Thromboembolic Disorders Research Articles

Rare thrombophilic conditions

Thrombophilia, either acquired or inherited, can be defined as a predisposition to developing thromboembolic complications. Since the discovery of antithrombin deficiency in the 1965, many other conditions have been described so far, which have then allowed to currently detect an inherited or acquired predisposition in approximately 60-70% of patients with thromboembolic disorders. These prothrombotic risk factors mainly include qualitative or quantitative defects of endogenous coagulation factor inhibitors, increased concentration or function of clotting proteins, defects in the fibrinolytic system, impaired platelet function, and hyperhomocysteinemia. In this review article, we aim to provide an overview on epidemiologic, clinic and laboratory aspects of both acquired and inherited rare thrombophilic risk factors, especially including dysfibrinogenemia, heparin cofactor II, thrombomodulin, lipoprotein(a), sticky platelet syndrome, plasminogen activator inhibitor-1 apolipoprotein E, tissue factor pathway inhibitor, paroxysmal nocturnal haemoglobinuria and heparin-induced thrombocytopenia.

Comparison of reversal activity and mechanism of action of UHRA, andexanet, and PER977 on heparin and oral FXa inhibitors

AbstractAnticoagulants such as unfractionated heparin (UFH), low-molecular-weight heparins (LMWHs), fondaparinux, and direct oral anticoagulants (DOACs) targeting thrombin (IIa) or factor Xa (FXa) are widely used in prevention and treatment of thromboembolic disorders. However, anticoagulant-associated bleeding is a concern that demands monitoring and neutralization. Protamine, the UFH antidote, has limitations, while there is no antidote available for certain direct FXa inhibitors. Improved antidotes in development include UHRA (Universal Heparin Reversal Agent) for all heparin anticoagulants; andexanet alfa (andexanet), a recombinant antidote for both direct FXa inhibitors and LMWHs; and ciraparantag (PER977), a small-molecule antidote for UFH, LMWHs, and certain DOACs. The binding affinities of these antidotes for their presumed anticoagulant targets have not been compared. Here, isothermal titration calorimetry (ITC) was used to determine the affinity of each antidote for its putative targets. Clotting and chromogenic FXa assays were used to characterize neutralization activity, and electron microscopy was used to visualize the effect of each antidote on clot morphology in the absence or presence of anticoagulant. ITC confirmed binding of UHRA to all heparins, and binding of andexanet to edoxaban and rivaroxaban, and to the antithrombin–enoxaparin complex. PER977 was found to bind heparins weakly, but not the direct FXa inhibitors studied. For UHRA and andexanet, an affinity at or below the micromolar level was found to correlate with neutralization activity, while no reversal activity was observed for the PER977/anticoagulant systems. Standard metrics of clot structure were found to correlate weakly with PER977's activity. This is the first study comparing 3 antidotes in development, with each exerting activity through a distinct mechanism.

Anticoagulation Knowledge Tool (AKT): Further evidence of validity in the Italian population.

IntroductionOral Anticoagulation therapy (OAC) is highly effective in the management of thromboembolic disorders. An adequate level of knowledge is important for self-management and optimizing clinical outcomes. The Anticoagulation Knowledge Tool (AKT) was developed to assess OAC knowledge and caters for both patients prescribed direct oral anticoagulants or vitamin K antagonist (VKA). However, evidence regarding its psychometric proprieties, validity and reliability are unavailable in non-English speaking settings. For this reason, the aim of this study is to provide further evidence of validity for AKT and also developing an Italian AKT version (I-AKT) supported by evidence of validity and reliability.MethodsA multiphase study was conducted which included the following: cultural and linguistic validity; i.e. content validity; construct validity; reliability assessment. The Construct validity was performed using the contrasted group approach using three groups comprised of health care providers, patients and the general public. Furthermore, Exploratory Structural Equation Modelling (ESEM) was performed to confirm the mono-dimensional structure of the items in the AKT.ResultsIn construct validity phase 334 participants were enrolled. One-way ANOVA and post hoc analysis test demonstrated significant differences between the means knowledge scores of the three groups: 30.42±3.04 vs 23.45± 4.57 vs14.32±6.07 (Statistic F = 266.83; p < .001). ESEM analysis demonstrates the I-AKT mono-dimensionally structure with an explained variance of 56.42%. The scale also showed both good internal consistency reliability (Cronbach’s α = 0.896) and test-retest reliability (r = 0.855).ConclusionThis study developed and validated I-AKT with supporting evidence for validity and reliability. The study also confirms the mono-dimensional of the items in the AKT. This suggest that the instrument can be useful in non-English setting for knowledge assessment and in potentially developing patient education materials.

Novel Therapeutic Agent against Platelet Activation In Vitro and Arterial Thrombosis In Vivo by Morin Hydrate.

Morin hydrate, a bioactive flavonoid, has been proven to prevent inflammation and apoptosis of cells. Flavonoids can reduce the risk of cardiovascular diseases, in which platelet activation plays a major role. This study investigated the effect of morin hydrate on platelet activation in vitro and in vivo. Morin hydrate markedly inhibited platelet aggregation stimulated by collagen in human platelets but not that stimulated by other agonists. In collagen-activated platelets, morin hydrate inhibited adenosine triphosphate (ATP) release; intracellular Ca2+ mobilization; P-selectin expression; and phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), and Akt. In mitogen-activated protein kinase (MAPK) activation, morin hydrate evidently diminished ERK2 or JNK1 activation, except for p38 MAPK. Additionally, morin hydrate markedly reduced the OH· signals in platelet suspensions but not in the cell-free system (Fenton reaction solution). Moreover, morin hydrate substantially increased the occlusion time of thrombotic platelet plug formation but had no effect on bleeding time in mice. In conclusion, morin hydrate crucially inhibits platelet activation through inhibition of the PLCγ2–PKC cascade and subsequent suppression of Akt and MAPK activation, thereby ultimately inhibiting platelet aggregation. Therefore, this paper suggests that morin hydrate constitutes a novel and potential natural therapeutic product for preventing or treating thromboembolic disorders.

Approaches to Direct Oral Anticoagulant Selection in Practice.

Direct oral anticoagulants (DOACs) carry many advantages over warfarin and are now considered first line or an alternative for mnay thromboembolic disorders. With the emergence of 5 DOAC agents to the market as well as the accumulating evidence gathered from head-to-head comparisons between the agents, we attempt to provide direction for clinicians when selecting the most appropriate DOAC agent. Important aspects such as efficacy, safety, cost effectiveness, approved indications, and other drug-related factors will be addressed to highlight the major similarities and diversities among the DOACs. When considering the safety profile of DOACs, evidence points toward apixaban as the safest followed by dabigatran and then rivaroxaban. On the other hand, dabigatran currently has the only approved antidote, idarucizumab. According to the approved DOAC indications, rivaroxaban may be favorable in European countries given its additional indication for secondary prevention of myocardial infarction. Following rivaroxaban, dabigatran and apixaban have the largest number of approved indications and lastly comes edoxaban and then betrixaban. For patients with renal impairment, betrixaban is the safest option, followed by apixaban and edoxaban, then rivaroxaban and lastly dabigatran. When considering DOAC dosing, rivaroxaban, edoxaban, and betrixaban are mainly dosed once daily compared to dabigatran and apixaban, which are dosed twice daily. However, rivaroxaban and betrixaban must be administered with food, which adds another level of complexity to the DOAC dosing. Lastly, taking into consideration drug interactions, dabigatran, edoxaban, and betrixaban have the least amount of interactions compared to apixaban and rivaroxaban. Each DOAC has its own set of features that makes it better suited than others based on the exact clinical situation. Therefore, no conclusion can be drawn to the most superior DOAC based on the aspects discussed in this review.

Nanoplasmonic biosensor device for the monitoring of acenocoumarol therapeutic drug in plasma

Acenocoumarol (Sintrom®) is an oral anticoagulant prescribed for the treatment of a variety of thromboembolic disorders such as atrial fibrillation and thrombosis or embolism. It inhibits fibrin production preventing clot formation. Acenocoumarol has a narrow therapeutic range, and its effects depend on several factors, such as body weight, age, metabolism, diet, certain medical conditions or the intake of additional drugs, among others. A higher dose may result in the risk of bleeding, while if it is too low, the risk of blood clot can increase. Complementary tools that allow the therapeutic drug monitoring (TDM) of acenocoumarol plasmatic levels from the starting of the treatment would be of paramount importance to personalize the treatment. Point-of-care (POC) devices can offer an added value in facilitating on-site monitoring (i.e. hospitals, primary care doctor or even by the patient itself) and can aid in dosage management. With this aim, we have developed a compact and simple nanoplasmonic sensing device based on gold nanodisks for the rapid monitoring of acenocoumarol, using highly specific polyclonal antibodies produced against this drug. A specific and reproducible label free indirect competitive assay has been developed and the viability of performing the evaluation directly in plasma diluted 1:1 has been demonstrated. A limit of detection (LOD) of only 0.77 ± 0.69 nM, an IC50 of 48.2 ± 5.12 nM and a dynamic range between 3.38 ± 1.33 nM and 1154 ± 437 nM were achieved, which easily fit within the drug plasma levels of acenocoumarol, making this approach a highly attractive option for its decentralized monitoring in human plasma.

Thromboembolic Disorders during Pregnancy: Cardiologist Perspective

AbstractThe hematologic changes which occur during pregnancy make it a hypercoagulable state. Various factors such as hereditary thrombophilia, obesity, etc. increase the risk of venous thromboembolism in these patients. Though the prevalence is low, it can contribute to significant mortality and morbidity. Deep vein thrombosis is the most common type of venous thromboembolism and pulmonary embolism can sometimes be fatal. Various diagnostic modalities like compression duplex ultrasound of leg veins, echo, ventilation-perfusion scan, and computed tomographic pulmonary angiogram can help in diagnosis. Proper treatment can improve both maternal and fetal outcome.

Thromboembolism in Pregnancy: Gynecologists Perspective

AbstractPregnancy is a thrombogenic condition in both antenatal and postpartum periods. Venous thromboembolism (VTE) is a common cause of morbidity, and the cause of maternal death in such situations is pulmonary embolism. There are several risk factors for thrombotic phenomena in pregnancy both acquired and hereditary. Accurate diagnosis of deep vein thrombosis (DVT) and its treatment are very important to prevent life-threatening pulmonary embolism. Among the diagnostic techniques, compression ultrasound is the mainstay for DVT diagnosis, whereas computed tomographic pulmonary angiography (CTPA) is for pulmonary embolism. Anticoagulants play a major role in therapy. They are used both in the active stage of thromboembolism and also in thromboprophylaxis in the postpartum period. Different types of heparins are available, which can be tailored to the individual requirements. During therapy they need monitoring to prevent hemorrhagic complications. Oral anticoagulants cannot be given in pregnancy as a general rule because of their teratogenicity, though they can be used in the postpartum period. Thrombolysis is can be taken up in selected cases in the acute situations. A very prolonged treatment of anticoagulants and compression stockings are needed in patients with past history of VTE. The most convenient drug regimen for prophylaxis is once-daily weight-adjusted low-molecular-weight heparin (LMWH). The goal of this article is to facilitate the recognition of thromboembolic disorders in pregnancy and different regimens in their management during antenatal, intrapartum, and postpartum periods. A few interesting and rare cases from the author’s experience are also presented at the end.

Anti-IIa activity and antitumor properties of a hybrid heparin/heparan sulfate-like compound from Litopenaeus vannamei shrimp

In this present study, the anti-IIa activity and the antitumor properties of a hybrid heparin/heparan sulfate-like compound (sH/HS) from Litopenaeus vannamei shrimp heads are related. In addition to inhibiting 90.7% of thrombin activity at the lowest tested concentration (0.5 μg/mL), sH/HS compound stimulated the synthesis of antithrombotic heparan sulfate by endothelial cells in a dose-dependent manner. In vitro experiments demonstrated that the molecule from shrimp displayed a potent anti-angiogenic effect, reducing over 80% of the tubular structures formation at 50 and 100 μg/mL. In addition, sH/HS compound was able to inhibit the migration of B16F10 cells at all tested concentrations without affecting the cell viability. Although the studied compound had no effect on the proliferation of such cells during a period of 24 h, it had a significant long-term anti-proliferative effect, reducing about 80% of colony formation and anchorage-independent growth at 50 and 100 μg/mL concentrations. When its effectiveness was tested in vivo, it was demonstrated that sH/HS promoted a reduction of more than 90% of tumor growth. In the context of thromboembolic disorders associated with cancer, such findings make the sH/HS compound an excellent target for studies on inhibiting of development and tumor progression, and the prevention of coagulopathies.

Structural basis for the selective inhibition of activated thrombin-activatable fibrinolysis inhibitor (TAFIa) by a selenium-containing inhibitor with chloro-aminopyridine as a basic group

Activated thrombin-activatable fibrinolysis inhibitor (TAFIa) is a target molecule for treating thromboembolic disorders. We previously reported that design and synthesis of compound 1 containing a selenol group and chloloaminopyridine. Compound 1 showed high inhibitory activity towards TAFIa, with a high degree of selectivity for TAFIa over carboxypeptidase N (CPN). Here we report investigation of this selectivity. To obtain co-crystal of 1/pp-CPB (a surrogate of TAFIa), we synthesized protected compound 5 as a stabilized precursor of 1. The X-ray crystal structure and docking study indicated that the Cl substituent is accommodated in the pp-CPB specific pocket whereas CPN has no identical pocket. This is important information for the design of drugs targeting TAFIa with high selectivity.

DNA‐PK Is Activated in Human Atherosclerotic Plaques And Its Partial Inhibition by Gene Heterozygosity Reduces Atherogenesis in Mouse Model of The Disease

Atherosclerosis is a chronic inflammatory condition with serious implications including coronary heart disease, cerebrovascular and thromboembolic disorders. Rupture of plaques, the subsequent formation of thrombi, and the consequent occlusion of arteries are the most important events in the onset of cardiovascular complications associated with atherosclerosis. The ultimate clinical goal to prevent plaque rupture and thrombosis is the stabilization and potential regression of vulnerable plaques. DNA‐PK is composed of a 450‐kDa catalytic subunit (DNA‐PKcs) and two DNA‐binding subunits (Ku70/Ku80). Although DNA‐PK is critical for repairing DSBs through non‐homologous end joining, only less than 1% is needed to achieve such function. We have recently reported that partial inhibition of DNA‐PK pharmacologically by NU7441 or genetically by gene heterozygosity reduces asthma‐like traits in 2 animal models of the disease in part by blocking lung VCAM‐1 expression, production of Th2 cytokines through down regulating the expression of several inflammatory genes. Since persistent inflammation is critical for plaque instability and rupture, we sought to examine the role of DNA‐PK in human atherogenesis and determine whether its activation correlates with factors of inflammation and/or markers of DNA damage/repair and to investigate whether inhibition of the enzyme promotes plaque regression in a mouse model of atherosclerosis. We report that DNA‐PKcs is activated in inflammatory as well as structural cells within human atherosclerotic plaques of carotid arteries. Reduction of DNA‐PKcs by gene heterozygosity, which reduces expression and activity of the enzyme by ~50%, promoted a significant reduction of the atherosclerotic burden in high fat diet‐fed (HFD) ApoE−/− mice. Such protective action was accompanied by a significant reduction in LDL levels and an increase in HDL. These effects were achieved without interference or activation of the DNA damage/repair pathways or the development of severe combined immunodeficiency (SCID) syndrome. Overall, our results support the notion that DNA‐PK is a key player in atherogenesis and that it may constitute a novel therapeutic target for the modulation of the disease.Support or Funding InformationNIH/COBRE 1P30GM106392‐01: COBRE Phase III Transitional Center Grant‐ Mentoring in Cardiovascular BiologyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Rivaroxaban Program and the Management of Unmet Needs in Thromboembolic Disease.

Rivaroxaban is a non-vitamin K antagonist oral anticoagulant that acts as a direct factor Xa inhibitor, and is widely used for the prevention and treatment of thromboembolic disorders. As further knowledge gaps are identified in thrombosis management, the rivaroxaban research program has expanded in an attempt to elucidate the wider benefits of rivaroxaban. An increased understanding of the interactions taking place within the coagulation cascade may support a broader role for rivaroxaban (2.5 mg twice daily [bid] or 5 mg bid) in the setting of vascular protection, either alone or in combination with an antiplatelet agent. The aim of this article is to describe the potential role of rivaroxaban in the context of vascular protection and provide an overview of recently completed and ongoing randomized controlled trials of rivaroxaban in the areas of stroke prevention, venous protection and vascular protection.

ORAL ANTICOAGULANT PRESCRIPTION ANALYSIS FOR UTILISATION PATTERN AMONG IN-PATIENTS AT A TERTIARY CARE HOSPITAL

Objective: Selection of oral anticoagulants (OACs) in patients with thromboembolic diseases is complex and equivocal in nature, owing majorly to the non-adherence to standard clinical guidelines. Moreover, there is a scarcity of data on utilisation pattern of OACs in Indian population. Our primary objective was to analyse the prescribing pattern of OACs among in-patients with thromboembolic disorders. The secondary objective was to determine the significant predictors that affect their utilisation pattern.Methods: This prospective observational study examined the clinical data over 6 mo from in-patients on oral anticoagulation with warfarin and acenocoumarol. Patients were recruited into 2 study groups: coronary artery disease (CAD) and non-CAD to analyse the prescription pattern. Potential predictors of utilisation pattern were evaluated for significance with logistic regression analysis for CAD group.Results: Prescription analysis highlights preference of acenocoumarol (72.4%) over warfarin among 232 in-patients in the study. Lack of achievement of target international normalised ratio (INR) levels was noticed in 74.2% of the study population. 57.8% of cases belonged to CAD group (males 76.7%; mean age 59.4±13.5 y). Valvular heart disease (VHD) was the significant predictor (p =0.001) of warfarin utilisation among CAD patients while male gender, heart failure (HF) and arrhythmia were significant for acenocoumarol.Conclusion: Predominance of age&lt;60 y and male gender was observed in the study. Acenocoumarol was preferred over warfarin in all the in-patient departments. VHD, male gender, HF and arrhythmia significantly affected the OAC utilisation.

Novel iridium (III)‑derived organometallic compound for the inhibition of human platelet activation.

Since cisplatin achieved clinical success, transition metal platinum (Pt) drugs have been effectively used for the treatment of cancer. Iridium (Ir) compounds are considered to be potential alternatives to Pt compounds, as they possess promising anticancer effects with minor side effects. Platelet activation is associated with the metastasis and progression of cancer, and also with arterial thrombosis. Therefore, it is necessary to develop novel, effective antithrombotic agents. An Ir (III)-derived complex, [Ir (Cp*) 1-(2-pyridyl)-3-(3-me-thoxyphenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-3), was developed as a novel antiplatelet drug. Ir-3 exerted more potent inhibitory activity on platelet aggregation stimulated by collagen compared with other agonists, including thrombin. In collagen-activated platelets, Ir-3 also inhibited adenosine trisphosphate release, intracellular Ca+2 mobilization and surface P-selectin expression, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) 1, but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinases. Ir-3 did not markedly affect phorbol 12, 13-dibutyrate-stimulated platelet aggregation. Neither the adenylate cyclase inhibitor SQ22536 nor the guanylate cyclase inhibitor 1H-[1, 2, 4] oxadiazolo [4,3-a]quinoxalin-1-one significantly reversed the Ir-3-mediated inhibition of platelet aggregation. Furthermore, Ir-3 had no considerable diminishing effects on OH radical signals in collagen-stimulated platelets or Fenton reaction solution. In conclusion, Ir-3 serves a novel function in the inhibition of platelet aggregation through inhibiting the PLCγ2-PKC cascade, and the subsequent suppression of Akt and JNK1 activation. Therefore, Ir-3 may be a potential novel therapeutic agent for the treatment of thromboembolic disorders, or the interplay between platelets and tumor cells which contributes to tumor cell proliferation and progression.

Personalisation of warfarin therapy using thermal ink-jet printing

Warfarin is a widely used anticoagulant that is critical in reducing patient morbidity and mortality associated with thromboembolic disorders. However, its narrow therapeutic index and large inter-individual variability can lead to complex dosage regimes. Formulating warfarin as an orodispersible film (ODF) using thermal ink-jet (TIJ) printing could enable personalisation of therapy to simplify administration. Commercial TIJ printers are currently unsuitable for printing the milligram dosages, typically required for warfarin therapy. As such, this study aimed to modify a commercial TIJ printing system to formulate personalised warfarin ODFs containing therapeutic dosages. A TIJ printer was modified successfully with the printer functionality intact; the substrate (paper) rolling mechanism of the printer was replaced by printing onto a stationary stage. Free film substrates were composed of hydroxypropyl methylcellulose (20%w/w) and glycerol (3%w/w). The resulting ODFs were characterised for morphology, disintegration, solid-state properties and drug content. Printed film stability was assessed at 40 °C/75% relative humidity for 30 days. Therapeutic warfarin doses (1.25 and 2.5 mg) were successfully printed onto the film substrates. Excellent linearity was observed between the theoretical and measured dose by changing the warfarin feed concentration (R2 = 0.9999) and length of the print objective, i.e. the Y-value, (R2 = 0.9998). Rapid disintegration of the ODFs was achieved. As such, this study successfully formulated personalised warfarin ODFs using a modified TIJ printer, widening the range of applications for TIJ printing to formulate narrow therapeutic index drugs.

Rodent vertical sleeve gastrectomy alters maternal immune health and fetoplacental development.

Bariatric surgery is increasingly employed to improve fertility and reduce obesity-related co-morbidities in obese women. Surgical weight loss not only improves the chance of conception but reduces the risk of pregnancy complications including pre-eclampsia, gestational diabetes, and macrosomia. However, bariatric procedures increase the incidence of intrauterine growth restriction (IUGR), fetal demise, thromboembolism, and other gestational disorders. Using our rodent model of vertical sleeve gastrectomy (VSG), we tested the hypothesis that VSG in diet-induced, obese dams would cause immune and placental structural abnormalities that may be responsible for fetal demise during pregnancy. VSG dams studied on gestational day (G) 19 had reduced circulating T-cell (CD3+ and CD8+) populations compared with lean or obese controls. Further, local interleukin (IL) 1β and IL 1 receptor antagonist (il1rn) cmRNA were increased in placenta of VSG dams. Placental barrier function was also affected, with increased transplacental permeability to small molecules, increased matrix metalloproteinase 9 expression, and increased apoptosis in VSG. Furthermore, we identified increased placental mTOR signaling that may contribute to preserving the body weight of the fetuses during gestation. These changes occurred in the absence of a macronutrient deficit or gestational hypertension in the VSG dams. In summary, previous VSG in dams may contribute to fetal demise by affecting maternal immune system activity and compromise placental integrity.

Norcantharidin, a clinical used chemotherapeutic agent, acts as a powerful inhibitor by interfering with fibrinogen-integrin αIIb β3 binding in human platelets.

During platelet activation, fibrinogen binds to its specific platelet receptor, integrin αII bβ3, thus completing the final common pathway for platelet aggregation. Norcantharidin (NCTD) is a promising anticancer agent in China from medicinal insect blister beetle. In this study, we provided the evidence to demonstrate NCTD (0.1–1.0 μM) possesses very powerful antiplatelet activity in human platelets; nevertheless, it had no effects on surface P‐selectin expression and only slight inhibition on ATP‐release reaction in activated platelets. Moreover, NCTD markedly hindered integrin αII bβ3 activation by interfering with the binding of FITC‐labelled PAC‐1. It also markedly reduced the number of adherent platelets and the single platelet spreading area on immobilized fibrinogen as well as clot retraction. Additionally, NCTD attenuated phosphorylation of proteins such as integrin β3, Src and FAK in platelets spreading on immobilized fibrinogen. These results indicate that NCTD restricts integrin αII bβ3‐mediated outside‐in signalling in human platelets. Besides, NCTD substantially prolonged the closure time in human whole blood and increased the occlusion time of thrombotic platelet plug formation and prolonged the bleeding time in mice. In conclusion, NCTD has dual activities, it can be a chemotherapeutic agent for cancer treatment, and the other side it possesses powerful antiplatelet activity for treating thromboembolic disorders.

Need of the hour: Warfarin-induced massive intraperitoneal bleed

Warfarin is an oral anticoagulant which is a natural coumarin derivative used for the treatment of various diseases such as thromboembolic disorders, prosthetic heart valves, and atrial fibrillation. Bleeding tendencies have been the most commonly reported adverse effects of warfarin, limiting its use and requiring the need for regular monitoring. Despite many warfarin management strategies being taken for the prevention, bleeding still continues to be a problem to be dealt with. The authors report a case of spontaneous intraperitoneal bleeding due to warfarin use in a 54-year-old female patient.

Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation.

Platelet activation has been reported to play a major role in arterial thrombosis, cancer metastasis, and progression. Recently, we developed a novel Ir(III)-based compound, [Ir(Cp∗)1-(2-pyridyl)-3-(4-dimethylaminophenyl)imidazo[1,5-a]pyridine Cl]BF4 or Ir-6 and assessed its effectiveness as an antiplatelet drug. Ir-6 exhibited higher potency against human platelet aggregation stimulated by collagen. Ir-6 also inhibited ATP-release, intracellular Ca2+ mobilization, P-selectin expression, and the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), v-Akt murine thymoma viral oncogene (Akt)/protein kinase B, and mitogen-activated protein kinases (MAPKs), in collagen-activated platelets. Neither the adenylate cyclase inhibitor SQ22536 nor the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one significantly reversed the Ir-6-mediated inhibition of collagen-induced platelet aggregation. Moreover, Ir-6 did not considerably diminish OH radical signals in collagen-activated platelets or Fenton reaction solution. At 2 mg/kg, Ir-6 markedly prolonged the bleeding time in experimental mice. In conclusion, Ir-6 plays a crucial role by inhibiting platelet activation through the inhibition of signaling pathways, such as the PLCγ2–PKC cascade and the subsequent suppression of Akt and MAPK activation, thereby ultimately inhibiting platelet aggregation. Therefore, Ir-6 is a potential therapeutic agent for preventing or treating thromboembolic disorders or disrupting the interplay between platelets and tumor cells, which contributes to tumor cell growth and progression.

КЛИНИЧЕСКАЯ ХАРАКТЕРИСТИКА ПАЦИЕНТОВ С НЕКЛАПАННОЙ ФИБРИЛЛЯЦИЕЙ ПРЕДСЕРДИЙ И СИНДРОМОМ ОБСТРУКТИВНОГО АПНОЭ/ГИПОПНОЭ СНА

Background. In recent years growing evidence has suggested the potential role of obstructive sleep apnoeahypopnoea (OSAH) in the genesis of atrial fibrillation (AF), but the precise mechanisms linking these two conditions are currently unknown. The aim. To assess the prevalence of OSAH in a sample of non-valvular AF patients and evaluate the clinical profile of non-valvular AF patients depending on the severity of sleep-disordered breathing. Material and methods. We enrolled into the study 172 patients with non-valvular AF (mean age 55.54±8.43 years; 68.02% males). The study subjects were divided into 4 groups according to the results of clinical laboratory evaluation (typical complaints, clinical markers, the Epworth scale scores and cardiorespiratory monitoring). Results. OSAH patients had higher body mass index, greater waist and neck circumference than non-OSAH patients (p<0.01); they more often had cardiac comorbidities (arterial hypertension, chronic heart failure) (p<0.01) and diabetes mellitus, and their parameters of blood oxygen saturation as well as apnea-hypopnea index (AHI) were significantly worse. Mild OSAH patients were less likely than moderate/severe OSAH patients to have permanent AF (p<0.01). Conclusion. OSAH appears to be highly prevalent in non-valvular AF patients and has been estimated to be present in approximately 78.49% in the study sample (it affects predominantly men with abdominal type of obesity). With the increase in OSAH severity and the level of AHI the prevalence of permanent AF and the risk of thromboembolic disorders by the CHA2DS2-VASc scale significantly rise.