Thromboinflammation response to tocilizumab in COVID-19.

Background: Coronavirus disease-19 (COVID-19) spans a wide spectrum of illness. Severe cases of COVID-19 can manifest inflammation in organs other than the lung, in tissues not known to support viral replication, and also in a hypercoagulable state. These observations have suggested that severe acute respiratory syndrome coronavirus 2 can provoke a hyperimmune response in some cases that could lead to secondary organ damage. Methods: With evidence of elevated levels of interleukin-6 (IL-6) in patients with severe COVID-19, we conducted a small pilot off-label compassionate care study of the IL-6 receptor inhibitor tocilizumab in patients with severe COVID-19. Results: A single infusion of tocilizumab in patients with severe COVID-19 manifested rapid declines in C-reactive protein and d-dimer and gradual rises in lymphocyte and platelet counts. Conclusions: These findings suggest both pathophysiological mechanisms and clinical benefit that might be seen with IL-6 inhibition in severe COVID-19.

COVID-19 and antiphospholipid antibodies.

Antiphospholipid syndrome and the coagulopathy of COVID-19 share many pathophysiologic features, including endotheliopathy, hypercoagulability, and activation of platelets, complement pathways, and neutrophil extracellular traps, all acting in concert via a model of immunothrombosis. Antiphospholipid antibody production in COVID-19 is common, with 50% of COVID-19 patients being positive for lupus anticoagulant in some studies, and with non-Sapporo criteria antiphospholipid antibodies being prevalent as well. The biological significance of antiphospholipid antibodies in COVID-19 is uncertain, as such antibodies are usually transient, and studies examining clinical outcomes in COVID-19 patients with and without antiphospholipid antibodies have yielded conflicting results. In this review, we explore the biology of antiphospholipid antibodies in COVID-19 and other infections and discuss mechanisms of thrombogenesis in antiphospholipid syndrome and parallels with COVID-19 coagulopathy. In addition, we review the existing literature on safety of COVID-19 vaccination in patients with antiphospholipid antibodies and antiphospholipid syndrome.

Mesenteric Ischemia in a Patient with Essential Thrombocythemia: Does COVID-19 Play Any Role? A Case Report and Overview of the Literature.

INTRODUCTION: Chronic mesenteric ischemia is a rare entity with non-specific symptomatology; combined with rare etiologies, it could lead to unwarranted surgical indication. CASE REPORT: We report the case of an 85-year-old woman, with a history of hypertension, persistent thrombocytosis, atherosclerosis, and recent minor COVID-19 infection, presenting to the hospital with postprandial abdominal pain and nonspecific clinical examination findings; upon abdominal CT, superior mesenteric artery circumferential thrombosis was revealed. A bone marrow biopsy was performed due to suspected essential thrombocythemia, confirming the diagnosis. An endovascular approach was chosen as therapy option and a stent was placed in the occluded area. Dual antiplatelet and cytoreductive therapies were initiated after the intervention. Clinical course was excellent, with no residual stenosis 1 month after stenting. CONCLUSIONS: The therapeutic strategy in elderly patients with exacerbated chronic mesenteric ischemia requires an interdisciplinary approach in solving both the exacerbation and the underlying conditions in order to prevent further thrombotic events. Although the patient presented a thrombotic state, other specific risk factors such as COVID-19 related-coagulopathy and essential thrombocythemia should be considered.

Thrombosis in COVID 2022: An Updated Narrative Review of Current Literature and Inpatient Management.

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.

Antigens and Antibodies of the Antiphospholipid Syndrome as New Allies in the Pathogenesis of COVID-19 Coagulopathy.

High prevalence of both criteria and extra-criteria antiphospholipid antibodies (aPL) has been reported in COVID-19 patients. However, the differences in aPL prevalence decreased when an age-matched control group was included. The association of aPL with thrombotic events in COVID-19 is very heterogeneous. This could be influenced by the fact that most of the studies carried out were conducted on small populations enriched with elderly patients in which aPL was measured only at a single point and they were performed with non-standardized assays. The few studies that confirmed aPL in a second measurement showed that aPL levels hardly changed, with the exception of the lupus anticoagulant that commonly reduced. COVID-19 coagulopathy is an aPL-independent phenomenon closely associated with the onset of the disease. Thrombosis occurs later in patients with aPL presence, which is likely an additional prothrombotic factor. B2-glycoprotein deficiency (mainly aPL antigen caused both by low production and consumption) is very common during the SARS-CoV2 infection and has been associated with a greater predisposition to COVID-19 complications. This could be a new prothrombotic mechanism that may be caused by the blockage of its physiological functions, the anticoagulant state being the most important.

Cerebral venous sinus thrombosis associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

Introduction/Objective Coagulopathy induced by severe acute respiratory syndrome coronavirus 2 infection (SARS-CoV-2) can be an underlying cause of cerebral venous sinus thrombosis (CVST), a less common type of stroke with a variable clinical presentation and high mortality rate. The objective of the paper is to present a series of CVST cases associated with SARS-CoV-2 infection. Methods This retrospective study evaluated clinical, laboratory and radiological presentations, risk factors, barriers to diagnosis, treatment and outcome of patients with SARS-CoV-2 infection-induced CVST. Results The study comprised six patients diagnosed with COVID-19-induced CVST during an 18-month period. The majority (66.7%) had no significant risk factors for developing CVST. The median time from the initial COVID-19 diagnosis to the onset of neurologic deficit was seven days (interquartile range 0.5–7 days). Clinical presentation comprised non specific neurological symptoms: headache (83.3%) and decreased consciousness (33.3%), together with elevated levels of D-dimer and inflammatory biomark-ers. The transverse (n = 4, or 66.7%), superior sagittal sinuses (n = 3, or 50%) and sigmoid sinus (n = 2, or 33.3%) were most commonly affected. Five patients (83.3%) had minimal to no symptoms at discharge (mRS ≤ 2). In-hospital mortality in our current series was relatively high (16.7%). Conclusion The high mortality rate of SARS-CoV-2-associated CVST urges clinicians to suspect CVST in patients with a history of COVID-19 infection presenting with non-specific neurological symptoms in order to provide proper treatment and prevent complications. © 2021, Serbia Medical Society. All rights reserved.

The evolution of clot strength in critically-ill COVID-19 patients: a prospective observational thromboelastography study.

BACKGROUND: Few studies detail the evolution of COVID-19 associated coagulopathy. We performed serial thromboelastography (TEG) and laboratory coagulation studies in 40 critically-ill, mechanically ventilated COVID-19 patients over a 14-day period and analysed differences between 30-day survivors and non-survivors. METHODS: Single-center prospective, observational study including 40 patients with severe COVID-19 pneumonia admitted to the intensive care unit (ICU) for mechanical ventilation. TEG analysis was performed on days 1, 7 and 14 of ICU admission and laboratory coagulation studies were performed on days 1 and 14. Coagulation variables were evaluated for change over the 14-day observation period. Differences between survivors and non-survivors at 30-days were analysed and compared. RESULTS: On admission, TEG maximum amplitude (MA) with heparinase correction was above the upper limit of the reference range in 32 (80%) patients while 33 (82.5%) presented with absent clot lysis at 30 min. The functional fibrinogen MA was also elevated above the upper limit of the reference range in 37 (92.5%) patients. All patients had elevated D-dimer and fibrinogen levels, mildly prolonged prothrombin times (PT), normal platelet counts and normal activated partial thromboplastin times (aPTT). The heparinase MA decreased significantly with time and normalised after 14 days (p = < 0.001) while the increased fibrin contribution to clot strength persisted with time (p = 0.113). No significant differences in TEG analysis were noted between 30-day survivors and non-survivors at all time points. No patients developed disseminated intravascular coagulopathy (DIC) after 14-days, however thrombosis and bleeding were each reported in 3 (7.5%) patients. CONCLUSION: Critically-ill patients with COVID-19 present in a hypercoagulable state characterised by an increased clot strength. This state normalises after 14 days despite a persistently increased fibrin contribution to clot strength. We were unable to demonstrate any significant differences in TEG parameters between 30-day survivors and non-survivors at all time points.

Clinical Features and Management of COVID-19-Associated Hypercoagulability.

COVID-19 is an acute respiratory disease of viral origin caused by SARS-CoV-2. This disease is associated with a hypercoagulable state resulting in arterial and venous thrombotic events. The latter are more frequent, especially in patients who develop a severe form of the disease and are associated with an increased mortality rate. It is therefore essential to identify patients at higher risk to initiate antithrombotic therapy. Hospitalized patients treated with treatment dose of anticoagulants had better outcomes than those treated with prophylactic dose. However, several trials are ongoing to better define the therapeutic and prevention strategies for this insidious complication.

Coronavirus Disease 2019 Infection as a Risk Factor for Infective Endocarditis.

Infective endocarditis (IE) is associated with relatively high morbidity and mortality and several risk factors have been identified in the past. Several predisposing factors for IE have been recognized in the literature, depending on the type of bacteria. Coronavirus disease 2019 (COVID-19) infection causes coagulopathy-associated complications and damage to many organ systems due to the inflammatory response induced by this viral infection. COVID-19 emerged only about a year ago and there are many unknown post-COVID-19 complications at this time. Here, we present the case of Streptococcus mitis IE in a patient with no prior predisposing factors other than diagnosis with COVID-19 a month ago.

Integral Use of Thromboelastography With Platelet Mapping to Guide Appropriate Treatment, Avoid Complications, and Improve Survival of Patients With Coronavirus Disease 2019-Related Coagulopathy.

OBJECTIVES: Coagulopathy of coronavirus disease 2019 is largely described as hypercoagulability, yet both thrombotic and hemorrhagic complications occur. Although therapeutic and prophylactic anticoagulant interventions have been recommended, empiric use of antifactor medications (heparin/enoxaparin) may result in hemorrhagic complications, including death. Furthermore, traditional (antifactor) anticoagulation does not address the impact of overactive platelets in coronavirus disease 2019. The primary aim was to evaluate if algorithm-guided thromboelastography with platelet mapping could better characterize an individual's coronavirus disease 2019-relatedcoagulopathic state and, secondarily, improve outcomes. DESIGN SETTING AND PATIENTS: Coronavirus disease 2019 patients (n = 100), receiving thromboelastography with platelet mapping assay upon admission to an 800-bed tertiary-care hospital, were followed prospectively by a hospital-based thromboelastography team. Treating clinicians were provided with the option of using a pre-established algorithm for anticoagulation, including follow-up thromboelastography with platelet mapping assays. Two groups evolved: 1) patients managed by thromboelastography with platelet mapping algorithm (algorithm-guided-thromboelastography); 2) those treated without thromboelastography with platelet mapping protocols (non-algorithm-guided). Outcomes included thrombotic/hemorrhagic complications, pulmonary failure, need for mechanical ventilation, acute kidney injury, dialysis requirement, and nonsurvival. INTERVENTIONS: Standard-of-care therapy with or without algorithm-guided-thromboelastography support. MEASUREMENTS AND MAIN RESULTS: Although d-dimer, C-reactive protein, and ferritin were elevated significantly in critically ill (nonsurvivors, acute kidney injury, pulmonary failure), they did not distinguish between coagulopathic and noncoagulopathic patients. Platelet hyperactivity (maximum amplitude-arachidonic acid/adenosine diphosphate > 50 min), with or without thrombocytosis, was associated with thrombotic/ischemic complications, whereas severe thrombocytopenia (platelet count < 100,000/µL) was uniformly fatal. Hemorrhagic complications were observed with decreased factor activity (reaction time > 8 min). Non-algorithm-guided patients had increased risk for subsequent mechanical ventilation (relative risk = 10.9; p < 0.0001), acute kidney injury (relative risk = 2.3; p = 0.0017), dialysis (relative risk = 7.8; p < 0.0001), and death (relative risk = 7.7; p < 0.0001), with 17 of 28 non-algorithm-guided patients (60.7%) dying versus four algorithm-guided-thromboelastography patients (5.6%) (p < 0.0001). Thromboelastography with platelet mapping-guided antiplatelet treatment decreased mortality 82% (p = 0.0002), whereas non-algorithm-guided (compared with algorithm-guided-thromboelastography) use of antifactor therapy (heparin/enoxaparin) resulted in 10.3-fold increased mortality risk (p = 0.0001). CONCLUSIONS: Thromboelastography with platelet mapping better characterizes the spectrum of coronavirus disease 2019 coagulation-related abnormalities and may guide more tailored, patient-specific therapies in those infected with coronavirus disease 2019.

Incidence of venous thromboembolism in coronavirus disease 2019: An experience from a single large academic center.

BACKGROUND: Infection with the novel severe acute respiratory syndrome coronavirus 2 has been associated with a hypercoagulable state. Emerging data from China and Europe have consistently shown an increased incidence of venous thromboembolism (VTE). We aimed to identify the VTE incidence and early predictors of VTE at our high-volume tertiary care center. METHODS: We performed a retrospective cohort study of 147 patients who had been admitted to Temple University Hospital with coronavirus disease 2019 (COVID-19) from April 1, 2020 to April 27, 2020. We first identified the VTE (pulmonary embolism [PE] and deep vein thrombosis [DVT]) incidence in our cohort. The VTE and no-VTE groups were compared by univariable analysis for demographics, comorbidities, laboratory data, and treatment outcomes. Subsequently, multivariable logistic regression analysis was performed to identify the early predictors of VTE. RESULTS: The 147 patients (20.9% of all admissions) admitted to a designated COVID-19 unit at Temple University Hospital with a high clinical suspicion of acute VTE had undergone testing for VTE using computed tomography pulmonary angiography and/or extremity venous duplex ultrasonography. The overall incidence of VTE was 17% (25 of 147). Of the 25 patients, 16 had had acute PE, 14 had had acute DVT, and 5 had had both PE and DVT. The need for invasive mechanical ventilation (adjusted odds ratio, 3.19; 95% confidence interval, 1.07-9.55) and the admission D-dimer level ≥1500 ng/mL (adjusted odds ratio, 3.55; 95% confidence interval, 1.29-9.78) were independent markers associated with VTE. The all-cause mortality in the VTE group was greater than that in the non-VTE group (48% vs 22%; P = .007). CONCLUSIONS: Our study represents one of the earliest reported from the United States on the incidence rate of VTE in patients with COVID-19. Patients with a high clinical suspicion and the identified risk factors (invasive mechanical ventilation, admission D-dimer level ≥1500 ng/mL) should be considered for early VTE testing. We did not screen all patients admitted for VTE; therefore, the true incidence of VTE could have been underestimated. Our findings require confirmation in future prospective studies.

Intensity of anticoagulation and survival in patients hospitalized with COVID-19 pneumonia.

BACKGROUND: SARS-CoV-2 infection has noted derangements in coagulation markers along with significant thrombotic complications. Post-mortem examinations show severe endothelial injury and widespread thrombotic microangiopathy in the pulmonary vasculature. Early reports describing the use of prophylactic anticoagulation demonstrated improved survival, leading to the adoption of prophylactic and therapeutic anticoagulation guided by D-dimer levels. The clinical usefulness of D-dimer values, trends, and more intensive anticoagulation remains an area of clinical interest. OBJECTIVES: Assess the outcomes and laboratory trends in COVID-19 patients stratified by intensity of anticoagulation at time of admission. PATIENTS AND METHODS: Retrospectively review the differences in clinical outcomes and laboratory trends in patients hospitalized with COVID-19 in the Lifespan Health System. RESULTS: Between 27 February and 24 April 2020, 468 patients were hospitalized. Initial use of high-intensity thromboprophylaxis was associated with improved 30-day mortality (adjusted RR 0.26; 95% confidence interval [CI], 0.07-0.97; p = 0.045) without a significant increased rate of bleeding (p = 0.11). In severe COVID-19, D-dimer significantly increased during hospitalization with standard thromboprophylaxis (p < 0.001) but remained stable or decreased with high-intensity prophylaxis or therapeutic anticoagulation. CONCLUSION: Patients who received high-intensity prophylactic anticoagulation had a downtrend in D-dimer levels and improved 30-day mortality. This suggests a role in anticoagulation in mitigating adverse outcomes associated with COVID-19; however, further randomized, prospective studies are needed.

Rehabilitative of COVID-19 patients with acute lower extremity Ischemia and amputation.

OBJECTIVE: To evaluate the clinical characteristics and rehabilitation management of patients who undergo amputation for COVID-19-associated coagulopathy. METHODS: Clinical and laboratory data for 3 patients were analysed and their rehabilitative management discussed. RESULTS: The medical records of 3 patients who had undergone amputation due to acute lower extremity ischaemia and who were provided with rehabilitation in our COVID-19 unit were reviewed. CONCLUSION: Coagulation changes related to SARS-CoV-2 may complicate recovery from this devastating disease. The rehabilitation management of amputated patients for COVID-19 acute lower extremity ischaemia is based on a multilevel approach for clinical, functional, nutritional and neuropsychological needs. Based on this limited experience, a dedicated programme for this specific group of patients seems advantageous to warrant the best functional outcome and quality of life.