COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection.
ABSTRACT: Patients with coronavirus disease 2019 (COVID-19) have elevated D-dimer levels. Early reports describe high venous thromboembolism (VTE) and disseminated intravascular coagulation (DIC) rates, but data are limited. This multicenter retrospective study describes the rate and severity of hemostatic and thrombotic complications of 400 hospital-admitted COVID-19 patients (144 critically ill) primarily receiving standard-dose prophylactic anticoagulation. Coagulation and inflammatory parameters were compared between patients with and without coagulation-associated complications. Multivariable logistic models examined the utility of these markers in predicting coagulation-associated complications, critical illness, and death. The radiographically confirmed VTE rate was 4.8% (95% confidence interval [CI], 2.9-7.3), and the overall thrombotic complication rate was 9.5% (95% CI, 6.8-12.8). The overall and major bleeding rates were 4.8% (95% CI, 2.9-7.3) and 2.3% (95% CI, 1.0-4.2), respectively. In the critically ill, radiographically confirmed VTE and major bleeding rates were 7.6% (95% CI, 3.9-13.3) and 5.6% (95% CI, 2.4-10.7), respectively. Elevated D-dimer at initial presentation was predictive of coagulation-associated complications during hospitalization (D-dimer >2500 ng/mL, adjusted odds ratio [OR] for thrombosis, 6.79 [95% CI, 2.39-19.30]; adjusted OR for bleeding, 3.56 [95% CI, 1.01-12.66]), critical illness, and death. Additional markers at initial presentation predictive of thrombosis during hospitalization included platelet count >450 × 109/L (adjusted OR, 3.56 [95% CI, 1.27-9.97]), C-reactive protein (CRP) >100 mg/L (adjusted OR, 2.71 [95% CI, 1.26-5.86]), and erythrocyte sedimentation rate (ESR) >40 mm/h (adjusted OR, 2.64 [95% CI, 1.07-6.51]). ESR, CRP, fibrinogen, ferritin, and procalcitonin were higher in patients with thrombotic complications than in those without. DIC, clinically relevant thrombocytopenia, and reduced fibrinogen were rare and were associated with significant bleeding manifestations. Given the observed bleeding rates, randomized trials are needed to determine any potential benefit of intensified anticoagulant prophylaxis in COVID-19 patients.
Project description:Background In this prospective cohort study, we aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) versus heparin/vitamin K antagonists for the treatment of venous thromboembolism (VTE) in patients with inherited thrombophilia. Methods and Results We enrolled consecutive patients with acute VTE and inherited thrombophilia treated with DOACs (cases) or heparin/vitamin K antagonists (controls), matched for age, sex, ethnicity, and thrombophilia type. End points were VTE recurrence and bleeding complications; residual vein thrombosis and post-thrombotic syndrome; VTE recurrence after anticoagulant discontinuation. Two hundred fifty-five cases (age 52.4±17.3 years, Female 44.3%, severe thrombophilia 33.1%) and 322 controls (age 49.7±18.1 years, Female 50.3%, severe thrombophilia 35.1%) were included. The cumulative incidence of VTE recurrence during anticoagulation was 1.09% in cases versus 1.83%, adjusted hazard ratio (HR) 0.67 (95% CI, 0.16-2.77). The cumulative incidence of bleeding was 10.2% in cases versus 4.97%, HR 2.24 (95% CI 1.10-4.58). No major bleedings occurred in cases (versus 3 in controls). No significant differences regarding residual vein thrombosis and post-thrombotic syndrome. After anticoagulant discontinuation, DOACs yielded a significantly lower 2-year VTE recurrence risk versus traditional anticoagulants (HR, 0.61 [95% CI, 0.47-0.82]). Conclusions DOACs and heparin/vitamin K antagonists showed a similar efficacy in treating VTE in patients with thrombophilia. Although major bleeding episodes were recorded solely with heparin/vitamin K antagonists, we noted an overall increased bleeding rate with DOACs. The use of DOACs was associated with a lower 2-year risk of VTE recurrence after anticoagulant discontinuation.
Project description:Identification of patients at risk of major bleeding is pivotal for optimal management of anticoagulant therapy in venous thromboembolism (VTE). Studies have suggested that D-dimer may predict major bleeding during anticoagulation; however, this is scarcely investigated in VTE patients. We aimed to investigate the role of D-dimer, measured at VTE diagnosis, as a predictive biomarker of major bleeding. The study population comprised 555 patients with a first community-acquired VTE (1994-2016), who were identified among participants from the Tromsø study. Major bleeding events were recorded during the first year after VTE and defined according to the criteria of the International Society on Thrombosis and Haemostasis. Cox-regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) adjusted for age, sex, and duration of anticoagulant therapy. In total, 29 patients experienced major bleeding (incidence rate: 5.7/100 person-years, 95% CI: 4.0-8.2). The major bleeding risk was highest during the first 3 months, especially in patients with D-dimer ≥8.3 µg/mL (upper 20th percentile), with 28.8 major bleedings/100 person-years (95% CI: 13.7-60.4). Patients with D-dimer ≥8.3 µg/mL had a 2.6-fold (95% CI: 1.1-6.6) higher risk of major bleeding than patients with D-dimer ≤2.3 µg/mL (lower 40th percentile). Major bleeding risk according to D-dimer ≥8.3 versus ≤2.3 µg/mL was particularly pronounced among those with deep vein thrombosis (HR: 4.6, 95% CI: 1.3-16.2) and provoked events (HR: 4.2, 95% CI: 1.0-16.8). In conclusion, our results suggest that D-dimer measured at diagnosis may serve as a predictive biomarker of major bleeding after VTE, especially within the initial 3 months.
Project description:<h4>Background</h4>Central venous catheter (CVC) insertion is an important risk factor for venous thromboembolism (VTE) among patients with cancer. Routine use of primary thromboprophylaxis in this patient population is not currently recommended. We sought to assess the feasibility of conducting a randomized controlled trial (RCT) assessing the safety and efficacy of rivaroxaban (10 mg daily) to prevent VTE complications in this patient population.<h4>Methods</h4>This is a two-center prospective, randomized, open blinded end point pilot trial including patients with active cancer and a newly inserted CVC. Patients were randomly assigned 1:1 to rivaroxaban or observation for 90 days. The primary feasibility outcome of this pilot study was the number of participants recruited per month. Secondary clinical outcomes included thrombotic complications, major VTE, and major bleeding episodes.<h4>Results</h4>Overall, 105 patients were enrolled over 11 months. The average enrollment rates were 7.5 and 2 patients per month at the two participating centers, respectively. Overall, thrombotic complications occurred in 3 patients in the rivaroxaban group (5.8%; 95% confidence interval [CI], 1.2-16.0) compared with 5 patients in the control group (9.4%; 95% CI, 3.1-20.7) (HR, 0.58; 95% CI, 0.14-2.5). Major VTE occurred in 2 (3.9%; 95% CI, 0.5-13.2) and 3 (5.7%; 95% CI, 1.2-15.7) patients in the rivaroxaban and control group, respectively (HR, 0.66; 95% CI, 0.11-3.9). One patient (1.9%) receiving rivaroxaban had a major bleeding event.<h4>Conclusions</h4>Thrombotic complications are common in patients with cancer and a newly inserted CVC. The pilot trial achieved its enrollment targets and supports that a large multicenter RCT is feasible in this area. ClinicalTrials.gov (NCT03506815).
Project description:BACKGROUND:Coronavirus disease 2019 (COVID-19) can lead to systemic coagulation activation and thrombotic complications. OBJECTIVES:To investigate the incidence of objectively confirmed venous thromboembolism (VTE) in hospitalized patients with COVID-19. METHODS:Single-center cohort study of 198 hospitalized patients with COVID-19. RESULTS:Seventy-five patients (38%) were admitted to the intensive care unit (ICU). At time of data collection, 16 (8%) were still hospitalized and 19% had died. During a median follow-up of 7 days (IQR, 3-13), 39 patients (20%) were diagnosed with VTE of whom 25 (13%) had symptomatic VTE, despite routine thrombosis prophylaxis. The cumulative incidences of VTE at 7, 14 and 21 days were 16% (95% CI, 10-22), 33% (95% CI, 23-43) and 42% (95% CI 30-54) respectively. For symptomatic VTE, these were 10% (95% CI, 5.8-16), 21% (95% CI, 14-30) and 25% (95% CI 16-36). VTE appeared to be associated with death (adjusted HR, 2.4; 95% CI, 1.02-5.5). The cumulative incidence of VTE was higher in the ICU (26% (95% CI, 17-37), 47% (95% CI, 34-58), and 59% (95% CI, 42-72) at 7, 14 and 21 days) than on the wards (any VTE and symptomatic VTE 5.8% (95% CI, 1.4-15), 9.2% (95% CI, 2.6-21), and 9.2% (2.6-21) at 7, 14, and 21 days). CONCLUSIONS:The observed risk for VTE in COVID-19 is high, particularly in ICU patients, which should lead to a high level of clinical suspicion and low threshold for diagnostic imaging for DVT or PE. Future research should focus on optimal diagnostic and prophylactic strategies to prevent VTE and potentially improve survival.
Project description: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.
Project description:<h4>Background</h4>There is limited data on the markers of coagulation and hemostatic activation (MOCHA) profile in Coronavirus disease 2019 (COVID-19) and its ability to identify COVID-19 patients at risk for thrombotic events and other complications.<h4>Methods</h4>Hospitalized patients with confirmed SARS-COV-2 from four Atlanta hospitals were included in this observational cohort study and underwent admission testing of MOCHA parameters (plasma d-dimer, prothrombin fragment 1.2, thrombin-antithrombin complex, fibrin monomer). Clinical outcomes included deep vein thrombosis, pulmonary embolism, myocardial infarction, ischemic stroke, access line thrombosis, ICU admission, intubation and mortality.<h4>Main results</h4>Of 276 patients (mean age 59 ± 6.4 years, 47% female, 62% African American), 45 (16%) had a thrombotic endpoint. Each MOCHA parameter was independently associated with a thrombotic event (p<0.05) and ≥ 2 abnormalities was associated with thrombotic endpoints (OR 3.3, 95% CI 1.2-8.8) as were admission D-dimer ≥ 2000 ng/mL (OR 3.1, 95% CI 1.5-6.6) and ≥ 3000 ng/mL (OR 3.6, 95% CI 1.6-7.9). However, only ≥ 2 MOCHA abnormalities were associated with ICU admission (OR 3.0, 95% CI 1.7-5.2) and intubation (OR 3.2, 95% CI 1.6-6.4). MOCHA and D-dimer cutoffs were not associated with mortality. MOCHA with <2 abnormalities (26% of the cohort) had 89% sensitivity and 93% negative predictive value for a thrombotic endpoint.<h4>Conclusions</h4>An admission MOCHA profile is useful to risk-stratify COVID-19 patients for thrombotic complications and more effective than isolated d-dimer for predicting risk of ICU admission and intubation.
Project description:Venous thromboembolism (VTE) in patients with COVID-19 in intensive care units (ICU) is frequent, but risk factors (RF) remain unidentified. In this meta-analysis (CRD42020188764) we searched for observational studies from ICUs reporting the association between VTE and RF in Medline/Embase up to 15 April 2021. Reviewers independently extracted data in duplicate and assessed the certainty of the evidence using the GRADE approach. Analyses were conducted using the random-effects model and produced a non-adjusted odds ratio (OR). We analysed 83 RF from 21 studies (5296 patients). We found moderate-certainty evidence for an association between VTE and the D-dimer peak (OR 5.83, 95%CI 3.18-10.70), and length of hospitalization (OR 7.09, 95%CI 3.41-14.73) and intubation (OR 2.61, 95%CI 1.94-3.51). We identified low-certainty evidence for an association between VTE and CRP (OR 1.83, 95% CI 1.32-2.53), D-dimer (OR 4.58, 95% CI 2.52-8.50), troponin T (OR 8.64, 95% CI 3.25-22.97), and the requirement for inotropic drugs (OR 1.67, 95% CI 1.15-2.43). Traditional VTE RF (i.e., history of cancer, previous VTE events, obesity) were not found to be associated to VTE in COVID-19. Anticoagulation was not associated with a decreased VTE risk. VTE RF in severe COVID-19 correspond to individual illness severity, and inflammatory and coagulation parameters.
Project description:Previous reports show increased incidence of venous thromboembolism [VTE, deep-vein thrombosis (DVT) and pulmonary embolus (PE)] in sickle cell disease (SCD) patients. The incidence, time course, and risk factors for VTE recurrence have been less well described. We determined the cumulative incidence of first VTE recurrence and bleeding in a cohort of SCD patients with incident VTE. Risk factors for recurrence and bleeding were also determined using multivariable Cox regression models, adjusting for gender, race/ethnicity, era of incident VTE, location and hospitalization-associated status of incident VTE, and SCD-related complications. Results are presented as adjusted hazard ratios (HR) and 95% confidence intervals (CI). Among 877 SCD patients with an incident VTE, the 1-year and 5-year cumulative incidence of recurrence was 13.2% (95% CI 11.0%-15.5%) and 24.1% (95% CI 21.2%-27.1%). Risk factors for VTE recurrence included more severe SCD (HR = 2.41; CI: 1.67-3.47), lower extremity DVT as the incident event (HR = 1.64; CI: 1.17-2.30), and pneumonia/acute chest syndrome (HR = 1.68; CI: 1.15-2.45). The cumulative incidence of bleeding was 4.9% (CI 3.5%-6.4%) at 6 months and 7.9% (CI: 6.2%-9.8%) at 1 year. More severe SCD (HR = 1.61; CI: 1.11-2.35) was associated with bleeding. The high incidence of VTE recurrence in patients with SCD suggests that extended anticoagulation may be indicated; however, this must be weighed against a relatively high risk of bleeding. Prospective, randomized studies of anticoagulation in SCD patients with VTE are needed.
Project description:African Americans (AAs) and obese individuals have increased thrombotic risk. This study evaluated the effectiveness and safety of rivaroxaban versus warfarin in obese, AAs with nonvalvular atrial fibrillation (NVAF) or venous thromboembolism (VTE). Optum® De-Identified Electronic Health Record (EHR) data was used to perform separate propensity-score matched analyses of adult, oral anticoagulant (OAC)-naïve AAs with NVAF or acute VTE, respectively; who had a body mass index?30kg/m2 and ?12-months EHR activity with ?1-encounter before OAC initiation. Cox regression was performed and reported as hazard ratios (HRs) with 95% confidence intervals (CIs). For the NVAF analysis, 1,969 rivaroxaban- and 1,969 warfarin-users were matched. Rivaroxaban was not associated with a difference in stroke/systemic embolism versus warfarin (HR = 0.88, 95%CI = 0.60-1.28), but less major bleeding (HR = 0.68, 95%CI = 0.50-0.94) was observed. Among 683 rivaroxaban-users with VTE, 1:1 matched to warfarin-users, rivaroxaban did not alter recurrent VTE (HR = 1.36, 95%CI = 0.79-2.34) or major bleeding (HR = 0.80, 95%CI = 0.37-1.71) risk versus warfarin at 6-months (similar findings observed at 3- and 12-months). Rivaroxaban appeared to be associated with similar thrombotic, and similar or lower major bleeding risk versus warfarin in these obese, AA cohorts.
Project description:We report the clinical and laboratory coagulation characteristics of 27 pediatric and young adult patients (2 months to 21 years) treated for symptomatic COVID-19 at a children's hospital in the Bronx, New York, between March 1 and May 31, 2020. D-Dimer was > 0.5 μg/mL (upper limit of normal) in 25 (93%) patients at admission; 11 (41%) developed peak D-dimer > 5 μg/mL during admission. Seven (26%) patients developed venous thromboembolism: three with deep vein thrombosis and four with pulmonary embolism. Requirement of increased ventilatory support was a risk factor for thrombosis (P = 0.006). Three of eight (38%) patients on prophylactic anticoagulation developed thrombosis; however, no patients developed VTE on low-molecular-weight heparin prophylaxis titrated to anti-Xa level. Manifestation of COVID-19 disease was severe or critical in 16 (59%) patients. Four (15%) patients died of COVID-19 complications: all had comorbidities. Elevated D-dimer and increased VTE rate were observed in this young cohort, particularly in those with severe respiratory complications, suggesting thrombotic coagulopathy. More data are needed to guide thromboprophylaxis in this age group.