OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press15710.17650/1818-8346-2015-10-3-10-25BASIC RESEARCHФУНДАМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯ В ПРАКТИЧЕСКОЙ МЕДИЦИНЕ НА СОВРЕМЕННОМ ЭТАПЕIntegrated laboratory coagulation tests in hypercoagulation diagnosis and thrombosis risk assessment. Part I. The pathophysiology of thrombosis and hypercoagulationИнтегральные лабораторные тесты гемостаза в диагностике гиперкоагуляции и оценке риска тромбоза. Часть I. Патофизиология гиперкоагуляции и тромбозаLipetsE. N.ЛипецЕ. Н.
Russian Federation

1 Samory Mashela St., Moscow, 117997;

4 Kosygina St., Moscow, 119991

117997, Москва, ул. Саморы Машела;

119991, Москва, ул. Косыгина, 4

AtaullakhanovF. I.АтауллахановФ. И.
Russian Federation

1 Samory Mashela St., Moscow, 117997;

4 Kosygina St., Moscow, 119991;

4th 8 Marta St., Moscow, 125319;

1 Lеninskie gory St., Moscow, 119991

117997, Москва, ул. Саморы Машела;

119991, Москва, ул. Косыгина, 4;

125319, Москва, 4-я ул. 8 Марта, 3;

119991, Москва, ул. Ленинские горы, 1

PanteleevM. A.ПантелеевМихаил Александрович
Russian Federation

1 Samory Mashela St., Moscow, 117997;

4 Kosygina St., Moscow, 119991;

4th 8 Marta St., Moscow, 125319;

1 Lеninskie gory St., Moscow, 119991

117997, Москва, ул. Саморы Машела;

119991, Москва, ул. Косыгина, 4;

125319, Москва, 4-я ул. 8 Марта, 3;

119991, Москва, ул. Ленинские горы, 1

mapanteleev@yandex.ruFederal Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry RоgachevФНКЦ детской гематологии, онкологии и иммунологии им. Дмитрия РогачеваTheoretical Problems Center of Physical and Chemical Pharmacology, Russian Academy of SciencesЦентр теоретических проблем физико-химической фармакологии РАНHemaCore CompanyООО «Гемакор»M.V. Lomonosov Moscow State UniversityМосковский государственный университет им. М.В. Ломоносоваru08102015201510373770810201508102015Received:08102015Accepted:08102015Published:08102015https://oncohematology.abvpress.ru/ongm/article/view/157

Thrombosis is a fatal hemostatic disorders occurring in various conditions ranging from pregnancy and surgery to cancer, sepsis and heart attack. Despite the availability of different anticoagulants and accumulated clinical experience, proving their effectiveness, thrombosis remains a major cause of morbidity and mortality. This is largely due to the fact that conventional laboratory coagulation tests are not sufficiently sensitive to the hypercoagulable state, and they are difficult to use for assessing the risk of thrombosis. Specific molecular markers (D-dimers, fibrinopeptide, thrombin-antithrombin complex) are more effective, but also have a large number of disadvantages. A possible solution is the use of integrated test, which simulate in vitro the majority of the physiological coagulation processes. In the first part of this paper the biochemical processes that cause the risk of thrombosis were discussed.

Тромбоз является смертельно опасным нарушением системы гемостаза, возникающим при различных патологиях и состояниях, начиная от беременности и состояния после операции до онкологии, сепсиса и инфаркта. Несмотря на доступность разнообразных антикоагулянтов и большой накопленный клинический опыт, подтверждающий их эффективность, тромбоз остается одной из главных причин смертности и заболеваемости в современном мире. Во многом это объясняется тем, что традиционные лабораторные тесты свертывания крови недостаточно чувствительны к гиперкоагуляции и их сложно использовать для оценки риска тромбоза. Специфические молекулярные маркеры, определяющие процесс свертывания (D-димеры, фибринопептид, тромбин-антитромбиновый комплекс), более эффективны, однако также обладают большим количеством недостатков. Возможным решением является использование интегральных тестов, которые in vitro имитируют большинство физиологических процессов, протекающих в организме в новки кровотечения. В I части данной работы обсуждаются биохимические процессы, вызывающие риск тромбоза.

integral coagulation testshypercoagulationthrombosisD-dimersfibrinopeptideantithrombin complexинтегральные тесты гемостазагиперкоагуляциятромбозD-димерыфибронопептидантитромбиновый комплекс1. Sinauridze E.I., Panteleev M.A., Ataullakhanov F.I. Anticoagulant therapy: basic principles, classic approaches and recent developments. Blood Coagul Fibrinolysis 2012;23:482–93.Sinauridze E.I., Panteleev M.A., Ataullakhanov F.I. Anticoagulant therapy: basic principles, classic approaches and recent developments. Blood Coagul Fibrinolysis 2012;23:482–93.2. Brummel-Ziedins K.E, Wolberg A.S. Global assays of hemostasis. Curr Opin Hematol 2014;21:395–403.Brummel-Ziedins K.E, Wolberg A.S. Global assays of hemostasis. Curr Opin Hematol 2014;21:395–403.3. Dargaud Y., Sorensen B., Shima M. et al. Global haemostasis and point of care testing. Haemophilia 2012;18(4):81–8.Dargaud Y., Sorensen B., Shima M. et al. Global haemostasis and point of care testing. Haemophilia 2012;18(4):81–8.4. van Geffen M., van Heerde W.L. Global haemostasis assays, from bench to bedside. Thromb Res 2012;129:681–7.van Geffen M., van Heerde W.L. Global haemostasis assays, from bench to bedside. Thromb Res 2012;129:681–7.5. L opez J.A., Chen J. Pathophysiology of venous thrombosis. Thromb Res 2009;123(4):30–4.L opez J.A., Chen J. Pathophysiology of venous thrombosis. Thromb Res 2009;123(4):30–4.6. Lo pez J.A., Kearon C., Lee A.Y. Deep venous thrombosis. Hematol Am Soc Hematol Educ Program 2004;2004:439–56.Lo pez J.A., Kearon C., Lee A.Y. Deep venous thrombosis. Hematol Am Soc Hematol Educ Program 2004;2004:439–56.7. Vir chov R.L.K. Gesammelte Abhandlungen zur wissenschaftlichen Medicin. Frankfurt am Main, 1856.Vir chov R.L.K. Gesammelte Abhandlungen zur wissenschaftlichen Medicin. Frankfurt am Main, 1856.8. Fri edman M.H., Brinkman A.M., Qin J.J., Seed W.A. Relation between coronary artery geometry and the distribution of early sudanophilic lesions. Atherosclerosis 1993;98:193–9.Fri edman M.H., Brinkman A.M., Qin J.J., Seed W.A. Relation between coronary artery geometry and the distribution of early sudanophilic lesions. Atherosclerosis 1993;98:193–9.9. Sevi tt S. The structure and growth of valve-pocket thrombi in femoral veins. J Clin Pathol 1974;27:517–28.Sevi tt S. The structure and growth of valve-pocket thrombi in femoral veins. J Clin Pathol 1974;27:517–28.10. von Bruhl M.L., Stark K., Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012;209:819–35.von Bruhl M.L., Stark K., Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012;209:819–35.11. Lawso n C.A., Yan S.D., Yan S.F. et al. Monocytes and tissue factor promote thrombosis in a murine model of oxygen deprivation. J Clin Invest 1997;99:1729–38.Lawso n C.A., Yan S.D., Yan S.F. et al. Monocytes and tissue factor promote thrombosis in a murine model of oxygen deprivation. J Clin Invest 1997;99:1729–38.12. Lacroi x R., Dubois C., Leroyer A.S. et al. Revisited role of microparticles in arterial and venous thrombosis. J Thromb Haemost 2013;11(1):24–35.Lacroi x R., Dubois C., Leroyer A.S. et al. Revisited role of microparticles in arterial and venous thrombosis. J Thromb Haemost 2013;11(1):24–35.13. Van Der Meijden P.E., Van Schilfgaarde M., Van Oerle R. et al. Platelet- and erythrocytederived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012;10:1355–62.Van Der Meijden P.E., Van Schilfgaarde M., Van Oerle R. et al. Platelet- and erythrocytederived microparticles trigger thrombin generation via factor XIIa. J Thromb Haemost 2012;10:1355–62.14. Shibeko A.M., Lobanova E.S., Panteleev M.A., Ataullakhanov F.I. Blood flow controls coagulation onset via the positive feedback of factor VII activation by factor Xa. BMC Syst Biol 2010;4:5.Shibeko A.M., Lobanova E.S., Panteleev M.A., Ataullakhanov F.I. Blood flow controls coagulation onset via the positive feedback of factor VII activation by factor Xa. BMC Syst Biol 2010;4:5.15. Tokarev A.A., Butylin A.A., Ataullakhanov F.I. Platelet adhesion from shear blood flow is controlled by near-wall rebounding collisions with erythrocytes. Biophys J 2011;100:799–808.Tokarev A.A., Butylin A.A., Ataullakhanov F.I. Platelet adhesion from shear blood flow is controlled by near-wall rebounding collisions with erythrocytes. Biophys J 2011;100:799–808.16. Davi G., P atrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357:2482–94.Davi G., P atrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357:2482–94.17. Sonneveld M.A., de Maat M.P., Leebeek F.W. Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis. Blood Rev 2014;28:167–78.Sonneveld M.A., de Maat M.P., Leebeek F.W. Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis. Blood Rev 2014;28:167–78.18. Kubisz P., R uiz-Arguelles G.J., Stasko J. et al. Sticky platelet syndrome: history and future perspectives. Semin Thromb Hemost 2014;40:526–34.Kubisz P., R uiz-Arguelles G.J., Stasko J. et al. Sticky platelet syndrome: history and future perspectives. Semin Thromb Hemost 2014;40:526–34.19. Undas A., Slo wik A., Gissel M. et al. Circulating activated factor XI and active tissue factor as predictors of worse prognosis in patients following ischemic cerebrovascular events. Thromb Res 2011;128:62–6.Undas A., Slo wik A., Gissel M. et al. Circulating activated factor XI and active tissue factor as predictors of worse prognosis in patients following ischemic cerebrovascular events. Thromb Res 2011;128:62–6.20. Zabczyk M., Bu tenas S., Plicner D. et al. Factors associated with the presence of circulating active tissue factor and activated factor XI in stable angina patients. Blood Coagul Fibrinolysis 2012;23:189–94.Zabczyk M., Bu tenas S., Plicner D. et al. Factors associated with the presence of circulating active tissue factor and activated factor XI in stable angina patients. Blood Coagul Fibrinolysis 2012;23:189–94.21. Zabczyk M., But enas S., Palka I. et al. Active tissue factor and activated factor XI in circulating blood of patients with systolic heart failure due to ischemic cardiomyopathy. Pol Arch Med Wewn 2010;120:334–40. 22. Weitz J.I. Insi ghts into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome. Thromb Haemost 2014;112:924–31.Zabczyk M., But enas S., Palka I. et al. Active tissue factor and activated factor XI in circulating blood of patients with systolic heart failure due to ischemic cardiomyopathy. Pol Arch Med Wewn 2010;120:334–40. 22. Weitz J.I. Insi ghts into the role of thrombin in the pathogenesis of recurrent ischaemia after acute coronary syndrome. Thromb Haemost 2014;112:924–31.23. Kwaan H.C. Micro vascular thrombosis: a serious and deadly pathologic process in multiple diseases. Semin Thromb Hemost 2011; 37:961–78.Kwaan H.C. Micro vascular thrombosis: a serious and deadly pathologic process in multiple diseases. Semin Thromb Hemost 2011; 37:961–78.24. Bellido-Martin L., Chen V., Jasuja R. et al. Imaging fibrin formation and platelet and endothelial cell activation in vivo. Thromb Haemost 2011;105:776–82.Bellido-Martin L., Chen V., Jasuja R. et al. Imaging fibrin formation and platelet and endothelial cell activation in vivo. Thromb Haemost 2011;105:776–82.25. Pfeiler S., Massber g S., Engelmann B. Biological basis and pathological relevance of microvascular thrombosis. Thromb Res 2014;133(1):35–7.Pfeiler S., Massber g S., Engelmann B. Biological basis and pathological relevance of microvascular thrombosis. Thromb Res 2014;133(1):35–7.26. Levi M., Schultz M., van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost 2013;39:559–66.Levi M., Schultz M., van der Poll T. Sepsis and thrombosis. Semin Thromb Hemost 2013;39:559–66.27. Langer F., Bokemeyer C. Crosstalk between cancer and haemostasis. Implications for cancer biology and cancer-associated thrombosis with focus on tissue factor. Hamostaseologie 2012;32:95–104.Langer F., Bokemeyer C. Crosstalk between cancer and haemostasis. Implications for cancer biology and cancer-associated thrombosis with focus on tissue factor. Hamostaseologie 2012;32:95–104.28. Barrabes J.A., Inserte J., Agullo L. et al. Microvascular thrombosis: an exciting but elusive therapeutic target in reperfused acute myocardial infarction. Cardiovasc Hematol Disord Drug Targets 2010;10:273–83.Barrabes J.A., Inserte J., Agullo L. et al. Microvascular thrombosis: an exciting but elusive therapeutic target in reperfused acute myocardial infarction. Cardiovasc Hematol Disord Drug Targets 2010;10:273–83.29. Blake-Haskins J.A., Lec hleider R.J., Kreitman R.J. Thrombotic microangiopathy with targeted cancer agents. Clin Cancer Res 2011;17:5858–66.Blake-Haskins J.A., Lec hleider R.J., Kreitman R.J. Thrombotic microangiopathy with targeted cancer agents. Clin Cancer Res 2011;17:5858–66.30. Gando S. Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med 2010;38:35–42.Gando S. Microvascular thrombosis and multiple organ dysfunction syndrome. Crit Care Med 2010;38:35–42.31. Semeraro N., Ammollo C.T., Semeraro F., Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res 2012;129:290–5.Semeraro N., Ammollo C.T., Semeraro F., Colucci M. Sepsis, thrombosis and organ dysfunction. Thromb Res 2012;129:290–5.32. Yu J.L., May L., Lhotak V. et al. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 2005;105:1734–41.Yu J.L., May L., Lhotak V. et al. Oncogenic events regulate tissue factor expression in colorectal cancer cells: implications for tumor progression and angiogenesis. Blood 2005;105:1734–41.33. Geddings J.E., Mackman N. T umorderived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood 2013;122:1873–80.Geddings J.E., Mackman N. T umorderived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood 2013;122:1873–80.34. Tesselaar M.E., Romijn F.P., Van Der Linden I.K. et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost 2007;5:520–7.Tesselaar M.E., Romijn F.P., Van Der Linden I.K. et al. Microparticle-associated tissue factor activity: a link between cancer and thrombosis? J Thromb Haemost 2007;5:520–7.35. Levi M. Cancer and thrombosi s. Clin Adv Hematol Oncol 2003;1:668–71.Levi M. Cancer and thrombosi s. Clin Adv Hematol Oncol 2003;1:668–71.36. Demers M., Wagner D.D. Neutrop hil extracellular traps: A new link to cancerassociated thrombosis and potential implications for tumor progression. Oncoimmunology 2013;2:22946.Demers M., Wagner D.D. Neutrop hil extracellular traps: A new link to cancerassociated thrombosis and potential implications for tumor progression. Oncoimmunology 2013;2:22946.37. Wahrenbrock M., Borsig L., Le D . et al. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Invest 2003;112: 853–62.Wahrenbrock M., Borsig L., Le D . et al. Selectin-mucin interactions as a probable molecular explanation for the association of Trousseau syndrome with mucinous adenocarcinomas. J Clin Invest 2003;112: 853–62.38. Bremme K.A. Haemostatic change s in pregnancy. Best Pract Res Clin Haematol 2003;16:153–68.Bremme K.A. Haemostatic change s in pregnancy. Best Pract Res Clin Haematol 2003;16:153–68.39. Medcalf R.L., Stasinopoulos S.J. The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2. FEBS J 2005;272:4858–67.Medcalf R.L., Stasinopoulos S.J. The undecided serpin. The ins and outs of plasminogen activator inhibitor type 2. FEBS J 2005;272:4858–67.40. Alijotas-Reig J., Palacio-Garcia C., Llurba E., Vilardell-Tarres M. Cell-derived microparticles and vascular pregnancy complications: a systematic and comprehensive review. Fertil Steril 2013;99:441–9.Alijotas-Reig J., Palacio-Garcia C., Llurba E., Vilardell-Tarres M. Cell-derived microparticles and vascular pregnancy complications: a systematic and comprehensive review. Fertil Steril 2013;99:441–9.41. Patil R., Ghosh K., Satoskar P., She tty S. Elevated procoagulant endothelial and tissue factor expressing microparticles in women with recurrent pregnancy loss. PLoS One 2013;8:81407.Patil R., Ghosh K., Satoskar P., She tty S. Elevated procoagulant endothelial and tissue factor expressing microparticles in women with recurrent pregnancy loss. PLoS One 2013;8:81407.42. Sandset P.M. Mechanisms of hormon al therapy related thrombosis. Thromb Res 2013;131(1):4–7.Sandset P.M. Mechanisms of hormon al therapy related thrombosis. Thromb Res 2013;131(1):4–7.43. Morel O., Jesel L., Abbas M., Morel N. Prothrombotic changes in diabetes mellitus. Semin Thromb Hemost 2013;39: 477–88.Morel O., Jesel L., Abbas M., Morel N. Prothrombotic changes in diabetes mellitus. Semin Thromb Hemost 2013;39: 477–88.44. Lipets E., Vlasova O., Urnova E. et al. Circulating contact-pathway-activating microparticles together with factors IXa and XIa induce spontaneous clotting in plasma of hematology and cardiologic patients. PLoS One 2014;9:87692.Lipets E., Vlasova O., Urnova E. et al. Circulating contact-pathway-activating microparticles together with factors IXa and XIa induce spontaneous clotting in plasma of hematology and cardiologic patients. PLoS One 2014;9:87692.45. Poort S.R., Rosendaal F.R., Reitsma P.H., Bertina R.M. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698–703.Poort S.R., Rosendaal F.R., Reitsma P.H., Bertina R.M. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698–703.46. Lindahl T.L., Lundahl T.H., Nilsson L. , Andersson C.A. APC-resistance is a risk factor for postoperative thromboembolism in elective replacement of the hip or knee – a prospective study. Thromb Haemost 1999;81:18–21.Lindahl T.L., Lundahl T.H., Nilsson L. , Andersson C.A. APC-resistance is a risk factor for postoperative thromboembolism in elective replacement of the hip or knee – a prospective study. Thromb Haemost 1999;81:18–21.47. Rosendaal F.R., Koster T., Vandenbrouc ke J.P., Reitsma P.H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995;85:1504–8.Rosendaal F.R., Koster T., Vandenbrouc ke J.P., Reitsma P.H. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995;85:1504–8.48. Koster T., Rosendaal F.R., Briet E. et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995;85: 2756–61.Koster T., Rosendaal F.R., Briet E. et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995;85: 2756–61.49. Lijfering W.M., Brouwer J.L., Veeger N.J . et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009;113:5314–22.Lijfering W.M., Brouwer J.L., Veeger N.J . et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009;113:5314–22.