The state of thrombotic readiness and its possible role in thrombosis realization in thrombophilia and/or with thrombogenic risk factors: 616.151.511-005.6

Abstract

Summary. The main objective of this report is to propose a new approach to identifying a noticeably smaller cohort of patients with thrombophilia who really need outpatient care and secondary thromboprophylaxis than the cohort is currently considered. The article presents new views on the relationship between thrombophilia, thrombogenic risk factors and the state of thrombotic readiness, preceding and
concomitant vascular ischemia. Modern laboratory approaches to assessing the presence of thrombogenic risk factors and the state of thrombotic readiness, as well as the prospects of using direct oral anticoagulants in the prevention and treatment of thrombophilia, are
noted.

For citation: Momot A.P., Neymark M.I., FedorovD.V., Strozenko L.A., Tsyvkina L.P. The state of thrombotic readiness and its possible role in thrombosis realization in thrombophilia and/or with thrombogenic risk factors. Tromboz, gemostaz i reologiya. 2025;(2):11–21. (In Russ.).

 References

1. Barkagan Z.S., Momot A.P. Diagnosis and controlled therapy of hemostatic disorders. Moscow: N’yudiamed, 2008. 292 рр. (In Russ.).
2. Beckman M.G., Hooper W.C., Critchley S.E., Ortel T.L. Venous thromboembolism: a public health concern. Am J Prev Med. 2010;38(4 Suppl): S495–501. DOI: 10.1016/j.amepre.2009.12.017.
3. Heit J. A. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost. 2005;3(8):1611–7. DOI: 10.1111/j.153 8-7836.2005.01415.x.
4. Khalafallah A.A., Kirkby B.E., Wong S. et al. Venous thromboembolism in medical patients during hospitalisation and 3 months after hospitalisation: a prospective observational study. BMJ Open. 2016;6(8): e012346. DOI: 10.1136/bmjopen-2016-012346.
5. Bokeriya L.A., Zatevakhin I.I., Kirienko A.I. et al. Russian clinical guidelines for the diagnosis, treatment and prevention of venous thromboembolism (VTE). Flebologiya. 2015;9(4–2):2–52. (In Russ.).
6. Momot A.P, Nikolaeva M.G., Serdyuk G.V. et al. Assessment of the state of the hemostasis system in physiologically occurring pregnancy. Algorithms of examination in risk groups. Tromboz, gemostaz i reologiya. 2019;(4):80–130. (In Russ.). DOI: 10.25555/ THR.2019.4.0903.
7. Egeberg O.Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh. 1965;13:516–30.
8. Lippi G., Franchini M. Pathogenesis of venous thromboembolism: when the cup runneth over. Semin Thromb Hemost. 2008;34(8):747– 61. DOI: 10.1055/s-0029-11452 57.
9. Bates S.M., Greer I.A., Pabinger I. et al. Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133(6 Suppl):844S-886S. DOI: 10.1378/chest.08-0761.
10. Barkagan Z.S. Hemostasis. In: Manual of Hematology. Ed. A. I. Vorob’ev. Moscow: N’yudiamed, 2005. 9–147. (In Russ.).
11. Kuznik B.I. Cellular and molecular mechanisms of regulation of the hemostasis system in norm and pathology: monograph. Chita: Ekspress-izdatel’stvo, 2010. 832 рр. (In Russ.).
12. Papayan L. P., Kapustin S.I., Shmeleva V.M., Kobilyanskaya V.A. Thrombophilia. Congenital and acquired disorders in the hemostasis system predisposing to the thrombosis development. In: Rational pharmacotherapy in hematology. Ed. O.A. Rukavitsyn. Moscow: Littera, 2021. 15–28. (In Russ.).
13. Colucci G., Tsakiris D.A. Thrombophilia screening revisited: an issue of personalized medicine. J Thromb Thrombolysis. 2020;49(2):618–29. DOI:10.1007/s11239-020-02090-y.
14. Wu O., Bayoumi N., Vickers M.A., Clark P. ABO(H) blood groups and vascular disease: a systematic review and meta-analysis. J Thromb Haemost. 2008;6(1):62–9. DOI: 10.1111/j.1538-7836.2007.02818.x.
15. Franchini M., Mannucci P.M. ABO blood group and thrombotic vascular disease. Thromb Haemost. 2014;112(6):1103–9. DOI: 10.1160/TH14-05-0457.
16. Barsoum M.K., Heit J.A., Ashrani A.A. et al. Is progestin an independent risk factor for incident venous thromboembolism? A population-based case-control study. Thromb Res. 2010;126(5):373–8. DOI: 10.1016/j.thromres.2010.08.010.
17. Crous-Bou M., Harrington L.B., Kabrhel C. Environmental and genetic risk factors associated with venous thromboembolism. Semin Thromb Hemost. 2016;42(8):808–20. DOI: 10.1055/s-0036-15923 33.
18. Momot A.P., Tsyvkina L.P., Elykomov V.A. et al. Early ischemic strokes and hematogenous thrombophilia (diagnosis, treatment, prevention): A methodological guide for physicians: neurologists, vascular surgeons, obstetricians and gynecologists, traumatologists, internists, specialists inclinical laboratory diagnostics, students of the faculty of continuing medical education, students of medical universities. Barnaul: GU «Kraevoy spravochno-informatsionnyy farmatsevticheskiy tsentr», 2009. 58 рр. (In Russ.).
19. Belykh V.I., Berestov S.A., Buylova E.V. et al. The experience of clinical use of the drug “Angiovit” for the correction of hyperhomocysteinemia. Novosibirsk: Izdatel’stvo Sibirskogo otdeleniya Rossiyskoy akademii nauk, 2020. 109 рр. (In Russ.).
20. Mach F., Baigent C., Catapano A.L. et al. 2019 ESC/EAS Guidelines for themanagement of dyslipidaemias: lipid modification to reduce cardiovascular risk. Rossiyskiy kardiologicheskiy zhurnal. 2020;25(5):121–93. (In Russ.). DOI: 10.15829/1560-4071-2020-3826.
21. Makogon S.I., Momot A.P., Makogon A.S. et al. Nonpharmacological strengthening of fibrinolysis in complex therapy of primary open-angle glaucoma. Oftal’mologiya. 2020;17(1):96–104. (In Russ.). DOI: 10.18008/1816-5095-2020-1-96-104.
22. Momot A.P., Lebedeva E.I., Nikolaeva M.G. et al. Clinical effects of intermittent pneumatic compression. Problemy reproduktsii. 2019;25(4):35–42. (In Russ.). DOI: 10.17116/repro20192504135.
23. Roitman E.V., Dement’eva I.I. On the classification of certain types of thrombophilia (hemorheological forms). First All-Russian Conference “Clinical hemostasiology and hemorheology in cardiovascular surgery”. Moscow, 2003. 42–3. (In Russ.).
24. Pinjala R.K., Reddy L.R., Nihar R.P. et al. Thrombophilia — how far and how much to investigate? Indian J Surg. 2012;74(2):157–62. DOI: 10.1007/s12262-011-0407-2.
25. Momot A.P., Sidor N.V. A possible involvement of factor XIII in forming a trend to thrombosis in patients with different type thrombophilias. Klinicheskaya laboratornaya diagnostika. 2004;(2):45–7. (In Russ.).
26. Hethershaw E.L., Cilia La Corte A.L., Duval C. et al. The effect of blood coagulation factor XIII on fibrin clot structure and fibrinolysis. J Thromb Haemost. 2014;12(2):197–205. DOI: 10.1111/jth.12455.
27. Cushman M., O’Meara E.S., Folsom A.R., Heckbert S.R. Coagulation factors IX through XIII and the risk of future venous thrombosis: the Longitudinal Investigation of Thromboembolism Etiology. Blood. 2009;114(14):2878–83. DOI: 10.1182/blood-2009-05-219915.
28. Campello E., Spiezia L., Adamo A., Simioni P. Thrombophilia, risk factors and prevention. Expert Rev Hematol. 2019;12(3):147–58. DOI:10.1080/17474086.2019.1583555.
29. Momot A.P., Tsyvkina L.P., Taranenko I.A. et al. Modern methods of recognizing the state of thrombotic readiness: a monograph. Barnaul: Izd-vo AGMU, 2011. 138 pр. (In Russ.).
30. Hemker H.C., Giesen P., Al Dieri R. et al. Calibrated automated thrombin generation measurement in clotting plasma. Pathophysiol Haemost Thromb. 2003;33(1):4–15. DOI: 10.1159/000071636.
31. Hemker H.C., Al Dieri R., De Smedt E., Béguin S. Thrombin generation, a function test of the haemostatic-thrombotic system. Thromb Haemost. 2006;96(5):553–61.
32. Matvienko O. Yu., Smirnova O.A., Lerner A.A. et al. Assessment of the state of the hemostasis system in patients with coronavirus infection using a thrombin generation test. Byulleten’ meditsinskoy nauki. 2021;(2):95–8. (In Russ.). DOI: 10.31684/25418475_2021_2_95.
33. Mel’nichnikova O.S., Zhilenkova Yu.I., Zolotova E.A. et al. Thrombin generation test as an integral analysis of the hemostasis system: technical capabilities and application in laboratory practice. Rossiyskiy zhurnal personalizirovannoy meditsiny. 2022;2(3):119–28. (In Russ.). DOI: 10.18705/2782-3806-2022-2-3-119-128.
34. Namestnikov Yu. A. Thrombin generation test as an integral indicator of the blood clotting system status. Gematologiya i transfuziologiya. 2010;55(2):32–9. (In Russ.).
35. Duarte R. C.F., Ferreira C.N., Rios D.R.A. et al. Thrombin generation assays for global evaluation of the hemostatic system: perspectives and limitations. Rev Bras Hematol Hemoter. 2017;39(3):259–65. DOI: 10.1016/j.bjhh.2017.03.009.
36. Karpich S.A., Shmeleva V.M., Kapustin S.I. et al. Assessment of prothrombotic phenotype by thrombin generation test in asymptomatic carries of G1691A mutation in factor V and/or G20210A mutation in prothrombin gene. Tromboz, gemostaz i reologiya. 2018;(3):11–6. (In Russ.). DOI: 10.25555/THR.2018.3.0845.
37. Baglin T. Using the laboratory to predict recurrent venous thrombosis. Int J Lab Hematol. 2011;33(4):333–342. DOI:10.1111/ j.1751-553X.2011.01345.x.
38. Segers O., Simioni P., Tormene D., Castoldi E. Influence of single nucleotide polymorphisms on thrombin generation in factor V Leiden heterozygotes. Thromb Haemost. 2014;111(3):438–46. DOI: 10.1160/TH13-05-0360.
39. Momot A.P., Nikolaeva M.G, Zainulina M.S. et al. Effects of lowmolecular heparin on pregnant women with factor V mutation (GA genotype). J Hematol Blood Transfus Disord. 2018;5:20. DOI: 10.24966/HBTD-2999/100020.
40. Adam S.S., Key N.S., Greenberg C.S. D-dimer antigen: current concepts and future prospects. Blood. 2009;113(13):2878–87. DOI: 10.1182/blood-2008-06-165845.
41. Linkins L.A., Takach Lapner S.Review of D-dimer testing: good, bad, and ugly. Int J Lab Hematol. 2017;39(S1):98–103. DOI: 10.1111/ijlh.12665.
42. RileyR.S., Gilbert A.R., Dalton J.B. et al. Widely used types and clinical applications of D-dimer assay. Lab Med. 2016;47(2):90–102. DOI: 10.1093/labmed/lmw001.
43. ThachilJ., Lippi G., FavaloroE.J. D-dimer testing: laboratory aspects and current issues. Methods Mol Biol. 2017;1646:91–104. DOI: 10.1007/978-1-4939-7196-1_7.
44. MomotA.P., Kudinova I.Yu., TrukhinaD.A.Challenges related to the measurement of D-dimer level and standardization of the evaluation of this marker in intravascular coagulation. Byulleten’ meditsinskoy nauki. 2021;(4):88–94. (In Russ.). DOI: 10.31684/25418475-2021-4-88.
45. Momot D.A., Mamaev A.N., Nikolaeva M.G. et al. Advancing plasma D-dimer level determination: an applicability analysis for COVID-19 patients at the hospital stage. Byulleten’ meditsinskoy nauki. 2023;(2):79–86. (In Russ.). DOI: 10.31684/25418475-2023-2-79.
46. Favresse J., Lippi G., RoyP.M. еt al. D-dimer: Preanalytical, analytical, postanalytical variables, and clinical applications. Crit Rev Clin Lab Sci. 2018;55(8):548–77. DOI: 10.1080/10408363.2018.1529734.
47. Jennings I., WoodsT.A., Kitchen D.P. et al. Laboratory D-dimer measurement: improved agreement between methods through calibration. Thromb Haemost. 2007;98(5):1127–35. DOI: 10.1160/th07-05-0377.
48. Dahlbäck B., Carlsson M., Svensson P.J. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A. 1993;90(3):1004–8. DOI: 10.1073/pnas.90.3.1004.
49. Meinardi J.R., Middeldorp S., de Kam P.J. еt al. The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders. Br J Haematol. 2002;116(3):625–31. DOI: 10.1046/j.0007-1048.2001.03303.x.
50. Price D.T., Ridker P.M. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med. 1997;127(10):895–903. DOI: 10.7326/0003-4819-127-10-199711150-00007.
51. Lindqvist P.G., Svensson P., Dahlbäck B. Activated protein C resistance — in the absence of factor V Leiden — and pregnancy. J Thromb Haemost. 2006;4(2):361–6. DOI: 10.1111/j.1538-7836.2006.01714.x.
52. Ghorbani M., Hamidpour M., Nematallahi M.R., Niazkar H.R. Comparison of two methods for factor five Leiden detection in patientswith thromboembolism. Biomed Res (India). 2018;29(8):1685–8. DOI: 10.4066/biomedicalresearch.29-17-2646.
53. 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(10):3698–703.
54. Casas J.P., Hingorani A.D., Bautista L.E., Sharma P. Metaanalysis of genetic studies in ischemic stroke: thirty-two genes involving approximately 18 000 cases and 58 000 controls. Arch Neurol. 2004;61(11):1652–61. DOI: 10.1001/archneur.61.11.1652.
55. de Visser M.C., Rosendaal F.R., Bertina R.M. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood. 1999;93(4):1271–6.
56. Momot A.P., Molchanova I.V., Batrak T.A. etal. Reference values of hemostatic system parameters in normal pregnancy and after delivery. Problemy reproduktsii. 2015;21(1):89–97. (In Russ.). DOI: 10.17116/repro20152189-97.
57. Miyakis S., Lockshin MD., Atsumi T. et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost. 2006;4(2):295–306. DOI: 10.1111/j.1538-7836.2006.01753.x.
58. Rosendaal F.R., Reitsma P.H. Genetics of venous thrombosis. J Thromb Haemost. 2009;7(S1):301–4. DOI: 10.1111/j.1538-7836.2009.03394.x.
59. Castoldi E, Rosing J. APC resistance: biological basis and acquired influences. J Thromb Haemost. 2010;8(3):445–53. DOI: 10.1111/j.1538-7836.2009.03711.x.
60. MomotA.P., NikolaevaM.G., ElykomovV.A. et al. Importance of factor Va resistance to activated protein C with FVL(1691) GA mutation for development of thrombosis. Meditsinskiy alfavit. 2018;1(5):21–4. (In Russ.).
61. Nikolaeva M.G., Momot K.A., Yasafova N.N. et al. The role of the acquired risk factors in the development of venous thromboembolism in the women of reproductive age carrying factor V Leiden. Flebologiya. 2018;12(3):101–8. (In Russ.). DOI: 10.17116/flebo2018123101.
62. Nikolaeva M.G., Momot A.P., Serdyuk G.V. et al. APC resistance associated with factor V Leiden gene mutation (genotype GA): clinical occurrence in pregnancy. Tromboz, gemostaz i reologiya. 2018;(1):47–54. (In Russ.). DOI: 10.25555/THR.2018.1.0823.
63. Momot A.P., Nikolaeva M.G., Zainulina M.S. The main causes of thrombotic events in carriage of Leiden mutation in women of reproductive age. J Hematol Thrombo Dis. 2018;6(4):296. DOI: 10.4172/2329-8790.1000295.
64. Nikolaeva M.G., Yasafova N.N., Momot A.P. et al. Phenotypic manifestations of prothrombin gene mutation, F2(20210)GA genotype, in women of reproductive age. Flebologiya. 2019;13(4):285–92. (In Russ.). DOI: 10.17116/flebo201913041285.
65. Momot A.P., Nikolaeva M.G., Yasafova N.N. et al. Clinical and laboratory manifestations of the prothrombin gene mutation in women of reproductive age. J Blood Med. 2019;10:255–63. DOI: 10.2147/JBM.S212759.
66. Barkagan Z.S. Essays on antithrombotic pharmacoprophylaxis and therapy. Moscow: N’yudiamed, 2000. 148 pp. (In Russ.).
67. Barkagan Z.S. Modern antithrombotic prevention and therapy. Pharmacotherapy of cardiovascular diseases: Lectures for practitioners. VIII National Congress “Man and Medicine”. Moscow, 2002. 142–53. (In Russ.).
68. AndriyashkinA.V., AndriyashkinV.V., ArutyunovG.P. et al. Russian clinical guidelines for the diagnosis, treatment and prevention of venous thromboembolic complications. Flebologiya. 2015;9(2):4–52. (In Russ.).
69. Papayan L.P., Golovina O.G., Matvienko O.Yu., Silina N.N. Hereditary thrombophilia. A study guide. Saint Petersburg: OOO IPK «Gangut», 2022. 24 pр. (In Russ.).
70. SeliverstovE.I, LobastovK.V., Ilyukhin E.A. et al. Prevention, diagnostics and treatment of deep vein thrombosis. Russian experts consensus. Flebologiya. 2023;17(3):152–296. (In Russ.). DOI: 10.17116/flebo202317031152.
71. Clinical guidelines — Atrial fibrillation and flutter in adults —2020–2021–2022 (10.06.2021). Moscow: Ministerstvo zdravoohraneniya Rossijskoj Federacii, 2021. 126 рр. (In Russ.). Available at: http://disuria.ru/_ld/11/1114_kr20I48MZ.pdf. [Accessed:15.11.2024].
72. Shmakov R.G., Vavilova T.V., Nikolaeva M.G. et al. Brief algorithms for the diagnosis, prevention and treatment of venous thromboembolic complications during pregnancy. Akusherstvo i ginekologiya. 2022;(S12):4–12. (In Russ.).
73. Nojima Y., Ihara M., Adachi H. et al. Efficacy and safety of apixaban in a patient with systemic venous thromboembolism associated with hereditary antithrombin deficiency. J Cardiol Cases. 2019;19(3):106–9. DOI: 10.1016/j.jccase.2018.12.007.
74. Minami K., Kumagai K., Sugai Y. et al. Efficacy of oral factor Xa inhibitor for venous thromboembolism in a patient with antithrombin deficiency. Intern Med. 2018;57(14):2025–8. DOI: 10.2169/internalmedicine.0483-17.
75. Sun L., Li X., Li Q. et al. Multiple arterial and venous thromboembolism in a male patient with hereditary protein C deficiency: a case report. Medicine (Baltimore). 2021;100(15):e25575. DOI: 10.1097/MD.0000000000025575.
76. Menon N., Sarode R., Zia A. Rivaroxaban dose adjustment using thrombin generation in severe congenital protein C deficiency and warfarin-induced skin necrosis. Blood Adv. 2018;2(2):142–5. DOI: 10.1182/bloodadvances.2017012047.
77. Saito K., Ishii K., Furuta K. et al. Recurrent cerebral venous thrombosis treated with direct oral anticoagulants in a Japanese man with hereditary protein C deficiency. J Stroke Cerebrovasc Dis. 2021;30(1):105320. DOI: 10.1016/j.jstrokecerebrovasdis.2020.105320.
78. Wang T., Zhao X.-J., Zhu H.-D. et al. Clinical characteristics, genes identification and follow-up study of a patient with central venous thrombosis from a protein S deficiency pedigree. Eur Rev Med Pharmacol Sci. 2021;25(1):353–61. DOI: 10.26355/eurrev_202101_24402.
79. Lou J., Yin L., Ke X. et al. A case-report of two patients with hereditary protein S deficiency treated by rivaroxaban. Blood Coagul Fibrinolysis. 2020;31(6):405–9. DOI: 10.1097/MBC.0000000000000929.
80. LeeW.-C., Huang M.-P. Lead thrombus under standard-dose edoxaban in a patient with normal to high creatinine clearance and protein S deficiency. Thromb J. 2021;19(1):50. DOI: 10.1186/s12959-021-00302-w.
81. Costa R.L., Triggs M., Cole S.E. et al. Anticoagulation therapy in a patient with heterozygous factor V Leiden and coexisting homozygous prothrombin gene mutations. Cureus. 2020;12(12):e11949.DOI: 10.7759/cureus.11949.
82. Serrao A., Lucani B., Mansour D. et al. Direct oral anticoagulants in patients affected by major congenital thrombophilia. Mediterr J Hematol Infect Dis.2019;11(1): e2019044. DOI: 10.4084/MJHID.2019.044.
83. Stevens S.M., Woller S.C., Kreuziger L.B. et al. Antithrombotic therapy for VTE disease: second update of the CHEST Guideline and Expert Panel Report. Chest. 2021;160(6): e545-e608. DOI: 10.1016/j.chest.2021.07.055.
84. Konstantinides S.V., Meyer G., Becattini C. et al.; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur HeartJ. 2020;41(4):543–603. DOI: 10.1093/eurheartj/ehz405.