The coronavirus disease 2019 (COVID-19) pandemic has had a significant impact on global public health, social interactions and the economy (Han et al., 2020; Global Burden of Disease 2020 Health Financing Collaborator Network, 2021; Lal et al., 2021; Mcintyre et al., 2022). As of February 2022, nearly 400 million people have been diagnosed with COVID-19 worldwide, and more than 5.7 million people have died. COVID-19 can induce different complications and affect different organs (Drake et al., 2021; Wang et al., 2021), mainly the respiratory tract, heart, gastrointestinal tract (Serban et al., 2021; Bulte et al., 2022), central nervous system (Sriwastava et al., 2021), liver, and kidney (Gross et al., 2020). Elderly individuals and patients with underlying diseases are prone to severe cases, and their mortality rates are significantly higher than those of other populations (Ghasemiyeh et al., 2021). Patients who die from COVID-19 infection in the late stage of disease progression can develop acute respiratory distress syndrome (ARDS) (Zangrillo et al., 2022), cytokine storm syndrome (CSS) (Yongzhi, 2021), acute kidney injury (AKI) (Ronco et al., 2020), septic shock (Wei et al., 2021), multiple organ failure (MOF) (Devaux et al., 2020) and cardiac arrest (Shao et al., 2020), resulting in death. Especially in patients with severe COVID-19, cardiac manifestations such as arrhythmia, myocardial infarction, acute heart failure and cardiogenic shock are common and are associated with increased mortality (Bangalore et al., 2020; Lala et al., 2020). Researchers have proposed various hypotheses about the direct and indirect mechanisms of COVID-19-related heart damage, but the exact mechanism is still unclear (Chung et al., 2021). The earlier theory that COVID-19 heart damage is due to acute viral myocarditis has been disproved by the lack of cases meeting the histological criteria for myocarditis (Halushka and Vander Heide, 2021). Subsequently, further studies have suggested that coagulation abnormalities, including thrombotic microangiopathy and complications of venous and arterial thromboembolism, are common in critically ill patients with COVID-19 (Levi et al., 2020). The pathological results suggest that the most common pathological cause of myocardial cell necrosis is the occurrence of microthrombi (Pellegrini et al., 2021). Moreover, a series of studies have also found that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection promotes hypercoagulability, and there is a strong correlation between the use of anticoagulants and COVID-19 survival (Nadkarni et al., 2020; Fröhlich et al., 2021; Lawler et al., 2021). A series of studies have confirmed that COVID-19 is associated with venous thromboembolic events, including pulmonary embolism, lower extremity deep venous thrombosis and cerebral venous sinus thrombosis, and there is a correlation between thrombosis and mortality in patients with COVID-19 (Rosovsky et al., 2020). Some studies have even found a 51.5-fold increased risk of in-hospital mortality in patients with D-2mer ≥2.0 μg/ml (Zhang L. et al., 2020), but the actual prevalence and characteristics of venous thromboembolism (VTE) remain unclear (Sastry et al., 2022). The incidence of VTE reported by different studies varies significantly (ranging from 0.7% to 57%) due to differences in disease severity and diagnostic imaging techniques used (Cui et al., 2020; Klok et al., 2020; Lodigiani et al., 2020; Suh et al., 2021). Even with anticoagulant prophylaxis, the incidence of VTE in COVID-19 patients remains high and is much higher than that in non-COVID patients receiving thromboprophylaxis (Lodigiani et al., 2020). Cytokine storms were initially believed to be the main factor for COVID-19 thrombosis (Lowenstein and Solomon, 2020), antiphospholipid antibodies were later detected in COVID-19 (Zhang Y. et al., 2020; Zuo et al., 2020), and the presence of prothrombotic antibodies also constituted one of the risk factors. Studies have also suggested that elevated levels of neutrophil extracellular traps are closely related to thrombotic events (Zuo et al., 2021), but their overall role in COVID-19-related thrombosis remains unclear (Bonaventura et al., 2021). At present, most reports on thrombosis in patients with COVID-19 are case reports (Achim et al., 2022; Bleiziffer et al., 2022; Jeckelmann et al., 2022; Russell et al., 2022; Takasu et al., 2022) and some observational studies (Maier et al., 2020). Even after strict ethical review, only a small number of large studies have confirmed the relationship between the use of anticoagulants and the survival rate of COVID-19 (Lawler et al., 2021). There is a good correlation. Therefore, it is still necessary to obtain a theoretical basis for the mechanism of COVID-19 thrombosis. In summary, exploring targets that can be used to treat both COVID-19 and thrombosis has theoretical guiding significance for the assessment and treatment of COVID-19 patients. However, there are various difficulties in clinical research on COVID-19, including ethical requirements and limited patient contact. The use of public databases solves the above problems. Further analysis of relevant datasets from public databases we can be used to identify and develop reliable biomarkers and treatment strategies for thrombosis in patients with COVID-19 and thus to better understand the mechanism of thrombosis in patients with COVID-19 and identify the corresponding targets. Such studies will promote follow-up drug research and development. We identified 8320 upregulated genes and 7651 downregulated genes from blood samples of COVID-19 patients and 368 upregulated genes and 240 downregulated genes from blood samples of thrombosis patients. We identified hub genes that may contribute to the evaluation and treatment of COVID-19-related thrombosis.

Thrombosis and the inflammatory response were once thought to be two independent physiological processes, but in recent years, studies have gradually found that there is a clear correlation between them. Activation of the coagulation system is part of the host response to pathogens and primarily serves to limit their spread in the bloodstream, which is achieved through interactions between innate immune cells and platelets, termed immunothrombosis (Engelmann and Massberg, 2013). Due to the COVID-19 pandemic, this normal physiological response has received more attention (Stark and Massberg, 2021). Histological analysis of pulmonary vessels in COVID-19 patients showed extensive thrombosis with microangiopathy, and the incidence of pulmonary capillary microthrombosis in COVID-19 patients was 9 times higher than that in influenza patients; the difference was statistically significant (Ackermann et al., 2020). Furthermore, data show that immune thrombosis is also a key indicator of the severity of COVID-19 (Nicolai et al., 2020). Preliminary studies in Wuhan, China, showed that most patients with COVID-19 who died of disease had coagulation disorders, characterized by prolonged prothrombin time and partial prothrombin kinase time, similar to the characteristics observed in patients with disseminated intravascular coagulation (Zhou et al., 2020). When pathogens invade the bloodstream and pose a lethal threat to the host, the body tries to control the infection by all available means, and viral diseases induce the recruitment of platelets and neutrophils to the microvasculature to protect host cells from viral infection (Jenne et al., 2013). The main cellular drivers of this process are platelets and innate immune cells, including neutrophils, monocytes and macrophages. In general, the response to viral disease should be similar; however, immune thrombotic vaso-occlusion was less prominent in patients with influenza-related pneumonia than in patients with COVID-19 (Nicolai et al., 2021). This finding illustrates that the immunothrombosis in COVID-19 is not just a general feature of viral infections but may also be a characteristic factor, suggesting that it is worthy of further exploration to reduce the disease severity and mortality of patients with COVID-19. Bioinformatics analysis enables us to understand the molecular mechanisms of disease initiation and progression, providing a new and effective method for identifying potential biomarkers and therapeutic targets for assessing and treating COVID-19 thrombosis. In this study, six co-upregulated genes, RPS7, IGF1R, DICER1, ERH, MCTS1, and TNPO1, and two co-downregulated genes, FLNA and PXN, were identified from COVID-19 and thrombosis datasets. Ribosomal protein S7 (rps7) is an essential component of the 40s subunit of the ribosome and is essential in the translation process and assembly of the ribosome (Fatica and Tollervey, 2002). Studies have shown that RPS7 regulates cell proliferation, the cell cycle and apoptosis through the PI3K/AKT and MAPK signaling pathways (Wang et al., 2013). However, whether RPS7 is specifically overexpressed in patients with COVID-19 with a high risk of thrombosis remains to be determined. Insulin-like growth factor 1 receptor (IGF1R) is a widely expressed membrane-bound tyrosine kinase receptor that can recognize two main ligands, IGF1 and IGF2. IGF1R expression on lymphocytes and macrophages can cause the proliferation of target cells and the production and activation of cytokines. Phosphorylation of IGF1R exacerbates inflammation, and its overexpression increases cytokine levels during influenza infection (Li et al., 2019). IGF1R has also recently been defined by some studies as a novel biomarker for predicting mortality in severe COVID-19 patients (Fraser et al., 2020). Dicer 1, ribonuclease III (DICER1) is a highly conserved RNase III ribonuclease that plays a key role in biological processes related to microRNAs (miRNAs). Recent studies have shown that DICER1 may maintain homeostasis during inflammation (Jiang et al., 2019). If the inflammatory response is out of balance, the crosstalk between inflammation and thrombosis can have serious consequences because not only does inflammation lead to thrombosis, but thrombosis in turn directly triggers inflammation. Thrombin cleaves fibrinogen and activates the cytokine IL-1α, providing a direct link between coagulation and inflammation. ERH mRNA splicing and mitosis factor (ERH) is a small protein that is highly conserved in eukaryotes. Though it was discovered nearly 30 years ago, its biological function is still largely unknown. It is considered to play a role in transcriptional regulation and the cell cycle. Although a series of studies have found that ERH has some characteristics related to RNA metabolism, the molecular functions of the ERH protein family still need to be further explored (Graille and Rougemaille, 2020). Malignant T cell-amplified sequence 1 (MCTS1) is an that was oncogene originally found in human T-cell lymphoma. MCTS1 can affect the cell cycle by shortening the G1/S conversion time, which is achieved by an imbalance between G1 cyclin activators and inhibitors. It has been confirmed that the expression of MCTS1 increases after DNA damage (Huang et al., 2021). In addition, MCTS1 also acts as a translation enhancer. Translation control has been proven to be an important step in regulating gene expression and subsequently cell growth, differentiation and necrosis (Bohlen et al., 2020). These functions enable MCTS1 to play multiple roles in the occurrence and development of malignant tumors, but its mechanisms in the process of inflammation and thrombosis have not been reported and are worth further exploration. Transportin 1 (TNPO1) is a protein involved in protein transduction into the nucleus, and its main target is RNA binding proteins. Studies have shown that TNPO1 is related to the influenza A virus core shell (Larson et al., 2019; Miyake et al., 2019). Moreover, its expression level can significantly predict ARDS mortality (Liao et al., 2021). This finding indicates that TNPO1 plays a key role in the inflammatory response and the occurrence of viral diseases, which show similar pathway activation to COVID-19 and thrombosis. During the COVID-19 pandemic, the most worrisome complications were ARDS and cardiovascular events, such as venous thromboembolism, myocardial infarction and stroke (Bangalore et al., 2020; Zhang Y. et al., 2020; Poissy et al., 2020; Stefanini et al., 2020). This theoretical evidence provides the basis for studying the mechanism of TNPO1 in COVID-19. In addition, two co-downregulated genes, FLNA and PXN, were obtained through bioinformatics analysis. Filamin A (FLNA) is a large actin-binding cytoskeletal protein. It is important for cell movement because it stabilizes the actin network and integrates it with the cell membrane. There is increasing evidence that FLNA is involved in the pathogenesis of cardiovascular and respiratory diseases. The interaction of FLNA with transcription factors and cell signaling molecules determines the function of vascular cells (Bandaru et al., 2021). Paxillin (PXN) is a focal adhesion protein consisting of an LD motif and a conserved cysteine-rich domain. PXN is thought to play a role in active muscle protein uptake and cell adhesion sites. Although PXN itself lacks enzymatic activity, it contains a variety of domains that can bind signals and structural proteins (Tsai et al., 2017). Therefore, PXN is considered to be a cytoskeletal protein that can effectively transmit signals (Stiegler et al., 2012). Inducers of these two co-downregulated genes have theoretical therapeutic value for COVID-19 patients with thrombosis. Based on the correlation between thrombosis and the severity of COVID-19 (Nicolai et al., 2020), further research may even identify a specific mechanism to reduce the rate of severe COVID-19, thereby reducing the threat of COVID-19 to the elderly and people with underlying diseases.

A limitation of our study is that these identified biomarkers were only verified at a theoretical level. Further experimental studies and clinical trials should be performed for accurate validation.

Based on bioinformatics analysis and previous studies, this study identified hub genes (RPS7, IGF1R, DICER1, ERH, MCTS1, TNPO1, FLNA, and PXN) that may contribute to the evaluation and treatment of COVID-19 and thrombosis. These findings provide new ideas to treat COVID-19 thrombosis and reduce the rate of severe COVID-19, and further clinical studies are needed to explore these possibilities.