Therapeutic-dose Anticoagulation Research Articles

Clinical characteristics and anticoagulation patterns of patients with acute pulmonary thromboembolism and hemoptysis.

Hemoptysis is a frequently encountered manifestation in cases of acute pulmonary thromboembolism (PTE), significantly impacting clinical decision-making. Despite its clinical relevance, studies focusing on patients with acute PTE and hemoptysis are notably scarce. In this retrospective study, we examined data from hospitalized patients with acute PTE at Peking Union Medical College Hospital (PUMCH) between January 2012 and October 2020. Among the 896 patients analyzed, 105 (11.7%) presented with hemoptysis. Patients with hemoptysis were younger, had higher RRs, and frequently reported chest pain, predominantly showing a negative sPESI score. A significant association with autoimmune diseases was observed (39.0% vs. 16.1%; p < 0.001), along with higher occurrences of pulmonary infections (29.5%), lung cancer (21.0%), and chronic heart failure (16.2%). Hemoptysis in PTE is multifactorial; 51.4% of cases were PTE-related, with 85.2% experiencing mild hemoptysis. Among patients with disease-related hemoptysis (13.3%), 90.9% with massive hemoptysis had underlying diseases, predominantly lung cancer. In 35.2% of cases, the cause of hemoptysis remained undetermined, with vasculitis accounting for 29.7%. Anticoagulation strategies varied with the severity of hemoptysis; 82.9% with mild and only 27.3% with massive hemoptysis received therapeutic-dose anticoagulation. Multivariate analysis identified massive hemoptysis as the most significant determinant of anticoagulation decisions. Patients with massive hemoptysis had the poorest outcomes, with an in-hospital mortality rate of 36.4% and 72.7% receiving reduced or no anticoagulation.

A comparison of computational algorithms for the Bayesian analysis of clinical trials.

Clinical trials are increasingly using Bayesian methods for their design and analysis. Inference in Bayesian trials typically uses simulation-based approaches such as Markov Chain Monte Carlo methods. Markov Chain Monte Carlo has high computational cost and can be complex to implement. The Integrated Nested Laplace Approximations algorithm provides approximate Bayesian inference without the need for computationally complex simulations, making it more efficient than Markov Chain Monte Carlo. The practical properties of Integrated Nested Laplace Approximations compared to Markov Chain Monte Carlo have not been considered for clinical trials. Using data from a published clinical trial, we aim to investigate whether Integrated Nested Laplace Approximations is a feasible and accurate alternative to Markov Chain Monte Carlo and provide practical guidance for trialists interested in Bayesian trial design. Data from an international Bayesian multi-platform adaptive trial that compared therapeutic-dose anticoagulation with heparin to usual care in non-critically ill patients hospitalized for COVID-19 were used to fit Bayesian hierarchical generalized mixed models. Integrated Nested Laplace Approximations was compared to two Markov Chain Monte Carlo algorithms, implemented in the software JAGS and stan, using packages available in the statistical software R. Seven outcomes were analysed: organ-support free days (an ordinal outcome), five binary outcomes related to survival and length of hospital stay, and a time-to-event outcome. The posterior distributions for the treatment and sex effects and the variances for the hierarchical effects of age, site and time period were obtained. We summarized these posteriors by calculating the mean, standard deviations and the 95% equitailed credible intervals and presenting the results graphically. The computation time for each algorithm was recorded. The average overlap of the 95% credible interval for the treatment and sex effects estimated using Integrated Nested Laplace Approximations was 96% and 97.6% compared with stan, respectively. The graphical posterior densities for these effects overlapped for all three algorithms. The posterior mean for the variance of the hierarchical effects of age, site and time estimated using Integrated Nested Laplace Approximations are within the 95% credible interval estimated using Markov Chain Monte Carlo but the average overlap of the credible interval is lower, 77%, 85.6% and 91.3%, respectively, for Integrated Nested Laplace Approximations compared to stan. Integrated Nested Laplace Approximations and stan were easily implemented in clear, well-established packages in R, while JAGS required the direct specification of the model. Integrated Nested Laplace Approximations was between 85 and 269 times faster than stan and 26 and 1852 times faster than JAGS. Integrated Nested Laplace Approximations could reduce the computational complexity of Bayesian analysis in clinical trials as it is easy to implement in R, substantially faster than Markov Chain Monte Carlo methods implemented in JAGS and stan, and provides near identical approximations to the posterior distributions for the treatment effect. Integrated Nested Laplace Approximations was less accurate when estimating the posterior distribution for the variance of hierarchical effects, particularly for the proportional odds model, and future work should determine if the Integrated Nested Laplace Approximations algorithm can be adjusted to improve this estimation.

Anticoagulation in COVID-19 patients – An updated systematic review and meta-analysis

BackgroundThromboembolic events are common complications of COVID-19. Clinical study results on safety and efficacy of anticoagulation in COVID-19 are controversial. Material and methodsThis report is the second update of our systematic review with meta-analysis on randomized controlled trials (RCTs) comparing standard thromboprophylaxis, intermediate or therapeutic dose anticoagulation or no anticoagulation in COVID-19 in- and outpatients. We searched eligible studies up to 5 October 2023. Certainty of evidence was assessed using GRADE. ResultsFor this update we included fourteen new RCTs and a total of 27 RCTs with 16,789 patients. Certainty of evidence ranged from very low to high depending on outcome and comparison. Standard thromboprophylaxis with low dose anticoagulation may have little or no effect for COVID-19 outpatients compared to no anticoagulation. In inpatients with moderate or severe COVID-19, intermediate dose anticoagulation may decrease any thrombotic events or death, but may increase major bleeding compared to standard thromboprophylaxis. Therapeutic dose anticoagulation decreases thrombotic events or deaths in inpatients with moderate COVID-19, but probably has little or no effect in patients with severe COVID-19 compared to standard thromboprophylaxis with low or intermediate dose anticoagulation. With therapeutic dose anticoagulation, the risk of major bleeding probably increases regardless of COVID-19 severity. We are uncertain on the effect of thromboprophylaxis with low dose anticoagulation compared to no anticoagulation in the post-discharge setting. ConclusionsHospitalized, moderately-ill COVID-19 patients may benefit from intermediate or therapeutic dose anticoagulation, while critically ill patients may not. Risk of major bleeding must be considered.

Management of Deep Vein Thrombosis: An Update Based on the Revised AWMF S2k Guideline.

Deep vein thrombosis (DVT) and pulmonary embolism (PE) are the most common manifestations of venous thromboembolism (VTE). Most DVTs affect the lower-extremity veins. Since the symptoms of DVT are non-specific, a prompt and standardised diagnostic work-up is essential to minimise the risk of PE in the acute phase and to prevent thrombosis progression, post-thrombotic syndrome and VTE recurrence in the long-term. Only recently, the AWMF S2k guidelines on Diagnostics and Therapy of Venous Thrombosis and Pulmonary Embolism have been revised. In the present article, we summarize current evidence and guideline recommendations focusing on lower-extremity DVT (LEDVT). Depending on whether the diagnostic work-up is performed by a specialist in vascular medicine or by a primary care physician, different diagnostic algorithms are presented that combine clinical probability, D-dimer testing and diagnostic imaging. The diagnosis of ipsilateral recurrent DVT poses a particular challenge and is presented in a separate algorithm. Anticoagulant therapy is an essential part of therapy, with current guidelines clearly favouring regimens based on direct oral anticoagulants over the traditional sequential therapy of parenteral anticoagulants and vitamin K antagonists. For most DVTs, a duration of therapeutic-dose anticoagulation of at least 3 to 6 months is considered sufficient, and this raises the question of the risk of VTE recurrence after discontinuation of anticoagulation and the need for secondary prophylaxis in the long-term. Depending on the circumstances and trigger factors that have contributed to the occurrence of DVT, management strategies are presented that allow decision-making taking into account the individual bleeding risk and patient's preferences.

Clinical Characteristics, Outcomes, and Risk Factors for Mortality in Pregnant/Puerperal Women with COVID-19 Admitted to ICU in Turkey: A Multicenter, Retrospective Study from a Middle-Income Country.

Coronaviruses have been the cause of 3 major outbreaks during the last 2 decades. Information on coronavirus diseases in pregnant women is limited, and even less is known about seriously ill pregnant women. Data are also lacking regarding the real burden of coronavirus disease 2019 (COVID-19) infection in pregnant women from low/middle-income countries. The aim of this study was to determine the characteristics and clinical course of COVID-19 in pregnant/puerperal women admitted to ICUs in Turkey. This was a national, multicenter, retrospective study. The study population comprised all SARS-CoV-2-infected pregnant/puerperal women admitted to participating ICUs between 1 March 2020 and 1 January 2022. Data regarding demographics, comorbidities, illness severity, therapies, extrapulmonary organ injuries, non-COVID-19 infections, and maternal and fetal/neonatal outcomes were recorded. LASSO logistic regression and multiple logistic regression analyses were used to identify predictive variables in terms of ICU mortality. A total of 597 patients (341 pregnant women, 255 puerperal women) from 59 ICUs in 44 hospitals were included and of these patients, 87.1% were unvaccinated. The primary reason for ICU admission was acute hypoxemic respiratory failure in 522 (87.4%), acute hypoxemic respiratory failure plus shock in 14 (2.3%), ischemic cerebrovascular accident (CVA) in 5 (0.8%), preeclampsia/eclampsia/HELLP syndrome in 6 (1.0%), and post-caesarean follow-up in 36 (6.0%). Nonsurvivors were sicker than survivors upon ICU admission, with higher APACHE II (p < 0.001) and SOFA scores (p < 0.001). A total of 181 (30.3%) women died and 280 (46.6%) had received invasive mechanical ventilation (IMV). Myocardial injury, the highest SOFA score during ICU stay, LDH levels on admission, the highest levels of AST during ICU stay, average daily dose of corticosteroids, IMV, prophylactic dose anticoagulation (compared with therapeutic dose anticoagulation), PaO2/FiO2 ratio <100, pulmonary embolism, and shock were identified as predictors of mortality. Rates of premature birth (46.4%), cesarean section (53.7%), fetal distress (15.3%), stillbirth (6.5%), and low birth weight (19.4%) were high. Rates of neonatal death (8%) and respiratory distress syndrome (21%) were also high among live-born infants. Severe/critical COVID-19 infection during the pregnancy/puerperal period was associated with high maternal mortality and fetal/neonatal complication rates in Turkey.

Clinical Characteristics and Prognosis of Acute Pulmonary Embolism with Hemoptysis in Autoimmune Disease Patients.

Background: Hemoptysis is prevalent in acute pulmonary embolism (PE) and significantly influences clinical decision-making. Despite the increasing reports of PE in patients with autoimmune diseases, limited studies have investigated the association between acute PE with hemoptysis and autoimmune disease. Methods: The retrospective study aimed to investigate patients with autoimmune disease who presented with acute PE and hemoptysis at Peking Union Medical College Hospital (PUMCH) between January 2012 and October 2020. A comparative analysis was conducted between patients with and without hemoptysis, as well as between those with autoimmune diseases and those without. Clinical characteristics, PE severity stratification, the amount of hemoptysis, initial anticoagulation management, and prognosis were analyzed descriptively. Results: The study analyzed 896 patients diagnosed with acute PE, of whom 105 (11.7%) presented with hemoptysis. Hemoptysis in PE patients was frequently associated with autoimmune diseases (39%, 41/105), a younger patient population (42.0 vs. 52.7 years old, P =0.002), and a higher prevalence of low-risk PE (53.7 vs. 28.1, P=0.008) compared with non-autoimmune disease patients. Multivariate logistic analysis showed PE patients with primary or metastatic lung cancer, chest pain, age < 48 years old, chronic heart failure, autoimmune disease, pulmonary infection and male were more likely to develop hemoptysis. Patients were grouped based on maximum daily sputum blood volume and PE risk stratification. Most patients (73.2%) received therapeutic-dose anticoagulation. Poor prognosis is observed in patients with moderate to massive hemoptysis and intermediate-high-risk or high-risk PE. Conclusions: Hemoptysis is a relatively common manifestation in patients with PE, and its presence during the diagnostic workup of acute PE necessitates careful analysis of underlying comorbidities. In cases where hemoptysis occurs in individuals with autoimmune diseases in the context of PE, proactive management strategies targeting the primary disease are crucial. Therapeutic decisions should consider both PE severity stratification and the volume of hemoptysis.

Thrombotic anti-PF4 immune disorders: HIT, VITT, and beyond.

Antibodies against the chemokine platelet factor 4 (PF4) occur often, but only those that activate platelets induce severe prothrombotic disorders with associated thrombocytopenia. Heparin-induced thrombocytopenia (HIT) is the prototypic anti-PF4 disorder, mediated by strong activation of platelets through their FcγIIa (immunoglobulin G [IgG]) receptors (FcγRIIa). Concomitant pancellular activation (monocytes, neutrophils, endothelium) triggers thromboinflammation with a high risk for venous and arterial thrombosis. The classic concept of HIT is that anti-PF4/heparin IgG, recognizing antigen sites on (cationic) PF4 that form in the presence of (anionic) heparin, constitute the heparin-dependent antibodies that cause HIT. Accordingly, HIT is managed by anticoagulation with a nonheparin anticoagulant. In 2021, adenovirus vector COVID-19 vaccines triggered the rare adverse effect "vaccine-induced immune thrombotic thrombocytopenia" (VITT), also caused by anti-PF4 IgG. VITT is a predominantly heparin-independent platelet-activating disorder that requires both therapeutic-dose anticoagulation and inhibition of FcγRIIa-mediated platelet activation by high-dose intravenous immunoglobulin (IVIG). HIT and VITT antibodies bind to different epitopes on PF4; new immunoassays can differentiate between these distinct HIT-like and VITT-like antibodies. These studies indicate that (1) severe, atypical presentations of HIT ("autoimmune HIT") are associated with both HIT-like (heparin-dependent) and VITT-like (heparin-independent) anti-PF4 antibodies; (2) in some patients with severe acute (and sometimes chronic, recurrent) thrombosis, VITT-like antibodies can be identified independent of proximate heparin exposure or vaccination. We propose to classify anti-PF4 antibodies as type 1 (nonpathogenic, non- platelet activating), type 2 (heparin dependent, platelet activating), and type 3 (heparin independent, platelet activating). A key concept is that type 3 antibodies (autoimmune HIT, VITT) require anticoagulation plus an adjunct treatment, namely high-dose IVIG, to deescalate the severe anti-PF4 IgG-mediated hypercoagulability state.

Anticoagulation Use and Patient Outcomes in Paroxysmal Nocturnal Hemoglobinuria: A Province-Wide Retrospective Review

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder caused by somatic mutations in hematopoietic stem cells and is characterized by hemolysis, bone marrow failure, and thrombosis. Thrombotic events are the leading cause of morbidity and mortality in PNH, but little has been published about the role of prophylactic anticoagulation to prevent thrombotic events, and the ideal anticoagulant for patients who do experience thrombosis. Additionally, to our knowledge, bleeding outcomes in patients on prophylactic and therapeutic dose anticoagulants have not been examined. Our objective was therefore to examine our practice patterns regarding the use and outcomes of anticoagulation in PNH patients in our province. Methods: This multi-center, retrospective cohort study examined the epidemiology, management, thrombotic and bleeding complications of 31 adult patients with PNH in the province of Alberta, Canada during the period of January 1, 2000, to December 31, 2022. Patients were identified by International Classification of Diseases (ICD)-9 codes from hospital discharge summaries and ambulatory clinic records. Chart reviews were performed to collect patient demographics, clinical and laboratory characteristics, use of anticoagulation including agent and dose, and thrombotic and bleeding complications. Results: The median age of the cohort was 50 (interquartile range, IQR 35-70) years and 10 (32%) patients were male. Concurrent aplastic anemia and myelodysplastic syndrome were present in 15 (48%) and 3 (10%) patients, respectively. Disease presentation included thrombosis in 4 (13%) patients and bleeding in 5 (16%) patients. The majority of patients (74%) were treated with a complement inhibitor, most commonly eculizumab. Over the study period, 7 (23%) patients experienced 10 thrombotic events, including venous thromboembolism in 6 (60%) patients and arterial thromboembolism in 4 (40%) patients. The most common vascular sites of thrombosis were deep vein thrombosis of the lower extremity (3 patients) and stroke (2 patients). Of the 10 thrombotic events, 3 (30%) occurred while the patient was receiving a complement inhibitor. Thrombosis occurred at a median of 4.5 months from PNH diagnosis and the average granulocyte clone size at the time of thrombosis was 40.1% (IQR 11.3-82.9%). Of these 10 thrombotic events, 2 occurred on therapeutic-dose anticoagulation. In total, 8 (26%) patients experienced 13 bleeding events, 4 (13%) meeting criteria for ISTH major bleeding. The average platelet count at the time of bleeding was 96 (IQR 79-139). Of the 13 bleeding events, 5 occurred on an antiplatelet, 2 occurred on prophylactic-dose anticoagulation, and 2 occurred on therapeutic-dose anticoagulation. Thirteen (42%) patients were on anticoagulation: 7 (23%) patients on primary prophylaxis and 6 (19%) patients on secondary prophylaxis. For primary prophylaxis, 4 patients received a direct oral anticoagulant (DOAC), 3 at a prophylactic dose and 1 at a therapeutic dose, and 3 patients received warfarin at a therapeutic dose. Six (86%) patients on primary prophylaxis were also receiving a complement inhibitor. With regards to secondary prophylaxis, 2 patients received a DOAC, 3 patients received warfarin, and 1 patient received low molecular weight heparin. All secondary prophylaxis was given at a therapeutic dose. Five (83%) patients on secondary prophylaxis were also receiving a complement inhibitor. Of patients on a DOAC, 1 patient experienced a breakthrough arterial thromboembolism (stroke), and no patients experienced a breakthrough venous thromboembolism. Conclusion: Thrombosis in PNH is common and prevention is key to prevent long-term morbidity and mortality. Our practice patterns indicate that DOACs are being used in our province as primary prophylaxis, even in patients who are concurrently being treated with a complement inhibitor. DOACs are also being used more frequently than other anticoagulants as secondary prophylaxis, despite there not being robust data for DOAC use in this patient population. DOACs appear to be effective against VTE with no occurrence of breakthrough venous thrombosis. Major bleeding complications were observed at a higher rate than has been described in the literature and therefore the use of anticoagulants in this patient population must be weighed against the bleeding risk.

A Retrospective Analysis of COVID-19 Coagulopathy in Hospitalized and Intensive Care Patients with Sickle Cell Disease

Purpose/Objective: The implications of COVID-19 induced hypercoagulability in patients with sickle cell disease (SCD) remain largely unknown. Both COVID-19 and SCD have independent pathophysiological mechanisms which impact each aspect of Virchow's triad to induce a hypercoagulable state (Saxena and Muthu., 2023), however the joint impact of COVID-19-SCD on venous thromboembolism (VTE) remains understudied. As such, our primary objective involved investigating the incidence of VTE events in SCD patients with COVID-19. Our secondary objective involved assessing parameters of COVID-19 infection severity in SCD patients. Methods: We conducted a retrospective cross-sectional study at New York City Health and Hospitals, Kings County involving SCD, sickle cell trait (SCT) and the general population of COVID-19 patients (non-sickle). Data was collected from the onset of the pandemic on March 1, 2020 to December 31, 2021 for hospitalized and intensive care patients. We collected information on incidence of VTE, type of VTE (deep vein thrombosis or pulmonary embolism), age, sex, comorbidities, VTE prophylaxis, D-dimer, ferritin, LDH, BMI, sickle cell phenotype, transfusion requirements, COVID-19 management, SCD management, and outcomes. Data was analyzed on GraphPad PRISM, using one-way ANOVA and odds ratios. A p-value of &amp;lt;0.05 was considered statistically significant. Results: The study included three patient cohorts, consisting of 24 SCT, 26 SCD and 675 non-sickle patients (non-SS) to study incidence of VTE. Additional information regarding infection parameters was obtained on 146 non-sickle patients, and all SCT and SCD patients. We found that there was no significant difference between VTE risk in the SCD and non-sickle patients (OR=0.3736, 95% CI 0.0223 to 6.2675) or SCT and SCD patients (OR=0.2956, 95% CI 0.0115 to 7.6121). There was no significant difference in mortality (OR=0.4909, 95% CI 0.0606 to 3.9736) or intensive care requirements (OR=0.4137, 95% CI 0.1171 to 1.4608) between SCD and non-SS patients (Table 1). We also investigated markers of infection and hypercoagulability and found that there was no significant difference between D-dimer or LDH levels between the three cohorts, however ferritin was significantly increased in the SCD group compared to the non-sickle cohort (Figure 1, p=0.0123). Conclusions/Implications: Current ASH guidelines recommend use of prophylactic dose anticoagulation for critically ill COVID-19 patients and therapeutic dose anticoagulation for acute, but not critically ill patients (Cuker et. al., 2022). There are currently no formal recommendations regarding VTE prevention for hospitalized SCD patients with COVID-19. Our data supports prior reports on VTE in SCD (Singh et. al., 2022) which note that SCD patients with COVID-19 do not have an increased risk of VTE compared with uninfected SCD patients. Similarly, our data suggests that there is no statistical difference in VTE incidence in SCD-COVID-19 patients compared to the general population affected by COVID-19. Given no differences in VTE incidence, we recommend that anticoagulation parameters for the general population of hospitalized and intensive care patients be applied to SCD patients.

Effects of inflammation on thrombosis and outcomes in COVID-19: secondary analysis of the ATTACC/ACTIV-4a trial

BackgroundPatients hospitalized for COVID-19 are at high risk of thrombotic complications and organ failure, and often exhibit severe inflammation, which may contribute to hypercoagulability. ObjectivesTo determine whether patients hospitalized for COVID-19 experience differing frequencies of thrombotic and organ failure complications and derive variable benefits from therapeutic-dose heparin dependent on the extent of systemic inflammation and whether observed benefit from therapeutic-dose anticoagulation varies depending on the degree of systemic inflammation. MethodsWe analyzed data from 1346 patients hospitalized for COVID-19 enrolled in the ATTACC and ACTIV-4a platforms who were randomized to therapeutic-dose heparin or usual care for whom levels of C-reactive protein (CRP) were reported at baseline. ResultsIncreased CRP was associated with worse patient outcomes, including a >98% posterior probability of increased organ support requirement, hospital length of stay, risk of 28-day mortality, and incidence of major thrombotic events or death (patients with CRP 40-100 mg/L or ≥100 mg/L compared to patients with CRP <40 mg/L). Patients with CRP 40 to 100 mg/L experienced the greatest degree of benefit from treatment with therapeutic doses of unfractionated or low molecular weight heparin compared with usual-care prophylactic doses. This was most significant for an increase in organ support-free days (odds ratio: 1.63; 95% confidence interval, 1.09-2.40; 97.9% posterior probability of beneficial effect), with trends toward benefit for other evaluated outcomes. ConclusionModerately ill patients hospitalized for COVID-19 with CRP between 40 mg/L and 100 mg/L derived the greatest benefit from treatment with therapeutic-dose heparin.

Effect of therapeutic-dose heparin on severe acute kidney injury and death in noncritically ill patients hospitalized for COVID-19: a prespecified secondary analysis of the ACTIV4a and ATTACC randomized trial

BackgroundAcute kidney injury (AKI) in patients with COVID-19 is partly mediated by thromboinflammation. In noncritically ill patients with COVID-19, therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support. ObjectivesWe investigated whether therapeutic-dose heparin reduces the incidence of AKI or death in noncritically ill patients hospitalized for COVID-19. MethodsWe report a prespecified secondary analysis of the ACTIV4a and ATTACC open-label, multiplatform randomized trial of therapeutic-dose heparin vs usual-care pharmacologic thromboprophylaxis on the incidence of severe AKI (≥2-fold increase in serum creatinine or initiation of kidney replacement therapy (KDIGO stage 2 or 3) or all-cause mortality in noncritically ill patients hospitalized for COVID-19. Bayesian statistical models were adjusted for age, sex, D-dimer, enrollment period, country, site, and platform. ResultsAmong 1922 enrolled, 23 were excluded due to pre-existing end stage kidney disease and 205 were missing baseline or follow-up creatinine measurements. Severe AKI or death occurred in 4.4% participants assigned to therapeutic-dose heparin and 5.5% assigned to thromboprophylaxis (adjusted relative risk [aRR]: 0.72; 95% credible interval (CrI): 0.47, 1.10); the posterior probability of superiority for therapeutic-dose heparin (relative risk < 1.0) was 93.6%. Therapeutic-dose heparin was associated with a 97.7% probability of superiority to reduce the composite of stage 3 AKI or death (3.1% vs 4.6%; aRR: 0.64; 95% CrI: 0.40, 0.99) compared to thromboprophylaxis. ConclusionTherapeutic-dose heparin was associated with a high probability of superiority to reduce the incidence of in-hospital severe AKI or death in patients hospitalized for COVID-19.

A Case of Complete Resolution of Cauda Equina Syndrome Caused by Extensive Iliocaval Thrombosis: The Role of Thrombolysis and Venous Stents.

The cauda equina syndrome (CES) is a rare condition affecting less than 1 in 100,000 patients annually. Diagnosing CES is challenging because of its rare incidence, potentially subtle presentation, and various underlying etiologies. Vascular causes, such as inferior vena cava (IVC) thrombosis, are uncommon but should be considered, since timely recognition and treatment of deep vein thrombosis (DVT) as a cause of CES can avoid irreversible neurological damage. A 30-year-old male presented with partial CES caused by nerve root compression due to venous congestion from an extensive iliocaval DVT. He completely recovered after thrombolysis and stenting of the IVC. His iliocaval tract remained patent until the last date of follow-up at 1 year without signs of post-thrombotic syndrome. Broad molecular, infectious, and hematological laboratory tests did not reveal any underlying disease for the thrombotic event, particularly no hereditary or acquired thrombophilia. Timely recognition of venous thrombosis as a cause of CES is essential. This is the first case report of CES caused by an extensive iliocaval DVT successfully treated with thrombolysis and venous stenting with good resolution of DVT and CES. This case-report describes a patient with cauda equina syndrome resulting from an extensive iliocaval deep vein thrombosis due to an underlying stenosis of the inferior vena cava. Thrombolysis and venous stenting succesfully restored venous patency and thereby relieved symptoms and signs of cauda equina syndrome, in addition to (long-term) therapeutic dose anticoagulation. It is important to timely recognize deep vein thrombosis as a cause of cauda equina syndrome and to consider endovenous treatment in a specialized center.

Point of care ultrasound findings in critically ill SARS-COV2 patients in an HIV endemic, resourced constrained setting

ObjectivesTo describe the incidence of venous thromboembolism (VTE) in mechanically ventilated COVID-19 patients in an HIV endemic, resourced constrained setting. To describe the incidence of VTE in relation to HIV status and anticoagulant therapy, and to evaluate VTE-associated cardio-respiratory changes. To establish the contribution of HIV, anticoagulation therapy and other risk factors to mortality. DesignProspective descriptive study. SettingSingle-center tertiary teaching hospital. ParticipantsOne hundred and one consecutively admitted critically ill adult patients with COVID-19 acute respiratory distress syndrome. InterventionsPoint of care ultrasound (POCUS) assessment of the lower limbs and the cardio-respiratory system was performed on intensive care unit (ICU) admission and repeated if clinically indicated. Measurements and main resultsDVT was diagnosed by POCUS, whilst pulmonary embolism was diagnosed using a combination of clinical criteria and POCUS (echocardiography and chest wall ultrasound). VTE was diagnosed in 16/101 (16%) patients, despite 14/16 (88%) receiving prior therapeutic dosage of low molecular weight heparin. Clinically significant PE was diagnosed in 5/16 (31%) with 11/16 (69%) having DVT only. The majority of VTE patients, 12/16 (75%), demised 16/101 (16%) patients had HIV co-infection, and 4/16 (25%) with HIV had VTE. Valvular abnormalities were the most common cardiac abnormality with marked tricuspid regurgitation detected in 51/101 (51%). The absence of right atrial enlargement had a 93% negative predictive value for the absence of VTE. Univariate analysis did not demonstrate statistically significant individual risk factors for mortality. ConclusionsMechanically ventilated COVID- 19 patients at ICU admission had a low incidence of VTE (16%). Therapeutic dose anticoagulation did not reduce mortality compared to prophylactic dosage. In contrast to findings from other studies, no individual risk factor contributed significantly to mortality, likely due to small sample size. POCUS is an ideal screening tool to aid in the assessment of critically ill patients.

Impact of thromboprophylaxis on hospital acquired thrombosis following discharge in patients admitted with COVID-19: Multicentre observational study in the UK.

Post-discharge thromboprophylaxis in patients admitted with COVID-19 remains controversial. We aimed to determine the impact of thromboprophylaxis on hospital acquired thrombosis (HAT) in patients (≥18 years) discharged following admission for COVID-19 in an observational study across 26 NHS Trusts in the UK (01.04.2020-31.12.2021). Overall, 8895 patients were included to the study: 971 patients were discharged with thromboprophylaxis and propensity score matched (PSM) with a desired ratio of 1:1, from patients discharged without thromboprophylaxis. Patients with heparin induced thrombocytopenia, major bleeding during admission and pregnant women were excluded. As expected from 1:1 PSM, no difference was observed in parameters between the two groups, including duration of hospital stay, except the thromboprophylaxis group had a significantly higher proportion who had received therapeutic dose anticoagulation during admission. There were no differences in the laboratory parameters especially D-dimers between the two groups at admission or discharge. Median duration of thromboprophylaxis following discharge from hospital was 4 weeks (1-8 weeks). No difference was found in HAT in patients discharged with TP versus no TP (1.3% vs. 0.92%, p = 0.52). Increasing age and smoking significantly increased the risk of HAT. Many patients in both cohorts had raised D-dimer at discharge but D-dimer was not associated with increased risk of HAT.

The effect of antithrombotic treatment on mortality in patients with acute infection: A meta-analysis of randomized clinical trials

Background and aimsAcute infections cause relevant activation of innate immunity and inflammatory cascade. An excessive response against pathogens has been proved to trigger the pathophysiological process of thrombo-inflammation. Nevertheless, an association between the use of antithrombotic agents and the outcome of critically ill patients with infectious diseases is lacking. The aim of this meta-analysis is to determine the impact of antithrombotic treatment on survival of patients with acute infective disease. MethodsMEDLINE, Embase, Cinahl, Web of Science and Cochrane Central Register of Controlled Trials (CENTRAL) databases were systematically searched from inception to March 2021. We included randomized controlled trials (RCTs) that evaluated any antithrombotic agent in patients with infectious diseases other than COVID-19. Two authors independently performed study selection, data extraction and risk of bias evaluation. The primary outcome was all-cause mortality. Summary estimates for mortality were calculated using the inverse-variance random-effects method. ResultsA total of 16,588 patients participating in 18 RCTs were included, of whom 2141 died. Four trials evaluated therapeutic-dose anticoagulation, 1 trial prophylactic-dose anticoagulation, 4 trials aspirin, and 9 trials other antithrombotic agents. Overall, the use of antithrombotic agents was not associated with all-cause mortality (relative risk 0.96; 95% confidence interval, 0.90–1.03). ConclusionsThe use of antithrombotics is not associated with all-cause mortality in patients with infectious disease other than COVID-19. Complex pathophysiological interplays between inflammatory and thrombotic pathways may explain these results and need further investigation.REGISTRATION: PROSPERO, CRD42021241182.

Thromboprophylaxis and management of anticoagulation in hospitalized patients with COVID-19: clinical pathway and practices

Inpatients infected with SARS-CoV-2 are prone to various complications during clinical treatment, especially venous thromboembolism (VTE), which significantly increases the risk of unexpected death. In recent years, a series of authoritative guidelines and high-quality evidence-based medicine research evidence have been published internationally. This working group has recently formulated the Guidelines for Thrombosis Prevention and Anticoagulant Management of Hospitalized Patients with Novel Coronavirus Infection with multidisciplinary experts in the fields of VTE prevention, critical care and evidence-based medicine from international and domestic experts. Based on this, the working group elaborated on 13 clinical issues in urgent need of attention and solution in current clinical practice on the basis of the guidelines and defined standardized operational paths, including VTE risk and bleeding risk assessment in hospitalized patients with COVID-19, VTE prevention and anticoagulant management of hospitalized COVID-19 patients with different severity and special patient populations complicated with pregnancy, malignant tumors, underlying diseases or organ insufficiency, usage of antiviral and anti-inflammatory drugs or thrombocytopenia, in addition to VTE prevention and anticoagulant management of discharged COVID-19 patients, anticoagulant management of COVID-19 patients complicated with VTE during hospitalization, anticoagulant management in patients undergoing VTE therapy with COVID-19, risk factors of bleeding in hospitalized patients with COVID-19, clinical classification and corresponding management. In particular, by referring to the latest international guidelines and research evidence, this paper provides clear implementation recommendations on how to accurately determine the standard preventive dose anticoagulation and therapeutic dose anticoagulation for hospitalized patients with COVID-19. This paper is expected to provide standardized operational procedures and implementation norms for healthcare workers to managing thrombus prevention and anticoagulation in hospitalized patients with COVID-19.

Safety and Efficacy of Different Anticoagulant Doses for Patients with COVID-19 in the ICU: A Systematic Review and Meta-Analysis.

Critically ill COVID-19 patients have a high incidence of thromboembolic events, which significantly influence the risk of mortality. Anticoagulant therapy is generally recommended to these patients but the optimal dosing regimens require further investigations. The objective of this systematic review and meta-analysis was to assess the efficacy and safety of prophylactic, intermediate and therapeutic dose anticoagulation in COVID-19 patients admitted to the ICU. A systematic search for original prospective observational studies and clinical trials was performed in online databases from 2020 to 2022. A total of 13 studies (3239 patients) were included. The type of anticoagulant dosing showed no significant influence on short-term mortality (p = 0.84), deep vein thrombosis (p = 0.66), arterial thrombosis (p = 0.44), major bleeding (p = 0.35) and minor bleeding incidence (p = 0.46). An anticoagulation regimen significantly influenced pulmonary embolism occurrence (16% for prophylactic dose vs. 4% for therapeutic dose, p = 0.02), but the number of studies in the analysis was relatively low. In conclusion, the results of this meta-analysis suggest that critically ill COVID-19 patients admitted in the ICU have no benefit from therapeutic doses of anticoagulants and that all three thromboprophylaxis regimes have a comparable effect on short term mortality and venous thromboembolism incidence but for pulmonary embolism, for which the results were inconclusive.

Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19

BackgroundPrior studies of therapeutic-dose anticoagulation in patients with COVID-19 have reported conflicting results. ObjectivesWe sought to determine the safety and effectiveness of therapeutic-dose anticoagulation in noncritically ill patients with COVID-19. MethodsPatients hospitalized with COVID-19 not requiring intensive care unit treatment were randomized to prophylactic-dose enoxaparin, therapeutic-dose enoxaparin, or therapeutic-dose apixaban. The primary outcome was the 30-day composite of all-cause mortality, requirement for intensive care unit–level of care, systemic thromboembolism, or ischemic stroke assessed in the combined therapeutic-dose groups compared with the prophylactic-dose group. ResultsBetween August 26, 2020, and September 19, 2022, 3,398 noncritically ill patients hospitalized with COVID-19 were randomized to prophylactic-dose enoxaparin (n = 1,141), therapeutic-dose enoxaparin (n = 1,136), or therapeutic-dose apixaban (n = 1,121) at 76 centers in 10 countries. The 30-day primary outcome occurred in 13.2% of patients in the prophylactic-dose group and 11.3% of patients in the combined therapeutic-dose groups (HR: 0.85; 95% CI: 0.69-1.04; P = 0.11). All-cause mortality occurred in 7.0% of patients treated with prophylactic-dose enoxaparin and 4.9% of patients treated with therapeutic-dose anticoagulation (HR: 0.70; 95% CI: 0.52-0.93; P = 0.01), and intubation was required in 8.4% vs 6.4% of patients, respectively (HR: 0.75; 95% CI: 0.58-0.98; P = 0.03). Results were similar in the 2 therapeutic-dose groups, and major bleeding in all 3 groups was infrequent. ConclusionsAmong noncritically ill patients hospitalized with COVID-19, the 30-day primary composite outcome was not significantly reduced with therapeutic-dose anticoagulation compared with prophylactic-dose anticoagulation. However, fewer patients who were treated with therapeutic-dose anticoagulation required intubation and fewer died (FREEDOM COVID [FREEDOM COVID Anticoagulation Strategy]; NCT04512079)

High incidence of common femoral Deep Vein Thrombosis in critically ill Covid19 patients.

To estimate the incidence and prevalence of deep venous thrombosis, and to evaluate the discriminative capacity of D-dimer in its diagnosis. The prospective, observational study was conducted at the critical care unit of a tertiary care hospital in Pakistan from February to September 2021 and comprised consecutively admitted adult critically ill patients who were receiving therapeutic-dose anticoagulation therapy. All patients were screened on day one for deep venous thrombosis by colour doppler and compression ultrasonography. Patients who did not have deep venous thrombosis on the first scan were followed every 72 hours. Data was analysed using SPSS 26. Of the 142 patients, 99(69.7%) were male and 43(30.3%) were female. The overall mean age was 53.20+/-13.3 years. On the first scan, 25(17.6%) patients had deep venous thrombosis. Of the remaining 117 patients, 78(68.4%) were followed every 72 hours, and 23(29.48%) of them developed deep venous thrombosis. The most common site for DVT was the common femoral vein 46(95.8%) and most deep venous thrombosis cases were unilateral 28(58.33%). D-dimer levels showed no discriminative capacity for diagnosis of deep venous thrombosis (p=0.79). There were no significant risk factors for the development of deep venous thrombosis. There was a high incidence and prevalence of deep venous thrombosis despite therapeutic-dose anticoagulation therapy. The most common affected site was the common femoral vein and most deep venous thrombosis were unilateral. D-dimer levels had no discriminative capacity for the diagnosis of deep venous thrombosis DVT.

Effect of therapeutic dose anticoagulation vs prophylactic dose anticoagulation in reducing venous thromboembolism, arterial thrombosis or death events among hospitalized non-critically ill COVID19 pt

Abstract Funding Acknowledgements Type of funding sources: None. Title The Effect of Therapeutic Dose Anticoagulation Versus Prophylactic Dose Anticoagulation in Reducing Venous Thromboembolism (VTE), Arterial Thrombosis (ATE) or Death Events Among Hospitalized Non-critically Ill COVID-19 Patients: A Meta-analysis. Background Coagulopathy-associated thrombotic events, leading to venous and arterial thromboembolism are highly prevalent among COVID-19 patients. While pharmacologic thromboprophylaxis are the mainstays of treatment, the consideration for an escalated therapeutic dose anticoagulation in the non-critically ill remained a highly debated issue. Objectives This meta-analysis sought to evaluate whether therapeutic dose anticoagulation among hospitalized non-critically ill COVID-19 patients reduce the composite primary efficacy outcome (VTE, ATE or death), and the secondary outcomes of major bleeding risk and progression to intubation and mechanical ventilation compared to prophylactic dose anticoagulation. Methodology After extensive search, screening based on predefined inclusion and exclusion criteria and critical appraisal by 3 independent reviewers 3 eligible open label RTCs with a total of 1492 patients were included in the study. The event rates of the primary and secondary outcomes were assessed after 21-30 days of hospitalization. Results The Risk Ratio for VTE, ATE and death is higher in the prophylactic dose anticoagulation (RR 1.42; 95% CI 1.08-1.86), p-value &amp;lt;0.05) compared to therapeutic dose anticoagulation. The risk for major bleeding (RR 0.70; 95% CI 0.30-1.62, p-value &amp;gt;0.05) and progression to intubation and mechanical ventilation (RR of 1.13; 95% CI 0.93-1.38, p-value &amp;gt;0.05) were not significantly different between the dosing regimens. Conclusion Therapeutic-dose regimen among non-critically ill admitted COVID-19 patients conferred lower risk for the composite primary outcome of VTE, ATE and death with similar risk for bleeding compared to prophylactic dose regimen. Due to this outcome advantage, therapeutic-dose anticoagulation can be considered as initial regimen in the non-critically ill COVID-19 patients in the absence of contraindications.