ABSTRACT
Aim. We aimed to study the histological and thrombotic changes in lung vessels in patients who died with COVID-19, to access the correlation between anticoagulation therapy (ACT) and thrombotic events (TE), treatment results, clinical and laboratory patients' characteristics. Material and Methods. We retrospectively analyzed treatment results of patients hospitalized with COVID-19 and lung vessel samples of the deceased patients. Dynamic changes and highest levels of D-dimer and fibrinogen were studied in its correlation with the disease severity according to SOFA score, computer tomographic (CT) results, lung, renal and hepatic dysfunction. The association between different doses of ACT and treatment results, laboratory indicators and thrombotic events was accessed. The histological lung vessels examination was performed using Martius Scarlet Blue (MSB)staining. Results. 313 patients were included in the study (61 patients died). The median age of hospitalized patients was 60 years (IQR 51-66 years). The frequency of the intravitallyconfirmed TE was 4,8%. The strong statistical association was revealed between D-dimer level and 3-4 points SOFA score, patients' mortality, oxygen support requirement, CT3-CT4 pneumonia, glomerular filtration rate and TE. There was no mortality in patients with D-dimer normal references, but in cases with three times elevation reached 13%, 48,5% - in cases with 3-6 times elevation and 64,6% - in cases with more than 6 times elevation. The strong statistical association was registered between fibrinogen and SOFA score, CT 3-4 pneumonia, patients' mortality. D-dimer and fibrinogen levels demonstrated weak correlation. There was no statistical correlation between prophylactic, intermediate and therapeutic ACT and D-dimer and fibrinogen levels, CT results, patients' mortality. MSBstaining was used in 36 deceased patients tissue samples. 1394 lung vessels were analyzed. Lung vessels thrombi persisted in samples of all 36 patients (100%). Vessels with the diameter 3,5-30 mm were thrombosed in 7%, with the diameter 0,034-0,84 mm - in 48%, with the diameter 0,85-3,4 mm - in 45%. The frequency of thrombi persisted 0-6 hours, 6-12 hours, 12-18hours, 18-24 hours and more than 24 hours was 12%, 14%, 62%, 5% and 7% respectively. Conclusion. Thrombi of different ages from fresh to organized were observed in one third of lung vessels in all deceased patients. Lung vessels thrombosis plays an important role in pathogenesis and thanatogenesis of COVID-19. The D-dimer level correlates with lung, renal dysfunction, patients' mortality and doesn't show any correlation with ACT and can be accepted as a criterion of lung vessel thrombotic progression.
ABSTRACT
The review presents the modern concept of the pathogenesis of diffuse alveolar damage, including acute respiratory distress sYndrome in coronavirus infection. It has been established that the so-called "cytokine storm”, which consists in the increased release of substances that are biologically active against the vascular wall and effector cells, leading to the progressive damage to endotheliocytes and alveolocytes, the development of alveolar and interstitial pulmonary edema with fatal respiratory failure and coagulopathy. An important factor in interstitial aggression is the appearance of autoreactive clones of plasma cells, dissemination of virusinfected leucocytes throughout the body with the involvement of various organs and systems, which exacerbates multiple organ failure. A poor prognosis for patients, the likelihood of developing pulmonary fibrosis after infection, according to several researchers, can be corrected by cell therapy. Allogeneic multipotent mesenchymal stromal cells (mesenchymal stem cells) are considered as first-line therapeutic cells. The accumulated experience of preclinical experiments made it possible to urgently proceed to conduct clinical trials of the safety of their use in patients with ARDS and to search for optimal indications to obtain maximum benefits for patients after transplantation. The combined efforts of many research groups can lead to reliable information on the cell therapy benefit and the need to include it in the standards of treatment of patients with this extremely severe pathology. В обзоре представлена современная концепция патогенеза диффузного альвеолярного повреждения, в том числе и острого респираторного дистресс синдрома (ОРДС), при коронавирусной инфекции. Установлено, что важными звеньями развертывания клинической картины является т. н. «цитокиновый шторм», который заключается в повышенном выделении биологически активных в отношении сосудистой стенки и клеток-эффекторов субстанций, приводящих к прогрессированию повреждения альвеолоцитов и эндотелиоцитов, развитию альвеолярного и интерстициального отека с губительной дыхательной недостаточностью и коагулопатиией. Немаловажным фактором внутритканевой агрессии становятся появление аутореактивных клонов плазматических клеток, диссеминация зараженных вирусом лейкоцитов по всему организму с вовлечением различных органов и систем, что усугубляет полиорганную недостаточность. Плохой прогноз для пациентов и вероятность развития фиброза легких после перенесенной инфекции по мнению ряда исследователей могут быть скоррегированы клеточной терапией. В качестве терапевтических клеток первой линии рассматриваются аллогенные мультипотентные мезенхиамальные стромальные клетки (мезенхимальные стволовые клетки). Накопленный опыт доклинических экспериментов позволил экстренно перейти к проведению клинических исследований безопасности их применения при ОРДС и поиска оптимальных показаний для получения максимальных выгод для пациентов после трансплантации. Совокупные усилия многих исследовательских групп могут привести к получению достоверной информации о полезности клеточной терапии и необходимости включения ее в стандарты лечения больных с этой чрезвычайно тяжелой патологией.