scholarly journals The Cross-Talk between Thrombosis and Inflammatory Storm in Acute and Long-COVID-19: Therapeutic Targets and Clinical Cases

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1904
Author(s):  
Domenico Acanfora ◽  
Chiara Acanfora ◽  
Marco Matteo Ciccone ◽  
Pietro Scicchitano ◽  
Alessandro Santo Bortone ◽  
...  
Keyword(s):  
Cross Talk ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Endothelial Damage ◽  
Coagulation Cascade ◽  
Residual Cardiovascular Risk ◽  
Platelet Factor ◽  
The Cross

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) commonly complicates with coagulopathy. A syndrome called Long-COVID-19 is emerging recently in COVID-19 survivors, characterized, in addition to the persistence of symptoms typical of the acute phase, by alterations in inflammatory and coagulation parameters due to endothelial damage. The related disseminated intravascular coagulation (DIC) can be associated with high death rates in COVID-19 patients. It is possible to find a prothrombotic state also in Long-COVID-19. Early administration of anticoagulants in COVID-19 was suggested in order to improve patient outcomes, although exact criteria for their application were not well-established. Low-molecular-weight heparin (LMWH) was commonly adopted for counteracting DIC and venous thromboembolism (VTE), due to its pharmacodynamics and anti-inflammatory properties. However, the efficacy of anticoagulant therapy for COVID-19-associated DIC is still a matter of debate. Thrombin and Factor Xa (FXa) are well-known components of the coagulation cascade. The FXa is known to strongly promote inflammation as the consequence of increased cytokine expression. Endothelial cells and mononuclear leucocytes release cytokines, growth factors, and adhesion molecules due to thrombin activation. On the other hand, cytokines can activate coagulation. The cross-talk between coagulation and inflammation is mediated via protease-activated receptors (PARs). These receptors might become potential targets to be considered for counteracting the clinical expressions of COVID-19. SARS-CoV-2 is effectively able to activate local and circulating coagulation factors, thus inducing the generation of disseminated coagula. LMWH may be considered as the new frontier in the treatment of COVID-19 and Long-COVID-19. Indeed, direct oral anticoagulants (DOACs) may be an alternative option for both early and later treatment of COVID-19 patients due to their ability to inhibit PARs. The aim of this report was to evaluate the role of anticoagulants—and DOACs in particular in COVID-19 and Long-COVID-19 patients. We report the case of a COVID-19 patient who, after administration of enoxaparin developed DIC secondary to virosis and positivity for platelet factor 4 (PF4) and a case of Long-COVID with high residual cardiovascular risk and persistence of blood chemistry of inflammation and procoagulative state.

scholarly journals Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant Medications

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Alok Dabi ◽  
Aristides P. Koutrouvelis
Keyword(s):  
Side Effects ◽  
Intracranial Hemorrhage ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Reversal Agents ◽  
United States Food ◽  
Life Threatening

Direct oral anticoagulants (DOACs) are a new class of anticoagulants that directly inhibit either thrombin or factor Xa in the coagulation cascade. They are being increasingly used instead of warfarin or other vitamin K antagonists (VKAs). Adverse side effects of DOACs may result in hemorrhagic complications, including life-threatening intracranial hemorrhage (ICH), though to a much lesser degree than VKAs. Currently there are relatively limited indications for DOACS but their usage is certain to expand with the availability of their respective specific reversal agents. Currently, only idarucizumab (antidote for dabigatran) has been United States Food and Drug Administration- (FDA-) approved, but others (andexanet-α and ciraparantag) may be approved in near future, and the development and availability of such reversal agents have the potential to dramatically change the current anticoagulant use by providing reversal of multiple oral anticoagulants. Until all the DOACs have FDA-approved reversal agents, the treatment of the dreaded side effects of bleeding is challenging. This article is an attempt to provide an overview of the management of hemorrhage, especially ICH, related to DOAC use.

scholarly journals Update on Edoxaban for the Prevention and Treatment of Thromboembolism: Clinical Applications Based on Current Evidence

2015 ◽  
Vol 2015 ◽  
pp. 1-19 ◽  
Author(s):  
Ali Zalpour ◽  
Thein Hlaing Oo
Keyword(s):  
Vitamin K Antagonists ◽  
Dabigatran Etexilate ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Current Evidence ◽  
Thrombin Inhibitor ◽  
Prevention And Treatment ◽  
Financial Impacts

Vitamin K antagonists (VKA) and heparins have been utilized for the prevention and treatment of thromboembolism (arterial and venous) for decades. Targeting and inhibiting specific coagulation factors have led to new discoveries in the pharmacotherapy of thromboembolism management. These targeted anticoagulants are known as direct oral anticoagulants (DOACs). Two pharmacologically distinct classes of targeted agents are dabigatran etexilate (Direct Thrombin Inhibitor (DTI)) and rivaroxaban, apixaban, and edoxaban (direct oral factor Xa inhibitors (OFXaIs)). Emerging evidence from the clinical trials has shown that DOACs are noninferior to VKA or low-molecular-weight heparins in the prevention and treatment of thromboembolism. This review examines the role of edoxaban, a recently approved OFXaI, in the prevention and treatment of thromboembolism based on the available published literature. The management of edoxaban in the perioperative setting, reversibility in bleeding cases, its role in cancer patients, the relevance of drug-drug interactions, patient satisfaction, financial impacts, and patient education will be discussed.

scholarly journals Noncanonical Effects of Oral Thrombin and Factor Xa Inhibitors in Platelet Activation and Arterial Thrombosis

2020 ◽  
Author(s):  
Amin Polzin ◽  
Lisa Dannenberg ◽  
Manuela Thienel ◽  
Martin Orban ◽  
Georg Wolff ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Platelet Activity ◽  
Vein Thrombosis

AbstractNonvitamin K oral anticoagulants (NOACs) or direct oral anticoagulants comprise inhibitors of factor Xa (rivaroxaban, apixaban, edoxaban) or factor IIa (dabigatran). Both classes efficiently interfere with the final or penultimate step of the coagulation cascade and showed superior net clinical benefit compared with vitamin K antagonists for prevention of thromboembolic events in patients with AF and for prevention and therapy of deep vein thrombosis and pulmonary embolism. None the less, accumulating data suggested, that there may be differences regarding the frequency of atherothrombotic cardiovascular events between NOACs. Thus, the optimal individualized NOAC for each patient remains a matter of debate. Against this background, some basic and translational analyses emphasized NOAC effects that impact on platelet activity and arterial thrombus formation beyond inhibition of plasmatic coagulation. In this review, we will provide an overview of the available clinical and translational evidence for so-called noncanonical NOAC effects on platelet activation and arterial thrombosis.

scholarly journals Mechanisms of action of new oral coagulants

2021 ◽  
Vol 40 (2) ◽  
pp. 33-40
Author(s):  
Arina A. Kokorina ◽  
Margarita O. Sokolova ◽  
Pavel A. Slizhov
Keyword(s):  
Therapeutic Effect ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Coagulation Factors ◽  
Mechanisms Of Action ◽  
Coagulation Cascade ◽  
Active Centers ◽  
Blood Coagulation Factors ◽  
Urgent Surgery ◽  
Direct Anticoagulants

The article provides a brief description of drugs in the class of direct oral anticoagulants. The mechanisms of the therapeutic effect and the ways of excretion of drugs-inhibitors of blood coagulation factors Xa and IIa are considered. It was shown that all of them are characterized by high selectivity to the active centers of target molecules, successfully affect the coagulation cascade and have a quick therapeutic effect. A comparative analysis of drugs of the class of direct oral anticoagulants showed that rivaroxaban, apixaban, edoxaban, betrixaban (inhibitors of FXa) and dabigatran (inhibitor of factor IIa) do not have significant advantages over each other in terms of mechanism and speed of action. A comparison of the main characteristics of direct oral anticoagulants and the indirect anticoagulant warfarin is presented. It is shown that, first of all, the advantage of the former is associated with an immediate pharmacological response. The decision to prescribe this drug requires consideration of risk factors for the patient, such as age, the presence of chronic diseases of the gastrointestinal tract, liver and kidneys. The article presents the most frequent complications of anticoagulant therapy, as well as the mechanisms of action of specific and universal antidotes indicated for use in patients with life-threatening bleeding or in need of urgent surgery when using direct oral anticoagulants. However, such neutralizing agents have not yet found widespread use due to their high cost and low availability. Nevertheless, the emergence of direct anticoagulants on the market has undoubtedly led to significant progress in the treatment of thrombotic and cardiovascular diseases (1 table, bibliography: 28 refs).

Nonhemostatic Activities of Factor Xa: Are There Pleiotropic Effects of Anti-FXa Direct Oral Anticoagulants?

Angiology ◽  
2019 ◽  
Vol 70 (10) ◽  
pp. 896-907 ◽  
Author(s):  
Styliani Papadaki ◽  
Alexandros D. Tselepis
Keyword(s):  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Anticoagulation Therapy ◽  
Factor Xa ◽  
Cell Types ◽  
Pleiotropic Effects ◽  
Coagulation Cascade ◽  
Protease Activated Receptors ◽  
Cellular Effects ◽  
Thrombotic Diseases

Factor Xa (FXa) is the key serine protease of the coagulation cascade as it is the point of convergence of the intrinsic and extrinsic pathways, leading to the formation of thrombin. Factor Xa is an established target of anticoagulation therapy, due to its central role in coagulation. Over the past years, several direct oral anticoagulants (DOACs) targeting FXa have been developed. Rivaroxaban, apixaban, and edoxaban are used in clinical practice for prevention and treatment of thrombotic diseases. Increasing evidence suggests that FXa exerts nonhemostatic cellular effects that are mediated mainly through protease-activated receptors-1 and -2 and are involved in pathophysiological conditions, such as atherosclerosis, inflammation, and fibrosis. Direct inhibition of FXa by DOACs could be beneficial in these conditions. This is a narrative review that focuses on the cellular effects of FXa in various cell types and conditions, as well as on the possible pleiotropic effects of FXa-targeting DOACs.

scholarly journals Outcomes in Heparin-Induced Thrombocytopenia Managed with Direct Oral Anticoagulants

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4975-4975 ◽  
Author(s):  
Nwabundo Anusim ◽  
Filip Ionescu ◽  
Anish S Konde ◽  
Vishal Jindal ◽  
Ruby Gupta ◽  
...  
Keyword(s):  
Platelet Count ◽  
Conflicts Of Interest ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Beaumont Hospital ◽  
Coagulation Cascade ◽  
Bleeding Events ◽  
Platelet Factor ◽  
Heparin Induced Thrombocytopenia

Background: Heparin-induced thrombocytopenia (HIT) occurs as a result of autoantibodies to the platelet factor 4 (PF4)-heparin complex, which activate the coagulation cascade with subsequent thrombosis. HIT can be fatal if not diagnosed and treated promptly with replacement of all heparin with non-heparin anticoagulants. Classic options are parenteral direct anti-thrombin agents which require intravenous administration and can prolong hospital stay. Direct oral anticoagulants (DOACs) address these inconveniences and are an interesting alternative. However, data regarding their efficacy and safety in HIT is limited. Methods: We retrospectively identified patients with HIT using ICD code 9: 289.84 and ICD code 10: D75.82 at Beaumont Hospital (Royal Oak) between December 2013 and December 2018. Only patients with HIT confirmed by positive serotonin release assay and managed with DOACs were included. Data regarding diagnostic tests, bleeding and thrombosis during the 30-day follow-up were recorded. Results: A total of 229 patients were identified using the ICD codes; only 8 patients had confirmed diagnosis of HIT and were treated with DOACs. The average age was 70 years (51-92 years); most were male (5, 62.5%) and Caucasian (6, 75%). The median optical density of PF4-heparin antibody was 1.97 (0.85-3.108). Six patients (75%) had confirmed HIT-associated thrombosis; one had negative Doppler ultrasonography of the lower extremities (upper extremities were not assessed) and one patient was not assessed for thrombosis. Seven patients (87.5%) received apixaban and one patient received rivaroxaban. The lowest platelet count prior to initiating DOAC was 40,000/microL, while three patients started DOACs when their platelet count was above 150,000/microL. Within the follow-up period, none of the patients on apixaban had bleeding episodes or clot progression. The only patient treated with rivaroxaban was re-admitted within one week of discharge for right upper extremity deep vein thrombosis. Unfortunately, this was the one patient who was not evaluated for thrombosis at the time of HIT diagnosis. Conclusion: In the 30 days following HIT diagnosis, treatment with apixaban resulted in adequate anticoagulation and was not associated with increased bleeding events despite relative thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Direct oral anticoagulants: first airbag

2019 ◽  
pp. 6-12
Author(s):  
A. N. Sokolova ◽  
A. I. Skripka
Keyword(s):  
Large Scale ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Coagulation Factors ◽  
Evidence Base ◽  
Coagulation Cascade ◽  
Blood Coagulation Factors ◽  
Hemorrhagic Event ◽  
Increased Risk ◽  
Neutralizing Agent

The safety profile of oral anticoagulants (DOACs) was confirmed in the large-scale studies, the increased risk of hemorrhagic events does still exist, which may be caused by the nature of the patient’s concomitant pathology, the resulting injury or the need for emergency surgical procedures. Such measures to restore the coagulation cascade as the use of prothrombin complex concentrates or hemodialysis have not been widely used in the clinical practice to stop the anti-coagulant effect of DOACs and do not have an evidence base. Today, idarutsizumab (Praxbind) is the only specific antagonist to DOACs registered in the Russian Federation, a neutralizing agent that interacts with free and thrombin-related dabigatran, without affecting other blood coagulation factors and platelet function. RE-VERSE AD study showed that administration of idarucizumab in patients receiving dabigatran therapy and who developed life-threatening bleeding provided complete neutralization of the anti-coagulant effect of dabigatran for 4 hours, and after 1.5 hours emergency surgical treatment was performed, achieving at the same time, normal perioperative hemostasis in 93.4% of cases. The availability of a specific neutralizing agent for a specific DOAC could be identified as arguments in favour of choosing this drug for patients who have a high risk of a hemorrhagic event, emergency surgery or thrombolysis.

scholarly journals Factor XI as a Target for New Anticoagulants

2021 ◽  
Vol 41 (02) ◽  
pp. 104-110
Author(s):  
James C. Fredenburgh ◽  
Jeffrey I. Weitz
Keyword(s):  
Vitamin K ◽  
Animal Studies ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factors ◽  
Clotting Factors ◽  
Factor Xi ◽  
Factor Xi Deficiency

AbstractDespite advances in anticoagulant therapy, thrombosis remains the leading cause of morbidity and mortality worldwide. Heparin and vitamin K antagonists (VKAs), the first anticoagulants to be used successfully for the prevention and treatment of thrombosis, are associated with a risk of bleeding. These agents target multiple coagulation factors. Thus, by activating antithrombin, heparin mainly inhibits factor Xa and thrombin, whereas VKAs lower the levels of the vitamin K–dependent clotting factors. Direct oral anticoagulants, which have replaced VKAs for many indications, inhibit only factor Xa or thrombin. Although the direct oral anticoagulants are associated with less bleeding than VKAs, bleeding remains their major side effect. Epidemiological and animal studies have identified factor XI as a target for potentially safer anticoagulant drugs because factor XI deficiency or inhibition protects against thrombosis and is associated with little or no bleeding. Several factor XI–directed strategies are currently under investigation. This article (1) reviews the rationale for the development of factor XI inhibitors, (2) identifies the agents in most advanced stages of development, (3) describes the results of completed clinical trials and provides a summary of those underway, and (4) highlights the opportunities and challenges for this next generation of anticoagulants.

scholarly journals Heparin is more effective than apixaban in inhibiting in vitro contact activated coagulation

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M.M Engelen ◽  
C Van Laer ◽  
M Jacquemin ◽  
C Vandenbriele ◽  
K Peerlinck ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Heart Valves ◽  
Thrombus Formation ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Mechanical Heart Valves ◽  
Contact Activation

Abstract Introduction Contact of blood with artificial surfaces such as mechanical support devices, catheters, and mechanical heart valves activates the contact activation (CA) pathway of coagulation. Furthermore, recent animal data and clinical studies suggest a more important contribution of CA in pathological thrombus formation in other cardiovascular diseases. Direct oral anticoagulants (DOACs) are recommended as first-line treatment in most patients who require long-term anticoagulation. However, because DOACs directly inhibit a single downstream coagulation factor (thrombin (fXIIa) or factor Xa (fXa)), it has been suggested that their efficacy could be reduced in the presence of strong activation of the CA pathway as compared to anticoagulants that target multiple, more upstream located coagulation factors. Purpose To compare the efficacy of a DOAC (apixaban) and heparin to suppress thrombin generation in the presence of strong CA pathway activation. Methods Pooled platelet-poor plasma was spiked with either apixaban (dissolved in DMSO and PBS) or unfractionated heparin to achieve therapeutic plasma levels. SynthASil, a commercially available mixture of phospholipids and silica, was used to stimulate the CA pathway in two different dilutions (1–80 and 5–80). Downstream coagulation was accessed by Thrombin Generation Test using Thrombinoscope by Stago and associated Thrombin Calibrator (activity 640 nM). The endogenous thrombin potential (area under the thrombin generation curve; ETP), peak thrombin generation (PTG), time to peak (ttPeak) and time to start (ttStart) were accessed. Results With decreasing concentrations of apixaban, stimulation with the lower dose SynthASil reveals an increasing ETP and PTG. As expected, ttPeak and ttStart decreased. Even supratherapeutic levels of apixaban (i.e. 1120 ng/mL) could not inhibit thrombin from being generated, in striking contrast with UFH where no thrombin was formed. Using a five times higher dose of SynthASil showed comparable ETP for all concentrations of apixaban, allocated around the control value. PTG, however, slightly increased with decreasing concentrations of apixaban. ttPeak and ttStart slightly decreased. Except for the subtherapeutic UFH concentration of 0,114 IU/mL, no thrombin was generated with UFH. Conclusion UFH is more effective in inhibiting downstream thrombin generation compared to apixaban as a response to activation of the CA pathway in vitro. These findings could help explain why direct inhibitors were not able to show non-inferiority in patients with mechanical heart valves and support the development of specific CA pathway inhibitors for patients with conditions that activate the CA pathway. Thrombin generation curves Funding Acknowledgement Type of funding source: None

Influence of Direct Oral Anticoagulants on Anti–Factor Xa Measurements Utilized for Monitoring Heparin

2017 ◽  
Vol 52 (2) ◽  
pp. 154-159 ◽  
Author(s):  
Kelly A. Macedo ◽  
Peter Tatarian ◽  
Kenneth R. Eugenio
Keyword(s):  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Factor Xa
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