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.

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None declared.