Pharmacotherapy of Thromboembolism

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 25 October 2026 | Viewed by 29788

Special Issue Editors


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Guest Editor
1. Department of Internal Medicine I., Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin University Hospital, 03659 Martin, Slovakia
2. Division of acute and interventional cardiology, Department of Cardiology and Angiology II, Mid-Slovakian Institiute of Heart and Vessel Diseases (SÚSCCH) in Banská Bystrica, Slovakia
Interests: antithrombotic therapy; direct oral anticoagulants; laboratory monitoring of antithrombotic therapy; factors influencing the efficacy of antithrombotic therapy; stent thrombosis

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Guest Editor
Department of Internal Medicine I, Jesseniuss Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
Interests: direct oral anticoagulants; gastroprotection and antithrombotic therapy; bleeding on antithrombotic agents; factors influencing the efficacy of antithrombotic therapy

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Guest Editor
Department of Internal Medicine I, Jesseniuss Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia
Interests: type 2 diabetes and thromboembolism; antithrombotic therapy in diabetic patients; direct oral anticoagulants; hypoglycemia

Special Issue Information

Dear Colleagues,

Thromboembolism (arterial and venous) is still an emergency clinical situation with high mortality and postevent morbidity. Moreover, the number of patients at risk for antithrombotic therapy-related complications who require long-term anticoagulation is increasing. Long-term antithrombotic therapy in patients with chronic diseases, elderly and frail patients, patients with cancer-related thromboembolism, or patients with the need for chronic anticoagulation who undergo vascular interventions could be problematic. Currently, the long-term pharmacotherapy of thromboembolism remains challenging and needs further research.

In addition, with the growing complexity of interventional procedures, the risk of future thrombotic complications increases. Antithrombotic therapy is crucial to prevent or to treat these complications. The role of modern antiplatelet agents in the prevention of thrombotic target lesion failure is being questioned and widely studied, but still with conflicting results, not allowing any final recommendations.

Finally, several novel antithrombotic agents, namely activated factor XI inhibitors, platelet glycoprotein VI antagonists, PAR4 antagonists, and PI3K inhibitors, are being either intensively studied, or introduced to phase II or III clinical testing. These novel agents could improve the efficacy and/or safety of long-term anticoagulation in future and require our attention.

This Special Issue has the aim to summarize the state-of-the-art drug discovery and drug design, and the latest findings in the field of long-term antithrombotic therapy, management of antithrombotic therapy in challenging clinical situations, and antithrombotic strategies in acute thrombotic complications during invasive vascular procedures. Original articles and reviews are welcomed for publication in this Special Issue.

Some of the questions that could tackle the Special Issue theme include, but are not limited to, the following:  

  • Activated factor XI inhibitors as an anti-thrombotica and anticoagulant agent in treatment of thromboembolism.
  • Synthesis, biological evaluation and molecular modeling studies of different platelet glycoprotein VI antagonists.
  • Small molecules in the field of antiplatelet agents with Protease activated receptor 4 (PAR4) antagonistic mechanism.
  • Current progress of using PI3K inhibitors in therapy.
  • Safety of long-term anticoagulant therapy use.
  • Drug-drug interactions of anticoagulants with different therapeutics.

Dr. Matej Samoš
Dr. Tomáš Bolek
Prof. Dr. Marián Mokáň
Guest Editors

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Keywords

  • activated factor XI inhibitors
  • platelet glycoprotein VI antagonists
  • PAR4 antagonists
  • PI3K inhibitorslong-term anticoagulation
  • antiplatelet therapy
  • novel antithrombotic drugs
  • anticoagulation-related bleeding
  • post-vascular procedure-related thrombosis

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Published Papers (8 papers)

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Research

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24 pages, 382 KB  
Article
An Investigational Study on the Role of ADME Agents’ Genetic Variation on DD217 Pharmacokinetics and Safety Profile
by Dmitry A. Sychev, Sherzod P. Abdullaev, Anastasia V. Rudik, Alexander V. Dmitriev, Svetlana N. Tuchkova, Natalia P. Denisenko, Denis S. Makarov and Karin B. Mirzaev
Pharmaceuticals 2025, 18(11), 1617; https://doi.org/10.3390/ph18111617 - 27 Oct 2025
Viewed by 1322
Abstract
Background/Objectives: Direct oral anticoagulants (DOACs) have transformed the prevention of thromboembolic events, but their efficacy and safety remain highly variable across individuals. DD217, a novel oral direct factor Xa inhibitor, has demonstrated potent anticoagulant activity in preclinical and clinical studies. No pharmacogenetic [...] Read more.
Background/Objectives: Direct oral anticoagulants (DOACs) have transformed the prevention of thromboembolic events, but their efficacy and safety remain highly variable across individuals. DD217, a novel oral direct factor Xa inhibitor, has demonstrated potent anticoagulant activity in preclinical and clinical studies. No pharmacogenetic data are currently available for this compound. Based on in silico predictions of metabolic pathways and transporter involvement, and evidence from other DOACs, we hypothesized that variants in CYP2C and P-glycoprotein genes may contribute to variability in pharmacokinetics (PK) and clinical outcomes. Methods: Fifty-two patients undergoing total knee arthroplasty were enrolled, of whom 34 received the investigational drug (40 mg/day, n = 16; 60 mg/day, n = 18). DNA was extracted from peripheral blood cells, and genotyping of CYP2C9, CYP2C19, CYP2C8, CYP3A4, CYP3A5, and ABCB1 was performed by real-time PCR. Pharmacokinetics (PK) parameters (Tmax, AUClast, Cmax) were assessed. In silico docking and pathway modeling predicted CYP2C and P-glycoprotein (ABCB1) involvement in drug disposition. Associations of genetic variants with PK parameters and adverse events (thrombosis, bleeding) were analyzed. Results: Carriers of reduced-function CYP2C9 alleles (intermediate [IM] or poor metabolizers [PM]) in the 60 mg group had a significantly shorter Tmax compared with normal metabolizers (p = 0.005227), with trends toward higher AUClast (p = 0.06926) and Cmax (p = 0.1259). No significant associations were observed for CYP2C19, CYP3A4/5, or CYP2C8. In contrast, ABCB1 polymorphisms were associated with systemic exposure: carriers of the C allele at rs1045642 had higher AUClast and Cmax compared to TT (wild-type) homozygotes, while rs2032582 T allele carriers showed lower exposure (p < 0.05). At the haplotype level, the C–G–C–T combination of ABCB1 was more frequent in patients with thrombotic events at the 40 mg dose (p = 0.038). Overall, 5 thrombosis events and 1 bleedings were recorded on DD217, with no consistent associations to single SNPs. Conclusions: This first pharmacogenetic evaluation of DD217 shows that CYP2C9 variants are associated with differences in early-phase pharmacokinetics (Tmax), while ABCB1 polymorphisms appear to modulate systemic exposure (AUClast, Cmax) and may influence thrombotic risk. These observations are consistent with in silico predictions of metabolic and transporter pathways. Despite limitations in sample size and event frequency, the study highlights the feasibility and importance of early pharmacogenetic evaluation during the drug development cycle of novel DOACs. Full article
(This article belongs to the Special Issue Pharmacotherapy of Thromboembolism)
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20 pages, 2804 KB  
Article
A Descriptive Analysis of Direct Oral Anticoagulant Drugs Dosing Errors Based on Spontaneous Reports from the EudraVigilance Database
by Claudiu Morgovan, Carmen Maximiliana Dobrea, Adriana Aurelia Chis, Anca Maria Juncan, Anca Maria Arseniu, Luca Liviu Rus, Felicia Gabriela Gligor, Simona Alexandrina Ardelean, Laurentiu Stoicescu, Steliana Ghibu and Adina Frum
Pharmaceuticals 2023, 16(3), 455; https://doi.org/10.3390/ph16030455 - 17 Mar 2023
Cited by 21 | Viewed by 4598
Abstract
Direct oral anticoagulant drugs (DOACs) interfere with the coagulation process, thus improving patient care for those who require anticoagulant treatment. This study presents a descriptive analysis of adverse reactions (ADRs) attributed to DOAC dosage errors (overdose, underdose, and improper dose). The analysis was [...] Read more.
Direct oral anticoagulant drugs (DOACs) interfere with the coagulation process, thus improving patient care for those who require anticoagulant treatment. This study presents a descriptive analysis of adverse reactions (ADRs) attributed to DOAC dosage errors (overdose, underdose, and improper dose). The analysis was performed based on the Individual Case Safety Reports from the EudraVigilance (EV) database. Results show that data reported for rivaroxaban, apixaban, edoxaban, and dabigatran are mostly regarding underdosing (51.56%) compared to overdosing (18.54%). The most dosage error reports were identified for rivaroxaban (54.02%), followed by apixaban (33.61%). Dabigatran and edoxaban had similar percentages (6.26% and 6.11%, respectively) regarding dosage error reports. Since coagulation issues can become life-threatening events, and factors such as advanced age and renal failure can influence the pharmacokinetics of drugs, the correct usage of DOACs is of utmost importance for the management and prevention of venous thromboembolism. Thus, the collaboration and the complementarity of knowledge of physicians and pharmacists may offer a reliable solution for DOAC dose management and improve patient care. Full article
(This article belongs to the Special Issue Pharmacotherapy of Thromboembolism)
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Review

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25 pages, 4686 KB  
Review
Beyond Direct Fibrinolysis: Novel Approaches to Thrombolysis
by Alexey M. Shibeko, Nikita S. Nikitin, Nadezhda A. Podoplelova, Valentin A. Manuvera and Vassili N. Lazarev
Pharmaceuticals 2026, 19(1), 10; https://doi.org/10.3390/ph19010010 - 20 Dec 2025
Viewed by 1827
Abstract
Fibrinolysis is a natural component of hemostasis in which a no-longer-needed clot is gradually dissolved to restore blood flow. Under pathological thrombotic conditions, this process can be pharmacologically enhanced to promote clot removal. However, thrombolytic therapy has limited efficacy and is associated with [...] Read more.
Fibrinolysis is a natural component of hemostasis in which a no-longer-needed clot is gradually dissolved to restore blood flow. Under pathological thrombotic conditions, this process can be pharmacologically enhanced to promote clot removal. However, thrombolytic therapy has limited efficacy and is associated with a risk of bleeding complications, including intracranial hemorrhage. Fibrinolysis targets only the fibrin-rich part of the thrombus, whereas a substantial fraction of the clot is enriched with non-fibrin components such as extracellular DNA, von Willebrand factor, and extracellular matrix proteins, including collagen, fibronectin, and laminin. These structural regions, which may constitute half or more of the clot volume, remain resistant to classical fibrinolytic agents. To overcome these limitations, recent therapeutic strategies aim to degrade these non-fibrin elements to improve thrombolytic efficacy and reduce adverse effects. In this review, we summarize current trends in pharmacological clot dissolution, discuss novel agents in clinical use and development, and outline how targeting non-fibrin components may influence the future of thrombolytic therapy. Full article
(This article belongs to the Special Issue Pharmacotherapy of Thromboembolism)
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23 pages, 758 KB  
Review
Danaparoid—Consensus Recommendations on Its Clinical Use
by Rupert M. Bauersachs, Edelgard Lindhoff-Last, Robert Klamroth, Andreas Koster, Marc Schindewolf and Harry Magnani
Pharmaceuticals 2024, 17(12), 1584; https://doi.org/10.3390/ph17121584 - 25 Nov 2024
Cited by 7 | Viewed by 4490
Abstract
(1) Background: Danaparoid sodium is a heparinoid antithrombotic that has been used for over 40 years for prophylaxis of DVT in non-HIT patients and for the treatment of heparin-induced thrombocytopenia (HIT) with and without thrombosis. This update summarises current information on its pharmacology [...] Read more.
(1) Background: Danaparoid sodium is a heparinoid antithrombotic that has been used for over 40 years for prophylaxis of DVT in non-HIT patients and for the treatment of heparin-induced thrombocytopenia (HIT) with and without thrombosis. This update summarises current information on its pharmacology and reviews danaparoid dose management in a broad spectrum of clinical situations, including off-label indications. (2) Methods: Evidence from published clinical studies, case reports, compassionate use of danaparoid, and spontaneously reported serious adverse events is summarised and analysed by an interdisciplinary expert group to develop a consensus on dosing regimens of danaparoid for complex clinical situations, including vulnerable patient populations. (3) Results: Dosing regimens are proposed, together with monitoring recommendations and target anti-factor Xa ranges. (4) Conclusion: In a comprehensive summary detailed interdisciplinary dosing recommendations are described to provide a basis for safe and effective use of danaparoid. Full article
(This article belongs to the Special Issue Pharmacotherapy of Thromboembolism)
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34 pages, 981 KB  
Review
Evaluating Thromboprophylaxis Strategies for High-Risk Pregnancy: A Current Perspective
by Lucia Stančiaková, Kristína Brisudová, Ingrid Škorňová, Tomáš Bolek, Matej Samoš, Kamil Biringer, Ján Staško and Juraj Sokol
Pharmaceuticals 2024, 17(6), 773; https://doi.org/10.3390/ph17060773 - 13 Jun 2024
Cited by 11 | Viewed by 6709
Abstract
Venous thromboembolism (VTE) represents one of the leading causes of death during pregnancy. The greatest risk for it is the presence of medical or family history of VTE, stillbirth, cesarean section and selected thrombophilia. Appropriate thromboprophylaxis has the potential to decrease the risk [...] Read more.
Venous thromboembolism (VTE) represents one of the leading causes of death during pregnancy. The greatest risk for it is the presence of medical or family history of VTE, stillbirth, cesarean section and selected thrombophilia. Appropriate thromboprophylaxis has the potential to decrease the risk of VTE in at-risk pregnant patients by 60–70%. Based on this, the authors reviewed the PubMed, Web of Science and Scopus databases to identify the possibilities of thromboprophylaxis in pregnant patients with a high risk of VTE. Moreover, they summarized its management in specific situations, such as cesarean delivery or neuraxial blockade. Currently, low-molecular-weight heparins (LMWH) are the preferred drugs for anticoagulant thromboprophylaxis in the course of pregnancy and postpartum due to easy administration and a lower rate of adverse events. Full article
(This article belongs to the Special Issue Pharmacotherapy of Thromboembolism)
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16 pages, 1340 KB  
Review
The Anti-Thrombotic Effects of PCSK9 Inhibitors
by Martin Jozef Péč, Jakub Benko, Jakub Jurica, Monika Péčová, Marek Samec, Tatiana Hurtová, Tomáš Bolek, Peter Galajda, Martin Péč, Matej Samoš and Marián Mokáň
Pharmaceuticals 2023, 16(9), 1197; https://doi.org/10.3390/ph16091197 - 22 Aug 2023
Cited by 9 | Viewed by 4742
Abstract
Atherosclerosis is the primary process that underlies cardiovascular disease. The connection between LDL cholesterol and the formation of atherosclerotic plaques is established by solid evidence. PCSK9 inhibitors have proven to be a valuable and practical resource for lowering the LDL cholesterol of many [...] Read more.
Atherosclerosis is the primary process that underlies cardiovascular disease. The connection between LDL cholesterol and the formation of atherosclerotic plaques is established by solid evidence. PCSK9 inhibitors have proven to be a valuable and practical resource for lowering the LDL cholesterol of many patients in recent years. Their inhibitory effect on atherosclerosis progression seems to be driven not just by lipid metabolism modification but also by LDL-independent mechanisms. We review the effect of PCSK9 inhibitors on various mechanisms involving platelet activation, inflammation, endothelial dysfunction, and the resultant clot formation. The main effectors of PCSK9 activation of platelets are CD36 receptors, lipoprotein(a), oxidised LDL particles, tissue factor, and factor VIII. Many more molecules are under investigation, and this area of research is growing rapidly. Full article
(This article belongs to the Special Issue Pharmacotherapy of Thromboembolism)
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13 pages, 681 KB  
Review
How to Treat Today? Oral and Facial Cancer-Associated Venous Thromboembolism
by Mária Janíčková, Tomáš Bolek, Lucia Stančiaková, Norbert Nagy, Marián Mokáň and Matej Samoš
Pharmaceuticals 2023, 16(7), 1011; https://doi.org/10.3390/ph16071011 - 17 Jul 2023
Viewed by 1892
Abstract
The exact incidence of cancer-associated venous thromboembolism (CA-VTE) in patients with oral and facial cancer (OFC) is not exactly known, and this risk is empirically considered to be low. However, this suggestion may result in disease underdiagnosis, prolong the initiation of adequate therapy, [...] Read more.
The exact incidence of cancer-associated venous thromboembolism (CA-VTE) in patients with oral and facial cancer (OFC) is not exactly known, and this risk is empirically considered to be low. However, this suggestion may result in disease underdiagnosis, prolong the initiation of adequate therapy, and consecutively increase CA-VTE-related morbidity and mortality. In addition, there might be specific clinical problems in the treatment of CA-VTE in patients with oral and facial cancer, such as swallowing difficulties, that might limit the possibilities of oral anticoagulation. Finally, there are limited data regarding the optimal treatment of CA-VTE in patients with oral and facial cancer, and this includes data on novel therapeutic strategies, including the use of direct oral anticoagulants. This article reviews current data on the optimal treatment strategy for CA-VTE in patients with OFC. Full article
(This article belongs to the Special Issue Pharmacotherapy of Thromboembolism)
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Other

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25 pages, 602 KB  
Systematic Review
Machine Learning for Warfarin Therapy: A Systematic Review
by Pavol Fülöp, Štefan Tóth, Tibor Porubän, Zuzana Fülöpová, Anna Borovská and Mariana Dvorožňáková
Pharmaceuticals 2025, 18(10), 1544; https://doi.org/10.3390/ph18101544 - 14 Oct 2025
Cited by 2 | Viewed by 2741
Abstract
Background: Despite the availability of direct oral anticoagulants, warfarin remains essential for mechanical valves, renal impairment, and resource-limited settings. Traditional dosing achieves therapeutic range in only 55–65% of patients, increasing bleeding and thrombotic complications. This systematic review evaluates the literature on machine learning [...] Read more.
Background: Despite the availability of direct oral anticoagulants, warfarin remains essential for mechanical valves, renal impairment, and resource-limited settings. Traditional dosing achieves therapeutic range in only 55–65% of patients, increasing bleeding and thrombotic complications. This systematic review evaluates the literature on machine learning (ML) approaches for warfarin dose prediction (2022–2025). Methods: We analysed 14 studies encompassing 122,400 patients across nine countries following PRISMA guidelines. Studies utilizing ML algorithms for warfarin dosing with quantifiable performance metrics were included. Risk of bias was assessed using PROBAST. Results: Reinforcement learning demonstrated superior performance, achieving an 80.8% excellent responder ratio versus 41.6% for standard practice and 99.5% safety responder ratio versus 83.1%. Support vector machines achieved R2 up to 0.98 in homogeneous populations. Mean absolute error ranged from 0.11 to 1.8 mg/day, consistently outperforming traditional methods. Seven studies included external validation, whilst 78.6% were retrospective designs. Limited implementation studies showed therapeutic INR rates improving from 47.5% to 61.1%. Critically, only three studies (21.4%) reported any safety outcomes, with none adequately powered to detect differences in major bleeding events. Conclusions: While ML algorithms demonstrate improved dosing accuracy in retrospective analyses, the near-complete absence of adequately powered safety outcome data represents the primary barrier to clinical implementation. Without robust evidence on bleeding, thromboembolism, and mortality, the risk–benefit profile remains unknown. Implementation requires addressing: the predominance of retrospective studies (78.6%), limited prospective validation, restricted geographic diversity (43% from China), absence of African and South American studies, and no new Hispanic population data. Multicentre prospective trials with safety endpoints, population-specific validation, and interpretable models are essential before widespread clinical adoption can be recommended. Full article
(This article belongs to the Special Issue Pharmacotherapy of Thromboembolism)
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