• <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

    一级黄色大片毛片| 啦啦啦视频在线资源免费观看| 女警被强在线播放| 丰满人妻熟妇乱又伦精品不卡| av电影中文网址| 中文字幕制服av| 久久狼人影院| 国产亚洲精品久久久久5区| 久久国产精品大桥未久av| videosex国产| 色网站视频免费| 国产在线免费精品| 国产成人一区二区在线| 国产一区有黄有色的免费视频| 韩国高清视频一区二区三区| 久久人人爽人人片av| 亚洲一区中文字幕在线| 亚洲精品一卡2卡三卡4卡5卡 | 国产免费福利视频在线观看| 日韩人妻精品一区2区三区| 90打野战视频偷拍视频| 欧美人与善性xxx| 捣出白浆h1v1| 国产在线视频一区二区| www.999成人在线观看| 美女高潮到喷水免费观看| 啦啦啦 在线观看视频| 国产高清不卡午夜福利| 高清视频免费观看一区二区| 婷婷丁香在线五月| 精品久久久久久久毛片微露脸 | 美国免费a级毛片| 国产一区亚洲一区在线观看| 成人免费观看视频高清| 考比视频在线观看| 婷婷色av中文字幕| 亚洲av成人不卡在线观看播放网 | 亚洲av在线观看美女高潮| 国产一区二区三区综合在线观看| 婷婷色综合大香蕉| 美女福利国产在线| 男女午夜视频在线观看| 成在线人永久免费视频| 久久久久视频综合| 欧美精品啪啪一区二区三区 | 欧美变态另类bdsm刘玥| 国产精品国产三级专区第一集| 激情五月婷婷亚洲| 热re99久久精品国产66热6| 久久毛片免费看一区二区三区| 亚洲一码二码三码区别大吗| 国产精品亚洲av一区麻豆| 18禁裸乳无遮挡动漫免费视频| 69精品国产乱码久久久| 亚洲一区中文字幕在线| 丝袜在线中文字幕| 国产精品香港三级国产av潘金莲 | 别揉我奶头~嗯~啊~动态视频 | 亚洲熟女毛片儿| 在线观看www视频免费| 久久国产亚洲av麻豆专区| 777久久人妻少妇嫩草av网站| 欧美日韩av久久| 精品福利观看| 一级a爱视频在线免费观看| 9热在线视频观看99| 欧美人与性动交α欧美软件| 在线观看www视频免费| 午夜免费观看性视频| 亚洲国产精品999| 成年美女黄网站色视频大全免费| 99精品久久久久人妻精品| www.自偷自拍.com| 成年av动漫网址| 日韩 欧美 亚洲 中文字幕| 在线精品无人区一区二区三| 国产av精品麻豆| 嫁个100分男人电影在线观看 | 国产97色在线日韩免费| 免费人妻精品一区二区三区视频| 一区二区三区精品91| 女人精品久久久久毛片| 一级毛片电影观看| 国产男女内射视频| 国产av国产精品国产| 久久青草综合色| 天天躁日日躁夜夜躁夜夜| 99国产精品一区二区三区| 久久热在线av| 好男人视频免费观看在线| 老司机在亚洲福利影院| 999久久久国产精品视频| 男人舔女人的私密视频| 人人妻,人人澡人人爽秒播 | h视频一区二区三区| 欧美黑人精品巨大| 免费高清在线观看日韩| 欧美在线一区亚洲| 大香蕉久久成人网| 最新的欧美精品一区二区| 永久免费av网站大全| 久久性视频一级片| 十八禁人妻一区二区| 精品熟女少妇八av免费久了| 久久这里只有精品19| 免费不卡黄色视频| 91麻豆av在线| xxx大片免费视频| svipshipincom国产片| 欧美日韩视频高清一区二区三区二| 一级毛片我不卡| 中文字幕制服av| 伊人久久大香线蕉亚洲五| 久久久久久免费高清国产稀缺| 秋霞在线观看毛片| 秋霞在线观看毛片| 精品国产国语对白av| av国产精品久久久久影院| 丰满人妻熟妇乱又伦精品不卡| 多毛熟女@视频| 在现免费观看毛片| 99热全是精品| www.自偷自拍.com| 赤兔流量卡办理| 丝袜美腿诱惑在线| 别揉我奶头~嗯~啊~动态视频 | 国产高清国产精品国产三级| 久久 成人 亚洲| 黄色视频在线播放观看不卡| 国产高清视频在线播放一区 | 天天躁狠狠躁夜夜躁狠狠躁| www.自偷自拍.com| 精品亚洲成a人片在线观看| 国产日韩欧美亚洲二区| 欧美变态另类bdsm刘玥| 国产精品二区激情视频| 老司机影院毛片| 免费高清在线观看日韩| 国产男女超爽视频在线观看| 久久久亚洲精品成人影院| av福利片在线| 别揉我奶头~嗯~啊~动态视频 | 精品国产乱码久久久久久小说| 男女边摸边吃奶| 免费人妻精品一区二区三区视频| 赤兔流量卡办理| 欧美性长视频在线观看| av不卡在线播放| 秋霞在线观看毛片| 免费黄频网站在线观看国产| 国产主播在线观看一区二区 | 婷婷丁香在线五月| 王馨瑶露胸无遮挡在线观看| 婷婷色av中文字幕| 国产免费福利视频在线观看| 校园人妻丝袜中文字幕| 国产一区有黄有色的免费视频| 国产精品久久久久久人妻精品电影 | 久久久久久久大尺度免费视频| 午夜福利在线免费观看网站| 777米奇影视久久| 国产精品免费视频内射| 精品久久久久久久毛片微露脸 | 欧美大码av| 美女视频免费永久观看网站| 成年美女黄网站色视频大全免费| 91老司机精品| 国产亚洲精品第一综合不卡| 1024视频免费在线观看| 亚洲国产最新在线播放| 精品视频人人做人人爽| 亚洲美女黄色视频免费看| 日日摸夜夜添夜夜爱| 波多野结衣av一区二区av| 9191精品国产免费久久| 在线观看免费视频网站a站| 欧美成狂野欧美在线观看| 精品少妇内射三级| 日韩电影二区| 观看av在线不卡| 一级毛片我不卡| 久久亚洲精品不卡| 你懂的网址亚洲精品在线观看| 黄色一级大片看看| 18禁观看日本| 两个人免费观看高清视频| 免费高清在线观看日韩| 欧美成狂野欧美在线观看| 国产男女内射视频| 免费一级毛片在线播放高清视频 | 午夜福利一区二区在线看| 只有这里有精品99| 国产成人a∨麻豆精品| 国产野战对白在线观看| 色94色欧美一区二区| 一级,二级,三级黄色视频| 久久免费观看电影| 18禁黄网站禁片午夜丰满| 亚洲欧洲日产国产| 色视频在线一区二区三区| 成年人午夜在线观看视频| av天堂在线播放| 国产精品九九99| 欧美成狂野欧美在线观看| 午夜91福利影院| 久久亚洲精品不卡| 99久久精品国产亚洲精品| 国产精品一区二区精品视频观看| 久久精品人人爽人人爽视色| 成人影院久久| 搡老岳熟女国产| 最新的欧美精品一区二区| 国产成人精品久久二区二区免费| 免费看不卡的av| 99热国产这里只有精品6| 免费在线观看视频国产中文字幕亚洲 | 80岁老熟妇乱子伦牲交| 黄色片一级片一级黄色片| 曰老女人黄片| 看免费成人av毛片| svipshipincom国产片| 伊人久久大香线蕉亚洲五| 伊人亚洲综合成人网| 免费一级毛片在线播放高清视频 | 欧美亚洲日本最大视频资源| 纵有疾风起免费观看全集完整版| 人人妻人人添人人爽欧美一区卜| 99久久人妻综合| 纵有疾风起免费观看全集完整版| 王馨瑶露胸无遮挡在线观看| 国产91精品成人一区二区三区 | 日韩一本色道免费dvd| 一区二区三区四区激情视频| 人妻 亚洲 视频| 亚洲人成电影免费在线| 亚洲熟女毛片儿| 90打野战视频偷拍视频| 我的亚洲天堂| 精品人妻在线不人妻| 18禁黄网站禁片午夜丰满| 欧美精品亚洲一区二区| 男女之事视频高清在线观看 | 久久精品熟女亚洲av麻豆精品| 成年人黄色毛片网站| 超碰成人久久| 亚洲精品美女久久久久99蜜臀 | 国产精品二区激情视频| svipshipincom国产片| 99久久人妻综合| 18在线观看网站| 日韩免费高清中文字幕av| 亚洲久久久国产精品| 啦啦啦在线观看免费高清www| 欧美亚洲日本最大视频资源| 免费看十八禁软件| 久久精品亚洲熟妇少妇任你| 久久国产精品大桥未久av| 久久影院123| 国产精品麻豆人妻色哟哟久久| 午夜av观看不卡| 亚洲精品日本国产第一区| 日韩,欧美,国产一区二区三区| 国产激情久久老熟女| 成人国产一区最新在线观看 | 中文字幕亚洲精品专区| 亚洲人成电影观看| 亚洲国产精品成人久久小说| 久久中文字幕一级| 真人做人爱边吃奶动态| 在线精品无人区一区二区三| 国产精品一区二区在线不卡| 精品一区二区三卡| 成人国语在线视频| 国产成人欧美| 大香蕉久久成人网| 亚洲精品成人av观看孕妇| 黑丝袜美女国产一区| 久久国产精品人妻蜜桃| 午夜免费观看性视频| 亚洲av男天堂| 国产深夜福利视频在线观看| av福利片在线| 999精品在线视频| 国产成人精品久久二区二区91| 中文字幕av电影在线播放| 免费看不卡的av| av又黄又爽大尺度在线免费看| 每晚都被弄得嗷嗷叫到高潮| 久久性视频一级片| 麻豆乱淫一区二区| 一级片免费观看大全| 咕卡用的链子| 夫妻性生交免费视频一级片| 国精品久久久久久国模美| 日韩欧美一区视频在线观看| 大片电影免费在线观看免费| 国产日韩欧美在线精品| 成人国语在线视频| 涩涩av久久男人的天堂| 性少妇av在线| www.自偷自拍.com| 国产极品粉嫩免费观看在线| 晚上一个人看的免费电影| 中国美女看黄片| 夜夜骑夜夜射夜夜干| 国产三级黄色录像| 校园人妻丝袜中文字幕| 亚洲久久久国产精品| 欧美另类一区| 成年动漫av网址| 99久久精品国产亚洲精品| 欧美 日韩 精品 国产| 欧美亚洲 丝袜 人妻 在线| 美女国产高潮福利片在线看| 久久99一区二区三区| 大片免费播放器 马上看| 亚洲久久久国产精品| 精品一区在线观看国产| 午夜福利一区二区在线看| 久久久久国产一级毛片高清牌| 少妇人妻 视频| 妹子高潮喷水视频| 欧美亚洲 丝袜 人妻 在线| 国产精品久久久久久精品电影小说| 叶爱在线成人免费视频播放| 好男人视频免费观看在线| 日本黄色日本黄色录像| 国产精品一区二区免费欧美 | 日韩一本色道免费dvd| 欧美性长视频在线观看| 天堂中文最新版在线下载| 男男h啪啪无遮挡| 99国产精品免费福利视频| 欧美精品av麻豆av| 精品人妻在线不人妻| 啦啦啦在线观看免费高清www| 国产日韩欧美亚洲二区| 99久久精品国产亚洲精品| 狠狠精品人妻久久久久久综合| 久久九九热精品免费| 国产片特级美女逼逼视频| 夫妻性生交免费视频一级片| 久久精品国产综合久久久| 国产三级黄色录像| av在线播放精品| 一本一本久久a久久精品综合妖精| 久久久精品94久久精品| 少妇被粗大的猛进出69影院| www.熟女人妻精品国产| 久久久欧美国产精品| 亚洲欧洲日产国产| 日韩 欧美 亚洲 中文字幕| 国产成人免费观看mmmm| 欧美+亚洲+日韩+国产| 日本色播在线视频| 老司机靠b影院| 久久精品成人免费网站| 水蜜桃什么品种好| 视频在线观看一区二区三区| 日韩一区二区三区影片| 大香蕉久久成人网| 欧美日韩黄片免| 亚洲一区二区三区欧美精品| 一级黄色大片毛片| 只有这里有精品99| 亚洲av综合色区一区| 国产黄频视频在线观看| 欧美日韩黄片免| 国产色视频综合| 韩国高清视频一区二区三区| 日本av免费视频播放| 在线观看www视频免费| 久久99精品国语久久久| 亚洲熟女毛片儿| 亚洲人成电影观看| 免费看av在线观看网站| 如日韩欧美国产精品一区二区三区| 一本综合久久免费| 午夜免费男女啪啪视频观看| 亚洲人成电影观看| 黄片播放在线免费| 丝瓜视频免费看黄片| 久久九九热精品免费| 国产老妇伦熟女老妇高清| 天天添夜夜摸| 人人澡人人妻人| 国产主播在线观看一区二区 | 一边摸一边抽搐一进一出视频| 看十八女毛片水多多多| 男女国产视频网站| 久久国产精品男人的天堂亚洲| 国产欧美日韩综合在线一区二区| 亚洲成人免费电影在线观看 | 一本综合久久免费| 看免费成人av毛片| 中文精品一卡2卡3卡4更新| 婷婷成人精品国产| 久久国产精品大桥未久av| 精品一区在线观看国产| 十八禁高潮呻吟视频| 大话2 男鬼变身卡| 丰满人妻熟妇乱又伦精品不卡| 在线亚洲精品国产二区图片欧美| 少妇裸体淫交视频免费看高清 | 性色av一级| 国产免费福利视频在线观看| 高清不卡的av网站| av欧美777| 精品一区二区三区四区五区乱码 | 尾随美女入室| 免费不卡黄色视频| 999精品在线视频| 欧美精品一区二区大全| 手机成人av网站| 欧美精品一区二区大全| 欧美成人午夜精品| 69精品国产乱码久久久| 亚洲专区中文字幕在线| 精品久久久久久电影网| 国产野战对白在线观看| 成人三级做爰电影| 国产欧美日韩一区二区三 | 啦啦啦中文免费视频观看日本| 在线天堂中文资源库| 中文字幕av电影在线播放| 久久精品人人爽人人爽视色| 一本大道久久a久久精品| 男女免费视频国产| 又紧又爽又黄一区二区| 亚洲天堂av无毛| 飞空精品影院首页| 色婷婷av一区二区三区视频| 国产真人三级小视频在线观看| 午夜久久久在线观看| 80岁老熟妇乱子伦牲交| 50天的宝宝边吃奶边哭怎么回事| 成人免费观看视频高清| 我要看黄色一级片免费的| 51午夜福利影视在线观看| 在线 av 中文字幕| 亚洲激情五月婷婷啪啪| 美女视频免费永久观看网站| 老司机午夜十八禁免费视频| 国产真人三级小视频在线观看| 国产亚洲午夜精品一区二区久久| 国产成人一区二区在线| 国产成人a∨麻豆精品| 丝袜美腿诱惑在线| 欧美日韩精品网址| 久久精品亚洲av国产电影网| 国产爽快片一区二区三区| 两人在一起打扑克的视频| 免费黄频网站在线观看国产| 国产精品欧美亚洲77777| 欧美黄色片欧美黄色片| 国产1区2区3区精品| 99国产综合亚洲精品| 国产精品久久久久成人av| 欧美精品一区二区大全| 免费看av在线观看网站| 又紧又爽又黄一区二区| 日韩人妻精品一区2区三区| 国产精品一二三区在线看| av福利片在线| 亚洲国产毛片av蜜桃av| 国产片内射在线| 老汉色av国产亚洲站长工具| 欧美乱码精品一区二区三区| 高清黄色对白视频在线免费看| 侵犯人妻中文字幕一二三四区| 欧美日韩视频精品一区| 女人高潮潮喷娇喘18禁视频| 国产亚洲午夜精品一区二区久久| 精品少妇黑人巨大在线播放| 久久精品国产综合久久久| 亚洲国产精品一区二区三区在线| 亚洲五月色婷婷综合| 后天国语完整版免费观看| www.自偷自拍.com| 大片电影免费在线观看免费| 深夜精品福利| 亚洲欧美一区二区三区久久| 亚洲国产欧美一区二区综合| 日韩精品免费视频一区二区三区| 亚洲国产精品一区三区| 国产精品一区二区在线观看99| 老司机深夜福利视频在线观看 | 亚洲精品乱久久久久久| 亚洲视频免费观看视频| 久久综合国产亚洲精品| 成在线人永久免费视频| 亚洲欧美精品综合一区二区三区| 国产一区二区三区av在线| 自线自在国产av| 国产男人的电影天堂91| 宅男免费午夜| 人人妻人人添人人爽欧美一区卜| 丝袜美腿诱惑在线| 亚洲五月色婷婷综合| 久久精品久久久久久噜噜老黄| 欧美精品高潮呻吟av久久| 久久ye,这里只有精品| 大香蕉久久网| netflix在线观看网站| 满18在线观看网站| 一区二区三区激情视频| av片东京热男人的天堂| 久热这里只有精品99| 高潮久久久久久久久久久不卡| 人人妻人人澡人人爽人人夜夜| 欧美性长视频在线观看| 久久性视频一级片| 涩涩av久久男人的天堂| 成人影院久久| 天天添夜夜摸| 精品少妇一区二区三区视频日本电影| 精品国产乱码久久久久久小说| 欧美av亚洲av综合av国产av| 欧美久久黑人一区二区| 久久中文字幕一级| 亚洲成人免费电影在线观看 | 欧美黑人精品巨大| 中文字幕av电影在线播放| 亚洲av日韩在线播放| 另类精品久久| 久久久久久亚洲精品国产蜜桃av| 国产不卡av网站在线观看| 黄色毛片三级朝国网站| 人成视频在线观看免费观看| 久久久久久久大尺度免费视频| 大码成人一级视频| 亚洲精品美女久久久久99蜜臀 | 超色免费av| 日韩制服丝袜自拍偷拍| 国产精品免费大片| 久久久久精品人妻al黑| 超碰成人久久| 波多野结衣一区麻豆| 亚洲欧美色中文字幕在线| 久久综合国产亚洲精品| 免费观看av网站的网址| 欧美日韩黄片免| 亚洲精品乱久久久久久| 欧美人与善性xxx| 老司机深夜福利视频在线观看 | 精品一区二区三区av网在线观看 | 免费黄频网站在线观看国产| 9色porny在线观看| 肉色欧美久久久久久久蜜桃| 欧美日韩黄片免| 成年女人毛片免费观看观看9 | 国产亚洲欧美精品永久| 老汉色av国产亚洲站长工具| 9191精品国产免费久久| 亚洲欧美一区二区三区黑人| 欧美日韩av久久| 国产精品偷伦视频观看了| 国产高清国产精品国产三级| www.自偷自拍.com| 久久女婷五月综合色啪小说| 欧美久久黑人一区二区| 亚洲中文av在线| 国产免费视频播放在线视频| 欧美日韩综合久久久久久| 高清欧美精品videossex| 亚洲七黄色美女视频| 国产精品熟女久久久久浪| 久久免费观看电影| 精品少妇一区二区三区视频日本电影| 久久99一区二区三区| 精品国产一区二区久久| 亚洲欧美色中文字幕在线| 中文字幕最新亚洲高清| videosex国产| 久久久久网色| 伊人亚洲综合成人网| 亚洲熟女毛片儿| 欧美日韩视频精品一区| 婷婷色av中文字幕| 成人黄色视频免费在线看| 亚洲国产成人一精品久久久| 美女主播在线视频| av线在线观看网站| 亚洲av男天堂| 日韩电影二区| 国产视频首页在线观看| www.999成人在线观看| 少妇猛男粗大的猛烈进出视频| 人体艺术视频欧美日本| 国产老妇伦熟女老妇高清| 中国美女看黄片| 999精品在线视频| 亚洲国产av新网站| 欧美在线黄色| 亚洲av电影在线观看一区二区三区| 亚洲精品美女久久久久99蜜臀 | 精品视频人人做人人爽| 中文字幕最新亚洲高清| 日本黄色日本黄色录像| 咕卡用的链子| 伊人亚洲综合成人网| 啦啦啦啦在线视频资源| 一区二区av电影网| 国产免费又黄又爽又色| av天堂久久9| 五月开心婷婷网| 超碰成人久久| 久久久亚洲精品成人影院| 欧美+亚洲+日韩+国产| 丰满迷人的少妇在线观看| 久久99一区二区三区| 久久精品国产a三级三级三级| 男女国产视频网站| 国产伦人伦偷精品视频| 亚洲专区中文字幕在线|