. Knoebl P.N. Severe congenital protein C deficiency: The use of protein C concentrates (human) as replacement therapy for life-threatening bloodclotting complications. Biol Targets Ther 2008; 2: 285–96.
4. Ettingshausen C.E., Veldmann A., Beeg T., Schneider W., Jager G., Kreuz W. Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans. Semin Thromb Hemost 1999; 25: 537–41.
5. Perillo T., Muggeo P., Arcamone G., De Leonardis F., Santoro N. Non activated protein C supplementation in septic pediatric hematological patients. Pediatr Rep 2016; 8: 30–3.
6. Landoni G., Monti G., Facchini A., Cama F., Bignami E., Cabrini L., et al. Human protein C concentrate in pediatric septic patients. Signa Vitae 2010; 5: 13–9.
7. de Kort E.H.M., Vrancken S.L.A.G., van Heijst A.F.J., Binkhorst M., Cuppen M.P.J.M., Brons P.P.T. Long-term Subcutaneous Protein C Replacement in Neonatal Severe Protein C Deficiency. Pediatrics 2011; 127: e1338–e1342.
8. Veldman A., Fischer D., Wong F.Y., Kreuz W., Sasse M., Eberspächer B., et al. Human protein C concentrate in the treatment of purpura fulminans: A retrospective analysis of safety and outcome in 94 pediatric patients. Critical Care 2010; 14: R156.
9. Инструкция по медицинскому при- менению препарата Сепротин, 2017. http://grls.rosminzdrav.ru/InstrImg/0001417361/ЛС-002446-130617%5B2017%5D_1.pdf
10. Faioni B.E.M., Krachmalnicoff A., Bearman S., Federici A.B., Decarli A., Gianni A.M., et al. Naturally occurring anticoagulants and bone marrow transplantation: plasma protein C predicts the development of venocclusive disease of the liver. Blood 1993; 81: 3458–62.
11. De A.K., Pal S., Das S., Bhattacharya T. Protein C deficiency. Indian J Hematol Blood 2014; Transfus 30: 142–4.
12. Mesters R.M., Helterbrand J., Yan S.B., Utterback B.G., Chao Y.B., Fernandez J.A., et al. Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Crit Care Med 2000; 28: 2209–16.
13. Marlar R.A., Kleiss A.J., Griffin J.H. Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982; 59: 1067–72.
14. Andrew M., Paes B., Johnston M. Development of the hemostatic system in the neonate and young infant. J Pediatr Hematol Oncol 1990; 12: 95–104.
15. Haire W.D., Ruby E.I., Gordon B.G., Patil K.D., Stephens L.C., Kotulak G.D., et al. Multiple organ dysfunction syndrome in bone marrow trans-plantation. JAMA 1995; 274: 1289–95.
16. Tullius B.P., Athale U., van Ommen C.H., Chan A.K.C., Palumbo J.S., Balagtas J.M.S. The identification of atrisk patients and prevention of venous thromboembolism in pediatric cancer: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16: 175–80.
17. Athale U., Siciliano S., Thabane L., Pai N., Cox S., Lathia A., et al. Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer. Pediatr Blood Cancer 2008; 51: 792–7.
18. Bordbar M., Karimi M., Shakibazad N. Thrombosis in pediatric malignancy. Blood Coagul Fibrinolysis 2018; 29: 596–601.
19. Müller F.M., Ehrenthal W., Hafner G., Schranz D. Purpura fulminans in severe congenital protein C deficiency: Monitoring of treatment with protein C concentrate. Eur J Pediatr 1996; 155: 20–5.
20. Pollack M.M., Holubkov R., Funai T., Dean J.M., Berger J.T., Wessel D.L. The Pediatric Risk of Mortality Score: Update 2015. Pediatr Crit Care Med 2016; 17: 2–9.
21. Shah A., Matthew D.J. Glasgow Meningococcal Septicemia Prognostic Score in meningococcal septicemia. Crit Care Med 1992; 20: 1495–6.
22. Dreyfus M., Masterson M., David M., Rivard G., Müller .F-M., Kreuz W. Replacement Therapy with a Monoclonal Antibody Purified Protein C Concentrate in Newborns with Severe Congenital Protein C Deficiency. Semin Thromb Hemost 1995; 21: 371–81.
23. Abbott L.S., Deevska M., Fernandez C.V., Dix D., Price V.E., Wang H. The impact of prophylactic fresh-frozen plasma and cryoprecipitate on the incidence of central nervous system thrombosis and hemorrhage in children with acute lymphoblastic leukemia receiving asparaginase. Blood 2009; 114: 5146–51.
Pediatric Hematology/Oncology and Immunopathology. 2019; 18: 59-65
Experience of protein C administration in children with acquired deficiency
https://doi.org/10.24287/1726-1708-2019-18-2-59-65Abstract
Тhere is increasing experience of protein C concentrate administration in world practice, but despite that, information of this drug administration in patients with oncohematological diseases and primary immunodeficiency syndromes is lacking. Objective: to study the effectiveness of protein C concentrate administration in pediatric patients with acquired protein C deficiency during the treatment of oncological, hematological or immunological diseases. Medical charts of 12 patients who received inpatient treatment and protein C concentrate administration in the Dmitry Rogachev National Clinical Research Center from 01/01/2012–12/31/18 were analyzed. Depending on the presence or absence of thrombosis, the patients were divided into two groups. Single and daily doses, the number of injections per day, the duration of therapy and the percentage of activity of protein C activity were studied in both groups. Вoth groups included 6 patients, median of a single administrated dose of protein C was lower in the group of patients with thrombosis than in patients without them (20 and 71.4 IU/kg, p < 0.0001), while there were obtained no differences between treatment efficacy (p = 0.45). When comparing the administered dose of the drug in children with unresolved and resolved thrombosis, it was found that the median single dose in patients with ineffective treatment was lower than in those who had effective treatment (8.78 and 71.4 IU/kg, respectively, p < 0.0001); the median daily dose was also lower in the group with ineffective treatment (20 and 71.4 IU/kg, respectively, p < 0.005). Рrotein C administration in children with acquired deficiency for the purpose of antithrombotic prophylaxis can be potentially effective, especially in those patients who already have a thrombosis at the moment of administration. The effectiveness of such prophylaxis may depend on the dose of the injected concentrate. To determine the appropriate dose and mode of administration of the drug in children a prospective study is required. The study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology.
References
1. Silvetti S., Crivellari M., Muchetti M., Taddeo D., Franco A., Landoni G., Zangrillo A. Administration of protein C concentrates in patients without congenital deficit: A systematic review of the literature. Signa Vitae 2013; 8: 15–9.
2. Manco-Johnson M.J., Bomgaars L., Palascak J., Shapiro A., Geil J., Fritsch S., et al. Efficacy and safety of protein C concentrate to treat purpura fulminans and thromboembolic events in severe congenital protein C deficiency. Thromb Haemost 2016; 116: 58–68.
3. Knoebl P.N. Severe congenital protein C deficiency: The use of protein C concentrates (human) as replacement therapy for life-threatening bloodclotting complications. Biol Targets Ther 2008; 2: 285–96.
4. Ettingshausen C.E., Veldmann A., Beeg T., Schneider W., Jager G., Kreuz W. Replacement therapy with protein C concentrate in infants and adolescents with meningococcal sepsis and purpura fulminans. Semin Thromb Hemost 1999; 25: 537–41.
5. Perillo T., Muggeo P., Arcamone G., De Leonardis F., Santoro N. Non activated protein C supplementation in septic pediatric hematological patients. Pediatr Rep 2016; 8: 30–3.
6. Landoni G., Monti G., Facchini A., Cama F., Bignami E., Cabrini L., et al. Human protein C concentrate in pediatric septic patients. Signa Vitae 2010; 5: 13–9.
7. de Kort E.H.M., Vrancken S.L.A.G., van Heijst A.F.J., Binkhorst M., Cuppen M.P.J.M., Brons P.P.T. Long-term Subcutaneous Protein C Replacement in Neonatal Severe Protein C Deficiency. Pediatrics 2011; 127: e1338–e1342.
8. Veldman A., Fischer D., Wong F.Y., Kreuz W., Sasse M., Eberspächer B., et al. Human protein C concentrate in the treatment of purpura fulminans: A retrospective analysis of safety and outcome in 94 pediatric patients. Critical Care 2010; 14: R156.
9. Instruktsiya po meditsinskomu pri- meneniyu preparata Seprotin, 2017. http://grls.rosminzdrav.ru/InstrImg/0001417361/LS-002446-130617%5B2017%5D_1.pdf
10. Faioni B.E.M., Krachmalnicoff A., Bearman S., Federici A.B., Decarli A., Gianni A.M., et al. Naturally occurring anticoagulants and bone marrow transplantation: plasma protein C predicts the development of venocclusive disease of the liver. Blood 1993; 81: 3458–62.
11. De A.K., Pal S., Das S., Bhattacharya T. Protein C deficiency. Indian J Hematol Blood 2014; Transfus 30: 142–4.
12. Mesters R.M., Helterbrand J., Yan S.B., Utterback B.G., Chao Y.B., Fernandez J.A., et al. Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Crit Care Med 2000; 28: 2209–16.
13. Marlar R.A., Kleiss A.J., Griffin J.H. Mechanism of action of human activated protein C, a thrombin-dependent anticoagulant enzyme. Blood 1982; 59: 1067–72.
14. Andrew M., Paes B., Johnston M. Development of the hemostatic system in the neonate and young infant. J Pediatr Hematol Oncol 1990; 12: 95–104.
15. Haire W.D., Ruby E.I., Gordon B.G., Patil K.D., Stephens L.C., Kotulak G.D., et al. Multiple organ dysfunction syndrome in bone marrow trans-plantation. JAMA 1995; 274: 1289–95.
16. Tullius B.P., Athale U., van Ommen C.H., Chan A.K.C., Palumbo J.S., Balagtas J.M.S. The identification of atrisk patients and prevention of venous thromboembolism in pediatric cancer: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16: 175–80.
17. Athale U., Siciliano S., Thabane L., Pai N., Cox S., Lathia A., et al. Epidemiology and clinical risk factors predisposing to thromboembolism in children with cancer. Pediatr Blood Cancer 2008; 51: 792–7.
18. Bordbar M., Karimi M., Shakibazad N. Thrombosis in pediatric malignancy. Blood Coagul Fibrinolysis 2018; 29: 596–601.
19. Müller F.M., Ehrenthal W., Hafner G., Schranz D. Purpura fulminans in severe congenital protein C deficiency: Monitoring of treatment with protein C concentrate. Eur J Pediatr 1996; 155: 20–5.
20. Pollack M.M., Holubkov R., Funai T., Dean J.M., Berger J.T., Wessel D.L. The Pediatric Risk of Mortality Score: Update 2015. Pediatr Crit Care Med 2016; 17: 2–9.
21. Shah A., Matthew D.J. Glasgow Meningococcal Septicemia Prognostic Score in meningococcal septicemia. Crit Care Med 1992; 20: 1495–6.
22. Dreyfus M., Masterson M., David M., Rivard G., Müller .F-M., Kreuz W. Replacement Therapy with a Monoclonal Antibody Purified Protein C Concentrate in Newborns with Severe Congenital Protein C Deficiency. Semin Thromb Hemost 1995; 21: 371–81.
23. Abbott L.S., Deevska M., Fernandez C.V., Dix D., Price V.E., Wang H. The impact of prophylactic fresh-frozen plasma and cryoprecipitate on the incidence of central nervous system thrombosis and hemorrhage in children with acute lymphoblastic leukemia receiving asparaginase. Blood 2009; 114: 5146–51.
