Thrombosis In Coronavirus Disease 2019 Research Articles

Abstract 13121: Incidence, Predictors, and Outcomes of Venous and Arterial Thrombosis in COVID-19: A Nationwide Analysis

Introduction: Coronavirus disease 2019 (COVID-19) is known to increase the risk of venous (VTE) and arterial (ATE) thromboembolism. However, the incidence, predictors, and outcomes of clinical thrombosis for inpatients with COVID-19 are not well known. We evaluated the incidence, associated factors, and mortality outcomes of VTE and ATE in COVID-19 infection. Hypothesis: COVID-19 is associated with a higher risk of thrombosis and mortality. Methods: Hospitalized patients with COVID-19 during 2020 were identified from the National Inpatient Sample database and data was retrieved regarding clinical characteristics, incident VTE and ATE and mortality outcomes. Multivariate regression was performed to identify clinical factors associated with thrombosis and in-hospital mortality in COVID-19 inpatients. Results: Overall, 1,583,135 COVID-19 inpatients were identified out of which patients with thrombosis were 41% females with a mean age 65.4 (65.1-65.6) years. The incidence of thrombosis was 6.1%, including VTE 4.8%, ATE 3.0%, and in-hospital mortality rate was 13.4%. The main factors associated with overall thrombosis, VTE and ATE were paralysis, ventilation, solid tumors without metastasis, and metastatic cancer. Patients with thrombosis were more likely to have respiratory symptoms of COVID-19 (76.7% vs 75%, p<0.001) compared to patients without thrombosis, along with comorbidities like complicated diabetes mellitus and congestive heart failure, and acute presentations like septic shock, acute respiratory distress syndrome and acute kidney injury. Symptomatic and severe COVID-19 disease were associated with a higher risk of thrombosis (OR 1.37 (1.31-1.43) and OR 1.62 (1.49-1.76), respectively, p<0.001) and VTE (OR 1.40 (1.33-1.46) and OR 1.66 (1.52-1.80) respectively, p<0.001). Although all thrombosis categories were associated with higher in-hospital mortality for COVID-19 inpatients in univariable analyses (p<0.001), they were not significant in multivariate analyses. Conclusions: Overall, thrombosis, especially VTE was found in approximately 5% of COVID-19 inpatients, while ATE was rare, with important associated factors identified, however they were not independently associated with higher in-hospital mortality.

D-dimer in Coronavirus 2019: An Acute Phase Reactant?

D-dimers are released following the breakdown of blood clots, essentially representing a byproduct of the degradation of fibrin by plasmin activity. Normal values are less than 0.50 mg/L (in fibrinogen equivalent units), and the negative predictive values of D-dimer measurements are excellent to rule out pulmonary embolism, deep vein thrombosis, and disseminated intravascular coagulation, since it would otherwise increase substantially in those settings. However, the D-dimer assay only represents a screening test and should be interpreted in the context of the patient’s clinical signs and symptoms.[1] Overt coagulation abnormalities are common in patients with coronavirus disease 2019 (COVID-19) and have led to an increase in requests of laboratory biomarkers, such as blood cell counts, acute phase reactants, coagulation tests, and platelet function assays, as aids in the clinical decision-making processes throughout the pandemic.[2] [3] D-dimer levels are among the most frequently and thoroughly studied, and the International COVID-19 Thrombosis Biomarkers Colloquium concluded that they were associated with patient prognosis and were helpful in clinical decision-making in patients requiring imaging studies, in the administration of thromboprophylaxis, and to detect and prevent complications.[4] While the consensus suggests that an elevated D-dimer is associated with worse disease outcomes,[5] the literature is not consistent in terms of whether the increase in D-dimer in COVID-19 can predict thrombotic events. Moreover, some issues have been identified in various publications, whereby comparisons between studies reporting D-dimer levels in different hospital units only reach confusing conclusions on their clinical significance.[6]

Common Coagulopathies Associated With COVID-19 Patients.

The coronavirus disease 2019 (COVID-19) outbreak, which first appeared in the Chinese province of Hubei city of Wuhan, has been spreading internationally since December 2019. The World Health Organization (WHO) declared the coronavirus illness from 2019 to be a pandemic on March 11, 2020. Patients hospitalised with severe coronavirus or comorbid conditions (like cardiovascular disease and obesity) are linked to a worse prognosis. The rise in D-dimer and its relationship to prognosis are the most often documented aberrations in coagulation/fibrinolysis in COVID-19. However, the D-dimer assessment's utility is not limitless. Since the coagulation/fibrinolytic state might occasionally change over a short period of time, routine exams are also advantageous in understanding the relevance of the inquiry. Both thrombotic and hemorrhagic diseases should be taken into consideration, despite the fact that the pathophysiology of disseminated intravascular coagulation (DIC) linked with coronavirus disease 19 differs significantly from that of septic disseminated intravascular coagulation. Coagulation as well as fibrinolysis indicators are used to make the diagnosis of COVID-19 thrombosis, which encompasses both macro- and micro-thrombosis. Compared to bacterial-sepsis-associated coagulopathy/DIC, COVID-19 has a lower prevalence of prolonged prothrombin time, activated partial thromboplastin time, and decreased antithrombin activity. However, the causes of coagulopathy remain poorly understood. Hypoxia, endothelial injury, dysregulated immunological responses mediated by inflammatory cytokines, and lymphocyte cell death are thought to be implicated. While blood loss tends to be rare, it is uncertain if COVID-19 suffers from thrombosis or whether the current recommendations for regular venous thromboembolic dose are appropriate. It is important to decide on the COVID-19 therapy phases. Antiviral therapy, cytokine storm therapy, and thrombosis therapy are the steps. Future advancements are predicted, such as a therapy that combines heparin and nafamostat.

Thrombosis Occurrence in COVID-19 Compared With Other Infectious Causes of ARDS: A Contemporary Cohort.

Thrombosis occurrence in coronavirus disease 2019 (COVID-19) has been mostly compared to historical cohorts of patients with other respiratory infections. We retrospectively evaluated the thrombotic events that occurred in a contemporary cohort of patients hospitalized between March and July 2020 for acute respiratory distress syndrome (ARDS) according to the Berlin Definition and compared those with positive and negative real-time polymerase chain reaction results for wild-type severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) using descriptive analysis. The association between COVID-19 and thrombotic risk was evaluated using logistic regression. 264 COVID-19-positive (56.8% male, 59.0 years [IQR 48.6-69.7], Padua score on admission 3.0 [2.0-3.0]) and 88 COVID-19-negative patients (58.0% male, 63.7 years [51.2-73.5], Padua score 3.0 [2.0-5.0]) were included. 10.2% of non-COVID-19 and 8.7% of COVID-19 patients presented ≥ 1 clinically relevant thrombotic event confirmed by imaging exam. After adjustment for sex, Padua score, intensive care unit stay, thromboprophylaxis, and hospitalization length, the odds ratio for thrombosis in COVID-19 was 0.69 (95% CI, 0.30-1.64). We, therefore, conclude that infection-induced ARDS carries an inherent thrombotic risk, which was comparable between patients with COVID-19 and other respiratory infections in our contemporary cohort.

Coagulopathy and thromboembolism in children with COVID-19 – pathophysiology, thrombotic risk, clinical manifestations and management

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Since the beginning of the pandemic, it has been generally accepted that children infected with SARS-CoV-2 either stay asymptomatic or present benign symptoms. Yet SARS-CoV-2 is widely known to cause serious consequences in children and adolescents. Complications may develop during infection, several weeks afterwards, or in the course of multisystem inflammatory syndrome in children (MIS-C). MIS-C manifests with fever, gastrointestinal, cardiovascular and/or neurological symptoms. Moreover, thromboembolism is a relatively common complication of COVID-19 and MIS-C. The purpose of this work was to review current reports on thromboembolic complications among children who underwent SARS-CoV-2 infection. Among the published cases of MIS-C, thromboembolic incidents ranged from 1.4% to 6.5%, taking the form of a brain infarct, deep vein thrombosis, pulmonary embolism, or splenic infarct. Several mechanisms leading to thrombosis in COVID-19 in children are considered. The development of acute infection in the lungs results in local clot formation in the pulmonary microcirculation, leading to perfusion disturbances. ADAMTS13 activity is also mildly reduced in patients infected with SARS-CoV-2, increasing the risk of microthrombosis. COVID-19-associated coagulopathy is characterized by elevated D-dimers and fibrinogen levels. Significantly increased D-dimers probably represent activation of coagulation caused by viremia and cytokine storm, as well as possible organ dysfunction. The treatment of thromboembolism in children includes low and high molecular weight heparins and acetylsalicylic acid. Pediatricians should be aware of the possible multiple complications associated with COVID-19 in children, including thromboembolic incidents.

Abstract 14833: Senescent Endothelial Cells Are Highly Susceptible to SARS-CoV-2 Infection, Which Might Account for the Aggravation of COVID-19 in the Elderly

Introduction: The pandemic of coronavirus disease 2019 (COVID-19), induced by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, has posed a global health emergency. COVID-19 vaccines are certainly effective to prevent infection, severe disease, and hospitalization; however, its spreading remains to be uncontrolled worldwide. The striking feature of COVID-19 is the high mortality in the elderly; every 1,000 people infected with SARS-CoV-2, around 116 will die if they are mid-seventies or older, while little will die if they are under the age of 50. Though elderly is more fragile than younger people in general, this substantial difference in mortality strongly suggest a specific factor(s) that aggravate the disease in elder people. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Hypothesis: Senescent endothelial cells are highly susceptible to SARS-CoV-2 infection. Methods: We experimentally investigated the SARS-CoV-2 infection in ECs, and performed a comparative analysis for post-infection molecular events using young and replicative senescent ECs. Results: We identify that; 1) SARS-CoV-2 infects ECs largely through endocytosis, 2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, possibly through enhanced caveolae-mediated endocytosis, 3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, 4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in young ECs, which might causes further exacerbated dysfunction in senescent ECs, 5) SARS-CoV-2 infection significantly affected coagulation cascade only in senescent ECs. Conclusions: These data strongly suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.

Radial arterial thrombosis in COVID-19: A case report

Thrombosis due to hypercoagulable state is an important cause of morbidity and mortality in coronavirus disease 2019 (COVID-19). . Increased D-dimer levels are an important marker of the presence and risk of thrombosis. In this report, we present that a 59-yearold male patient developed thrombosis in the distal radial arteries despite normal D-dimer level. The patient was treated with enoxaparin, iloprost infusion, and cilostazol. This

Radial arterial thrombosis in COVID-19: A case report

Thrombosis due to hypercoagulable state is an important cause of morbidity and mortality in coronavirus disease 2019 (COVID-19).
 Increased D-dimer levels are an important marker of the presence and risk of thrombosis. In this report, we present that a 59-yearold
 male patient developed thrombosis in the distal radial arteries despite normal D-dimer level. The patient was treated with
 enoxaparin, iloprost infusion, and cilostazol. This case should lead us to be very careful that people diagnosed with COVID-19 with
 normal D-dimer levels may also have thrombosis.

Role of Thromboelastography and Thromboelastometry in Predicting Risk of Hypercoagulability and Thrombosis in Critically Ill COVID-19 Patients: A Qualitative Systematic Review.

Thromboelastography and rotational thromboelastometry are the viscoelastic point of care devices that use whole blood samples to assess coagulation and fibrinolysis. These devices give information from initiation of the coagulation cascade, activation of clotting factors to fibrin cross-linking, and contribution of fibrinogen and platelet to clot strength and clot lysis. Viscoelastic point of care tests are well established in hypocoaguable states like trauma, cardiac surgery, liver transplantation, and their use in critical care settings with coronavirus disease 2019 (COVID-19) is not so well-known. We performed a systematic review of studies on thromboelastography and rotational thromboelastometry and their modifications to assess their role in critically ill patients with COVID-19. Inclusion criteria were any kind of studies using thromboelastography or rotational thromboelastometry during coronavirus disease critical illness published in English. Ninety-three articles, from December 1, 2019, to August 31, 2020, were identified in the initial search, out of which 12 articles (a total of 380 patients) satisfied the inclusion and exclusion criteria. Thromboelastography and rotational thromboelastometry were observed to detect the hypercoagulable changes and fibrinolysis shutdown associated with COVID-19. Hypercoagulability is associated with an increased risk of venous thrombosis and micro-thrombosis. This review identifies the role of thromboelastography and rotational thromboelastometry in studying the mechanisms contributing to coagulopathy and incidence of thrombosis in COVID-19.

Senescent endothelial cells are predisposed to SARS-CoV-2 infection and subsequent endothelial dysfunction

The coronavirus disease 2019 (COVID-19), caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains to spread worldwide. COVID-19 is characterized by the striking high mortality in elderly; however, its mechanistic insights remain unclear. Systemic thrombosis has been highlighted in the pathogenesis of COVID-19, and lung microangiopathy in association with endothelial cells (ECs) injury has been reported by post-mortem analysis of the lungs. Here, we experimentally investigated the SARS-CoV-2 infection in cultured human ECs, and performed a comparative analysis for post-infection molecular events using early passage and replicative senescent ECs. We found that; (1) SARS-CoV-2 infects ECs but does not replicate and disappears in 72 hours without causing severe cell damage, (2) Senescent ECs are highly susceptible to SARS-CoV-2 infection, (3) SARS-CoV-2 infection alters various genes expression, which could cause EC dysfunctions, (4) More genes expression is affected in senescent ECs by SARS-CoV-2 infection than in early passage ECs, which might causes further exacerbated dysfunction in senescent ECs. These data suggest that sustained EC dysfunctions due to SARS-CoV-2 infection may contribute to the microangiopathy in the lungs, leading to deteriorated inflammation and thrombosis in COVID-19. Our data also suggest a possible causative role of EC senescence in the aggravated disease in elder COVID-19 patients.

P1673: THROMBOTIC COMPLICATIONS IN MERS-COV COMPARED TO COVID-19

Background: Several observational studies have reported the rate of thrombotic events in patients infected with coronavirus disease 2019 (COVID-19), with conflicting results. Middle east respiratory syndrome (MERS-COV) is another coronavirus had been initially reported in Saudi Arabia in 2012. A genome scan has shown a 50% similarity between covid-19 and. Several common features of covid-19 and MERS-COV including transmissibility, and clinical presentation have been identified. However, data about thrombotic complications in patients with MERS-COV are limited. Aims: To compare the rate of thrombotic events between COVID-19 and MERS-COV. Methods: We included all confirmed COVID-19 patients who were admitted to intensive care unit (ICU) in 3 major hospitals in Saudi Arabia between February to July 2020. We included all confirmed cases of MERS-COV who were admitted to ICU from these centers between March to May 2014. Patients were excluded if they were transferred in or out from one of these three hospital to another hospitals. Patients also excluded is they were admitted for less than 24 hours. Data were collected retrospectively from the first day of admission until discharge or death. The primary outcome was the rate of venous thromboembolism (VTE). The secondary outcomes were the rate of arterial events, the rate of composite events (venous and arterial) and the rate of bleeding. VTE included all symptomatic or incidentally diagnosed cases of pulmonary embolism (PE), deep vein thrombosis (DVT) and thrombosis in unusual sites (cerebral, mesenteric, portal, splenic, hepatic, and renal veins). Screening for VTE in asymptomatic patients was not performed. If more than on type of VTE occurred in the same patient, it was considered one event. Arterial events included cerebrovascular accidents (CVAs), mesenteric ischemia, and limb ischemia and were confirmed by the appropriate imaging modality. Myocardial infarction (MI) was diagnosed based on the suspicion of the attending physician using clinical criteria as well as biomarker elevations or electrocardiographic changes. Composite events were defined as any VTE or arterial event. Bleeding events were classified as major and nonmajor based on the definition of international society of thrombosis and hemostasis (ISTH)5. Informed consent was waived. Results: After exclusion, 234 COVID-19 and 58 MERS-COV patients were included. The majority of patients with COVID-19 (97%, n=230) and more than (67%,n =39) of those with MERS-COV group received pharmacological prophylaxis according to local hospital practice. The most frequently prescribed regimen in both groups was enoxaparin (40 mg twice per day). Over a median length of stay in the COVID-19 group of 22 days, the rate of VTE 9.8 (6.64–14.3) and was 3.4 (0.95–11.7) in the MESR-COV group over median length of stay of 10 days. Image:Summary/Conclusion: Conclusions: To our knowledge, this is the first study compared thrombotic risk between COVID-19 and MERS-COV critically ill patients. We found unexpected similar rate of composite thrombotic events (venous and arterial) between COVID-19 and MERS-COV with higher rate of venous thrombosis in COVID-19 and higher arterial thrombosis in MERS-COV. This may indicate that thrombotic complication is a unique complication of coronaviruses. These result needs to be confirmed in studies with larger sample size. Helms J, et al. Intensive Care Med. 2020;46:1089-98. Schulman S, et al. J Thromb Haemost. 2005;3:692-4.

Role of LL-37 in thrombotic complications in patients with COVID-19

Blood clot formation induced by dysfunctional coagulation is a frequent complication of coronavirus disease 2019 (COVID-19) and a high-risk factor for severe illness and death. Neutrophil extracellular traps (NETs) are implicated in COVID-19-induced immunothrombosis. Furthermore, human cathelicidin, a NET component, can perturb the interaction between the SARS-CoV-2 spike protein and its ACE2 receptor, which mediates viral entry into cells. At present, however, the levels of cathelicidin antimicrobial peptides after SARS-CoV-2 infection and their role in COVID-19 thrombosis formation remain unclear. In the current study, we analyzed coagulation function and found a decrease in thrombin time but an increase in fibrinogen level, prothrombin time, and activated partial thromboplastin time in COVID-19 patients. In addition, the cathelicidin antimicrobial peptide LL-37 was upregulated by the spike protein and significantly elevated in the plasma of patients. Furthermore, LL-37 levels were negatively correlated with thrombin time but positively correlated with fibrinogen level. In addition to platelet activation, cathelicidin peptides enhanced the activity of coagulation factors, such as factor Xa (FXa) and thrombin, which may induce hypercoagulation in diseases with high cathelicidin peptide levels. Injection of cathelicidin peptides promoted the formation of thrombosis, whereas deletion of cathelicidin inhibited thrombosis in vivo. These results suggest that cathelicidin antimicrobial peptide LL-37 is elevated during SARS-CoV-2 infection, which may induce hypercoagulation in COVID-19 patients by activating coagulation factors.

Post–COVID-19 Arterial Thrombosis: A Systematic Review

COVID-19 (coronavirus disease 2019) is associated with coagulation defects, including endothelial dysfunction, inflammation, hypoxia, cytokine release, and hypercoagulability. We aimed to summarize the available cases of arterial peripheral thrombosis in the setting of post–COVID-19 infection and the use of biomarkers and related pharmacologic therapies to describe the better medical and surgical treatments based on the reported outcomes. We executed a systematic review following the 2020 PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. We searched PubMed, Embase, Scopus, and the Cochrane Library for studies reported from March 2020 to September 2021 with serologic confirmation of a resolved SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection. Related questions regarding high-yield end points included the location of the thrombosis, amputation, reintervention rates, mortality, anticoagulant therapy, and biomarkers. Of the 398 matching results, 23 reports met the inclusion criteria of post–COVID-19 thrombosis, arterial, venous, peripheral, and cured. The literature review included 12 case reports, 3 incidence reports, 3 literature reviews, 2 meta-analyses, 1 observational cohort study, and 2 prospective analyses. The overall presentation consisted of peripheral arterial thrombosis (33.3%), venous thrombosis (63.2%), and mixed events (3.5%). Most of the studies had used low-molecular-weight heparin monotherapy as a part of the medical management. There was no difference in the use of clopidogrel and aspirin as antiplatelet agents. Other pharmacologic alternatives were nonfractionated heparin, enoxaparin, warfarin, rivaroxaban, and apixaban. Open thrombectomy was the most common procedure used for COVID-19 thrombosis complications (40%), with mortality of 27.2%, followed by endovascular thrombectomy (15%), amputation (12.5%), exploratory laparotomy (5%), and endarterectomy (2.5%). We found 38 reported biomarkers, which were classified into seven categories related to an inflammatory process, coagulation time, clotting factors, cardiorespiratory function, kidney function, metabolic profile, and autoimmunity. An initial D-dimer level >1.250 ng/mL might identify COVID-19 patients at risk of arterial thrombotic events. Additional end points were associated with increased creatinine, interleukin-6, interferon gamma-induced protein-10, D-dimer, and C-reactive protein levels. COVID-19 infection is associated with a high risk of arterial and venous post-thrombotic complications, with a variable clinical and anatomic presentation, high mortality, and high amputation risk. Microcirculatory alterations can be reflected by a panel of biomarkers. The medical and surgical management of these patients could depend on the availability of resources regarding the context of medical attention. Nevertheless, considering the highly inflammatory context, endovascular interventions with less systemic stress should be considered in addition to thromboprophylaxis measures.

Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

The COVID Complex: A Review of Platelet Activation and Immune Complexes in COVID-19.

Coronavirus disease 2019 (COVID-19) is a highly prothrombotic viral infection that primarily manifests as an acute respiratory syndrome. However, critically ill COVID-19 patients will often develop venous thromboembolism with associated increases in morbidity and mortality. The cause for this prothrombotic state is unclear but is likely related to platelet hyperactivation. In this review, we summarize the current evidence surrounding COVID-19 thrombosis and platelet hyperactivation. We highlight the fact that several studies have identified a soluble factor in COVID-19 patient plasma that is capable of altering platelet phenotype in vitro. Furthermore, this soluble factor appears to be an immune complex, which may be composed of COVID-19 Spike protein and related antibodies. We suggest that these Spike-specific immune complexes contribute to COVID-19 platelet activation and thrombosis in a manner similar to heparin-induced thrombocytopenia. Understanding this underlying pathobiology will be critical for advancement of future research and therapeutic options.

Major Bleeding and Thrombosis Events in COVID-19 Versus Influenza Patients Requiring Extracorporeal Membrane Oxygenation.

Initial reports described a hypercoagulable state and an increased risk of thrombosis in patients who tested positive for SARS-CoV-2. Infected patients with severe acute respiratory distress syndrome in the setting of coronavirus disease 2019 (COVID-19) may require extracorporeal membrane oxygenation (ECMO), leading to coagulopathies and further increasing the risk for bleeding and thrombosis. We conducted a single-center retrospective cohort study to compare the incidence of major bleeding and thrombosis in COVID-19 versus influenza-positive patients requiring ECMO. There was no difference in the incidence of major bleeding (67.7% vs. 85.7%, p = 0.287) or major thrombosis (9.7% vs. 21.4%, p = 0.356) between COVID-19 and influenza patients, respectively. COVID-19 patients experienced significantly fewer major bleeding events per ECMO days compared with influenza (0.1 [interquartile range 0-0.2] vs. 0.2 [interquartile range 0.1-0.5], p = 0.026). Influenza patients may be at higher risk for developing coagulopathies that contribute to bleeding. Larger evaluations are needed to confirm these results and further assess bleeding and thrombosis risk in these populations.

Current and novel biomarkers of thrombotic risk in COVID-19: a Consensus Statement from the International COVID-19 Thrombosis Biomarkers Colloquium.

Coronavirus disease 2019 (COVID-19) predisposes patients to thrombotic and thromboembolic events, owing to excessive inflammation, endothelial cell activation and injury, platelet activation and hypercoagulability. Patients with COVID-19 have a prothrombotic or thrombophilic state, with elevations in the levels of several biomarkers of thrombosis, which are associated with disease severity and prognosis. Although some biomarkers of COVID-19-associated coagulopathy, including high levels of fibrinogen and d-dimer, were recognized early during the pandemic, many new biomarkers of thrombotic risk in COVID-19 have emerged. In this Consensus Statement, we delineate the thrombotic signature of COVID-19 and present the latest biomarkers and platforms to assess the risk of thrombosis in these patients, including markers of platelet activation, platelet aggregation, endothelial cell activation or injury, coagulation and fibrinolysis as well as biomarkers of the newly recognized post-vaccine thrombosis with thrombocytopenia syndrome. We then make consensus recommendations for the clinical use of these biomarkers to inform prognosis, assess disease acuity, and predict thrombotic risk and in-hospital mortality. A thorough understanding of these biomarkers might aid risk stratification and prognostication, guide interventions and provide a platform for future research.

What We Know (and Do not Know) Regarding the Pathogenesis of Pulmonary Thrombosis in COVID-19.

The clinical course of coronavirus disease 2019 (COVID-19) is often complicated by the onset of venous thrombosis and thromboembolism (VTE), encompassing also pulmonary thrombosis. Recent statistics attests that the cumulative frequency of VTE can be as high as 30% in COVID-19 hospitalized patients, increasing to nearly 40 to 70% (depending on systematic screening) in those with severe illness, mechanical ventilation, or intensive care unit admission. The risk of venous thrombosis seems mostly limited to the active phase of disease, and is directly associated with some genetic (i.e., inherited prothrombotic predisposition) and demographical factors (male sex, overweight/obesity), disease severity (risk increasing progressively from hospitalization to development of severe illness, being the highest in patients needing mechanical ventilation and/or intensive care), presence and extent of pulmonary disease, coexistence of multiple risk factors (immobilization, mechanical ventilation, co- or superinfections), along with increased values of inflammatory and thrombotic biomarkers. At least three different phenotypes of pulmonary thrombosis may develop in COVID-19 patients, one caused by typical embolization from peripheral venous thrombosis (e.g., deep vein thrombosis), a second type triggered by local inflammation of nearby pulmonary tissue, and a third one mostly attributable to the prothrombotic state consequent to the pronounced systemic inflammatory response (i.e., the so-called cytokine storm) that is frequently observed in COVID-19. Although the pathogenesis of these three conditions has different features, their discrimination is essential for diagnostic and therapeutic purposes. The prognosis of COVID-19 patients who develop pulmonary thrombosis is also considerably worse than those who do not, thus probably needing frequent monitoring and more aggressive therapeutic management.

Absence of COVID-19-associated changes in plasma coagulation proteins and pulmonary thrombosis in the ferret model

BackgroundMany patients who are diagnosed with coronavirus disease 2019 (COVID-19) suffer from venous thromboembolic complications despite the use of stringent anticoagulant prophylaxis. Studies on the exact mechanism(s) underlying thrombosis in COVID-19 are limited as animal models commonly used to study venous thrombosis pathophysiology (i.e. rats and mice) are naturally not susceptible to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). Ferrets are susceptible to SARS-CoV-2 infection, successfully used to study virus transmission, and have been previously used to study activation of coagulation and thrombosis during influenza virus infection.ObjectivesThis study aimed to explore the use of (heat-inactivated) plasma and lung material from SARS-CoV-2-inoculated ferrets studying COVID-19-associated changes in coagulation and thrombosis.Material and methodsHistology and longitudinal plasma profiling using mass spectrometry-based proteomics approach was performed.ResultsLungs of ferrets inoculated intranasally with SARS-CoV-2 demonstrated alveolar septa that were mildly expanded by macrophages, and diffuse interstitial histiocytic pneumonia. However, no macroscopical or microscopical evidence of vascular thrombosis in the lungs of SARS-CoV-2-inoculated ferrets was found. Longitudinal plasma profiling revealed minor differences in plasma protein profiles in SARS-CoV-2-inoculated ferrets up to 2 weeks post-infection. The majority of plasma coagulation factors were stable and demonstrated a low coefficient of variation.ConclusionsWe conclude that while ferrets are an essential and well-suited animal model to study SARS-CoV-2 transmission, their use to study SARS-CoV-2-related changes relevant to thrombotic disease is limited.

Arterial and Venous Thrombosis Complicated in COVID-19: A Retrospective Single Center Analysis in Japan.

Background: Thrombosis is a characteristic complication in coronavirus disease 2019 (COVID-19). Since coagulopathy has been observed over the entire clinical course, thrombosis might be a clue to understanding the specific pathology in COVID-19. Currently, there is limited epidemiological data of COVID-19-associated thrombosis in the Japanese population and none regarding variant strains of SARS-CoV-2. Here, we elucidate the risk factors and the pattern of thrombosis in COVID-19 patients.Methods: The patients consecutively admitted to Tokyo Medical and Dental University Hospital with COVID-19 were retrospectively analyzed. SARS-CoV-2 variants of concern/interest (VOC/VOI) carrying the spike protein mutants E484K, N501Y, or L452R were identified by PCR-based analysis. All thrombotic events were diagnosed by clinical symptoms, ultrasonography, and/or radiological tests.Results: Among the 516 patients, 32 patients experienced 42 thromboembolic events. Advanced age, severe respiratory conditions, and several abnormal laboratory markers were associated with the development of thrombosis. While thrombotic events occurred in 13% of the patients with a severe respiratory condition, those events still occurred in 2.5% of the patients who did not require oxygen therapy. Elevated D-dimer and ferritin levels on admission were independent risk factors of thrombosis (adjusted odds ratio 9.39 and 3.11, 95% confidence interval 2.08–42.3, and 1.06–9.17, respectively). Of the thrombotic events, 22 were venous, whereas 20 were arterial. While patients with thrombosis received anticoagulation and antiinflammatory therapies with a higher proportion, the mortality rate, organ dysfunctions, and bleeding complications in these patients were higher than those without thrombosis. The incidence of thrombosis in COVID-19 became less frequent over time, such as during the replacement of the earlier strains of SARS-CoV-2 by VOC/VOI and during increased use of anticoagulatory therapeutics.Conclusion: This study elucidated that elevated D-dimer and ferritin levels are useful biomarkers of thrombosis in COVID-19 patients. The comparable incidence of arterial thrombosis with venous thrombosis and the development of thrombosis in less severe patients required further considerations for the management of Japanese patients with COVID-19. Further studies would be required to identify high-risk populations and establish appropriate interventions for thrombotic complications in COVID-19.