ABSTRACT
Introduction. Coronavirus infection is associated with severe endotheliopathy, thromboinflammation and immunothrombosis leading to excessive release of von Willebrand factor (vWF) multimers from Weibel-Palade bodies, which can affect activity of ADAMTS-13 metalloproteinase (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) and the ADAMTS-13/vWF axis previously shown by us to be altered in non-pregnant women with severe COVID-19. Aim(s): to study a clinical role of hemostasis activation particularly ADAMTS-13/vWF axis in pregnant women after COVID-19. Materials and Methods. A prospective case-control study was conducted with pregnant women (n = 135) divided into 3 groups: group 1 included 45 women with prior COVID-19 during pregnancy, group 2 - 45 women in the acute phase of the infection during pregnancy, group 3 - 45 healthy pregnant women. The level of vWF and ADAMTS-13 was assessed in all patients. Results. The concentration of vWF antigen (vWF:Ag) in the acute period of the disease in pregnant women with COVID-19 was significantly higher compared to the control group (p < 0.001). ADAMTS-13 level in pregnant women after COVID-19 did not differ from that of in control group, while vWF level was significantly higher in 66.7 % (30/45). The ADAMTS-13/vWF ratio was increased and significantly differed both in pregnant patients during the acute period of the disease (p < 0.001) and pregnant women after infection (p = 0.0002) compared with the control group. Conclusion. Our results show that endotheliopathy was prominently manifested in pregnant women with COVID-19 and persisted for several months after disease. The ADAMTS-13/vWF ratio determines the pathway functioning, the risk of microcirculation disorders and clinical complications.Copyright © 2023 Vestnik Sankt-Peterburgskogo Universiteta, Yazyk i Literatura. All rights reserved.
ABSTRACT
Advances in biology have allowed us to substantially deepen our knowledge about hemostasis functioning both in health and disease. ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) and von Willebrand factor (vWF) are components of the hemostasis system, which physiological interaction holds an important place in maintaining homeostasis. ADAMTS-13 is a metalloproteinase mainly acting to release vWF fragments into the blood plasma, as well as regulating its activity by cleaving ultra-large vWF multimers (UL-vWF) into smaller and less active forms. The study of such factors is of great clinical importance, since a decrease in ADAMTS-13 activity and an increase in vWF level can be predictors of microcirculatory disorders that play an important role in developing multiple organ failure. However, very few and fully contradictory studies devoted to the physiological aspects of the ADAMTS-13/vWF axis functioning in the mother-fetus system are available, therefore requiring to be further investigated.Copyright © 2023 Russian Journal of Forensic Medicine. All rights reserved.
ABSTRACT
Introduction. Coronavirus infection is associated with severe endotheliopathy, thromboinflammation and immunothrombosis leading to excessive release of von Willebrand factor (vWF) multimers from Weibel-Palade bodies, which can affect activity of ADAMTS-13 metalloproteinase (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) and the ADAMTS-13/vWF axis previously shown by us to be altered in non-pregnant women with severe COVID-19. Aim: to study a clinical role of hemostasis activation particularly ADAMTS-13/vWF axis in pregnant women after COVID-19. Materials and Мethods. A prospective case-control study was conducted with pregnant women (n = 135) divided into 3 groups: group 1 included 45 women with prior COVID-19 during pregnancy, group 2 - 45 women in the acute phase of the infection during pregnancy, group 3 - 45 healthy pregnant women. The level of vWF and ADAMTS-13 was assessed in all patients. Results. The concentration of vWF antigen (vWF:Ag) in the acute period of the disease in pregnant women with COVID-19 was significantly higher compared to the control group (p < 0.001). ADAMTS-13 level in pregnant women after COVID-19 did not differ from that of in control group, while vWF level was significantly higher in 66.7 % (30/45). The ADAMTS-13/vWF ratio was increased and significantly differed both in pregnant patients during the acute period of the disease (p < 0.001) and pregnant women after infection (p = 0.0002) compared with the control group. Conclusion. Our results show that endotheliopathy was prominently manifested in pregnant women with COVID-19 and persisted for several months after disease. The ADAMTS-13/vWF ratio determines the pathway functioning, the risk of microcirculation disorders and clinical complications. © 2023 Vestnik Sankt-Peterburgskogo Universiteta, Yazyk i Literatura. All rights reserved.
ABSTRACT
Introduction. Coronavirus infection is associated with severe endotheliopathy, thromboinflammation and immunothrombosis leading to excessive release of von Willebrand factor (vWF) multimers from Weibel-Palade bodies, which can affect activity of ADAMTS-13 metalloproteinase (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) and the ADAMTS-13/vWF axis previously shown by us to be altered in non-pregnant women with severe COVID-19. Aim(s): to study a clinical role of hemostasis activation particularly ADAMTS-13/vWF axis in pregnant women after COVID-19. Materials and Methods. A prospective case-control study was conducted with pregnant women (n = 135) divided into 3 groups: group 1 included 45 women with prior COVID-19 during pregnancy, group 2 - 45 women in the acute phase of the infection during pregnancy, group 3 - 45 healthy pregnant women. The level of vWF and ADAMTS-13 was assessed in all patients. Results. The concentration of vWF antigen (vWF:Ag) in the acute period of the disease in pregnant women with COVID-19 was significantly higher compared to the control group (p < 0.001). ADAMTS-13 level in pregnant women after COVID-19 did not differ from that of in control group, while vWF level was significantly higher in 66.7 % (30/45). The ADAMTS-13/vWF ratio was increased and significantly differed both in pregnant patients during the acute period of the disease (p < 0.001) and pregnant women after infection (p = 0.0002) compared with the control group. Conclusion. Our results show that endotheliopathy was prominently manifested in pregnant women with COVID-19 and persisted for several months after disease. The ADAMTS-13/vWF ratio determines the pathway functioning, the risk of microcirculation disorders and clinical complications.Copyright © 2023 Vestnik Sankt-Peterburgskogo Universiteta, Yazyk i Literatura. All rights reserved.
ABSTRACT
The COVID-19 pandemic has become the greatest challenge to humanity of this century and has raised many new questions in various fields, primarily in medicine—in the field of microbiology, pathological anatomy and pathophysiology, immunology, clinical hemostasis, and almost all clinical disciplines, including, of course, obstetrics and perinatology. Systemic effects of SARS-CoV-2 are largely associated with thromboinflammation. The cause of death from COVID-19 is mainly pulmonary insufficiency and/or thrombosis (macro- and microcirculation). Pregnancy, even under normal conditions, is accompanied by changes in hemostasis with a shift toward hypercoagulation and increased inflammation, mainly in the third trimester of pregnancy. This in itself creates conditions for unfavorable outcomes for the mother and fetus. At the same time, pregnancy is a unique condition when a semiallogeneic fetus is reliably protected by the placenta from pathogenic influences under normal conditions. Despite this, the issue of transplacental transmission of the SARS-CoV-2 virus from mother to fetus is still debatable—individual observations allow us to judge this possibility. The issue of vaccination in pregnant women and its effect on the fetus is also extremely relevant. The chapter discusses the pathogenesis of complications in COVID-19, epidemiology, as well as possible ways to predict and prevent SARS-CoV-2-mediated pregnancy complications. © 2023 Elsevier Inc. All rights reserved.
ABSTRACT
The von Willebrand factor (vWF) is a multimeric plasma glycoprotein, which quantification has important prognostic value. The current literature review demonstrates a relationship between the disease severity and vWF level. For example, von Willebrand disease is characterized by a quantitative/qualitative genetic vWF deficiency resulting in potentially developed massive bleeding, which knowledge can prevent development of formidable complications. We should also not forget about an opportunity of developing acquired Willebrand syndrome most often occurring in response to autoimmune diseases. A marked vWF increase during pregnancy may evidence about developing preeclampsia, whereas in newborns exposed to additional risk factors, it can lead to thrombosis. In cancer patients, a substantially elevated vWF level correlates with low survival, especially in those with ovarian cancer, glioblastomas, esophageal and lung cancer. The emergence of a novel coronavirus infection COVID-19 allowed us to take a fresh look at prognostic value of vWF, because numerous studies show that increased blood plasma vWF:Ag is associated with more adverse outcome in patients with COVID-19. Here, we demonstrate an importance of determining vWF level, because early diagnostics and treatment can improve the outcomes of all such patients. Copyright © 2022 Obstetrics, Gynecology and Reproduction. All rights reserved.
ABSTRACT
Background. The severe acute respiratory syndrome of the SARS-CoV-2 virus-mediated coronavirus disease 2019 (COVID-19) highlighted the central role of immunothrombosis. Severe endothelial damage with the release of unusually large multimers of von Willebrand factor (vWF) and subsequent consumption of ADAMTS-13 is described during severe COVID-19. The activation of innate immune cells among which neutrophils contribute to the formation of extracellular neutrophil traps (NETs) and to the release of myeloperoxidase (MPO) potentially contributing to the spread of inflammation and microvascular thrombosis. Objective - to evaluate the ability of vWF, ADAMTS-13 and MPO to predict in-hospital mortality in severe COVID-19 patients needing mechanical ventilation. Methods. We performed a one-center observational study of 79 severe COVID-19 patients entering intensive care unit for mechanical ventilation, examining vWF, ADAMTS-13 and MPO among other potential predictors for in-hospital death. Results. After multivariate analysis, vWF antigen (vWF:Ag) and MPO antigen (MPO:Ag) were finally the single two parameters which increasing values were independently associated with non-survival;vWF:Ag (U/dL): adjusted OR 3.360, 95% CI 1.562-7.228, p = 0.0019;MPO:Ag (ng/ml): adjusted OR 1.062, 95% CI 1.024-1.101, p = 0.0011. From these results a simplified mortality score was derived and patients categorized as having a score value higher or lower that the median value of the score: a high score value was associated with a lower cumulative survival rate (p < 0.0001), 50% of the cases being dead at day 13 post-hospital admission. Conclusions. In severe COVID-19 necessitating mechanical ventilation, increasing values of MPO activity and of vWF antigen tested at admission are associated with poor survival. Copyright © 2022 Izdatel'stvo Meditsina. All rights reserved.
ABSTRACT
Introduction. Currently, endothelial dysfunction caused by inflammation and immunothrombosisis considered as one of the crucial mechanisms in developing the SARS-CoV-2 virus-mediated coronavirus disease 2019 (COVID-19). A mass endothelial damage followed by release of untypical large quantity of von Willebrand factor (vWF) multimers and subsequent consumption of metalloproteinase ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) is described during severe COVID-19. The activation of innate immune cells including neutrophils results in formation of neutrophil extracellular traps (NETs) and myeloperoxidase (MPO) release that, in turn, contributes to spread of inflammation and microvascular thrombosis. Aim: to evaluate a pathogenetic role and predictive significance for serum markers of inflammation, endothelial dysfunction and hemostatis activation such as vWF, ADAMTS-13 and MPO for in-hospital mortality in severe COVID-19 patients requiring mechanical lung ventilation. Materials and Methods. There was performed a single-center observational study with 129 severe COVID-19 patients on mechanical lung ventilation at the intensive care unit, by assessing serum in all subjects vWF, ADAMTS-13 as well as in 79 patients MPO level along with other potential predictors for in-hospital mortality. Results. A multivariate analysis revealed that increased serum level for vWF antigen (vWF:Ag) and MPO antigen (MPO:Ag) were significantly and independently related to high mortality probability: vWF:Ag (IU/ml) - adjusted odds ratio (OR) = 3.360;95 % confidence interval (95 % Cl) = 1.562-7,228 (р = 0,0019);MPO:Ag (ng/ml) - adjusted OR = 1.062;95 % = 1.024-1.101 (p = 0.0011). Such data allowed to obtained a simplified mortality score for categorizing patients as those having a higher or lower score compared with the median score level: a high score was associated with lower cumulative survival rate (p < 0.0001), with 50 % of the cases linked to lethal outcome on day 13 post-hospital admission. Conclusion. Severe COVID-19 patients requiring mechanical lung ventilation were found to have elevated level of serum MPO activity and vWF correlating with poor survival.
ABSTRACT
The main role of platelets is traditionally assigned to participation in hemostasis reactions. In recent years, the data have appeared on the non-hemostatic platelet-related role and their active participation in inflammatory reactions. These platelet functions are predetermined by their ability to activate and secrete various immunomodulatory cytokines and chemokines. In addition, activated platelets can directly interact with viral receptors. Recently, there has been growing the knowledge regarding platelet-related regulation of diverse cell types. The result of this interaction is, among others, the formation of platelet-leukocyte aggregates, the focusing of neutrophils at the sites of injury, and generation of a scaffold for developing extracellular traps. Thus, platelets are not only participants in coagulation processes, but also important players in the inflammatory process. This lecture details the issues of platelets controlling and modulating host response to viral infection, as well as potential targets for therapeutic intervention.
ABSTRACT
These days, anticoagulants are in great demand. They are used as a prophylaxis for thromboembolic complications in various diseases and conditions in general therapeutic practice, cardiology, neurology, as well as obstetrics to manage high-risk pregnancies. The relevance of anticoagulants competent use has come to the fore in connection with the emergence of a new disease – COVID-19 and its serious complications such as developing thrombotic storm, in which the timely applied anticoagulant therapy is the key to the success of therapy. The risk of bleeding should be considered when using any anticoagulant. Age, impaired renal function and concomitant use of antiplatelet agents are common risk factors for bleeding. Moreover, only vitamin K antagonists and heparin have specific antidotes – vitamin K and protamine, respectively. Inhibitors of other anticoagulants are universal presented as inactivated or activated prothrombin complex concentrate and recombinant factor VIIa. Hemodialysis effectively reduces dabigatran concentration, activated charcoal is effective in the case of recent oral administration of lipophilic drugs. Research on new antidotes of currently available anticoagulants is under way, similar to testing of new types of anticoagulants that are sufficiently effective in preventing and treating thromboembolic complications with minimal risk of hemorrhagic. The main contraindication to anticoagulants use is the doctor's ignorance of the mechanisms of drug action and opportunities for suppressing its effect.
ABSTRACT
A novel coronavirus (SARS-CoV-2) causing coronavirus disease 2019 (COVID-19) is largely associated with various coagulopathies, which can lead to either bleeding and thrombocytopenia or hypercoagulation and thrombosis. Thrombohemorrhagic complications also could accompany the development of cancer process. In addition, circulating inflammatory biomarkers such as fibrin, D-dimer, P-selectin and von Willebrand factor (vWF) typical to both coronavirus infection and malignancy process are of special interest. In this review, we discuss potential interplay between COVID-19 and cancer related to endothelial dysfunction, platelets, and systemic inflammatory response syndrome. Most importantly, patients should be treated in early stage of the disease process when elevated levels of fibrinogen, D-dimer, vWF, and P-selectin are observed. The level of these markers will rise rapidly upon disease progression, followed by a cytokine storm, would evidence about a poor prognosis. © 2021 IRBIS LLC. All Rights Reserved.
ABSTRACT
As shown by numerous studies conducted during the pandemic, the severe course of COVID-19 is accompanied by multiple organ failure. Cytokine storm, hypercoagulation, complement hyperactivation and other arms comprise the overall picture of the pathogenesis of the severe disease course. The frequent diagnosis of multiple microvascular thrombosis in lung, heart, and kidneys, as well as the presence of platelet-fibrin thrombi there and signs of terminal organ damage, suggest a possible involvement of thrombotic microangiopathy (TMA) in the development of multiple organ failure. In this regard, it is especially important to timely diagnose TMA and start pathogenetic therapy. These measures can significantly reduce mortality due to the novel disease. Heparins and direct oral anticoagulants are the mainstay for prevention and treatment of venous thromboembolism in patients with COVID-19, but their effectiveness in the presence of TMA is questionable. It has been proven that anticoagulants use in critically ill patients with COVID-19 for prevention of large vessel thrombosis is effective, but their role in the prevention of microthrombosis is not clear. Here we review the currently available information on thrombotic microangiopathy, as well as a review of literature data describing TMA-like conditions in COVID-19, discuss potential pathophysiology of the condition development and proposed therapeutic approaches. © Obstetrics, Gynecology and Reproduction 2021.
ABSTRACT
After the vaccination campaign initiation in Europe and the UK, reports of rare cases of atypical thrombosis, including sinus vein thrombosis and splanchnic venous thrombosis, began to appear in association with the use of AstraZeneca (ChAdOx1) and J&J/Janssen adenovirus vector vaccines. The syndrome called VITT (vaccine-induced immune thrombotic thrombocytopenia) is manifested as thrombosis simultaneously with decreased platelet count, significantly increased D-dimer levels and detected anti-factor 4 platelet (PF4) antibodies. We present a detailed review on the epidemiology, pathogenesis, clinical picture, diagnostics and treatment of VITT, which by its nature is an immune complication similar to the processes occurring in heparin-induced thrombocytopenia (HIT). All international and national organizations and regulatory authorities, including experts in the field of thrombosis and hemostasis and the VITT expert council recommend continuing the prompt mass vaccination against COVID-19 as the only method able to reduce the incidence of severe cases, stop the spread of COVID-19 infection and emergence of new dangerous mutations in the viral genome. Failure to vaccinate poses an incomparably greater risk of fatal thrombotic and inflammatory complications associated with infections, compared with the risks of extremely rare adverse events that can occur after vaccination. It should be noted that information on VITT, described as a sporadic phenomenon of abnormal immune response to some variants of vaccines against COVID-19, cannot be translated to other vaccines (including those registered in the Russian Federation) and, moreover, cannot be a reason to refuse their administration. © 2021 Obstetrics, Gynecology and Reproduction. All rights reserved.
ABSTRACT
The rate of thrombosis and disseminated intravascular coagulation (DIC) has been increasing in COVID-19 patients. Key features related to such condition include minimal or no risk of bleeding, moderate thrombocytopenia, high plasma fibrinogen as well as increased complement components level in the areas of thrombotic microangiopathy. The clinical picture is not typical for classic DIC. This review systematizes the pathogenetic mechanisms of hypercoagulation in sepsis and its extreme forms in patients with COVID-19. The latter consist of the thrombosis-related immune mechanisms, the complement activation, the macrophage activation syndrome, the formation of antiphospholipid antibodies, the hyperferritinemia, and the dysregulation of the renin-angiotensin system. Taking into consideration the pathogenetic mechanisms, the biomarkers had been identified related to the prognosis of the disease development. Patients with pre-existing cardiovascular disease and other risk factors, including obesity, diabetes, hypertension, and aging pose the peak risk of dying from COVID-19. We also summarize new data on platelet and endothelial dysfunction, immunothrombosis, and, as a result, thrombotic storm as essential components of COVID-19 severe features. © 2021 Obstetrics, Gynecology and Reproduction. All rights reserved.
ABSTRACT
Antiphospholipid syndrome (APS) is an autoimmune process that increases the risk of arterial and venous thrombosis. The mechanism of damage to the central nervous system (CNS) can be not only due to thrombosis, but also antiphospholipid antibodies (APA) circulating in the peripheral blood. The latter can damage the cerebral vascular endothelium, alter the resistance of the blood-brain barrier and penetrate into the central nervous system, exerting a damaging effect on astroglia and neurons, as evidenced by the release of neurospecific proteins into the peripheral bloodstream. The role of APS in developing cerebral ischemia, migraine, epilepsy, chorea, transverse myelitis, multiple sclerosis, cognitive impairment and mental disorders, as well as the peripheral nervous system is described. It should also be noted about a role of APS for emerging neurological disorders in COVID-19, enabled apart from thrombogenesis due to APA via 2 potential mechanisms - molecular mimicry and neoepitope formation. Further study of the APS pathogenesis and interdisciplinary interaction are necessary to develop effective methods for patient management.
ABSTRACT
Numerous studies have proven a close relationship between inflammatory diseases and the state of hypercoagulability. In fact, thromboembolic complications represent one of the main causes of disability and mortality in acute and chronic inflammatory diseases, cancer and obstetric complications. Despite this, the processes of hemostasis and immune responses have long been considered separately;currently, work is underway to identify the molecular basis for a relationship between such systems. It has been identified that various pro-inflammatory stimuli are capable of triggering a coagulation cascade, which in turn modulates inflammatory responses. Neutrophil extracellular traps (NETs) are the networks of histones of extracellular DNA generated by neutrophils in response to inflammatory stimuli. The hemostasis is activated against infection in order to minimize the spread of infection and, if possible, inactivate the infectious agent. Another molecular network is based on fibrin. Over the last 10 years, there has been accumulated a whole body of evidence that NETs and fibrin are able to form a united network within a thrombus, stabilizing each other. Similarities and molecular cross-reactions are also present in the processes of fibrinolysis and lysis of NETs. Both NETs and von Willebrand factor (vWF) are involved in thrombosis as well as inflammation. During the development of these conditions, a series of events occurs in the microvascular network, including endothelial activation, NETs formation, vWF secretion, adhesion, aggregation, and activation of blood cells. The activity of vWF multimers is regulated by the specific metalloproteinase ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). Studies have shown that interactions between NETs and vWF can lead to arterial and venous thrombosis and inflammation. In addition, the contents released from activated neutrophils or NETs result in decreased ADAMTS-13 activity, which can occur in both thrombotic microangiopathies and acute ischemic stroke. Recently, NETs have been envisioned as a cause of endothelial damage and immunothrombosis in COVID-19. In addition, vWF and ADAMTS-13 levels predict COVID-19 mortality. In this review, we summarize the biological characteristics and interactions of NETs, vWF, and ADAMTS-13, the effect of NETs on hemostasis regulation and discuss their role in thrombotic conditions, sepsis, COVID-19, and obstetric complications.
ABSTRACT
Our knowledge regarding chemical structure and properties of heparin and its derivatives, including biological properties in blood plasma, on the cell surface and while interacting with receptors, has been progressively growing. New insights are followed by the expansion of therapeutic opportunities and indications for the use of heparins. There are prerequisites for the creation of new generation drugs with modified properties that reduce a bleeding risk while applied for a non-anticoagulant goal. The non-anticoagulant heparin properties allow to consider it as a candidate for pathogenetic treatment of patients with COVID-19. This review focuses on the anticoagulant and non-anticoagulant heparin properties as well as the underlying molecular mechanisms.
ABSTRACT
The pandemic of a novel coronavirus infection COVID-19 has become a real challenge to the mankind and medical community and has raised a number of medical and social issues. Based on the currently available information on COVID-19 clinical cases, it follows that COVID-19 patients in critical condition exhibit a clinical picture of disseminated intravascular coagulation (DIC), septic shock with developing multiple organ failure, which justifies use of anticoagulant therapy in COVID-19 patients. In addition to isolating virus RNA from biological material and polymerase chain reaction diagnostics, use of simple and easily accessible laboratory blood markers is necessary for management of COVID-19 patients. If the activation of coagulation processes is sufficient enough, consumption of platelets and blood clotting factors can be diagnosed by laboratory methods as prolongation of routine blood clotting tests and increasing thrombocytopenia. Hyperfibrinogenemia, increased D-dimer level, prolonged prothrombin time, thrombocytopenia, lymphopenia, leukocytopenia, increased concentration of interleukin-6 and ferritin are observed in most COVID-19 patients. The degree of increase in these changes correlates with severity of the inflammatory process and serves as a prognostically unfavorable sign. Here we discuss value of laboratory monitoring playing an essential role in such pathological crisis that contributes to patient screening, diagnosis as well as further monitoring, treatment and rehabilitation.
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Dear editors of Obstetrics, Gynecology and Reproduction Journal! Due to the particular urgency of the problem of managing patients with a new coronavirus infection (COVID-19), we are sending a letter outlining our position on this issue.