Secondary prevention of thrombosis with direct oral anticoagulants for hereditary hematogenous thrombophilia

Prevention Of Thrombosis ◽

Congenital Deficiency ◽

Hemorrhagic Complications ◽

Hereditary Factors ◽

Aim. The article describes the experience of using direct oral anticoagulants – drugs Dabigatran, Rivaroxaban and Apixaban for the secondary prevention of thrombosis in patients with the most common variants of hereditary hematogenous thrombophilia.Materials and methods. 86 patients were under observation: 53 men, 33 women. Only the registered fact of thrombosis, thromboembolism, ischemia or organ infarction was the basis for the diagnosis of hematogenous thrombophilia and further secondary prevention of thrombosis. In 80 cases, there was a combined form of thrombophilia. In addition to hereditary factors, there were acquired thrombogenic factors. Dabigatran etexilate (Pradaxa®) for the prevention of thrombus formation was prescribed to 41 patients aged 20 to 60 years; duration of admission from 12 months to 9 years, the dose of the drug was selected individually from 150 to 300 mg per day. Rivaroxaban (Xarelto®) for the prevention of thrombus formation was prescribed to 25 patients aged 18 to 54 years, duration of admission from 12 months to 7 years, the dose of the drug is 10-20 mg per day. Apixaban (Eliquis®) was prescribed to 10 patients, aged 30 to 50 years, the duration of admission was from 6 months up to 2 years, dosage 5-10 mg per day. For hyperhomocysteinemia, Angiovit® or Pentavit® was prescribed. Protein C and antithrombin III preparations with their congenital deficiency were used according to indications.Results. After Dabigatran was prescribed, only one patient had a recurrent pulmonary embolism due to low adherence to treatment. In other patients who were prescribed direct oral anticoagulants, no recurrence of thrombotic complications was recorded. No hemorrhagic complications were diagnosed with the use of Dabigatran and Apixaban. In 5 patients receiving Rivaroxaban, there were minor epistaxis; in three cases they stopped when the dose was reduced from 20 to 15-10 mg, two patients were transferred to dabigatran. No life-threatening bleeding has been reported.Conclusion. Dabigatran, Rivaroxaban and Apixaban are effective and safe drugs for antithrombotic therapy. The absence of the need for constant laboratory monitoring and extremely rare hemorrhagic complications makes it possible to use them in patients living in areas remote from large medical centers. Only 10 patients under our supervision with a diagnosis of “hematogenous thrombophilia” are currently taking warfarin. Timely diagnosis of the variant of hematogenous thrombophilia and the appointment of adequate anti-thrombotic therapy contributes to the relapse-free course of the disease.

Faculty Opinions recommendation of Efficacy and Harms of Direct Oral Anticoagulants in the Elderly for Stroke Prevention in Atrial Fibrillation and Secondary Prevention of Venous Thromboembolism: Systematic Review and Meta-Analysis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725514028.793512947 ◽

2016 ◽

Author(s):

Nanette Wenger

Keyword(s):

Atrial Fibrillation ◽

Systematic Review ◽

Venous Thromboembolism ◽

Secondary Prevention ◽

Stroke Prevention ◽

Meta Analysis ◽

Oral Anticoagulants ◽

The Elderly

A Review on the Use of Reversal Agents of Direct Oral Anticogulant Drugs in Case of Gastrointestinal Bleeding

Reviews on Recent Clinical Trials ◽

10.2174/1574887115666200624193938 ◽

2020 ◽

Vol 15 ◽

Author(s):

Veronica Ojetti ◽

Angela Saviano ◽

Mattia Brigida ◽

Luisa Saviano ◽

Alessio Migneco ◽

...

Keyword(s):

Gastrointestinal Bleeding ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Medical Emergency ◽

Management Approach ◽

Emergency Setting ◽

Reversal Agents ◽

Life Threatening ◽

Andexanet Alfa

Background : Major bleeding is a life-threatening condition and a medical emergency with high mortality risk. It is often the complication of anticoagulant’s intake. Anticoagulants are commonly used for the prevention and the treatment of thrombotic events. The standard therapy with vitamin K antagonist (warfarin) has been frequently replaced by direct oral anticoagulants (DOACs). The latter agents (rivaroxaban, apixaban, edoxaban, dabigatran, betrixaban) showed a better efficacy and safety compared to standard warfarin treatment and they are recommended for the reduction of ischemic stroke. Literature data reported a high risk of gastrointestinal bleeding with DOACs, in particular with dabigatran and rivaroxaban. In case of life-threatening gastrointestinal bleeding, these patients could benefit from the use of reversal agents. Methods: We performed an electronic search on PUBMED of the literature concerning reversal agents for DOACs and gastrointestinal bleeding in the Emergency Department from 2004 to 2020. AIM: This review summarizes the current evidences about three reversal agents idarucizumab, andexanet alfa and ciraparantag, and the use of the first two in the emergency setting in patients with an active major bleeding or who need urgent surgery to offer physicians indications for a better management approach in order to increase patient’s safety. Conclusion: Although these agents have been marketed for five years (idarucizumab) and two years (andexanet alfa) respectively, and despite guidelines considering antidotes as first-line agents in treating life-threatening hemorrhage when available, these antidotes seem to gain access very slowly in the clinical practice. Cost, logistical aspects and need for plasma level determination of DOAC for an accurate therapeutic use probably have an impact on this phenomenon.. An expert multidisciplinary bleeding team should be established so as to implement international guidelines based on local resources and organization.

Apixaban versus Warfarin in Patients with Left Ventricular (LV) Thrombus, a prospective randomized trial

European Heart Journal ◽

10.1093/ehjci/ehaa946.1545 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

R Alcalai ◽

R Rashad ◽

A Butnaru ◽

G Moravsky ◽

D Leibowitz

Keyword(s):

Major Bleeding ◽

Thrombus Formation ◽

Oral Anticoagulants ◽

Left Ventricular ◽

Systemic Embolism ◽

Bleeding Events ◽

Open Label ◽

Warfarin Group ◽

Acute Mi

Abstract Background Patients with acute myocardial infarction (MI) have an elevated risk of stroke, mostly due to left ventricular (LV) thrombus formation, which typically occur within the first 2 weeks following an anterior MI. Currently the recommended management of LV thrombus after acute MI is anticoagulation with vitamin K antagonist. To date, there are no prospective data on the use of direct oral anticoagulants (DOACS) for stroke prevention in the setting of LV thrombus. Aim To assess the efficacy of apixaban vs. warfarin in treating LV thrombus after MI. Methods The study is a prospective, randomized, multi-center open label trial comparing apixaban (at a dose of 5 mg twice daily) with s.c enoxaparin 1mg/kg BID followed by dose-adjusted warfarin to achieve a target international normalized ratio (INR) of 2.0 to 3.0 for 3 months in patients with LV thrombus detected by echocardiography 3 to 14 days after acute MI. The primary outcome was the presence and size of LV thrombus 3 months after initiation of anticoagulation as assessed by 2D echocardiogram. Secondary outcomes were stroke or systemic embolism, major bleeding and death from any cause. Results 25 patients have been enrolled to date in 3 medical centers, 13 were randomized to apixaban and 12 to warfarin. Mean age was 59.8±10.7 and 19 (76%) were males with no difference between the study groups. Mean LV thrombus size at enrollment was 24X15 mm in the apixaban group and 19X14 in the warfarin group (p=NS). After 3 months of treatment thrombus completely resolved in all patients in the warfarin group and in 12 of 13 in the apixaban group. In one patient in the apixaban group who had a very large thrombus of 40x20mm size upon enrollment the thrombus size was reduced significantly to 20x12 after 3 months. No death, stroke or systemic embolism was documented in either group. There were two patients with major bleeding in the warfarin group, one had sub-arachnoid hemorrhage after 2 months and anticoagulation was stopped, and another had GI bleeding after 1 month and was switched to enoxaparin. One patient in the warfarin group refused to continue the treatment after 3 weeks. No major bleeding events were recorded in the apixaban group and all patients completed 3 months of treatment. Conclusions Our preliminary results indicate that apixaban is a safe and effective treatment for patients with LV thrombus post anterior wall MI. Funding Acknowledgement Type of funding source: None

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

European Heart Journal ◽

10.1093/ehjci/ehaa946.3776 ◽

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 ◽

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

Life-Threatening Non-Allergic Drug Hypersensitivity Reaction as a Very Rare Side Effect of Rivaroxaban Administration in the Netherlands

Vascular and Endovascular Surgery ◽

10.1177/15385744211004763 ◽

2021 ◽

pp. 153857442110047

Author(s):

Nadia A. G. Hakkenbrak ◽

Maarten Truijers

Keyword(s):

The Netherlands ◽

Hypersensitivity Reaction ◽

Anaphylactic Reaction ◽

Side Effect ◽

Drug Hypersensitivity ◽

Oral Anticoagulants ◽

Clinical Signs ◽

Hemorrhagic Complications ◽

Drug Hypersensitivity Reaction ◽

Background: Anticoagulant therapy is indicated for the prevention and treatment of thromboembolic disease. Direct oral anticoagulants (DOACs) are frequently prescribed and Rivaroxaban is the most frequently administered DOAC in the Netherlands. Most side effects relate to hemorrhagic complications, however, also non-hemorrhagic side effect may be potentially life threatening. Case presentation: A 74-year-old man presented at the emergency department with a ruptured infrarenal abdominal aortic aneurysm for which open aneurysm repair was performed. Postoperatively, the patient developed neurological deficit, respiratory and circulatory failure following rivaroxaban administration, initiated for atrial fibrillation. Even though, the clinical signs resembled an anaphylactic reaction, the skin-prick test was negative and complications most likely resulted from a non-allergic drug hypersensitivity reaction. Conclusion: This case report shows that non-allergic drug hypersensitivity reactions may mimic an anaphylactic reaction and can be potentially life threatening. In addition, severe non-hemorrhagic complications after rivaroxaban administration do occur and should be considered in case of acute clinical deterioration.

Reversal Strategies for Intracranial Hemorrhage Related to Direct Oral Anticoagulant Medications

Critical Care Research and Practice ◽

10.1155/2018/4907164 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 7

Author(s):

Alok Dabi ◽

Aristides P. Koutrouvelis

Keyword(s):

Side Effects ◽

Intracranial Hemorrhage ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Factor Xa ◽

Coagulation Cascade ◽

Reversal Agents ◽

United States Food ◽

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.

Azolo[1,5-a]pyrimidines and Their Condensed Analogs with Anticoagulant Activity

Molecules ◽

10.3390/molecules27010274 ◽

2022 ◽

Vol 27 (1) ◽

pp. 274

Author(s):

Konstantin V. Savateev ◽

Victor V. Fedotov ◽

Vladimir L. Rusinov ◽

Svetlana K. Kotovskaya ◽

Alexandr A. Spasov ◽

...

Keyword(s):

Bacterial Infections ◽

Anticoagulant Activity ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Antiviral Agents ◽

Multiple Organ ◽

Thrombin Time ◽

Cytokine Storm ◽

Reference Drug

Hypercytokinemia, or cytokine storm, is one of the severe complications of viral and bacterial infections, involving the release of abnormal amounts of cytokines, resulting in a massive inflammatory response. Cytokine storm is associated with COVID-19 and sepsis high mortality rate by developing epithelial dysfunction and coagulopathy, leading to thromboembolism and multiple organ dysfunction syndrome. Anticoagulant therapy is an important tactic to prevent thrombosis in sepsis and COVID-19, but recent data show the incompatibility of modern direct oral anticoagulants and antiviral agents. It seems relevant to develop dual-action drugs with antiviral and anticoagulant properties. At the same time, it was shown that azolo[1,5-a]pyrimidines are heterocycles with a broad spectrum of antiviral activity. We have synthesized a new family of azolo[1,5-a]pyrimidines and their condensed polycyclic analogs by cyclocondensation reactions and direct CH-functionalization and studied their anticoagulant properties. Five compounds among 1,2,4-triazolo[1,5-a]pyrimidin-7-ones and 5-alkyl-1,3,4-thiadiazolo[3,2-a]purin-8-ones demonstrated higher anticoagulant activity than the reference drug, dabigatran etexilate. Antithrombin activity of most active compounds was confirmed using lipopolysaccharide (LPS)-treated blood to mimic the conditions of cytokine release syndrome. The studied compounds affected only the thrombin time value, reliably increasing it 6.5–15.2 times as compared to LPS-treated blood.

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

Advances in Hematology ◽

10.1155/2015/920361 ◽

2015 ◽

Vol 2015 ◽

pp. 1-19 ◽

Cited By ~ 5

Author(s):

Ali Zalpour ◽

Thein Hlaing Oo

Keyword(s):

Vitamin K Antagonists ◽

Dabigatran Etexilate ◽

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.

Combining antiplatelet and anticoagulant therapy in cardiovascular disease

Hematology ◽

10.1182/hematology.2020000151 ◽

2020 ◽

Vol 2020 (1) ◽

pp. 642-648

Author(s):

Geoffrey D. Barnes

Keyword(s):

Randomized Clinical Trials ◽

Oral Anticoagulants ◽

Thrombotic Event ◽

Bleeding Risk ◽

Antithrombotic Agents ◽

Thrombotic Risk ◽

Coronary Syndrome ◽

Combined Use ◽

Abstract Up to 10% of the >3 million Americans with atrial fibrillation will experience an acute coronary syndrome or undergo percutaneous coronary intervention. Therefore, concurrent indications for multiple antithrombotic agents is a common clinical scenario. Although each helps reduce thrombotic risk, their combined use significantly increases the risk of major bleeding events, which can be life threatening. In the past 5 years, a number of randomized clinical trials have explored different combinations of anticoagulation plus antiplatelet agents aimed at minimizing bleeding risk while preserving low thrombotic event rates. In general, shorter courses with fewer antithrombotic agents have been found to be effective, particularly when direct oral anticoagulants are combined with clopidogrel. Combined use of very low-dose rivaroxaban plus aspirin has also demonstrated benefit in atherosclerotic diseases, including coronary and peripheral artery disease. Use of proton pump inhibitor therapy while patients are taking multiple antithrombotic agents has the potential to further reduce upper gastrointestinal bleeding risk in select populations. Applying this evidence to patients with multiple thrombotic conditions will help to avoid costly and life-threatening adverse medication events.