Lucia Stančiaková

Endothelial and platelet markers in diabetes mellitus type 2.

Diabetes mellitus (DM) is an extremely common disorder which carries a risk of vascular impairment. DM type 2 (DM2) can be characterized by the dysfunction of haemostasis manifesting by stimulated coagulation process, disorder of platelet function and decreased fibrinolytic activity. These all are the reasons why DM2 is the most common acquired thrombophilia. Endothelial dysfunction along with platelet hyperactivity are unquestionably involved in the hyperactivation of platelets and clotting factors in DM. As a natural consequence of continuous investigation, many markers of endothelial dysfunction and diabetic thrombocytopathy have been identified and considered for implementation in clinical practice. Endothelial function can be assessed by the evaluation of endothelial markers, circulating molecules synthesised in various amounts by the endothelium. These markers precede the signs of evident microangiopathy. Platelets have an ethiopathogenic relation to the microangiopathy in DM. Their increased activity was confirmed in both types of DM. Predictors of endothelial and platelet disorder could improve the screening of individuals at increased risk, thus leading to the early diagnosis, appropriate treatment, as well as to the effective prevention of the complications of DM2. In the article we deal with the mechanisms involved in the pathogenesis of endothelial and platelet functional abnormalities, endothelial and platelet markers of DM2 considered for implementation in clinical practice and possibilities of their detection.

Yes or no for secondary prophylaxis in afibrinogenemia

We read with great interest the article written by Ozdemir et al. [1], published in a recent issue of Blood Coagulation and Fibrinolysis as well as further interesting articles [2,3] describing life-threatening thrombotic and bleeding complications in afibrinogenemia. We hereby report on the only case of this disorder in Slovakia, successfully managed by secondary prophylaxis of bleeding events with the regular administration of fibrinogen without any thrombotic complications.

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.

Congenital afibrinogenemia: from etiopathogenesis to challenging clinical management

ABSTRACT Introduction: Congenital afibrinogenemia belongs to the group of autosomal recessive bleeding disorders and represents the absolute deficiency of fibrinogen detected by an antigenic test. This can lead to severe clinical manifestations of the disorder. Therefore, it is very important to take afibrinogenemia into account in the process of the differential diagnostics of the patients. Areas covered: The authors provide a summary of currently available literature about afibrinogenemia. They collected the information from the scientific journals dedicated to thrombosis and hemostasis and searched world-wide databases. Expert commentary: The most frequent clinical manifestation of this disorder is mucosal bleeding, but musculoskeletal bleeding pattern, gynecologic and obstetric issues, spontaneous bleeding, episodes provoked by minor injury or any other intervention, and even paradoxical thromboembolic events have been published. Afibrinogenemia is the consequence of mutations of the homozygous or compound heterozygous type in gene FGA, FGB or FGG encoding fibrinogen. Pregnant women with a family history, or with a history of consanguinity ought to be properly counselled. However, primary prophylaxis of bleeding events is not suggested. The article deals with actual information about afibrinogenemia contributing to its early diagnosis and effective treatment, which in many cases requires multidisciplinary approach.

Sticky platelet syndrome: an important cause of life-threatening thrombotic complications.

Sticky platelet syndrome (SPS) is a prothrombotic thrombocytopathy with familial occurrence, characterized by hyperaggregability of platelets in response to adenosine diphosphate (ADP), epinephrine (EPI) or both. The syndrome has been identified in approximately 21% of unexplained arterial thrombotic episodes, regarded to be the most common thrombophilia in arterial thrombosis and 13.2% of unexplained venous thromboembolism (VTE). The relatively young age at the first manifestation, relation to fertility and pregnancy, seriousness of the symptoms, easy and effective management of the disorder indicate to the necessity to take it into account in the differential diagnosis of the underlying cause of the thrombotic event. As the various localizations of the thrombosis in SPS have been reported, its management often requires a multidisciplinary approach. This review deals with the clinical aspects of thrombophilia, its etiopathogenesis, diagnosis as well as novel advances in the treatment and outlines the challenges for the further research.

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.

Novel fibrinogen bbeta chain mutation as an underlying mechanism of afibrinogenemia

We read with great interest the updated article written by de Moerloose et al1 in your journal regarding congenital fibrinogen disorders, including afibrinogenemia. We wish to report a novel mutation in fibrinogen β chain, and furthermore, propose a new underlying mechanism of this rare bleeding disorder. To our knowledge, the variant has not been previously described. Fibrinogen is produced by the liver and comprises two sets of three polypeptides (Aα, Bβ, and γ), as encoded by the genes, FGA, FGB, and FGG, all localized within 50 kb on 4q31. Mutations in these genes can cause a deficiency of fibrinogen by the following mechanisms: they may affect production at the level of DNA, RNA influencing mRNA splicing or its stability, or interacting with the protein synthesis, as well as assembly and secretion.1,2 FGA, FGB, and FGG are transcribed and translated to polypeptides independent of each other: FGA (7.6 kb) comprises 6 exons producing 3 distinct transcripts leading to the formation of polypeptide of 644 amino acids Aα; FGB (8 kb) contains 8 exons which encode the only 1.9 kb transcript with the 1.5 kb coding sequence leading to the production of the 491-amino acid polypeptide Bβ; FGG (8.5 kb) comprises 10 exonswith 2mRNA products translating to the 437-amino acid polypeptide γ. Assembly in endoplasmic reticulum contributes to the creation of the Aα-γ or Bβ-γ intermediate product. Addition of Bβ or Aα chain produces an AαBβγ molecule, dimerizing to functional hexamer undergoing posttranslational modifications in Golgi apparatus.1,2 Afibrinogenemia, an extraordinary rare autosomal recessive bleeding disorder, is defined by the absence of fibrinogen activity and its antigen.1,2 We report on the first results of genetic analysis of DNA of the only patient suffering from afibrinogenemia in Slovakia. A 26-year-old man experienced most of the typical clinical signs of afibrinogenemia, including umbilical cord and intracranial bleeding.1 At baseline, fibrindependent coagulation tests, including prothrombin time, activated partial thromboplastin time, thrombin time, and also reptilase time, were unmeasurably prolonged and fibrinogen level measured by both the Clauss functional method as well as the Laurel immunologic assay was undetectable. With the aim to identify the exact genetic defect responsible for his bleeding disorder, we performed DNA sequencing with subsequent genetic analysis. To our knowledge, the genetic analysis revealed a previously unidentified mutation in FGB, exon 4, nucleotide position 9661, caused by themutation C > T, leading to the switch of amino acid glutamine to stop codon (proposed mutation nomenclature: NM_005141.4:c.538C > T, NP_005132.2:p.Gln180Stop) (►Fig. 1). In addition to this novel mutation, the previously described single nucleotide polymorphism, rs6050 (NM_000508.3(FGA):c.991A > G (p.Thr331Ala), NC_000004.12:g.154586438T > C) in exon 5 of FGA with the overall frequency 0.28918, and previously reported tomodulate the risk of cardiovascular diseases and inflammation, was found.3 As it has already been reported, the occurrence of the stop codon, caused in our patient by the mutation C9661T, could lead to the elimination of aberrant mRNA, which encodes incomplete Bβ polypeptide by the mechanism of nonsensemediated mRNA decay.4 Moreover, the Bβ polypeptide is the major rate-limiting factor in the synthesis of fibrinogen by the Letter to the Editor

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.

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.