Assessment of Jordanian physicians' knowledge about venous thromboembolism risk and management among COVID-19 patients

Objectives: The aim of this study was to assess Jordanian physicians' awareness about venous thromboembolism (VTE) risk among COVID-19 patients and its treatment protocol. Method(s): This was a cross-sectional-based survey that was conducted in Jordan in 2020. During the study period, a convenience sample of physicians working in various Jordanian hospitals were invited to participate in this study. Physicians' knowledge was evaluated and physicians gained one point for each correct answer. Then, a knowledge score out of 23 was calculated for each. Key Findings: In this study, 102 physicians were recruited. Results from this study showed that most of the physicians realize that all COVID-19 patients need VTE risk assessment (n = 69, 67.6%). Regarding VTE prophylaxis, the majority of physicians (n = 91, 89.2%) agreed that low molecular weight heparin (LMWH) is the best prophylactic option for mild-moderate COVID-19 patients with high VTE risk. Regarding severe/critically ill COVID-19 patients, 75.5% of physicians (n = 77) recognized that LMWH is the correct prophylactic option in this case, while 80.4% of them (n = 82) knew that mechanical prevention is the preferred prophylactic option for severe/critically ill COVID-19 patients with high bleeding risk. Moreover, 77.5% of physicians (n = 79) knew that LMWH is the treatment of choice for COVID-19 patients diagnosed with VTE. Finally, linear regression analysis showed that consultants had an overall higher knowledge score about VTE prevention and treatment in COVID-19 patients compared with residents (P = 0.009). Conclusion(s): All physicians knew about VTE risk factors for COVID-19 patients. However, consultants showed better awareness of VTE prophylaxis and treatment compared with residents. We recommend educational workshops be conducted to enhance physicians' knowledge and awareness about VTE thromboprophylaxis and management in COVID-19 patients.Copyright © 2022 The Author(s). Published by Oxford University Press on behalf of the Royal Pharmaceutical Society. All rights reserved.

Fondaparinux Sodium: Recent Advances in the Management of Thrombosis.

Fondaparinux sodium is a chemically synthesized selective factor Xa inhibitor approved for the prevention and treatment of venous thromboembolic events, that is, deep vein thrombosis, pulmonary embolism, and superficial vein thrombosis, in acutely ill (including those affected by COVID-19 or cancer patients) and those undergoing surgeries. Since its approval in 2002, the efficacy and safety of fondaparinux is well demonstrated by many clinical studies, establishing the value of fondaparinux in clinical practice. Some of the advantages with fondaparinux are its chemical nature of synthesis, minimal risk of contamination, 100% absolute bioavailability subcutaneously, instant onset of action, a long half-life, direct renal excretion, fewer adverse reactions when compared with direct oral anticoagulants, and being an ideal alternative in conditions where oral anticoagulants are not approved for use or in patients intolerant to low molecular weight heparins (LMWH). In the last decade, the real-world use of fondaparinux has been explored in other conditions such as acute coronary syndromes, bariatric surgery, in patients developing vaccine-induced immune thrombotic thrombocytopenia (VITT) and in pregnant women with heparin-induced thrombocytopenia (HIT), or those intolerant to LMWH. The emerging data from these studies have culminated in recent updates in the guidelines that recommend the use of fondaparinux under various conditions. This paper aims to review the recent data and the subsequent updates in the recommendations of various guidelines on the use of fondaparinux sodium.

D-dimer-driven versus standard prophylactic anticoagulation with fondaparinux in critically ill patients with COVID-19 and coagulopathy: An open-label, randomized controlled trial

Background: Anticoagulation with fondaparinux (FPX) has shown benefit to improve clinical outcomes in hospitalized patients with COVID-19. However, optimal thromboprophylaxis dosing in critically ill patients remains unknown. Purpose(s): To evaluate the effects of D-dimer-driven (DDD) FPX compared with standard prophylactic-dose (SPD) FPX in critically ill patients with COVID-19 and associated coagulopathy. Method(s): This was a single-center, open-label, two-arms, parallel-group, randomized controlled trial conducted between April 1, 2021 and Feb 28, 2022. The eligible COVID-19 patients who were critically ill (defined as a presence of critical care-level organ support at enrollment) and presented with coagulopathy were randomly assigned (1:1 ratio) to receive pragmatically defined regimens of either DDD FPX or SPD FPX throughout hospitalization. The primary efficacy outcome was a composite of all-cause mortality (ACM), acute myocardial infarction (MI), confirmed arterial (ATE) or venous thromboembolisms (VTE), assessed up to 30 days. The secondary efficacy outcomes were 30-day ACM, composite thrombotic events, progression to invasive mechanical ventilation (IMV) or ARDS, and acute kidney injury (AKI). The safety outcomes included major bleeding and clinically relevant non-major bleeding (CRNMB). Outcomes were blindly adjudicated and analysed on a 30-day intention-to-treat basis. Result(s): During allocated period, 270 (58%) of 465 patients were eligible and were equally assigned to DDD and SPD groups. The baseline characteristics were well-matched between groups (all p>0.05). At 30 days, the primary efficacy outcome was met in 49 of 135 patients (36.3%) with DDD FPX versus 47 of 135 patients (34.8%) with SPD FPX (hazard ratio [HR], 1.32;95% CI, 0.89-1.98;p=0.17). DDD group compared with SPD group revealed no significant difference in 30-day ACM (22.9% vs 31.8%;HR, 0.73;p=0.17). At 30 days, DDD group demonstrated no significant reduction in thromboembolism, i.e. acute MI (14.1% vs 11.8%;HR, 1.53;p=0.21);ATE (3.0% vs 3.0%;HR, 1.27;p=0.74);and VTE (2.2% vs 4.4%;HR, 0.69;p=0.59) when compared with SPD group. Among those not on IMV at randomization, DDD group showed no significant reduction in the proportion of patients meeting the need for IMV (18.5% vs 32.6%;HR, 0.72;p=0.18) or progression to ARDS (17.8% vs 27.4%;HR, 0.81;p=0.43). Allocation to DDD FPX had no significant effect on the proportion of patients experiencing AKI within 30 days (17.8% vs 14.8%;HR, 1.36;p=0.39). There was no significant difference between DDD and SPD groups in terms of major bleeding (2.2% vs 0%;HR, 8.35;p=0.35) or CRNMB (3.0% vs 2.2%;HR, 1.70;p=0.48) at 30 days. Conclusion(s): In critically ill patients with COVID-19 and coagulopathy, D-dimer-driven anticoagulation with fondaparinux did not significantly improve clinical outcomes at 30 days as compared to standard prophylacticdose. The risk of bleeding was not significantly increased in this trial. (Table Presented).

Use of fondaparinux in patients with heparin-induced thrombocytopenia on veno-venous extracorporeal membrane oxygenation: A three-patient case series report.

Heparin-induced thrombocytopenia is a life-threatening immune-mediated complication of unfractionated heparin therapy. Fondaparinux is a therapeutic alternative, but it has limited evidence for its use in patients on extracorporeal membrane oxygenation (ECMO). We present a series of three adult patients with COVID-19 on ECMO who were diagnosed with heparin-induced thrombocytopenia after 7-12 days of unfractionated heparin treatment and were switched to fondaparinux. Fondaparinux was initiated with an intravenous loading dose of 5 mg, followed by a dose of 2.5 mg subcutaneously every 8-12 h. Dosage was adjusted according to daily measured anti-Xa concentration with a target range of 0.4-0.7 mg/L. The total duration of treatment with fondaparinux and ECMO ranged from 13 to 26 days. One major bleeding episode unrelated to fondaparinux therapy was observed, and the transfusions requirement was also low in all patients. The ECMO circuit was changed once in each patient. This series provides a deep insight into the use of fondaparinux over an extended period of time in patients on ECMO. Based on the presented data, fondaparinux can be considered a reasonable and affordable anticoagulant in patients without a high risk of bleeding.

Comparison between unfractionated heparin (UFH) and fondaparinux on platelets and D-dimer level in COVID-19 patients with hypercoagulation

Introduction: This study aimed to compare the clinical effects between UFH and fondaparinux in COVID-19 patients with hypercoagulation. Material(s) and Method(s): This was a prospective cohort study. Samples were taken consecutively from hospitalized COVID-19 patients with hypercoagulation who received UFH or fondaparinux based on the standardized guidelines. A total of 71 patients met the inclusion criteria. Patients were evaluated for platelet and D-dimer values before and after administration of UFH or fondaparinux. Result(s): Although there was no difference in D-dimer reduction between the two groups (p = 0.44), fondaparinux showed a greater reduction, 26% against 22% for UFH. While on platelets, there was a significant difference (p = 0.04) between fondaparinux and UFH. Fondaparinux showed a reduced thrombocytopenia impact, as seen by an increase in pre-and post-therapy platelets of up to 50%, compared to 16% in UFH. In regard to the incidence of Heparin-Induced Thrombocytopenia (HIT), there was no significant difference between post-UFH therapy and post-fondaparinux therapy (p = 0.361). Conclusion(s): Fondaparinux did not reduce platelet levels as much as UFH, but there was no difference between the fondaparinux group compared to the UFH group in the effect of decreasing D-dimer levels and the sign of HIT. Copyright © 2022 Via Medica.

Sindrome De Trombose Com Trombocitopenia Induzida Por Vacina Para Covid-19: Relato De Diagnostico E Manejo Precoce

Objetivo: Relatar caso de paciente com Sindrome de Trombose com Trombocitopenia (TTS) identificado precocemente e com boa evolucao clinica. Relato do caso: Paciente de 21 anos, do sexo masculino, apresentou inicio dos sintomas sete dias apos terceira dose da vacina contra COVID-19, sendo esta a primeira dose de vacina de plataforma adenoviral (ChAdOx-1). Inicialmente com mal-estar e obstrucao nasal, procurou atendimento apos febre nao aferida e dor abdominal e lombalgia. Internado apos achado de trombocitopenia (13.500 plaquetas/mm3). Sorologia negativa para dengue e teste PCR para COVID-19 negativo. Tomografia computadorizada de abdome e pelve mostravam sinais de trombose de pequenos ramos tributarios das veias hepaticas direita e media, area compativel com infarto esplenico, nefrograma heterogeneo no rim esquerdo, predominando no polo superior, sugestivo de foco de infarto renal, e presenca de imagem sugestiva de trombo nao oclusivo na veia renal esquerda, ao nivel do hilo. Hemograma de admissao: Hb 15,3 Leucocitos 4.588 Plaquetas 13.370. TP e TTPa normais. Nadir plaquetario foi de 9.493. Fibrinogenio 178 mg/dL. Dimero D de 61,80 mg/L (VR <0,50). Paciente tratado com imunoglobulina humana (dose total de 2 g/kg) e dexametasona 40 mg /dia por 4 dias, apos quadro de cefaleia na vigencia de plaquetopenia grave, porem com TC de cranio contrastada sem sinais de sangramento ou de trombose venosa cerebral. Evoluiu com boa resposta plaquetaria, com contagem acima de 50.000 mm3 a partir de dois dias apos primeira dose de imunoglobulina. O paciente foi anticoagulado com fondaparinux e posteriormente rivaroxabana. Seguindo a norma tecnica ndegree 933/2021 do Ministerio da Saude, a amostra foi encaminhada para laboratorio de referencia, com resultado positivo para anticorpos anti-PF4 em altos titulos pelo metodo ELISA. Pesquisas de sorologias, anticorpos antifosfolipideos e para trombofilias hereditarias tambem resultaram negativas. Paciente seguiu estavel, com plaquetas de 160.000 mm3 e em anticoagulacao, quatro semanas apos a alta hospitalar. Discussao: A Sindrome de Trombose com Trombocitopenia (TTS) e uma rara complicacao da vacina de plataforma adenoviral nao-replicante, com uma incidencia de 0,5 a 6,8 casos a cada 100.000 vacinacoes. Sua mortalidade esta atualmente relatada em torno de 17%, mas chegando a 50% nos primeiros estudos, dependendo do tempo para diagnostico e inicio do tratamento. Manifesta-se entre 4 e 30 dias apos exposicao vacinal. Caso contempla todos os criterios para caso confirmado de TTS, alem de ser um caso provavel conforme o algoritmo de Naranjo para causalidade de reacao adversa. Apesar de complicacao potencialmente grave, nao compromete a seguranca vacinal, sendo evento clinico tratavel. Conclusao: A complicacao de TTS induzida por vacina com vetor adenoviral nao replicante, apesar de rara, e potencialmente fatal se nao identificada a tempo, alem de ter abordagem e tratamento que reduz de forma significativa a taxa de mortalidade. A divulgacao das informacoes para diagnostico precoce e manejo clinico devem ser ampliadas para melhoria dos desfechos. Copyright © 2022

Promising Drug Fondaparinux for the Treatment of COVID-19: an In Silico Analysis of Low Molecular Weight Heparin, Direct Oral Anticoagulant, and Antiplatelet Drug Interactions with Host Protease Furin.

PURPOSE: As of July 2022, the COVID-19 pandemic has affected over 555 million worldwide confirmed cases and caused more than 6.3 million deaths. The studies showed that the D-dimer levels were increased in non-survivors compared to survivors and heparin treatment has begun to be administered to the patients in severe clinics. As we knew that the entrance of SARS-CoV-2 to the host cell needs to be facilitated by host proteases; we published our hypothesis that heparin as a serine protease inhibitor may block the interaction between spike protein receptor-binding domain and host proteases. In our study, we aimed to investigate the interactions between not only heparins but also other antiplatelet and anticoagulant drugs including fondaparinux. METHODS: In this study, docking studies were carried out to evaluate the interactions between low molecular weight heparins (LMWHs) (enoxaparin, dalteparin, tinzaparin), direct oral anticoagulant, and antiplatelet drugs with host proteases. Molecular docking studies were performed by using Schrödinger molecular modeling software. 3D structures of the ligands were obtained from the 2D structures by assigning the OPLS-2005 force field using the Maestro 12.7. The 3D crystal structure of the furin complexed with an inhibitor, 2,5-dideoksistreptamin derivative, was extracted from the Protein Data Bank (PDB ID: 5MIM). Docking studies were carried out using the Grid-based Ligand Docking with Energetics module of the Schrödinger Software. RESULTS: The docking studies revealed that fondaparinux was the most relevant molecule to interact with furin with a docking score of - 12.74. It showed better interaction than the natural ligand of furin with an increased score compared to the docking score of - 8.155 of the natural ligand. AnaGA*IsA structure representing LMWH structure has shown a docking score of - 11.562 which was also better than the score of the natural ligand of furin. CONCLUSION: Our findings have shown that LMWHs and fondaparinux can be used for their possible antiviral effects in COVID-19 patients. Our results have shown that in accordance with heparin and LMWH, fondaparinux can also be a candidate for "drug repurposing" in COVID-19 therapy, not only because of their anticoagulant but also possible antiviral effects.

A PATIENT WITH COVID-19 PNEUMONIA, PULMONARY EMBOLISM, AND OSA

SESSION TITLE: Global Case Reports in Critical Care SESSION TYPE: Global Case Reports PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Thrombotic complications in patients diagnosed with COVID-19 pneumonia are emerging as an important and significant morbidity and mortality burden, with overwhelming inflammation, hypoxia, immobilization, and diffuse intravascular coagulation among possible causes of a procoagulant state (1). Obstructive sleep apnea (OSA), with intermittent arterial oxygen desaturation, may in its turn contribute to a procoagulant state, causing hemodynamic alterations as polycythemia and sluggish blood flow (2). Here we report on a case of sudden and massive non-lethal pulmonary thromboembolism (PTE) in a patient with COVID-19 severe pneumonia, for whom OSA was suspected and documented as a possible concurrent mechanism of thromboembolic complication during follow-up. CASE PRESENTATION: A 55-year-old male non-smoker obese (BMI 33 Kg/m2) was admitted to our hospital after 9 days of fever. In the Emergency Room, a chest HRCT scan showed bilateral diffuse ground glass opacities. He was treated with subcutaneous Tocilizumab (324 mg) single shot, Remdesivir (200 mg/day for first day and 100/daily for further 4 days), methyl-prednisolone 40 mg/daily, Enoxaparin 6000 UI/twice daily, azithromycin 500 mg/daily, high flow nasal cannula oxygen (50 L/min, TC 34°C, FiO2 35%) for moderate acute respiratory failure due to COVID-19 pneumonia (pO2: 58 mmHg, PCO2 34 mmHg pH 7.50, P/F 275). After 10 days, patient's clinical conditions worsened, needing non-invasive respiratory support;D-dimer increased abruptly, rising to 10 ng/mL, with findings consistent with PTE at a computed tomographic angiography (CTA, Fig 1). The patient was successfully treated with 10 mg/daily subcutaneous fondaparinux for 12 days, while assisted in the Intensive Care Unit, being discharged home in room air shortly later with oral anticoagulants. At the 3-month follow-up visit, OSA was suspected due to reported excessive daytime sleepiness and weakness, snoring, disturbed night sleep, morning headache in the last 4 years. The patient underwent a home sleep apnea test (HSAT) overnight. Test results revealed an AHI of 50 events/h, with several prolonged episodes of obstructive sleep apnea (307 apnea and hypopnea (A+H) events, 70 obstructive apnea and 233 hypopnea events, with a mean duration of 10% and an average arterial saturation of 93% (Fig. 2). He was adapted to CPAP therapy, with benefit and good correction of polygraphic indexes. DISCUSSION: The pathogenetic mechanisms of COVID 19 and OSA could have played a synergistic effect on endothelial damage, thus increasing the risk of thromboembolism. CONCLUSIONS: The presence of underdiagnosed comorbidities may well worsen the clinical course and complication of COVID-19;an earlier diagnosis of OSA is a prerequisite for timely treatment and, potentially, improved long-term clinical outcomes. Reference #1: Suh YJ, et al. Pulmonary embolism and deep vein thrombosis in COVID 19: a systematic review and meta-analysis. Radiology 2021;298 (2): E70-E80. Reference #2: Alfonso-Fernandez A., Garcia Surquia A., de la Pena M. OSA is a risk factor for recurrent VTE Chest. 2016;150 (6): 1291-1301. DISCLOSURES: no disclosure on file for Antonietta Esposito;no disclosure on file for Antonella Frattari;no disclosure on file for Giustino Parruti;no disclosure on file for Giorgia Patrizio;no disclosure on file for Pierpaolo Prosperi;no disclosure on file for Giorgia Rapacchiale;No relevant relationships by ANTONELLA SPACONE no disclosure on file for Giacomo Zuccarini;

The pharmacology of anticoagulant drug treatment options in COVID-19 patients: reviewing real-world evidence in clinical practice.

INTRODUCTION: The optimal anticoagulation strategy for venous thromboembolism (VTE) prevention among COVID-19 patients, hospitalized or in the community setting, is still challenging and largely based on real-world evidence. AREAS COVERED: We analyzed real-world data regarding the safety and effectiveness of anticoagulant treatment, both parenteral and oral, for VTE prevention or atrial fibrillation (AF)/VTE treatment among COVID-19 patients. EXPERT OPINION: The efficacy of low-molecular-weight heparin (LMWH) doses for VTE prevention correlates with COVID-19 disease status. LMWH prophylactic dose may be useful in COVID-19 patients at the early stage of the disease. LMWH intermediate or therapeutic dose is recommended in COVID-19 patients with an advanced stage of the disease. COVID-19 patients on VKA therapy for atrial fibrillation (AF) and VTE should switch to NOACs in the community setting or LMWH in the hospital setting. No definitive data on de-novo starting of NOACs or VKA therapy for VTE prevention in COVID-19 outpatients are available. In patients at high risk discharged after hospitalization due to COVID-19, thromboprophylaxis with NOACs may be considered.

The role of DOACs in anticoagulant treatment in a tertiary Hospital of Thessaloniki, Greece

Introduction: Low molecular weight heparins are used extensively in anticoagulant therapy, due to their safer profile, in comparison to other anticoagulants. Direct Oral AntiCogulants (DOACs) have been initiated in anticoagulant therapy as a safer treatment choice than coumarin derivatives. Objectives: The aim of this study was to investigate the use of oral and injectable anticoagulants, and especially the place of DOACs in anticoagulant treatment, in a tertiary Hospital of Thessaloniki, Greece. Methods: The data were collected by investigating prescriptions from the Hospital Pharmacy of a tertiary Hospital in Thessaloniki, Greece. Prescriptions of oral and injectable anticoagulants for hospitalized patients were collected during the period from June to September 2021. The consumption of the following oral and injectable anticoagulants was recorded in DDDs: acenocumarol, rivaroxaban, apixaban, dabigatran, heparin, enoxaparin, tinzaparin, bemiparin and fondaparinux. Results: The total amount of anticoagulants used was 53,041 DDDs, of which 97,9% were injectable anticoagulants whereas 2,1% were oral anticoagulants. DOACs represented the 1,8% of the anticoagulants used. The consumption of injectable anticoagulants for the hospitalized patients was 51,936 DDDs, of which 63.5% was enoxaparin, 18.5% was tinzaparin, 6.3% was heparin, 6.1% was bemiparin, and 5.6% was fondaparinux. The consumption of acenocumarol was 176 DDDs and the consumption of DOACs was 929 DDDs, with the percentage of rivaroxaban, apixaban, and dabigatran being 46%, 45% and 9% respectively. Indications with the highest prevalence for patients on enoxaparin was COVID 19, heart failure, stroke, angina pectoris, malignancy. Indications with the highest prevalence for patients on tinzaparin was COVID 19, malignancy, stroke. Indications with the highest prevalence for patients on bemiparin was malignancy, COVID 19, aortic valve disease, stroke. Heart failure, stroke and atrial fibrillation were the indications with highest prevalence in patients on DOACs. Acenocumarol was used mainly for heart failure, stroke and aortic valve stenosis. Conclusion: Injectable anticoagulants, and mainly low molecular weight heparins were the treatment of choice in hospitalized patients. Oral anticoagulants represented only a very small proportion (2,1%) of the anticoagulants used. DOACs have replaced coumarin derivatives, representing the 86% of oral anticoagulants in clinical use. Nevertheless, the percentage of DOACs was very low (1.8%) in the total consumption of anticoagulants, with rivaroxaban and apixaban being the most commonly used DOACs. Injectable anticoagulants, especially enoxaparin, are preferred by the clinicians as a safer choice for managing high risk thrombosis in hospitalized patients. DOACs, Direct Oral AntiCogulants, anticoagulants, NOACs.

STAY ALERT ABOUT COAGULATION PARAMETERS - IMPLICATIONS OF THROMBOSIS TREATMENT IN COVID-19

Objective: The case report presents two patients with COVID-19 history. The first patient, treated with enoxaparin, was diagnosed with pulmonary embolism, and later developed heparin-induced thrombocytopenia. The second patient with history of chronic pulmonary thromboembolism and multiple comorbidities, treated with rivaroxaban and acetylsalicylic acid, reported haemorrhagic events. The objective of this case report is to highlight possible complications of anticoagulant treatment and the role of accurate and rapid response of clinicians in COVID-19 patients. Design and method: Case report of two patients with COVID-19 - related thrombotic complications treated respectively with low molecular weight heparin and rivaroxaban. Observation of the treatment process revealed complications in both cases, demanding change of medications within the same group of drugs. Results: Development of thrombotic episodes was noticed and treated in time. Both patients developed complications of treatment. Modifications of anticoagulation drugs (low molecular weight heparin replaced with fondaparinux and rivaroxaban with apixaban respectively) were provided with positive outcomes. Conclusions: SARS-CoV-2 infection is associated with a high risk of thrombotic events whereas anticoagulant treatment can also lead to various complications. The necessity of watchful observation of coagulation parameters in patients with COVID-19, but also potential complications of any anticoagulant treatment is crucial for the positive long-term outcomes.

EFFECTS OF LOW MOLECULAR WEIGHT HEPARIN AND FONDAPARINUX ON MORTALITY, HEMORRHAGIC AND THROMBOTIC COMPLICATIONS IN COVID-19 PATIENTS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Background and aims: Coronavirus disease 2019 (COVID-19) is associated with increased thrombosis prevalence. However, there are insufficient data supporting the appropriate anticoagulation (AC) dose in COVID-19. Methods: We conducted a living systematic review and meta-analysis on the effects of different low molecular weight heparin (LMWH) and/ or fondaparinux doses on mortality, thrombotic and hemorrhagic events in COVID-19 patients. MEDLINE, Scopus, Embase, Cochrane Library, Cochrane COVID-19 study register, European Union Drug Regulating Authorities Clinical Trials Database and ClinicalTrials.gov were searched to detect observational cohort studies and randomized-controlled clinical trials (RCTs) comparing difference doses of LMWH or fondaparinux among confirmed COVID-19 cases. Results: Thirty-one eligible studies (6 RCTs and 25 cohort studies) with 11,430 hospitalized patients were included. No association was found between AC and mortality during the following comparisons: a) no AC versus any AC;b) prophylactic versus higher than prophylactic AC;c) prophylactic versus therapeutic AC;d) intermediate versus therapeutic AC;and e) lower than therapeutic versus therapeutic AC. However, the risk for all-cause mortality was higher in patients receiving prophylactic versus intermediate AC (OR=2.01;95%CI: 1.19-3.39). No associations were detected between the intensity of AC and the risk of thrombotic and hemorrhagic events, except the significantly lower risk for hemorrhage in patients on prophylactic compared to higher AC doses. Conclusions: The risk for all-cause mortality was significantly higher in patients receiving prophylactic AC compared to those on an intermediate dose of AC. These results should be interpreted in light of the moderate quality and heterogeneity of the included studies.

Heparin for patients with coronavirus disease 2019 and hypercoagulation complications: A cohort study.

Background: Thrombotic complications of coronavirus disease 2019 (COVID-19) are a worrisome aspect of the disease due to their high incidence in critically ill patients and their poor clinical outcomes. The aim of this study was to compare the effectiveness of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) (fondaparinux) in hospitalized COVID-19 patients with hypercoagulable complications. Material and methods: The study design used a retrospective cohort approach incorporating pre- and post-tests via secondary data extracted from the medical records of inpatients with confirmed COVID-19. Results: Among the 98 individuals studied (52% women; 30.6% at >60 years of age), 35 patients received UFH, while the remaining 63 patients received LMWH (fondaparinux). The greatest decrease in the D-dimer value (0.01 ± 0.5 g fibrinogen equivalent units/mL) was observed in 12 (34.3%) and 15 (23.8%) patients in the UFH and LMWH (fondaparinux) groups, respectively. Most inpatients with confirmed COVID-19 were aged 50-59 years and were women. Conclusion: There was a tendency toward increased D-dimer, normal prothrombin time, normal activated partial thromboplastin clotting time, and increased fibrinogen values in each COVID-19 patient. The results demonstrated a significant relationship between the D-dimer and prothrombin time parameter in confirmed COVID-19 inpatients.

Effects of low molecular weight heparin and fondaparinux on mortality, hemorrhagic and thrombotic complications in COVID-19 patients.

Background: Coronavirus disease 2019 (COVID-19) is associated with increased thrombosis prevalence. However, there are insufficient data supporting the appropriate anticoagulation dose in COVID-19. Objective: We aim to systematically assess the currently available data regarding the effects of different dosing regimens of low molecular weight heparin and/or fondaparinux (LMWH/F) on mortality risk as well as the risk of arterial/venous thrombotic events and hemorrhagic complications in confirmed COVID-19 cases. Design: We conducted a living systematic review and meta-analysis on the effects of different LMWH/F doses on mortality, thrombotic and hemorrhagic events in COVID-19 patients. Data Sources and Methods: MEDLINE, Scopus, Embase, Cochrane Library, Cochrane COVID-19 study register, European Union Drug Regulating Authorities Clinical Trials Database, and ClinicalTrials.gov were searched to detect observational cohort studies and randomized-controlled clinical trials (RCTs) comparing difference doses of LMWH/F among confirmed COVID-19 cases. Results: Thirty-one eligible studies (6 RCTs and 25 cohort studies) with 11,430 hospitalized patients were included. No association was found between LMWH/F and mortality during the following comparisons: (1) no LMWH/F versus any LMWH/F; (2) prophylactic versus higher than prophylactic LMWH/F; (3) prophylactic versus therapeutic LMWH/F; (4) intermediate versus therapeutic LMWH/F; and (5) lower than therapeutic versus therapeutic LMWH/F. Mortality was higher in patients receiving prophylactic versus intermediate LMWH/F (OR = 2.01; 95% CI: 1.19-3.39). However, this effect was mostly driven by observational data. No associations were detected between the intensity of LMWH/F and the risk of thrombotic and hemorrhagic events, except the lower risk for hemorrhage in patients on prophylactic compared to higher LMWH/F doses. Conclusion: The risk for all-cause mortality was higher in patients receiving prophylactic LMWH/F compared to those on an intermediate dose of LMWH/F, based on observational data. These results should be interpreted in light of the moderate quality and heterogeneity of the included studies. Registration: The study protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (Registration number: CRD42021229771).

Unexplained pulmonary embolism post SARS-CoV2 pneumonia in a patient with MYH9-related disease: a case report

This report describes the case of a man affected by Myosin Heavy Chain 9 (MYH9)-related platelet disorder, with a recent history of SARS-CoV-2 pneumonia, who developed pulmonary embolism (PE). At the admittance the patient presented a marked thrombocytopenia. The rotational thromboelastometry (ROTEM) showed a reduction in maximum clot firmness. The CT scan showed a lobar PE while and no sign of superficial or deep venous thrombosis was found. Given the contraindication of anticoagulant therapy due to severe thrombocytopenia, after collegial evaluation of the case, an inferior vena cava filter was applied. The patient was discharged after 5 days of hospitalization, and fondaparinux 2.5 mg subcutaneously was prescribed for two months. Could MYH9 mutation contribute to thrombotic predisposition? Or rather the endothelial dysfunction induced by SARS-CoV-2 infection? The report presents a dissertation on the possible causes for the PE and describes the therapeutic strategy adopted. (www.actabiomedica.it).

Efficacy and safety of therapeutic versus prophylactic dose of anticoagulation in hospitalized patients with severe COVID-19 pneumonia and coagulopathy: An open-label, randomized controlled trial

Background and Aims: The use of therapeutic anticoagulation to improve outcomes in COVID-19-associated coagulopathy remains unclear. We aimed to compare the efficacy and safety of therapeutic versus standard prophylactic anticoagulation in this population. Methods and Results: This was a single-center, open-label, two-arms, randomized controlled study conducted from 1st April to 15th July 2021. Two-hundred fifty severe COVID-19 patients with coagulopathy were randomly assigned (1:1 ratio) to receive either prophylactic anticoagulation (subcutaneous unfractionated heparin/UFH 5000IU b.i.d or fondaparinux 2.5mg o.d) or therapeutic anticoagulation (weightadjusted dose UFH or fondaparinux). Anticoagulation was administered until hospital discharge or at the treating physician's discretion. All patients received international COVID-19 guideline-driven therapy throughout the study. Baseline characteristics were not significantly different (p>0.05) between both arms, except for the Ddimer and CRP level at admission (p=0.04;p=0.001;respectively). During a 30-day follow-up, therapeutic arm revealed significant higher need for NIV/invasive MV (41.3% vs. 29%, p=0.02), higher progression to ARDS (34.1% vs. 16.1%, p=0.001), and increased 30-day all-cause mortality (58.7% vs. 15.3%, p<0.001) as compared with prophylactic arm. There was no significant difference between both arms in the incidence of acute MI (20% vs. 13.6%, p=0.07), VTE (4.8% vs. 0.8%, p=0.09), arterial thromboembolism (3.2% vs. 0%, p=0.29) and overall bleeding (17.6% vs. 6.4%, p=0.18) at 30-days. Conclusion: Therapeutic anticoagulation was considered safe and effective in preventing thromboembolic events, but not in the need for NIV/invasive MV, progression to ARDS and 30-day all-cause mortality in hospitalized patients with severe COVID-19 and coagulopathy.

[Anticoagulation in coronavirus disease 2019 (COVID-19): confirmed and controversial aspects]. / Antikoagulation bei "coronavirus disease 2019" (COVID-19) ­ Gesichertes und Kontroverses.

Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with a high risk of microvascular immunothrombosis as well as symptomatic and incidental thromboembolisms, predominantly in the venous system but also in the arterial system. This explains among other things the high cardiovascular morbidity and mortality of the patients. The present state of knowledge on the pathophysiology of immunothrombosis and the strategies of anticoagulation in patients with coronavirus disease 2019 (COVID-19) are summarized and illuminated in this article. According to the current guidelines moderately to severely ill patients who are being treated in hospital should receive thrombosis prophylaxis with low molecular weight or unfractionated heparin or alternatively with fondaparinux, as long as there is no clearly increased risk of bleeding. Apart from the established indications for treatment, an intensified or therapeutic dose prophylaxis should be considered very cautiously in these critically ill patients, also due to the increased bleeding complications. The routine continuation of prophylactic anticoagulation after discharge from hospital is currently not recommended.

Efficacy and safety of fondaparinux versus unfractionated heparin in patients hospitalised with severe COVID-19 pneumonia and coagulopathy: A randomised, open-label clinical trial

Background: The use of unfractionated heparin (UFH) has been renowned to reduce mortality in COVID-19. There are no data about the efficacy and safety of fondaparinux (FPX) in COVID-19. Purpose: To evaluate the efficacy and safety of FPX as compared to UFH in patients hospitalised with severe COVID-19 and coagulopathy. Methods: This was a single-center, open-label, equally randomised, parallel-group study conducted between April 1st and July 15th, 2021. Eligible and consenting patients were randomly assigned (1:1 ratio) to receive either FPX or UFH, in prophylactic and therapeutic dose. The primary efficacy endpoint was 28-day all-cause mortality;and secondary efficacy endpoints were episode of acute myocardial infarction (MI), objectively confirmed venous (VTE) or arterial thromboembolism (ATE), progression to non-invasive ventilation (NIV) or invasive mechanical ventilation (IMV), progression to ARDS, sepsis, acute kidney injury (AKI) and acute lung oedema (ALO). The primary safety endpoint was major bleeding (MB);and secondary safety endpoint was clinically relevant non-major bleeding (CRNMB). All composite endpoints were analysed on a 28-day intention-to-treat basis. All patients received guideline-driven therapy throughout the study. Results: During allocated period, 250 (71%) of 352 patients were eligible and were assigned to either FPX or UFH group. The baseline characteristics were well-matched between the two groups (all p > 0.05). FPX compared with UFH revealed no significant difference in 28- day all-cause mortality (35.2% vs. 39.2%, hazard ratio [HR] 0.88, p = 0.59). FPX exhibited no significant difference in the trend of thromboembolic events i.e. acute MI (16.8% vs. 16.8%, HR 0.78, p = 0.53);VTE (2.4% vs. 3.2%, HR 0.49, p = 0.42);and ATE (1.6% vs. 1.6%, HR 0.94, p = 0.95) compared to UFH. Among those not on NIV or IMV at randomisation, FPX showed no significant difference in the proportion of patients meeting the composite endpoint of progression to NIV/IMV (33.6% vs. 35.2%, HR 0.91, p = 0.74) or ARDS (25.6% vs. 24.8%, HR 0.91, p = 0.77). FPX group demonstrated no significant difference in the progression to septic shock (24% vs. 24.8%, HR 0.97, p = 0.92), AKI (19.2% vs. 16%, HR 1.01, p = 0.98), and ALO (10.4% vs. 12%, HR 1.19, p = 0.79) than UFH. Allocation to FPX had no significant effect on the proportion of patients discharged from hospital within 28 days (64% vs. 59.2%, HR 0.72, p = 0.43). Regarding safety, there was no significant difference between FPX and UFH group in terms of major bleeding (1.6% vs. 1.6%, HR 0.88, p = 0.88) or CRNMB (8% vs. 8.8%, HR 0.74, p = 0.53) at 28 days. Our prespecified sub-analysis comparing patients who received the respective therapeutic or prophylactic dose revealed that the efficacy and safety outcomes at 28 days did not differ between the FPX and UFH group (all p > 0.05). Conclusion: In patients hospitalised with severe COVID-19 and coagulopathy, FPX was associated with similar efficacy and safety as compared to UFH. (Figure Presented).

Appearing and disappearing right-heart thrombus: A case reporto in COVID- 19 patient

Aims: Venous thromboembolism represents frequent complication of patients with severe COVID-19 disease. Several reports about atypical thrombosis are described, rarely it has been described a right venticular thrombus during the course of infection. We report a case of right endoventricular thrombosis in a patient with SARSCov- 2 pneumonia. Methods and results: A 58-year-old man was admitted to our ward for severe respiratory failure in interstitial pneumonia. The nasopharyngeal swab for COVID-19 resulted positive. Steroids and prophylaxis with LMWHwere started, associated to CPAP to maintain good gas exchange. During hospitalization a venous ECD was performed with evidence of left popliteal thrombosis despite the therapy. D-Dimer was 44±3 ng/ml. A new onset AF was documented at the telemetry, without troponin elevation. A cardiac ultrasound was performed showing a right endoventricular lesion of 1.8 cm adhering to the free wall of the right ventricle. A CT-pulmonary angiogram (CTPA) resulted negative for pulmonary embolism and confirmed suspected right ventricular thrombus. Treatment with fondaparinux 7.5mg was started. After 10 days, cardiac ultrasound shown complete resolution of thrombosis, and CT confirmed the disappearing of the mass. Dabigatran 150 mg twice/day was started. Patient clinically improved and he was discharged after 20 days of hospitalization. Conclusions: SARS-CoV-2 infection may cause inflammation with cytokine storm and hypercoagulability leading to venous thromboembolism. Atypical thrombus formation was reported, including right-ventricle free wall. Early caridac ultrasound was critical to make diagnosis and starting prompt treatment, therefore routine cardiac ultrasound is mandatory in severe COVID-19 patients.