Thromboembolic Disorder in COVID-19 Infection.

Coronavirus (COVID-19) is a global pandemic with over 600 million cases identified. In addition to extensive pulmonary complications of COVID-19, one feature unique to many patients with severe COVID-19 infections is coagulopathy with a rising prevalence of multi-systemic thromboembolic manifestations. Global data suggests a relationship between coagulopathy and mortality. In this review, we highlight multiple COVID-19 thromboembolic complications with emphasis on pathophysiology, clinical management, and radiological manifestations.

Thrombosis and coagulopathy in COVID-19 patients rceiving ECMO: A narrative review of current literature.

Extracorporeal membrane oxygenation (ECMO) is an established part of the treatment algorithm for coronavirus disease 2019 (COVID-19)-related acute respiratory distress syndrome. An intense inflammatory response may cause an imbalance in the coagulation cascade making both thrombosis and bleeding common and notable features of the clinical management of these patients. Large observational and retrospective studies provide a better understanding of the pathophysiology and management of bleeding and thrombosis in COVID-19 patients requiring ECMO. Clinically significant bleeding, including intracerebral hemorrhage, is an independent predictor of mortality, and thrombosis (particularly pulmonary embolism) is associated with mortality, especially if occurring with right ventricular dysfunction. The incidence of heparin-induced thrombocytopenia is higher than the general patient cohort with acute respiratory distress syndrome or other indications for ECMO. The use of laboratory parameters to predict bleeding or thrombosis has a limited role. In this review, the authors discuss the complex pathophysiology of bleeding and thrombosis observed in patients with COVID-19 during ECMO support, and their effects on outcomes.

COVID-19 in Patients with Diabetes: Clinical Course, Metabolic Status, Inflammation, and Coagulation Disorder.

The aim of the investigation was to study the clinical course of COVID-19 in the presence of diabetes mellitus (DM) and elucidate possible mechanisms of their mutual aggravation. Materials and Methods: The study included 64 patients with COVID-19; of them, 32 were with DM (main group) and 32 were DM-free (control group). The groups were formed according to the "case-control" principle. During hospitalization, the dynamics of clinical, glycemic, and coagulation parameters, markers of systemic inflammation, as well as kidney and liver functions were monitored and compared. Results: Among patients with DM, the course of viral pneumonia was more severe, as evidenced by a 2.2-fold higher number of people with extensive (>50%) lung damage (p=0.05), an increased risk of death according to the CURB-65 algorithm (1.3-fold, p=0.043), and a longer duration of insufficient blood oxygen saturation (p=0.0004). With the combination of COVID-19 and DM, hyperglycemia is persistent, without pronounced variability (MAGE - 1.5±0.6 mmol/L), the levels of C-reactive protein (p=0.028), creatinine (p=0.035), and fibrinogen (p=0.013) are higher, manifestations of hypercoagulability persist longer, including slower normalization of antithrombin III (p=0.012), fibrinogen (p=0.037), and D-dimer (p=0.035). Conclusion: The course of COVID-19 in patients with DM is associated with a high severity and extension of pneumonia, persistent decrease in oxygen supply, high hyperglycemia, accelerated renal dysfunction, systemic inflammation, and hypercoagulability.

Coagulation abnormalities & thromboprophylaxis in COVID-19.

The ongoing pandemic of novel coronavirus 2019 is rapidly evolving, and newer organ- and system-specific manifestations are being observed. Thrombotic complications and coagulopathy are frequent manifestations of the disease, especially in sick patients, which appear to be unique and distinct from sepsis-induced coagulopathy, disseminated intravascular coagulation and other viral infection-induced coagulation abnormalities. Elevated D-dimers and fibrinogen in the early stage of the disease with minimally deranged prothrombin time and platelet counts are prominent and distinguishing features. Venous and arterial thromboses, as opposed to bleeding events, are the major clinical correlates. There is much to be known about the pathogenesis of COVID-associated coagulopathy; however, the mechanisms overlap with thrombotic microangiopathy, haemophagocytic syndrome and antiphospholipid syndrome compounded by the diffuse endothelial damage. The recommendations regarding the treatment are still evolving, but antithrombotic therapy has a definite role in positive outcomes of sick patients.

Mechanisms of immunothrombosis in COVID-19.

PURPOSE OF REVIEW: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus-2. Over the past year, COVID-19 has posed a significant threat to global health. Although the infection is associated with mild symptoms in many patients, a significant proportion of patients develop a prothrombotic state due to a combination of alterations in coagulation and immune cell function. The purpose of this review is to discuss the pathophysiological characteristics of COVID-19 that contribute to the immunothrombosis. RECENT FINDINGS: Endotheliopathy during COVID-19 results in increased multimeric von Willebrand factor release and the potential for increased platelet adhesion to the endothelium. In addition, decreased anticoagulant proteins on the surface of endothelial cells further alters the hemostatic balance. Soluble coagulation markers are also markedly dysregulated, including plasminogen activator inhibitor-1 and tissue factor, leading to COVID-19 induced coagulopathy. Platelet hyperreactivity results in increased platelet-neutrophil and -monocyte aggregates further exacerbating the coagulopathy observed during COVID-19. Finally, the COVID-19-induced cytokine storm primes neutrophils to release neutrophil extracellular traps, which trap platelets and prothrombotic proteins contributing to pulmonary thrombotic complications. SUMMARY: Immunothrombosis significantly contributes to the pathophysiology of COVID-19. Understanding the mechanisms behind COVID-19-induced coagulopathy will lead to future therapies for patients.

COVID-19-associated coagulopathy and antithrombotic agents-lessons after 1 year.

COVID-19 is associated with a high incidence of thrombotic complications, which can be explained by the complex and unique interplay between coronaviruses and endothelial cells, the local and systemic inflammatory response, and the coagulation system. Empirically, an intensified dose of thrombosis prophylaxis is being used in patients admitted to hospital with COVID-19 and several guidelines on this topic have been published, although the insufficiency of high quality and direct evidence has led to weak recommendations. In this Viewpoint we summarise the pathophysiology of COVID-19 coagulopathy in the context of patients who are ambulant, admitted to hospital, and critically ill or non-critically ill, and those post-discharge from hospital. We also review data from randomised controlled trials in the past year of antithrombotic therapy in patients who are critically ill. These data provide the first high-quality evidence on optimal use of antithrombotic therapy in patients with COVID-19. Pharmacological thromboprophylaxis is not routinely recommended for patients who are ambulant and post-discharge. A first ever trial in non-critically ill patients who were admitted to hospital has shown that a therapeutic dose of low-molecular-weight heparin might improve clinical outcomes in this population. In critically ill patients, this same treatment does not improve outcomes and prophylactic dose anticoagulant thromboprophylaxis is recommended. In the upcoming months we expect numerous data from the ongoing antithrombotic COVID-19 studies to guide clinicians at different stages of the disease.

Children and young adults hospitalized for severe COVID-19 exhibit thrombotic coagulopathy.

We report the clinical and laboratory coagulation characteristics of 27 pediatric and young adult patients (2 months to 21 years) treated for symptomatic COVID-19 at a children's hospital in the Bronx, New York, between March 1 and May 31, 2020. D-Dimer was > 0.5 µg/mL (upper limit of normal) in 25 (93%) patients at admission; 11 (41%) developed peak D-dimer > 5 µg/mL during admission. Seven (26%) patients developed venous thromboembolism: three with deep vein thrombosis and four with pulmonary embolism. Requirement of increased ventilatory support was a risk factor for thrombosis (P = 0.006). Three of eight (38%) patients on prophylactic anticoagulation developed thrombosis; however, no patients developed VTE on low-molecular-weight heparin prophylaxis titrated to anti-Xa level. Manifestation of COVID-19 disease was severe or critical in 16 (59%) patients. Four (15%) patients died of COVID-19 complications: all had comorbidities. Elevated D-dimer and increased VTE rate were observed in this young cohort, particularly in those with severe respiratory complications, suggesting thrombotic coagulopathy. More data are needed to guide thromboprophylaxis in this age group.

Association of coagulation dysfunction with cardiac injury among hospitalized patients with COVID-19.

Cardiac injury is a common complication of the coronavirus disease 2019 (COVID-19), and is associated with adverse clinical outcomes. In this study, we aimed to reveal the association of cardiac injury with coagulation dysfunction. We enrolled 181 consecutive patients who were hospitalized with COVID-19, and studied the clinical characteristics and outcome of these patients. Cardiac biomarkers high-sensitivity troponin I (hs-cTnI), myohemoglobin and creatine kinase-myocardial band (CK-MB) were assessed in all patients. The clinical outcomes were defined as hospital discharge or death. The median age of the study cohort was 55 (IQR, 46-65) years, and 102 (56.4%) were males. Forty-two of the 181 patients (23.2%) had cardiac injury. Old age, high leukocyte count, and high levels of aspartate transaminase (AST), D-dimer and serum ferritin were significantly associated with cardiac injury. Multivariate regression analysis revealed old age and elevated D-dimer levels as being strong risk predictors of in-hospital mortality. Interleukin 6 (IL6) levels were comparable in patients with or without cardiac injury. Serial observations of coagulation parameters demonstrated highly synchronous alterations of D-dimer along with progression to cardiac injury. Cardiac injury is a common complication of COVID-19 and is an independent risk factor for in-hospital mortality. Old age, high leukocyte count, and high levels of AST, D-dimer and serum ferritin are significantly associated with cardiac injury, whereas IL6 are not. Therefore, the pathogenesis of cardiac injury in COVID-19 may be primarily due to coagulation dysfunction along with microvascular injury.

Risk assessment and prognostic aspect of coagulopathy in COVID-19.

Since December 2019, the rapid spread of SARS CoV-2 across the border, shuffled into a world pandemic situation with an alarming rate of morbidity and mortality. Concerns are mounting as the reports indicate tangled circumstances among the COVID-19 patients due to blood coagulopathy followed by organ dysfunction. COVID-19 induced an alteration in coagulation function increase the risk of pulmonary embolism and deep vein thrombosis associated with poor prognosis as well as high mortality. An elevated level D-dimer and other fibrin degrading protein are documented among the patients with COVID-19; especially in severe cases. Differences in coagulopathy among severe and non-severe cases, required prompt attention to adopt a more effective management strategy.

Dangerous liaisons? The role of inflammation and comorbidities in HIV and SARS-CoV-2 infection.

INTRODUCTION: In people living with HIV (PLWH), immune activation and inflammation levels are high even when viral suppression is maintained, potentially contributing to several comorbidities, and hampering the immune response to infections such as the recent SARS-CoV-2 disease 2019 (COVID-19). AREAS COVERED: Immune activation and inflammation play a role in SARS-CoV-2 infection. Severe COVID-19 patients may experience cytokine release syndrome (CRS), leading to alveolar damage, pulmonary fibrinolysis, dysregulated coagulation, and pulmonary injury. Into the systemic circulation, cytokines in excess might leak out of pulmonary circulation, causing systemic symptoms and possibly a multiple-organ dysfunction syndrome. Preexisting comorbidities are also linked to worse COVID-19 outcome: studies suggest that diabetes and hypertension are linked to higher mortality rates. Such comorbidities are more frequent in PLWH, but it is unclear if they have worse outcomes in the case of COVID-19. The literature was searched in PubMed/MEDLINE and EMBASE, and manually in COVID-19 resources. EXPERT OPINION: A body of evidence shows that HIV and SARS-CoV-2 are able to activate inflammatory pathways, acute in the case of SARS-CoV-2, chronic in the case of HIV, while the comorbidities seem to represent, in the first case, a contributory cause, in the second an effect of the virus-induced damage.

Direct oral anticoagulant use and risk of severe COVID-19.

BACKGROUND: Hypercoagulability and thromboembolism are prominent features of severe COVID-19, and ongoing anticoagulant use might be protective. METHODS: We conducted a nationwide register-based cohort study in Sweden, February through May, 2020, to assess whether ongoing direct oral anticoagulant (DOAC) use was associated with reduced risk of hospital admission for laboratory-confirmed COVID-19, or a composite of intensive care unit (ICU) admission or death due to laboratory-confirmed COVID-19. RESULTS: DOAC use (n = 103 703) was not associated with reduced risk of hospital admission for COVID-19 (adjusted hazard ratio [aHR] [95% confidence interval] 1.00 [0.75-1.33] vs. nonuse atrial fibrillation comparator [n = 36 875]; and aHR 0.94 [0.80-1.10] vs. nonuse cardiovascular disease comparator [n = 355 699]), or ICU admission or death due to COVID-19 (aHRs 0.76 [0.51-1.12], and 0.90 [0.71-1.15], respectively). CONCLUSION: Ongoing DOAC use was not associated with reduced risk of severe COVID-19, indicating that prognosis would not be modified by early outpatient DOAC initiation.

Coagulopathy in patients with COVID-19: a systematic review and meta-analysis.

COVID-19 patients frequently exhibit coagulation abnormalities and thrombotic events. In this meta-analysis, we investigated the association between coagulopathy and the severity of COVID-19 illness. Using PubMed, Embase, Cochrane, WanFang Database, CNKI, and medRxiv, a systematic literature search was conducted for studies published between December 1, 2019 and May 1, 2020. We then analyzed coagulation parameters in COVID-19 patients exhibiting less severe and more severe symptoms. All statistical analyses were performed using Stata14.0 software. A total of 3,952 confirmed COVID-19 patients from 25 studies were included in the meta-analysis. Patients with severe symptoms exhibited higher levels of D-dimer, prothrombin time (PT), and fibrinogen (FIB) than patients with less severe symptoms (SMD 0.83, 95% CI: 0.70-0.97, I2 56.9%; SMD 0.39, 95% CI: 0.14-0.64, I2 79.4%; and SMD 0.35, 95% CI: 0.17-0.53, I2 42.4%, respectively). However, platelet and activated partial thromboplastin times did not differ (SMD -0.26, 95% CI: -0.56-0.05, I2 82.2%; and SMD -0.14, 95% CI: -0.45-0.18, I2 75.7%, respectively). These findings demonstrate that hypercoagulable coagulopathy is associated with the severity of COVID-19 symptoms and that D-dimer, PT, and FIB values are the main parameters that should be considered when evaluating coagulopathy in COVID-19 patients.

Potential of therapeutic plasmapheresis in treatment of COVID-19 patients: Immunopathogenesis and coagulopathy.

Therapeutic plasmapheresis (TP) is the process of the separation and removal of plasma from other blood components and is considered as an adjunctive treatment strategy to the discarded abnormal agent in the management of respiratory viral pandemics. This article reviews the mechanisms of immunopathogenesis and coagulopathy induced by SARS-CoV-2 and the potential benefits of TP as adjunctive treatment in critically COVID-19 patients.

Thrombosis and Coagulopathy in COVID-19.

Since December 2019, an outbreak of coronavirus disease 2019 (COVID-19) which initially occurred in the city of Wuhan, located in China's Hubei province, spread around the world and on March 11, 2020, the World Health Organization declared the new Coronavirus disease 2019 (COVID-19) as a pandemic. The presence of comorbidities (eg, cardiovascular disease, obesity), Sepsis Induced Coagulopathy score >4, elevation of D-dimer (>6 times the normal value), C-reactive protein, troponins and other disseminated intravascular coagulation markers; is associated to a worse prognosis in hospitalized patients with severe COVD-19, reaching a hospital mortality of 42%. Initial anticoagulant treatment with low molecular weight heparin has been shown to reduce mortality by 48% at 7 days and 37% at 28 days and achieve a significant improvement in the arterial oxygen pressure/inspired fraction of O2 (PaO2/FiO2) by mitigating the formation of microthrombi and associated pulmonary coagulopathy.

Acute thrombotic manifestations of coronavirus disease 2019 infection: Experience at a large New York City health care system.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a novel coronavirus that has typically resulted in upper respiratory symptoms. However, we have encountered acute arterial and venous thrombotic events after COVID-19 infection. Managing acute thrombotic events from the novel virus has presented unprecedented challenges during the COVID-19 pandemic. In our study, we have highlighted the unique treatment required for these patients and discussed the role of anticoagulation for patients diagnosed with COVID-19. METHODS: The data from 21 patients with laboratory-confirmed COVID-19 disease and acute venous or arterial thrombosis were collected. The demographics, comorbidities, home medications, laboratory markers, and outcomes were analyzed. The primary postoperative outcome of interest was mortality, and the secondary outcomes were primary patency and morbidity. To assess for significance, a univariate analysis was performed using the Pearson χ2 and Fisher exact tests for categorical variables and the Student t test for continuous variables. RESULTS: A total of 21 patients with acute thrombotic events met our inclusion and exclusion criteria. Most cases were acute arterial events (76.2%), with the remainder venous cases (23.8%). The average age for all patients was 64.6 years, and 52.4% were male. The most prevalent comorbidity in the group was hypertension (81.0%). Several markers were markedly abnormal in both arterial and venous cases, including an elevated neutrophil/lymphocyte ratio (8.8) and D-dimer level (4.9 µg/mL). Operative intervention included percutaneous angiography in 25.00% of patients and open surgical embolectomy in 23.8%. Most of the patients who had undergone arterial intervention had developed a postoperative complication (53.9%) compared with a 0% complication rate after venous interventions. Acute kidney injury on admission was a factor in 75.0% of those who died vs 18.2% in the survivors (P = .04). CONCLUSIONS: We have described our experience in the epicenter of the pandemic of 21 patients who had experienced major thrombotic events from infection with COVID-19. The findings from our cohort have highlighted the need for increased awareness of the vascular manifestations of COVID-19 and the important role of anticoagulation for these patients. More data are urgently needed to optimize treatment and prevent further vascular complications of COVID-19 infections.

Methodological Issues and Controversies in COVID-19 Coagulopathy: A Tale of Two Storms.

Venous thromboembolism, occlusion of dialysis catheters, circuit thrombosis in ECMO devices, all in the face of prophylactic and sometimes even therapeutic anti-coagulation, are frequent features of COVID-19 coagulopathy. The trials available to guide clinicians are methodologically limited. There are several unresolved controversies including 1) Should all hospitalized patients with COVID-19 receive prophylactic anti-coagulation? 2) Which patients should have their dosage escalated to intermediate dose? 3) Which patients should be considered for full-dose anti-coagulation even without a measurable thromboembolic event and how should that anti-coagulation be monitored? 4) Should patients receive post-discharge anti-coagulation? 5) What thrombotic issues are related to the various medications being used to treat this coagulopathy? 6) Is anti-phospholipid anti-body part of this syndrome? 7) How do the different treatments for this disease impact the coagulation issues? The aims of this article are to explore these questions and interpret the available data based on the current evidence.