INTRODUCTION: It is well known that platelets from diabetic patients can be resistant to clinically used antiplatelet drugs. METHODS: To assess the phenomenon in more detail, 50 adult patients suffering from type 1 diabetes mellitus (T1D) were recruited and their responses to 7 platelet aggregation inducers, as well as to 3 clinically used antiplatelet drugs (acetylsalicylic acid /ASA/, ticagrelor and vorapaxar) and one experimental compound, 4-methylcatechol, were assessed ex vivo. A control group of 50 generally healthy age-matched controls was also included for comparison. RESULTS: T1D patients exhibited a lower aggregation reaction to 3 inducers but were conversely more resistant to the effect of ASA and vorapaxar than controls. Ticagrelor tended to be less active in T1D as well. On the other hand, 4-methylcatechol was equally or even more potent in T1D than in healthy controls. Plasma glucose levels above 7 mM were associated with lower platelet aggregation responses to four aggregation inducers. In contrast, the effect of 4-methylcatechol, unlike that of ASA, did not appear to be strongly influenced by glycemia. Further subanalyses, excluding hypertensive patients and significantly more frequently administered drugs, did not substantially modify the results. CONCLUSION: Conclusively, 4-methylcatechol seems to be a prototypical antiplatelet compound with a strong effect even in diabetic patients.

• Keywords
• 4-methylcatechol, Aggregation, Diabetes mellitus, Platelets,
• MeSH
• Platelet Aggregation * drug effects   MeSH
• Aspirin * therapeutic use   pharmacology   adverse effects   MeSH
• Diabetes Mellitus, Type 1 * blood   diagnosis   drug therapy   MeSH
• Adult MeSH
• Platelet Aggregation Inhibitors * therapeutic use   adverse effects   pharmacology   MeSH
• Catechols * therapeutic use   pharmacology   MeSH
• Blood Glucose metabolism   drug effects   MeSH
• Lactones * therapeutic use   pharmacology   MeSH
• Drug Resistance MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Pyridines * therapeutic use   pharmacology   MeSH
• Case-Control Studies MeSH
• Ticagrelor therapeutic use   MeSH
• Blood Platelets * drug effects   metabolism   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Aspirin * MeSH
• Platelet Aggregation Inhibitors * MeSH
• Catechols * MeSH
• Blood Glucose MeSH
• Lactones * MeSH
• Pyridines * MeSH
• Ticagrelor MeSH
• vorapaxar MeSH Browser

The abnormalities in blood coagulation in patients with diabetes can lead to a prothrombotic state and requirement for the administration of direct anticoagulants. However, no comparative studies have been conducted on the effects of different direct anticoagulants. A head-to-head investigation of the impact of anticoagulants in 50 patients of type 1 diabetes mellitus (DMT1) was performed, and the data were compared to 50 generally healthy individuals. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were measured in plasma treated with vehicle, heparin, or four direct anticoagulants at 1 μM. In addition to common biochemical parameters, novel inflammatory markers (neopterin, kynurenine/tryptophan ratio) and major vitamin K forms were measured. Heparin and dabigatran treatments resulted in prolonged coagulation in DMT1 patients compared to healthy individuals in both tests (both p < 0.001). The same phenomenon was observed for rivaroxaban and apixaban-treated samples in PT (p < 0.001). Interestingly, healthy volunteers had higher total vitamin K levels than DMT1. Further analysis suggested that observed coagulation differences were not caused by differences in glycemia but were rather associated with an unexpected, better lipid profile of our DMT1 group. There were also correlations between prolongation of coagulation brought about by the most active anticoagulants and inflammatory markers, and hence inflammatory state probably also contributed to the differences, as well as the mentioned differences in vitamin K levels. Conclusively, this paper suggests the suitability for controlling the effects of direct anticoagulants in DMT1 patients.

• MeSH
• Anticoagulants * pharmacology   therapeutic use   MeSH
• Dabigatran pharmacology   MeSH
• Diabetes Mellitus, Type 1 * blood   drug therapy   MeSH
• Adult MeSH
• Blood Coagulation drug effects   MeSH
• Heparin pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Partial Thromboplastin Time MeSH
• Prothrombin Time MeSH
• Rivaroxaban pharmacology   MeSH
• Case-Control Studies MeSH
• Vitamin K * blood   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anticoagulants * MeSH
• Dabigatran MeSH
• Heparin MeSH
• Rivaroxaban MeSH
• Vitamin K * MeSH

Familial hypercholesterolemia (FH) is a relatively rare genetic disease associated with high serum cholesterol levels but also with abnormalities in blood coagulation. Novel pharmacotherapeutic approaches in FH including proprotein convertase subtilisin/kexin type 9 antibodies (PCSK9Ab) are very efficient in decreasing cholesterol levels but their impact on coagulation in FH is not yet established. Therefore, we hypothesized that these novel antidyslipidemic drugs can positively impact blood coagulation due to their more potent effect on cholesterol. A total of 15 healthy volunteers and all 15 available patients with severe FH treated at the University Hospital Hradec Králové were enrolled, coagulation was assessed by mechanic coagulometer, and the impact of four clinically used direct anticoagulants was analyzed ex vivo. FH patients were treated effectively as their total cholesterol was 4.11 ± 1.57 mM and LDL cholesterol was 2.44 ± 1.46 mM, which were even lower values than detected in our generally healthy controls. Twelve from the 15 FH patients were finally analyzed as 3 were treated with anticoagulants. Coagulation in FH patients was prolonged more extensively by dabigatran and rivaroxaban, when compared to healthy controls. Treatment with PCSK9Ab or lipid apheresis did not seem to have a significant effect on coagulation. The latter procedure however significantly decreased serum levels of one vitamin K form, MK4. Shorter coagulation time was associated with higher levels of LDL, non-HDL, and total cholesterol. Current treatment of FH seems to improve the effects of direct anticoagulants beyond known effects on LDL cholesterol levels.

• Keywords
• Direct anticoagulants, Familial hypercholesterolemia, Proprotein convertase subtilisin/kexin type 9, Vitamin K,
• MeSH
• Anticholesteremic Agents therapeutic use   MeSH
• Anticoagulants * therapeutic use   pharmacology   MeSH
• Cholesterol blood   MeSH
• Dabigatran therapeutic use   pharmacology   MeSH
• Adult MeSH
• Blood Coagulation * drug effects   MeSH
• Hyperlipoproteinemia Type II * blood   drug therapy   MeSH
• Hypolipidemic Agents * therapeutic use   pharmacology   MeSH
• Cholesterol, LDL blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• PCSK9 Inhibitors MeSH
• Rivaroxaban therapeutic use   pharmacology   MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Anticholesteremic Agents MeSH
• Anticoagulants * MeSH
• Cholesterol MeSH
• Dabigatran MeSH
• Hypolipidemic Agents * MeSH
• Cholesterol, LDL MeSH
• PCSK9 Inhibitors MeSH
• PCSK9 protein, human MeSH Browser
• Proprotein Convertase 9 MeSH
• Rivaroxaban MeSH

PURPOSE: The incidence of acute myocardial infarctions (AMI) shows circadian variation typically peaking during morning hours with a decline at night. However, this variation does not occur in patients with diabetes mellitus (DM). The night's decline of AMI may be partially explained by melatonin-related platelet inhibition. Whether this effect is absent in diabetic patients is unknown. The aim was to study the effect of melatonin on in-vitro platelet aggregation in healthy individuals and patients with type 2 DM. METHODS: Platelet aggregation was measured in blood samples from healthy individuals (n = 15) and type 2 DM patients (n = 15) using multiple electrode aggregometry. Adenosine diphosphate (ADP), arachidonic acid (ASPI) and thrombin (TRAP) were used as agonists. Aggregability for each subject was tested after adding melatonin in two concentrations. RESULTS: In healthy individuals, melatonin inhibited platelet aggregation in both higher (10-5 M) and lower concentrations (10-9 M) induced by ADP, ASPI, and TRAP (p < 0.001, p = 0.002, p = 0.029, respectively). In DM patients, melatonin did not affect platelet aggregation in both concentrations induced by ADP, ASPI, and TRAP. Melatonin decreased platelet aggregation induced by ADP, ASPI, and TRAP significantly more in healthy individuals compared to patients with DM. (p = 0.005, p = 0.045 and p = 0.048, respectively). CONCLUSION: Platelet aggregation was inhibited by melatonin in healthy individuals. In-vitro antiplatelet effect of melatonin in type 2 DM patients is significantly attenuated.

• Keywords
• Acute myocardial infarction, Circadian variation, Diabetes mellitus, Melatonin, Platelet aggregation,
• MeSH
• Adenosine Diphosphate pharmacology   MeSH
• Platelet Aggregation physiology   MeSH
• Diabetes Mellitus, Type 2 * drug therapy   MeSH
• Myocardial Infarction * MeSH
• Platelet Aggregation Inhibitors pharmacology   therapeutic use   MeSH
• Humans MeSH
• Melatonin * pharmacology   therapeutic use   MeSH
• Blood Platelets physiology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Adenosine Diphosphate MeSH
• Platelet Aggregation Inhibitors MeSH
• Melatonin * MeSH

Elevated low-density lipoprotein (LDL) cholesterol levels lead to atherosclerosis and platelet hyperaggregability, both of which are known culprits of arterial thrombosis. Normalization of LDL cholesterol in familial hypercholesterolemia (FH) is not an easy task and frequently requires specific treatment, such as regularly performed lipid apheresis and/or novel drugs such as proprotein convertase subtilisin kexin 9 monoclonal antibodies (PCSK9Ab). Moreover, a high resistance rate to the first-line antiplatelet drug acetylsalicylic acid (ASA) stimulated research of novel antiplatelet drugs. 4-methylcatechol (4-MC), a known metabolite of several dietary flavonoids, may be a suitable candidate. The aim of this study was to analyse the antiplatelet effect of 4-MC in FH patients and to compare its impact on two FH treatment modalities via whole-blood impedance aggregometry. When compared to age-matched, generally healthy controls, the antiplatelet effect of 4-MC against collagen-induced aggregation was higher in FH patients. Apheresis itself improved the effect of 4-MC on platelet aggregation and blood from patients treated with this procedure and pretreated with 4-MC had lower platelet aggregability when compared to those solely treated with PCKS9Ab. Although this study had some inherent limitations, e.g., a low number of patients and possible impact of administered drugs, it confirmed the suitability of 4-MC as a promising antiplatelet agent and also demonstrated the effect of 4-MC in patients with a genetic metabolic disease for the first time.

• Keywords
• 4-methylcathechol, familial hypercholesterolemia, lipid apheresis, platelet,
• MeSH
• Hyperlipoproteinemia Type II * drug therapy   MeSH
• Cholesterol, LDL MeSH
• Humans MeSH
• Antibodies, Monoclonal pharmacology   therapeutic use   MeSH
• Proprotein Convertase 9 MeSH
• Proprotein Convertases therapeutic use   MeSH
• Blood Component Removal * methods   MeSH
• Subtilisin MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 4-methylcatechol MeSH Browser
• Cholesterol, LDL MeSH
• Antibodies, Monoclonal MeSH
• Proprotein Convertase 9 MeSH
• Proprotein Convertases MeSH
• Subtilisin MeSH