Editorial

2 pages, 187 KiB

Open AccessEditorial

by Pierpaolo Di Micco, Egidio Imbalzano and Giuseppe Camporese

Viruses 2022, 14(7), 1425; https://doi.org/10.3390/v14071425 - 29 Jun 2022

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Since the pandemic began, an association among COVID-19 and venous thromboembolism has been reported, in particular for inpatients [...] Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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13 pages, 1011 KiB

Open AccessArticle

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

by Kristina Zguro, Margherita Baldassarri, Francesca Fava, Giada Beligni, Sergio Daga, Roberto Leoncini, Lucrezia Galasso, Michele Cirianni, Stefano Rusconi, Matteo Siano, Daniela Francisci, Elisabetta Schiaroli, Sauro Luchi, Giovanna Morelli, Enrico Martinelli, Massimo Girardis, Stefano Busani, Saverio Giuseppe Parisi, Sandro Panese, Carmelo Piscopo, Mario Capasso, Danilo Tacconi, Chiara Spertilli Raffaelli, Annarita Giliberti, Giulia Gori, Peter D. Katsikis, Maria Lorubbio, Paola Calzoni, Agostino Ognibene, Monica Bocchia, Monica Tozzi, Alessandro Bucalossi, Giuseppe Marotta, Simone Furini, GEN-COVID Multicenter Study, Alessandra Renieri and Chiara Fallerini Show full author list Hide full author list

Viruses 2022, 14(6), 1185; https://doi.org/10.3390/v14061185 - 29 May 2022

Cited by 2 | Viewed by 2635

Abstract

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, [...] Read more.

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF–platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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9 pages, 1085 KiB

Open AccessCommunication

Detection of Platelet-Activating Antibodies Associated with Vaccine-Induced Thrombotic Thrombocytopenia by Flow Cytometry: An Italian Experience

by Francesca Cesari, Silvia Sorrentino, Anna Maria Gori, Angela Rogolino, Raimondo De Cristofaro, Betti Giusti, Elena Sticchi, Erica De Candia and Rossella Marcucci

Viruses 2022, 14(6), 1133; https://doi.org/10.3390/v14061133 - 24 May 2022

Cited by 3 | Viewed by 1693

Abstract

Rare cases of thrombocytopenia and thrombosis after anti-COVID-19 adenovirus-associated mRNA vaccines (VITT) due to platelet-activating anti-platelet-factor 4 (PF4)/polyanion antibodies have been reported. VITT laboratory diagnosis, similarly to heparin-induced thrombocytopenia (HIT) diagnosis, requires immunoassays for anti-PF4/polyanion antibodies identification, such as ELISA assays and platelet-activating [...] Read more.

Rare cases of thrombocytopenia and thrombosis after anti-COVID-19 adenovirus-associated mRNA vaccines (VITT) due to platelet-activating anti-platelet-factor 4 (PF4)/polyanion antibodies have been reported. VITT laboratory diagnosis, similarly to heparin-induced thrombocytopenia (HIT) diagnosis, requires immunoassays for anti-PF4/polyanion antibodies identification, such as ELISA assays and platelet-activating functional tests, such as heparin-induced platelet activation test (HIPA), to confirm their pathogenicity. We compared the flow cytometry (FC) measurement of platelet p-selectin exposure to the gold standard functional test HIPA for diagnosis confirmation in 13 patients with a clinical VITT syndrome (6M/7F; median age 56 (33–78)) who resulted positive to anti-PF4/polyanion antibodies ELISA assays (12/13). FC and HIPA similarly identified three different patterns: (1) a typical non-heparin-dependent VITT pattern (seven and six patients by FC and HIPA, respectively); (2) low/no platelet activation in patients under IvIg therapy (five out of five and two out of four patients by FC and HIPA, respectively); (3) a HIT pattern. Antibodies investigated by FC became negative after 7, 17, and 24 days of therapy in three patients. FC measurement of P-selectin exposure was as sensitive as HIPA but simpler to detect anti-PF4/polyanion antibodies in VITT patients. FC could reliably discriminate VITT from HIT, thus helping for the choice of the anticoagulant. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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8 pages, 1719 KiB

Open AccessCommunication

Molecular Cross-Talk between Integrins and Cadherins Leads to a Loss of Vascular Barrier Integrity during SARS-CoV-2 Infection

by Danielle Nader and Steve W. Kerrigan

Viruses 2022, 14(5), 891; https://doi.org/10.3390/v14050891 - 25 Apr 2022

Cited by 10 | Viewed by 2087

Abstract

The vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19. This endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure. The mechanisms surrounding COVID-19 associated [...] Read more.

The vascular barrier is heavily injured following SARS-CoV-2 infection and contributes enormously to life-threatening complications in COVID-19. This endothelial dysfunction is associated with the phlogistic phenomenon of cytokine storms, thrombotic complications, abnormal coagulation, hypoxemia, and multiple organ failure. The mechanisms surrounding COVID-19 associated endotheliitis have been widely attributed to ACE2-mediated pathways. However, integrins are emerging as possible receptor candidates for SARS-CoV-2, and their complex intracellular signaling events are essential for maintaining endothelial homeostasis. Here, we showed that the spike protein of SARS-CoV-2 depends on its RGD motif to drive barrier dysregulation by hijacking integrin αVβ3, expressed on human endothelial cells. This triggers the redistribution and internalization of major junction protein VE-Cadherin which leads to the barrier disruption phenotype. Both extracellular and intracellular inhibitors of integrin αVβ3 prevented these effects, similarly to the RGD-cyclic peptide compound Cilengitide, which suggests that the spike protein—through its RGD motif—binds to αVβ3 and elicits vascular leakage events. These findings support integrins as an additional receptor for SARS-CoV-2, particularly as integrin engagement can elucidate many of the adverse endothelial dysfunction events that stem from COVID-19. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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15 pages, 670 KiB

Open AccessArticle

New Insights in the Occurrence of Venous Thromboembolism in Critically Ill Patients with COVID-19—A Large Postmortem and Clinical Analysis

by Fabian Heinrich, Kevin Roedl, Dominik Jarczak, Hanna-Lisa Goebels, Axel Heinemann, Ulrich Schäfer, Frank Ludwig, Martin Bachmann, Berthold Bein, Christian Friedrich Weber, Karsten Sydow, Marc Bota, Hans-Richard Paschen, Andreas de Weerth, Carsten Veit, Oliver Detsch, Philipp-Alexander Brand, Stefan Kluge, Benjamin Ondruschka and Dominic Wichmann

Viruses 2022, 14(4), 811; https://doi.org/10.3390/v14040811 - 14 Apr 2022

Cited by 5 | Viewed by 1897

Abstract

Critically ill COVID-19 patients are at high risk for venous thromboembolism (VTE), namely deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and death. The optimal anticoagulation strategy in critically ill patients with COVID-19 remains unknown. This study investigated the ante mortem incidence as [...] Read more.

Critically ill COVID-19 patients are at high risk for venous thromboembolism (VTE), namely deep vein thrombosis (DVT) and/or pulmonary embolism (PE), and death. The optimal anticoagulation strategy in critically ill patients with COVID-19 remains unknown. This study investigated the ante mortem incidence as well as postmortem prevalence of VTE, the factors predictive of VTE, and the impact of changed anticoagulation practice on patient survival. We conducted a consecutive retrospective analysis of postmortem COVID-19 (n = 64) and non-COVID-19 (n = 67) patients, as well as ante mortem COVID-19 (n = 170) patients admitted to the University Medical Center Hamburg-Eppendorf (Hamburg, Germany). Baseline patient characteristics, parameters related to the intensive care unit (ICU) stay, and the clinical and autoptic presence of VTE were evaluated and statistically compared between groups. The occurrence of VTE in critically ill COVID-19 patients is confirmed in both ante mortem (17%) and postmortem (38%) cohorts. Accordingly, comparing the postmortem prevalence of VTE between age- and sex-matched COVID-19 (43%) and non-COVID-19 (0%) cohorts, we found the statistically significant increased prevalence of VTE in critically ill COVID-19 cohorts (p = 0.001). A change in anticoagulation practice was associated with the statistically significant prolongation of survival time (HR: 2.55, [95% CI 1.41–4.61], p = 0.01) and a reduction in VTE occurrence (54% vs. 25%; p = 0.02). In summary, in the autopsy as well as clinical cohort of critically ill patients with COVID-19, we found that VTE was a frequent finding. A change in anticoagulation practice was associated with a statistically significantly prolonged survival time. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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17 pages, 859 KiB

Open AccessArticle

Intensive-Dose Tinzaparin in Hospitalized COVID-19 Patients: The INTERACT Study

by Karolina Akinosoglou, Christos Savopoulos, Abraham Pouliakis, Charalampos Triantafyllidis, Eleftherios Markatis, Foteini Golemi, Angelos Liontos, Charikleia Vadala, Ilias C. Papanikolaou, Vasiliki Dimakopoulou, Panagiotis Xarras, Katerina Varela, Georgia Kaiafa, Athanasios Mitsianis, Anastasia Chatzistamati, Efthalia Randou, Spyridon Savvanis, Maria Pavlaki, Georgios Efraimidis, Vasileios Samaras, Dimitrios Papazoglou, Alexandra Konstantinidou, Periklis Panagopoulos, Haralampos Milionis and on behalf of the INTERACT Study Group Show full author list Hide full author list

Viruses 2022, 14(4), 767; https://doi.org/10.3390/v14040767 - 07 Apr 2022

Cited by 4 | Viewed by 2691

Abstract

(1) Background: It is well-established that coronavirus disease-2019 (COVID-19) is highly pro-inflammatory, leading to activation of the coagulation cascade. COVID-19-induced hypercoagulability is associated with adverse outcomes and mortality. Current guidelines recommend that hospitalized COVID-19 patients should receive pharmacological prophylaxis against venous thromboembolism (VTE). [...] Read more.

(1) Background: It is well-established that coronavirus disease-2019 (COVID-19) is highly pro-inflammatory, leading to activation of the coagulation cascade. COVID-19-induced hypercoagulability is associated with adverse outcomes and mortality. Current guidelines recommend that hospitalized COVID-19 patients should receive pharmacological prophylaxis against venous thromboembolism (VTE). (2) INTERACT is a retrospective, phase IV, observational cohort study aiming to evaluate the overall clinical effectiveness and safety of a higher than conventionally used prophylactic dose of anticoagulation with tinzaparin administered for VTE prevention in non-critically ill COVID-19 patients with moderate disease severity. (3) Results: A total of 705 patients from 13 hospitals in Greece participated in the study (55% men, median age 62 years). Anticoagulation with tinzaparin was initiated immediately after admission. A full therapeutic dose was received by 36.3% of the participants (mean ± SD 166 ± 33 IU/Kgr/day) and the remaining patients (63.9%) received an intermediate dose (mean ± SD 114 ± 22 IU/Kgr/day). The median treatment duration was 13 days (Q1–Q3: 8–20 days). During the study (April 2020 to November 2021), 14 thrombotic events (2.0%) were diagnosed (i.e., three cases of pulmonary embolism (PE) and 11 cases of deep venous thrombosis, DVT). Four bleeding events were recorded (0.6%). In-hospital death occurred in 12 patients (1.7%). Thrombosis was associated with increasing age (median: 74.5 years, Q1–Q3: 62–79, for patients with thrombosis vs. 61.9 years, Q1–Q3: 49–72, p = 0.0149), increased D-dimer levels for all three evaluation time points (at admission: 2490, Q1–Q3: 1580–6480 vs. 700, Q1–Q3: 400–1475, p < 0.0001), one week ± two days after admission (3510, Q1–Q3: 1458–9500 vs. 619, Q1–Q3: 352–1054.5, p < 0.0001), as well as upon discharge (1618.5, Q1–Q3: 1010–2255 vs. 500, Q1–Q3: 294–918, p < 0.0001). Clinical and laboratory improvement was affirmed by decreasing D-dimer and CRP levels, increasing platelet numbers and oxygen saturation measurements, and a drop in the World Health Organization (WHO) progression scale. (4) Conclusions: The findings of our study are in favor of prophylactic anticoagulation with an intermediate to full therapeutic dose of tinzaparin among non-critically ill patients hospitalized with COVID-19. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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11 pages, 258 KiB

Open AccessArticle

Risk Factors of Venous Thromboembolism in Noncritically Ill Patients Hospitalized for Acute COVID-19 Pneumonia Receiving Prophylactic-Dose Anticoagulation

by Francesco Poletto, Luca Spiezia, Chiara Simion, Elena Campello, Fabio Dalla Valle, Daniela Tormene, Giuseppe Camporese and Paolo Simioni

Viruses 2022, 14(4), 737; https://doi.org/10.3390/v14040737 - 31 Mar 2022

Cited by 7 | Viewed by 1722

Abstract

Background: Therapeutic/intermediate-dose heparin reduces the risk of thromboembolic events but increases the risk of major bleeding in patients hospitalized for acute COVID-19 pneumonia. Objectives: To prospectively assess the incidence of objectively proven venous thromboembolism (VTE) and identify predisposing risk factors in [...] Read more.

Background: Therapeutic/intermediate-dose heparin reduces the risk of thromboembolic events but increases the risk of major bleeding in patients hospitalized for acute COVID-19 pneumonia. Objectives: To prospectively assess the incidence of objectively proven venous thromboembolism (VTE) and identify predisposing risk factors in a cohort of hospitalized patients with acute COVID-19 pneumonia undergoing prophylactic-dose heparin. Patients and methods: All consecutive patients admitted for acute COVID-19 pneumonia to the General Internal Medicine Unit of Padova University Hospital, Italy between November 2020 and April 2021, and undergoing prophylactic-dose heparin, were enrolled. Demographic and clinical characteristics and laboratory and radiological findings were recorded on admission. Cases were patients who developed VTE during their hospital stay. Univariable and multivariable logistic regression analyses were used to ascertain the risk factors associated with developing in-hospital VTE. Results: 208 patients (median age: 77 years; M/F 98/110) were included; 37 (18%) developed in-hospital VTE during a median follow-up of 10 days (IQR, 4–18). VTE patients were significantly younger (p = 0.004), more obese (p = 0.002), and had a lower Padua prediction score (p < 0.03) and reduced PaO2/FIO2 ratio (p < 0.03) vs. controls. Radiological findings of bilateral pulmonary infiltrates were significantly more frequent in VTE patients than controls (p = 0.003). Multivariable regression showed that obesity (1.75, 95% CI 1.02–3.36; p = 0.04) and bilateral pulmonary infiltrates on X-rays (2.39, 95% CI 1.22–5.69; p = 0.04) were correlated with increased risk of in-hospital VTE. Conclusions: Obesity and bilateral pulmonary infiltrates on imaging may help clinicians to identify patients admitted to medical wards for acute COVID-19 pneumonia at risk of developing VTE despite prophylactic-dose heparin. Further studies are needed to evaluate whether the administration of therapeutic/intermediate-dose heparin may help prevent VTE episodes without further increasing the bleeding risk. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

13 pages, 3668 KiB

Open AccessArticle

The Role of Von Willebrand Factor in the Pathogenesis of Pulmonary Vascular Thrombosis in COVID-19

by Anastasiya S. Babkina, Irina V. Ostrova, Mikhail Ya Yadgarov, Artem N. Kuzovlev, Andrey V. Grechko, Alexey V. Volkov and Arkady M. Golubev

Viruses 2022, 14(2), 211; https://doi.org/10.3390/v14020211 - 21 Jan 2022

Cited by 9 | Viewed by 2706

Abstract

The increased plasma levels of von Willebrand factor (VWF) in patients with COVID-19 was reported in many studies, and its correlation with disease severity and mortality suggest its important role in the pathogenesis of thrombosis in COVID-19. We performed histological and immunohistochemical studies [...] Read more.

The increased plasma levels of von Willebrand factor (VWF) in patients with COVID-19 was reported in many studies, and its correlation with disease severity and mortality suggest its important role in the pathogenesis of thrombosis in COVID-19. We performed histological and immunohistochemical studies of the lungs of 29 patients who died from COVID-19. We found a significant increase in the intensity of immunohistochemical reaction for VWF in the pulmonary vascular endothelium when the disease duration was more than 10 days. In the patients who had thrombotic complications, the VWF immunostaining in the pulmonary vascular endothelium was significantly more intense than in nonsurvivors without thrombotic complications. Duration of disease and thrombotic complications were found to be independent predictors of increased VWF immunostaining in the endothelium of pulmonary vessels. We also revealed that bacterial pneumonia was associated with increased VWF staining intensity in pulmonary arterial, arteriolar, and venular endothelium, while lung ventilation was an independent predictor of increased VWF immunostaining in arterial endothelium. The results of the study demonstrated an important role of endothelial VWF in the pathogenesis of thrombus formation in COVID-19. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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15 pages, 3576 KiB

Open AccessArticle

Venous Thrombosis within 30 Days after Vaccination against SARS-CoV-2 in a Multinational Venous Thromboembolism Registry

by Behnood Bikdeli, David Jiménez, Pablo Demelo-Rodriguez, Francisco Galeano-Valle, José Antonio Porras, Raquel Barba, Cihan Ay, Radovan Malý, Andrei Braester, Egidio Imbalzano, Vladimir Rosa, Ramón Lecumberri, Carmine Siniscalchi, Ángeles Fidalgo, Salvador Ortiz, Manuel Monreal and for the RIETE Investigators

Viruses 2022, 14(2), 178; https://doi.org/10.3390/v14020178 - 18 Jan 2022

Cited by 18 | Viewed by 3746

Abstract

Background: Venous thromboembolism (VTE)—including deep vein thrombosis, pulmonary embolism, and cerebral venous sinus thrombosis (CVST)—may occur early after vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We sought to describe the site, clinical characteristics, and outcomes of VTE after vaccination against [...] Read more.

Background: Venous thromboembolism (VTE)—including deep vein thrombosis, pulmonary embolism, and cerebral venous sinus thrombosis (CVST)—may occur early after vaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We sought to describe the site, clinical characteristics, and outcomes of VTE after vaccination against SARS-CoV-2. Methods: In a prospective study using the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) platform, patients with VTE 4–30 days after vaccination against SARS-CoV-2 (1 February 2021 through 30 April 2021) were included. VTE patients recruited from the same centers into RIETE in the same months in 2018–2019 were selected as the reference group. All-cause mortality and major bleeding were the main study outcomes. Results: As of 30 April 2020, 102 patients with post-vaccination VTEs had been identified (28 after adenovirus-based vaccination [ChAdOx1 nCov-19; AstraZeneca] and 74 after mRNA-based vaccination [mRNA-1273; Moderna, and BNT162b2; Pfizer]). Compared with 911 historical controls, patients with VTE after adenovirus-based vaccination more frequently had CVST (10.7% vs. 0.4%, p < 0.001) or thrombosis at multiple sites (17.9% vs. 1.3%, p < 0.001), more frequently had thrombocytopenia (40.7% vs. 14.7%, p < 0.001), and had higher 14-day mortality (14.3% vs. 0.7%; odds ratio [OR]: 25.1; 95% confidence interval [CI]: 6.7–94.9) and major bleeding rates (10.3% vs. 1.0%, OR: 12.03, 95% CI: 3.07–47.13). The site of thrombosis, accompanying thrombocytopenia, and 14-day mortality rates were not significantly different for patients with VTE after mRNA-based vaccination, compared with historical controls. Conclusions: Compared with historical controls, VTE after adenovirus-based vaccination against SARS-CoV-2 is accompanied by thrombocytopenia, occurs in unusual sites, and is associated with worse clinical outcomes. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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11 pages, 805 KiB

Open AccessArticle

Mid-Regional Pro-Adrenomedullin, Methemoglobin and Carboxyhemoglobin as Prognosis Biomarkers in Critically Ill Patients with COVID-19: An Observational Prospective Study

by Crhistian-Mario Oblitas, Francisco Galeano-Valle, Jesús Ramírez-Navarro, Jorge López-Cano, Ángel Monterrubio-Manrique, Mercedes García-Gámiz, Milagros Sancho-González, Sara Arenal-López, Luis-Antonio Álvarez-Sala Walther and Pablo Demelo-Rodríguez

Viruses 2021, 13(12), 2445; https://doi.org/10.3390/v13122445 - 06 Dec 2021

Cited by 10 | Viewed by 2509

Abstract

Mid-regional pro-adrenomedullin (MR-proADM), methemoglobin (MetHb), and carboxyhemoglobin (COHb) levels have been associated with sepsis. In this study, we assessed the role of this potential biomarkers in critically ill COVID-19 patients. Outcomes were mortality and a combined event (mortality, venous or arterial thrombosis, and [...] Read more.

Mid-regional pro-adrenomedullin (MR-proADM), methemoglobin (MetHb), and carboxyhemoglobin (COHb) levels have been associated with sepsis. In this study, we assessed the role of this potential biomarkers in critically ill COVID-19 patients. Outcomes were mortality and a combined event (mortality, venous or arterial thrombosis, and orotracheal intubation (OTI)) during a 30-day follow-up. A total of 95 consecutive patients were included, 51.6% required OTI, 12.6% patients died, 8.4% developed VTE, and 3.1% developed arterial thrombosis. MetHb and COHb levels were not associated with mortality nor combined event. Higher MR-proADM levels were found in patients with mortality (median of 1.21 [interquartile range-IQR-0.84;2.33] nmol/L vs. 0.76 [IQR 0.60;1.03] nmol/L, p = 0.011) and combined event (median of 0.91 [IQR 0.66;1.39] nmol/L vs. 0.70 [IQR 0.51;0.82] nmol/L, p < 0.001); the positive likelihood ratio (LR+) and negative likelihood ratio (LR−) for mortality were 2.40 and 0.46, respectively. The LR+ and LR− for combined event were 3.16 and 0.63, respectively. MR-proADM ≥1 nmol/L was the optimal cut-off for mortality and combined event prediction. The predictive capacity of MR-proADM showed an area under the ROC curve of 0.73 (95% CI, 0.62–0.81) and 0.72 (95% CI, 0.62–0.81) for mortality and combined event, respectively. In conclusion, elevated on-admission MR-proADM levels were associated with higher risk of 30-day mortality and 30-day poor outcomes in a cohort of critically ill patients with COVID-19. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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10 pages, 814 KiB

Open AccessArticle

Validation of a Prognostic Score to Identify Hospitalized Patients with COVID-19 at Increased Risk for Bleeding

by Pablo Demelo-Rodriguez, Francisco Galeano-Valle, Lucía Ordieres-Ortega, Carmine Siniscalchi, Mar Martín Del Pozo, Ángeles Fidalgo, Aída Gil-Díaz, José Luis Lobo, Cristina De Ancos, Manuel Monreal and For the RIETE-Bleeding Investigators

Viruses 2021, 13(11), 2278; https://doi.org/10.3390/v13112278 - 15 Nov 2021

Cited by 9 | Viewed by 1948

Abstract

Introduction: Hospitalized patients with COVID-19 are at increased risk for venous thromboembolism (VTE), but also for bleeding. We previously derived a prognostic score including four variables (elevated D-dimer, elevated ferritin, critical illness, and therapeutic-dose anticoagulation) that identified those at increased risk for major [...] Read more.

Introduction: Hospitalized patients with COVID-19 are at increased risk for venous thromboembolism (VTE), but also for bleeding. We previously derived a prognostic score including four variables (elevated D-dimer, elevated ferritin, critical illness, and therapeutic-dose anticoagulation) that identified those at increased risk for major bleeding. Methods: We aimed to validate the score in a subsequent cohort of hospitalized patients with COVID-19 receiving standard-, intermediate- or therapeutic doses of VTE prophylaxis. We evaluated its capacity to predict major bleeding, non-major bleeding, and bleeding-related death. Results: The cohort included 972 patients from 29 hospitals, of whom 280 (29%) received standard-; 412 (42%) intermediate-, 157 (16%) therapeutic doses of VTE prophylaxis and 123 (13%) other drugs. Median duration of prophylaxis was 14.7 ± 10.3 days. Major bleeding occurred in 65 patients (6.7%) and non-major bleeding in 67 (6.9%). Thirty patients with major bleeding (46%) died within the first 30 days after bleeding. The prognostic score identified 203 patients (21%) at very low risk, 285 (29%) at low risk, 263 (27%) intermediate-risk and 221 (23%) at high risk for bleeding. Major bleeding occurred in 1.0%, 2.1%, 8.7% and 15.4% of the patients, respectively. Non-major bleeding occurred in 0.5%, 3.5%, 9.5% and 14.2%, respectively. The c-statistics was: 0.74 (95% confidence intervals [CI]: 0.68–0.79) for major bleeding, 0.73 (95% CI: 0.67–0.78) for non-major bleeding and 0.82 (95% CI: 0.76–0.87) for bleeding-related death. Conclusions: In hospitalized patients with COVID-19, we validated that a prognostic score including 4 easily available items may identify those at increased risk for bleeding. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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17 pages, 1567 KiB

Open AccessEditor’s ChoiceArticle

SARS-CoV-2 Spike Protein S1-Mediated Endothelial Injury and Pro-Inflammatory State Is Amplified by Dihydrotestosterone and Prevented by Mineralocorticoid Antagonism

by Nitin Kumar, Yu Zuo, Srilakshmi Yalavarthi, Kristina L. Hunker, Jason S. Knight, Yogendra Kanthi, Andrea T. Obi and Santhi K. Ganesh

Viruses 2021, 13(11), 2209; https://doi.org/10.3390/v13112209 - 03 Nov 2021

Cited by 38 | Viewed by 5720

Abstract

Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial injury are not defined. We [...] Read more.

Men are disproportionately affected by the coronavirus disease-2019 (COVID-19), and face higher odds of severe illness and death compared to women. The vascular effects of androgen signaling and inflammatory cytokines in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-mediated endothelial injury are not defined. We determined the effects of SARS-CoV-2 spike protein-mediated endothelial injury under conditions of exposure to androgen dihydrotestosterone (DHT) and tumor necrosis factor-a (TNF-α) and tested potentially therapeutic effects of mineralocorticoid receptor antagonism by spironolactone. Circulating endothelial injury markers VCAM-1 and E-selectin were measured in men and women diagnosed with COVID-19. Exposure of endothelial cells (ECs) in vitro to DHT exacerbated spike protein S1-mediated endothelial injury transcripts for the cell adhesion molecules E-selectin, VCAM-1 and ICAM-1 and anti-fibrinolytic PAI-1 (p < 0.05), and increased THP-1 monocyte adhesion to ECs (p = 0.032). Spironolactone dramatically reduced DHT+S1-induced endothelial activation. TNF-α exacerbated S1-induced EC activation, which was abrogated by pretreatment with spironolactone. Analysis from patients hospitalized with COVID-19 showed concordant higher circulating VCAM-1 and E-Selectin levels in men, compared to women. A beneficial effect of the FDA-approved drug spironolactone was observed on endothelial cells in vitro, supporting a rationale for further evaluation of mineralocorticoid antagonism as an adjunct treatment in COVID-19. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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12 pages, 293 KiB

Open AccessArticle

PICO Questions and DELPHI Methodology for the Management of Venous Thromboembolism Associated with COVID-19

by Antoni Riera-Mestre, Luis Jara-Palomares, Ramón Lecumberri, Javier Trujillo-Santos, Enric Grau, Angeles Blanco-Molina, Ana Piera Carbonell, Sonia Jiménez, Manuel Frías Vargas, Mari Paz Fuset, Sergi Bellmunt-Montoya, Manuel Monreal, David Jiménez and on behalf of the COVILAX Project

Viruses 2021, 13(11), 2128; https://doi.org/10.3390/v13112128 - 22 Oct 2021

Cited by 4 | Viewed by 3808

Abstract

Patients with coronavirus disease 2019 (COVID-19) have a higher risk of venous thromboembolic disease (VTE) than patients with other infectious or inflammatory diseases, both as macrothrombosis (pulmonar embolism and deep vein thrombosis) or microthrombosis. However, the use of anticoagulation in this scenario remains [...] Read more.

Patients with coronavirus disease 2019 (COVID-19) have a higher risk of venous thromboembolic disease (VTE) than patients with other infectious or inflammatory diseases, both as macrothrombosis (pulmonar embolism and deep vein thrombosis) or microthrombosis. However, the use of anticoagulation in this scenario remains controversial. This is a project that used DELPHI methodology to answer PICO questions related to anticoagulation in patients with COVID-19. The objective was to reach a consensus among multidisciplinary VTE experts providing answers to those PICO questions. Seven PICO questions regarding patients with COVID-19 responded with a broad consensus: 1. It is recommended to avoid pharmacological thromboprophylaxis in most COVID-19 patients not requiring hospital admission; 2. In most hospitalized patients for COVID-19 who are receiving oral anticoagulants before admission, it is recommended to replace them by low molecular weight heparin (LMWH) at therapeutic doses; 3. Thromboprophylaxis with LMWH at standard doses is suggested for COVID-19 patients admitted to a conventional hospital ward; 4. Standard-doses thromboprophylaxis with LMWH is recommended for COVID-19 patients requiring admission to Intensive Care Unit; 5. It is recommended not to determine D-Dimer levels routinely in COVID-19 hospitalized patients to select those in whom VTE should be suspected, or as a part of the diagnostic algorithm to rule out or confirm a VTE event; 6. It is recommended to discontinue pharmacological thromboprophylaxis at discharge in most patients hospitalized for COVID-19; 7. It is recommended to withdraw anticoagulant treatment after 3 months in most patients with a VTE event associated with COVID-19. The combination of PICO questions and DELPHI methodology provides a consensus on different recommendations for anticoagulation management in patients with COVID-19. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

Review

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8 pages, 253 KiB

Open AccessReview

Coronary Stent Thrombosis in COVID-19 Patients: A Systematic Review of Cases Reported Worldwide

by Wojciech Jan Skorupski, Marek Grygier, Maciej Lesiak and Marta Kałużna-Oleksy

Viruses 2022, 14(2), 260; https://doi.org/10.3390/v14020260 - 27 Jan 2022

Cited by 10 | Viewed by 2802

Abstract

Approximately 5 million percutaneous coronary interventions are performed worldwide annually. Therefore, stent-related complications pose a serious public health concern. Stent thrombosis, although rare, is usually catastrophic, often associated with extensive myocardial infarction or death. Because little progress has been made in outcomes following [...] Read more.

Approximately 5 million percutaneous coronary interventions are performed worldwide annually. Therefore, stent-related complications pose a serious public health concern. Stent thrombosis, although rare, is usually catastrophic, often associated with extensive myocardial infarction or death. Because little progress has been made in outcomes following stent thrombosis, ongoing research is focusing on further understanding the predictors as well as frequency and timing in various patient subgroups. Coronavirus disease-2019 (COVID-19), a viral illness caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), activates inflammatory mechanisms that potentially create a prothrombotic environment and increases the risk of local micro thromboembolism and all types of stent thrombosis. In-stent thrombosis occurrence increased during the COVID-19 pandemic, however, there is still lack of comprehensive studies describing this population. This review and worldwide analysis of coronary stent thrombosis cases related to COVID-19 summarizes all available data. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

21 pages, 1729 KiB

Open AccessReview

Coagulation System Activation for Targeting of COVID-19: Insights into Anticoagulants, Vaccine-Loaded Nanoparticles, and Hypercoagulability in COVID-19 Vaccines

by Mohamed S. Abdel-Bakky, Elham Amin, Mohamed G. Ewees, Nesreen I. Mahmoud, Hamdoon A. Mohammed, Waleed M. Altowayan and Ahmed A. H. Abdellatif

Viruses 2022, 14(2), 228; https://doi.org/10.3390/v14020228 - 24 Jan 2022

Cited by 6 | Viewed by 4103

Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, is currently developing into a rapidly disseminating and an overwhelming worldwide pandemic. In severe COVID-19 cases, hypercoagulability and inflammation are two crucial complications responsible for poor prognosis and mortality. In addition, [...] Read more.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as COVID-19, is currently developing into a rapidly disseminating and an overwhelming worldwide pandemic. In severe COVID-19 cases, hypercoagulability and inflammation are two crucial complications responsible for poor prognosis and mortality. In addition, coagulation system activation and inflammation overlap and produce life-threatening complications, including coagulopathy and cytokine storm, which are associated with overproduction of cytokines and activation of the immune system; they might be a lead cause of organ damage. However, patients with severe COVID-19 who received anticoagulant therapy had lower mortality, especially with elevated D-dimer or fibrin degradation products (FDP). In this regard, the discovery of natural products with anticoagulant potential may help mitigate the numerous side effects of the available synthetic drugs. This review sheds light on blood coagulation and its impact on the complication associated with COVID-19. Furthermore, the sources of natural anticoagulants, the role of nanoparticle formulation in this outbreak, and the prevalence of thrombosis with thrombocytopenia syndrome (TTS) after COVID-19 vaccines are also reviewed. These combined data provide many research ideas related to the possibility of using these anticoagulant agents as a treatment to relieve acute symptoms of COVID-19 infection. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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9 pages, 472 KiB

Open AccessReview

Heparin and SARS-CoV-2: Multiple Pathophysiological Links

by Pierpaolo Di Micco, Egidio Imbalzano, Vincenzo Russo, Emilio Attena, Vincenzo Mandaliti, Luana Orlando, Maurizio Lombardi, Gianluca Di Micco, Giuseppe Camporese, Saverio Annunziata, Gaetano Piccinocchi, Walter Pacelli and Michele Del Guercio

Viruses 2021, 13(12), 2486; https://doi.org/10.3390/v13122486 - 11 Dec 2021

Cited by 9 | Viewed by 2824

Abstract

Low molecular weight heparin, enoxaparin, has been one of most used drugs to fight the SARS-CoV-2 pandemic. Pharmacological properties of heparin recognize its specific ability, as with other oligosaccharides and glycosaminoglycan, to bind several types of viruses during their pass through the extracellular [...] Read more.

Low molecular weight heparin, enoxaparin, has been one of most used drugs to fight the SARS-CoV-2 pandemic. Pharmacological properties of heparin recognize its specific ability, as with other oligosaccharides and glycosaminoglycan, to bind several types of viruses during their pass through the extracellular matrix of the respiratory tract, as well as its anticoagulant activity to prevent venous thromboembolism. Antithrombotic actions of enoxaparin have been testified both for inpatients with COVID-19 in regular ward and for inpatients in Intensive Care Units (ICUs). Prophylactic doses seem to be able to prevent venous thromboembolism (VTE) in inpatients in the regular ward, while intermediate or therapeutic doses have been frequently adopted for inpatients with COVID-19 in ICU. On the other hand, although we reported several useful actions of heparin for inpatients with COVID-19, an increased rate of bleeding has been recorded, and it may be related to several conditions such as underlying diseases with increased risks of bleeding, increased doses or prolonged administration of heparin, personal trend to bleed, and so on. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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Other

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6 pages, 234 KiB

Open AccessBrief Report

Pre-Exposure Prophylaxis with Hydroxychloroquine Does Not Prevent COVID-19 nor Virus Related Venous Thromboembolism

by Alessandro Perrella, Valentina Orlando, Ugo Trama, Francesca F. Bernardi, Enrica Menditto and Enrico Coscioni

Viruses 2021, 13(10), 2052; https://doi.org/10.3390/v13102052 - 13 Oct 2021

Cited by 4 | Viewed by 1560

Abstract

Different and several public health strategies have been planned to reduce transmission of pandemic due to SARS-CoV-2 since it started. None drugs have been confirmed as able to prevent viral transmission. Hydroxychloroquine with its immunomodulatory properties has been proposed as potential anti-viral drug [...] Read more.

Different and several public health strategies have been planned to reduce transmission of pandemic due to SARS-CoV-2 since it started. None drugs have been confirmed as able to prevent viral transmission. Hydroxychloroquine with its immunomodulatory properties has been proposed as potential anti-viral drug in particular for prevention once viral exposure has been happen or in first phases of infection. Furthermore, in several immunological systemic disease hydroxychloroquine was able to reduce the number of thrombotic complications. So, because COVID-19 was associated to immunological imbalance and to thrombotic complications, we retrospectively analyzed the rate of infection in those patients being under treatment with this drug during COVID-19 epidemic outbreak from 8 March until 28 April in particular comparing those with pre-exposure to this treatment and those that were not taking this medication before SARS-CoV-2 viral infections. Full article

(This article belongs to the Special Issue COVID-19 and Thrombosis)

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