Predictors of acute deep venous thrombosis in patients hospitalized for COVID-19.

ABSTRACT: Deep venous thrombosis (DVT) is associated with high mortality in coronavirus disease 2019 (COVID-19) but there remains uncertainty about the benefit of anti-coagulation prophylaxis and how to decide when ultrasound screening is indicated. We aimed to determine parameters predicting which COVID-19 patients are at risk of DVT and to assess the benefit of prophylactic anti-coagulation.Adult hospitalized patients with positive severe acute respiratory syndrome coronavirus-2 reverse transcription-polymerase chain reaction (RT-PCR) undergoing venous duplex ultrasound for DVT assessment (n = 451) were retrospectively reviewed. Clinical and laboratory data within 72 hours of ultrasound were collected. Using split sampling and a 10-fold cross-validation, a random forest model was developed to find the most important variables for predicting DVT. Different d-dimer cutoffs were examined for classification of DVT. We also compared the rate of DVT between the patients going and not going under thromboprophylaxis.DVT was found in 65 (14%) of 451 reverse transcription-polymerase chain reaction positive patients. The random forest model, trained and cross-validated on 2/3 of the original sample (n = 301), had area under the receiver operating characteristic curve = 0.91 (95% confidence interval [CI]: 0.85-0.97) for prediction of DVT in the test set (n = 150), with sensitivity = 93% (95%CI: 68%-99%) and specificity = 82% (95%CI: 75%-88%). The following variables had the highest importance: d-dimer, thromboprophylaxis, systolic blood pressure, admission to ultrasound interval, and platelets. Thromboprophylaxis reduced DVT risk 4-fold from 26% to 6% (P < .001), while anti-coagulation therapy led to hemorrhagic complications in 14 (22%) of 65 patients with DVT including 2 fatal intra-cranial hemorrhages. D-dimer was the most important predictor with area under curve = 0.79 (95%CI: 0.73-0.86) by itself, and a 5000 ng/mL threshold at 7 days postCOVID-19 symptom onset had 75% (95%CI: 53%-90%) sensitivity and 81% (95%CI: 72%-88%) specificity. In comparison with d-dimer alone, the random forest model showed 68% versus 32% specificity at 95% sensitivity, and 44% versus 23% sensitivity at 95% specificity.D-dimer >5000 ng/mL predicts DVT with high accuracy suggesting regular monitoring with d-dimer in the early stages of COVID-19 may be useful. A random forest model improved the prediction of DVT. Thromboprophylaxis reduced DVT in COVID-19 patients and should be considered in all patients. Full anti-coagulation therapy has a risk of life-threatening hemorrhage.

Thromboprophylaxis strategies to improve the prognosis of COVID-19.

The outbreak of 2019 novel coronavirus disease (Covid-19) has deeply challenged the world population, but also our medical knowledge. Special attention has been paid early to an activation of coagulation, then to an elevated rate of venous thromboembolism (VTE) in patients hospitalized with severe COVID-19. These data suggested that anticoagulant drugs should be evaluated in the treatment of patients with COVID-19. The publication of unexpected high rates of VTE in patients hospitalized with COVID-19, despite receiving thromboprophylaxis, open the way to dedicated trials, evaluating modified regimens of thromboprophylaxis. Moreover, the further improvement in our comprehension of the disease, particularly the pulmonary endothelial dysfunction increased the hope that anticoagulant drugs may also protect patients from pulmonary thrombosis. In this comprehensive review, we cover the different situations where thromboprophylaxis standard may be modified (medically-ill inpatients, ICU inpatients, outpatients), and describe some of the current randomized controls trials evaluating new regimens of thromboprophylaxis in patients with COVID-19, including the preliminary available results. We also discuss the potential of anticoagulant drugs to target the thromboinflammation described in patients with severe COVID-19.

Effect of Intermediate-Dose vs Standard-Dose Prophylactic Anticoagulation on Thrombotic Events, Extracorporeal Membrane Oxygenation Treatment, or Mortality Among Patients With COVID-19 Admitted to the Intensive Care Unit: The INSPIRATION Randomized Clinical Trial.

Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.

Venous Thromboembolism in Patients Discharged after COVID-19 Hospitalization.

BACKGROUND: Venous thromboembolism (VTE) is a frequent complication of COVID-19, so that the importance of adequate in-hospital thromboprophylaxis in patients hospitalized with COVID-19 is well established. However, the incidence of VTE after discharge and whether postdischarge thromboprophylaxis is beneficial and safe are unclear. In this prospective observational single-center study, we report the incidence of VTE 6 weeks after hospitalization and the use of postdischarge thromboprophylaxis. METHODS: Patients hospitalized with confirmed COVID-19 were invited to a multidisciplinary follow-up clinic 6 weeks after discharge. D-dimer and C-reactive protein were measured, and all patients were screened for deep vein thrombosis with venous duplex-ultrasound. Additionally, selected high-risk patients received computed tomography pulmonary angiogram or ventilation-perfusion (V/Q) scan to screen for incidental pulmonary embolism. RESULTS: Of 485 consecutive patients hospitalized from March through June 2020, 146 patients were analyzed, of which 39% had been admitted to the intensive care unit (ICU). Postdischarge thromboprophylaxis was prescribed in 28% of patients, but was used more frequently after ICU stay (61%) and in patients with higher maximal D-dimer and C-reactive protein levels during hospitalization. Six weeks after discharge, elevated D-dimer values were present in 32% of ward and 42% of ICU patients. Only one asymptomatic deep vein thrombosis (0.7%) and one symptomatic pulmonary embolism (0.7%) were diagnosed with systematic screening. No bleedings were reported. CONCLUSION: In patients who had been hospitalized with COVID-19, systematic screening for VTE 6 weeks after discharge revealed a low incidence of VTE. A strategy of selectively providing postdischarge thromboprophylaxis in high-risk patients seems safe and potentially effective.

Venous thromboembolism in COVID-19: A systematic review and meta-analysis.

Severe coronavirus disease 2019 (COVID-19) is associated with increased risk of venous thromboembolism events (VTE). This study performed a systematic review in PubMed/EMBASE of studies reporting the prevalence of VTE in patients with COVID-19 who were totally screened/assessed for deep vein thrombosis (DVT) and/or for pulmonary embolism (PE). Among 47 candidate studies (n = 6459; 33 in Europe), 17 studies (n = 3973; weighted age 63.0 years, males 60%, intensive care unit (ICU) 16%) reported the prevalence of PE with a pooled estimate of 32% (95% CI: 25, 40%), and 32 studies (n = 2552; weighted age 62.6 years, males 57%, ICU 49%) reported the prevalence of DVT with a pooled estimate of 27% (95% CI: 21, 34%). A total of 36 studies reported the use of at least prophylactic antithrombotic treatment in the majority of their patients. Meta-regression analysis showed that the prevalence of VTE was higher across studies with a higher percentage of ICU patients and higher study population mean D-dimer values, and lower in studies with mixed dosing of anticoagulation in ⩾ 50% of the population compared to studies with standard prophylactic dosing of anticoagulation in < 50% of the population. The pooled odds ratio for death in patients with COVID-19 and VTE versus those without VTE (17 studies, n = 2882) was 2.1 (95% CI: 1.2, 3.6). Hospitalized patients with severe COVID-19 are at high VTE risk despite prophylactic anticoagulation. Further research should investigate the individualized VTE risk of patients with COVID-19 and the optimal preventive antithrombotic therapy. PROSPERO Registration No.: CRD42020185543.

Incidence of Venous Thromboembolism and Mortality in Patients with Initial Presentation of COVID-19.

Venous thromboembolism (VTE) has emerged as an important issue in patients with COVID-19. The purpose of this study is to identify the incidence of VTE and mortality in COVID-19 patients initially presenting to a large health system. Our retrospective study included adult patients (excluding patients presenting with obstetric/gynecologic conditions) across a multihospital health system in the New York Metropolitan Region from March 1-April 27, 2020. VTE and mortality rates within 8 h of assessment were described. In 10,871 adults with COVID-19, 118 patients (1.09%) were diagnosed with symptomatic VTE (101 pulmonary embolism, 17 deep vein thrombosis events) and 28 patients (0.26%) died during initial assessment. Among these 146 patients, 64.4% were males, 56.8% were 60 years or older, 15.1% had a BMI > 35, and 11.6% were admitted to the intensive care unit. Comorbidities included hypertension (46.6%), diabetes (24.7%), hyperlipidemia (14.4%), chronic lung disease (12.3%), coronary artery disease (11.0%), and prior VTE (7.5%). Key medications included corticosteroids (22.6%), statins (21.2%), antiplatelets (20.6%), and anticoagulants (20.6%). Highest D-Dimer was greater than six times the upper limit of normal in 51.4%. Statin and antiplatelet use were associated with decreased VTE or mortality (each p < 0.01). In COVID-19 patients who initially presented to a large multihospital health system, the overall symptomatic VTE and mortality rate was over 1.0%. Statin and antiplatelet use were associated with decreased VTE or mortality. The potential benefits of antithrombotics in high risk COVID-19 patients during the pre-hospitalization period deserves study.

SARS-CoV-2 and finding of vein thrombosis: can IMPROVE and IMPROVEDD scores predict COVID-19 outcomes?

OBJECTIVE: Diffuse thrombosis represents one of the most predominant causes of death by COVID-19 and SARS-CoV-2 infection seems to increase the risk of developing venous thromboembolic diseases (VTE). Aim of this study is to analyze the relationship between validated predictive scores for VTE such as IMPROVE and IMPROVEDD and: (1) Intensification of Care (IoC, admission to Pulmonology Department or Intensive Care Unit) (2) in-hospital mortality rate 3) 30-days mortality rate. PATIENTS AND METHODS: We retrospectively evaluated 51 adult patients with laboratory diagnosis of SARS-CoV-2 infection and calculated IMPROVE and IMPROVEDD scores. All patients underwent venous color-Doppler ultrasound of the lower limbs to assess the presence of superficial vein thrombosis (SVT) and/or deep vein thrombosis (DVT). Patients with normal values of D-dimer did not receive heparin therapy (LMWH); patients with ≥ 4 ULN values of D-dimer or with a diagnosis of DVT were treated with therapeutic LMWH dosage, while the remaining patients were treated with prophylactic LMWH dosages. RESULTS: We found strong relations between IMPROVE score and the need for IoC and with the in-hospital mortality rate and between the IMPROVEDD score and the need for IoC. We defined that an IMPROVE score greater than 4 points was significantly associated to in-hospital mortality rate (p = 0.05), while an IMPROVEDD score greater than 3 points was associated with the need for IoC (p = 0.04). Multivariate logistic analysis showed how IMPROVE score was significantly associated to in-hospital and 30-days mortality rates. CONCLUSIONS: IMPROVE score can be considered an independent predictor of in-hospital and 30-days mortality.

A systematic review and meta-analysis of incidence, prognosis, and laboratory indicators of venous thromboembolism in hospitalized patients with coronavirus disease 2019.

OBJECTIVE: We have summarized the incidence, anticoagulation panels, laboratory characteristics, and mortality of venous thromboembolism (VTE) in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: After systematically searching PubMed, Embase, the Cochrane Library, MedRxiv, and BioRxiv, a systematic review and meta-analysis of 18 retrospective, 6 prospective observational, and 2 cross-sectional studies was performed according to the guidelines of the PRISMA (preferred reporting items for systematic reviews and meta-analyses) statement. RESULTS: Overall, 4382 hospitalized patients with COVID-19 were included. Men accounted for significantly more patients than did women (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.25-2.02; P < .001). The total incidence of VTE among the patients with COVID-19 was 28.3% (95% CI, 21.6%-35.4%), with an incidence of 38.0% (95% CI, 29.1%-47.4%) and 17.2% (95% CI, 11.4%-23.8%) among those with severe and general COVID-19, respectively. The total incidence of deep vein thrombosis (DVT) of the lower extremities was 18.3% (95% CI, 10.8%-27.2%). The incidence of DVT was 22.1% (95% CI, 11.0%-35.5%) and 12.8% (95% CI, 5.0%-23.3%) in those with severe and general COVID-19, respectively. The total incidence of pulmonary embolism was 17.6% (95% CI, 12.3%-23.5%), with a rate of 21.7% (95% CI, 14.8%-29.3%) in severe cases and 12.5% (95% CI, 6.1%-23.5%) in general cases. When COVID-19 severity was unclassified, the mortality for the patients with VTE was not significantly greater (25.2%; 95% CI, 12.2%-40.5%) than that for those without VTE (10.2%; 95% CI, 3.4%-19.5%; OR, 1.88; 95% CI, 0.46-7.64; P = .377). However, among the patients with severe COVID-19, those who had developed VTE had significantly greater mortality compared with those without VTE (OR, 2.02; 95% CI, 1.15-3.53; P = .014). The patients with COVID-19 and VTE had significantly higher D-dimer levels than did similar patients without VTE in multiple studies. CONCLUSIONS: The occurrence of VTE, DVT, and pulmonary embolism has been substantial among hospitalized patients with COVID-19, especially among those with severe COVID-19. Patients with severe COVID-19 and VTE had significantly greater mortality compared with similar patients without VTE. An increased D-dimer level might be an indicator of the occurrence of VTE in patients with COVID-19.

Incidence of symptomatic venous thromboembolism following hospitalization for coronavirus disease 2019: Prospective results from a multi-center study.

BACKGROUND: Thrombosis and pulmonary embolism appear to be major causes of mortality in hospitalized coronavirus disease 2019 (COVID-19) patients. However, few studies have focused on the incidence of venous thromboembolism (VTE) after hospitalization for COVID-19. METHODS: In this multi-center study, we followed 1529 COVID-19 patients for at least 45 days after hospital discharge, who underwent routine telephone follow-up. In case of signs or symptoms of pulmonary embolism (PE) or deep vein thrombosis (DVT), they were invited for an in-hospital visit with a pulmonologist. The primary outcome was symptomatic VTE within 45 days of hospital discharge. RESULTS: Of 1529 COVID-19 patients discharged from hospital, a total of 228 (14.9%) reported potential signs or symptoms of PE or DVT and were seen for an in-hospital visit. Of these, 13 and 12 received Doppler ultrasounds or pulmonary CT angiography, respectively, of whom only one patient was diagnosed with symptomatic PE. Of 51 (3.3%) patients who died after discharge, two deaths were attributed to VTE corresponding to a 45-day cumulative rate of symptomatic VTE of 0.2% (95%CI 0.1%-0.6%; n = 3). There was no evidence of acute respiratory distress syndrome (ARDS) in these patients. Other deaths after hospital discharge included myocardial infarction (n = 13), heart failure (n = 9), and stroke (n = 9). CONCLUSIONS: We did not observe a high rate of symptomatic VTE in COVID-19 patients after hospital discharge. Routine extended thromboprophylaxis after hospitalization for COVID-19 may not have a net clinical benefit. Randomized trials may be warranted.

COVID-19 and Major Organ Thromboembolism: Manifestations in Neurovascular and Cardiovascular Systems.

COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been shown to cause multisystemic damage. We undertook a systematic literature review and comprehensive analysis of a total of 55 articles on arterial and venous thromboembolism in COVID-19 and articles on previous pandemics with respect to thromboembolism and compared the similarities and differences between them. The presence of thrombosis in multiple organ systems points to thromboembolism being an integral component in the pathogenesis of this disease. Thromboembolism is likely to be the main player in the morbidity and mortality of COVID -19 in which the pulmonary system is most severely affected. We also hypothesize that D-dimer values could be used as an early marker for prognostication of disease as it has been seen to be raised even in the pre-symptomatic stage. This further strengthens the notion that thromboembolism prevention is necessary. We also examined literature on the neurovascular and cardiovascular systems, as the manifestation of thromboembolic phenomenon in these two systems varied, suggesting different pathophysiology of damage. Further research into the role of thromboembolism in COVID-19 is important to advance the understanding of the virus, its effects and to tailor treatment accordingly to prevent further casualties from this pandemic.

Prognosis of COVID-19 in patients with vein thrombosis: a systematic review and meta-analysis.

OBJECTIVE: SARS-CoV-2 is currently affecting millions of humans worldwide, thus contributing to the COVID-19 pandemic. Thromboembolic events have a higher incidence among patients with COVID-19, but there are few reports on the relationship between the prognosis of COVID-19 patients and thromboembolic events. The objectives of this meta-analysis were to explore the relationship between the prognosis of COVID-19 patients and thromboembolic events. MATERIALS AND METHODS: Medline (PubMed), the Web of Science, Embase, and the Cochrane Library were searched for case-control studies that included data on vein thrombosis in patients with COVID-19 and were published in English, between January 1 and July 25, 2020. According to the inclusion and exclusion criteria, the included data were confirmed, the prognoses of patients with and without concurrent thromboembolic events were compared, and the odds ratio (OR) was used as the effect size. RESULTS: Eighteen studies (2,030 patients) were included. Thromboembolic events complicated a total of 609 COVID-19 patients. The combined OR of the mortality of COVID-19 patients with thromboembolic events was 1.93 (95% CI: 1.13-3.27), that of ICU treatment rate was 2.63 (95% CI: 1.49-4.67), and that of treatment with invasive mechanical ventilation was 3.14 (95% CI: 1.97-5.02). CONCLUSIONS: As compared with COVID-19 patients with and without thromboembolism, the mortality, ICU treatment rate, and invasive mechanical ventilation treatment rate of COVID-19 patients with thromboembolism were found to be increased significantly, and the prognosis was worse.

COVID-19 coagulopathy: An in-depth analysis of the coagulation system.

BACKGROUND: Abnormal coagulation parameters have been reported in COVID-19-infected patients. Although the underlying mechanism of COVID-19 coagulopathy remains unknown, it has been suggested to be a form of disseminated intravascular coagulation (DIC). OBJECTIVES: The aim of our study was to analyze the coagulation parameters of patients with COVID-19, determine whether coagulation factors consumption occurs and identify potential prognostic biomarkers of the disease. PATIENTS/METHODS: Blood samples from hospitalized patients with COVID-19 pneumonia were collected. We performed basic coagulation tests and quantification of coagulation factors and physiological inhibitor proteins. Laboratory data were compared with clinical data and outcomes. RESULTS: The study involved 206 patients (63.6% male). D-dimer was particularly elevated (median 450 ng/mL; IQR 222.5-957.3). Free protein S levels were below the normal range (median 56.6%; IQR: 43.6-68.9), and factor VIII showed an increasing trend (median 173.4%; IQR: 144.1-214.9). However, all coagulation factors were within normal limits. We found no correlation between abnormal coagulation parameters and thrombosis, except for higher D-dimer (HR 1.99; 95% CI 1.3-3.1; P = .002). CONCLUSIONS: COVID-19 is associated with coagulopathy that correlates with poor prognosis. However, we did not demonstrate a consumption of coagulation factors, as seen in DIC.

COVID-19-Associated Coagulopathy and Inflammatory Response: What Do We Know Already and What Are the Knowledge Gaps?

Patients with coronavirus disease 2019 (COVID-19) frequently experience a coagulopathy associated with a high incidence of thrombotic events leading to poor outcomes. Here, biomarkers of coagulation (such as D-dimer, fibrinogen, platelet count), inflammation (such as interleukin-6), and immunity (such as lymphocyte count) as well as clinical scoring systems (such as sequential organ failure assessment [SOFA], International Society on Thrombosis and Hemostasis disseminated intravascular coagulation [ISTH DIC], and sepsis-induced coagulopathy [SIC] score) can be helpful in predicting clinical course, need for hospital resources (such as intensive care unit [ICU] beds, intubation and ventilator therapy, and extracorporeal membrane oxygenation [ECMO]) and patient's outcome in patients with COVID-19. However, therapeutic options are actually limited to unspecific supportive therapy. Whether viscoelastic testing can provide additional value in predicting clinical course, need for hospital resources and patient's outcome or in guiding anticoagulation in COVID-19-associated coagulopathy is still incompletely understood and currently under investigation (eg, in the rotational thromboelastometry analysis and standard coagulation tests in hospitalized patients with COVID-19 [ROHOCO] study). This article summarizes what we know already about COVID-19-associated coagulopathy and-perhaps even more importantly-characterizes important knowledge gaps.