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Coronavirus disease 2019 (COVID-19), the disease responsible for the devastating pandemic that began at the end of 2019, has been associated with a significantly increased risk of pulmonary thrombosis, even in patients receiving prophylactic anticoagulation. The predilection for thrombosis in COVID-19 may be driven by at least two distinct, but interrelated, processes: a hypercoagulable state responsible for large vessel thrombosis and thromboembolism, and direct vascular and endothelial injury responsible for in situ microvascular thrombosis. The presence of pulmonary thrombosis may explain why hypoxemia is out of proportion to impairment in lung compliance in some patients with COVID-19 pneumonia. Because pulmonary embolism and COVID-19 pneumonia share many signs and symptoms, diagnosing pulmonary embolism in patients with COVID-19 can be challenging. Given the high mortality and morbidity associated with severe COVID-19, and the concern that aspects of the disease may be driven by thrombosis, many hospital systems have instituted aggressive anticoagulation protocols above standard venous thromboembolism prophylaxis. In this review, the epidemiology, pathophysiology, diagnosis, and treatment of COVID-19 pulmonary thrombosis and thromboembolism are discussed.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel virus that belongs to the coronaviruses and causes coronavirus disease 2019 (COVID-19). In this study, we explored the demographic details, clinical features, and routinely conducted laboratory investigations of patients with COVID-19 during the second and third waves of the pandemic to understand their possible diagnostic and prognostic values in Egypt. Methods In this retrospective cohort study, the demographic characteristics, detailed medical history, laboratory findings, and symptoms of all enrolled patients with SARS-CoV-2 were collected from the medical records of Beni Suef University Hospitals between December 15, 2020, and April 15, 2021. Results This retrospective study included 473 patients, almost all of whom were elderly. The median age of the patients was 48 years, and those with moderate and severe disease were older than those with mild infections. The proportion of females was higher (63.4%) than males (36.6%). Diabetes mellitus (DM) was the most common comorbidity (17.3%), and fever was the most typical manifestation of COVID-19 (62.6%). Those with severe disease showed a higher C-reactive protein level (CRP) than those with moderate (p-value 0.009) or mild (p-value 0.01) diseases. Serum ferritin levels were significantly higher in patients with severe disease than in those with moderate disease (p-value 0.018). In contrast, d -dimer and serum creatinine were normal and showed no significant difference in all comparisons (p-value overall 0.21). Conclusion This study observed several variations in COVID-19 patients’ characteristics. The new manifestations included skin rash, bone and low back pains, and rigors. In contrast to females, most males had moderate-to-severe illness. Old age and higher body mass index was associated with increasing severity. d -dimer and complete blood count were normal and could not identify potential COVID‐19 patients. Patients who had mild illness were still at risk of developing post-COVID complications.

Objectives Determine whether D-dimer concentration in the absence of imaging can differentiate patients that require anti-coagulation from patients who do not require anti-coagulation. Methods Data was obtained retrospectively from 366 hemodynamically stable adult ED patients with suspected pulmonary embolism (PE). Patients were categorized by largest occluded artery and aggregated into: ‘Require anti-coagulation’ (main, lobar, and segmental PE), ‘Does not require anti-coagulation’ (sub-segmental and No PE), ‘High risk of deterioration’ (main and lobar PE), and ‘Not high risk of deterioration’ (segmental, sub-segmental, and No PE) groups. Wilcoxon rank-sum test was used for 2 sample comparisons of median D-dimer concentrations. Receiver operating characteristic (ROC) curve analysis was utilized to determine a D-dimer cut-off that could differentiate ‘Require anti-coagulation’ from ‘Does not require anti-coagulation’ and ‘High risk of deterioration’ from ‘Low risk of deterioration’ groups. Results The ‘Require anti-coagulation’ group had a maximum area under the curve (AUC) of 0.92 at an age-adjusted D-dimer cut-off of 1540 with a specificity of 86% (95% CI, 81–91%), and sensitivity of 84% (79–90%). The ‘High risk of deterioration’ group had a maximum AUC of 0.93 at an age-adjusted D-dimer cut-off of 2500 with a specificity of 90% (85–93%) and sensitivity of 83% (77–90%). Conclusions An age-adjusted D-dimer cut-off of 1540 ng/mL differentiates suspected PE patients requiring anti-coagulation from those not requiring anti-coagulation. A cut-off of 2500 differentiates those with high risk of clinical deterioration from those not at high risk of deterioration. When correlated with clinical outcomes, these cut-offs can provide an objective method for clinical decision making when imaging is unavailable., Highlights • ED providers are faced with risks and benefits when empirically administering anti-coagulation for suspected PE patients. • We show that D-dimer concentration can be used as a clinical decision making tool to minimize these risks. • A D-dimer cut-off of 1540 ng/mL can be used to minimize unnecessary anti-coagulation exposure in patients who do not need it. • A D-dimer cut-off of 2500 ng/mL can be used to minimize risk of withholding treatment for patients at risk of clinical deterioration. • Together these cut-offs provide an objective measure that can be combined with clinical gestalt to weight the risks and benefits of empiric anti-coagulation.

Objective: To describe clinical characteristics of patients after intensive care unit (ICU) treatment for coronavirus disease 2019 (COVID-19) who were admitted for inpatient rehabilitation.Design: A cross-sectional design.Setting: Inpatient rehabilitation care in the Netherlands.Participants: All post-ICU patients with COVID-19 admitted to the rehabilitation center between April 2 and May 13, 2020, were invited to participate in the study. Included were patients older than 18 years needing inpatient rehabilitation after ICU treatment for COVID-19 (N=60; mean age, 59.9y; 75% male).Interventions: Not applicable.Main Outcome Measures: The following information was collected in the first week of inpatient rehabilitation care: (1) demographics; (2) ICU stay parameters; (3) medical, physical, and functional characteristics; and (4) self-reported symptoms.Results: The most important findings for rehabilitation were the following: in the first week after discharge to the rehabilitation center, 38.3% of all patients experienced exercise-induced oxygen desaturation, in 72.7% muscle weakness was present in all major muscle groups, and 21.7% had a reduced mobility in 1 or both shoulders. Furthermore 40% had dysphagia, and 39.2% reported symptoms of anxiety.Conclusion: Post-ICU patients with COVID-19 display physical and anxiety symptoms as reported in other post-ICU patient groups. However, this study showed some remarkable clinical characteristics of post-ICU patients with COVID-19. Rehabilitation programs need to anticipate on this. Long-term follow-up studies are necessary.

Introduction One of the most prominent and concerning complications associated with coronavirus disease 2019 (COVID-19) is venous and arterial thromboembolisms. The aim of the present study was to delineate the prevalence of thromboembolic events and the current status of prophylactic anticoagulation therapy in patients with COVID-19 in Japan. Methods Between February 1 and August 31, 2020, we performed a dual-center, retrospective cohort study based on data obtained from the medical charts of COVID-19 patients admitted to healthcare facilities in Japan. The primary outcome was any thromboembolic event including pulmonary embolism (PE), deep vein thrombosis (DVT), myocardial infarction, ischemic stroke and other systemic thromboemboli. Results During the study period, we extracted 628 consecutive patients admitted for COVID-19. Prophylactic anticoagulant therapy was administered in 63 (10%) patients of whom 20 (31.7%) were admitted to the intensive care unit (ICU). Thromboembolic events occurred in 18 (2.9%) patients (14.3% of patients in ICU and 2.2% of patients in the general wards). DVT were detected in 13 (2.1%) patients, PE in 11 (1.8%), and both DVT and PE in 6 (0.96%) patients. An increasing prevalence in thromboembolic events was noted with progressive clinical severity. Overall in-hospital mortality was 4.8%. Conclusions Prophylactic anticoagulation therapy was administered in only 10% of all hospitalized COVID-19 patients. The prevalence of any thromboembolic events was 2.9% in COVID-19 patients with most events occurring in severe and critical patients. Therefore, prophylactic anticoagulation therapy may be warranted in severe and critical patients but in asymptomatic to moderate patients the practice remains controversial.

COVID-19 has been associated with an increased risk of thrombotic events; however, the reported incidence of deep vein thrombosis varies depending, at least in part, on the severity of the disease. Aim of this prospective, multicenter, observational study was to investigate the incidence of lower limb deep vein thrombosis as assessed by compression ultrasound in consecutive patients admitted to three pulmonary medicine wards designated to care for patients with COVID-19 related pneumonia, with or without respiratory failure but not requiring admission to an intensive care unit. Consecutive patients admitted between March 27 and May 6, 2020 were enrolled. Patients were excluded if they were less than 18-year-old or if compression ultrasound could not be performed for any reason. Patients were assessed at admission (t0) and after 7 days (t1). Major and non-major clinically relevant bleedings were recorded. Sixty-eight patients were enrolled. Two were excluded due to anatomical abnormalities that prevented compression ultrasound; sixty patients were retested at (t1). All patients were started on antithrombotic prophylaxis, unless therapeutic anticoagulation was required. Deep vein thrombosis as assessed by compression ultrasound was observed in 2 patients (3%); one of them was later deemed to represent a previous episode. No new episodes were detected at t1. One major and 2 non-major clinically relevant bleedings were observed. In the setting of patients with COVID-related pneumonia not requiring admission to an intensive care unit, the incidence of deep vein thrombosis is low and our data support not screening asymptomatic patients., Highlights • COVID-19 is characterized by increased risk of thrombotic events. • Compression ultrasound is an easy and reliable method to detect deep vein thrombosis. • The incidence of deep vein thrombosis in our COVID-19 patients not in ICU is very low. • Screening for deep vein thrombosis in these patients is not warranted.

COVID-19 associated coagulopathy and mortality related to thrombotic complications have been suggested as biological mediators in racial disparities related to COVID-19. We studied the adjusted prevalence of acute ischemic stroke, pulmonary embolism, myocardial infarction, and deep venous thrombosis stratified by race in hospitalized patients in one New York City borough during the local COVID-19 surge. The multi-racial cohort included 4299 patients hospitalized with COVID-19, 9% of whom were white, 40% black, 41% Hispanic and 10% Asian or other. We found a 6.1% prevalence of composite thrombotic events. There were no significant race-specific differences in thrombotic events when adjusting for basic demographics, socioeconomic factors, medical comorbidities or biomarkers using a stepwise regression model. We therefore found no evidence that the racial disparities related to COVID-19, and specifically thrombotic complications, are caused by biological differences in race.

A 19-year-old man presented with chest pain after a trans-Pacific flight. Venous thromboembolism was diagnosed and treated with catheter-directed thrombolysis. Genetic testing revealed factor V Leiden mutation. In addition to the flight history and genetic hypercoagulability, a renal abnormality causing an external compression over the inferior vena cava was suspected to be a contributing factor. (Level of Difficulty: Intermediate.), Graphical abstract

Highlights • Clinical signs are not useful for detecting DVT in critically ill COVID-19 patients • DVT occurs despite full dose anticoagulation in critically ill COVID-19 patients • Severe COVID-19 patients present a high prevalence of bilateral DVT

This case demonstrates the importance of considering septic pulmonary embolism (SPE) on the differential for chest pain in the pediatric population, especially in patients with a history of skin and soft tissue infection. The adolescent patient in this report, with a history of axillary hidradenitis suppurativa complicated by methicillin-resistant Staphylococcus aureus (MRSA) superinfection and recent completion of a 3-month course of doxycycline, presented with isolated focal chest pain in the absence of other infectious or respiratory signs or symptoms. Initial pulmonary imaging revealed multiple bilateral wedge-shaped nodules. Three specialty teams were consulted in the patient's evaluation, resulting in biopsy of a suspicious lesion that confirmed the diagnosis of MRSA SPE. Following a course of targeted antibiotic therapy, the patient's chest pain resolved and imaging findings improved. Insights gleaned from the workup of this patient are useful in formulating a framework for recognition of SPE in children presenting with chest pain, and also highlight the importance of considering insidious SPE presentation in the setting of antibiotic pretreatment.

Background Many patients with cancer have a hypercoagulable state and an increased risk of developing venous thromboembolism (VTE), arterial occlusion, and pulmonary emboli. Patients with cancer may also have an increased risk of bleeding with anticoagulant treatment. Recent trials have reported that direct oral anticoagulants (DOACs) are noninferior to the low-molecular-weight heparin, dalteparin, in preventing VTE, but have a higher bleeding rate. Objectives This study compared the efficacy and risks of DOACs versus dalteparin in patients with cancer-related VTEs across all randomized controlled trials (RCTs). Methods This study performed a systematic analysis of RCTs published in PubMed, SCOPUS, and Google Scholar from September 1, 2007 through March 31, 2020 that reported clinical outcomes of treatment with DOACs versus dalteparin in patients with cancer with acute VTE. Two investigators independently performed study selection and data extraction. Extracted data were recorded and exported to statistical software for all analyses (OpenMetaAnalyst). Results This study included 4 randomized trials (N = 2,907). Compared with DOACs, dalteparin was associated with higher VTE recurrence (risk ratio [RR]: 1.55; 95% confidence interval [CI]: 1.19 to 2.03; p = 0.001), whereas clinically relevant nonmajor bleeding (CRNMB) was significantly less frequent with dalteparin than that with DOACs (RR: 0.68; 95% CI: 0.54 to 0.86; p = 0.001). The risk of CRNMB was largely observed with patients with gastrointestinal malignancies. No significant differences were observed in major bleeding (RR: 0.74; 95% CI: 0.52 to 1.06; p = 0.11). Conclusions DOACs were noninferior to dalteparin in preventing VTE recurrence in patients with cancer without a significantly increased risk of major bleeding. However, DOACs were associated with higher rates of CRNMB compared with dalteparin, primarily in patients with gastrointestinal malignancies., Central Illustration

COVID-19 induces a hypercoagulable state with early case reports of death from undetected venous thromboembolism. Various protocols and consensus statements have been proposed to address the optimal prophylaxis strategy for hospitalized patients. We offer our single institution experience with a d-dimer driven prophylaxis model with no deep vein thrombosis identified on discharge lower extremity ultrasounds.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic that has infected over a hundred million people globally. There have been more than two million deaths recorded worldwide, with no end in sight until a widespread vaccination will be achieved. Current research has centred on different aspects of the virus interaction with cell surface receptors, but more needs to be done to further understand its mechanism of action in order to develop a targeted therapy and a method to control the spread of the virus. Lipids play a crucial role throughout the viral life cycle, and viruses are known to exploit lipid signalling and synthesis to affect host cell lipidome. Emerging studies using untargeted metabolomic and lipidomic approaches are providing new insight into the host response to COVID-19 infection. Indeed, metabolomic and lipidomic approaches have identified numerous circulating lipids that directly correlate to the severity of the disease, making lipid metabolism a potential therapeutic target. Circulating lipids play a key function in the pathogenesis of the virus and exert an inflammatory response. A better knowledge of lipid metabolism in the host-pathogen interaction will provide valuable insights into viral pathogenesis and to the development of novel therapeutic targets.

Highlights • Heparin, used clinically over 80 years, has shown potential for COVID-19 treatment. • The evidence and possible mechanisms of heparin for COVID-19 treatment are discussed. • The prospect of heparin therapy for COVID-19 is presented in this review., The pandemic coronavirus disease 2019 (COVID-19), caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rapidly spreading globally. Clinical observations found that systemic symptoms caused by SARS-CoV-2 infection are attenuated when using the anticoagulant agent heparin, indicating that heparin may play other roles in managing COVID-19, in addition to prevention of pulmonary thrombosis. Several biochemical studies show strong binding of heparin and heparin-like molecules to the Spike protein, which resulted in inhibition of viral infection to cells. The clinical observations and in vitro studies argue for a potential multiple-targeting effects of heparin. However, adverse effects of heparin administration and some of the challenges using heparin therapy for SARS-CoV-2 infection need to be considered. This review discusses the pharmacological mechanisms of heparin regarding its anticoagulant, anti-inflammatory and direct antiviral activities, providing current evidence concerning the effectiveness and safety of heparin therapy for this major public health emergency.

Coronavirus disease 2019 (COVID-19) is associated with considerable morbidity and mortality. The number of confirmed cases of infection with SARS-CoV-2, the virus causing COVID-19 continues to escalate with over 70 million confirmed cases and over 1.6 million confirmed deaths. Severe-to-critical COVID-19 is associated with a dysregulated host immune response to the virus, which is thought to lead to pathogenic immune dysregulation and end-organ damage. Presently few effective treatment options are available to treat COVID-19. Leronlimab is a humanized IgG4, kappa monoclonal antibody that blocks C–C chemokine receptor type 5 (CCR5). It has been shown that in patients with severe COVID-19 treatment with leronlimab reduces elevated plasma IL-6 and chemokine ligand 5 (CCL5), and normalized CD4/CD8 ratios. We administered leronlimab to 4 critically ill COVID-19 patients in intensive care. All 4 of these patients improved clinically as measured by vasopressor support, and discontinuation of hemodialysis and mechanical ventilation. Following administration of leronlimab there was a statistically significant decrease in IL-6 observed in patient A (p=0.034) from day 0–7 and patient D (p=0.027) from day 0–14. This corresponds to restoration of the immune function as measured by CD4+/CD8+ T cell ratio. Although two of the patients went on to survive the other two subsequently died of surgical complications after an initial recovery from SARS-CoV-2 infection., Highlights • Leronlimab is a monoclonal antibody in clinical trials to treat the cytokine storm. • Critically ill patients received leronlimab through compassionate use and had remarkable recoveries measured objectively. • The CCR5 receptor is important in recruiting inflammatory cells mainly T cells and macrophages. • Leronlimab disrupted this signal and may have been responsible for restoration of the immune system, improved survival and decrease in IL-6.

Patients with the severe form of coronavirus disease 2019 (COVID-19) have been frequently found to suffer from both arterial and venous thrombotic events due to the perpetuation of a hypercoagulable state. This phenomenon, termed COVID-19-associated coagulopathy (CC), is now considered a major component of the pathophysiology of this novel infectious disease, leading to widespread thrombosis. While at first, the vascular insults may be limited to the pulmonary microvasculature, as the disease progresses, systemic involvement occurs, culminating in distant organ thrombosis and multi-organ dysfunction syndrome. In this review article, we discuss recent insights into the pathophysiologic mechanisms of CC and review the clinical, histopathologic, and laboratory evidence, which leads us to conclude that COVID-19 is both a pulmonary and vascular disorder., Highlights: • Arterial and venous thrombotic events are frequent in patients with severe COVID-19 • The underlying trigger of COVID-19-associated coagulopathy encompasses immuno-thrombo-inflammation • The coagulopathy initiates with vascular insults to pulmonary microvasculature • As the disease progresses, the prothrombotic state becomes systemic, culminating in multiple organ thrombosis

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The novel coronavirus SARS-CoV-2 is known to cause hypoxemia and acute respiratory distress syndrome (ARDS) in a significant portion of those with severe disease. Survivors of critical illness and ARDS often experience neurocognitive impairment but, to date, there is scant literature correlating radiographic hypoxic brain injury to hypoxemia related to ARDS. In this case series, we describe three cases of hypoxic brain injury seen on magnetic resonance imaging (MRI) in patients with hypoxemia secondary to COVID-19-related ARDS. The lack of severe observed hypoxemia in two of the cases suggests that unrecognized or asymptomatic hypoxemia may play a role in hypoxic brain injury related to COVID-19., Highlights • Cases of hypoxic ischemic brain injury in COVID-19 ARDS are described, in absence of cardiopulmonary arrest. • Lack of severe hypoxemia suggests unrecognized or asymptomatic hypoxemia is involved in hypoxic brain injury. • Other factors such as cytokine release syndrome may play a role in prolonged encephalopathy in COVID-19.

We present the characteristics and outcomes of the first two cases of catheter-directed thrombolysis performed in patients presenting with COVID-19 related iliocaval thrombosis, Graphical abstract

Purpose Critically ill patients with Coronavirus Disease 2019 (COVID-19) have high rates of line thrombosis. Our objective was to examine the safety and efficacy of a low dose heparinized saline (LDHS) arterial line (a-line) patency protocol in this population. Materials and Methods In this observational cohort study, patients ≥18 years with COVID-19 admitted to an ICU at one institution from March 20–May 25, 2020 were divided into two cohorts. Pre-LDHS patients had an episode of a-line thrombosis between March 20–April 19. Post-LDHS patients had an episode of a-line thrombosis between April 20–May 25 and received an LDHS solution (10 units/h) through their a-line pressure bag. Results Forty-one patients (pre-LDHS) and 30 patients (post-LDHS) were identified. Baseline characteristics were similar between groups, including age (61 versus 54 years; p = 0.24), median Sequential Organ Failure Assessment score (6 versus 7; p = 0.67) and systemic anticoagulation (47% versus 32%; p = 0.32). Median duration of a-line patency was significantly longer in post-LDHS versus pre-LDHS patients (8.5 versus 2.9 days; p, Graphical abstract Unlabelled Image, Highlights • Critically ill COVID-19 patients have frequent arterial line (a-line) thrombosis. • A low dose heparinized saline (LDHS) a-line patency protocol was examined. • Two a-line thrombosis cohorts were identified: “post-LDHS” and “pre-LDHS”. • A-line patency was longer in post- vs. pre-LDHS patients (8.5 vs. 2.9 d; p

A 12-year-old female with SARS-CoV-2 infection presented as phlegmasia cerulea dolens with venous gangrene.. Emergent mechanical thrombectomy was complicated by a massive pulmonary embolism and cardiac arrest for which extracorporeal cardiopulmonary resuscitation and therapeutic hypothermia were employed. Staged-ultrasound assisted catheter directed thrombolysis was employed for treatment of bilateral pulmonary emboli and the extensive lower extremity deep vein thrombosis while the patient received extracorporeal membrane oxygenation support. We highlight the need for heightened suspicion for occult SARS-CoV-2 infection among children presenting with unusual thrombotic complications.

Objective To determine whether the pulmonary embolism (PE) categories of massive, submassive, PE with no right ventricle dysfunction (NRVD), and subsegmental only (SSO) adequately predict clinical outcome. Methods Patients treated for acute PE (March 1, 2013, through July 31, 2019) were followed forward prospectively to compare venous thromboembolism (VTE) recurrence, all-cause mortality, major bleeding, and clinically relevant nonmajor bleeding (CRNMB) across 4 PE categories. Results Of 2703 patients with VTE, 1188 (44%) had PE, of which 1021 (85.9%) completed at least 3 months of therapy or had clinical outcomes precluding further treatment (27 with massive, 217 submassive, 557 NRVD, and 220 SSO PE). One patient with massive, 8 with submassive, 23 with NRVD, and 5 with SSO PE had recurrent VTE (3.90, 5.33, 5.36, and 3.66 per 100 person-years, respectively; P=.84). There were 3 deaths in massive, 27 in submassive, 140 in NRVD, and 34 in SSO PE groups (11.59, 17.37, 31.74, and 24.74 per 100 person-years, respectively; P=.02); when adjusted for cancer, the relationship was no longer significant (P=.27). One patient with massive, 5 with submassive, 22 with NRVD, and 5 with SSO PE had major bleeding (3.90, 3.31, 5.24, and 3.75 per 100 person-years, respectively; P=.66). Similar cumulative rates for CRNMB were observed (P=.87). Three-month rates of VTE recurrence, death, major bleeding, and CRNMB did not differ by PE category. Conclusion In the setting of anticoagulation therapy with maximal standardization and evidence-based practice, there is no evidence of a difference between PE categories and outcomes. Trial Registration clinicaltrials.gov Identifier : NCT03504007

Background Cardiovascular complications, including myocardial infarction, ischemic stroke, and pulmonary embolism, represent an important source of adverse outcomes in coronavirus disease-2019 (COVID-19). Objectives To assess the frequency of arterial and venous thromboembolic disease, risk factors, prevention and management patterns, and outcomes in patients with COVID-19, the authors designed a multicenter, observational cohort study. Methods We analyzed a retrospective cohort of 1,114 patients with COVID-19 diagnosed through our Mass General Brigham integrated health network. The total cohort was analyzed by site of care: intensive care (n = 170); hospitalized nonintensive care (n = 229); and outpatient (n = 715). The primary study outcome was a composite of adjudicated major arterial or venous thromboembolism. Results Patients with COVID-19 were 22.3% Hispanic/Latinx and 44.2% non-White. Cardiovascular risk factors of hypertension (35.8%), hyperlipidemia (28.6%), and diabetes (18.0%) were common. Prophylactic anticoagulation was prescribed in 89.4% of patients with COVID-19 in the intensive care cohort and 84.7% of those in the hospitalized nonintensive care setting. Frequencies of major arterial or venous thromboembolism, major cardiovascular adverse events, and symptomatic venous thromboembolism were highest in the intensive care cohort (35.3%, 45.9%, and 27.0 %, respectively) followed by the hospitalized nonintensive care cohort (2.6%, 6.1%, and 2.2%, respectively) and the outpatient cohort (0% for all). Conclusions Major arterial or venous thromboembolism, major adverse cardiovascular events, and symptomatic venous thromboembolism occurred with high frequency in patients with COVID-19, especially in the intensive care setting, despite a high utilization rate of thromboprophylaxis., Central Illustration

A higher risk of thrombosis has been described as a prominent feature of coronavirus disease 2019 (COVID-19). This systematic review synthesizes current data on thrombosis risk, prognostic implications, and anticoagulation effects in COVID-19. We included 37 studies from 4070 unique citations. Meta-analysis was performed when feasible. Coagulopathy and thrombotic events were frequent among patients with COVID-19 and further increased in those with more severe forms of the disease. We also present guidance on the prevention and management of thrombosis from a multidisciplinary panel of specialists from Mayo Clinic. The current certainty of evidence is generally very low and continues to evolve.

Background Emerging evidence shows that severe COVID-19 can be complicated by a significant coagulopathy, that likely manifests in the form of both microthrombosis and venous thromboembolism (VTE). This recognition has led to the urgent need for practical guidance regarding prevention, diagnosis, and treatment of VTE. Methods A group of approved panelists developed key clinical questions by using the PICO (population, intervention, comparator, and outcome) format that addressed urgent clinical questions regarding the prevention, diagnosis and treatment of venous thromboembolism in patients with COVID-19. MEDLINE (via PubMed or Ovid), Embase and Cochrane Controlled Register of Trials were systematically searched for relevant literature and references were screened for inclusion. Validated evaluation tools were used to grade the level of evidence to support each recommendation. When evidence did not exist, guidance was developed based on consensus using the modified Delphi process. Results The systematic review and critical analysis of the literature based on13 PICO questions resulted in 22 statements. Very little evidence exists in the COVID-19 population. The panel thus used expert consensus and existing evidence-based guidelines to craft the guidance statements. Conclusions The evidence on the optimal strategies to prevent, diagnose, and treat venous thromboembolism in patients with COVID-19 is sparse, but rapidly evolving.

Patients with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pneumonia with SARS-CoV-2 present with coagulation disorders and marked susceptibility to thrombosis ([1][1],[2][2]). However, the exact prevalence of deep vein thrombosis (DVT) has been poorly investigated, although the risk

We report the case of a 35-year-old pregnant woman (gravida 3, para 1) with antithrombin deficiency who was successfully treated with apixaban. She had a history of heparin-induced thrombocytopenia and venous thromboembolic events. Pregnancy was confirmed while the patient was having anticoagulant therapy for a persistent thrombus. Choice of anticoagulation during her pregnancy was limited because of her antithrombin deficiency: heparin was not an option because of her history of heparin-induced thrombocytopenia; antithrombin-dependent anticoagulant drugs were not an option because of her antithrombin deficiency, and she preferred outpatient management. Despite the fact that there are no reports of its use in pregnant women, we selected apixaban (10 mg/day), a direct Xa inhibitor, as the best solution. No progression of thrombus was noted during the pregnancy. The newborn baby had no external congenital anomalies, intracranial hemorrhage, or bleeding tendency. Thus, apixaban may be a candidate for anticoagulant therapy in pregnant women with a history of venous thromboembolic events and heparin-induced thrombocytopenia., Highlights • Pregnant women are at higher risk for venous thromboembolism than women who are not pregnant. • Anticoagulant therapy is limited for a pregnant woman with heparin-induced thrombocytopenia caused by congenital antithrombin deficiency. • Apixaban may be an alternative option of anticoagulant therapy during pregnancy.

Objectives: To report our experience with the emerging technique of thulium laser enucleation of the prostate (ThuLEP) for the treatment for prostate hyperplasia. Patients and methods: Our inclusion criteria were an International Prostate Symptom Score (IPSS) of >15 and a quality-of-life (QoL) score of >3 in patients with confirmed bladder outflow obstruction, no longer responsive to medical therapy, with a significant post-void residual urine volume (PVR; >100 mL), with or without recurrent urinary tract infection and/or acute urinary retention. Patients with neurogenic bladder, urethral strictures, bladder stones, and previously failed transurethral prostate surgery were excluded. Results: In all, 139 men were included in the study. The mean age was 67.8 years. The IPSS and QoL score improved by 17.6 and 2.6, respectively. The flow rate increased from a mean of 9.6 mL to 31.2 mL and the PVR decreased from a mean of 131 mL to 30 mL. On univariate and multivariate analyses, operating time was a predictive factor for haemoglobin drop during the operation. Heparin prophylaxis was the only risk factor identified for postoperative bleeding. Two patients (0.01%) required blood transfusion. One patient (0.007%) required re-intervention for bleeding control, and two patients developed urethral and bladder neck strictures (0.01%). Conclusion: ThuLEP is safe and reproducible. Whilst it significantly reduces intraoperative bleeding as compared to transurethral resection of the prostate, operating time and perioperative heparin prophylaxis may still lead to a Hb drop and constitute a risk factor for postoperative bleeding. Therefore, a potential risk of deep vein thrombosis requiring heparin prophylaxis should be carefully considered and balanced with the expected clinical benefit of the operation. Keywords: Prostate enlargement, Thulium laser, Endoscopy, Treatment

Highlights • Acute adrenal insufficiency, although rare, is the most frequently reported endocrine manifestation of the APS. • Major surgery has been identified as a precipitating factor for this potentially fatal condition. • Effective treatment requires timely diagnosis and intervention at the acute phase. Therefore, a high index of suspicion is crucial. The APLS patients who overcome the acute phase bear a favorable prognosis regarding restoration of their adrenal function., Introduction Spontaneous bilateral adrenal hemorrhage or hemorrhagic necrosis due to adrenal vein thrombosis is an uncommon condition that may lead to acute adrenal insufficiency and death. The objective of this report is to enhance recognition of this potentially fatal disorder in surgical patients. Presentation of cases We present two cases of acute adrenal insufficiency due to bilateral adrenal hemorrhage associated with primary antiphospholipid antibody syndrome (APS). Both cases occurred in the early postoperative period after major colorectal surgery. Major vein thrombosis, abdominal pain, anorexia, asthenia, lethargy and an unexplained drop in patient’s hemoglobin without evidence of sepsis were the principal symptoms and signs that, with a high index of suspicion, led to the correct diagnosis. Discussion Antiphospholipid syndrome is an acquired thrombophilia caused by circulating antibodies against a heterologous group of phospholipids. Recent literature has identified a causative relation between APS and primary adrenal insufficiency (AI), identifying it as its most common endocrine manifestation. Surgeries along with inflammation or hormones have been identified as precipitating factors. Spontaneous haemorrhagic infarction of the adrenal glands has been observed in patients with APS in the postoperative period during anticoagulant treatment. Signs and symptoms are non-specific and are easily confused with those of the underlying condition. Conclusions Early recognition and prompt treatment of adrenal insufficiency due to APS in surgical patient is of vital importance. Patients correctly diagnosed and treated that survive the critical phase have a better prognosis regarding restoration of adrenal function.

Highlights • Transplanted pancreas venous thrombosis is a complex to diagnose. • Urgent and prompt treatment is necessary. • Endovascular pharmacomechanical thrombectomy sometimes possible. • Early intervention can salvage graft organs in those receiving simultaneous pancreas and kidney transplantation., Introduction Simultaneous kidney and pancreas transplant is the preferred treatment option for end-stage renal disease due to type 1 diabetic nephropathy. Vascular complications are detrimental to graft survival and can lead to graft loss in the early postoperative phase of transplantation. Generally, duplex Doppler ultrasound is used for vascular patency monitoring and pancreatectomy followed by re-transplantation is required in the majority of cases. Recently, pancreatic graft salvage with non-operative management, including medical anticoagulation and endovascular thrombectomy, in the early postoperative period has been described with success. Presentation of case We report a case of early detection of pancreas venous graft thrombosis via clinical suspicion and radiological methods, and early intervention with endovascular thrombolysis. As a result, the pancreatic graft was successfully salvaged. Discussion A limited number of studies had showed successful graft salvage in only 30–45% of thrombosed pancreatic graft with surgical thrombectomy. Our patient also had bleeding from the vascular access site and ultimately required blood transfusion, however she recovered well after procedure. Conclusion Given the complexity and significance of PVGT, urgent and prompt treatment is necessary. Interpreting outcomes from our case and other small studies, it appears that endovascular pharmacomechanical thrombectomy can be a vital tool to salvage graft organs in those receiving SPK.

Graphical abstract, Despite endorsed and exponential research to improve diagnostic and therapeutic strategies, efforts have not yet converted into a better prospect for patients infected with the novel coronavirus (2019nCoV), and still, the name of SARS-CoV-2 is coupled with numerous unanswered questions. One of these questions is concerning how this respiratory virus reduces the number of platelets (PLTs)? The results of laboratory examinations showed that about a quarter of COVID-19 cases experience thrombocytopenia, and more remarkably, about half of these patients succumb to the infection due to coagulopathy. These findings have positioned PLTs as a pillar in the management as well as stratifying COVID-19 patients; however, not all the physicians came into a consensus about the prognostic value of these cells. The current review aims to unravel the contributory role of PLTs s in COVID-19; and also to summarize the original data obtained from international research laboratories on the association between COVID-19 and PLT production, activation, and clearance. In addition, we provide a special focus on the prognostic value of PLTs and their related parameters in COVID-19. Questions on how SARS-CoV-2 induces thrombocytopenia are also responded to. The last section provides a general overview of the most recent PLT- or thrombocytopenia-related therapeutic approaches. In conclusion, since SARS-CoV-2 reduces the number of PLTs by eliciting different mechanisms, treatment of thrombocytopenia in COVID-19 patients is not as simple as it appears and serious cautions should be considered to deal with the problem through scrutiny awareness of the causal mechanisms.

Background: The clinical epidemiology of hospitalized COVID-19 patients has never been described before in Lebanon. Moreover, the hospital admission and PCR positivity rates have not been assessed and compared yet. Objectives: To describe the characteristics and outcomes of hospitalized patients with coronavirus induced disease 2019 (COVID-19) in Lebanon and identify risk factors for severe disease or death. Study design: This is a retrospective mono-center cohort study in which we used patients’ files to extract and analyse data on demographic and clinical characteristics, as well as mortality. Moreover, we tracked the pandemic by recording the daily total and ICU inpatient census and the PCR positivity rate for admitted and outpatients. Results: Although the total admission rate increased from September to April, the ICU census switched this trend in December to stabilize at an average of around 10 patients/day until April. The case fatality rate was 19% for the 902 hospitalized patients, of which the majority (80%) had severe COVID-19. The severity odds ratio is significantly decreased in immunosuppressed cases (OR, 0.18; CI, 0.05-0.67; p=0.011). Additionally, the odds of COVID-19 related death are significantly greater if consolidations are found in the chest computed tomography (CT) scan (OR, 12; CI, 2.63-55.08; p=0.0013). Conclusion: Consolidations in the lungs significantly increase the COVID-19 death risk. Risk factors identification is important to improve patients’ management and vaccination strategies. In addition, hospital statistics are good indicators of a pandemic's track.

Although immune-checkpoint inhibitors (ICIs) have become an important choice of treatment for advanced NSCLC, recent reports show hyperprogressive disease (HPD) after ICI administration. The clinico-pathological features of HPD still remain unclear. Here we report a 65-year-old man with lung adenocarcinoma who abruptly presented HPD two days after pembrolizumab administration. The primary tumor increased in size from 40 mm to 57 mm on the chest HRCT. The patient died on day 37 after pembrolizumab administration. The autopsy demonstrated widespread progression of cancer cells into the alveolar spaces and lymphangitic carcinomatosis in the left lung, with plenty of bloody pleural effusion. We compared the pathohistology and immunohistochemical expression of PD-L1 between the pretreatment biopsy material and posttreatment autopsy materials, and found a change in PD-L1 expression which may be related to HPD. We also discuss the possibility of HPD, pseudoprogression, and interstitial lung disease when there is evidence of tumor growth or ground glass shadows on chest images after ICI treatment. Keywords: Hyperprogressive disease, Immune checkpoint inhibitors, Non-small cell lung cancer, PD-L1

Objective: Reteplase (recombinant plasminogen activator) is a mutant of alteplase. It has a longer half-life than its parent molecule and has shown better vessel patency rates in acute myocardial infarction. In this study, we analyzed the efficacy and safety of reteplase in acute pulmonary embolism (PE). Methods: This observational study included patients with high- and intermediate-risk acute PE, presenting within 14 days of symptom onset. The patients were treated with reteplase, which was given in two bolus doses of 10 U each, 30 min apart, along with intravenous heparin. Patients with hemodynamic compromise (high-risk or massive PE) and normotensive patients with evidence of right ventricular (RV) dysfunction (intermediate-risk or submassive PE) on echocardiography or computed tomography were included in the study. The efficacy outcomes assessed were in-hospital death and improvement of RV function by echocardiography. The safety outcomes were major bleeding, minor bleeding, and ischemic or hemorrhagic stroke during hospitalization. Results: Of the 40 patients included, 25% were classified as high risk with hemodynamic compromise and 75% were classified as intermediate risk. RV dysfunction was present in all the patients (100%). Concomitant lower extremity deep vein thrombosis was present in 55% of the patients. The mortality rate was 5%. There was significant improvement in RV function and reduction in pulmonary artery systolic pressure and tricuspid regurgitation severity. There was no major bleeding event or stroke, and 7.5% patients had minor extracranial bleeding. Conclusions: Double-bolus reteplase given with heparin is effective in the treatment of high- and intermediate-risk PE, with minimal risk of bleeding. Keywords: Acute pulmonary embolism, Reteplase, Thrombolysis

Introduction Neurofibromatosis type 1 (NF-1) or von Recklinghausen's disease, an autosomal dominant genetic disorder, is characterized by a café au lait spot and cutaneous neurofibromas. It typically involves the skin, nerves, bones, muscles, and eyes, and occasionally involves vascular complications and can lead to life-threatening hemorrhage. Case presentation We present the case of a 77-year-old female with a posterior tibial artery rupture with NF-1. She presented with sudden right lower leg swelling, pain, paresthesia, and paralysis; computed tomography images revealed popliteal artery aneurysm with surrounding hematoma, expanding from the posterior aspect of the knee to the calf. Diagnosed with compartment syndrome, due to a ruptured right popliteal artery aneurysm, she underwent prosthetic replacement of the popliteal aneurysm. Intraoperatively, the fragility of the popliteal artery was noted, although no perforation site was recognized despite the aneurysm; active bleeding originated from the hematoma between the calf muscles. Intraoperative digital subtraction angiography revealed an extravasation at the branch of the posterior tibial artery that was managed by coil embolization of the posterior tibial artery. Clinical discussion Although the frequency of NF-1 vasculopathy is unknown, vasculopathy is the second most common cause of mortality in patients with NF-1, after malignancy. The less invasive endovascular approach might be preferable for treating NF-1-related aneurysm. The NF-related vasculopathy lesion sites are diverse, and intraoperative angiography would help confirm the diagnosis. Conclusion NF-1-related vasculopathy may be associated with vascular fragility, and the endovascular approach might be preferable. Endovascular-first approach could have helped in correct diagnosis in the present case., Highlights • Vasculopathy in neurofibromatosis type1 (NF-1) occurs in any blood vessels and preoperative diagnosis is sometimes difficult • Open surgery for NF-1 vasculopathy is sometimes difficult due to vascular fragility • Endovascular approach is not only less invasive, but also useful for diagnosis

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.

Introduction Warfarin is the most commonly used antithrombotic drug. Single nucleotide polymorphisms (SNPs) of CYP2C9, CYP4F2, VKORC1 1173 and VKORC1-1639 influence warfarin maintenance dosage. We aimed to determine the impact of SNPs of these genes on mean daily warfarin dosage (MDWD) in Han-Chinese patients. Methods Strict literature inclusion criteria were established, and literature searching was performed on PubMed, Embase and Cochrane Library for English articles and CNKI, CBM and Wanfang database for Chinese articles before September 2, 2014. Revman 5.3 was used to analyze the relationship between gene SNPs and MDWD in Han-Chinese subjects. Results We included 33 studies researching the impact of gene SNPs on MDWD in Han-Chinese subjects. CYP2C9 *3/*3, *1/*3 and *3 carriers needed a 72% (95% confidence interval [CI]: 62.0%–81.0%), 28% (22.0%–33.0%) and 26% (21.0%–32.0%) lower MDWD, respectively, than CYP2C9 *1/*1 carriers. CYP4F2 TT, CT and T carriers required a 18% (7.0%–30.0%), 7% (7.0%–7.0%) and 11% (7.0%–14.0%) higher MDWD, respectively, than CYP4F2 CC carriers. VKORC1 1173 CC, CT and C carriers required a 98% (78.0%–118.0%), 49% (37.0%–62.0%) and 56% (44.0%–67.0%) higher MDWD, respectively, than VKORC1 1173 TT carriers. VKORC1-1639 GG, GA and G carriers needed a 101% (53.0%–149.0%), 40% (36.0%–45.0%) and 38% (35.0%–42.0%) higher MDWD, respectively, than VKORC1-1639 AA carriers. Conclusions This meta-analysis is the first to report the relationship between genotypes and MDWD among Han-Chinese patients. The results showed that SNPs of CYP2C9, CYP4F2, VKORC1 1173 and VKORC1-1639 significantly influenced the MDWD in Han-Chinese patients., Highlights • This meta-analysis examined the effects of genotype on mean daily warfarin dosage. • CYP2C9, CYP4F2 and VKORC1 genotypes were studied in Han-Chinese patients. • CYP2C9, CYP4F2, VKORC1-1173 and VKORC1-1639 polymorphisms affected warfarin dosage. • VKORC1-1173 C and VKORC1-1639 G mutations had similar frequencies and effects. • Either genotype can be tested for to guide drug usage and lower medical costs.

Objectives To detect the incidence of immediate postoperative deep vein thrombosis (DVT) using screening lower extremity ultrasonography (US) in patients undergoing radical cystectomy (RC) and to determine the rate of symptomatic pulmonary embolism (PE) after RC and identify risk factors for venous thromboembolic (VTE) events in a RC population. Patients and methods We performed a retrospective review of prospective data collected on patients who underwent RC between July 2008 and January 2012. These patients underwent screening US at 2/3 days after RC to determine the rate of asymptomatic DVT. A chart review was completed to identify those who had a symptomatic PE. Univariate and multivariable analysis was used to identify risk factors associated with DVT, PE and total VTE events. Results In all, 221 patients underwent RC and asymptomatic DVT was identified in 21 (9.5%) on screening US. Nine (4.5%) developed symptomatic PE at a median of 9 days, of which no patients had positive lower extremity US postoperatively. Increased length of hospital stay, increased estimated blood loss, and lower body mass index were linked to risk of PE, and only a previous history of DVT was associated with postoperative DVT. Conclusion Patients who undergo RC are at high-risk for thromboembolic events and multimodal prophylaxis should be administered. Clinicians should be especially vigilant in those who demonstrate factors associated with higher risk for VTE events.

Highlights • Prevalence of pulmonary thromboembolic disease (PTE) is 38% in COVID-19 patients who underwent CTPA. Patients with more severe COVID-19 changes are more likely to have PTE. • Majority of PTE is observed within smaller pulmonary vessels (75%) and lungs demonstrating COVID-19 changes (72%). Subsegmental vessels should be scrutinized for presence of PTE. • D-dimer values may have potential in guiding anticoagulation therapy and evaluating prognosis in these patients., Objectives To define the prevalence of pulmonary thromboembolic (PTE) disease diagnosed on CT pulmonary angiography (CTPA) in COVID-19 patients. To assess distribution of PTE and to evaluate for association between severity of COVID-19 disease, D-dimer values and incidence of PTE. Methods Patients with diagnosis of COVID-19 presenting to 5 different hospitals across Greater Manchester between 1st March 2020 and 30th April 2020 who had CTPA were included. CTPA images were evaluated for presence of PTE, distribution of PTE (in small and/or large vessels) and distribution of PTE within lungs with or without COVID-19 CT changes. Severity of COVID lung changes were graded. D-dimer values within 72 hours of CTPA were obtained. Statistical analyses were performed to evaluate for any significant association between variables. p values of ≤ 0.05 were regarded as statistically significant. Results A total of 974 patients presented across five hospital sites with COVID-19 infection. Eighty-four (n = 84) COVID-19 patients underwent CTPA. Of these, 38% (32/84) had PTE. PTE was seen in small vessels in 75% (24/32) and in lungs demonstrating COVID-19 changes in 72% (23/32). 84% (27/32) of PTE positive patients had disease severity of moderate or higher score (p = 0.005). D-dimer values were significantly higher (p ≤ 0.001) in PTE patients, median value in PTE group was 6441mcg/L(range219-90925). A D-dimer cut off value of 2247mcg/L provides sensitivity of 0.72 and specificity of 0.74. Conclusion There is increased prevalence of PTE in patients with moderate to severe COVID-19 disease. D-dimer values may have potential in guiding anticoagulation therapy and prognostication.