Systemic thrombin generation by glucose


Background: Systemic thrombin activity (F2a), i.e. thrombin protected and transported by a2- macroglobulin, is a new biomarker for the activation state of coagulation in vivo. F2a > 120% of normal diagnoses a pathologic disseminated intravascular coagulation (PIC) in humans, either acute or chronic. Since glucose triggers intrinsic coagulation, the present work aimed to quantify systemic thrombin generation induced by glucose in vivo in mice. Material and Methods: Balb/c mice were i.p. injected with different concentrations of glucose (0 - 0.3 mmoles). After 0 - 3 h EDTA-blood was withdrawn, centrifuged, and the plasma was stabilized 1 + 1 with 2.5 M arginine, pH 8.6, and analyzed for systemically circulating F2a (that is F2a.α2M). The F2a.α2M activity in mice without glucose injection was defined as 100% of murine norm. Results: 1 h after i.p. injection 0.1 - 0.3 mmoles glucose resulted in about 1.4 fold increase of plasmatic glucose and in about 2.5 fold increase of systemic F2a activity. At the 45 min time interval between i.p. injection of 0.038 mmoles glucose and blood withdrawing an approximately 1.5fold increase of plasma glucose caused a 4fold increase in systemic F2a. Discussion: When systemic F2a reaches 120% of the normal, the normal human intravascular coagulation (NIC) turns to the pre-phase of pathologic plasmatic intravascular coagulation (PIC-0 also defined as pre-PIC). At 150% systemic F2a, the PIC-0 changes to PIC-1 which is the common pathologic plasmatic intravascular coagulation (typical PIC). At 200% systemic F2a, PIC-1 changes to PIC-2 (consumption PIC). The present assay technique seems to be suitable in judging the coagulation activation state of any mammalian blood. Diabetic patients should be monitored for the new biomarker systemic F2a similarly as for the old biomarker glycated hemoglobin (HbA1c). The target systemic F2a range should be NIC, preferably around 100% of normal.

Share and Cite:

Mohrez, M. , Harb, H. , Spies, A. , Renz, H. and Stief, T. (2012) Systemic thrombin generation by glucose. Journal of Diabetes Mellitus, 2, 47-51. doi: 10.4236/jdm.2012.21008.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Stubbs, M.T. and Bode, W. (1995) The clot thickens: Clues provided by thrombin structure. Trends in Biochemical Sciences, 20, 23-28. doi:10.1016/S0968-0004(00)88945-8
[2] Guillin, M.C., Bezeaud, A., Bouton, M.C. and Jandrot-Perrus, M. (1995) Thrombin specificity. Thrombosis and Haemostasis, 74, 129-133.
[3] Furie, B. and Furie, B.C. (1992) Molecular and cellular biology of blood coagulation. New England Journal of Medicine, 326, 800-806. doi:10.1056/NEJM199203193261205
[4] Montoro-Garcia, S., Shantsila, E., Marin, F., Blann, A. and Lip, G.Y. (2011) Circulating microparticles: New insights into the biochemical basis of microparticle release and activity. Basic Research in Cardiology, 106, 911-923. doi:10.1007/s00395-011-0198-4
[5] Stief, T.W. (2010) Thrombin generation by the amino acid glycine. Hemostasis Laboratory, 3, 129-133.
[6] Stief, T.W. and Mohrez M. (2011) Thrombin generation by valproate. Hemostasis Laboratory, 4, 101-144.
[7] Stief, T.W. (2012) Glucose activates the early phase of intrinsic coagulation. Hemostasis Laboratory, 5, 67-81.
[8] Stief, T.W. and Mohrez M. (2012) Glucose activates human intrinsic coagulation in vivo. Hemostasis Laboratory, 5, 83-89.
[9] Stief, T.W. (2011) Factor 12 activation in two purified systems. Hemostasis Laboratory, 4, 385-408.
[10] Stief, T.W. (2011) Zn2+, hexane, or glucose activate factor 12 and/or prekallikrein in two purified systems. Hemostasis Laboratory, 4, 409-426.
[11] Stief, T.W. (2012) Zn2+, hexane, valproate, or glucose in two purified systems of F12-PK-HMWK. Hemostasis Laboratory, 5, 35-50.
[12] Hu, T. and Desai, J.P. (2004) Soft-tissue material properties under large deformation: Strain rate effect. Proceedings of the 26th Annual International Conference of the IEEE EMBS, San Francisco, 2758-2761.
[13] Liu, N., Mori, N., Iehara, N., Uemura, K., Fukastu, A., Kita, T., Matsuda, M. and Ono, T. (2007) Soluble fibrin formation in the mesangial area of IgA nephropathy. Clinical and Experimental Nephrology, 11, 71-76. doi:10.1007/s10157-006-0457-0
[14] Nomura, K., Liu, N., Nagai, K., Hasegawa, T., Kobayashi, I., Nogaki, F., Tanaka, M., Arai, H., Fukatsu, A., Kita, T. and Ono, T. (2007) Roles of coagulation pathway and factor Xa in rat mesangioproliferative glomerulonephritis. Laboratory Investigation, 87, 150-160. doi:10.1038/labinvest.3700502
[15] Frank, R.D., Schabbauer, G., Holscher, T., Sato, Y., Tencati, M., Pawlinski, R. and Mackman, N. (2005) The synthetic pentasaccharide fondaparinux reduces coagulation, inflammation and neutrophil accumulation in kidney ischemia-reperfusion injury. Journal of Thrombosis and Haemostasis, 3, 531-540. doi:10.1111/j.1538-7836.2005.01188.x
[16] Ayaka, S., Natsuko, Y.H., Fan, B., Toshiaki, M., Hajime, M. and Takahiko, O. (2011) Roles of Coagulation Pathway and Factor Xa in the Progression of Diabetic Nephropathy in db/db Mice. Biological & Pharmaceutical Bulletin, 34, 824-830. doi:10.1248/bpb.34.824
[17] Wiggins, R.C., Njoku, N. and Sedor, J.R. (1990) Tissue factor production by cultured rat mesangial cells. Stimulation by TNF alpha and lipopolysaccharide. Kidney International, 37, 1281-1285. doi:10.1038/ki.1990.112
[18] Ono, T., Liu, N., Kasuno, K., Kusano, H., Nogaki, F., Kamata, T., Suyama, K., Muso, E. and Sasayama, S. (2001) Coagulation process proceeds on cultured human mesangial cells via expression of factor V. Kidney International, 60, 1009-1017. doi:10.1046/j.1523-1755.2001.0600031009.x
[19] Mohrez, M., Alrifai, M. and Stief, T.W. (2011) Systemic thrombin generation by valproate. Hemostasis Laboratory, 4, 427-438.
[20] Stief, T.W. (2007) The fibrinogen antigenic turbidimetric assay (FIATA). The X2X Test: The corrected chi-square comparison against the control-mean. Clinical and Applied Thrombosis/Hemostasis, 13, 73-100.
[21] Stief, T.W. (2010) Drug-induced thrombin generation: the breakthrough. Hemostasis Laboratory, 3, 3-5.
[22] Stief, T.W. (2006) Specific determination of plasmatic thrombin activity. Clinical and Applied Thrombosis/Hemostasis, 12, 324-329. doi:10.1177/1076029606291381
[23] Stief, T.W. (2008) The laboratory diagnosis of the pre-phase of pathologic disseminated intravascular coagulation. Hemostasis Laboratory, 1, 3-19.
[24] Stief, T.W. (2010) Circulating thrombin activity in unselected routine plasmas. Hemostasis Laboratory; 3, 7-16.

Copyright © 2022 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.