Coagulation parameters predict COVID-19-related thrombosis in a neural network with a positive predictive value of 98.

Thrombosis is a major clinical complication of COVID-19 infection. COVID-19 patients show changes in coagulation factors that indicate an important role for the coagulation system in the pathogenesis of COVID-19. However, the multifactorial nature of thrombosis complicates the prediction of thrombotic events based on a single hemostatic variable. We developed and validated a neural net for the prediction of COVID-19-related thrombosis. The neural net was developed based on the hemostatic and general (laboratory) variables of 149 confirmed COVID-19 patients from two cohorts: at the time of hospital admission (cohort 1 including 133 patients) and at ICU admission (cohort 2 including 16 patients). Twenty-six patients suffered from thrombosis during their hospital stay: 19 patients in cohort 1 and 7 patients in cohort 2. The neural net predicts COVID-19 related thrombosis based on C-reactive protein (relative importance 14%), sex (10%), thrombin generation (TG) time-to-tail (10%), α2-Macroglobulin (9%), TG curve width (9%), thrombin-α2-Macroglobulin complexes (9%), plasmin generation lag time (8%), serum IgM (8%), TG lag time (7%), TG time-to-peak (7%), thrombin-antithrombin complexes (5%), and age (5%). This neural net can predict COVID-19-thrombosis at the time of hospital admission with a positive predictive value of 98%-100%.

Coagulation parameters predict COVID-19-related thrombosis in a neural network with a positive predictive value of 98%

Thrombosis is a major clinical complication of COVID-19 infection. COVID-19 patients show changes in coagulation factors that indicate an important role for the coagulation system in the pathogenesis of COVID-19. However, the multifactorial nature of thrombosis complicates the prediction of thrombotic events based on a single hemostatic variable. We developed and validated a neural net for the prediction of COVID-19-related thrombosis. The neural net was developed based on the hemostatic and general (laboratory) variables of 149 confirmed COVID-19 patients from two cohorts: at the time of hospital admission (cohort 1 including 133 patients) and at ICU admission (cohort 2 including 16 patients). Twenty-six patients suffered from thrombosis during their hospital stay: 19 patients in cohort 1 and 7 patients in cohort 2. The neural net predicts COVID-19 related thrombosis based on C-reactive protein (relative importance 14%), sex (10%), thrombin generation (TG) time-to-tail (10%), α2-Macroglobulin (9%), TG curve width (9%), thrombin-α2-Macroglobulin complexes (9%), plasmin generation lag time (8%), serum IgM (8%), TG lag time (7%), TG time-to-peak (7%), thrombin-antithrombin complexes (5%), and age (5%). This neural net can predict COVID-19-thrombosis at the time of hospital admission with a positive predictive value of 98%-100%.

Lupus anticoagulant associates with thrombosis in patients with COVID‐19 admitted to intensive care units: A retrospective cohort study

Background Thrombosis is a frequent and severe complication in patients with coronavirus disease 2019 (COVID‐19) admitted to the intensive care unit (ICU). Lupus anticoagulant (LA) is a strong acquired risk factor for thrombosis in various diseases and is frequently observed in patients with COVID‐19. Whether LA is associated with thrombosis in patients with severe COVID‐19 is currently unclear. Objective To investigate if LA is associated with thrombosis in critically ill patients with COVID‐19. Patients/Methods The presence of LA and other antiphospholipid antibodies was assessed in patients with COVID‐19 admitted to the ICU. LA was determined with dilute Russell's viper venom time (dRVVT) and LA‐sensitive activated partial thromboplastin time (aPTT) reagents. Results Of 169 patients with COVID‐19, 116 (69%) tested positive for at least one antiphospholipid antibody upon admission to the ICU. Forty (24%) patients tested positive for LA;of whom 29 (17%) tested positive with a dRVVT, 19 (11%) tested positive with an LA‐sensitive aPTT, and 8 (5%) tested positive on both tests. Fifty‐eight (34%) patients developed thrombosis after ICU admission. The odds ratio (OR) for thrombosis in patients with LA based on a dRVVT was 2.5 (95% confidence interval [CI], 1.1–5.7), which increased to 4.5 (95% CI, 1.4–14.3) in patients at or below the median age in this study (64 years). LA positivity based on a dRVVT or LA‐sensitive aPTT was only associated with thrombosis in patients aged less than 65 years (OR, 3.8;95% CI, 1.3–11.4) and disappeared after adjustment for C‐reactive protein. Conclusion Lupus anticoagulant on admission is strongly associated with thrombosis in critically ill patients with COVID‐19, especially in patients aged less than 65 years.

Lupus anticoagulant associates with thrombosis in patients with COVID-19 admitted to intensive care units: A retrospective cohort study.

Background: Thrombosis is a frequent and severe complication in patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Lupus anticoagulant (LA) is a strong acquired risk factor for thrombosis in various diseases and is frequently observed in patients with COVID-19. Whether LA is associated with thrombosis in patients with severe COVID-19 is currently unclear. Objective: To investigate if LA is associated with thrombosis in critically ill patients with COVID-19. Patients/Methods: The presence of LA and other antiphospholipid antibodies was assessed in patients with COVID-19 admitted to the ICU. LA was determined with dilute Russell's viper venom time (dRVVT) and LA-sensitive activated partial thromboplastin time (aPTT) reagents. Results: Of 169 patients with COVID-19, 116 (69%) tested positive for at least one antiphospholipid antibody upon admission to the ICU. Forty (24%) patients tested positive for LA; of whom 29 (17%) tested positive with a dRVVT, 19 (11%) tested positive with an LA-sensitive aPTT, and 8 (5%) tested positive on both tests. Fifty-eight (34%) patients developed thrombosis after ICU admission. The odds ratio (OR) for thrombosis in patients with LA based on a dRVVT was 2.5 (95% confidence interval [CI], 1.1-5.7), which increased to 4.5 (95% CI, 1.4-14.3) in patients at or below the median age in this study (64 years). LA positivity based on a dRVVT or LA-sensitive aPTT was only associated with thrombosis in patients aged less than 65 years (OR, 3.8; 95% CI, 1.3-11.4) and disappeared after adjustment for C-reactive protein. Conclusion: Lupus anticoagulant on admission is strongly associated with thrombosis in critically ill patients with COVID-19, especially in patients aged less than 65 years.

Population-wide persistent hemostatic changes after vaccination with ChAdOx1-S.

Various vaccines were developed to reduce the spread of the Severe Acute Respiratory Syndrome Cov-2 (SARS-CoV-2) virus. Quickly after the start of vaccination, reports emerged that anti-SARS-CoV-2 vaccines, including ChAdOx1-S, could be associated with an increased risk of thrombosis. We investigated the hemostatic changes after ChAdOx1-S vaccination in 631 health care workers. Blood samples were collected 32 days on average after the second ChAdOx1-S vaccination, to evaluate hemostatic markers such as D-dimer, fibrinogen, α2-macroglobulin, FVIII and thrombin generation. Endothelial function was assessed by measuring Von Willebrand Factor (VWF) and active VWF. IL-6 and IL-10 were measured to study the activation of the immune system. Additionally, SARS-CoV-2 anti-nucleoside and anti-spike protein antibody titers were determined. Prothrombin and fibrinogen levels were significantly reduced after vaccination (-7.5% and -16.9%, p < 0.0001). Significantly more vaccinated subjects were outside the normal range compared to controls for prothrombin (42.1% vs. 26.4%, p = 0.026) and antithrombin (23.9% vs. 3.6%, p = 0.0010). Thrombin generation indicated a more procoagulant profile, characterized by a significantly shortened lag time (-11.3%, p < 0.0001) and time-to-peak (-13.0% and p < 0.0001) and an increased peak height (32.6%, p = 0.0015) in vaccinated subjects compared to unvaccinated controls. Increased VWF (+39.5%, p < 0.0001) and active VWF levels (+24.1 %, p < 0.0001) pointed toward endothelial activation, and IL-10 levels were significantly increased (9.29 pg/mL vs. 2.43 pg/mL, p = 0.032). The persistent increase of IL-10 indicates that the immune system remains active after ChAdOx1-S vaccination. This could trigger a pathophysiological mechanism causing an increased thrombin generation profile and vascular endothelial activation, which could subsequently result in and increased risk of thrombotic events.

Association of genetic variations in ACE2, TIRAP and factor X with outcomes in COVID-19.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can manifest with varying disease severity and mortality. Genetic predisposition influences the clinical course of infectious diseases. We investigated whether genetic polymorphisms in candidate genes ACE2, TIRAP, and factor X are associated with clinical outcomes in COVID-19. METHODS: We conducted a single-centre retrospective cohort study. All patients who visited the emergency department with SARS-CoV-2 infection proven by polymerase chain reaction were included. Single nucleotide polymorphisms in ACE2 (rs2285666), TIRAP (rs8177374) and factor X (rs3211783) were assessed. The outcomes were mortality, respiratory failure and venous thromboembolism. Respiratory failure was defined as the necessity of >5 litres/minute oxygen, high flow nasal oxygen suppletion or mechanical ventilation. RESULTS: Between March and April 2020, 116 patients (35% female, median age 65 [inter quartile range 55-75] years) were included and treated according to the then applicable guidelines. Sixteen patients (14%) died, 44 patients (38%) had respiratory failure of whom 23 required endotracheal intubation for mechanical ventilation, and 20 patients (17%) developed venous thromboembolism. The percentage of TIRAP polymorphism carriers in the survivor group was 28% as compared to 0% in the non-survivor group (p = 0.01, Bonferroni corrected p = 0.02). Genotype distribution of ACE2 and factor X did not differ between survivors and non-survivors. CONCLUSION: This study shows that carriage of TIRAP polymorphism rs8177374 could be associated with a significantly lower mortality in COVID-19. This TIRAP polymorphism may be an important predictor in the outcome of COVID-19.

Platelet Activation Mechanisms and Consequences of Immune Thrombocytopenia.

Autoimmune disorders are often associated with low platelet count or thrombocytopenia. In immune-induced thrombocytopenia (IIT), a common mechanism is increased platelet activity, which can have an increased risk of thrombosis. In addition, or alternatively, auto-antibodies suppress platelet formation or augment platelet clearance. Effects of the auto-antibodies are linked to the unique structural and functional characteristics of platelets. Conversely, prior platelet activation may contribute to the innate and adaptive immune responses. Extensive interplay between platelets, coagulation and complement activation processes may aggravate the pathology. Here, we present an overview of the reported molecular causes and consequences of IIT in the most common forms of autoimmune disorders. These include idiopathic thrombocytopenic purpura (ITP), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), drug-induced thrombocytopenia (DITP), heparin-induced thrombocytopenia (HIT), COVID-19 vaccine-induced thrombosis with thrombocytopenia (VITT), thrombotic thrombocytopenia purpura (TTP), and hemolysis, the elevated liver enzymes and low platelet (HELLP) syndrome. We focus on the platelet receptors that bind auto-antibodies, the immune complexes, damage-associated molecular patterns (DAMPs) and complement factors. In addition, we review how circulating platelets serve as a reservoir of immunomodulatory molecules. By this update on the molecular mechanisms and the roles of platelets in the pathogenesis of autoimmune diseases, we highlight platelet-based pathways that can predispose for thrombocytopenia and are linked thrombotic or bleeding events.

Assessing Plasmin Generation in Health and Disease.

Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing. Plasmin is a central enzyme in this process via its capacity to cleave fibrin. The kinetics of plasmin generation (PG) and inhibition during fibrinolysis have been poorly understood until the recent development of assays to quantify these metrics. The assessment of plasmin kinetics allows for the identification of fibrinolytic dysfunction and better understanding of the relationships between abnormal fibrin dissolution and disease pathogenesis. Additionally, direct measurement of the inhibition of PG by antifibrinolytic medications, such as tranexamic acid, can be a useful tool to assess the risks and effectiveness of antifibrinolytic therapy in hemorrhagic diseases. This review provides an overview of available PG assays to directly measure the kinetics of plasmin formation and inhibition in human and mouse plasmas and focuses on their applications in defining the role of plasmin in diseases, including angioedema, hemophilia, rare bleeding disorders, COVID-19, or diet-induced obesity. Moreover, this review introduces the PG assay as a promising clinical and research method to monitor antifibrinolytic medications and screen for genetic or acquired fibrinolytic disorders.

Vascular activation is a strong predictor of mortality in coronavirus disease 2019 patients on the ICU.

Respiratory failure in coronavirus disease 2019 (COVID-19) patients is one of the most frequent causes for referral to the ICU. A significant percentage of these patients does not survive the infection due to thromboembolic complications. Furthermore, the vascular system seems also to be involved in the pathogenesis. To investigate the role of hemostasis and endothelium on the outcome of COVID-19 patients admitted to the ICU. Blood was drawn from 16 ICU COVID-19 patients for hemostatic analysis. Patients were followed-up till discharge (n = 11) or death (n = 5). Parameters related to both coagulation and fibrinolysis, though disturbed, were not associated with mortality. Contrarily, activated Von Willebrand factor was increased and ADAMTS13 levels were decreased by two-fold in nonsurvivors compared with survivors. Our data established the involvement of the Von Willebrand factor-ADAMTS13 axis in the COVID-19 pathogenesis, thereby demonstrating that these plasma proteins seem to be strong predictors for ICU mortality.

COVID-19 and Sepsis Are Associated With Different Abnormalities in Plasma Procoagulant and Fibrinolytic Activity.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with derangement in biomarkers of coagulation and endothelial function and has been likened to the coagulopathy of sepsis. However, clinical laboratory metrics suggest key differences in these pathologies. We sought to determine whether plasma coagulation and fibrinolytic potential in patients with COVID-19 differ compared with healthy donors and critically ill patients with sepsis. Approach and Results: We performed comparative studies on plasmas from a single-center, cross-sectional observational study of 99 hospitalized patients (46 with COVID-19 and 53 with sepsis) and 18 healthy donors. We measured biomarkers of endogenous coagulation and fibrinolytic activity by immunoassays, thrombin, and plasmin generation potential by fluorescence and fibrin formation and lysis by turbidity. Compared with healthy donors, patients with COVID-19 or sepsis both had elevated fibrinogen, d-dimer, soluble TM (thrombomodulin), and plasmin-antiplasmin complexes. Patients with COVID-19 had increased thrombin generation potential despite prophylactic anticoagulation, whereas patients with sepsis did not. Plasma from patients with COVID-19 also had increased endogenous plasmin potential, whereas patients with sepsis showed delayed plasmin generation. The collective perturbations in plasma thrombin and plasmin generation permitted enhanced fibrin formation in both COVID-19 and sepsis. Unexpectedly, the lag times to thrombin, plasmin, and fibrin formation were prolonged with increased disease severity in COVID-19, suggesting a loss of coagulation-initiating mechanisms accompanies severe COVID-19. CONCLUSIONS: Both COVID-19 and sepsis are associated with endogenous activation of coagulation and fibrinolysis, but these diseases differently impact plasma procoagulant and fibrinolytic potential. Dysregulation of procoagulant and fibrinolytic pathways may uniquely contribute to the pathophysiology of COVID-19 and sepsis.