Pulmonary Embolism in Covid-19 Pandemic: A Threat to Recovery of the Infected Patients

Severe Acute Respiratory Syndrome Coronavirus 2 is a new type of coronavirus that can cause Coronavirus Disease 2019 (Covid-19) and is associated with an increased risk of thrombosisrelated pulmonary embolism. Globally, doctors have revised their management strategies for Review Article Obeagu et al.; JPRI, 33(42A): 90-98, 2021; Article no.JPRI.71873 91 suspected and confirmed PD in patients with Coronavirus disease (Covid-19) in 2019. Choosing the right drug and the right dose requires consideration of potential comorbidities, which can be explained by the direct and indirect pathological consequences of Covid-19, complement activation, cytokine release, endothelial dysfunction, and the interaction between different types of blood cells. Discuss the pathophysiological events, therapeutic mortality strategies, risk factors and clinical management of patients with Covid-19 pulmonary embolism.


INTRODUCTION
SARSCoV2 appears to use angiotensinconverting enzyme receptor 2 to enter lung cells [1]. These proteins are also expressed in endothelial cells, so this cell type may be a virus target [2]. In addition, a large number of severely ill patients with Covid-19 have hypoxia, which can lead to thrombosis by increasing blood viscosity and increasing systemic inflammation [3]. Patients with severe pneumonia caused by Covid-19 can cause sepsis and can induce the release of inflammatory cytokines (such as IL6, IL8, TNFα, etc.), which can promote the activation of hypercoagulable state [4]. Some patients even have more prominent inflammation, which is related to increase Ddimer levels [5]. Since the onset of Coronavirus Disease (Covid-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARSCoV2) infection in 2019, there have been several reports describing severe procoagulant events in these patients, including lifethreatening pulmonary embolism [6,7]. Abnormalities in various coagulation parameters are often reported and are related to poor prognosis [8]. Unfortunately, due to the lack of large-scale prospective studies in this area, little is known about the epidemiology and pathophysiological mechanisms of Covid-19related PD. Understanding these aspects is essential for the early diagnosis and proper management of this potentially fatal complication. Especially the optimal dose and the duration of preventive anticoagulation are the main problems. In fact, it is reported that despite thrombosis prevention, severely ill patients with Covid-19 still develop PD, questioning the possible effect of implementing higher thrombosis prevention doses than used in standard practice [9]. Pulmonary embolism (PE) is a blood clot that forms in a blood vessel in the body (usually in the legs). It then enters the pulmonary artery, where it suddenly blocks blood flow. The current literature on this topic defines the epidemiology, possible underlying pathophysiological mechanisms, mortality, risk factors, and therapeutic importance of Covid-19related PD.

EPIDEMIOLOGY
The incidence of PE in hospitalized patients with Covid-19 is reported to be approximately 1.9% to 8.9% [10][11][12][13]. Interestingly, when the follow-up increased from 1 week to 2 weeks, the incidence of PE increased to 33.3%. At this time, increased awareness of the common occurrence of PD may lead to a higher index of suspicion and more diagnostic procedures to detect these types of complications [14]. Few cohort studies have reported the epidemiology of PD in Covid-19 patients, regardless of the severity of the disease and the need for hospitalization. The prevalence of pulmonary embolism is frequently reported in Covid-19 and is often seen in Covid-19 patients without other standard risk factors, indicating that it is an independent risk factor for VTE [7]. Data from previous experience in France show that the prevalence of PD in patients with severe Covid-19 infection is 23%. The requirement for mechanical ventilation is also closely related to the presence of PE on imaging [10]. There is currently no evidence to define the incidence of PE after rehabilitation [15].
High-level PE physiopathology observed in patients with Covid-19 observed in patients with Covid-19, not only continues to systemic inflammation but also reflects the true thrombotic diseases induced by cellular activation caused by viruses [16]. In addition, a split of 3.0 μg / ml for d-dimer had 76.9%, 94.9% and 92.5% sensitivity, specificity and negative predicted value to predict VTE. After receiving anticoagulation therapy, the D-dimer level decreases gradually, and D-dimer levels only predict thrombosis but also to monitor the effectiveness of the anticoagulant. Viral infections are predisposed to VTE and the systemic inflammatory response can be activated, which causes an imbalance between the influence of the accelerator and the influence of the anticoagulant. The coagulation pathway

Pathological Events of Pulmonary Embolism Caused by Covid-19
However, there is currently no strategy to understand pulmonary embolism, but by understanding the coagulation pathway and identifying its markers, we can diagnose PD early, and follow-up events can better understand pulmonary embolism and thrombosis formation leads to pulmonary embolism.

Crosstalk between Endothelial Dysfunction and Haemostasis
Covid-19 has worse clinical results in patients with endothelial dysfunction-related diseases (such as systemic hypertension, diabetes, and obesity), and there is evidence in the Covid-19 autopsy series that endothelial dysfunction [23,24].
The mechanism of endothelial dysfunction can be caused by SARS CoV2 directly invading endothelial cells or indirect inflammation [24]. The initiation of the host serine protease TMPRSS2 promotes the binding of the SARS CoV2 peak protein to the ACE2 receptor, followed by viral endocytosis and replication [25]. Subsequent endothelial damage and virus release will trigger a significant immune response, which can lead to further endothelial dysfunction.

Overview of Haemostasis
Endothelial injury and destruction of cell-to-cell connections in Covid-19 exposed the subendothelial matrix containing tissue factor (TF) and collagen [26]. This activates the clotting cascade and leads to the production of thrombin and the conversion of fibrinogen to fibrin, which together with the aggregates of platelets form a blood clot. Markers of endothelial activation (VWF, FVIII, Pselectin) are increased in Covid-19, and elevated soluble thrombomodulin (an endoglin) and VWF are associated with poor clinical outcomes [27].

Platelets
The rupture of the endothelial layer exposes the subendothelial matrix containing collagen and leads to platelet activation and recruitment [29]. Subsequent platelet degranulation and aggregation will produce platelet plugs that serve as adhesion sites for clotting factors [30]. Platelet activation markers in COVID-19 (such as pselectin, soluble CD40L) are increased and pselectin can induce TF expression in monocytes, resulting in a procoagulant phenotype [31].

Hypoxia
Hypoxia occurs in moderate to severe COVID-19, which can lead to endothelial dysfunction and hypercoagulable state [32]. Upregulation of endothelial P-selectin and adhesion molecules (eg, Intercellular Adhesion Molecule 1 (ICAM1)) during hypoxia leads to the recruitment of platelets and leukocytes [33]. Monocytes bind to activated endothelial cells through P-selectin glycoprotein ligand 1, and also express TF and other pro-thrombotic factors [34].  Elevated plasma levels of pro-inflammatory cytokines (IL2, IL6, IL7, IL8, granulocyte colonystimulating factor, interferon-gamma-inducible protein 10 (IP10), monocyte chemoattractant protein 1 (MCP1), macrophage inflammation Protein release 1A (MIP1A)) and tumor necrosis factor (TNFα), the so-called "cytokine storm", is a common feature of sepsis. It is secondary to hemophagocytic lymphohistiocytosis and activates coagulation function and increases blood vessels. Despite the best anticoagulation therapy and the recurrence of clinically significant VTE in the case of absolute contraindications to anticoagulation therapy, PE is one of the few cases in which the application of inferior vena cava filters can be considered. Even in these cases, anticoagulation should be resumed as soon as possible [37,48].

Post-Discharge Strategy
Due to the procoagulant effect of Covid-19, apparently stable and asymptomatic patients may continue for several weeks after discharge. Therefore, among Covid-19 patients who are readmitted after initial hospitalization, PD is suspected to be prudent in clinical practice. After discharge from the hospital for acute medical conditions, the decision to extend preventive treatment for LMWH should be made by balancing the reduced risk of VTE with the increased risk of bleeding episodes (including major bleeding). In the absence of high-quality data, drug prophylaxis in this setting should be reserved for patients at higher risk, including those with mobility problems and a history of VTE or active malignancies [

Risk Factors
Genetic diseases, genetic problems, such as Factor V Leiden, abnormal blood vessels such as varicose veins, certain diseases such as cancer or heart disease, pregnancy or within 6 weeks postpartum, smoking, obesity, prolonged bed rest, major surgery or trauma, Oral contraceptives/hormonal drugs, age factors (70 years or older), people with a history of thrombosis and not taking prescription blood thinners are at increased risk of pulmonary embolism. The coexistence of pneumonia and PE has been known for many years and remains a diagnostic challenge today [49]. Data from the international RIETE cohort show that patients with respiratory infections have a higher risk of PD than patients with other types of infections [50]. Other studies have shown that as many as 90% of patients admitted to the hospital for pneumonia have elevated procoagulant markers, and D-dimer is the most common one [51]. Ddimer is a very useful biomarker that can exclude PD in the general population when the clinical probability is low. However, it is usually not helpful in diagnosing the presence of PD, because other inflammatory conditions increase its value. In addition, this biomarker is not sufficient to exclude or confirm PD in patients with pneumonia who also have elevated D-dimer levels [52,53]. The same situation seems to occur in the Covid-19 disease [52].
There are many risk factors for thrombosis, but they are generally considered to be caused by three key mechanisms (Virchow's triad); endothelial injury, reduced blood flow/stasis, and hypercoagulable state [54]. Although there are many unknowns about this new disease, more and more experience shows that patients with severe Covid-19 infection have all three elements [15] [5]. After being discharged from the hospital for the first time, it was also observed that our patients had mobility problems, exercise difficulties, and fatigue easily. Obesity is a risk factor for VTE, which explains the risk of thromboembolism [15].

2.13PD Mortality Rate
With more and more reports of PD after Covid-19 infection, studies have shown that among the 1,835 Covid-19 patients, nearly two out of ten patients develop PD. Fixation, inflammation, coagulation activation, and fibrinolysis have been proposed to explain the development of PD in Covid-19 patients; however, the incidence of PE in Covid-19 patients is higher than that of pandemic and seasonal influenza patients (3%) [55]. In addition, compared with general cases, the mortality rate of Covid-19 patients with PD can reach up to 45% (in-hospital mortality rate is 4%) [56]. Therefore, front-line health care professionals should be wary of severe and lifethreatening complications of PD in patients with Covid-19 [57,58].

Diagnosis of Pulmonary Embolism
Pulmonary embolism can be difficult to diagnose, especially in people with underlying heart or lung disease. For this reason, your doctor may review your medical history, perform a physical examination, and perform one or more of the following tests, including blood tests; Ddimer, a substance that dissolves clots, chest X-rays, magnetic resonance imaging, Computed tomography pulmonary angiography, ultrasound, ventilation-perfusion scan (V/Q scan) and pulmonary angiography.

Covid-19
Blood Markers of Coagulation, Fibrinolysis and Inflammation  patients may have mild thrombocytopenia, slightly prolonged prothrombin time, increased fibrinogen and increased D-dimer (Table 1), all of which are The blood pressure rises and becomes more pronounced [59]. It is a fibrin degradation product that is sensitive to fibrinolysis for detecting intravascular thrombus (ie VTE), but lacks specificity, and may increase in inflammation and other diseases [60]. Elevated D-dimer may be related to acute lung injury caused by covid-19, which is produced by the degradation of fibrin in the alveoli deposited in ARDS [24,61]. Other markers of clotting and inflammation in COVID19 can also be abnormal, such as ferritin, von Willebrand factor (VWF), C-reactive protein (CRP), complement, and cytokines (Table 1). This suggests that the complex interaction between the haemostatic system and the immune system can lead to a thrombotic phenotype.

Clinical Management of Pulmonary Embolism
Once PD has been diagnosed, it is recommended to use composite materials that include clinical manifestations, systolic blood pressure, heart rate, respiratory rate, oxygen demand, PD severity index or PD severity index simplified, RV dysfunction imaging (CTA) Perform standard risk stratification or echocardiography) and / or biomarkers (troponin, brain natriuretic peptide, or NTprobrain natriuretic

CONCLUSIONS AND FUTURE PERSPECTIVES
Most of the Covid-19 studies are cross-sectional studies of patients with more serious diseases. To fully understand the crosstalk of immune hemostasis leading to pulmonary embolism, longitudinal measurements are needed in different cohorts, which will guide the best time and cohort when intervention will be beneficial. A greater understanding of the complex pathobiological interactions between the immune system and haemostasis in Covid-19 will help develop new treatments and reduce the effects of off-target regulation.

CONSENT
It is not approval.

ETHICAL APPROVAL
It is not approval.