• <tr id="yyy80"></tr>
  • <sup id="yyy80"></sup>
  • <tfoot id="yyy80"><noscript id="yyy80"></noscript></tfoot>
  • 99热精品在线国产_美女午夜性视频免费_国产精品国产高清国产av_av欧美777_自拍偷自拍亚洲精品老妇_亚洲熟女精品中文字幕_www日本黄色视频网_国产精品野战在线观看 ?

    Impaired coagulation, liver dysfunction and COVID-19 : Discovering an intriguing relationship

    2022-03-31 08:07:28DamianoArdesAndreaBoccatondaGiulioCoccoStefanoFabianiIlariaRossiMarcoBucciMariaTeresaGuagnanoCosimaSchiavoneFrancescoCipollone
    World Journal of Gastroenterology 2022年11期

    Damiano D'Ardes, Andrea Boccatonda, Giulio Cocco, Stefano Fabiani, Ilaria Rossi,Marco Bucci,,Maria TeresaGuagnano,Cosima Schiavone,Francesco Cipollone

    Abstract Coronavirus disease 2019 (COVID-19 ) is, at present, one of the most relevant global health problems. In the literature hepatic alterations have been described in COVID-19 patients, and they are mainly represented by worsening of underlying chronic liver disease leading to hepatic decompensation and liver failure with higher mortality. Several potential mechanisms used by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ) to cause liver damage have been hypothesized. COVID-19 primary liver injury is less common than secondary liver injury. Most of the available data demonstrate how liver damage in SARSCoV-2 infection is likely due to systemic inflammation, and it is less likely mediated by a cytopathic effect directed on liver cells. Moreover, liver alterations could be caused by hypoxic injury and drugs (antibiotics and non-steroidal antiinflammatory drugs, remdesivir, tocilizumab, tofacitinib and dexamethasone).SARS-CoV-2 infection can induce multiple vascular district atherothrombosis by affecting simultaneously cerebral, coronary and peripheral vascular beds. Data in the literature highlight how the virus triggers an exaggerated immune response,which added to the cytopathic effect of the virus can induce endothelial damage and a prothrombotic dysregulation of hemostasis. This leads to a higher incidence of symptomatic and confirmed venous thrombosis and of pulmonary embolisms,especially in central, lobar or segmental pulmonary arteries, in COVID-19 . There are currently fewer data for arterial thrombosis, while myocardial injury was identified in 7 %-17 % of patients hospitalized with SARS-CoV-2 infection and 22 %-31 % in the intensive care unit setting. Available data also revealed a higher occurrence of stroke and more serious forms of peripheral arterial disease in COVID-19 patients. Hemostasis dysregulation is observed during the COVID-19 course. Lower platelet count, mildly increased prothrombin time and increased Ddimer are typical laboratory features of patients with severe SARS-CoV-2 infection, described as“COVID-19 associated coagulopathy.” These alterations are correlated to poor outcomes.Moreover, patients with severe SARS-CoV-2 infection are characterized by high levels of von Willebrand factor with subsequent ADAMTS13 deficiency and impaired fibrinolysis. Platelet hyperreactivity, hypercoagulability and hypofibrinolysis during SARS-CoV-2 infection induce a pathological state named as “immuno-thromboinflammation.” Finally, liver dysfunction and coagulopathy are often observed at the same time in patients with COVID-19 . The hypothesis that liver dysfunction could be mediated by microvascular thrombosis has been supported by postmortem findings and extensive vascular portal and sinusoidal thrombosis observation. Other evidence has shown a correlation between coagulation and liver damage in COVID-19 , underlined by the transaminase association with coagulopathy, identified through laboratory markers such as prothrombin time, international normalized ratio, fibrinogen, D-dimer, fibrin/fibrinogen degradation products and platelet count. Other possible mechanisms like immunogenesis of COVID-19 damage or massive pericyte activation with consequent vessel wall fibrosis have been suggested.

    Key Words: COVID-19 ; SARS-CoV-2 ; Liver; Coagulation

    lNTRODUCTlON

    Coronavirus disease 2019 (COVID-19 ) is, at present, one of the most relevant global health problems,declared a pandemic on March 11 , 2020 by the World Health Organization[1 ]. It is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 ), a novel positive-sense single-stranded RNA betacoronavirus[2 ,3 ]. The pulmonary manifestation of COVID-19 , including pneumonia and acute respiratory distress syndrome, are well known, but it is necessary to emphasize that the coronavirus deleterious effects are also exerted on many other organ systems and are responsible for extrapulmonary manifestations[4 ].

    SARS-CoV-2 can cause both direct and indirect cardiovascular sequelae (myocardial injury, acute coronary syndromes, cardiomyopathy, acute cor pulmonale, arrhythmias and cardiogenic shock), acute kidney injury and gastrointestinal symptoms, such as diarrhea, nausea, vomiting, abdominal pain and anorexia[4 ]. Neurological complications include headaches, dizziness, ageusia, myalgia, anosmia up to stroke, Guillain-Barré and encephalopathy, and dermatological signs have also been described(petechiae, urticaria, vesicles, erythematous rash, livedo reticularis)[4 ]. Hepatobiliary manifestations can be observed especially in patients with severe presentations of COVID-19 and occur mainly with increased plasma levels of transaminases and bilirubin[4 ]. Thromboembolic events have also been described in COVID-19 , such as acute limb ischemia, which can occur in patients without existing peripheral arterial disease and in those receiving thromboprophylaxis. Acute abdominal-thoracic aortic thrombosis and mesenteric ischemia are less common but associated with significant morbidity and mortality[5 ]. Several studies have also demonstrated increased rates of deep vein thrombosis and pulmonary embolism in COVID-19 patient[5 -7 ]. Acute cerebrovascular disease, including ischemic stroke, and disseminated intravascular coagulation are also severe thrombotic complications of COVID-19 that must not be forgotten[5 ].

    This article aims to explore the possible mechanisms underlying hepatic and hemocoagulative alterations in COVID-19 through the search of published, readily accessible, peer-reviewed, full articles related to this topic written in English and found on PubMed.

    COVlD-19 AND LlVER

    Pathophysiology

    SARS-CoV-2 has the capacity to infect cells through the angiotensin-converting enzyme 2 (ACE2 )receptor that is mainly expressed on the type 2 alveolar cells[8 ]. The ACE2 receptor is mainly present in the liver, lung, heart, renal and gastrointestinal system[9 ]. Regarding hepatic involvement, the level of ACE2 expression in cholangiocytes (59 .7 %) is higher than hepatocytes (2 .9 %)[10 ]. SARS-CoV-2 cell entry is mediated by its S protein, which specifically interacts with the host cell ACE2 and transmembrane serine protease 2 [11 ]. The major expression of ACE2 in cholangiocytes reveals that SARS-CoV-2 may cause bile duct dysfunction. Cholangiocytes play critical roles in liver regeneration and immune responses, indicating that viral immunologic injury might be important in liver injury in COVID-19 [12 ].

    Even if there is a substantial difference in ACE2 receptor expression between the liver and biliary tract, the liver is not unaffected by the SARS-CoV-2 infection. In fact, current data have shown that in patients with COVID-19 aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase levels are increased, while alkaline phosphatase and gamma glutamyl transferase,representatives of bile duct injury, did not increase significantly[12 ]. Indeed, in the literature many clinical findings and hepatic alterations are described, and there are several reported potential mechanisms used by the virus to cause liver disease.

    Most of the available data demonstrate that hepatic injury during SARS-CoV-2 infection is more likely due to systemic inflammation, and it is less likely mediated by a cytopathic effect directed on liver cells. Viral RNA can be detected in liver tissue of patients with COVID-19 , but infection of liver cells has not yet been demonstrated[13 ]. During a viral infection, the innate and the acquired immune systems recognize pathogen associated molecular patterns and specific viral antigens and release inflammatory molecules, such as cytokines and chemokines, that activate macrophages and T cells to clear the virus and kill infected cells. In patients affected by COVID-19 , high levels of inflammatory cytokines have been observed, and this context could cause significant liver damage when SARS-CoV-2 infects host hepatocytes. The most involved inflammatory molecules are tumor necrosis factor, interleukin-2 (IL-2 ),IL-6 , IL-7 , IL-18 , granulocyte-colony stimulating factor, interferon-γ and ferritin[14 ]. An early hypercytokinemia could lead to multiorgan injuries, including the liver (Figure 1 ). The literature demonstrates that worse outcomes of COVID-19 are more common in patients with early cytokine elevation[15 ].

    Another potentially harming mechanism is represented by hypoxic injury. The complex vascularization of the liver makes it particularly exposed to circulatory alterations that could be generated in cardiac, circulatory, respiratory failure or in septic shock, causing decreased perfusion of the liver[12 ].About 1 .1 %-20 .0 % of COVID-19 patients are affected by septic shock, and 23 .0 % of patients have heart failure[16 ].

    Drugs are also involved with damage mechanisms, particularly causing drug induced liver injury.Antibiotics and non-steroidal anti-inflammatory drugs, which are one of the most common causes of drug induced liver injury in the general population, can contribute to liver damage in COVID-19 patients when used to treat bacterial superinfection, myalgias or fever. Furthermore, drug induced liver injury has been shown in 15 .2 % of patients receiving remdesivir and in 37 .2 % of patients in treatment with lopinavir/ritonavir[17 ]. Finally, dexamethasone, tocilizumab and tofacitinib, used to treat COVID-19 , could potentially create hepatic injuryviapre-existing chronic liver disease reactivation, especially hepatitis B virus[18 ].

    Clinical characteristics

    During SARS-CoV-2 infection, patients can be asymptomatic or present clinical symptoms such as fever,dry cough, headache, dyspnea and fatigue and up to acute respiratory distress syndrome, shock and cardiac failure[19 ,20 ]. Hepatic involvement can occur through all the pathophysiological pathways previously investigated and still other studies are needed to better characterize them. In current reports,COVID-19 primary liver injury is less common than secondary liver injury[21 ,22 ]. SARS-CoV-2 liver involvement is mainly represented by worsening of underlying chronic liver disease, leading to hepatic decompensation and acute-on-chronic liver failure, with higher mortality. Symptoms mainly reported in the literature associated to liver injury and gastrointestinal involvement are diarrhea, nausea, vomiting and loss of appetite. Abnormal liver function was also observed with the increase of AST, ALT, lactate dehydrogenase and bilirubin and the decrease of albumin[21 -25 ].

    According to the current data, hepatic dysfunction is significantly higher in critically ill patients and is associated with a poor outcome, underlining its importance in clinical settings. Elevated liver enzymes are observed predominantly in severe and critical cases of COVID-19 . For example, increased AST was observed in 62 % of patients in the intensive care unit (ICU) compared to 25 % in non-ICU patients[23 ]. Chen et al[21 ] reported that AST, ALT, alkaline phosphatase, gamma glutamyl transferase and bilirubin levels were significantly higher in non-survivors than in survivors. Also hypoalbuminemia was found significantly lower in deceased patients rather than in surviving patients.Furthermore, according to Bangashet al[24 ] the mortality rate in patients with underlying chronic liver disease was 0 %-2 %. According to the literature data, liver injury is most common in critically ill patients who have diabetes and hypertension[22 ,25 ].

    Figure 1 Structure of severe acute respiratory syndrome coronavirus 2 hepatic receptors that induce hepatic injury mediated by cytokine storm. Inflammatory mediators secreted by lymphocytes and macrophages aggravate inflammatory responses causing hepatic damage. IL: Interleukin; GC-SF:Granulocyte colony stimulating factor; ACE-2 : Angiotensin-converting enzyme 2 .

    The fact that liver injury in COVID-19 is mostly hepatocellular rather than cholestatic is demonstrated by the more frequent elevation of ALT, AST and lactate dehydrogenase than of alkaline phosphatase and gamma glutamyl transferase. The latter two did not increase significantly, and jaundice is uncommon[12 ,26 ]. Moreover, the current data demonstrate that AST could represent an important hepatocellular injury marker because its elevation is associated with a major mortality risk[27 ].According to a meta-analysis, the pooled prevalence of abnormal liver functions (12 studies, 1267 patients) was 19 %, and in subgroup analysis patients with severe COVID-19 had higher rates of abdominal pain and abnormal liver function including increased ALT and AST[28 ].

    In a hospital setting, drugs also have to be considered in liver injury; moreover COVID-19 critically ill patients are treated with multiple drugs, such as antibiotics, immunosuppressants and antiviral and antipyretic agents that are associated to abnormal liver function, especially when used in patients with severe COVID-19 [23 ,29 ]. In the literature, drug induced liver injury has been shown to result in AST and ALT elevation and reactivation of pre-existing chronic liver disease, above all hepatitis B virus infection[17 ,18 ]. Indeed, a retrospective study has shown that patients with chronic hepatitis B virus hepatitis had a worse prognosis for COVID-19 and for a higher mortality and a higher incidence of acute-on-chronic liver failure[30 ]. In a trial by Goldman et al[31 ] comparing remdesivir treatment for either 5 d or 10 d, severe but not life-threatening ALT/AST elevations were reported in 4 %-6 % of patients and life-threatening AST/ALT elevations in 2 %-3 % of patients.

    COVlD-19 AND COAGULATlON DlSORDERS

    Clinical characteristics

    SARS-CoV-2 infection can induce multiple vascular district atherothrombosis by simultaneously affecting cerebral, coronary and peripheral vascular beds. Data in the literature highlight how the virus can trigger an exaggerated immune response, which added to the cytopathic effect of the virus can induce endothelial damage and a prothrombotic dysregulation of hemostasis[32 -34 ]. Nowadays, there are several reports and original papers on cases of venous thromboembolism and pulmonary embolism related to COVID-19 [35 -40 ].

    Incidence of symptomatic and confirmed venous thrombosis in COVID-19 patients hospitalized in the ICU can reach 30 %-40 %[41 ]. Data from a study performed in China demonstrated that 25 % of COVID-19 patients developed lower extremity deep vein thrombosis without venous thromboembolism prophylaxis[42 ]. A work by Klok et al[36 ] described pulmonary embolisms in 25 of 184 ICU patients with COVID-19 (13 .6 %), 72 % of which were in central, lobar or segmental pulmonary arteries, despite standard dose pharmacological prophylaxis[36 ,43 ]. In Italy, Lodigiani et al[35 ] showed thromboembolic events (venous and arterial) in 7 .7 % of patients admitted with COVID-19 , corresponding to a cumulative rate of 21 .0 %.

    There are currently fewer data for arterial thrombosis. A study from Wuhan showed that about 12 %of patients displayed Hs-troponin I above the threshold of 28 pg/mL[14 ]. Other data revealed that myocardial injury was diagnosed in 7 %-17 % of patients hospitalized with SARS-CoV-2 infection and 22 %-31 % in the ICU setting[16 ,25 ]. Dysregulated inflammatory response enhances atherosclerotic plaque disruption[21 ,44 -46 ]. Previous studies demonstrated that influenza and community-acquired pneumonia are related to an increased risk of myocardial infarction, within the first 7 d of diagnosis and even after hospitalization[47 ]. Regarding cerebrovascular disease, occurrence of stroke in COVID-19 patients ranges between 2 .7 % and 3 .8 %, and these subgroup of patients often displayed comorbidities such as hypertension and were older on average[48 ,49 ]. Moreover, there are some reports documenting more serious forms of peripheral arterial disease in patients with SARS-CoV-2 infection[50 ].

    Laboratory findings

    Hemostasis dysregulation has been described as an early pathological change in the COVID-19 course.Lower platelet count, mildly increased prothrombin time and increased D-dimer are typical laboratory features of patients with severe SARS-CoV-2 infection, and they are correlated to poor outcomes[51 ].Those changes have been described as “COVID-19 associated coagulopathy”[52 -54 ]. Moreover, patients with severe SARS-CoV-2 infection are characterized by high levels of IL-6 , thus leading to a subsequent increase in proteins such as fibrinogen and von Willebrand factor (vWF)[55 ]. High lactate dehydrogenase and ferritin values are other laboratory findings of patients with severe COVID-19 infection,resembling a thrombotic microangiopathy[51 ,55 ,56 ]. Furthermore, complement components C5 b-9 , C4 d and mannose-binding lectin-associated serine protease 2 have been detected in the small vessels of the lung due to complement-associated microvascular injury[57 ]. High levels of vWF and subsequent ADAMTS13 deficiency seem to be other typical findings of severe COVID-19 infection[52 ,58 ,59 ].Decreased levels of ADAMTS13 can induce increased platelet-endothelial interaction generating a thrombotic microangiopathy-like state[52 ,60 -63 ].

    Recent data demonstrate that fibrinolysis is impaired in patients with severe COVID-19 [64 ,65 ].Critical COVID-19 patients are characterized by low levels of plasminogen, as for a consumptive state[65 ]. Nougier et al[66 ] reported elevated levels of plasminogen activator inhibitor 1 and low levels of tissue plasminogen activator, along with high thrombin generation, thus demonstrating a significant imbalance between inhibitor and activator factors of fibrinolysis.

    Pathogenetic mechanisms

    Platelet hyperreactivity, hypercoagulability and hypofibrinolysis induce a pathological state that has been named “immuno-thromboinflammation” during SARS-CoV-2 infection[67 ]. SARS-CoV-2 binds to the ACE2 receptor on the surface of endothelial and arterial smooth muscle cells, inducing a cytopathic effect and a subsequent endothelial injury[68 ]. As it is well known, endothelial damage triggers platelet activation, adhesion to the subendothelial matrix and aggregation, thus generating a platelet plug[69 ].Moreover, a release of vWF, inefficient cleavage of ultralarge vWF catalyzed by ADAMTS13 , direct contact with activating surfaces in the subendothelial matrix, loss of heparan sulfates at the surface of injured blood vessels, disrupted generation of nitric oxide, prostaglandin E2 and prostaglandin I2 and loss of surface expression of ectonucleotidases occur[70 ,71 ]. Platelet activation may represent a consequence of the production of a consistent level of thrombin after initiation of coagulation[64 ].

    Furthermore, high IL-6 levels can induce megakaryocytopoiesis generation and platelet formation,which could play a role to generate a hypercoagulability state, in particular within the lung. Intriguing,SARS-CoV-2 can bind directly to platelets since they express both ACE2 and transmembrane serine protease 2 on their surface[72 ]; this binding can favor platelet activation and the release of clotting factors, inflammatory molecules and leukocyte-platelet aggregates[72 ].

    In patients affected by severe COVID-19 pneumonia, levels of tissue factor (TF) on monocytes are higher than normal, together with P-selectin expression and the amount of platelet-neutrophil and platelet-monocyte aggregates[2 ]. Therefore, platelet activation due to adenosine diphosphate, thrombin and collagen stimulation is enhanced in these patients. Platelet hyperactivation induced by SARS-CoV-2 infection induce the release of inflammatory molecules such as cytokines, chemokines, growth factors and even procoagulant factors like fibrinogen and vWF[73 ]. This mechanism seems to generate a vicious cycle since inflammatory molecules worsen endothelial injury by decreasing nitric oxide availability and enhancing oxidative stress and/or favoring leukocyte-endothelial interaction[74 ,75 ].

    Endothelial injury triggers the release of TF in the blood stream. Moreover, TF can derive from macrophage/monocyte cells and through their microparticles, as a consequence of macrophage activation syndrome shown in patients with severe COVID-19 infection[76 ]. SARS-CoV-2 can directly induce macrophage activation, which can even occur as a consequence of the inflammatory hyperactivation (cytokine storm), as demonstrated by high levels of interferon-g, C-C motif chemokine ligand 2 and C-X-C motif chemokine 9 and 10 detected in critical COVID-19 patients[77 ,78 ].

    Neutrophils can also be activated both directly by SARS-CoV-2 and by other inflammatory cells, thus generating neutrophil extracellular traps that may activate Factor XII and the intrinsic pathway of coagulation[79 ]. Hemostasis dysregulation in SARS-CoV-2 infection is also characterized by a decreased activity of endogenous anticoagulants like antithrombin, TF pathway inhibitor and anticoagulation proteins C and S[78 ,80 ]. Endothelial injury and platelet hyper-activation in severe COVID-19 patients enhance the release of plasminogen activator inhibitor 1 (PAI-1 )[81 ]. High levels of PAI-1 can further inhibit fibrinolysis, thus worsening the thrombotic burden[82 ,83 ]. Therefore, as the pulmonary inflammation progresses, there is consumption of plasminogen, along with high levels of PAI-1 and depletion of tPA, thus inducing a state of hypofibrinolysis and allowing perpetuation of prothrombotic state[84 ].

    In patients with SARS-CoV-2 infection, the presence of antiphospholipid antibodies has been demonstrated, which may directly induce endothelial cell activation and enhance TF expression by monocytes, thus contributing to the procoagulant and prothrombotic state[85 -87 ]. Particularly, antiphospholipid antibodies can bind to the platelets and trigger their activation decreasing levels of inhibitors such as activated protein C and antithrombin and increasing clotting factors such as FXa and thrombin[88 -90 ].

    SARS-CoV-2 can dysregulate the ACE pathway by its binding to the ACE2 receptor on tissues; high levels of angiotensin (Ang) II favor PAI-1 and TF expression, thus promoting hypercoagulability and impairing fibrinolysis[60 ]. Furthermore, Ang II receptors on platelets can induce platelet activation and aggregation[91 ]. Ang 1 ,7 levels are lower in COVID-19 patients who develop severe disease[92 ]. Ang 1 ,7 is a vasoprotective molecule by mediating vasodilation and blocking platelet aggregation through nitric oxide release[93 -95 ]. Therefore, low Ang 1 ,7 levels can contribute to the procoagulant state in COVID-19 infection. Finally, obesity is a main risk factor for thrombosis due to adipocytokine-mediated mechanisms, increased inflammatory molecules, Ang II/Ang 1 ,7 imbalance, reactive oxygen speciesmediated endothelial dysfunction and lipid and glucose metabolism changes[96 -98 ].

    RELATlONSHlP BETWEEN COVlD-19 , LlVER AND COAGULATlON

    Liver dysfunction and coagulopathy are often observed in patients with COVID-19 . Japanese researchers found that patients with high ALT had higher levels of D-dimer and fibrin/fibrinogen degradation products. In particular elevation of ALT and D-dimer were identified simultaneously[99 ].Moreover D-dimer was independently associated to ALT elevation[99 ].

    This study suggests the hypothesis that liver dysfunction could be mediated by microvascular thrombosis, and intrahepatic microvascular thrombosis could theoretically play a role in this physiopathological context. This hypothesis is supported by post-mortem findings by Sonzogniet al[100 ] who found marked derangement of intrahepatic blood vessels with aspects of intravascular thrombosis, suggesting a possible liver damage linked to thrombotic processes. Other evidence has shown a correlation between coagulation and liver damage in COVID-19 . In fact, a Chinese study on COVID-19 patients demonstrated the association between AST and ALT values with coagulopathy,identified through laboratory markers such as prothrombin time, international normalized ratio,fibrinogen, D-dimer and platelet count[101 ]. Pathological findings are consistent with a vascular-related damage caused by impaired blood flow, with lesions similar to histological characteristics of hepatopulmonary syndrome and in obliterative portal venopathy[100 ]. Indeed it has been shown a diffuse network of sinusoids decorated by CD34 suggesting an abnormal hepatic circulation of blood[100 ].

    A likely explanation could be related to increased hepatic blood flow: this aspect may be linked to heart distress or to thrombotic phenomena in portal and sinusoidal vessels[100 ]. The abnormal high levels of transaminases in some patients whose liver sample were analyzed post-mortem could be explained by extensive vascular portal and sinusoidal thrombosis, leading to confluent parenchymal necrosis and hepatic cells accelerating apoptosis[100 ]. Attention must be paid to the evidence of massive pericyte activation in liver samples obtained post-mortem[100 ]. Pericytes are involved in the recruitment of inflammatory cells in liver injury, and their transformation in myofibroblast-like cells leads to the production of abundant amounts of extracellular matrix proteins and to the consequent vessel wall fibrosis[100 ].

    CONCLUSlON

    Liver abnormalities and coagulopathy are physiopathological characteristics of COVID-19 that represent the most relevant global health problem. Hypercoagulability, hypofibrinolysis and platelet alterations during SARS-CoV-2 infection induce a sort of “immuno-thromboinflammation,” while mildly increased prothrombin time and increased D-dimer are typical laboratory features of patients with severe SARSCoV-2 infection, described as “COVID-19 associated coagulopathy.” These phenomena are clinically relevant with manifestations of thrombosis in a large variety of anatomic districts. Moreover, hepatic alterations are mainly represented by worsening of underlying chronic liver disease leading to hepatic decompensation and liver failure with higher mortality, and they appear to be mediated more by systemic inflammation, direct cytopathic effect on liver cells, hypoxic injury and drugs. Liver dysfunction and coagulopathy are also observed at the same time in patients with COVID-19 , probably mediated by microvascular thrombosis, immunological mechanisms and pericyte activation. More data are needed to better investigate the relevant relationship between coagulation, liver dysfunction and COVID-19 with the aim to understand more deeply the physiopathological mechanisms of SARS-CoV-2 and to evaluate new therapeutic strategies to prevent mortality.

    FOOTNOTES

    Author contributions:All authors have designed, written and revised the manuscript.

    Conflict-of-interest statement:There is no conflict of interest associated with the authors of this manuscript.

    Open-Access:This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BYNC 4 .0 ) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is noncommercial. See: https://creativecommons.org/Licenses/by-nc/4 .0 /

    Country/Territory of origin:Italy

    ORClD number:Damiano D’Ardes 0000 -0001 -5573 -4536 ; Andrea Boccatonda 0000 -0001 -9303 -7790 ; Giulio Cocco 0000 -0003 -3458 -5468 ; Stefano Fabiani 0000 -0001 -6821 -103 X; Ilaria Rossi 0000 -0001 -5163 -9929 ; Marco Bucci 0000 -0002 -5213 -7768 ; Maria Teresa Guagnano 0000 -0001 -7225 -0891 ; Cosima Schiavone 0000 -0002 -8453 -4936 ; Francesco Cipollone 0000 -0002 -5993 -9341 .

    S-Editor:Wu YXJ

    L-Editor:Filipodia

    P-Editor:Wu YXJ

    亚洲色图综合在线观看| 视频在线观看一区二区三区| 亚洲国产精品成人久久小说| 精品一区二区三区四区五区乱码| 丝袜美腿诱惑在线| 人妻 亚洲 视频| 国产精品久久久久久精品古装| netflix在线观看网站| 国产激情久久老熟女| 欧美日韩一级在线毛片| 国产亚洲精品久久久久5区| 波多野结衣av一区二区av| 又紧又爽又黄一区二区| 淫妇啪啪啪对白视频 | 国产伦人伦偷精品视频| 国产一区有黄有色的免费视频| 中文字幕精品免费在线观看视频| 国产成人啪精品午夜网站| 国产精品成人在线| 少妇裸体淫交视频免费看高清 | 久久av网站| 少妇 在线观看| 爱豆传媒免费全集在线观看| 18禁国产床啪视频网站| 国产精品熟女久久久久浪| 久久九九热精品免费| 宅男免费午夜| 亚洲欧美日韩另类电影网站| 亚洲人成电影观看| 欧美精品高潮呻吟av久久| 久久国产亚洲av麻豆专区| 免费观看a级毛片全部| 国产免费现黄频在线看| 水蜜桃什么品种好| 欧美中文综合在线视频| 久9热在线精品视频| 国产欧美日韩一区二区三 | 久久久精品区二区三区| 亚洲av片天天在线观看| 亚洲精品国产一区二区精华液| 亚洲欧美精品自产自拍| 亚洲伊人色综图| 青春草亚洲视频在线观看| av在线播放精品| 男女免费视频国产| 人人妻人人澡人人爽人人夜夜| 97精品久久久久久久久久精品| 国产片内射在线| 成人黄色视频免费在线看| 日本a在线网址| a级片在线免费高清观看视频| 国产精品久久久av美女十八| 国产高清视频在线播放一区 | 精品人妻熟女毛片av久久网站| 亚洲精品久久成人aⅴ小说| 久久精品国产a三级三级三级| 国产精品国产三级国产专区5o| www日本在线高清视频| 国产成人免费无遮挡视频| 国产精品欧美亚洲77777| 最新在线观看一区二区三区| 亚洲五月婷婷丁香| 满18在线观看网站| 亚洲性夜色夜夜综合| 免费高清在线观看日韩| 亚洲,欧美精品.| 精品一区二区三卡| 日韩欧美国产一区二区入口| 日韩 亚洲 欧美在线| 国产亚洲精品一区二区www | 日韩制服丝袜自拍偷拍| 欧美日韩精品网址| 亚洲中文日韩欧美视频| 最近最新中文字幕大全免费视频| 午夜福利视频在线观看免费| 丰满饥渴人妻一区二区三| 欧美乱码精品一区二区三区| 欧美少妇被猛烈插入视频| 精品久久久久久电影网| 亚洲国产欧美一区二区综合| 日韩熟女老妇一区二区性免费视频| 欧美黑人精品巨大| av在线app专区| 悠悠久久av| 亚洲va日本ⅴa欧美va伊人久久 | 不卡一级毛片| 精品国产国语对白av| 中国国产av一级| 日韩一卡2卡3卡4卡2021年| 一区二区三区精品91| 久久精品国产亚洲av高清一级| 在线永久观看黄色视频| 国产在线观看jvid| 国产精品影院久久| 另类精品久久| 亚洲自偷自拍图片 自拍| 国产成人啪精品午夜网站| 亚洲伊人久久精品综合| 久久免费观看电影| 99精国产麻豆久久婷婷| 人人妻人人澡人人爽人人夜夜| www.999成人在线观看| 日韩视频在线欧美| 亚洲伊人色综图| 热re99久久精品国产66热6| www日本在线高清视频| netflix在线观看网站| 中文字幕av电影在线播放| 久久影院123| 国产精品免费大片| 国产成人欧美在线观看 | 国产免费一区二区三区四区乱码| √禁漫天堂资源中文www| 日韩有码中文字幕| 如日韩欧美国产精品一区二区三区| 精品国产一区二区三区久久久樱花| 欧美午夜高清在线| 午夜福利一区二区在线看| h视频一区二区三区| 欧美97在线视频| 国产精品影院久久| 韩国精品一区二区三区| 少妇粗大呻吟视频| 少妇粗大呻吟视频| 18禁观看日本| 亚洲精品一区蜜桃| 国产亚洲av片在线观看秒播厂| 久久久久久人人人人人| 热re99久久精品国产66热6| 九色亚洲精品在线播放| 国产精品久久久久久精品电影小说| av不卡在线播放| 亚洲一区中文字幕在线| 又黄又粗又硬又大视频| 国产亚洲精品一区二区www | 无遮挡黄片免费观看| 中文字幕制服av| 亚洲三区欧美一区| 飞空精品影院首页| 亚洲欧美日韩另类电影网站| 亚洲国产精品成人久久小说| 一区二区三区四区激情视频| 成人影院久久| 中文字幕最新亚洲高清| 国产激情久久老熟女| 国产日韩一区二区三区精品不卡| 久久影院123| 人人澡人人妻人| 我的亚洲天堂| 在线观看免费高清a一片| 我要看黄色一级片免费的| 下体分泌物呈黄色| 国产亚洲av高清不卡| 精品少妇一区二区三区视频日本电影| 国产视频一区二区在线看| 日韩一区二区三区影片| 老司机靠b影院| 新久久久久国产一级毛片| h视频一区二区三区| 宅男免费午夜| 国产一区二区激情短视频 | 亚洲欧洲精品一区二区精品久久久| 亚洲欧洲日产国产| 国产精品一区二区在线不卡| 免费在线观看视频国产中文字幕亚洲 | 国产高清国产精品国产三级| 欧美另类一区| 91大片在线观看| 国产av国产精品国产| 99九九在线精品视频| 97精品久久久久久久久久精品| 老司机在亚洲福利影院| 亚洲精品一卡2卡三卡4卡5卡 | 麻豆乱淫一区二区| 一二三四在线观看免费中文在| 一级黄色大片毛片| 国产在线一区二区三区精| 亚洲第一av免费看| 热99久久久久精品小说推荐| 欧美97在线视频| 国产又爽黄色视频| 国产av一区二区精品久久| 亚洲av美国av| 99精品欧美一区二区三区四区| 十八禁网站免费在线| 一本一本久久a久久精品综合妖精| 国产伦理片在线播放av一区| 人人妻人人爽人人添夜夜欢视频| kizo精华| 19禁男女啪啪无遮挡网站| 亚洲av电影在线进入| 国产男女超爽视频在线观看| 精品国产一区二区三区久久久樱花| 国产精品av久久久久免费| 丝袜美腿诱惑在线| 欧美xxⅹ黑人| 国产精品 国内视频| 亚洲一卡2卡3卡4卡5卡精品中文| 久久久精品国产亚洲av高清涩受| 欧美日韩亚洲国产一区二区在线观看 | 免费高清在线观看视频在线观看| 在线观看免费午夜福利视频| 国产成人欧美在线观看 | 天天躁狠狠躁夜夜躁狠狠躁| 国产免费av片在线观看野外av| 国产欧美日韩精品亚洲av| 日本a在线网址| tocl精华| 成年女人毛片免费观看观看9 | 女人爽到高潮嗷嗷叫在线视频| 国产老妇伦熟女老妇高清| 性色av一级| 97在线人人人人妻| 一区二区日韩欧美中文字幕| 日韩,欧美,国产一区二区三区| 俄罗斯特黄特色一大片| 大香蕉久久成人网| 国产区一区二久久| 欧美大码av| 亚洲精品国产av成人精品| 久久人人爽人人片av| 天天躁夜夜躁狠狠躁躁| 久久狼人影院| 成人免费观看视频高清| 日韩人妻精品一区2区三区| 欧美成狂野欧美在线观看| 成人国语在线视频| 国产成人av激情在线播放| 我要看黄色一级片免费的| 丰满饥渴人妻一区二区三| 在线观看人妻少妇| 女性生殖器流出的白浆| 交换朋友夫妻互换小说| tocl精华| 精品国产乱码久久久久久小说| 可以免费在线观看a视频的电影网站| 搡老乐熟女国产| 国产成人免费无遮挡视频| 一本久久精品| 亚洲专区国产一区二区| 男人舔女人的私密视频| 久久精品国产a三级三级三级| 国产精品麻豆人妻色哟哟久久| 久久精品熟女亚洲av麻豆精品| 亚洲精品美女久久av网站| 欧美激情高清一区二区三区| av超薄肉色丝袜交足视频| 美女主播在线视频| 色婷婷av一区二区三区视频| 国产精品免费大片| 久久久久久久久免费视频了| 老司机在亚洲福利影院| 天堂俺去俺来也www色官网| 99国产极品粉嫩在线观看| 久久久欧美国产精品| videosex国产| 高清黄色对白视频在线免费看| 免费观看a级毛片全部| 中文精品一卡2卡3卡4更新| 国产av国产精品国产| 九色亚洲精品在线播放| 每晚都被弄得嗷嗷叫到高潮| 黄色 视频免费看| 亚洲avbb在线观看| 精品一区二区三区四区五区乱码| 91精品三级在线观看| 少妇猛男粗大的猛烈进出视频| 美女大奶头黄色视频| 亚洲美女黄色视频免费看| 成人三级做爰电影| 脱女人内裤的视频| 欧美日韩精品网址| 日本五十路高清| 十八禁网站免费在线| av网站免费在线观看视频| 精品久久久久久电影网| 两个人看的免费小视频| 亚洲国产精品成人久久小说| 国产在线观看jvid| 高清黄色对白视频在线免费看| 99热国产这里只有精品6| 午夜免费鲁丝| 欧美日韩精品网址| av在线老鸭窝| 中国美女看黄片| 91精品伊人久久大香线蕉| 天天影视国产精品| 国产一区二区三区在线臀色熟女 | 日本a在线网址| 99久久国产精品久久久| 亚洲av电影在线观看一区二区三区| 老司机影院成人| 日韩视频在线欧美| 精品国产一区二区三区久久久樱花| 欧美精品一区二区免费开放| 免费av中文字幕在线| 人妻人人澡人人爽人人| 三上悠亚av全集在线观看| 中文字幕人妻丝袜一区二区| 久久免费观看电影| 国产男女内射视频| 美国免费a级毛片| 成人国产一区最新在线观看| 深夜精品福利| 麻豆av在线久日| 午夜激情久久久久久久| 亚洲欧美清纯卡通| 乱人伦中国视频| 女性生殖器流出的白浆| 一区二区av电影网| 国产av国产精品国产| 丝袜在线中文字幕| 在线永久观看黄色视频| 欧美精品一区二区大全| 久久久久国产一级毛片高清牌| 99久久综合免费| 国产深夜福利视频在线观看| 一二三四社区在线视频社区8| 久久性视频一级片| 亚洲欧洲精品一区二区精品久久久| 欧美日韩av久久| 少妇被粗大的猛进出69影院| 中亚洲国语对白在线视频| 可以免费在线观看a视频的电影网站| 精品久久久精品久久久| 97在线人人人人妻| 精品久久久久久久毛片微露脸 | 国产精品一区二区在线不卡| 午夜激情av网站| 久久亚洲精品不卡| 伊人亚洲综合成人网| 欧美国产精品一级二级三级| 一边摸一边抽搐一进一出视频| 国产在线一区二区三区精| 成人免费观看视频高清| 老司机午夜十八禁免费视频| 丝袜美足系列| 日本91视频免费播放| 中文字幕另类日韩欧美亚洲嫩草| 一本—道久久a久久精品蜜桃钙片| 我要看黄色一级片免费的| videos熟女内射| 男女之事视频高清在线观看| 美女扒开内裤让男人捅视频| 欧美精品亚洲一区二区| 久久国产精品男人的天堂亚洲| 黄色视频,在线免费观看| 老司机午夜十八禁免费视频| 热re99久久国产66热| 国产成人欧美| 亚洲精品粉嫩美女一区| 国产极品粉嫩免费观看在线| 精品国内亚洲2022精品成人 | 国产真人三级小视频在线观看| 国产精品.久久久| 在线观看免费午夜福利视频| 真人做人爱边吃奶动态| 韩国高清视频一区二区三区| 80岁老熟妇乱子伦牲交| 51午夜福利影视在线观看| 一本色道久久久久久精品综合| 欧美 亚洲 国产 日韩一| 女人高潮潮喷娇喘18禁视频| 叶爱在线成人免费视频播放| 国产97色在线日韩免费| 免费在线观看视频国产中文字幕亚洲 | 久久国产精品男人的天堂亚洲| 中文字幕另类日韩欧美亚洲嫩草| 国产区一区二久久| netflix在线观看网站| 免费黄频网站在线观看国产| 成年美女黄网站色视频大全免费| 夜夜夜夜夜久久久久| 午夜91福利影院| 亚洲伊人色综图| 免费观看av网站的网址| av网站在线播放免费| 777久久人妻少妇嫩草av网站| 精品人妻1区二区| 亚洲欧美一区二区三区黑人| 成人三级做爰电影| 国产精品一二三区在线看| 国产三级黄色录像| 日本wwww免费看| 欧美 亚洲 国产 日韩一| 亚洲精品一二三| 国产成人一区二区三区免费视频网站| 一级毛片女人18水好多| 久久久久久久大尺度免费视频| 黄色视频,在线免费观看| 午夜激情久久久久久久| 婷婷成人精品国产| 精品少妇黑人巨大在线播放| 91麻豆av在线| 动漫黄色视频在线观看| 欧美日本中文国产一区发布| 国产精品免费大片| 麻豆乱淫一区二区| 狠狠婷婷综合久久久久久88av| 亚洲精品久久午夜乱码| 日本欧美视频一区| 中亚洲国语对白在线视频| 中文字幕高清在线视频| 欧美变态另类bdsm刘玥| 国产精品秋霞免费鲁丝片| 黄网站色视频无遮挡免费观看| 最近最新中文字幕大全免费视频| 大片免费播放器 马上看| 欧美黑人欧美精品刺激| 亚洲avbb在线观看| kizo精华| 国产av国产精品国产| 90打野战视频偷拍视频| 不卡av一区二区三区| 天天操日日干夜夜撸| 久久国产精品影院| 成年人黄色毛片网站| 在线亚洲精品国产二区图片欧美| 99久久精品国产亚洲精品| 日本91视频免费播放| av网站在线播放免费| av视频免费观看在线观看| 9色porny在线观看| 91成年电影在线观看| 一区二区三区乱码不卡18| 最近最新中文字幕大全免费视频| 国产亚洲av高清不卡| 波多野结衣一区麻豆| 亚洲av成人不卡在线观看播放网 | 国产精品香港三级国产av潘金莲| 国产精品一区二区在线不卡| 大香蕉久久网| 欧美 亚洲 国产 日韩一| 老鸭窝网址在线观看| 天堂俺去俺来也www色官网| 69精品国产乱码久久久| 91成人精品电影| 国产亚洲欧美精品永久| 黄色 视频免费看| 99精品久久久久人妻精品| 99久久人妻综合| 欧美黄色淫秽网站| av视频免费观看在线观看| 色视频在线一区二区三区| 国产免费现黄频在线看| 国产老妇伦熟女老妇高清| 亚洲av国产av综合av卡| 久久久久久久国产电影| 日韩中文字幕视频在线看片| 热99久久久久精品小说推荐| 一级毛片精品| 中文字幕另类日韩欧美亚洲嫩草| 久久国产精品影院| 免费在线观看黄色视频的| 国产野战对白在线观看| 免费久久久久久久精品成人欧美视频| 亚洲男人天堂网一区| 美女福利国产在线| 永久免费av网站大全| 日韩中文字幕欧美一区二区| 日本一区二区免费在线视频| 久久国产精品男人的天堂亚洲| 欧美精品av麻豆av| 久久精品人人爽人人爽视色| 男人爽女人下面视频在线观看| 欧美日韩成人在线一区二区| 亚洲av成人不卡在线观看播放网 | 欧美黑人欧美精品刺激| 国产免费一区二区三区四区乱码| 欧美精品人与动牲交sv欧美| 悠悠久久av| 十分钟在线观看高清视频www| 美女中出高潮动态图| 国产一区二区 视频在线| 国产精品.久久久| 免费日韩欧美在线观看| 国产色视频综合| 99国产极品粉嫩在线观看| 亚洲精品国产一区二区精华液| 亚洲男人天堂网一区| 亚洲国产欧美网| 大型av网站在线播放| 久久久精品区二区三区| 两人在一起打扑克的视频| 一区二区日韩欧美中文字幕| 日日爽夜夜爽网站| 最近最新中文字幕大全免费视频| 久久久久久免费高清国产稀缺| 日韩一卡2卡3卡4卡2021年| 国产精品香港三级国产av潘金莲| 一级毛片女人18水好多| 亚洲欧美精品自产自拍| 久久久久久免费高清国产稀缺| 日本vs欧美在线观看视频| 午夜免费观看性视频| 精品国内亚洲2022精品成人 | 国产又爽黄色视频| 国产成人av激情在线播放| 99国产综合亚洲精品| 国产精品1区2区在线观看. | 亚洲人成77777在线视频| 丝袜脚勾引网站| 如日韩欧美国产精品一区二区三区| av在线app专区| 亚洲精品国产色婷婷电影| 欧美日韩中文字幕国产精品一区二区三区 | 日本av手机在线免费观看| 国产精品av久久久久免费| 亚洲精品第二区| 国产精品秋霞免费鲁丝片| 精品一品国产午夜福利视频| 中文字幕av电影在线播放| 国产成人精品久久二区二区91| 婷婷色av中文字幕| 老司机午夜福利在线观看视频 | 丝袜美腿诱惑在线| 亚洲欧美激情在线| 精品一区二区三区四区五区乱码| av视频免费观看在线观看| 美女福利国产在线| 啪啪无遮挡十八禁网站| 久久久久久人人人人人| 熟女少妇亚洲综合色aaa.| 精品人妻熟女毛片av久久网站| 两性午夜刺激爽爽歪歪视频在线观看 | 国产老妇伦熟女老妇高清| 日本av免费视频播放| 一个人免费看片子| 亚洲欧美日韩高清在线视频 | 2018国产大陆天天弄谢| 亚洲精品粉嫩美女一区| 手机成人av网站| 69精品国产乱码久久久| 日韩精品免费视频一区二区三区| 亚洲色图综合在线观看| 亚洲黑人精品在线| 嫩草影视91久久| 久久久精品94久久精品| 黑丝袜美女国产一区| 国产亚洲av高清不卡| 色婷婷av一区二区三区视频| a级片在线免费高清观看视频| 亚洲av片天天在线观看| a在线观看视频网站| videos熟女内射| 久久人人爽av亚洲精品天堂| 精品免费久久久久久久清纯 | 国产视频一区二区在线看| 99久久精品国产亚洲精品| 久久中文看片网| 中文字幕精品免费在线观看视频| 如日韩欧美国产精品一区二区三区| 午夜影院在线不卡| 日日夜夜操网爽| 老鸭窝网址在线观看| 日韩制服丝袜自拍偷拍| 久久ye,这里只有精品| 久久中文字幕一级| 亚洲中文字幕日韩| 精品久久蜜臀av无| 国产精品九九99| 久热爱精品视频在线9| 99热网站在线观看| 99精品欧美一区二区三区四区| 热99国产精品久久久久久7| 亚洲一卡2卡3卡4卡5卡精品中文| 在线观看免费视频网站a站| 免费一级毛片在线播放高清视频 | 中文字幕最新亚洲高清| 美女脱内裤让男人舔精品视频| 性色av一级| 人妻久久中文字幕网| 成人免费观看视频高清| 热99久久久久精品小说推荐| 日韩免费高清中文字幕av| 波多野结衣一区麻豆| 亚洲精品久久成人aⅴ小说| 王馨瑶露胸无遮挡在线观看| 国产精品成人在线| 男人添女人高潮全过程视频| 亚洲中文日韩欧美视频| 欧美亚洲 丝袜 人妻 在线| 欧美av亚洲av综合av国产av| av国产精品久久久久影院| 亚洲精华国产精华精| 91成人精品电影| 啦啦啦中文免费视频观看日本| 电影成人av| 涩涩av久久男人的天堂| svipshipincom国产片| 老汉色av国产亚洲站长工具| 咕卡用的链子| 成人黄色视频免费在线看| 国产淫语在线视频| netflix在线观看网站| 亚洲精品久久久久久婷婷小说| 国产一区有黄有色的免费视频| 精品国内亚洲2022精品成人 | 国产日韩欧美视频二区| 亚洲欧美成人综合另类久久久| 亚洲专区中文字幕在线| 91麻豆av在线| 日韩三级视频一区二区三区| 老司机在亚洲福利影院| 两人在一起打扑克的视频| 老汉色av国产亚洲站长工具| 一二三四在线观看免费中文在| 成人国产av品久久久| 男女免费视频国产| 嫩草影视91久久| 人人澡人人妻人| 一级片免费观看大全| 男女午夜视频在线观看| 亚洲 欧美一区二区三区| 18在线观看网站|