Anticoagulants and Antiplatelet Drugs

Higher risk of major hemorrhage associated with concomitant use of dabigatran and simvastatin compared to other statins was previously reported with a suggestion of P-glycoprotein-mediated interaction. The aim of this study was to evaluate the effects of simvastatin on pharmacokinetics and anticoagulant effects of dabigatran, a direct oral anticoagulant. A total of 12 healthy subjects were enrolled in an open-label, two-period, single sequence study. Subjects were given 150 mg of dabigatran etexilate followed by 40 mg of once-daily simvastatin for seven days. Dabigatran etexilate was administered with simvastatin on the seventh day of simvastatin administration. Blood samples for pharmacokinetic and pharmacodynamic analyses were obtained until 24 h post-dose of dabigatran etexilate with or without co-administration of simvastatin. Pharmacokinetic parameters were derived from noncompartmental analysis for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide. When simvastatin was co-administered, geometric mean ratios of area under time-concentration curves for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were 1.47, 1.21, and 1.57, respectively, compared to when dabigatran etexilate was administered alone. Thrombin generation assay and coagulation assay showed similar profiles between before and after co-administration of simvastatin. This study provides evidence that simvastatin treatment plays a minor role in modulating pharmacokinetics and anticoagulant effects of dabigatran etexilate. Full article

Doxorubicin (Dox) is a widely utilized chemotherapeutic; however, it carries side effects, including drug-induced immune thrombocytopenia (DITP) and increased risk of venous thromboembolism (VTE). Currently, the mechanisms for Dox-associated DITP and VTE are poorly understood, and an effective inhibitor to relieve these complications remains to be developed. In this study, we found that Dox significantly induced platelet activation and enhanced platelet phagocytosis by macrophages and accelerated platelet clearance. Importantly, we determined that salvianolic acid C (SAC), a water-soluble compound derived from Danshen root traditionally used to treat cardiovascular diseases, inhibited Dox-induced platelet activation more effectively than current standard-of-care anti-platelet drugs aspirin and ticagrelor. Mechanism studies with tyrosine kinase inhibitors indicate contributions of phospholipase C, spleen tyrosine kinase, and protein kinase C signaling pathways in Dox-induced platelet activation. We further demonstrated that Dox enhanced platelet-cancer cell interaction, which was ameliorated by SAC. Taken together, these findings suggest SAC may be a promising therapy to reduce the risk of Dox-induced DITP, VTE, and the repercussions of amplified platelet-cancer interaction in the tumor microenvironment. Full article

Background: Phenprocoumon has been used as an oral anticoagulant in patients with thromboembolic disease for more than 40 years. So far its pharmacokinetics have not been analyzed in emergency situations. Methods: Phenprocoumon-treated patients with major bleeding or urgent surgery were included in a prospective, observational registry. Phenprocoumon drug concentrations were analyzed in samples, collected as part of routine care using ultraperformance liquid chromatography tandem mass spectrometry. Moreover, anticoagulant intensity and drug half-life (t1/2) were calculated. Results: 115 patients were included. Phenprocoumon levels declined over time with a half-life of 5.27 and 5.29 days in patients with major bleedings (n = 82) and with urgent surgery (n = 33). Baseline phenprocoumon levels were 2.2 times higher in the bleeding group compared to the surgery group (1.92 vs. 0.87 ng/mL, p < 0.0001). International normalized ratio (INR) values decreased rapidly during the first 24 h. In 27.6% of patients a rebound of INR (recurrent increase > 1.5) was observed which was associated with significantly increased bleeding rates (22% vs. 4.2% in patients with or without INR rebound, p = 0.012). Conclusions: In emergency situations, the long half-life of phenprocoumon may cause INR rebound and associated recurrent bleedings. Optimal management may need to include repeated vitamin K supplementation over days. Full article

New antithrombotic drugs are needed to combat thrombosis, a dangerous pathology that causes myocardial infarction and ischemic stroke. In this respect, thrombin (FIIa) represents an important drug target. We herein report the synthesis and biological activity of a series of 1H-pyrazol-5-amine-based thrombin inhibitors with a serine-trapping mechanism of action. Among synthesized compounds, flexible acylated 1H-pyrazol-5-amines 24e, 34a, and 34b were identified as potent 16–80 nM thrombin inhibitors, which showed practically no off-targeting effect against other physiologically relevant serine proteases. To prove that synthesized compounds are covalent thrombin inhibitors, the most potent derivative 24e (FIIa IC₅₀ = 16 nM) was studied in a mass-shift assay, where it has been shown that 24e transfers its acyl moiety (pivaloyl) to the catalytic Ser195 of thrombin. Performed herein docking studies also confirmed the covalent mechanism of thrombin inhibition by synthesized compounds. Acylated aminopyrazoles found during this study showed only limited effects on plasma coagulation in activated partial thrombin time (aPTT) and prothrombin time (PT) in vitro assays. However, such thrombin inhibitors are expected to have virtually no effect on bleeding time and can be used as a starting point for developing a safer alternative to traditional non-covalent anticoagulants. Full article

We have previously demonstrated that platelet-poor plasma (PPP) obtained from patients with Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is characterized by a hypercoagulable state and contains hyperactivated platelets and considerable numbers of already-formed amyloid fibrin(ogen) or fibrinaloid microclots. Due to the substantial overlap in symptoms and etiology between Long COVID/PASC and ME/CFS, we investigated whether coagulopathies reflected in Long COVID/PASC—hypercoagulability, platelet hyperactivation, and fibrinaloid microclot formation—were present in individuals with ME/CFS and gender- and age-matched healthy controls. ME/CFS samples showed significant hypercoagulability as judged by thromboelastography of both whole blood and platelet-poor plasma. The area of plasma images containing fibrinaloid microclots was commonly more than 10-fold greater in untreated PPP from individuals with ME/CFS than in that of healthy controls. A similar difference was found when the plasma samples were treated with thrombin. Using fluorescently labelled PAC-1, which recognizes glycoprotein IIb/IIIa, and CD62P, which binds P-selectin, we observed hyperactivation of platelets in ME/CFS hematocrit samples. Using a quantitative scoring system, the ME/CFS platelets were found to have a mean spreading score of 2.72 ± 1.24 vs. 1.00 (activation with pseudopodia formation) for healthy controls. We conclude that ME/CFS is accompanied by substantial and measurable changes in coagulability, platelet hyperactivation, and fibrinaloid microclot formation. However, the fibrinaloid microclot load was not as great as was previously noted in Long COVID/PASC. Fibrinaloid microclots, in particular, may contribute to many ME/CFS symptoms, such as fatigue, seen in patients with ME/CFS, via the (temporary) blockage of microcapillaries and hence ischemia. Furthermore, fibrinaloid microclots might damage the endothelium. The discovery of these biomarkers represents an important development in ME/CFS research. It also points to possible uses for treatment strategies using known drugs and/or nutraceuticals that target systemic vascular pathology and endothelial inflammation. Full article

Acute myocardial infarction (AMI) is associated with heightened thrombin generation. There are limited data relating to thrombin generation and left ventricular (LV) scarring and LV dilatation in post-MI LV remodeling. We studied 113 patients with ST-segment elevation myocardial infarction (STEMI) who had undergone primary percutaneous coronary intervention (PPCI) (n = 76) or pharmaco-invasive management (thrombolysis followed by early PCI, n = 37). Endogenous thrombin potential (ETP) was measured at baseline, 1 month and 6 months. Cardiovascular magnetic resonance imaging was performed at baseline and 6 months post-MI. Outcomes studied were an increase in scar change, which was defined as an increase in left ventricular infarct size of any magnitude detected by late gadolinium enhancement, adverse LV remodeling, defined as dilatation (increase) of left ventricular end-diastolic volume (LVEDV) by more than 20% and an increase in left ventricular ejection fraction (LVEF). The mean age was 55.19 ± 8.25 years and 91.2% were men. The baseline ETP was similar in the PPCI and pharmaco-invasive groups (1400.3 nM.min vs. 1334.1 nM.min, p = 0.473). Each 10-unit increase in baseline ETP was associated with a larger scar size (adjusted OR 1.020, 95% CI 1.002–1.037, p = 0.027). Baseline ETP was not associated with adverse LV remodeling or an increase in LVEF. There was no difference in scar size or adverse LV remodeling among patients undergoing PPCI vs. pharmaco-invasive management or patients receiving ticagrelor vs. clopidogrel. Enhanced thrombin generation after STEMI is associated with a subsequent increase in myocardial scarring but not LV dilatation or an increase in LVEF at 6 months post-MI. Full article

Growth differentiation factor (GDF)-15 inhibits platelet activation, prevents thrombus formation, and has been linked to bleeding events. This was a prospective study including 51 left-ventricular assist device (LVAD) patients on aspirin and phenprocoumon. Platelet surface expression of activated glycoprotein (GP) IIb/IIIa was assessed by flow cytometry, and platelet aggregation was measured by multiple electrode aggregometry (MEA) in response to arachidonic acid (AA), adenosine diphosphate (ADP), and thrombin receptor-activating peptide (TRAP), a protease-activated-receptor-1 (PAR-1) agonist. GDF-15 was determined with a commercially-available assay. There was a trend towards an inverse correlation of GDF-15 with activated GPIIb/IIIa in response to TRAP (r = −0.275, p = 0.0532) but not in response to AA and ADP. Moreover, GDF-15 correlated with MEA TRAP (r = −0.326, p = 0.0194), whereas it did not correlate with MEA ADP and MEA AA. In a second step, GDF-15 levels in the fourth quartile were defined as high GDF-15. Patients with high GDF-15 showed significantly lower TRAP-inducible platelet aggregation by MEA compared to patients in the first quartile (63 AU vs. 113 AU, p = 0.0065). In conclusion, in LVAD patients receiving state-of-the-art antithrombotic therapy, GDF-15 correlates inversely with residual platelet reactivity via PAR-1. Full article

The association between cancer and a hypercoagulatory environment is well described. Thrombotic complications serve not only as a major mortality risk but the underlying molecular structure and function play significant roles in enhancing tumour progression, which is defined as the tumour’s capacity to survive, invade and metastasise, amongst other hallmarks of the disease. The use of anticoagulant or antiplatelet drugs in cardiovascular disease lessens thrombotic effects, but the consequences on tumour progression require interrogation. Therefore, this review considered developments in the management of platelet activation pathways (thromboxane, ADP and thrombin), focusing on the use of Aspirin, Clopidogrel and Atopaxar, and their potential impacts on tumour progression. Published data suggested a cautionary tale in ensuring we adequately investigate not only drug–drug interactions but also those unforeseen reciprocal interactions between drugs and their targets within the tumour microenvironment that may act as selective pressures, enhancing tumour survival and progression. Full article

Peripheral arterial disease (PAD), a manifestation of systemic atherosclerosis, is underdiagnosed in the general population. Despite the extensive research performed to unravel its pathophysiology, inadequate knowledge exists, thus preventing the development of new treatments. This review aims to highlight the essential elements of atherosclerosis contributing to the pathophysiology of PAD. Furthermore, emphasis will be placed on the role of thrombo-inflammation, with particular focus on platelet and coagulation activation as well as cell–cell interactions. Additional insight will be then discussed to reveal the contribution of hypercoagulability to the development of vascular diseases such as PAD. Lastly, the current antithrombotic treatments will be discussed, and light will be shed on promising new targets aiming to aid the development of new treatments. Full article