Matej Samoš

Monitoring the Efficacy of ADP Inhibitor Treatment in Patients With Acute STEMI Post-PCI by VASP-P Flow Cytometry Assay

Introduction: Dual antiplatelet treatment (DAPT) with clopidogrel and aspirin represents common approach in prevention of thromboembolic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention (PCI). The drawback of clopidogrel treatment is large interindividual variability in response. Aim: Our article aims to suggesting the most convenient method in monitoring the DAPT of post-PCI patients. Methods: We analyzed the on-treatment platelet reactivity by light transmission aggregometry and vasodilator-stimulated phosphoprotein (VASP) flow cytometric assay. Samples were obtained in 3 intervals: first prior to PCI, then 1, and 30 days after PCI. Results: Based on VASP-platelet reactivity index (PRI), we observed 100% response rate in prasugrel-treated patients and 62% to 73 % in the clopidogrel group. Overall, only 2 (7%) patients with the VASP-PRI value in therapeutic range had major adverse cardiovascular events. Conclusion: Our results hint VASP-phosphorylation assay as a relevant method for guiding and tailoring DAPT.

Sticky platelets syndrome in a young patient with massive pulmonary embolism.

Patient: Female, 51 Final Diagnosis: Sticky platelets syndrome Symptoms: Pulmonary embolism Medication: — Clinical Procedure: Thrombolysis Specialty: Hematology Objective: Disease of unknown ethiology Background: Sticky platelets syndrome (SPS) is an inherited thrombophilia characterized by platelet hyperaggregability, which can lead to the higher risk of thrombosis. The etiology of SPS remains unclear, but several gene polymorphisms have been recently studied and autosomal dominant heredity is suspected. Although SPS is traditionally connected with arterial thrombosis, several cases of SPS as a cause of venous thromboembolism have been described. Case Report: We report the case of a 51-year-old apparently healthy woman with massive pulmonary embolism, who required thrombolytic therapy. In this patient SPS was identified as the only condition leading to higher risk of developing thromboembolic disease. Conclusions: Although at present few physicians have practical experience with SPS, this syndrome may lead to serious health problems or even death. The presented case points to the benefit of SPS diagnostics in standard screening of inherited thrombophilia for effective prophylaxis and treatment in patients with venous thromboembolism.

Clopidogrel resistance in diabetic patient with acute myocardial infarction due to stent thrombosis.

Stent thrombosis is a morbid complication after percutaneous coronary intervention. Dual antiplatelet therapy significantly reduces stent thrombosis risk and forms currently the basis in acute ST elevation myocardial infarction pharmacologic treatment. The introduction of clopidogrel has made a major advance in the acute coronary syndrome treatment. However, there is growing evidence about failure in antiplatelet response after clopidogrel, which may lead to subsequent risk of future thrombotic events. The antiplatelet inhibitory effect of clopidogrel varies widely among individuals. High on-treatment platelet reactivity has been repeatedly associated with a hazard for cardiovascular events, including stent thrombosis. Laboratory monitoring of antiplatelet therapy efficacy may help identify patients with insufficient antiplatelet response. Prasugrel therapy was repeatedly described as an effective method to overcome clopidogrel resistance. We report a case of diabetic patient in whom myocardial reinfarction due to stent thrombosis developed. Clopidogrel resistance was detected in this patient using light transmission aggregometry and vasodilator-stimulated phosphoprotein phosphorylation assessment. After prasugrel administration, no other ischemic event occurred, and patient was released to outpatient care in good general condition.

Heparin-induced Thrombocytopenia Presenting With Deep Venous Thrombosis and Pulmonary Embolism Successfully Treated With Rivaroxaban: Clinical Case Report and Review of Current Experiences.

Abstract: Heparin-induced thrombocytopenia (HIT) is a life or limb-threatening thrombotic thrombocytopenia. HIT is traditionally treated with factor-IIa inhibitors such as bivalirudin, lepirudin, or argatroban. However, these agents usually require parenteral administration and are not generally available in all countries. Recently, several experiences with novel oral anticoagulants (NOACs) administration to treat HIT had been reported. NOACs generally offer advantages such as consistent and predictable anticoagulation, oral administration with good patient compliance, and a good safety profile. We report a case of HIT with severe thrombotic complications successfully treated with rivaroxaban and discuss the current knowledge about the use of NOACs for the treatment of this potentially fatal thrombocytopenia.

Ticagrelor: a safe and effective approach for overcoming clopidogrel resistance in patients with stent thrombosis?

Stent thrombosis is a morbid complication following percutaneous coronary intervention (PCI). Dual antiplatelet therapy significantly reduces stent thrombosis risk. However, the antiplatelet response to clopidogrel – the most frequently used ADP receptor antagonist in post-PCI patients – varies among individuals. High on-treatment platelet reactivity was repeatedly associated with the risk of stent thrombosis. Ticagrelor is a novel ADP receptor blocker that has shown greater, more rapid and more consistent platelet inhibition than clopidogrel. This agent offers a unique mechanism of action, no relevant pharmacological interactions, consistent platelet inhibition, and a good safety profile. This article reviews the prospective use of ticagrelor in the treatment of stent thrombosis in acute coronary syndrome patients undergoing PCI of culprit coronary lesion.

Does type 2 diabetes affect the on-treatment levels of direct oral anticoagulants in patients with atrial fibrillation?

AIMS Type 2 diabetes (T2D) is connected with several abnormalities in haemostasis; and with higher risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NV-AF). However, it is recently unknown whether T2D affects the activity of direct oral anticoagulants (DOACs). The aim of this study was to determine the impact of T2D on DOACs activity in patients with NV-AF. METHODS This pilot prospective study enrolled totally 65 patients with NV-AF (20 dabigatran-treated, 110 mg/twice daily; 28 rivaroxaban-treated, 15 mg/daily; 17 apixaban-treated, 5 mg/twice daily). 25 patients had T2D (8 dabigatran-treated, 11 rivaroxaban-treated, and 6 apixaban-treated). DOAC activity was tested with Hemoclot® Thrombin Inhibitor assay in dabigatran-treated patients, and with factor Xa-calibrated anti-Xa chromogenic analysis in rivaroxaban- and apixaban-treated patients prior and two hours after drug administration. RESULTS There were no significant differences in dabigatran baseline (62.1 ± 8.0 vs. 51.8 ± 38.9 ng/ml, p = .76) and 2-h-post-drug-administration (91.7 ± 57.2 vs. 72.2 ± 33.2 ng/ml, p = .48) activity comparing T2D and non-diabetic patients. Similarly, no significant differences were found in rivaroxaban baseline (35.9 ± 22.5 vs. 55.3 ± 45.1 ng/ml, p = .19) and 2-h-post-drug-administration (145.7 ± 74.1 vs. 202.6 ± 135.0 ng/ml, p = .22) anti-Xa activity. In addition, no significant differences were present in apixaban baseline (96.0 ± 54.5 vs. 63.9 ± 36.8 ng/ml, p = .24) and 2-h-post-drug-administration (151.0 ± 78.3 vs. 151.7 ± 59.1 ng/ml, p = .98) anti-Xa activity between T2D and non-diabetic patients. CONCLUSIONS This pilot study did not detect differences in DOACs activity according to T2D status in patients with NV-AF.

Apixaban - Metabolism, Pharmacologic Properties and Drug Interactions

BACKGROUND Apixaban is an oral, potent, highly selective, reversible and direct inhibitor of activated coagulation factor X, that is the end point of the intrinsic and extrinsic coagulation pathway. Additionally, apixaban has the capacity to indirectly inhibit thrombin-induced platelet aggregation. This new oral anticoagulant represents an immediate-release form of peroral drug with quick dissolution, linear pharmacokinetics, good bioavailability and rapid onset and offset of action. No clinically relevant age- or sex-dependent difference in the apixaban pharmacokinetics and pharmacodynamics which would lead to the modification of the dose exists, apixaban may even be administered with or without food. Its elimination is mediated by metabolism, renal elimination of unmodified drug and excretion in the gastrointestinal tract. OBJECTIVE The authors aim to provide a review of currently available literature about apixaban. METHOD The authors summed-up the data from the scientific journals related to thrombosis and hemostasis and searched the available databases. RESULTS AND CONCLUSION Apixaban has many advantages including predictable pharmacokinetics and pharmacodynamics, low number of drug and food interactions, and relatively wide therapeutic window.

Type 2 Diabetes and ADP Receptor Blocker Therapy

Type 2 diabetes (T2D) is associated with several abnormalities in haemostasis predisposing to thrombosis. Moreover, T2D was recently connected with a failure in antiplatelet response to clopidogrel, the most commonly used ADP receptor blocker in clinical practice. Clopidogrel high on-treatment platelet reactivity (HTPR) was repeatedly associated with the risk of ischemic adverse events. Patients with T2D show significantly higher residual platelet reactivity on ADP receptor blocker therapy and are more frequently represented in the group of patients with HTPR. This paper reviews the current knowledge about possible interactions between T2D and ADP receptor blocker therapy.

Role of VASP Phosphorylation Assay in Monitoring the Antiplatelet Therapy

Abstract Dual antiplatelet treatment with clopidogrel and aspirin represents standard regimen in prevention of thromboembolic events in patients with ischemic heart disease undergoing percutaneous coronary intervention (PCI). One of the greatest pitfalls of clopidogrel treatment is large inter-individual variability in response. Large amount of patients does not respond adequately and therefore are not „protected“ even in spite of receiving the therapy. Poor responders are exposed to three-fold increased risk of myocardial infarction, stent thrombosis and cardiac death. Clopidogrel is an antiplatelet prodrug, whose active metabolite inhibits platelet function by irreversible binding to the (adenosine diphosphate) platelet receptor P2Y12. Receptor P2Y12 plays primal role in ADP-mediated platelet activation, and also in mechanism of action of ADP inhibitors such as clopidogrel, prasugrel etc. Reasons stated above, raised the necessity for implementing reliable laboratory test in order to identify the unprotected patients. In an ideal scenario, such test would serve to adjust the dose and guide the individual tailored treatment. Vasodilator Stimulated Phosphoprotein (VASP) is an intracellular platelet protein which is non phosphorylated at basal state. Since its relation in cascade with P2Y12 receptor, VASP phosphorylation corerlates with inhibition of P2Y12 which is the receptor of prime importance in ADP mediated activation of platelets and as is primary target of ADP inhibitors action. Outcome of the assay is represented as the value of platelet reactivity index (PRI), where PRI values above 50% are considered inadequate response to treatment and signal exposure to increased risk of myocardial infarction, post-PCI stent thrombosis and cardiac death. VASP-P flow cytometric assay is emerging into the spotlight as the promising method, mostly for its specificity for ADP inhibitors, better outlook for standardising results and lesser sample manipulation compared to multiple electrode aggregometry.

How to proceed with long-term anticoagulation in patient after total gastrectomy and atrial fibrillation?

To the Editor: Long-term oral anticoagulation is recommended to prevent stroke and systemic embolism in patients with atrial fibrillation (AF) [1]. Non-vitamin K antagonist oral anticoagulants (NOACs) have emerged as the preferred choice in these patients [2].However, published data has recently demonstrated that dabigatran-PPI interaction significantly reduces dabigatran plasma levels [3, 4], most probably mediated through the effect on gastric pH [5]. This implies that dabigatran would not be highly soluble also among posttotal gastrectomy patients, as they have no gastric acid secretion. Nevertheless, there are no data about post-total gastrectomy patients with non-valvular atrial fibrillation treated with dabigatran. A 68-year-old post-total gastrectomy patient due to the diffuse large B cell lymphoma, in complete remission, and with permanent AF, was admitted to the Department of Internal Medicine I. He had been taking 150 mg of dabigatran etexilate therapy twice daily before his admission (the length of dabigatran therapy was 50 days) for AF and continued with dabigatran etexilate therapy during the first days of his inhospital stay. He had a CHA2DS2-VASc score of 3 and no history of bleeding. Dabigatran was administered at 7:00 PM and 7:00 AM. Blood samples were taken 12 h after the previous drug administration (at 7:00 AM) for the assessment of the dabigatran trough level and 2 h after the next drug administration (at 9:00 AM) for the assessment of his dabigatran peak level. The patient was tested on the fifth day of his in-hospital stay, and had fasted before the blood sampling; dabigatran levels were assessed with Hemoclot® Thrombin Inhibitor Assay (Hyphen BioMed, Neuville-sur-Oise, France). The analysis of the dabigatran trough and peak levels demonstrated very low dabigatran levels (trough dabigatran level was 28 ng/ml, and peak dabigatran level was 55 ng/ml). With this knowledge, we decided to exchange dabigatran for apixaban. Apixaban therapy was started in a standard dose regiment of 5 mg twice daily. After 7 days of apixaban administration, repeated blood testing was performed: trough and peak samples were taken, the patient was fasting before the blood sampling, and anti-Xa activity analysis was performed with factor Xa-calibrated anti-Xa chromogenic analysis (the BIOPHEN® Heparin Assay and BIOPHEN® Apixaban Calibrator). Repeated analysis showed sufficient on-treatment anti-Xa apixaban activity in the trough and peak samples (trough apixaban anti-Xa activity was 142 ng/ml; and peak apixaban anti-Xa activity was 231 ng/ml). The ROTEM® analysis (INTEM® and EXTEM® reagent) on dabigatran etexilate and apixaban is reported in supplementary documents. In fact, there are only limited data regarding the optimal strategy for long-term oral anticoagulant therapy with NOAC in post-total gastrectomy patients with atrial fibrillation. Since the absorption of NOACs is mediated through the gastrointestinal tract, the bioavailability of NOACs could be reduced in post-total gastrectomy patients [6–9]. Recently, a preliminary study in post-bariatric surgery patients treated with NOACs showed that rivaroxaban plasma levels could be affected after bariatric surgery [10]. On the other hand, all apixaban-treated patients in this study had normal ontreatment apixaban plasma levels. This study enrolled only Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-018-2571-9) contains supplementary material, which is available to authorized users.