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1.
Shock ; 57(1): 1-6, 2022 01 01.
Article in English | MEDLINE | ID: covidwho-2191212

ABSTRACT

BACKGROUND: The pathomechanisms of hypoxemia and treatment strategies for type H and type L acute respiratory distress syndrome (ARDS) in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced coronavirus disease 2019 (COVID-19) have not been elucidated. MAIN TEXT: SARS-CoV-2 mainly targets the lungs and blood, leading to ARDS, and systemic thrombosis or bleeding. Angiotensin II-induced coagulopathy, SARS-CoV-2-induced hyperfibrin(ogen)olysis, and pulmonary and/or disseminated intravascular coagulation due to immunothrombosis contribute to COVID-19-associated coagulopathy. Type H ARDS is associated with hypoxemia due to diffuse alveolar damage-induced high right-to-left shunts. Immunothrombosis occurs at the site of infection due to innate immune inflammatory and coagulofibrinolytic responses to SARS-CoV-2, resulting in microvascular occlusion with hypoperfusion of the lungs. Lung immunothrombosis in type L ARDS results from neutrophil extracellular traps containing platelets and fibrin in the lung microvasculature, leading to hypoxemia due to impaired blood flow and a high ventilation/perfusion (VA/Q) ratio. COVID-19-associated ARDS is more vascular centric than the other types of ARDS. D-dimer levels have been monitored for the progression of microvascular thrombosis in COVID-19 patients. Early anticoagulation therapy in critical patients with high D-dimer levels may improve prognosis, including the prevention and/or alleviation of ARDS. CONCLUSIONS: Right-to-left shunts and high VA/Q ratios caused by lung microvascular thrombosis contribute to hypoxemia in type H and L ARDS, respectively. D-dimer monitoring-based anticoagulation therapy may prevent the progression to and/or worsening of ARDS in COVID-19 patients.


Subject(s)
COVID-19/physiopathology , Hemostasis/physiology , Hypoxia/physiopathology , Respiratory Distress Syndrome/physiopathology , Thrombosis/physiopathology , Anticoagulants/therapeutic use , Biomarkers/blood , Blood Platelets/metabolism , COVID-19/drug therapy , Extracellular Traps/metabolism , Fibrin/metabolism , Fibrin Fibrinogen Degradation Products/analysis , Fibrinolysis , Humans , Lung/blood supply , Microvessels/physiopathology , Phenotype , Respiratory Distress Syndrome/drug therapy , SARS-CoV-2 , Thrombosis/drug therapy
2.
J Med Microbiol ; 71(11)2022 Nov.
Article in English | MEDLINE | ID: covidwho-2107718

ABSTRACT

Introduction. Coronavirus disease 2019 (COVID-19) identified in December 2019 in Wuhan, China, is associated with high mortality rates worldwide.Hypothesis/Gap Statement. Thrombotic problems, such as coagulopathy, are common in COVID-19 patients. Despite anticoagulation, thrombosis is more common in patients in the intensive care unit and patients with more severe disease. Although the exact mechanisms of coagulopathy in COVID-19 patients are still unclear, studies showed that overactivation of the renin-angiotensin system (RAS), cytokine storm, endothelial damage, formation of neutrophil extracellular traps (NETs), and also extracellular vesicles (EVs) in response to COVID-19 induced inflammation can lead to systemic coagulation and thrombosis.Aim. The management of COVID-19 patients requires the use of basic and readily available laboratory markers, both on admission and during hospitalization. Because it is critical to understand the pathophysiology of COVID-19 induced coagulopathy and treatment strategies, in this review we attempt to explain the underlying mechanism of COVID-19 coagulopathy, its diagnosis, and the associated successful treatment strategies.Conclusion. The exact mechanisms behind COVID-19-related coagulopathy are still unclear, but several studies revealed some mechanisms. More research is needed to determine the best anticoagulant regimen and to study other therapeutic options.


Subject(s)
COVID-19 , Thrombosis , Humans , COVID-19/complications , SARS-CoV-2 , Thrombosis/drug therapy , Anticoagulants/therapeutic use , China
3.
ACS Nano ; 16(7): 10566-10580, 2022 Jul 26.
Article in English | MEDLINE | ID: covidwho-2106345

ABSTRACT

Intravenously infusible nanoparticles to control bleeding have shown promise in rodents, but translation into preclinical models has been challenging as many of these nanoparticle approaches have resulted in infusion responses and adverse outcomes in large animal trauma models. We developed a hemostatic nanoparticle technology that was screened to avoid one component of the infusion response: complement activation. We administered these hemostatic nanoparticles, control nanoparticles, or saline volume controls in a porcine polytrauma model. While the hemostatic nanoparticles promoted clotting as marked by a decrease in prothrombin time and both the hemostatic nanoparticles and controls did not active complement, in a subset of the animals, hard thrombi were found in uninjured tissues in both the hemostatic and control nanoparticle groups. Using data science methods that allow one to work across heterogeneous data sets, we found that the presence of these thrombi correlated with changes in IL-6, INF-alpha, lymphocytes, and neutrophils. While these findings might suggest that this formulation would not be a safe one for translation for trauma, they provide guidance for developing screening tools to make nanoparticle formulations in the complex milieux of trauma as well as for therapeutic interventions more broadly. This is important as we look to translate intravenously administered nanoparticle formulations for therapies, particularly considering the vascular changes seen in a subset of patients following COVID-19. We need to understand adverse events like thrombi more completely and screen for these events early to make nanomaterials as safe and effective as possible.


Subject(s)
COVID-19 , Hemostatics , Nanoparticles , Thrombosis , Swine , Animals , Cytokines , Polyesters , Disease Models, Animal , Nanoparticles/therapeutic use , Thrombosis/drug therapy , Polyethylene Glycols
4.
Circulation ; 146(18): 1344-1356, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2020592

ABSTRACT

BACKGROUND: The efficacy and safety of prophylactic full-dose anticoagulation and antiplatelet therapy in critically ill COVID-19 patients remain uncertain. METHODS: COVID-PACT (Prevention of Arteriovenous Thrombotic Events in Critically-ill COVID-19 Patients Trial) was a multicenter, 2×2 factorial, open-label, randomized-controlled trial with blinded end point adjudication in intensive care unit-level patients with COVID-19. Patients were randomly assigned to a strategy of full-dose anticoagulation or standard-dose prophylactic anticoagulation. Absent an indication for antiplatelet therapy, patients were additionally randomly assigned to either clopidogrel or no antiplatelet therapy. The primary efficacy outcome was the hierarchical composite of death attributable to venous or arterial thrombosis, pulmonary embolism, clinically evident deep venous thrombosis, type 1 myocardial infarction, ischemic stroke, systemic embolic event or acute limb ischemia, or clinically silent deep venous thrombosis, through hospital discharge or 28 days. The primary efficacy analyses included an unmatched win ratio and time-to-first event analysis while patients were on treatment. The primary safety outcome was fatal or life-threatening bleeding. The secondary safety outcome was moderate to severe bleeding. Recruitment was stopped early in March 2022 (≈50% planned recruitment) because of waning intensive care unit-level COVID-19 rates. RESULTS: At 34 centers in the United States, 390 patients were randomly assigned between anticoagulation strategies and 292 between antiplatelet strategies (382 and 290 in the on-treatment analyses). At randomization, 99% of patients required advanced respiratory therapy, including 15% requiring invasive mechanical ventilation; 40% required invasive ventilation during hospitalization. Comparing anticoagulation strategies, a greater proportion of wins occurred with full-dose anticoagulation (12.3%) versus standard-dose prophylactic anticoagulation (6.4%; win ratio, 1.95 [95% CI, 1.08-3.55]; P=0.028). Results were consistent in time-to-event analysis for the primary efficacy end point (full-dose versus standard-dose incidence 19/191 [9.9%] versus 29/191 [15.2%]; hazard ratio, 0.56 [95% CI, 0.32-0.99]; P=0.046). The primary safety end point occurred in 4 (2.1%) on full dose and in 1 (0.5%) on standard dose (P=0.19); the secondary safety end point occurred in 15 (7.9%) versus 1 (0.5%; P=0.002). There was no difference in all-cause mortality (hazard ratio, 0.91 [95% CI, 0.56-1.48]; P=0.70). There were no differences in the primary efficacy or safety end points with clopidogrel versus no antiplatelet therapy. CONCLUSIONS: In critically ill patients with COVID-19, full-dose anticoagulation, but not clopidogrel, reduced thrombotic complications with an increase in bleeding, driven primarily by transfusions in hemodynamically stable patients, and no apparent excess in mortality. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04409834.


Subject(s)
COVID-19 , Thrombosis , Venous Thrombosis , Humans , Critical Illness , Thrombosis/drug therapy , Clopidogrel/therapeutic use , Hemorrhage/chemically induced , Anticoagulants/adverse effects , Venous Thrombosis/drug therapy , Venous Thrombosis/epidemiology , Venous Thrombosis/prevention & control , Platelet Aggregation Inhibitors/adverse effects , Treatment Outcome
5.
Surg Infect (Larchmt) ; 23(8): 705-711, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2017669

ABSTRACT

Background: Thrombosis (T) is common in coronavirus disease 2019 (COVID-19) patients, and d-dimer concentrations correlate with outcomes. Controversy exists with regards to anticoagulation (AC) for patients. We implemented a full-heparinization AC protocol from the onset of the pandemic and hypothesized that a safety signal would be undetectable. Patients and Methods: Prospective evaluation of 111 patients with COVID-19 critical illness hospitalized from March to June 2020. All patients received therapeutic heparinoid-based AC from admission. Incidences of T, bleeding (B), or both (BT) were noted. The primary outcome was mortality. Kruskal-Wallis test and logistic regression were performed. Results are expressed as n (%), median (interquartile range) and odds ratios with 95% confidence intervals. Alpha was set at 0.05. Results: Thirty-two patients (28%) had T, 23 (20%) had B, and 14 (12%) had BT; 42 (40%) patients were unaffected. Two logistic regression models (outcome = mortality) evaluated BT as T, or BT as B. For BT as T, neither T, B, nor male gender predicted mortality; similarly, for BT as B, neither T, B, nor male gender predicted mortality. Factors associated with higher odds of death included higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.00-1.13; p = 0.0045), higher d-dimer concentration (OR, 1.00; 95% CI, 1.00-1.01; p = 0.043), and higher activated partial thromboplastin time (aPTT; OR, 1.09; 95% CI, 1.02-1.16; p = 0.010). Conclusions: Neither T nor B predicted mortality in this prospective cohort of anticoagulated patients with COVID-19 critical illness. These data support continued full-dose heparinoid prophylaxis.


Subject(s)
COVID-19 , Heparinoids , Thrombosis , Anticoagulants/adverse effects , COVID-19/complications , Critical Illness , Humans , Male , SARS-CoV-2 , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control
6.
Thromb Res ; 218: 151-156, 2022 10.
Article in English | MEDLINE | ID: covidwho-1996587

ABSTRACT

BACKGROUND: Coagulation dysfunction represents a serious complication in patients during the COVID-19 infection, while fulminant thrombotic complications emerge as critical issues in individuals with severe COVID-19. In addition to a severe clinical presentation, comorbidities and age significantly contribute to the development of thrombotic complications in this disease. However, there is very little data on association of congenital thrombophilia and thrombotic events in the setting of COVID-19. Our study aimed to evaluate the risk of COVID-19 associated thrombosis in patients with congenital thrombophilia. METHODS: This prospective, case-control study included patients with confirmed COVID-19 infection, followed 6 months post-confirmation. The final outcome was a symptomatic thrombotic event. In total, 90 COVID-19 patients, 30 with known congenital thrombophilia and 60 patients without thrombophilia within the period July 2020-November 2021, were included in the study. Evaluation of hemostatic parameters including FVIII activity and D-dimer was performed for all patients at 1 month, 3 months and 6 months post-COVID-19 diagnosis. RESULTS: Symptomatic thrombotic events were observed in 7 out of 30 (23 %) COVID-19 patients with thrombophilia, and 12 out of 60 (20 %) without thrombophilia, P = 0.715. In addition, the two patient groups had comparable localization of thrombotic events, time to thrombotic event, effect of antithrombotic treatment and changes in FVIII activity, while D-dimer level were significantly increased in patients without thrombophilia. CONCLUSION: Our findings suggest that patients with congenital thrombophilia, irrespective of their age, a mild clinical picture and absence of comorbidities, should receive anticoagulant prophylaxis, adjusted based on the specific genetic defect.


Subject(s)
COVID-19 , Hemostatics , Thrombophilia , Thrombosis , Anticoagulants/therapeutic use , COVID-19/complications , COVID-19 Testing , Case-Control Studies , Fibrinolytic Agents/therapeutic use , Hemostatics/therapeutic use , Humans , Prospective Studies , Risk Assessment , Thrombophilia/complications , Thrombosis/drug therapy
7.
Mol Immunol ; 150: 99-113, 2022 10.
Article in English | MEDLINE | ID: covidwho-1996438

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 is associated with a clinical spectrum ranging from asymptomatic carriers to critically ill patients with complications including thromboembolic events, myocardial injury, multisystemic inflammatory syndromes and death. Since the beginning of the pandemic several therapeutic options emerged, with a multitude of randomized trials, changing the medical landscape of COVID-19. The effect of various monoclonal antibodies, antiviral, anti-inflammatory and anticoagulation drugs have been studied, and to some extent, implemented into clinical practice. In addition, a multitude of trials improved the understanding of the disease and emerging evidence points towards a significant role of the complement system, kallikrein-kinin, and contact activation system as drivers of disease in severe COVID-19. Despite their involvement in COVID-19, treatments targeting these plasmatic cascades have neither been systematically studied nor introduced into clinical practice, and randomized studies with regards to these treatments are scarce. Given the multiple-action, multiple-target nature of C1 inhibitor (C1-INH), the natural inhibitor of these cascades, this drug may be an interesting candidate to prevent disease progression and combat thromboinflammation in COVID-19. This narrative review will discuss the current evidence with regards to the involvement of these plasmatic cascades as well as endothelial cells in COVID-19. Furthermore, we summarize the evidence of C1-INH in COVID-19 and potential benefits and pitfalls of C1-INH treatment in COVID-19.


Subject(s)
COVID-19 , Thrombosis , Antibodies, Monoclonal , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Complement C1 Inhibitor Protein/therapeutic use , Disease Progression , Endothelial Cells , Humans , Inflammation/drug therapy , Kallikreins , Kinins , SARS-CoV-2 , Thromboinflammation , Thrombosis/drug therapy
8.
J Infect Chemother ; 28(8): 1208-1211, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1983457

ABSTRACT

A 53-year-old male Japanese patient with COVID-19 was admitted to our hospital after his respiratory condition worsened on day 9 of the disease. With the diagnosis of severe COVID-19, treatment with remdesivir, dexamethasone, and unfractionated heparin was started for the prevention of thrombosis. Although the patient's respiratory status data improved after treatment, severe respiratory failure persisted. Thrombocytopenia and D-dimer elevation were observed on day 8 after heparin therapy initiation. Heparin-induced thrombocytopenia (HIT) antibody measured by immunological assay was positive, and contrast computed tomography showed pulmonary artery thrombus. The patient was diagnosed with HIT because the pre-test probability score (4Ts score) for HIT was 7 points. Heparin was changed to apixaban, a direct oral anticoagulant, which resulted in a reduction of the pulmonary thrombus and improvement of the respiratory failure. In patients with COVID-19, anticoagulant therapy with heparin requires careful monitoring of thrombocytopenia and elevated D-dimer as possible complications related to HIT. (151/250 words).


Subject(s)
COVID-19 , Pulmonary Embolism , Respiratory Insufficiency , Thrombocytopenia , Thrombosis , Anticoagulants/adverse effects , COVID-19/drug therapy , Heparin/adverse effects , Humans , Male , Middle Aged , Pulmonary Embolism/drug therapy , Respiratory Insufficiency/chemically induced , Thrombocytopenia/chemically induced , Thrombocytopenia/diagnosis , Thrombocytopenia/drug therapy , Thrombosis/drug therapy
9.
ASAIO J ; 68(7): 920-924, 2022 07 01.
Article in English | MEDLINE | ID: covidwho-1967929

ABSTRACT

Extracorporeal membrane oxygenation (ECMO) contributes to coagulopathy, necessitating systemic anticoagulation to prevent thrombosis. Traditionally, unfractionated heparin (UFH) has been the anticoagulant of choice, however, due to many inadequacies new evidence suggests benefit with the use of direct thrombin inhibitors. This retrospective cohort sought to evaluate the safety and efficacy of bivalirudin compared to UFH in ECMO patients. Primary endpoints included incidence of bleeding and thrombosis. Percent time in therapeutic range (TR), time to achieve TR and number of dose titrations required to maintain TR were calculated to assess efficacy of institutional protocols. Overall incidence of thrombosis was low, with one event in the bivalirudin group and no events in the UFH group. No difference was found in rates of bleeding between groups (6% vs . 10%, P = 0.44). Bivalirudin yielded higher percent time in TR (86% vs. 33%, P < 0.001), faster time to TR (2 vs . 18 hr, P < 0.001) and required fewer dose adjustments to maintain TR (2 vs . 11, P < 0.001) compared to UFH. These results suggest bivalirudin and UFH are associated with similar rates of bleeding and thrombosis in patients requiring ECMO support. Our results demonstrate the favorable pharmacokinetic profile of bivalirudin, and its ability to consistently maintain TR when compared to UFH.


Subject(s)
Extracorporeal Membrane Oxygenation , Thrombosis , Adult , Anticoagulants/adverse effects , Anticoagulants/therapeutic use , Antithrombins/therapeutic use , Extracorporeal Membrane Oxygenation/adverse effects , Fibrinolytic Agents/therapeutic use , Hemorrhage/chemically induced , Hemorrhage/complications , Hemorrhage/prevention & control , Heparin/adverse effects , Heparin/therapeutic use , Hirudin Therapy , Hirudins/adverse effects , Humans , Peptide Fragments/adverse effects , Peptide Fragments/therapeutic use , Recombinant Proteins/adverse effects , Recombinant Proteins/therapeutic use , Retrospective Studies , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control , Treatment Outcome
10.
R I Med J (2013) ; 105(6): 36-40, 2022 08 01.
Article in English | MEDLINE | ID: covidwho-1958239

ABSTRACT

Early in the pandemic, it was recognized that infection with COVID-19 was associated with an increased incidence in both venous and arterial thrombotic events leading to poor patient outcomes. Given the rapid rise of the pandemic, anticoagulation strategies were initially based upon retrospective and observational data with few high-quality randomized control trials to help direct strategies regarding the use of thromboprophylaxis during hospitalization, empiric therapeutic anticoagulation, and extended-duration thromboprophylaxis after discharge. Over the past year, several randomized control trials have now been published evaluating these strategies. In this article, we hope to review the current literature surrounding the use of intermediate-dose thromboprophylaxis, empiric therapeutic anticoagulation, and the use of extended-duration thromboprophylaxis for patients hospitalized with COVID-19.


Subject(s)
COVID-19 , Thrombosis , Venous Thromboembolism , Anticoagulants/therapeutic use , Humans , Inpatients , Retrospective Studies , SARS-CoV-2 , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control
11.
BMJ ; 378: e070022, 2022 07 04.
Article in English | MEDLINE | ID: covidwho-1932663

ABSTRACT

OBJECTIVE: To assess the benefits and harms of different types and doses of anticoagulant drugs for the prevention of venous thromboembolism in patients who are acutely ill and admitted to hospital. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Cochrane CENTRAL, PubMed/Medline, Embase, Web of Science, clinical trial registries, and national health authority databases. The search was last updated on 16 November 2021. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Published and unpublished randomised controlled trials that evaluated low or intermediate dose low-molecular-weight heparin, low or intermediate dose unfractionated heparin, direct oral anticoagulants, pentasaccharides, placebo, or no intervention for the prevention of venous thromboembolism in acutely ill adult patients in hospital. MAIN OUTCOME MEASURES: Random effects, bayesian network meta-analyses used four co-primary outcomes: all cause mortality, symptomatic venous thromboembolism, major bleeding, and serious adverse events at or closest timing to 90 days. Risk of bias was also assessed using the Cochrane risk-of-bias 2.0 tool. The quality of evidence was graded using the Confidence in Network Meta-Analysis framework. RESULTS: 44 randomised controlled trials that randomly assigned 90 095 participants were included in the main analysis. Evidence of low to moderate quality suggested none of the interventions reduced all cause mortality compared with placebo. Pentasaccharides (odds ratio 0.32, 95% credible interval 0.08 to 1.07), intermediate dose low-molecular-weight heparin (0.66, 0.46 to 0.93), direct oral anticoagulants (0.68, 0.33 to 1.34), and intermediate dose unfractionated heparin (0.71, 0.43 to 1.19) were most likely to reduce symptomatic venous thromboembolism (very low to low quality evidence). Intermediate dose unfractionated heparin (2.63, 1.00 to 6.21) and direct oral anticoagulants (2.31, 0.82 to 6.47) were most likely to increase major bleeding (low to moderate quality evidence). No conclusive differences were noted between interventions regarding serious adverse events (very low to low quality evidence). When compared with no intervention instead of placebo, all active interventions did more favourably with regard to risk of venous thromboembolism and mortality, and less favourably with regard to risk of major bleeding. The results were robust in prespecified sensitivity and subgroup analyses. CONCLUSIONS: Low-molecular-weight heparin in an intermediate dose appears to confer the best balance of benefits and harms for prevention of venous thromboembolism. Unfractionated heparin, in particular the intermediate dose, and direct oral anticoagulants had the least favourable profile. A systematic discrepancy was noted in intervention effects that depended on whether placebo or no intervention was the reference treatment. Main limitations of this study include the quality of the evidence, which was generally low to moderate due to imprecision and within-study bias, and statistical inconsistency, which was addressed post hoc. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020173088.


Subject(s)
Thrombosis , Venous Thromboembolism , Anticoagulants/adverse effects , Bayes Theorem , Hemorrhage/chemically induced , Hemorrhage/drug therapy , Heparin/adverse effects , Heparin, Low-Molecular-Weight/adverse effects , Hospitals , Humans , Network Meta-Analysis , Randomized Controlled Trials as Topic , Thrombosis/drug therapy , Venous Thromboembolism/drug therapy
12.
Anticancer Res ; 42(7): 3261-3274, 2022 07.
Article in English | MEDLINE | ID: covidwho-1924868

ABSTRACT

Cancer and COVID-19 are both well-established risk factors predisposing to thrombosis. Both disease entities are correlated with increased incidence of venous thrombotic events through multifaceted pathogenic mechanisms involving the interaction of cancer cells or SARS-CoV2 on the one hand and the coagulation system and endothelial cells on the other hand. Thromboprophylaxis is recommended for hospitalized patients with active cancer and high-risk outpatients with cancer receiving anticancer treatment. Universal thromboprophylaxis with a high prophylactic dose of low molecular weight heparins (LMWH) or therapeutic dose in select patients, is currentlyindicated for hospitalized patients with COVID-19. Also, prophylactic anticoagulation is recommended for outpatients with COVID-19 at high risk for thrombosis or disease worsening. However, whether there is an additive risk of thrombosis when a patient with cancer is infected with SARS-CoV2 remains unclear In the current review, we summarize and critically discuss the literature regarding the epidemiology of thrombotic events in patients with cancer and concomitant COVID-19, the thrombotic risk assessment, and the recommendations on thromboprophylaxis for this subgroup of patients. Current data do not support an additive thrombotic risk for patients with cancer and COVID-19. Of note, patients with cancer have less access to intensive care unit care, a setting associated with high thrombotic risk. Based on current evidence, patients with cancer and COVID-19 should be assessed with well-established risk assessment models for medically ill patients and receive thromboprophylaxis, preferentially with LMWH, according to existing recommendations. Prospective trials on well-characterized populations do not exist.


Subject(s)
COVID-19 , Neoplasms , Thrombosis , Venous Thromboembolism , Anticoagulants/therapeutic use , COVID-19/complications , Endothelial Cells , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Neoplasms/complications , Neoplasms/drug therapy , Prospective Studies , RNA, Viral , Risk Factors , SARS-CoV-2 , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control , Venous Thromboembolism/drug therapy , Venous Thromboembolism/etiology , Venous Thromboembolism/prevention & control
13.
Exp Physiol ; 107(7): 749-758, 2022 07.
Article in English | MEDLINE | ID: covidwho-1916373

ABSTRACT

NEW FINDINGS: What is the topic of this review? Overview of the coagulation abnormalities, including elevated D-dimers widely reported with COVID-19, often labelled as COVID coagulopathy. What advances does it highlight? The review highlights the changes in bronchoalveolar haemostasis due to apoptosis of alveolar cells, which contributes to acute lung injury and acute respiratory distress syndrome; the pathophysiological mechanisms, including endothelial dysfunction and damage responsible for thrombosis of pulmonary microcirculation and potential contribution to the hypoxaemia of COVID-19 acute lung injury; and changes in coagulation proteins responsible for the hypercoagulability and increased risk of thrombosis in other venous and arterial beds. The rationale for anticoagulation and fibrinolytic therapies is detailed, and potential confounders that might have led to less than expected improvement in the various randomised controlled trials are considered. ABSTRACT: Coronavirus disease 19 (COVID-19) causes acute lung injury with diffuse alveolar damage, alveolar-capillary barrier disruption, thrombin generation and alveolar fibrin deposition. Clinically, hypoxaemia is associated with preserved lung compliance early in the disease, suggesting the lack of excessive fluid accumulation typical of other lung injuries. Notably, autopsy studies demonstrate infection of the endothelium with extensive capillary thrombosis distinct from the embolic thrombi in pulmonary arteries. The inflammatory thrombosis in pulmonary vasculature secondary to endothelial infection and dysfunction appears to contribute to hypoxaemia. This is associated with elevated D-dimers and acquired hypercoagulability with an increased risk of deep vein thrombosis. Hypercoagulability is secondary to elevated plasma tissue factor levels, von Willebrand factor, fibrinogen, reduced ADAMTS-13 with platelet activation and inhibition of fibrinolysis. Multi-platform randomised controlled studies of systemic therapeutic anticoagulation with unfractionated and low molecular mass heparins demonstrated a survival benefit over standard care with full-dose anticoagulation in patients with non-severe disease who require supplemental oxygen, but not in severe disease requiring ventilatory support. Late intervention and the heterogeneous nature of enrolled patients can potentially explain the apparent lack of benefit in severe disease. Improvement in oxygenation has been demonstrated with intravenous fibrinolytics in small studies. Inhaled anticoagulants, thrombolytic agents and non-specific proteolytic drugs in clinical trials for decreasing alveolar fibrin deposition might benefit early disease. Essentially, COVID-19 is a multi-system disorder with pulmonary vascular inflammatory thrombosis that requires an interdisciplinary approach to combination therapies addressing both inflammation and intravascular thrombosis or alveolar fibrin deposits to improve outcomes.


Subject(s)
Acute Lung Injury , COVID-19 , Thrombophilia , Thrombosis , Acute Lung Injury/drug therapy , Anticoagulants/therapeutic use , Fibrin/metabolism , Humans , Hypoxia/drug therapy , SARS-CoV-2 , Thrombophilia/drug therapy , Thrombophilia/etiology , Thrombosis/drug therapy
14.
J Thromb Haemost ; 20(10): 2226-2236, 2022 10.
Article in English | MEDLINE | ID: covidwho-1916260

ABSTRACT

Despite the emergence of high quality randomized trial data with the use of antithrombotic agents to reduce the risk of thromboembolism, end-organ failure, and possibly mortality in patients with coronavirus disease 2019 (COVID-19), questions still remain as to optimal patient selection for these strategies, the use of antithrombotics in outpatient settings and in-hospital settings (including critical care units), thromboprophylaxis in special patient populations, and the management of acute thrombosis in hospitalized COVID-19 patients. In October 2021, the International Society on Thrombosis and Haemostasis (ISTH) formed a multidisciplinary and international panel of content experts, two patient representatives, and a methodologist to develop recommendations on treatment with anticoagulants and antiplatelet agents for COVID-19 patients. The ISTH Guideline panel discussed additional topics to be well suited to a non-Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for Good Practice Statements (GPS) to support good clinical care in the antithrombotic management of COVID-19 patients in various clinical settings. The GPS panel agreed on 17 GPS: 3 in the outpatient (pre-hospital) setting, 12 in the hospital setting both in non-critical care (ward) as well as intensive care unit settings, and 2 in the immediate post-hospital discharge setting based on limited evidence or expert opinion that supports net clinical benefit in enacting the statements provided. The antithrombotic therapies discussed in these GPS should be available in low- and middle-income countries.


Subject(s)
COVID-19 , Fibrinolytic Agents , Anticoagulants/therapeutic use , COVID-19/drug therapy , Fibrinolytic Agents/therapeutic use , Hemostasis , Humans , Platelet Aggregation Inhibitors/therapeutic use , Thrombosis/drug therapy , Thrombosis/prevention & control , Venous Thromboembolism/prevention & control
15.
J Thromb Haemost ; 20(10): 2394-2406, 2022 10.
Article in English | MEDLINE | ID: covidwho-1916259

ABSTRACT

BACKGROUND: Severe COVID-19 disease is associated with thrombotic complications and extensive fibrin deposition. This study investigates whether the hemostatic complications in COVID-19 disease arise due to dysregulation of the fibrinolytic system. METHODS: This prospective study analyzed fibrinolytic profiles of 113 patients hospitalized with COVID-19 disease with 24 patients with non-COVID-19 respiratory infection and healthy controls. Antigens were quantified by Ella system or ELISA, clot lysis by turbidimetric assay, and plasminogen activator inhibitor-1 (PAI-1)/plasmin activity using chromogenic substrates. Clot structure was visualized by confocal microscopy. RESULTS: PAI-1 and its cofactor, vitronectin, are significantly elevated in patients with COVID-19 disease compared with those with non-COVID-19 respiratory infection and healthy control groups. Thrombin activatable fibrinolysis inhibitor and tissue plasminogen activator were elevated in patients with COVID-19 disease relative to healthy controls. PAI-1 and tissue plasminogen activator (tPA) were associated with more severe COVID-19 disease severity. Clots formed from COVID-19 plasma demonstrate an altered fibrin network, with attenuated fiber length and increased branching. Functional studies reveal that plasmin generation and clot lysis were markedly attenuated in COVID-19 disease, while PAI-1 activity was elevated. Clot lysis time significantly correlated with PAI-1 levels. Stratification of COVID-19 samples according to PAI-1 levels reveals significantly faster lysis when using the PAI-1 resistant (tPA) variant, tenecteplase, over alteplase lysis. CONCLUSION: This study shows that the suboptimal fibrinolytic response in COVID-19 disease is directly attributable to elevated levels of PAI-1, which attenuate plasmin generation. These data highlight the important prognostic potential of PAI-1 and the possibility of using pre-existing drugs, such as tenecteplase, to treat COVID-19 disease and potentially other respiratory diseases.


Subject(s)
COVID-19 , Carboxypeptidase B2 , Hemostatics , Thrombosis , COVID-19/drug therapy , Chromogenic Compounds , Fibrin , Fibrinolysin/pharmacology , Fibrinolysis , Hemostatics/pharmacology , Humans , Plasminogen Activator Inhibitor 1 , Prospective Studies , Tenecteplase , Thrombosis/drug therapy , Tissue Plasminogen Activator/pharmacology , Vitronectin
16.
Phytomedicine ; 100: 154083, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1895370

ABSTRACT

BACKGROUND: The high incidence of thrombotic events is one of the clinical characteristics of coronavirus disease of 2019 (COVID-19), due to a hyperinflammatory response caused by the virus. Gegen Qinlian Pills (GQP) is a Traditional Chinese Medicine that is included in the Chinese Pharmacopoeia and played an important role in the clinical fight against COVID-19. Although GQP has shown the potential to treat thrombosis, there is no relevant research on its treatment of thrombosis so far. HYPOTHESIS: We hypothesized that GQP may be capable inhibit inflammation-induced thrombosis. STUDY DESIGN: We tested our hypothesis in a carrageenan-induced thrombosis mouse model in vivo and lipopolysaccharide (LPS)-induced human endothelial cells (HUVECs) in vitro. METHODS: We used a carrageenan-induced mouse thrombus model to confirm the inhibitory effect of GQP on inflammation-induced thrombus. In vitro, studies in human umbilical vein endothelial cells (HUVECs) and in silico network pharmacology analyses were performed to reveal the underlying mechanisms of GQP and determine the main components, targets, and pathways of GQP, respectively. RESULTS: Oral administration of 227.5 mg/kg, 445 mg/kg and 910 mg/kg of GQP significantly inhibited thrombi in the lung, liver, and tail and augmented tail blood flow of carrageenan-induced mice with reduced plasma tumor necrosis factor α (TNF-α) and diminished expression of high mobility group box 1 (HMGB1) in lung tissues. GQP ethanol extract (1, 2, or 5 µg/ml) also reduced the adhesion of platelets to LPS stimulated HUVECs. The TNF-α and the expression of HMGB1, nuclear factor kappa B (NF-κB), and NLR family pyrin domain containing 3 (NLRP3) in LPS stimulated HUVECs were also attenuated. Moreover, we analyzed the components of GQP and inferred the main targets, biological processes, and pathways of GQP in the treatment of inflammation-induced thrombosis through network pharmacology. CONCLUSION: Overall, we demonstrated that GQP could reduce inflammation-induced thrombosis by inhibiting HMGB1/NFκB/NLRP3 signaling and provided an accurate explanation for the multi-target, multi-function mechanism of GQP in the treatment of thromboinflammation, and provides a reference for the clinical usage of GQP.


Subject(s)
Drugs, Chinese Herbal , HMGB1 Protein , Thrombosis , Animals , Carrageenan , Disease Models, Animal , Drugs, Chinese Herbal/pharmacology , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Inflammation/drug therapy , Inflammation/metabolism , Lipopolysaccharides , Mice , NF-kappa B/metabolism , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Thrombosis/chemically induced , Thrombosis/drug therapy , Tumor Necrosis Factor-alpha/metabolism
17.
Blood Coagul Fibrinolysis ; 33(5): 239-256, 2022 Jul 01.
Article in English | MEDLINE | ID: covidwho-1891118

ABSTRACT

During sepsis, an initial prothrombotic shift takes place, in which coagulatory acute-phase proteins are increased, while anticoagulatory factors and platelet count decrease. Further on, the fibrinolytic system becomes impaired, which contributes to disease severity. At a later stage in sepsis, coagulation factors may become depleted, and sepsis patients may shift into a hypo-coagulable state with an increased bleeding risk. During the pro-coagulatory shift, critically ill patients have an increased thrombosis risk that ranges from developing micro-thromboses that impair organ function to life-threatening thromboembolic events. Here, thrombin plays a key role in coagulation as well as in inflammation. For thromboprophylaxis, low molecular weight heparins (LMWH) and unfractionated heparins (UFHs) are recommended. Nevertheless, there are conditions such as heparin resistance or heparin-induced thrombocytopenia (HIT), wherein heparin becomes ineffective or even puts the patient at an increased prothrombotic risk. In these cases, argatroban, a direct thrombin inhibitor (DTI), might be a potential alternative anticoagulatory strategy. Yet, caution is advised with regard to dosing of argatroban especially in sepsis. Therefore, the starting dose of argatroban is recommended to be low and should be titrated to the targeted anticoagulation level and be closely monitored in the further course of treatment. The authors of this review recommend using DTIs such as argatroban as an alternative anticoagulant in critically ill patients suffering from sepsis or COVID-19 with suspected or confirmed HIT, HIT-like conditions, impaired fibrinolysis, in patients on extracorporeal circuits and patients with heparin resistance, when closely monitored.


Subject(s)
COVID-19 , Sepsis , Thrombocytopenia , Thrombosis , Venous Thromboembolism , Anticoagulants/adverse effects , Arginine/analogs & derivatives , Critical Illness , Heparin/adverse effects , Heparin, Low-Molecular-Weight/therapeutic use , Humans , Pipecolic Acids , Sepsis/drug therapy , Sulfonamides , Thrombocytopenia/chemically induced , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control , Venous Thromboembolism/drug therapy
18.
Rinsho Ketsueki ; 63(5): 471-480, 2022.
Article in Japanese | MEDLINE | ID: covidwho-1879649

ABSTRACT

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 and is known to have thrombotic complications. Various-sized thrombosis occurs in the arteries and veins, especially in lung tissue. The prevention and treatment of thrombosis is an important issue that is directly linked to its prognosis. Additionally, the drastic fibrinolytic enhancement and lethal bleeding in some severe COVID-19 are important issues. The efficacy of antiplatelet for COVID-19 is controversial. Thus, warfarin or tranexamic acid alone should be avoided. Heparin is effective for mild to moderate COVID-19 but is ineffective in severe cases since the anticoagulant activity of heparin is insufficient or heparin increases major bleeding. In severe COVID-19 cases with drastic fibrinolytic enhancement, heparin and nafamostat combination therapy may avoid lethal bleeding. In COVID-19 clinical practice, not only the coagulation activation was evaluated but also the fibrinolytic activation to consider treatment strategies.


Subject(s)
COVID-19 , Thrombosis , Anticoagulants/therapeutic use , COVID-19/complications , Fibrinolytic Agents/therapeutic use , Hemorrhage/drug therapy , Heparin , Humans , SARS-CoV-2 , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control
19.
Circ J ; 86(7): 1137-1142, 2022 06 24.
Article in English | MEDLINE | ID: covidwho-1879294

ABSTRACT

BACKGROUND: The potential benefit of therapeutic-dose anticoagulation for critically ill patients with coronavirus disease 2019 (COVID-19) is still controversial.Methods and Results: In the CLOT-COVID study, 225 patients with severe COVID-19 on admission requiring mechanical ventilation or extracorporeal membrane oxygenation were divided into patients with therapeutic-dose anticoagulation (N=110) and those with prophylactic-dose anticoagulation (N=115). There was no significant difference in the incidence of thrombosis between the groups (9.1% vs. 7.8%, P=0.73). CONCLUSIONS: Among a cohort of critically ill patients with COVID-19, approximately half received therapeutic-dose anticoagulation, although it did not show a potential benefit compared with prophylactic-dose anticoagulation.


Subject(s)
COVID-19 , Thrombosis , Anticoagulants/therapeutic use , Blood Coagulation , Critical Illness/therapy , Humans , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control
20.
Thromb Res ; 213 Suppl 1: S72-S76, 2022 05.
Article in English | MEDLINE | ID: covidwho-1867825

ABSTRACT

Cancer patients are at risk for a more severe COVID-19 infection as well as an adverse outcome of such infection. This may be caused by the cancer itself (e.g haematological malignancies and lung cancer) or due to immune suppression caused by anti-cancer treatment. Severe COVID-19 infections are often complicated by a coagulopathy that clinically results in a high incidence of venous thromboembolic disease. Cancer itself is associated with a hypercoagulable state and a markedly increased incidence of thromboembolic complications, hence the combination of cancer and COVID-19 may amplify this risk. COVID-19 vaccination seems safe and effective in most cancer patients although adapted and bespoke vaccination schemes may increase the seroconversion rate and immune response in selected patients. Specific management strategies to improve outcomes of cancer patients in COVID-19 (e.g. higher intensity antithrombotic prophylaxis) are lacking and should be evaluated in clinical studies simultaneously focusing on efficacy and safety.


Subject(s)
Blood Coagulation Disorders , COVID-19 , Neoplasms , Thromboembolism , Thrombosis , Anticoagulants/therapeutic use , Blood Coagulation Disorders/complications , Blood Coagulation Disorders/drug therapy , COVID-19/complications , COVID-19 Vaccines , Fibrin Fibrinogen Degradation Products/therapeutic use , Fibrinolytic Agents/therapeutic use , Humans , Neoplasms/drug therapy , Neoplasms/therapy , SARS-CoV-2 , Thromboembolism/drug therapy , Thrombosis/drug therapy
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