Optimization Of Methods For The Prevention Of Pulmonary Embolism

This review examines changes in the hemostatic system parameters in patients with COVID-19 and analyzes their practical significance. The article discusses modern approaches to the prevention and treatment of thrombotic/thromboembolic complications in COVID-19.


INTRODUCTION
Coronavirus infection , an acute infectious disease caused by the SARS-CoV-2 virus, is characterized by activation of the hemostasis system, which in the most severe cases can lead to the development of consumption coagulopathy. At present, it remains unclear whether COVID-19 is the direct cause of these disorders or they arise as the infectious process progresses [1]. In COVID-19, the incidence of asymptomatic and clinically pronounced thrombotic/thromboembolic complications (TEC) remains unclear, which is largely due to the difficulties of their diagnosis (problems of instrumental examination of patients lying on their stomach, the desire to limit the involvement of additional equipment and personnel). At the same time, according to some reports, the frequency of venous and  [2]. At the same time, objectively confirmed venous feasibility studies prevailed (27%, in the majority PE), while the incidence of arterial thrombosis was only 3.7%. According to a single-center retrospective study in China in patients with severe pneumonia with COVID-19, who was in the intensive care unit (n = 81), the incidence of venous thrombosis of the lower extremities was 25% [3]. When analyzing 107 patients with pneumonia with CODID-19, who were consecutively admitted to the intensive care unit in Lille (France), the detection rate of PE was 20.6% and was much higher than in patients of similar severity for the same period of 2019 (6.1% ) [4]. During autopsies, microthrombi in small vessels of the lungs in the absence of a feasibility study has also been described [5,6]. The role and causes of these disorders (specific effects of viral infection, inflammation, progressive coagulopathy) are being actively discussed.
The state of the hemostasis system in patients with COVID-19 Among the changes in indicators characterizing the state of the hemostasis system and associated with the severity of the disease and its prognosis, COVID-19 indicates an increase in the level of D-dimer in the blood, an increase in prothrombin time, as well as thrombin and activated partial thromboplastin time (APTT). Initially, there may be an increase in the concentration of fibrinogen; then, as the disorder progresses, the levels of fibrinogen and antithrombin in the blood decrease. Thrombocytopenia is also associated with the severity and prognosis of the disease, but it is rarely severe [7,8].
One of the factors contributing to the activation of the blood coagulation system is an increase in the concentration of proinflammatory cytokines, which fits into the concept of the relationship between inflammation and thrombosis (the so-called "immunothrombosis"). Published data on 3 critically ill COVID-19 patients with multiple cerebral infarctions, who had high blood levels of antiphospholipid antibodies (anticardiolipin IgA in combination with anti-β2-glycoprotein 1 immunoglobulins A and G), which is believed to be most likely a consequence of severe inflammation, and can occur in any severe infection [9]. There is a hypothesis about the leading role of immunothrombosis with damage to lung microvessels in the progression of respiratory failure in COVID-19 [10].
Changes in indicators characterizing the state of the hemostasis system and their prognostic value were assessed in a retrospective study on 183 patients with confirmed COVID-19 who were consistently admitted to Tongji University Hospital in Wuhan (China). Of these, 11.5% died [11]. During hospitalization, the later deceased had higher D-dimer values than the survivors (median 2.12 vs 0.61 μg / ml; p <0.001), fibrin degradation products (median 7.6 vs 4.0 μg / ml; p <0.001) and prothrombin time (median 15.5 vs 13.6 sec; p <0.001). At the same time, in patients with an unfavorable outcome, these indicators continued to increase in the future, while in survivors they changed little, rarely and slightly exceeding the upper limit of the norm (0.5 μg / ml for D-dimer and 14.5 sec for prothrombin time).

MATERIALS AND METHODS OF RESEARCH
In a retrospective study of electronic medical records of 499 patients with severe manifestations of COVID-19 who were subsequently admitted to the same Tongji University Hospital in Wuhan, an increased level of D-dimer along with age, an increase in prothrombin time and a lower concentration of platelets in blood was an independent predictor of death in the next 28 days. [12].
A similar result was obtained in a retrospective study of patients with COVID-19 admitted to a respiratory hospital in Wuhan (n = 191), 54 of whom died in hospital [13]. D-dimer levels at hospital admission exceeding 1 μg / ml were an independent predictor of death (relative risk (RR) 18.42 at 95% confidence intervals (CI): 2.64 -128.55) along with age and the sum of points on the SOFA (Sequential Organ Failure Assessment) scale. At the same time, in deceased patients, it gradually increased, sometimes to a very high level, while in survivors it changed little and rarely exceeded the upper limit of the norm.
According to a retrospective analysis of electronic records from 260 outpatient offices and 4 emergency hospitals in New York, an independent risk factor for the severity of the disease to critical (the need to stay in an intensive care unit, mechanical ventilation, death or transfer to a hospice) in 4103 patients with confirmed COVID-19 along with blood oxygen saturation <88%, ferritin levels> 2500 ng/ml and C-reactive protein> 200 mg / L was a D-dimer level> 2500 ng/ml (RR 6.9 at 95% CI: 3.2-15.2) [14].

RESULTS AND DISCUSSION
In general, it is believed that of the studied indicators characterizing the state of the hemostasis system, D-dimer is the most attractive as a marker of severity and unfavorable prognosis in COVID-19 -its definition is widely available and standardized, and the differences between the groups of living and dead are well expressed [7]. The prothrombin time also has a prognostic value, however, during hospitalization, its changes in patients with a poor prognosis are not as pronounced as in the D-dimer, and, in general, slightly exceed the upper limit of the norm.
Experts of the International Society for Thrombosis and Hemostasis recommend that during hospitalization, determine the level of D-dimer in the blood, prothrombin time, fibrinogen concentration and perform a detailed general blood test, including the level of platelets, followed by regular monitoring of these indicators (daily or more often with a pronounced increase in D-dimer, increased prothrombin time, blood platelet level <100 × 109 / L, fibrinogen level <2.0 g / L), so as not to miss an aggravation of the disease and the development of severe consumption coagulopathy, when intensification of COVID-19 treatment may be required and/or the introduction of blood components [7]. At the same time, it is proposed to consider the level of D-dimer in the blood as expressed as 3-4 times higher than the upper limit of the norm and to classify such patients as candidates for hospitalization even in the absence of other severe manifestations of COVID-19. In addition, it is emphasized that the prothrombin time and prothrombin ratio cannot be replaced by an international normalized ratio, which does not capture the relatively small changes that occur with COVID-19, and also that the clinical interpretation of these indicators should take into account all other possible reasons for their changes (for example, progression of liver disease, use of anticoagulants). At the same time, not all medical organizations insist on such frequent monitoring of hemostatic system parameters -for example, in the algorithms of Massachusetts General Hospital, daily determination of these parameters is recommended only in the intensive care unit or when the level of D-dimer in the blood is> 1000 ng / ml [15]. It is known that an increase in the concentration of D-dimer in the blood indicates the activation of the processes of thrombus formation and fibrinolysis, but does not always indicate the presence of a thrombus. Thus, in a one-center retrospective study in China in 81 patients with severe pneumonia with COVID-19 who were in the intensive care unit, the Ddimer level> 1500 ng / ml had a sensitivity of 85.0%, a specificity of 88.5%, and a predictive the value of a negative result is 94.7% in relation to the detection of venous thrombosis of the lower extremities (for the level of D-dimer> 3000 ng/ml these indicators were 76.9%, 94.2%, and 92.5%, respectively) [3]. Given the undesirability of additional instrumental examinations in patients with COVID-19 without strict indications, most specialists now believe that routine screening for venous feasibility studies in asymptomatic patients with very high D-dimer levels should not be performed (68% of 46 members voted for this) international working group of experts [1]).
To assess the nature of disorders of the hemostasis system in patients with COVID-19, it was proposed to use two scales that are widely used in sepsis [16]. Obviously, the first of them -the scale of coagulopathy caused by sepsischaracterizes the activation of blood coagulation processes and indicates that stage of the process when there is still no pronounced coagulopathy of consumption. There is evidence that this scale can be used to select patients with COVID-19 who benefit most from anticoagulant use. Thus, in a retrospective study of electronic case histories of 499 patients with severe manifestations of COVID-19 who were sequentially admitted to Tongji University Hospital in Wuhan (China), it turned out that patients who received mainly prophylactic doses of heparin (mainly enoxaparin 40-60 mg / days, less often unfractionated heparin (UFH) 10,000-1500 U / day for at least 7 days), 28-day mortality is lower in cases when the sum of points on the sepsis-induced coagulopathy scale was ≥4 or there was a marked increase in the level of Ddimer in the blood (> 6 times the upper limit of normal) [12].
The presence of obvious disseminated intravascular coagulation (DIC) indicates the development of consumption coagulopathy, when the replacement of the missing components of the blood coagulation system may be required.  [17][18][19][20].
In the future, when deciding on the advisability of prevention, it was recommended to use the risk stratification scales, in particular, the validated Padua scale [21,22]. Obviously, COVID-19 patients hospitalized with pneumonia have at least 2 points on this scale, and with an additional restriction of the motor regime, they fall into the category of venous feasibility studies in need of prevention. There are other scales for assessing the risk of venous  [23]. In a subsequent large randomized controlled trial, APEX (Acute Medically III VTE Prevention With Extended Duration Betrixaban Study), it was shown that an increased level of D-dimer can be used to select patients in need of prevention of venous TEO: as it turned out, patients hospitalized with the acute nonsurgical disease (heart failure, respiratory failure, infection, rheumatic disease, or ischemic stroke) and those with elevated Ddimer levels (at least 2 times the upper limit of normal) benefit from prolonged use of anticoagulants to prevent venous TEO [24].
Based on the database of this study, a modified IMPROVE scale -IMPROVED -was proposed, in which the level of D-dimer in the hospital was added (as a risk factor for venous thrombosis) [25]. It is characteristic that according to this scale, patients hospitalized with COVID-19 and having an increased level of D-dimer in the blood immediately fall into the group of increased risk of a venous feasibility study.

CONCLUSION
Thus, based on the totality of accumulated facts, most patients hospitalized with COVID-19 meet the criteria for a high risk of venous feasibility studies and need their prevention. The group of experts of the International Society for Thrombosis and Hemostasis believes that the use of anticoagulants for the prevention of venous feasibility study should be in all patients hospitalized with COVID-19 [7]. In addition, in the most severe cases (sepsis-induced coagulopathy score ≥4 or blood D-dimer level> 6 times the upper limit of normal), heparin can be expected to reduce mortality [12]. At the same time, another international group of experts proposes a more conservative approach, when in patients hospitalized with COVID- 19 15]. In addition, as the severity of COVID-19 increases, APTT rises. Accordingly, this indicator is difficult to use for the selection of the dose of UFH and the only way out is to regularly assess anti-Xa activity.
In patients with heparin-induced immune thrombocytopenia, a history of subcutaneous fondaparinux sodium or intravenous infusion of bivalirudin may be considered. At the same time, it is known that, unlike heparin preparations, fondaparinux sodium does not reduce the level of platelets in the blood. At the same time, it is most likely devoid of the potentially beneficial pleiotropic, primarily antiinflammatory, effects inherent in heparin [26].
LMWH and fondaparinux sodium is contraindicated in severe renal failure -the threshold values for creatinine clearance / glomerular filtration rate differ for different drugs. In addition, they act for a long time and it is impossible to quickly eliminate their effect (the antidote of LMWH, protamine sulfate, only partially eliminates its effect, fondaparinux sodium has no antidote). Therefore, these drugs are not recommended for use in patients with rapidly changing renal function [15]. With severe renal failure, UFH may be used. In addition, a more controlled intravenous infusion of UFH, which has a shorter duration and has a complete antidote, appears to be preferable in cases where invasive interventions are required.
The proposed doses of heparin preparations are presented in Table 4. At present, it is not clear whether prophylactic doses of parenteral anticoagulants should be reduced in patients with renal insufficiency, low body weight, and increased in severe obesity [26]. authors point out the widespread prevalence of obesity among hospital admissions [4]. It is possible that in difficult cases when choosing a prophylactic dose of heparin for obesity, it is worth considering the presence of other risk factors for venous feasibility studies (including an increased level of D-dimer), as well as monitoring anti-Xa activity in the blood.
Among other remaining uncertainties is whether the use of a higher than a prophylactic dose of heparin should be considered when the level of D-dimer in the blood is very high (for example, 6-8 times the upper limit of the norm), as well as in patients who need more intense respiratory support / in the development of acute respiratory distress syndrome [26].
When DIC occurs without overt bleeding, it is usually recommended to use a prophylactic dose of UFH or LMWH and emphasize that there is insufficient evidence to support the routine use of higher doses. In patients who have received therapeutic doses of an anticoagulant at the time of the development of DIC, it is proposed to reduce the intensity of anticoagulation, unless the danger of thrombosis is too great. In general, the decision to change the dose of heparin or to cancel it in a given clinical situation should be strictly individual, taking into account the indications for the use of anticoagulants on the one hand and the risk of bleeding on the other. In case of coagulopathy of consumption and absence of bleeding, it is recommended to maintain the level of platelets> 20 × 109 / L, fibrinogen> 1.5-2.0 g / L, and in case of bleeding -the level of platelets> 50 × 109 / L, fibrinogen> 1.5-2, 0 g / l, prothrombin ratio <1.5 due to the introduction of missing blood components [1,7].
There is a hypothesis that in patients with severe respiratory distress syndrome, intravenous administration of low doses of fibrinolytic may be useful to combat microcirculation disorders due to the formation of fibrin-rich microthrombi in the lung vessels [29]. The experience of long-term intravenous administration of low doses of tissue plasminogen activator (25 mg for 2 hours, then another 25 mg for 22 hours with the cessation of UFH infusion at this time) in 3 such patients indicates the possibility of a temporary decrease in respiratory disorders during infusion in the absence of bleeding [30]. However, it is obvious that there is still no sufficient reason to propose these scientific experiments for widespread use. In addition, it is possible that heparin may be beneficial in patients with respiratory distress syndrome. According to a meta-analysis of 9 studies, including a total of 465 patients with acute lung injury / respiratory distress syndrome (before the onset of the COVID-19 pandemic), adding LMWH to standard treatment reduced 7-day mortality (RR 0.52 at 95% CI: 0, 31-0.87), 28-day mortality (RR0.63 at 95% CI: 0.41-0.96), decreased APTT (median differences -1.1 sec at 95% CI: -1.97 to -0.23) and increased the PaO2 / FiO2 ratio (median difference 74.48 at 95% CI: 52.18-96.78) [31]. At the same time, the most pronounced positive effect on oxygenation was exerted by LMWH doses of ≥5000 IU / day, which is slightly higher than the usual prophylactic ones.
Accounting for drug interactions is an essential component of antithrombotic therapy in COVID-19. Data on the clinical significance of antithrombotic drug-drug interactions for the treatment of COVID-19 are presented in tables published by the University of Liverpool's Drug Interactions Group [32] and discussed in documents prepared by international expert groups [1,33].

ACKOWLEDGMENT
Thrombosis activation and, less commonly, thrombotic/thromboembolic complications are an important element in the pathogenesis of COVID-19. Their severity is associated with the severity of the manifestations of COVID-19 and its prognosis. Much in the prevention and treatment of feasibility studies for COVID-19 remains unclear. The choice of treatment methods for a particular patient remains the priority of the attending physicians, who are currently acting on the basis of previously known facts, the considerations of the expert community, the rapidly accumulating data on the results of the use of various interventions for COVID-19 and their own experience.
It should also be borne in mind that at the time of this writing, a number of cited documents were posted on the Internet before their official peer review and the decision to publish them in the relevant scientific journal.