ASSESSMENT OF HEMOSTASIS SYSTEM AND FACTORS ASSOCIATED WITH HYPERCOAGULATION IN MEN WITH METABOLIC SYNDROME AND INITIAL DECREASE OF GLOMERULAR FILTRATION RATE

THE AIM. To assess hypercoagulation factors in men with initial decrease of glomerular filtration rate (IDGFR) and metabolic syndrome (MS) depending on carbohydrate metabolism disorders (CMD). PATIENTS AND METHODS. The study included 79 men with IDGFR and MS. Two groups were assessed: main – patients IDGFR and CMD with MS (n=44) and control group – with IDGFR and MS without CMD (n=35). Besides examinations for confirming IDGFR and CMD type specification all patients were performed following tests: estimated thrombodynamics factors, serum concentration of common testosterone (CT), leptin (L), adiponectin (A), D-dimer (DD), activated platelets count (CD41+CD62P+) (APC), PAI-1, homocysteine (H). We also studied polymorphism of the genes associated with hyperhomocysteinemia (HHC). RESULTS. 90% cases of hyperhomocysteinemia (HHC) in men with IDGFR and MS were associated with genetic defects in enzyme systems regulating this amino acid metabolism.. Patients from the main group in comparison with the subjects without CMD had significantly higher density of the fibrin clot  (28012,21±1013,60 vs. 25209,15±1176,90 c.u., р<0,05), serum levels of PAI-1 (78,78±13,00 vs. 43,66±4,00 ng/ml, p<0,01), leptin (13,56±1,40 vs. 8,95±1,60 ng/ml, p<0,01) and lower serum concentration of CT (11,54±0,70 vs. 14,50±1,10 nmol/l, p<0,05). In men with IDGFR and MS with CMD we found positive correlations between activated platelets count and fasting glucose (rs=0,4; р<0,05), activated platelets count and postprandial glucose (rs=0,5; р<0,05), PAI-1 and adiponectin (rs=0,4;  р<0,05), PAI-1 and leptin (rs=0,4; р<0,05), homocysteine and MCH (rs=0,5; р<0,05), homocysteine and density of the fibrin clot (rs=0,5; р<0,05), insulin and PAI-1 (rs=0,4; р<0,05), adiponectin and density of the fibrin clot (rs=0,4; р<0,05), hemoglobin and clot growth rate (rs=0,4; р<0,05), RDW and D-dimer (rs=0,4; р<0,05), RDW and density of the fibrin clot (rs=0,6;  р<0,05); a negative correlation – between fasting glucose and adiponectin (rs= -0,4; р<0,05). CONCLUSION. CMD in men with IDGFR and MS are associated with procoagulant status via direct and indirect influence on hypercoaculation factors. The role  of adiponectin in thrombogenesis is controversial and requires further investigations. 

1. Сушкевич ГН. Тромбогенерирующие системы при тромбофилиях различного генеза. Медицина неотложных состояний 2015; (6): 147-167 [Sushkevich GN. Trombogenerirujushhie sistemy pri trombofilijah razlichnogo geneza. Medicina neotlozhnyh sostojanij 2015; (6): 147-167]

2. Шишкин АН, Худякова НВ, Никитина ЕА, Смирнов ВВ. Метаболический синдром у женщин в перименопаузе. Вестн Санкт-Петербургск ун-та Серия 11 2013; (3): 39-56 [Shishkin AN, Hudjakova NV, Nikitina EA, Smirnov VV. Metabolicheskij sindrom u zhenshhin v perimenopauze. Vestn S.-Peterb un-ta Ser 11 2013; (3): 39-56]

3. Singh AK, Kari JA. Metabolic syndrome and chronic kidney disease. Curr Opin Nephrol Hypertens 2013;22(2): 198-203. doi: 10.1097/MNH.0b013e32835dda78

4. Смирнов АВ, Добронравов ВА, Кисина АА и др. Клинические рекомендации по диагностике и лечению диабетической нефропатии. Нефрология 2015;19(1):67-77 [Smirnov AV, Dobronravov VA, Kisina AA i dr. Clinicheskie rekomendatcii po diagnostike i lecheniiu diabeticheskoi` nefropatii. Nefrologiia. 2015;19(1):67-77]

5. Худякова НВ, Пчелин ИЮ, Шишкин АН и др. Гипергомоцистеинемия и кардиоренальный анемический синдром при сахарном диабете. Нефрология 2015; 19 (6): 20-27 [Hudjakova NV, Pchelin IJu, Shishkin AN i dr. Gipergomocisteinemija i kardiorenal'nyj anemicheskij sindrom pri saharnom diabete. Nefrologija 2015; 19 (6): 20-27]

6. Yang T, Chu CH, Hsu CH et al. Impact of metabolic syndrome on the incidence of chronic kidney disease: a Chinese cohort study. Nephrology (Carlton) 2012;17(6):532-538. doi: 10.1111/j.14401797.2012.01607.x

7. Khurana KK, Navaneethan SD, Arrigain S et al. Serum testosterone levels and mortality in men with CKD stages 3-4. Am J Kidney Dis 2014;64(3):367-374. doi: 10.1053/j.ajkd.2014.03.010

8. Ryu S, Chang Y, Woo HY et al. Time-dependent association between metabolic syndrome and risk of CKD in Korean men without hypertension or diabetes. Am J Kidney Dis 2009;53(1): 59-69. doi: 10.1053/j.ajkd.2008.07.027

9. Alberti КG, Eckel RH, Grundy SM et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120(16):1640-1645. doi: 10.1161/CIRCULATIONAHA.109.192644

10. Agrawal NK, Kant S. Targeting inflammation in diabetes: Newer therapeutic options. World J Diabetes 2014;5(5):697-710. doi: 10.4239/wjd.v5.i5.697

11. Mao S, Xiang W, Huang S, Zhang A. Association between homocysteine status and the risk of nephropathy in type 2 diabetes mellitus. Clin Chim Acta 2014;431:206-210. doi: 10.1016/j.cca.2014.02.007

12. Смирнов АВ, Добронравов ВА, Голубев РВ и др. Распространенность гипергомоцистеинемии в зависимости от стадии хронической болезни почек. Нефрология 2005; 9 (2): 48-52 [Smirnov AV, Dobronravov VA, Golubev RV i dr. Rasprostranennost’ gipergomocisteinemii v zavisimosti ot stadii hronicheskoj bolezni pochek. Nefrologija 2005; 9 (2): 48-52]

13. Ruan L, Chen W, Srinivasan SR et al. Plasma homocysteine is adversely associated with glomerular filtration rate in asymptomatic black and white young adults: the Bogalusa heart study. Eur J Epidemiol 2009;24(6):315-319. doi: 10.1007/s10654-009-9340-0

14. Malinowska J, Kolodziejczyk J, Olas B. The disturbance of hemostasis induced by hyperhomocysteinemia; the role of antioxidants. Acta Biochim Pol 2012;59(2):185-194

15. Zhao MJ, Yang YH, Zhou SJ et al. [Serum homocysteine and metabolic syndrome in middle-aged and elderly men]. [Article in Chinese, abstract in English] Zhonghua Nan Ke Xue 2016;22(2):138-142

16. Owens AP 3rd, Mackman N. Microparticles in hemostasis and thrombosis. Circ Res 2011;108(10):1284-1297. doi: 10.1161/CIRCRESAHA.110.233056

17. Сухарева ЕГ, Левин ГЯ. Влияние микровезикул эритроцитов на конечный этап свертывания крови. Вестн Нижегород ун-та им Н.И. Лобачевского 2014; 1 (2): 233-236 [Suhareva EG, Levin GJa. Vlijanie mikrovezikul jeritrocitov na konechnyj jetap svertyvanija krovi. Vestn Nizhegorod un-ta im. N.I. Lobachevskogo 2014; 1 (2): 233-236]

18. Schiepers OJG, Durga J. Response to Baggott and Tamura: «Serum iron parameters and plasma total homocysteine concentrations». J Gerontol A Biol Sci Med Sci 2011; 66A: 657-658

19. Baggott JE, Tamura T. Homocysteine, iron and cardiovascular disease: a hypothesis. Nutrients 2015;7(2):1108-1118. doi: 10.3390/nu7021108

20. Acharya U, Gau JT, Horvath W et al. Hemolysis and hyperhomocysteinemia caused by cobalamin deficiency: three case reports and review of the literature. J Hematol Oncol 2008;1:26. doi: 10.1186/1756-8722-1-26

21. Zittan E, Preis M, Asmir I et al. High frequency of vitamin B12 deficiency in asymptomatic individuals homozygous to MTHFR C677T mutation is associated with endothelial dysfunction and homocysteinemia. Am J Physiol Heart Circ Physiol 2007;293(1):H860-H865. doi: 10.1152/ajpheart.01189.2006

22. Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond) 2013;124(3):139-152. doi: 10.1042/CS20120198

23. Malinowska J, Olas B. Homocysteine and its thiolactone-mediated modification of fibrinogen affect blood platelet adhesion. Platelets 2012;23(5):409-412. doi: 10.3109/09537104.2011.625509

24. Olas B, Malinowska J, Rywaniak J. Homocysteine and its thiolactone may promote apoptotic events in blood platelets in vitro. Platelets 2010;21(7):533-540. doi: 10.3109/09537104.2010.501119

25. Hara K, Uchida T, Takebayashi K et al. Determinants of serum high molecular weight (HMW) adiponectin levels in patients with coronary artery disease: associations with cardio-renalanemia syndrome. Intern Med 2011;50(24):2953-2960

26. Xie R, Jia D, Gao C et al. Homocysteine induces procoagulant activity of red blood cells via phosphatidylserine exposure and microparticles generation. Amino Acids 2014;46(8):1997-2004. doi: 10.1007/s00726-014-1755-6

27. Marchi R, Carvajal Z, Weisel JW. Comparison of the effect of different homocysteine concentrations on clot formation using human plasma and purified fibrinogen. Thromb Haemost 2008;99(2):451–452. doi: 10.1160/TH07-06-0404

28. Sauls DL, Arnold EK, Bell CW et al. Pro-thrombotic and prooxidant effects of diet-induced hyperhomocysteinemia. Thromb Res 2007;120(1):117–126. doi: 10.1016/j.thromres.2006.08.001

29. Кучер АГ, Смирнов АВ, Каюков ИГ и др. Лептин – новый гормон жировой ткани: значение в развитии ожирения, патологии сердечно-сосудистой системы и почек 2005; 9(1): 9-19 [Kucher AG, Smirnov AV, Kaiukov IG i dr. Leptin – novy`i` gormon zhirovoi` tkani: znachenie v razvitii ozhireniia, patologii serdechnososudistoi` sistemy` i pochek 2005; 9(1): 9-19]

30. Aso Y, Wakabayashi S, Terasawa T et al. Elevation of serum high molecular weight adiponectin in patients with Type 2 diabetes and orthostatic hypotension: association with arterial stiffness and hypercoagulability. Diabet Med 2012;29(1):80-87. doi: 10.1111/j.1464-5491.2011.03364.x

31. Aso Y, Suganuma R, Wakabayashi S et al. Anemia is associated with an elevated serum level of high-molecular-weight adiponectin in patients with type 2 diabetes independently of renal dysfunction. Transl Res 2009;154(4):175-182. doi: 10.1016/j.trsl.2009.07.005

32. Grant PJ. Diabetes mellitus as a protrombotic condition J Intern Med 2007;262 (2):157-172. doi: 10.1111/j.13652796.2007.01824.x

33. Иванов НВ, Сильницкий ПА, Ворохобина НВ. Нарушения репродуктивной функции у мужчин с метаболическим синдромом. Балтийск журн соврем эндокринол 2011; (2): 98-105 [Ivanov NV, Sil'nickij PA, Vorohobina NV. Narushenija reproduktivnoj funkcii u muzhchin s metabolicheskim sindromom. Baltijskij zhurnal sovremennoj jendokrinologii 2011; (2): 98-105]

34. Ventimiglia E, Capogrosso P, Serino A et al. Metabolic syndrome in White-European men presenting for secondary couple’s infertility: an investigation of the clinical and reproductive burden. Asian J Androl 2016. doi: 10.4103/1008-682X.175783. [Epub ahead of print]

35. Dhindsa S, Reddy A, Karam JS et al. Prevalence of subnormal testosterone concentrations in men with type 2 diabetes and chronic kidney disease. Eur J Endocrinol 2015;173(3):359-366. doi: 10.1530/EJE-15-0359

36. Glueck CJ, Wang P. Testosterone therapy, thrombosis, thrombophilia, cardiovascular events. Metabolism 2014;63(8):989994. doi: 10.1016/j.metabol.2014.05.005

37. Holmegard HN, Nordestgaard BG, Schnohr P. et al. Endogenous sex hormones and risk of venous thromboembolism in women and men. J Thromb Haemost 2014;12(3):297-305. doi: 10.1111/jth.12484.

38. Гарипова МИ, Усманова РР, Веселов СЮ и др. Закономерности транспорта гидрофильных гормонов в крови человека Вестн Башкирск ун-та 2013; 18 (4): 1062-1064 [Garipova MI, Usmanova RR, Veselov SJu i dr. Zakonomernosti transporta gidrofilnyh gormonov v krovi cheloveka Vestn Bashkirsk un-ta 2013, 18 (4): 1062-1064]

39. Салтыков ББ, Пауков ВС. Диабетическая микроангиопатия. Медицина, М., 2002; 238 [Saltykov BB, Paukov VS. Diabeticheskaja mikroangiopatija / B.B. Saltykov, B.C. Paukov. Medicina, M., 2002; 238]