key: cord-0989494-beu232l9 authors: Katneni, Upendra K.; Alexaki, Aikaterini; Hunt, Ryan C.; Schiller, Tal; DiCuccio, Michael; Buehler, Paul W.; Ibla, Juan C.; Kimchi-Sarfaty, Chava title: Coagulopathy and Thrombosis as a Result of Severe COVID-19 Infection: A Microvascular Focus date: 2020-08-24 journal: Thromb Haemost DOI: 10.1055/s-0040-1715841 sha: 65c67825826695e3aecf812a06d9ee2322601532 doc_id: 989494 cord_uid: beu232l9 Coronavirus disease of 2019 (COVID-19) is the clinical manifestation of the respiratory infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). While primarily recognized as a respiratory disease, it is clear that COVID-19 is systemic illness impacting multiple organ systems. One defining clinical feature of COVID-19 has been the high incidence of thrombotic events. The underlying processes and risk factors for the occurrence of thrombotic events in COVID-19 remain inadequately understood. While severe bacterial, viral, or fungal infections are well recognized to activate the coagulation system, COVID-19-associated coagulopathy is likely to have unique mechanistic features. Inflammatory-driven processes are likely primary drivers of coagulopathy in COVID-19, but the exact mechanisms linking inflammation to dysregulated hemostasis and thrombosis are yet to be delineated. Cumulative findings of microvascular thrombosis has raised question if the endothelium and microvasculature should be a point of investigative focus. von Willebrand factor (VWF) and its protease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), play important role in the maintenance of microvascular hemostasis. In inflammatory conditions, imbalanced VWF-ADAMTS-13 characterized by elevated VWF levels and inhibited and/or reduced activity of ADAMTS-13 has been reported. Also, an imbalance between ADAMTS-13 activity and VWF antigen is associated with organ dysfunction and death in patients with systemic inflammation. A thorough understanding of VWF-ADAMTS-13 interactions during early and advanced phases of COVID-19 could help better define the pathophysiology, guide thromboprophylaxis and treatment, and improve clinical prognosis. Coronavirus disease of 2019 (COVID-19) is a respiratory illness caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is an enveloped, positive-sense single-stranded ribonucleic acid virus belonging to the Coronaviridae family. 1 The COVID-19 outbreak started in Wuhan, China, in late 2019 and rapidly spread to rest of the world. On March 11, 2020 , the World Health Organization declared COVID-19 outbreak as pandemic. As of June 24, 2020, the global number of COVID-19 cases stood at 9.26 million with 478,000 deaths (Source: Johns Hopkins Coronavirus Resource Center, https://coronavirus.jhu.edu/). Disease course is markedly different between individuals while some are completely asymptomatic, others develop mild symptoms including mild fever, loss of taste or smell, dry cough, sore throat, shortness of breath, and myalgia. [2] [3] [4] In susceptible individuals, the disease progresses to pneumonia, hypoxemia, acute respiratory distress, and multiorgan dysfunction that may lead to death. 3 The predominance of asymptomatic or mild infections has contributed to the rapid spread of COVID-19 compared with earlier coronavirus outbreaks of SARS and Middle East respiratory syndrome in 2002 and 2012, respectively. 4, 5 Consumptive Coagulopathy and the High Incidence of Thrombosis in COVID-19 Patients Altered coagulation is a common feature of acute systemic diseases, specifically to those affecting primarily the respiratory system. Based on studies in patients with acute respiratory distress syndrome (ARDS), the coexistence of disseminated intravascular coagulation (DIC) with subsequent consumption of procoagulation proteins and platelets has been consistently described. 6 This in turn leads to the formation of microthrombi in the vascular bed of organs resulting from excess coagulation byproducts and suppression of endogenous anticoagulation factors. 7 The coexistence of consumptive coagulopathy and thrombosis are the result of a common pathologic pathway; however, the exact mechanisms that tilts the balance toward thrombosis in COVID-19 are less well understood. 8 In this sense, some features of the coagulopathy associated with COVID-19 may be not unique to this disease; however, the magnitude of the thrombotic response and its impact on mortality suggests the presence of additional mechanisms, beyond what is known for similar respiratory acute inflammatory diseases. Several studies have linked coagulation abnormalities to severe COVID-19 illness 9,10 (►Table 1). In a study evaluating 449 severe COVID-19 patients, Tang et al 11 reported positive correlation of 28-day mortality with fibrin degradation product (FDP), D-dimers and prothrombin time (PT), and negative correlation with platelet count. Laboratory parameters were recorded at the time of onset of severe COVID-19 in the study. In an earlier study comprising 183 patients, Tang et al 12 reported elevated D-dimer levels and FDP levels and prolonged PT and activated partial thromboplastin times (aPTTs) at the time of admission in nonsurvivors compared with survivors. In the same study, significantly lower levels of fibrinogen and antithrombin levels were observed during the late hospitalization in nonsurvivors. Huang Multiple studies have reported a higher incidence of thrombotic events, particularly pulmonary embolism, as a frequent complication in COVID-19 patients (►Table 1). Llitjos et al 20 reported overall rate of 69% venous thromboembolism (VTE) in severe COVID-19 patients admitted to ICU. In this study, VTE incidence was found to be significantly higher in patients treated with prophylactic anticoagulation compared with those treated with therapeutic anticoagulation. Helms et al 7 reported 64 clinically relevant thrombotic complications in 150 ICU-admitted patients. Importantly, the incidence of thrombotic complications in COVID-19 ARDS patients was significantly higher than non-COVID-19 ARDS patients in this study. Ackermann et al 21 compared lung sections of COVID-19 patients with those died from ARDS secondary to influenza A (H1N1) infection and found relatively higher: (1) endothelial cell injury, (2) alveolar microthrombi (ninefold), and (3) intussusceptive angiogenesis in COVID-19 lung sections. Similarly, higher incidence of thromboembolic complications in ICU-admitted COVID-19 patients was also reported by Klok et al (31%), 22 Lodigiani et al (27.6%), 23 Middeldorp et al (47%), 24 Nahum et al (79%), 25 and Cui et al (25%). 26 For comparison, in a study by Zhang et al, the reported cumulative incidence of VTE in ICU-admitted patients receiving guideline-recommended thromboprophylaxis was 9.55% (95% confidence interval: 6.55-13.81). VWF/ADAMTS-13 in COVID-19 Pathophysiology Katneni et al. This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. A high incidence of DIC diagnosed by D-dimer, fibrinogen, and antithrombin III levels has become a focus for the initiation of anticoagulation therapy in severe COVID-19 patients, 28 with some studies relying on D-dimers alone. 11,29 A retrospective analysis of 183 patients performed by Tang et al 12 suggested that more than 70% of severe COVID-19 patients who succumb to the infection demonstrate increased risk of thrombosis, further this group suggests that all of these patients meet the International Society on Thrombosis and Haemostasis definition of DIC. Subsequently, Tang et al 11 reported an equivalent 28-day mortality rate (30%) in 99 patients receiving low molecular weight or unfractionated heparin for 7 days compared with 350 nonheparin treated patients or those receiving a less than 7-day course of therapy. A case series reported by Wang et al 28 detailed the use and outcome following tissue plasminogen activator (tPA) in three patients with ARDS and coagulopathy consistent with DIC. Intravenous dosing with tPA indicated a potential benefit in each of the three cases of COVID-19. However, this study also warns of both unrelated effects and high risk of severe bleeding secondary to off-label tPA use. Several of the studies in coagulopathic COVID-19 patients suspected of DIC rely heavily on analysis of fibrin degradation and D-dimer levels, which are expected to be increased during DIC, arterial and venous thromboses, strokes, and thrombotic microangiopathies. 30 However, D-dimers are a nonspecific indicator of thrombosis in severe COVID-19 patients with pulmonary injury. Fibrin accumulation and lysis continuously occur during nonthrombotic inflammation as well as tissue necrosis, and therefore, significant D-dimer elevations also accumulate during cancers 31 and infections, consistent with inflammatory processes that coincide with the progression of severe COVID-19-related macrophage activation syndrome. 32 Therefore, we suggest that more comprehensive and robust assays be used to evaluate changes in hemostasis. For example, to date the use of thrombin, plasmin, or simultaneous thrombin/plasmin generation assays have not been reported within the context of hemostasis management of COVID-19 patients. Since their introduction thrombin and plasmin generation assays have been highly informative regarding the assessment of hemorrhage, coagulation, and fibrinolysis. 33, 34 Assessment of impairment of these systems would provide a useful and appropriate guidance needed for and monitoring of therapeutic interventions in the unique coagulopathies associated with COVID-19. 33, 34 Because patients are often on unfractionated or low molecular weight heparin and plasminogen activator inhibitor 1, von Willebrand factor (VWF), plasminogen, fibrinogen, and factor VIII are all reported to be elevated in SARS infection, 35 and therefore careful modification of these assays may be warranted to optimize the concentrations of added tPA, tissue factor, and thrombomodulin. These studies present a heterogeneous picture that is difficult to evaluate in the aggregate. Inclusion criteria for patients varied across these studies, making direct comparisons between the studies difficult. Further, the studies used different regimens of thromboprophylaxis, which could impact outcomes. In some studies, a high proportion of patients were still hospitalized at the end of the reporting period; conclusions and clinical courses therefore were based on incomplete information, and completion of these patients' clinical course could alter the final conclusions. The picture of coagulopathy in COVID-19 is complex. Specific, sensitive, and temporal assessments of coagulation and fibrinolysis should be established and further work is needed to untangle the roles of the host inflammatory response, preexisting thrombotic risk, and prehospitalization pharmacologic regimens in the optimal management of coagulopathy in the setting of COVID-19. The risk of hospitalization, morbidity, and mortality from COVID-19 is highest for older patients with preexisting conditions such as hypertension, diabetes, cardiovascular disease, and obesity. 13, 14, 16, 17, 36, 37 A common theme of all these comorbidities is their association with vascular inflammation and endothelial dysfunction. 38, 39 Proinflammatory conditions affect hemostasis by blocking of fibrinolysis and induction of prothrombotic conditions through activation of endothelial cells and innate immune cells via release of several factors including tissue factor, VWF, and neutrophil extracellular traps (NETs) that promote thrombosis. 40 Induction of proinflammatory conditions was reported in the pathophysiology of several viral diseases including influenza and SARS. 41 Increased inflammation is commonly observed in COVID-19 patients, while severe cases are characterized by immune dysregulation and hyperinflammation, with a markedly increased serum interleukin (IL)-6. 42 Cytokine release syndrome has also been reported in COVID-19 patients and correlates with adverse . A concurrent increase in the levels of anti-inflammatory cytokine IL-10, probably in response to overwhelming systemic inflammation, was also observed in several studies. The role of IL-6, in particular, is considered central in the pathogenesis of COVID-19 complications, 54 and therefore tocilizumab, an IL-6 inhibitor, is being used in ongoing clinical trials to prevent catastrophic inflammation. [55] [56] [57] [58] Liver injury during COVID-19 infections was described in multiple studies, including elevated levels of alanine aminotransferase, aspartate aminotransferase, and bilirubin. 14, 16, 17, 36, 44, 47 The liver is the primary source of plasma proteins, particularly those involved in hemostasis. Thus, the occurrence of liver injury may contribute further to derangements of key hemostasis proteins and contributes to coagulopathy. 59 Similarly, hypoxemia observed in COVID-19 patients induces prothrombotic conditions through upregulation of plasminogen activator inhibitor and stimulation of endothelial synthesis of procoagulants, including tissue factor and VWF. [60] [61] [62] [63] Thus, multiple clinical characteristics observed in COVID-19 patients contribute to altered coagulation and lead to increased incidence of thrombosis. However, the early onset of coagulopathy-before systemic organic effects occur-suggests proinflammatory conditions as the primary driving cause of thrombotic events in COVID-19 patients. VWF and its cleaving protease, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13), play an important role in hemostasis particularly within the microvasculature. 64 VWF is a large multimeric glycoprotein primarily expressed by endothelial cells and platelets. Endothelial cells show both basal secretion and regulated release of VWF stored in Weibel-Palade bodies in response to various stimuli. On the other hand, platelets secrete VWF stored in α-granules only upon activation. 65 ADAMTS-13 is expressed both by hepatic stellate cells and endothelial cells; the relative contribution of hepatic and microvascular expression is not clear. 66 ADAMTS-13 regulates the biological activity of VWF by cleaving prothrombotic ultra-large VWF multimers (> 10,000 kDa) secreted from endothelial cells into hemostatically active high molecular weight multimers (< 10,000 kDa) under shear stress conditions. 67 Severe deficiency of ADAMTS-13 results in accumulation of ultra-large VWF multimers leading to microvascular thrombosis and consumptive thrombocytopenia, a condition termed thrombotic thrombocytopenic purpura (TTP). 64 In the event of vascular injury, VWF facilitates binding of platelets to subendothelium through its interactions with glycoprotein Ib and collagen, thereby inducing thrombus formation. 64 A reciprocal relationship exists between VWF and ADAMTS-13 levels where elevated circulatory VWF antigen levels are associated with concomitant decrease in ADAMTS-13 activity and vice versa. [68] [69] [70] Abnormal VWF-ADAMTS-13 ratios are implicated in arterial thrombosis, 71 ischemic stroke, 72,73 pediatric stroke, 74 and perioperative thrombosis in infants. 75 In addition, abnormal VWF/ADAMTS-13 metabolism has been positively associated with myocardial infarction in young women. 76 It is worth highlighting that in the case of perioperative thrombosis, elevated VWF even in the absence of significant deficiency of ADAMTS-13 was associated with thrombosis. 75 Severe hypoxia and acidosis likely caused a higher increase in VWF during cardiac surgery and were at higher risk of thrombosis. 75 CRP and IL-6 Tan et al 53 Severe (25) This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Elevated levels of VWF are found in several inflammatory and metabolic disorders including diabetes, obesity, and sickle cell disease. 77 In patients with systemic inflammatory response syndrome, active VWF predicted 28-day mortality. 78 VWF is an acute-phase response protein released by activated endothelial cells in response to inflammatory stimuli. 77 Inflammatory cytokines, IL-8 and tumor necrosis factor-α induced the release of VWF from human umbilical vein endothelial cells. 79 VWF released in inflammation binds to NETs released from activated neutrophils and recruits platelets and leukocytes to promote thrombosis. 77 ADAMTS-13 deficiency in inflammatory conditions was demonstrated to promote VWF-dependent leukocyte adhesion and extravasation in mice. 80 In patients with systemic inflammation, ADAMTS-13 activity decreases proportional to the inflammatory response; an imbalance between ADAMTS-13 activity and VWF antigen is associated with organ dysfunction and death. 81, 82 Dysregulated host response to infection including inflammation can result in septic shock. In septic shock, ADAMTS-13 activity was significantly lower [83] [84] [85] and elevated ratio of VWF propeptide (VWFpp) that is secreted along with ultra-large VWF multimers in to blood stream and ADAMTS-13 was associated with disease severity. 86 In patients with DIC, ADAMTS-13 activity decreased with DIC score 87 and VWFpp/ADAMTS-13 ratio was significantly elevated in nonsurvivors compared with survivors. 88 An interesting observation is that smoking, which is associated with adverse outcomes in COVID-19 patients, 89 was also found to be associated with decreased plasma ADAMTS-13 levels in a study of 3,244 individuals. 90 Increased expression of angiotensin-converting enzyme 2, the entry receptor for SARS-CoV-2, in the small airway epithelia of smokers was suggested as the potential mechanism for increased risk of severe COVID-19 in smokers. 91 Smoking is also associated with increased inflammatory markers. 92 The imbalance between ADAMTS-13 and VWF in heightened inflammation could be a result of inhibition and/or deficiency of ADAMTS-13 activity. 93 The inhibition of VWF cleavage by ADAMTS-13 in inflammatory conditions was suggested to be mediated by several mechanisms: (1) thrombospondin-1 released from α-granules of activated platelets by binding to the A2-A3 domain of VWF 94,95 ; (2) α-defensins released from neutrophils by binding to the A2 domain of Despite playing an important role in the maintenance of hemostasis and the occurrence of micro-and macrovascular thrombosis, VWF-ADAMTS-13 interactions have not received much investigative attention in the evaluation of COVID-19 pathophysiology, specifically in relation to elevated incidence of VTE. Importantly, reduced ADAMTS-13 activity has been shown to correlate with increased inflammation in multiple sys-tems, 100-102 while IL-6 has been shown to inhibit the cleavage of ultra-large VWF strings by ADAMTS-13 under flowing conditions. 79, 103 The authors could find only five studies evaluating both VWF and ADAMTS-13 levels in COVID-19 patients in literature [104] [105] [106] [107] [108] . Majority of these studies reported lower ADAMTS-13 activity concurrent with higher VWF in COVID-19 patients. [104] [105] [106] [107] In one of these studies, Bazzan et al 104 reported lower ADAMTS-13 levels in 88 COVID-19 patients compared with healthy controls (48.71 AE 18.7% vs. healthy control, 108 AE 9.1%; normal value 60-130%). Within patient cohort, lower ADAMTS-13 and higher VWF levels were found in nonsurvivors (9/88) compared with survivors. Further, lower than 30% ADAMTS-13 activity were significantly associated with mortality in survivor analysis. Huisman et al 105 observed low ADAMTS-13 activity levels (0.48 AE 0.14 IU/mL against a reference range of 0.61-1.31) in parallel with elevated VWF antigen and activity ($ fourfold) in 12 ICU-admitted patients. A similar reduction in ADAMTS-13 and increased VWF levels was also reported by Adam et al 106 A secondary mechanism potentially contributing to ADAMTS-13 deficiency relates to the antiphospholipid antibody generation during SARS-CoV-2 infection. 7,110-112 Antiphospholipid antibodies have been inconsistently reported in all cases of COVID 19, 7, 111, 112 but strongly associated to prolong aPTT as reported by Bowles et al. 112 Patients with antiphospholipid syndrome have been found to have abnormal ADAMTS-13 plasmatic activity further increasing the risk of thrombosis. 113 The exact mechanisms by which antiphospholipid antibodies interfere with ADAMTS-13 cleaving activity are unclear. We speculate that antiphospholipid antibodies generated during active SARS-CoV-2 infection can potentially bind the spacer domain of ADAMTS-13 interfering with the recognition and proteolysis of VWF. Such a mechanism is similar to the binding of autoantibodies against ADAMTS-13 present in TTP resulting in clinical thrombosis. 114 Based on the limited available data, we propose a mechanistic model in which: (1) SARS-CoV-2 causes endothelial activation and damage leading to overwhelming VWF release and (2) proinflammatory mediators or antibodies during the severe phase of COVID-19 result in reduced cleavage of high molecular weight VWF by ADAMTS-13, ultimately leading to thrombosis, see ►Fig. 1. This concept should be confirmed by large patient cohorts that encompass mild and severe clinical courses of COVID-19 disease. A mechanistic understanding of thrombosis In inflammation, cleavage of VWF by ADAMT-S13 is prevented by multiple mechanisms that either inhibit or reduce the proteolytic activity of ADAMTS-13. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding Epidemiology Working Group for NCIP Epidemic Response, Chinese Center for Disease Control and Prevention. The epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (COVID-19) in China A review of coronavirus disease-2019 (COVID-19) Transmission of 2019-nCoV infection from an asymptomatic contact in Germany COVID-19, SARS and MERS: are they closely related? Association for Acute Medicine (JAAM) Focused Outcomes Research in Emergency Care in Acute Respiratory Distress Syndrome, Sepsis and Trauma (FORECAST) Study Group, et al; The significance of disseminated intravascular coagulation on multiple organ dysfunction during the early stage of acute respiratory distress syndrome Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis), et al; High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study Disseminated intravascular coagulation Coronavirus blood-clot mystery intensifies ISTH interim guidance on recognition and management of coagulopathy in COVID-19 Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China Prominent changes in blood coagulation of patients with SARS-CoV-2 infection Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study Narasimhan Mand the Northwell COVID-19 Research Consortium, et al; Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID-19) infections: a meta-analysis High incidence of venous thromboembolic events in anticoagulated severe COVID-19 patients Pulmonary vascular endothelialitis, thrombosis, and angiogenesis in Covid-19 Incidence of thrombotic complications in critically ill ICU patients with COVID-19 Carenzo LHumanitas COVID-19 Task Force, et al; Venous and arterial thromboembolic complications in COVID-19 patients admitted to an academic hospital in Incidence of venous thromboembolism in hospitalized patients with COVID-19 Venous thrombosis among critically ill patients with coronavirus disease 2019 (COVID-19) Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia The cumulative venous thromboembolism incidence and risk factors in intensive care patients receiving the guideline-recommended thromboprophylaxis Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): a case series D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19 PURLs: it's time to use an agebased approach to D-dimer Cancer as an overhealing wound: an old hypothesis revisited Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages Calibrated automated thrombin generation measurement in clotting plasma Simultaneous thrombin and plasmin generation capacities in normal and abnormal states of coagulation and fibrinolysis in children and adults Analysis of thrombotic factors in severe acute respiratory syndrome (SARS) patients Clinical characteristics of Covid-19 in New York City Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China Diabetes, hypertension, and cardiovascular disease: clinical insights and vascular mechanisms Effects of natural aging and gender on pro-inflammatory markers Thrombosis as an intravascular effector of innate immunity Should we stimulate or suppress immune responses in COVID-19? Cytokine and anticytokine interventions Complex immune dysregulation in COVID-19 patients with severe respiratory failure Cytokine release syndrome in severe COVID-19: interleukin-6 receptor antagonist tocilizumab may be the key to reduce mortality Hu YChina Medical Treatment Expert Group for Covid-19, et al; Clinical characteristics of coronavirus disease 2019 in China VWF/ADAMTS-13 in COVID-19 Pathophysiology Katneni Clinical characteristics of 3,062 COVID-19 patients: a meta-analysis COVID-19 and its implications for thrombosis and anticoagulation Clinical and immunological features of severe and moderate coronavirus disease 2019 Factor VIII and functional protein C activity in critically ill patients with coronavirus disease 2019: a case series Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors Clinical characteristics of 182 pediatric COVID-19 patients with different severities and allergic status Longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of SARS-CoV-2 infected patients Clinical features of 69 cases with coronavirus disease Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou Detectable serum SARS-CoV-2 viral load (RNAaemia) is closely correlated with drastically elevated interleukin 6 (IL-6) level in critically ill COVID-19 patients COVID-19 Pneumonia (TOCIVID-19). Available at Tocilizumab for Prevention of Respiratory Failure in Patients With Severe COVID-19 Infection Tocilizumab in the Treatment of Coronavirus Induced Disease (COVID-19). Available at Coagulation failure is associated with bleeding events and clinical outcome during systemic inflammatory response and sepsis in acute-onchronic liver failure: an observational cohort study Hypoxia results in upregulation and de novo activation of von Willebrand factor expression in lung endothelial cells Vascular wall hypoxia promotes arterial thrombus formation via augmentation of vascular thrombogenicity Hypoxia induces endothelial cell synthesis of membrane-associated proteins Induction of plasminogen activator inhibitor 1 gene expression in murine liver by lipopolysaccharide. Cellular localization and role of endogenous tumor necrosis factor-alpha Willebrand factor/ADAMTS-13 interactions at birth: implications for thrombosis in the neonatal period Of von Willebrand factor and platelets ADAMTS13 and von Willebrand factor in thrombotic thrombocytopenic purpura Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis Plasma levels of von Willebrand factor regulate ADAMTS-13, its major cleaving protease Changes in von Willebrand factor-cleaving protease (ADAMTS13) activity after infusion of desmopressin Changes in ADAMTS13 (von-Willebrand-factor-cleaving protease) activity after induced release of von Willebrand factor during acute systemic inflammation Von Willebrand factor and ADAMTS13 in arterial thrombosis: a systematic review and meta-analysis High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability Low ADAMTS13 activity is associated with an increased risk of ischemic stroke Role of reduced ADAMTS13 in arterial ischemic stroke: a pediatric cohort study Elevated preoperative von Willebrand factor is associated with perioperative thrombosis in infants and neonates with congenital heart disease High VWF, low ADAMTS13, and oral contraceptives increase the risk of ischemic stroke and myocardial infarction in young women The role of von Willebrand factor in vascular inflammation: from pathogenesis to targeted therapy Active von Willebrand factor predicts 28-day mortality in patients with systemic inflammatory response syndrome Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow ADAMTS13: a new link between thrombosis and inflammation Inflammation-associated ADAMTS13 deficiency promotes formation of ultra-large von Willebrand factor Imbalance of von Willebrand factor and its cleaving protease ADAMTS13 during systemic inflammation superimposed on advanced cirrhosis ADAMTS-13, von Willebrand factor and related parameters in severe sepsis and septic shock Reduced ADAMTS13 in children with severe meningococcal sepsis is associated with severity and outcome Ul Haq A. Deficiency of ADAMTS-13 in pediatric patients with severe sepsis and impact on in-hospital mortality Ratio of von Willebrand factor propeptide to ADAMTS13 is associated with severity of sepsis Correlation between plasma activity of ADAMTS-13 and coagulopathy, and prognosis in disseminated intravascular coagulation Plasma ADAMTS13, von Willebrand factor (VWF) and VWF propeptide profiles in patients with DIC and related diseases COVID-19 and smoking: a systematic review of the evidence Genetic variants in ADAMTS13 as well as smoking are major determinants of plasma ADAMTS13 levels ACE-2 expression in the small airway epithelia of smokers and COPD patients: implications for COVID-19 Smoking and inflammation VWF excess and ADAMTS13 deficiency: a unifying pathomechanism linking inflammation to thrombosis in DIC, malaria, and TTP Thrombospondin-1 and ADAMTS13 competitively bind to VWF A2 and A3 domains in vitro Thrombospondin-1 controls vascular platelet recruitment and thrombus adherence in mice by protecting (sub)endothelial VWF from cleavage by ADAMTS13 Human neutrophil peptides inhibit cleavage of von Willebrand factor by ADAMTS13: a potential link of inflammation to TTP Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13 Proteolytic inactivation of ADAMTS13 by thrombin and plasmin Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure Reduced ADAMTS-13 level negatively correlates with inflammation factors in plasma of acute myeloid leukemia patients Platelet hyperaggregability is associated with decreased ADAMTS13 activity and enhanced endotoxemia in patients with acute cholangitis Decreased activity of plasma ADAMTS13 are related to enhanced cytokinemia and endotoxemia in patients with acute liver failure Inflammation, von Willebrand factor, and ADAMTS13 Low ADAMTS 13 plasma levels are predictors of mortality in COVID-19 patients Involvement of ADAMTS13 and von Willebrand factor in thromboembolic events in patients infected with SARS-CoV-2 A comprehensive assessment of the coagulation profile in critically ill COVID-19 patients Cardiac dysfunction and thrombocytopenia-associated multiple organ failure inflammation phenotype in a severe paediatric case of COVID-19 ADAMTS13 activity, von Willebrand factor, factor VIII and D-dimers in COVID-19 inpatients Severe COVID-19 infection associated with endothelial activation Thrombotic risk of reduced ADAMTS13 activity in patients with antiphospholipid antibodies Antiphospholipid antibodies are not elevated in patients with severe COVID-19 pneumonia and venous thromboembolism Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19 The VWF/ADAMTS13 axis in the antiphospholipid syndrome: ADAMTS13 antibodies and ADAMTS13 dysfunction Gain-of-function ADAMTS13 variants that are resistant to autoantibodies against ADAMTS13 in patients with acquired thrombotic thrombocytopenic purpura Thrombocytopenia in the course of COVID-19 infection Difference of coagulation features between severe pneumonia induced by SARS-CoV2 and non-SARS-CoV2 Incidence of asymptomatic deep vein thrombosis in patients with COVID-19 pneumonia and elevated D-dimer levels Systematic screening for venous thromboembolic events in COVID-19 pneumonia Thrombotic and hemorrhagic events in critically ill COVID-19 patients: a French monocenter retrospective study Determination of factor XII in blood products and correction of its deficiency after plasma transfusion in a case Image-proven thromboembolism in patients with severe COVID-19 in a tertiary critical care unit in the United Kingdom Pulmonary embolism: a complication of COVID 19 infection Severe arterial thrombosis associated with Covid-19 infection Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, singlecenter, clinicopathologic case series Thrombotic complications of patients admitted to intensive care with COVID-19 at a teaching hospital in the United Kingdom VWF/ADAMTS-13 in COVID-19 Pathophysiology Katneni COVID-19-related aortic thrombosis: a report of four cases The association between treatment with heparin and survival in patients with Covid-19 Attention should be paid to venous thromboembolism prophylaxis in the management of COVID-19 Systematic assessment of venous thromboembolism in COVID-19 patients receiving thromboprophylaxis: incidence and role of D-dimer as predictive factors Clinical impact of preadmission antithrombotic therapy in hospitalized patients with COVID-19: a multicenter observational study COVID-19-associated hyperviscosity: a link between inflammation and thrombophilia? Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases None declared.