Coagulopathy in the Acute Phase of Traumatic Brain Injury

Острая черепно-мозговая травма (ЧМТ) может сопровождаться развитием коагулопатии. При этом в условиях риска развития или прогрессирования геморрагических проявлений в веществе головного мозга, нормальное функционирование гемостаза имеет критическое значение. Цель исследования: определение частоты развития коагулопатии в остром периоде изолированной ЧМТ и выявление взаимосвязи вариантов нарушения гемостаза с тяжестью ЧМТ. Материалы и методы. Проанализировали 323 истории болезни пациентов с ЧМТ, госпитализированных в ОРИТ Центра нейрохирургии с 2008 г. по 2016 г., из них в исследование включили 118 пациентов. Критерии включения: острая изолированная ЧМТ, госпитализация в первые 72 часа после травмы, молодой и средний возраст пациентов. При поступлении в стационар все пациенты оценены по шкале комы Глазго (ШКГ) и разделены на две группы: 1 — тяжелая ЧМТ, 2 — ЧМТ умеренной и легкой степени тяжести. Всем пациентам проведены исследования гемостаза (АЧТВ, ПТИ, концентрация фибриногена, число тромбоцитов). Результаты. У 63,6% пациентов с острой ЧМТ выявили признаки нарушения гемостаза, большинство из которых (55,1%) носили гипокоагуляционный характер и наблюдались в группе тяжелой ЧМТ (62,5%). Наиболее частыми признаками коагулопатии являлись снижение уровня ПТИ менее 70% и тромбоцитопения — менее 150 109/л. Между развитием тромбоцитопении и неблагоприятным исходом (1–3 балла по Шкале Исходов Глазго (ШИГ) выявили корреляционную взаимосвязь слабой силы (r=0,276; p=0,002). Заключение. На этапе поступления в стационар коагулопатию диагностировали у 63,6% пациентов в остром периоде ЧМТ, при этом преобладали гипокоагуляционные изменения. Коагулопатию достоверно чаще выявляли у пациентов в остром периоде тяжелой ЧМТ (ШКГ 8 баллов). Механизмы ЧМТ-ассоциированной коагулопатии до сих пор не до конца изучены; необходимо дальнейшее исследование вклада тромбоцитарного, плазменного и фибринолитического компонентов в формирование коагулопатии, что, вероятно, требует использования, в том числе, интегральных методов диагностики гемостаза.


Introduction
Acute traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality in young and middle-aged people [1]. In some cases, TBI can be accompanied by abnormal coagulation [2][3][4], resulting in an increased risk of hemorrhagic transformation of contusion foci and an increase in the volume of intracranial hematoma. At the same time, the development of coagulopathy may lead to the formation of microthrombi, causing ischemic brain damage [5]. In addition, coagulopathy related to TBI associates with high rate of blood transfusions, prolonged treatment in the intensive care unit, increased risk of multiple organ failure, dramatic increase in the risk of death and significantly higher level of disability, and thus is one of the most important independent predictors of adverse outcome [6][7][8][9]. The study by Stein et al. [10] demonstrated that more than 80% of patients with hypocoagulability state found on hospital admission develop secondary brain damage, which in the absence of coagulopathy was seen only in 31% of cases. Allard et al. [8] showed a fourfold increase in the risk of death in patients with coagulopathy and signs of hemorrhagic foci progression revealed by CT data [4].
Currently, there is no precise definition of TBIassociated coagulopathy, therefore, its incidence varies widely according to different studies and can reach 90% [11,12]. The mechanisms of TBI-associated coagulopathy, as well as its typical laboratory signs, remain to be verified, and their understanding will allow to identify patients at risk of developing hemorrhagic or ischemic foci and improve the quality of their treatment.
The aim of this study was to determine the incidence of coagulopathy in the acute phase of isolated TBI, its most characteristic signs, as well as to check the correlation between types of coagulation disorders and TBI severity.

Materials and Methods
We analyzed 323 case records of patients with TBI hospitalized in the intensive care unit of the Neurosurgery Center from 2008 to 2016, of which 118 patients who met the criteria for inclusion were included in the retrospective study.
Epidemiological data for both groups are presented in table 1. The groups did not differ significantly by sex and age.
The statistical analysis of the results was performed using the «STATISTICA 6.0» software. During statistical analysis of data, the distribution normality was tested by Kolmogorov-Smirnov criterion. The data were presented as M±SD (M -mean, SD -standard deviation) in normal distribution and as median (25 and 75 percentiles) in non-normal distribution. The Mann-Whitney criterion was used for comparison of two groups, the differences were considered statistically significant at p<0.05. To determine the relationship between GOS outcomes and hemostasis, a correlation analysis was performed using Pearson and Spearman methods ( 0.2 was considered very weak correlation; 0.2-0.5 -weak correlation; 0.5-0.7 -moderate correlation; 0.7-0.9 -strong correlation; >0.9 -very strong correlation).

Results and Discussion
Epidemiology and type of hemostatic disorders in TBI. Coagulopathy was found in 63,6% of patients with acute TBI on admission to ICU (table 2). The majority of the patients (55.1%) had hypocoagulability states, while hypercoagulation was observed only in 8.5% of patients.
Hypocoagulability in TBI can be attributed to the excessive activation of hemostasis by the tissue factor present in large quantities in brain tissue, which leads to further depletion of blood-clotting factors [17]. However, the TBI-associated coagulopathy is a complex process that affects all stages w w w . r e a n i m a
Laboratory signs of TBI-associated coagulopathy. In most studies, the criterion for TBI-associated coagulopathy was hypocoagulability state manifested as abnormality of one or more laboratory hemostasis parameters (prolonged APTT, reduced PTI or platelet count) [21]. Our results (table  3) show that the most common signs of coagulopathy in the severe TBI group were reduced PTI (less than 70%) and platelet count below 150 10 9 /l ( fig.). Similar data were obtained in the Wafaisade et al. study, which included 3114 patients with isolated TBI [22]. The authors also point out that the decrease in platelet count and PTI is the most typical sign of hemostasis disorders in TBI.
Hypercoagulability was found in 8.5% of TBI patients and manifested as increased fibrinogen levels, which may have been due to a severe systemic inflammatory response associated with TBI, since inflammatory cytokines (such as interleukin-6 and interleukin-1), which become elevated after TBI, participate in the fibrinogen production [8]. However, this claim requires further research.
Correlation between coagulopathy and outcomes according to the GOS. Pearson's correlation coefficient was used to test the correlation between platelet count and GOS outcomes. A weak correlation (R=0.276; P=0.002) was found (table 3).
Our study did not show any correlation between outcomes on GCS and PTI values, which can be attributed to relatively small number of patients studied.
Unfortunately, standard tests of the hemostasis system such as APTT, PTI, fibrinogen concentration do not always represent the real state of the hemostasis as they are performed in a plasma sample without consideration of the interaction of coagulation factors with platelets, blood cells and vascular endothelium. Complex and multifactorial coagulation disorders, such as TBI-associated coagulopathy, probably require a more rigorous investigation using integral tests such as thromboelastography and thromboelastometry. The data from these tests will allow to discover more accurate predictors of adverse outcomes.