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1.
Lancet Respir Med ; 10(2): 214-220, 2022 02.
Article in English | MEDLINE | ID: covidwho-1537210

ABSTRACT

A proportion of people infected with SARS-CoV-2 develop moderate or severe COVID-19, with an increased risk of thromboembolic complications. The inflammatory response to SARS-CoV-2 infection can cause an acute-phase response and endothelial dysfunction, which contribute to COVID-19-associated coagulopathy, the clinical and laboratory features of which differ in some respects from those of classic disseminated intravascular coagulation. Understanding of the pathophysiology of thrombosis in COVID-19 is needed to develop approaches to management and prevention, with implications for short-term and long-term health outcomes. Evidence is emerging to support treatment decisions in patients with COVID-19, but many questions remain about the optimum approach to management. In this Viewpoint, we provide a summary of the pathophysiology of thrombosis and associated laboratory and clinical findings, and highlight key considerations in the management of coagulopathy in hospitalised patients with severe COVID-19, including coagulation assessment, identification of thromboembolic complications, and use of antithrombotic prophylaxis and therapeutic anticoagulation. We await the results of trials that are underway to establish the safety and benefits of prolonged thromboprophylaxis after hospital discharge.


Subject(s)
COVID-19 , Thrombosis , Venous Thromboembolism , Anticoagulants/therapeutic use , Humans , SARS-CoV-2 , Thrombosis/drug therapy , Thrombosis/prevention & control
2.
Eur J Intern Med ; 95: 38-39, 2022 01.
Article in English | MEDLINE | ID: covidwho-1525773
3.
JAMA Neurol ; 78(11): 1314-1323, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1439655

ABSTRACT

Importance: Thrombosis with thrombocytopenia syndrome (TTS) has been reported after vaccination with the SARS-CoV-2 vaccines ChAdOx1 nCov-19 (Oxford-AstraZeneca) and Ad26.COV2.S (Janssen/Johnson & Johnson). Objective: To describe the clinical characteristics and outcome of patients with cerebral venous sinus thrombosis (CVST) after SARS-CoV-2 vaccination with and without TTS. Design, Setting, and Participants: This cohort study used data from an international registry of consecutive patients with CVST within 28 days of SARS-CoV-2 vaccination included between March 29 and June 18, 2021, from 81 hospitals in 19 countries. For reference, data from patients with CVST between 2015 and 2018 were derived from an existing international registry. Clinical characteristics and mortality rate were described for adults with (1) CVST in the setting of SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia, (2) CVST after SARS-CoV-2 vaccination not fulling criteria for TTS, and (3) CVST unrelated to SARS-CoV-2 vaccination. Exposures: Patients were classified as having TTS if they had new-onset thrombocytopenia without recent exposure to heparin, in accordance with the Brighton Collaboration interim criteria. Main Outcomes and Measures: Clinical characteristics and mortality rate. Results: Of 116 patients with postvaccination CVST, 78 (67.2%) had TTS, of whom 76 had been vaccinated with ChAdOx1 nCov-19; 38 (32.8%) had no indication of TTS. The control group included 207 patients with CVST before the COVID-19 pandemic. A total of 63 of 78 (81%), 30 of 38 (79%), and 145 of 207 (70.0%) patients, respectively, were female, and the mean (SD) age was 45 (14), 55 (20), and 42 (16) years, respectively. Concomitant thromboembolism occurred in 25 of 70 patients (36%) in the TTS group, 2 of 35 (6%) in the no TTS group, and 10 of 206 (4.9%) in the control group, and in-hospital mortality rates were 47% (36 of 76; 95% CI, 37-58), 5% (2 of 37; 95% CI, 1-18), and 3.9% (8 of 207; 95% CI, 2.0-7.4), respectively. The mortality rate was 61% (14 of 23) among patients in the TTS group diagnosed before the condition garnered attention in the scientific community and 42% (22 of 53) among patients diagnosed later. Conclusions and Relevance: In this cohort study of patients with CVST, a distinct clinical profile and high mortality rate was observed in patients meeting criteria for TTS after SARS-CoV-2 vaccination.


Subject(s)
COVID-19 Vaccines/therapeutic use , Drug-Related Side Effects and Adverse Reactions/mortality , Registries , Sinus Thrombosis, Intracranial/mortality , Thrombocytopenia/mortality , Venous Thromboembolism/mortality , Adult , Aged , COVID-19 Vaccines/adverse effects , Cohort Studies , Female , Hospital Mortality , Humans , Male , Middle Aged , Outcome Assessment, Health Care , Sex Factors , Sinus Thrombosis, Intracranial/blood , Sinus Thrombosis, Intracranial/chemically induced , Syndrome , Thrombocytopenia/blood , Thrombocytopenia/chemically induced , Venous Thromboembolism/blood , Venous Thromboembolism/chemically induced , Young Adult
4.
Eur J Neurol ; 29(1): 339-344, 2022 01.
Article in English | MEDLINE | ID: covidwho-1429668

ABSTRACT

BACKGROUND AND PURPOSE: High mortality rates have been reported in patients with cerebral venous sinus thrombosis (CVST) due to vaccine-induced immune thrombotic thrombocytopenia (VITT) after vaccination with adenoviral vector SARS-CoV-2 vaccines. The aim of this study was to evaluate whether the mortality of patients with CVST-VITT has decreased over time. METHODS: The EudraVigilance database of the European Medicines Agency was used to identify cases of CVST with concomitant thrombocytopenia occurring within 28 days of SARS-CoV-2 vaccination. Vaccines were grouped based on vaccine type (adenoviral or mRNA). Cases with CVST onset until 28 March were compared to cases after 28 March 2021, which was the day when the first scientific paper on VITT was published. RESULTS: In total, 270 cases of CVST with thrombocytopenia were identified, of which 266 (99%) occurred after adenoviral vector SARS-CoV-2 vaccination (ChAdOx1 nCoV-19, n = 243; Ad26.COV2.S, n = 23). The reported mortality amongst adenoviral cases with onset up to 28 March 2021 was 47/99 (47%, 95% confidence interval 37%-58%) compared to 36/167 (22%, 95% confidence interval 16%-29%) in cases with onset after 28 March (p < 0.001). None of the four cases of CVST with thrombocytopenia occurring after mRNA vaccination died. CONCLUSION: The reported mortality of CVST with thrombocytopenia after vaccination with adenoviral vector-based SARS-CoV-2 vaccines has significantly decreased over time, which may indicate a beneficial effect of earlier recognition and/or improved treatment on outcome after VITT.


Subject(s)
COVID-19 , Sinus Thrombosis, Intracranial , Thrombocytopenia , COVID-19 Vaccines , Humans , SARS-CoV-2 , Vaccination/adverse effects
7.
JAMA ; 326(4): 332-338, 2021 07 27.
Article in English | MEDLINE | ID: covidwho-1355843

ABSTRACT

Importance: Cases of cerebral venous sinus thrombosis in combination with thrombocytopenia have recently been reported within 4 to 28 days of vaccination with the ChAdOx1 nCov-19 (AstraZeneca/Oxford) and Ad.26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccines. An immune-mediated response associated with platelet factor 4/heparin antibodies has been proposed as the underlying pathomechanism. Objective: To determine the frequencies of admission thrombocytopenia, heparin-induced thrombocytopenia, and presence of platelet factor 4/heparin antibodies in patients diagnosed with cerebral venous sinus thrombosis prior to the COVID-19 pandemic. Design, Setting, and Participants: This was a descriptive analysis of a retrospective sample of consecutive patients diagnosed with cerebral venous sinus thrombosis between January 1987 and March 2018 from 7 hospitals participating in the International Cerebral Venous Sinus Thrombosis Consortium from Finland, the Netherlands, Switzerland, Sweden, Mexico, Iran, and Costa Rica. Of 952 patients, 865 with available baseline platelet count were included. In a subset of 93 patients, frozen plasma samples collected during a previous study between September 2009 and February 2016 were analyzed for the presence of platelet factor 4/heparin antibodies. Exposures: Diagnosis of cerebral venous sinus thrombosis. Main Outcomes and Measures: Frequencies of admission thrombocytopenia (platelet count <150 ×103/µL), heparin-induced thrombocytopenia (as diagnosed by the treating physician), and platelet factor 4/heparin IgG antibodies (optical density >0.4, in a subset of patients with previously collected plasma samples). Results: Of 865 patients (median age, 40 years [interquartile range, 29-53 years], 70% women), 73 (8.4%; 95% CI, 6.8%-10.5%) had thrombocytopenia, which was mild (100-149 ×103/µL) in 52 (6.0%), moderate (50-99 ×103/µL) in 17 (2.0%), and severe (<50 ×103/µL) in 4 (0.5%). Heparin-induced thrombocytopenia with platelet factor 4/heparin antibodies was diagnosed in a single patient (0.1%; 95% CI, <0.1%-0.7%). Of the convenience sample of 93 patients with cerebral venous sinus thrombosis included in the laboratory analysis, 8 (9%) had thrombocytopenia, and none (95% CI, 0%-4%) had platelet factor 4/heparin antibodies. Conclusions and Relevance: In patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, and heparin-induced thrombocytopenia and platelet factor 4/heparin antibodies were rare. These findings may inform investigations of the possible association between the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines and cerebral venous sinus thrombosis with thrombocytopenia.


Subject(s)
COVID-19 Vaccines/adverse effects , Heparin/immunology , Platelet Factor 4/immunology , Sinus Thrombosis, Intracranial/complications , Thrombocytopenia/etiology , Adult , Antibodies/blood , Female , Heparin/adverse effects , Humans , Male , Middle Aged , Retrospective Studies , Sinus Thrombosis, Intracranial/immunology , Thrombocytopenia/epidemiology
8.
Thromb Haemost ; 122(1): 8-19, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1334019

ABSTRACT

Several viral infectious diseases have emerged or re-emerged from wildlife vectors that have generated serious threats to global health. Increased international travel and commerce increase the risk of transmission of viral or other infectious diseases. In addition, recent climate changes accelerate the potential spread of domestic disease. The coronavirus disease 2019 (COVID-19) pandemic is an important example of the worldwide spread, and the current epidemic will unlikely be the last. Viral hemorrhagic fevers, such as dengue and Lassa fevers, may also have the potential to spread worldwide with a significant impact on public health with unpredictable timing. Based on the important lessons learned from COVID-19, it would be prudent to prepare for future pandemics of life-threatening viral diseases. The key concept that connect COVID-19 and viral hemorrhagic fever is the coagulation disorder. This review focuses on the coagulopathy of acute viral infections since hypercoagulability has been a major challenge in COVID-19, but represents a different presentation compared with viral hemorrhagic fever. However, both thrombosis and hemorrhage are understood as the result of thromboinflammation due to viral infections, and the role of anticoagulation is important to consider.


Subject(s)
COVID-19/epidemiology , Hemorrhagic Fevers, Viral/epidemiology , Hemorrhagic Fevers, Viral/etiology , Pandemics , Blood Coagulation Disorders/etiology , COVID-19/etiology , COVID-19/therapy , Cytokine Release Syndrome/etiology , Global Health , Hemorrhagic Fevers, Viral/therapy , Humans , Immunity, Innate , Models, Biological , SARS-CoV-2 , Thrombosis/etiology
9.
Eur J Neurol ; 28(11): 3656-3662, 2021 11.
Article in English | MEDLINE | ID: covidwho-1320394

ABSTRACT

BACKGROUND AND PURPOSE: Cerebral venous sinus thrombosis (CVST) has been described after vaccination against SARS-CoV-2. The clinical characteristics of 213 post-vaccination CVST cases notified to the European Medicines Agency are reported. METHODS: Data on adverse drug reactions after SARS-CoV-2 vaccination notified until 8 April 2021 under the Medical Dictionary for Regulatory Activities Term 'Central nervous system vascular disorders' were obtained from the EudraVigilance database. Post-vaccination CVST was compared with 100 European patients with CVST from before the COVID-19 pandemic derived from the International CVST Consortium. RESULTS: In all, 213 CVST cases were identified: 187 after AstraZeneca/Oxford (ChAdOx1 nCov-19) vaccination and 26 after a messenger RNA (mRNA) vaccination (25 with Pfizer/BioNTech, BNT162b2, and one with Moderna, mRNA-1273). Thrombocytopenia was reported in 107/187 CVST cases (57%, 95% confidence interval [CI] 50%-64%) in the ChAdOx1 nCov-19 group, in none in the mRNA vaccine group (0%, 95% CI 0%-13%) and in 7/100 (7%, 95% CI 3%-14%) in the pre-COVID-19 group. In the ChAdOx1 nCov-19 group, 39 (21%) reported COVID-19 polymerase chain reaction tests were performed within 30 days of CVST symptom onset, and all were negative. Of the 117 patients with a reported outcome in the ChAdOx1 nCov-19 group, 44 (38%, 95% CI 29%-47%) had died, compared to 2/10 (20%, 95% CI 6%-51%) in the mRNA vaccine group and 3/100 (3%, 95% CI 1%-8%) in the pre-COVID-19 group. Mortality amongst patients with thrombocytopenia in the ChAdOx1 nCov-19 group was 49% (95% CI 39%-60%). CONCLUSIONS: Cerebral venous sinus thrombosis occurring after ChAdOx1 nCov-19 vaccination has a clinical profile distinct from CVST unrelated to vaccination. Only CVST after ChAdOx1 nCov-19 vaccination was associated with thrombocytopenia.


Subject(s)
COVID-19 , Sinus Thrombosis, Intracranial , COVID-19 Vaccines , Humans , Pandemics , SARS-CoV-2 , Vaccination/adverse effects
11.
JAMA ; 326(4): 332-338, 2021 07 27.
Article in English | MEDLINE | ID: covidwho-1293117

ABSTRACT

Importance: Cases of cerebral venous sinus thrombosis in combination with thrombocytopenia have recently been reported within 4 to 28 days of vaccination with the ChAdOx1 nCov-19 (AstraZeneca/Oxford) and Ad.26.COV2.S (Janssen/Johnson & Johnson) COVID-19 vaccines. An immune-mediated response associated with platelet factor 4/heparin antibodies has been proposed as the underlying pathomechanism. Objective: To determine the frequencies of admission thrombocytopenia, heparin-induced thrombocytopenia, and presence of platelet factor 4/heparin antibodies in patients diagnosed with cerebral venous sinus thrombosis prior to the COVID-19 pandemic. Design, Setting, and Participants: This was a descriptive analysis of a retrospective sample of consecutive patients diagnosed with cerebral venous sinus thrombosis between January 1987 and March 2018 from 7 hospitals participating in the International Cerebral Venous Sinus Thrombosis Consortium from Finland, the Netherlands, Switzerland, Sweden, Mexico, Iran, and Costa Rica. Of 952 patients, 865 with available baseline platelet count were included. In a subset of 93 patients, frozen plasma samples collected during a previous study between September 2009 and February 2016 were analyzed for the presence of platelet factor 4/heparin antibodies. Exposures: Diagnosis of cerebral venous sinus thrombosis. Main Outcomes and Measures: Frequencies of admission thrombocytopenia (platelet count <150 ×103/µL), heparin-induced thrombocytopenia (as diagnosed by the treating physician), and platelet factor 4/heparin IgG antibodies (optical density >0.4, in a subset of patients with previously collected plasma samples). Results: Of 865 patients (median age, 40 years [interquartile range, 29-53 years], 70% women), 73 (8.4%; 95% CI, 6.8%-10.5%) had thrombocytopenia, which was mild (100-149 ×103/µL) in 52 (6.0%), moderate (50-99 ×103/µL) in 17 (2.0%), and severe (<50 ×103/µL) in 4 (0.5%). Heparin-induced thrombocytopenia with platelet factor 4/heparin antibodies was diagnosed in a single patient (0.1%; 95% CI, <0.1%-0.7%). Of the convenience sample of 93 patients with cerebral venous sinus thrombosis included in the laboratory analysis, 8 (9%) had thrombocytopenia, and none (95% CI, 0%-4%) had platelet factor 4/heparin antibodies. Conclusions and Relevance: In patients with cerebral venous sinus thrombosis prior to the COVID-19 pandemic, baseline thrombocytopenia was uncommon, and heparin-induced thrombocytopenia and platelet factor 4/heparin antibodies were rare. These findings may inform investigations of the possible association between the ChAdOx1 nCoV-19 and Ad26.COV2.S COVID-19 vaccines and cerebral venous sinus thrombosis with thrombocytopenia.


Subject(s)
COVID-19 Vaccines/adverse effects , Heparin/immunology , Platelet Factor 4/immunology , Sinus Thrombosis, Intracranial/complications , Thrombocytopenia/etiology , Adult , Antibodies/blood , Female , Heparin/adverse effects , Humans , Male , Middle Aged , Retrospective Studies , Sinus Thrombosis, Intracranial/immunology , Thrombocytopenia/epidemiology
12.
Hemasphere ; 5(6): e571, 2021 Jun.
Article in English | MEDLINE | ID: covidwho-1254888

ABSTRACT

Many severe illnesses with a systemic impact may cause activation of coagulation. While systemic activation of coagulation leads to a coagulopathy that follows many common activation pathways and failure of endogenous regulatory anticoagulant systems, underlying conditions may utilize distinctive pathogenetic routes and may vary in clinical manifestations of the coagulopathy. The coagulation derangement associated with hematological malignancies and the coagulopathy of coronavirus disease 2019 (COVID-19) clearly demonstrate such differences. Malignancies are associated with venous thromboembolism due to the biological effect of malignant cells, frequent medical interventions, or the presence of indwelling vascular catheters. The underlying pathogenesis of cancer-associated coagulopathy relies on tissue factor-mediated activation of coagulation, cytokine-controlled defective anticoagulant pathways, fibrinolytic changes, and dysfunctional endothelium. There is an additional risk caused by anti-cancer agents including chemotherapy and immunotherapy. The underlying pathogenetic factor that contributes to the thrombotic risk associated with chemotherapy is endothelial cell injury (or loss of protection of endothelial integrity, for example, by vascular endothelial growth factor inhibition). In addition, individual anti-cancer agents may have specific prothrombotic effects. One of the remarkable features of severe COVID-19 infections is a coagulopathy that mimics but is not identical to the disseminated intravascular coagulation and thrombotic microangiopathy and has been identified as a strong marker for an adverse outcome. Severe COVID-19 infections cause inflammation-induced changes in coagulation in combination with severe endothelial cell injury. This coagulopathy likely contributes to pulmonary microvascular thrombosis, bronchoalveolar fibrin deposition (which is a hallmark of acute respiratory distress syndrome) and venous thromboembolic complications.

13.
Lancet Respir Med ; 9(6): 551-553, 2021 06.
Article in English | MEDLINE | ID: covidwho-1233648
14.
Crit Care Med ; 48(10): e989-e990, 2020 10.
Article in English | MEDLINE | ID: covidwho-1228542
15.
N Engl J Med ; 384(23): 2202-2211, 2021 06 10.
Article in English | MEDLINE | ID: covidwho-1189334

ABSTRACT

BACKGROUND: The mainstay of control of the coronavirus disease 2019 (Covid-19) pandemic is vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a year, several vaccines have been developed and millions of doses delivered. Reporting of adverse events is a critical postmarketing activity. METHODS: We report findings in 23 patients who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, we identify a novel underlying mechanism and address the therapeutic implications. RESULTS: In the absence of previous prothrombotic medical conditions, 22 patients presented with acute thrombocytopenia and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. All the patients had low or normal fibrinogen levels and elevated d-dimer levels at presentation. No evidence of thrombophilia or causative precipitants was identified. Testing for antibodies to platelet factor 4 (PF4) was positive in 22 patients (with 1 equivocal result) and negative in 1 patient. On the basis of the pathophysiological features observed in these patients, we recommend that treatment with platelet transfusions be avoided because of the risk of progression in thrombotic symptoms and that the administration of a nonheparin anticoagulant agent and intravenous immune globulin be considered for the first occurrence of these symptoms. CONCLUSIONS: Vaccination against SARS-CoV-2 remains critical for control of the Covid-19 pandemic. A pathogenic PF4-dependent syndrome, unrelated to the use of heparin therapy, can occur after the administration of the ChAdOx1 nCoV-19 vaccine. Rapid identification of this rare syndrome is important because of the therapeutic implications.


Subject(s)
Autoantibodies/blood , COVID-19 Vaccines/immunology , Platelet Factor 4/immunology , Thrombocytopenia/immunology , Thrombosis/immunology , Adult , Aged , Algorithms , Antibodies, Viral/blood , Anticoagulants/adverse effects , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Female , Flow Cytometry , Heparin/adverse effects , Humans , Male , Middle Aged , Thrombocytopenia/etiology , Thrombosis/etiology
16.
Nat Rev Immunol ; 21(5): 319-329, 2021 05.
Article in English | MEDLINE | ID: covidwho-1171402

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a clinical syndrome caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with severe disease show hyperactivation of the immune system, which can affect multiple organs besides the lungs. Here, we propose that SARS-CoV-2 infection induces a process known as immunothrombosis, in which activated neutrophils and monocytes interact with platelets and the coagulation cascade, leading to intravascular clot formation in small and larger vessels. Microthrombotic complications may contribute to acute respiratory distress syndrome (ARDS) and other organ dysfunctions. Therapeutic strategies aimed at reducing immunothrombosis may therefore be useful. Several antithrombotic and immunomodulating drugs have been proposed as candidates to treat patients with SARS-CoV-2 infection. The growing understanding of SARS-CoV-2 infection pathogenesis and how it contributes to critical illness and its complications may help to improve risk stratification and develop targeted therapies to reduce the acute and long-term consequences of this disease.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Cytokine Release Syndrome/pathology , Venous Thrombosis/immunology , Venous Thrombosis/pathology , Blood Coagulation/immunology , Blood Platelets/immunology , Critical Illness/therapy , Cytokine Release Syndrome/immunology , Endothelium, Vascular/pathology , Fibrinolytic Agents/therapeutic use , Humans , Immunity, Innate/immunology , Lung/blood supply , Lung/pathology , Lung/virology , Monocytes/immunology , Neutrophils/immunology , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Venous Thrombosis/prevention & control
17.
Expert Rev Respir Med ; 15(8): 1003-1011, 2021 08.
Article in English | MEDLINE | ID: covidwho-1118871

ABSTRACT

INTRODUCTION: The first patients with Coronavirus disease 2019 (COVID-19) emerged at the end of 2019. This novel viral infection demonstrated unique features that include prothrombotic clinical presentations. However, one year after the first occurrence, there remain many unanswered questions. We tried to address some of the important queries in this review. AREAS COVERED: We raised the following critical questions. 'Why is COVID-19 so hypercoagulable?', 'Why are most coagulation test results relatively normal?', 'Why is COVID-19-associated coagulopathy more thrombotic than most other infectious diseases?', 'Why is arterial thrombus formed frequently?', 'Is anticoagulant therapy for COVID-19 effective?', and 'Are there racial disparities in thrombosis in COVID-19?' EXPERT OPINION: There are commonalities and differences in the pathogeneses and clinical features between COVID-19 and other infectious diseases. Correct understanding will help discussing appropriate anticoagulation prophylaxis or treatment for thromboembolism.


Subject(s)
Blood Coagulation Disorders , COVID-19 , Thromboembolism , Thrombosis , Blood Coagulation Disorders/drug therapy , Blood Coagulation Disorders/etiology , Humans , SARS-CoV-2 , Thrombosis/drug therapy , Thrombosis/etiology , Thrombosis/prevention & control
18.
J Thromb Haemost ; 18(9): 2103-2109, 2020 09.
Article in English | MEDLINE | ID: covidwho-1096903

ABSTRACT

The COVID-19 pandemic has become an urgent issue in every country. Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)-like massive intravascular clot formation is frequently seen in this cohort. Therefore, coagulation tests may be considered useful to discriminate severe cases of COVID-19. The clinical presentation of COVID-19-associated coagulopathy is organ dysfunction primarily, whereas hemorrhagic events are less frequent. Changes in hemostatic biomarkers represented by increase in D-dimer and fibrin/fibrinogen degradation products indicate the essence of coagulopathy is massive fibrin formation. In comparison with bacterial-sepsis-associated coagulopathy/DIC, prolongation of prothrombin time, and activated partial thromboplastin time, and decrease in antithrombin activity is less frequent and thrombocytopenia is relatively uncommon in COVID-19. The mechanisms of the coagulopathy are not fully elucidated, however. It is speculated that the dysregulated immune responses orchestrated by inflammatory cytokines, lymphocyte cell death, hypoxia, and endothelial damage are involved. Bleeding tendency is uncommon, but the incidence of thrombosis in COVID-19 and the adequacy of current recommendations regarding standard venous thromboembolic dosing are uncertain.


Subject(s)
Blood Coagulation Disorders/blood , COVID-19/epidemiology , Disseminated Intravascular Coagulation/blood , Anticoagulants , Blood Coagulation , Blood Coagulation Disorders/complications , Blood Coagulation Tests , COVID-19/complications , Cytokines/metabolism , Disseminated Intravascular Coagulation/complications , Fibrin/chemistry , Fibrin Fibrinogen Degradation Products/metabolism , Fibrinogen/chemistry , Fibrinolysis , Hemorrhage , Hemostasis , Humans , Inflammation , Lung/metabolism , Lung/virology , Lymphocytes/metabolism , Partial Thromboplastin Time , Protease Inhibitors , Prothrombin Time , Sepsis , Thrombosis/metabolism
19.
Eur J Intern Med ; 83: 34-38, 2021 01.
Article in English | MEDLINE | ID: covidwho-1065032

ABSTRACT

BACKGROUND: Many COVID-19 patients develop a hyperinflammatory response which activates blood coagulation and may contribute to the occurrence of thromboembolic complications. Blockade of interleukin-6, a key cytokine in COVID-19 pathogenesis, may improve the hypercoagulable state induced by inflammation. The aim of this study was to evaluate the effects of subcutaneous tocilizumab, a recombinant humanized monoclonal antibody against the interleukin-6 receptor on coagulation parameters. METHODS: Hospitalized adult patients with laboratory-confirmed moderate to critical COVID-19 pneumonia and hyperinflammation, who received a single 324 mg subcutaneous dose of tocilizumab on top of standard of care were enrolled in this analysis. Coagulation parameters were measured before tocilizumab and at day 1, 3, and 7 after treatment. All patients were followed-up for 35 days after admission or until death. RESULTS: 70 patients (mean age 60 years, interquartile range 52-75) were included. Treatment with tocilizumab was associated with a reduction in D-dimer levels (-56%; 95% confidence interval [CI], -68% to -44%), fibrinogen (-48%; 95%CI, -60% to -35%), C-reactive protein (-93%; 95%CI, -99% to -87%), prothrombin time (-4%; 95%CI,-9% to 0.8%), and activated thromboplastin time (-4%; 95%CI,-8.7% to 0.8%), and an increase in platelet count (34%; 95%CI, 23% to 45%). These changes occurred already one day after treatment with sustained reductions throughout day 7. The improvement in coagulation was consistently observed in patients receiving prophylactic or therapeutic dose anticoagulants, and was paralleled by a rapid improvement in respiratory function. CONCLUSIONS: Subcutaneous tocilizumab was associated with significant improvement of blood coagulation parameters independently of thromboprophylaxis dose.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Blood Coagulation/physiology , COVID-19/blood , COVID-19/drug therapy , COVID-19/therapy , Receptors, Interleukin-6/antagonists & inhibitors , Adult , Aged , Blood Cell Count , Blood Coagulation Tests , C-Reactive Protein , Cohort Studies , Combined Modality Therapy , Female , Hospitalization , Humans , Injections, Subcutaneous , Italy , Male , Middle Aged
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