Markers of impaired plasma hemostasis in risk assessment of cerebral microangiopathy: 616-092:616-005

Abstract

Summary. Background. In the past decades, it has been proved and evidenced that there are relations between endothelial dysfunc- tion, hemostasis parameters and severity of vascular lesions of the white matter. It is critical to identify early diagnostic markers of cerebral microangiopathy (CMA), since the disease influences the risk of stroke and development of cognitive and other age- related disorders. Objectives: to assess plasma hemostasis in patients with MRI-markers of impaired small brain arteries damage. Patients/Methods. A prospective study included 117 people (aged 57.7 ± 11.5 years) with dyscirculatory encephalopathy. Laboratory testing included assessment of platelet function, blood clotting factor VIII (FVIII) activity, von Willebrand factor (vWF) level, as well as an integral assessment of plasma hemostasis using a thrombodynamic test (TD). All patients underwent magnetic resonance imaging (MRI) of the brain and diffuse tensor tractography. Results. According to MRI results, 2 groups were formed: 54 patients with CMA and 63 without CMA. According to TD test, CMA group had higher clot growth rate (V), fibrin clot size (CS), fibrin clot density (D) and higher vWF values (p=0.051). As to the time of spontaneous clots appearance (Tsp), such clots appeared 2.5 times more often in CMA group, ranging from 15 to 30 seconds (normal time is over 30 seconds). In determining the threshold values of TD parameters, the sensitivity of detecting pronounced (2–3 grade according to the Fazekas scale) subcortical lesion was 89.5% with an increase in V value over 30.6 μm/min and D index over 21688 conventional units. However, these parameters were insensitive for the diagnosis of periventricular white matter lesions. Conclusions. Study results show the relationship between changes in plasma hemostasis and the size of white matter lesions, and also confirm the hypothesis of heterogeneous pathophysiological mechanisms of subcortical and periventricular leukoaraiosis.

For citation: Khutorov D.N., Startseva O.N., Tikhomirova O.V., Zybina N.N. Markers of impaired plasma hemostasis in risk assessment of ce- rebral microangiopathy. Tromboz, gemostaz i reologiya. 2022;(4):54–63. (In Russ.).

References

1. The LADIS Study Group; Poggesi A., Pantoni L., Inzitari D. et al. 2001–2011: A decade of the LADIS (leukoaraiosis and disability) study: what have we learned about white matter changes and small-vessel disease? Cerebrovasc Dis. 2011;32(6):577–88. DOI: 10.1159/000334498.
2. Wardlaw J.M., Valdés Hernández M.C., Muñoz-Maniega S. What are white matter hyperintensities made of? Relevance to vascular cognitive impairment. J Am Heart Assoc. 2015;4(6):001140. DOI: 10.1161/JAHA.114.001140.
3. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9(7):689–701. DOI: 10.1016/S1474–4422(10)70104–6.
4. Levin O.S. Distsirkulyatorny encephalopathy: anachronism or clinical reality? Sovremennaya terapiya v psihiatrii i nevrologii. 2012;(3):40–6. (In Russ.).
5. Wardlaw J.M., Smith C., Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 2019;18:684–96. DOI: 10.1016/S1474–4422(19)30079–1.
6. Charidimou A., Pantoni L., Love S. The concept of sporadic cerebral small vessel disease: A road map on key definitions and current concepts. Int J Stroke. 2016;11(1):6–18. DOI: 10.1177/1747493015607485.
7. Lavallée P.C., Labreuche J., Faille D. et al. Lacunar-BICHAT Investigators. Circulating markers of endothelial dysfunction and platelet activation in patients with severe symptomatic cerebral small vessel disease. Cerebrovasc Dis. 2013;36(2):131–8. DOI: 10.1159/000353671.
8. Nagai M., Hoshide S., Kario K. Association of prothrombotic status with markers of cerebral small vessel disease in elderly hypertensive patients. Am J Hypertens. 2012;25(10):1088–94. DOI: 10.1038/ ajh.2012.85.
9. Markus H.S., Hunt B., Palmer K. et al. Markers of endothelial and hemostatic activation and progression of cerebral white matter hyperintensities: longitudinal results of the Austrian Stroke Prevention Study. Stroke. 2005;36(7):1410–4. DOI: 10.1161/01. STR.0000169924.60783.d4.
10. Fazekas F., Kleinert R., Offenbacher H. et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993;43(9):1683–9. DOI: 10.1212/wnl.43.9.1683.
11. Levashkina I.M., Serebryakova S.V., Kozhevnikova V.V., Aleksanin S.S. Possibilities of Diffusion tensor MRI potential for integrated assessment of Chernobyl accident liquidators’ cognitive disorders at the remote period (correlation between clinical and radiological findings). Mediko-biologicheskie i social’no-psihologicheskie problemy bezopasnosti v chrezvychajnyh situaciyah. 2017;(4):13–9. (In Russ.). DOI: 10.25016/2541–7487–2017–0–4– 13–19.
12. Levashkina I.M., Serebryakova S.V., Kitaigorodskaya E.V. Vascular dementia neurovisual markers according routine and diffusion-tensor MRI (publications’ review). Вестник СанктПетербургского университета. Медицина. 2021;16(2):16–128. (In English). DOI: 10.21638/spbu11.2021.205.
13. Poggesi A., Pasi M., Pescini F. et al. Circulating biologic markers of endothelial dysfunction in cerebral small vessel disease: A review. J Cereb Blood Flow Metab. 2016;36(1):72–94. DOI: 10.1038/ jcbfm.2015.116 20.
14. Pikula A., Beiser A.S., DeCarli C. et al. Multiple biomarkers and risk of clinical and subclinical vascular brain injury: the Framingham Offspring Study. Circulation. 2012;125(17):2100–7. DOI: 10.1161/CIRCULATIONAHA.110.989145.
15. Gottesman R.F., Cummiskey C., Chambless L. et al. Hemostatic factors and subclinical brain infarction in a community-based sample: the ARIC study. Cerebrovasc Dis. 2009;28(6):589–94. DOI: 10.1159/000247603.
16. Tomimoto H., Akiguchi I., Ohtani R. et al. The coagulationfibrinolysis system in patients with leukoaraiosis and Binswanger disease. Arch Neurol. 2001;58(10):1620–5. DOI: 10.1001/archneur.58.10.1620.
17. Hassan A., HuntB.J., O’Sullivan M. et al. Markers of endothelial dysfunction in lacunar infarction and ischaemic leukoaraiosis. Brain. 2003;126(Pt 2):424–32. DOI: 10.1093/brain/ awg040.
18. Kario K., Matsuo T., Kobayashi H. et al. Hyperinsulinemia and hemostatic abnormalities are associated with silent lacunar cerebral infarcts in elderly hypertensive subjects. J Am Coll Cardiol. 2001;37(3):871–7. DOI: 10.1016/S0735–1097(00)01172–4.
19. Wiseman S., Marlborough F., Doubal F. et al. Blood markers of coagulation, fibrinolysis, endothelial dysfunction and inflammation in lacunar stroke versus non-lacunar stroke and nonstroke: systematic review and meta-analysis. Cerebrovasc Dis. 2014;37(1):64–75. DOI: 10.1159/000356789.
20. Balandina A.N., Koltsova E.M., Shibeko A.M. et al. Thrombodynamics: a new method to the diagnosis of hemostasis system disorders. Voprosy gematologii/onkologii i immunopatologii v pediatrii. 2018;17(4):114–26. (In Russ.). DOI: 10.24287/1726–1708–2018– 17–4–114–126.
21. Levi M., van der Poll T., Büller H.R. Bidirectional relation between inflammation and coagulation. Circulation. 2004;109(22):2698– 704. DOI: 10.1161/01.CIR.0000131660.51520.9A.
22. MarkusH.S.,AllanC.L.,EbmeierK.P.Cerebralhemodynamics in cerebral small vessel disease. In: Cerebral small vessel disease. Eds. L. Pantoni, P.B. Gorelick. Cambridge, UK: Cambridge University Press, 2014. 180–91. DOI: 10.1111/bpa.12224.
23. Ueno M., Akiguchi I., Hosokawa M. et al. Blood-brain barrier permeability in the periventricular areas of the normal mouse brain. Acta Neuropathol. 2000;99(4):385–92. DOI: 10.1007/ s004010051140.
24. ten Dam V.H., van den Heuvel D.M., de Craen A.J. et al. Decline in total cerebral blood flow is linked with increase in periventricular but not deep white matter hyperintensities. Radiology. 2007;243(1):198–203. DOI: 10.1148/radiol.2431052111.
25. Thrippleton M.J., Backes W.H., Sourbron S. et al. Quantifying blood-brain barrier leakage in small vessel disease: Review and consensus recommendations. Alzheimers Dement. 2019;15(6):840– 58. DOI: 10.1016/j.jalz.2019.01.013.