Anticoagulants: dose control methods and inhibitors

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.

COVID-19 and thrombotic microangiopathy

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.

Thrombotic storm, hemostasis disorders and thromboinflammation in COVID-19

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.

Macrophage activation syndrome in COVID-19

The novel coronavirus epidemic is characterized by high rates of morbidity and relatively high mortality. Laboratory test results in patients include leukopenia, an increase in liver function tests and ferritin levels reaching hundreds, and sometimes thousands of units. These data remind us about the macrophage activation syndrome (MAC). Secondary hemophagocytic lymphohistiocytosis syndrome, MAC, which pathogenesis is based on a defect in the mechanisms of T-cell cytotoxicity and decreased level of natural killer cells associated with the defect in the perforin-encoding gene as well as hyperproduction of a number of cytokines - interleukin (IL)-1β, tumor necrosis factor-α, etc. by T-lymphocytes and histiocytes, indirectly leading to the activation of macrophages and production of proinflammatory cytokines, in particular IL-6 hyperproduction. MAC is one of "hyperferritinemic syndromes". These disorders have similar clinical and laboratory manifestations, and they also respond to similar treatments, suggesting that hyperferritinemia may be involved in the overall pathogenesis and is characterized by elevated ferritin level and cytokine storm. Despite the fact that data on the immune and inflammatory status in patients with COVID-19 have only started to appear, it is already clear that hyperinflammation and coagulopathy affect the disease severity and increase the risk of death in patients infected with SARS-CoV-2. Hence, understanding the pathogenesis of the novel coronavirus infection can help in its early diagnostics and treatment.

Neutrophil extracellular traps: A role in inflammation and dysregulated hemostasis as well as in patients with COVID-19 and severe obstetric pathology

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.

The effect of various types of anticoagulant therapy on the reduction of mortality in COVID-19

Coronavirus disease 2019 (COVID-19) is a viral infection that, in severe course, leads to the development of a cytokine storm, systemic inflammatory response and coagulopathy. Unlike other sepsis-associated disseminated intravascular coagulopathy, COVID-19 induced coagulopathy is realized mainly in thrombosis. Researchers around the world are currently developing adequate diagnostic, monitoring and anticoagulant therapy approaches to safely and effectively manage patients with severe COVID-19. The need to develop laboratory monitoring is due to the fact that 20% of patients have changes in hemostasis indicators, while in patients with a severe form of the disease, they are present in 100% of cases. In case of deaths from COVID-19, there is an increase in the concentration of D-dimer and fibrinogen degradation products. Thus, the severity of hemostasis disorders has an important prognostic value. Anticoagulant therapy is included in the list of all recommendations as an effective means of reducing mortality from COVID-19. The questions of the recommended groups and doses of anticoagulant drugs are still open. The approach to the choice of an anticoagulant should be based not only on risk factors, characteristics of the course of the disease, anamnesis, but also on the wishes of the patient during long-term therapy at the post-hospital stage.

Anticoagulant, anti-inflammatory, antiviral and antitumor properties of heparins

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.

Septic shock

Recently, it has been increasingly apparent that sepsis and septic shock become a pressing issue. Over the last decade, incidence rate of sepsis in obstetrics and gynecology has been increased by more than 2-fold. Here we review clinical forms of septic conditions, risk factors, pathogenesis of sepsis and septic shock, as well as major pathogens resulting in septic conditions. Special attention is paid to neonatal sepsis. The relationship between septic shock and viral infections is considered in the context of the novel coronavirus infection (COVID-19) pandemic caused by SARS-CoV-2. Impaired hemostasis is discussed in patients with septic shock, including those with disseminated intravascular coagulation (DIC). An importance of assessing ADAMTS-13 level to refine disease prognosis is discussed.