BACKGROUND: Unfractionated heparin is used as the most common anticoagulation for venovenous extracorporeal membrane oxygenation (VV ECMO) patients. However, it is accompanied by frequent bleeding and thrombotic complications. The aim of the study was to demonstrate the feasibility of Enoxaparin anticoagulation for VV ECMO patients. METHODS: This study is a retrospective analysis of VV ECMO patients on continuous intravenous Enoxaparin anticoagulation. The primary outcome was the incidence of bleeding, thrombotic, and neurological complications during ECMO support. The secondary outcome was an analysis of secondary and primary hemostasis profiles. RESULTS: Data from 38 patients were analyzed in this study. The incidence of bleeding complications was 5.3%, for thrombotic complications it was 2.6% and for neurological (bleeding/ischemic events) complications it was 10.5%. The targeted anti-Xa activity of 0.4-0.6 IU/mL was achieved and maintained during whole ECMO period in 28 patients (73.8%), not affecting the hemocoagulation profile represented by APTT-r 1.15 ± 0.2, TT 18.67 ± 3.35 s, PT/INR 1.21 ± 0.19, fibrinogen 5.39 ± 1.49 g/L, antithrombin, and platelet count. Primary hemostasis pathology was diagnosed in all patients by PFA 200 tests Col/EPI 279 ± 38 s and Col/ADP 249 ± 66 s. The running time of ECMO was 7.8 ± 3.4 days. CONCLUSIONS: Enoxaparin anticoagulation appears to be feasible for VV ECMO patients without an increase in adverse events. Further larger-sampled and comparative studies are needed in the future to support our findings.

• MeSH
• Anticoagulants administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Enoxaparin * administration & dosage   therapeutic use   adverse effects   MeSH
• Factor Xa Inhibitors administration & dosage   therapeutic use   MeSH
• Administration, Intravenous MeSH
• Hemorrhage * prevention & control   etiology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Extracorporeal Membrane Oxygenation * adverse effects   methods   MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Feasibility Studies MeSH
• Thrombosis prevention & control   etiology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Autoři jsou uváděni v abecedním pořadí, podíl jednotlivých autorů je uveden na konci práce. Souhrn doporučení Preventivní opatření a postupy Doporučujeme, aby v průběhu porodu u žen s rizikovými faktory pro PPH byla sledována krevní ztráta s využitím kalibrovaných kolektorů krve nebo jejich ekvivalentů. (Dobrá klinická praxe) Doporučujeme, aby ženy se závažnými rizikovými faktory pro PŽOK (např. placenta acrreta spectrum nebo hematologické poruchy vyžadující konziliární hematologickou péči) rodily v perinatologickém centru intenzivní péče nebo v perinatologickém centru intermediární péče. (Dobrá klinická praxe) Doporučujeme u pacientek s vysokým rizikem PŽOK v přiměřeném časovém předstihu před porodem formulování plánu péče za účasti multidisciplinárního týmu. (Dobrá klinická praxe) Doporučujeme léčbu anemie antepartálně. Těhotným ženám by měly být podávány preparáty železa, pokud hladina hemoglobinu klesne v I. trimestru < 110 g/l nebo < 105 g/l ve 28. týdnu těhotenství. (Dobrá klinická praxe) Navrhujeme zvážit parenterální podání železa u žen se sideropenickou anemií, nereagující na suplementaci železa perorální cestou. Příčina anemie by měla být zjištěna co nejdříve po ukončení těhotenství. (Slabé doporučení) Pokud se dítě dobře adaptuje, nedoporučujeme dřívější podvaz pupečníku než za 1 min. (Silné doporučení) Doporučujeme pro snížení rizika rozvoje PPH a PŽOK u všech vaginálních porodů profylaktické podání uterotonik ve III. době porodní po porodu dítěte a po podvazu pupečníku. Lékem první volby je oxytocin. (Silné doporučení) Pokud nebyla aktivně vedena III. doba porodní, navrhujeme pro zkrácení trvání III. doby porodní a pro snížení krevní ztráty u vaginálního porodu zvážit provedení masáže dělohy a řízenou trakci za pupečník, provádí-li ji kvalifikovaná osoba. (Slabé doporučení) Doporučujeme podání uterotonik k prevenci rozvoje PPH u žen po vybavení dítěte císařským řezem a po podvazu pupečníku. (Silné doporučení) Navrhujeme zvážit u žen se zvýšeným rizikem PŽOK podání carbetocinu. (Slabé doporučení) Doporučujeme u žen se zvýšeným rizikem PŽOK podstupujících císařský řez jednorázové podání kyseliny tranexamové (TXA). Klinická poznámka: Použití TXA před provedením císařského řezu není explicitně uvedeno v SPC přípravku. Recentní metaanalýza uvádí nejčastější dávkování 1 g i.v. (Silné doporučení) Organizace poskytování péče Doporučujeme, aby každé zdravotnické zařízení, kde je gynekologicko-porodnické pracoviště, mělo pro situace PŽOK vypracováno řízený dokument definující organizační a odborný postup. (Dobrá klinická praxe) Doporučujeme, aby řízený dokument (tj. krizový plán) jednoznačně vymezoval organizační a odborné role jednotlivých členů krizového týmu při vzniku PŽOK (nelékařský personál, porodník, anesteziolog, hematolog apod.) a definoval minimální rozsah vybavení pracoviště pro zajištění péče o pacientky s PŽOK. (Dobrá klinická praxe) Doporučujeme pravidelný simulační trénink krizové situace PŽOK celým krizovým týmem s následným debrífinkem nebo jeho formalizovaným ekvivalentem. (Dobrá klinická praxe) Doporučujeme na každém pracovišti definování indikátorů kvality diagnostiky a léčby PŽOK a jejich formalizované vyhodnocování v pravidelných intervalech, nejméně jednou ročně. (Dobrá klinická praxe) Diagnostický a léčebný postup při PŽOK Při nálezu hypotonie nebo atonie dělohy doporučujeme používat strukturovaný stupňovitý postup. (Dobrá klinická praxe) Na pracovištích s dostupností endovaskulárních intervencí navrhujeme u stavů PŽOK z důvodu hypotonie nebo atonie dělohy zvážit preferenční využití radiologických intervenčních metod (selektivní embolizace pánevních tepen), pokud to aktuální klinický kontext umožňuje. (Slabé doporučení) U všech stavů rozvoje PPH doporučujeme provedení tzv. předtransfuzního vyšetření. Pro posouzení aktuálního stavu koagulace jsou (kromě standardních laboratorních vyšetření) preferovány metody tzv. point-of-care-testing, zejména viskoelastické metody. (Dobrá klinická praxe) Každé porodnické pracoviště by mělo mít ve spolupráci s transfuzním oddělením a ústavní lékárnou trvale dostatečnou zásobu transfuzních přípravků a krevních derivátů pro jejich bezprostřední dostupnost v režimu 24/7. Doporučujeme u stavů rozvoje PŽOK zajistit iniciálně dostupnost čtyř transfuzních jednotek plazmy (preferována je tzv. solvent/detergent ošetřená plazma), čtyř transfuzních jednotek erytrocytů a 6 g fibrinogenu. Za minimální zásobu fibrinogenu považujeme 8 g fibrinogenu a dostupnost dalších 8 g do 1 hod. (Dobrá klinická praxe) Doporučujeme u všech pacientek s PPH zahájit okamžitou tekutinovou resuscitaci. Pro zahájení tekutinové resuscitace doporučujeme použití balancovaných roztoků krystaloidů. (Silné doporučení) Navrhujeme zvážit použití syntetických koloidních roztoků s obsahem želatiny při nedosažení nebo nedosahování hemodynamických cílů tekutinové resuscitace použitím krystaloidních roztoků a při trvající potřebě tekutin. (Slabé doporučení) Do doby dosažení kontroly zdroje krvácení doporučujeme u pacientek s PŽOK usilovat o dosažení hodnoty systolického krevního tlaku v pásmu 80–90 mmHg. (Silné doporučení) Doporučujeme u PŽOK použít vazopresory co nejdříve při nemožnosti dosažení cílových hodnot arteriálního krevního tlaku probíhající tekutinovou resuscitací. (Silné doporučení) V diagnostice a léčbě koagulopatie u PŽOK nereagujícího na standardní léčebné postupy doporučujeme spolupráci s hematologem. (Dobrá klinická praxe) K identifikaci typu koagulační poruchy u PŽOK, k její monitoraci a pro cílenou léčbu poruchy hemostázy doporučujeme kromě výše uvedených skupinových laboratorních vyšetření (minimálně KO, aPTT, fibrinogen) používat i viskoelastické metody (ROTEM, TEG). (Silné doporučení) K dosažení/obnovení účinnosti endogenních hemostatických mechanismů a léčebných postupů podpory koagulace doporučujeme maximální možnou korekci hypotermie, acidózy a hladiny ionizovaného kalcia. (Silné doporučení) Doporučujeme časné zahájení všech dostupných postupů k prevenci hypotermie a udržení nebo dosažení normotermie. (Silné doporučení) Doporučujeme monitorovat a udržovat hladinu ionizovaného kalcia v normálním referenčním rozmezí při podávání transfuzních přípravků. Ke korekci byl měl být přednostně podáván chlorid vápenatý. (Silné doporučení) Substituci fibrinogenu doporučujeme u pacientek s PPH při poklesu jeho hladiny < 2 g/l a/nebo při nálezu jeho funkčního deficitu zjištěném viskoelastickými metodami a/nebo při odůvodněném klinickém předpokladu deficitu fibrinogenu i bez znalosti jeho hladin. Jako úvodní dávku u PŽOK doporučujeme podání minimálně 4 g fibrinogenu. (Silné doporučení) Doporučujeme podat kyselinu tranexamovou (TXA) v úvodní dávce 1 g i.v. co nejdříve po vzniku PŽOK. Identická dávka může být opakována (nejdříve po 30 min), pokud krvácení pokračuje a je-li současně prokázána hyperfibrinolýza a/nebo je-li v aktuálním klinickém kontextu hyperfibrinolýza vysoce pravděpodobná. (Silné doporučení) Po dosažení kontroly krvácení další podání TXA u pacientek s PŽOK nedoporučujeme. (Silné doporučení) Doporučujeme podání plazmy v dávce 15–20 ml/kg u stavů PPH, kde je předpoklad koagulopatie jiné etiologie, než je nedostatek fibrinogenu a/nebo jsou přítomny abnormální výsledky koagulačních vyšetření, a kdy jejich výsledky neumožní identifikovat spolehlivě převažující mechanizmus koagulační poruchy a její cílenou korekci. (Silné doporučení) Doporučujeme podání faktorů protrombinového komplexu (PCC) u pacientek s PŽOK, kde je laboratorně prokázán deficit faktorů v PCC obsažených. Rutinní podávání PCC u pacientek s PŽOK nedoporučujeme. (Silné doporučení) Navrhujeme zvážit podání rFVIIa v době před rozhodnutím o endovaskulární nebo chirurgické intervenci. (Slabé doporučení) Doporučujeme u pacientek s PŽOK podávání erytrocytárních transfuzních přípravků k dosažení cílové hodnoty hemoglobinu v pásmu 70–80 g/l. (Silné doporučení) Doporučujeme u pacientek s PŽOK podávání trombocytů k dosažení cílové hodnoty minimálně 50 × 109/l a/nebo při předpokladu či průkazu poruchy jejich funkce. (Silné doporučení) Nedoporučujeme rutinní měření hladin antitrombinu III u pacientek s PŽOK. (Silné doporučení) Nedoporučujeme rutinní substituci antitrombinu III u pacientek s PŽOK. (Silné doporučení) Doporučujeme zahájit farmakologickou profylaxi trombembolické nemoci co nejdříve po dosažení kontroly zdroje PPH. Mechanickou tromboprofylaxi (intermitentní pneumatická komprese anebo elastické punčochy) doporučujeme zahájit neprodleně, jakmile to klinický stav dovolí. (Silné doporučení)

Summary of recommendations Preventive measures and procedures We recommend monitoring of blood loss in women with risk factors for PPH during labor using calibrated blood collectors or their equivalents. (Good Clinical Practice) We recommend that women with significant risk factors for PPH (e.g., placenta acrreta spectrum or hematologic disorders requiring consultative hematologic care) deliver in a perinatal intensive care center or perinatal intermediate care center. (Good Clinical Practice) We recommend formulating a plan of care in collaboration with a multidisciplinary team at a reasonable time prior to delivery for patients at high risk of PPH. (Good Clinical Practice) We recommend treating anemia antepartally. Pregnant women should be given iron supplements if the haemoglobin level falls to < 110 g/L in the 1st trimester or < 105 g/L at 28 weeks of pregnancy. (Good Clinical Practice) We suggest considering parenteral iron administration in women with sideropenic anemia unresponsive to oral iron supplementation. The cause of anemia should be identified as soon as possible after termination of pregnancy. (Weak recommendation) If the baby adapts well, we do not recommend cord ligation in less than 1 min. (Strong recommendation) In all vaginal deliveries, we recommend prophylactic administration of uterotonics in the third postpartum period after the delivery of the baby and cord ligation to reduce the risk of PPH. The first-choice drug is oxytocin. (Strong recommendation) If the third stage of labor has not been actively managed, we suggest that uterine massage and controlled umbilical cord traction be considered to shorten the duration of the third stage of labor and to reduce blood loss during vaginal delivery, if performed by a qualified healthcare professional. (Weak recommendation) We recommend the administration of uterotonics to prevent the development of PPH in women after the delivery of a child by caesarean section and umbilical cord ligation. (Strong recommendation) We suggest considering carbetocin administration in women at increased risk of PPH. (Weak recommendation) We recommend a single-dose administration of tranexamic acid (TXA) in women at increased risk of PPH undergoing a caesarean section. Clinical note: The use of TXA prior to the caesarean section is not explicitly stated in the product's SPC. A recent meta-analysis states the most common dosage to be 1 g i.v. (Strong recommendation) Organization of care We recommend that every health care facility with an OB/GYN unit should have the PPH management protocol (guided document is not specific or really used at all, I am not sure if my suggestion is sufficient) defining the organizational and professional procedure for PPH situations. (Good Clinical Practice) We recommend that the PPH management protocol (i.e. the crisis action plan) should clearly define the organizational and professional roles of the individual members of the crisis team in the event of PPH (non-medical staff), obstetrician, anesthetist, hematologist, etc.) and define the minimum scope of equipment for the care of patients with PPH. (Good Clinical Practice) We recommend regular simulation training of PPH crisis by the entire crisis team with a subsequent debriefing or its formalized equivalent. (Good Clinical Practice) We recommend defining quality indicators for the diagnosis and treatment of PPH and their formalized evaluation at regular intervals, at least once a year. (Good Clinical Practice) Diagnostic and treatment procedure at PPH When hypotonia or atony of the uterus is found, we recommend using a structured procedure. (Good Clinical Practice) At departments with an option of endovascular interventions, we suggest considering the preferential use of radiological interventional methods (selective pelvic artery embolization) in cases of PPH due to uterine hypotonia or atony, if the current clinical context allows it. (Weak recommendation) For all stages of PPH development, we recommend a pre-transfusion examination. In addition to standard laboratory tests, point-of-care-testing methods, especially viscoelastic methods, are preferred to assess the current coagulation status. (Good Clinical Practice) Each obstetric unit should ensure a sufficient stock of blood products and blood derivatives for their immediate availability 24/7 in collaboration with the transfusion department and the inpatient pharmacy. In case of PPH development, we recommend securing initial availability of 4 units of plasma (solvent/detergent-treated plasma is preferred), 4 units of erythrocytes and 6 g of fibrinogen. We consider 8 g to be a minimum supply of fibrinogen and additional 8 g should be available within 1 h. (Good Clinical Practice) We recommend the initiation of immediate fluid resuscitation in all patients with PPH. We recommend the use of balanced crystalloid solutions to initiate fluid resuscitation. (Strong recommendation) We propose considering the use of synthetic colloid solutions containing gelatin when hemodynamic goals of fluid resuscitation have not been achieved or are not being achieved using crystalloid solutions and when a fluid deficit persists. (Weak recommendation) Until the source of bleeding is controlled, we recommend aiming for a systolic blood pressure in a range of 80–90 mmHg in patients with PPH. (Strong recommendation) We recommend the use of vasopressors as soon as possible in PPH when target arterial blood pressure values cannot be reached by ongoing fluid resuscitation. (Strong recommendation) We recommend cooperation with a hematologist in the diagnosis and treatment of coagulopathy in PPH unresponsive to standard therapies. (Good Clinical Practice) In addition to the above-mentioned panel laboratory tests (at least KO, aPTT, fibrinogen), we also recommend using viscoelastic methods (ROTEM, TEG) to identify the type of coagulation disorder in PPH, to monitor it and for targeted treatment of hemostasis disorders. (Strong recommendation) To achieve/restore the efficacy of endogenous hemostatic mechanisms and coagulation support therapies, we recommend the maximum possible correction of hypothermia, acidosis and ionized calcium levels. (Strong recommendation) Early initiation of all available procedures to prevent hypothermia and maintain or achieve normothermia is recommended. (Strong recommendation) It is recommended monitoring and maintaining ionized calcium levels within the normal range when administering transfusion products. Preferably, calcium chloride should be administered for correction. (Strong recommendation) Fibrinogen replacement is recommended in patients with PPH when fibrinogen levels fall to < 2 g/L and/or when there is a functional fibrinogen deficiency detected by viscoelastic methods and/or when there is a reasonable clinical assumption of fibrinogen deficiency even without knowledge of fibrinogen levels. We recommend a minimum of 4 g of fibrinogen as an initial dose in PPH. (Strong recommendation) It is recommended to administer tranexamic acid (TXA) at an initial dose of 1 g i.v. as soon as possible after the onset of PPH. An identical dose may be repeated (after 30 min at the earliest) if bleeding continues and if hyperfibrinolysis is demonstrated and/or if hyperfibrinolysis is highly likely in the current clinical context. (Strong recommendation) We do not recommend further administration of TXA in patients with PPH after bleeding control has been achieved. (Strong recommendation) We recommend administration of plasma at a dose of 15–20 mL/kg in PPH conditions where coagulopathy of a different etiology than fibrinogen deficiency is suspected and/or abnormal coagulation test results are present, and where the results do not reliably identify the predominant mechanism of the coagulation disorder and its targeted correction. (Strong recommendation) We recommend the administration of prothrombin complex factors (PCC) in patients with PPH where there is a laboratory evidence of a deficiency of PCC factors. We do not recommend routine administration of PCC in patients with PPH. (Strong recommendation) We suggest considering administration of rFVIIa before making a decision on an endovascular or a surgical intervention. (Weak recommendation) In patients with PPH, we recommend administration of erythrocyte blood products to achieve a target hemoglobin value in the range 70–80 g/L. (Strong recommendation) In patients with PPH, we recommend platelet administration to achieve a target value of at least 50 × 109/L and/or when platelet function impairment is suspected or demonstrated. (Strong recommendation) We do not recommend routine measurement of antithrombin III levels in patients with PPH. (Strong recommendation) We do not recommend routine antithrombin III replacement in patients with PPH. (Strong recommendation) We recommend initiating pharmacological prophylaxis for thromboembolic disease as soon as possible after control of the source of PPH is achieved. We recommend initiating mechanical thromboprophylaxis (intermittent pneumatic compression or elastic stockings) as soon as the clinical condition permits. (Strong recommendation)

• Keywords
• profylaxe uterotoniky, peripartální krvácení, tlakové a podlatkové nitroděložní prostředky, hemostatické nitroděložní prostředky, viskoelastické metody, krizový management,
• MeSH
• Uterine Hemorrhage * diagnosis   therapy   MeSH
• Factor VIIa MeSH
• Hemorrhage diagnosis   therapy   MeSH
• Humans MeSH
• Peripartum Period MeSH
• Pregnancy MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Practice Guideline MeSH

For the treatment of bilateral limbal stem cell deficiency (LSCD), cell therapy with transplantation of cultivated oral mucosa epithelial cells (COMET) is a promising alternative. Although not yet established, current protocols on the cultivation of oral mucosal epithelial cell (OMECs) sheets are based mainly on substrates and xenobiotic additives that may lead to variable outcomes and undesirable immune responses by the patient. The aim of this study was to characterize OMECs cultivated in xenobiotic-free media (XF) seeded on fibrin gel, in comparison to conventional complex (COM) medium. Oral mucosal biopsies were retrieved from 31 donors. After cultivation in COM or XF medium, OMECs were compared based on growth kinetics, morphology, cell size and viability. Using immunofluorescence and gene expression analyses, the degree of stemness, proliferation and differentiation was evaluated in OMEC cultures. Our findings showed that although OMECs showed a similar morphology and viability, and comparable growth kinetics, immunofluorescence revealed the preservation of stemness (p63 + p40 positivity in cells ≤11 μm) and proliferation in both COM and XF. Gene expression analyses showed that keratin (K)13 and K15 expression levels were significantly higher in XF (adj. p < 0.001), but otherwise COM and XF-treated OMECs had comparable transcriptional profiles in a panel of stemness, proliferation and differentiation genes. These results demonstrate the feasibility of culturing OMECs on fibrin gel without xenogeneic additives, while maintaining their undifferentiated state and preserving stemness. In conclusion, both in terms of results and methodology, the procedures presented here are suitable for implementation in clinical practice.

• MeSH
• Cell Differentiation MeSH
• Cell Culture Techniques * MeSH
• Limbal Stem Cell Deficiency MeSH
• Adult MeSH
• Epithelial Cells * metabolism   drug effects   MeSH
• Fibrin * MeSH
• Gels MeSH
• Stem Cells * metabolism   cytology   MeSH
• Culture Media MeSH
• Cells, Cultured MeSH
• Middle Aged MeSH
• Humans MeSH
• Limbus Corneae * cytology   pathology   metabolism   MeSH
• Corneal Diseases pathology   drug therapy   metabolism   MeSH
• Cell Proliferation drug effects   MeSH
• Epithelium, Corneal metabolism   cytology   drug effects   pathology   MeSH
• Aged MeSH
• Stem Cell Transplantation methods   MeSH
• Mouth Mucosa * cytology   MeSH
• Cell Survival MeSH
• Xenobiotics pharmacology   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Extracorporeal membrane oxygenation (ECMO) is a critical intervention for patients with severe respiratory or cardiac failure, requiring careful management of anticoagulation to prevent thromboembolic complications. This review examines current practices and challenges in ECMO anticoagulation, focusing on strategies, agents, and emerging insights. Unfractionated heparin (UFH) remains the most commonly used anticoagulant, monitored via activated partial thromboplastin time (aPTT) or activated clotting time (ACT). Increasing attention is given to alternative tools like anti-Xa and viscoelastic assays (VEA), which offer potentially more reliable results. Supplementation with antithrombin should be considered if levels fall below 50%-70% to optimize heparin efficacy. Low molecular weight heparin (LMWH) is occasionally used due to its predictable pharmacokinetics, though challenges in dosing and reversal limit its application. Direct thrombin inhibitors, such as bivalirudin, are valuable alternatives, particularly for patients with heparin-induced thrombocytopenia (HIT), though their cost and availability remain barriers. Anticoagulation in ECMO patients is complex, balancing the risks of thrombosis and bleeding. Factors such as patient age, underlying conditions, and ECMO-induced coagulopathies complicate management. Personalized anticoagulation protocols and point-of-care VEA are emerging as effective tools for improving therapy. Routine no-anticoagulation strategies are not recommended unless there are significant bleeding complications. Ongoing research into novel anticoagulants and the long-term impact of anticoagulation on ECMO outcomes is critical. Anticoagulation management in ECMO continues to evolve, focusing on individualized approaches, improved monitoring, and better outcomes. Standardized protocols and further research are essential for optimizing care in this high-risk population.

• Publication type
• Journal Article MeSH
• Review MeSH

We investigated the sex-dependent effects of inflammatory responses in visceral adipose tissue (VAT) and perivascular adipose tissue (PVAT), as well as hematological status, in relation to cardiovascular disorders associated with prediabetes. Using male and female hereditary hypertriglyceridemic (HHTg) rats-a nonobese prediabetic model featuring dyslipidemia, hepatic steatosis, and insulin resistance-we found that HHTg females exhibited more pronounced hypertriglyceridemia than males, while HHTg males had higher non-fasting glucose levels. Additionally, HHTg females had higher platelet counts, larger platelet volumes, and lower antithrombin inhibitory activity. Regarding low-grade chronic inflammation, HHTg males exhibited increased serum leptin and leukocyte levels, while females had increased serum interleukin-6 (IL-6). Both sexes had increased circulating plasminogen activator inhibitor-1 (PAI-1), higher PAI-1 gene expression in VAT and PVAT, and elevated intercellular adhesion molecule-1 (ICAM-1) gene expression in the aorta, contributing to endothelial dysfunction in the HHTg strain. However, HHTg females had lower tumor necrosis factor alpha (TNFα) gene expression in the aorta. Severe dyslipidemia in this prediabetic model was associated with hypercoagulation and low-grade chronic inflammation. The increase in PAI-1 expression in both VAT and PVAT seems to indicate a link between inflammation and vascular dysfunction. Despite the more pronounced dyslipidemia and procoagulation status in females, their milder inflammatory response may reflect an association between reduced cardiovascular damage and prediabetes.

• MeSH
• Dyslipidemias * metabolism   pathology   genetics   MeSH
• Plasminogen Activator Inhibitor 1 * metabolism   genetics   MeSH
• Rats MeSH
• Disease Models, Animal * MeSH
• Vascular Diseases metabolism   pathology   etiology   genetics   MeSH
• Intra-Abdominal Fat * metabolism   pathology   MeSH
• Sex Characteristics MeSH
• Inflammation * metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

OBJECTIVES: To determine whether selected single nucleotide polymorphisms (SNPs) of genes encoding proteins responsible for the activation, transport, or metabolism of dabigatran and apixaban might be associated with a risk of gastrointestinal bleeding in a cohort of adult patients treated with these drugs. No previous study has focused specifically on the association with gastrointestinal bleeding. MATERIALS AND METHODS: Ninety-one patients treated with dabigatran or apixaban were genotyped for selected polymorphisms. The following polymorphisms were studied: ABCB1 gene rs1045642, rs4148738, rs1128503 and rs2032582; CES1 gene rs2244613, rs8192935 and rs2244614; and SULT1A1 gene rs9282861 and SULT1A2 gene rs1136703. Two groups divided by particular drugs and genotypes were compared in terms of the presence (bleeding group) or absence (nonbleeding group) of gastrointestinal bleeding. The genotype distribution was expressed via dominant and recessive models. RESULTS: In patients treated either with dabigatran or with apixaban, no evidence was found to support the association of gastrointestinal bleeding with any genotype for any of the studied SNPs. CONCLUSION: In both dabigatran- and apixaban-treated patients, no associations between the selected polymorphisms and gastrointestinal bleeding risk were found, however the results should be interpreted with caution because of the small cohort size.

• MeSH
• Antithrombins adverse effects   therapeutic use   MeSH
• Dabigatran * adverse effects   MeSH
• Adult MeSH
• Pharmacogenetics MeSH
• Gastrointestinal Hemorrhage * genetics   chemically induced   MeSH
• Genotype MeSH
• Factor Xa Inhibitors adverse effects   therapeutic use   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Middle Aged MeSH
• Humans MeSH
• ATP Binding Cassette Transporter, Subfamily B MeSH
• Pyrazoles * adverse effects   therapeutic use   MeSH
• Pyridones * adverse effects   therapeutic use   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

We report on the largest single dataset of patients with PMM2-CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (n = 80) of participants, followed by p.Pro113Leu (21.2%, n = 29), and p.Phe119Leu (12.4%, n = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease-associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2-CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease. Trial Registration: NCT03173300.

• MeSH
• Child MeSH
• Adult MeSH
• Phenotype MeSH
• Phosphotransferases (Phosphomutases) * genetics   chemistry   MeSH
• Genetic Association Studies * MeSH
• Genotype MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Mutation MeSH
• Child, Preschool MeSH
• Congenital Disorders of Glycosylation * genetics   diagnosis   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH

Antikoagulační terapie zabraňuje různými mechanismy genezi trombinu a následné přeměny fibrinogenu na fibrin. Heparin je parenterálně aplikované antikoagulancium, které po aktivaci antitrombinu nepřímo blokuje trombotický účinek trombinu. Mezi injekčně podávaná antikoagulancia patří dále nízkomolekulární hepariny (LMWH) a fondaparinux, které nepřímo, za účasti antitrombinu, inhibují aktivovaný F Xa. Mezi perorální antikoagulancia (OAC) řadíme warfarin, který potlačuje tvorbu funkčních prokoagulačních faktorů závislých na vitaminu K (protrombinu, F VII, F IX a F X), a tzv. přímá perorální antikoagulancia (DOAC), která vyvolávají buď přímou inhibici trombinu (dabigatran etexilát), nebo přímou inhibici aktivovaného F Xa (apixaban, edoxaban, rivaroxaban).

Anticoagulation therapy prevents the generation of thrombin and the subsequent conversion of fibrinogen to fibrin by various mechanisms. Heparin is a parenterally administered anticoagulant that indirectly blocks the thrombotic effect of thrombin after activation of antithrombin. Injectable anticoagulants also include low-molecular-weight heparins (LMWH) and fondaparinux, which indirectly, with the participation of antithrombin, inhibit activated F Xa. Oral anticoagulants (OACs) include warfarin, which suppresses the formation of functional procoagulation factors dependent on vitamin K (prothrombin, F VII, F IX, and F X), and so-called direct oral anticoagulants (DOACs), which cause either direct inhibition of thrombin (dabigatran etexilate) or direct inhibition of activated F Xa (apixaban, edoxaban, rivaroxaban).

Cíl studie: Zkoumání vztahu mezi závažností metabolických změn vyvolaných COVID-19 a strukturou a četností změn na sítnici podle dat z vyšetření očních pozadí pacientů s různým klinickým průběhem onemocnění COVID-19. Materiál a metody: Vyšetřeno bylo 117 pacientů s onemocněním COVID-19. Při vyšetření pacientů byla zjišťována závažnost průběhu onemocnění COVID-19 a expresivita metabolických změn; záznam obrazu očních pozadí byl pořizován pomocí přenosných fundus kamer Pictor Plus Fundus Camera a VistaView (Volk Optical). Výsledky: Výsledkem výzkumu je zjištění změn na sítnici u 49 (41,9 %) pacientů s onemocněním COVID-19. V 8 (16,3 %) případech byly pozorovány klinicky významné změny sítnice a oka indukované infekcí COVID-19 (krvácení do sklivce, pretrombóza centrální sítnicové žíly nebo větví centrální sítnicové žíly, trombóza centrální sítnicové žíly nebo větví centrální sítnicové žíly), které vedly ke snížení zrakové ostrosti. Ve 41 (83,7 %) případech byly pozorovány klinicky nevýznamné změny sítnice indukované infekcí COVID-19 (vatovitá ložiska, zúžené sítnicové cévy, intraretinální a petechiální krvácení, tortuozita a dilatace sítnicových venul). Klinicky významné změny na sítnici se vyskytly u pacientů se statisticky významně vyšší hladinou D-dimerů a vyšším procentuálním výskytem lézí plicního parenchymu oproti skupině pacientů s klinicky nevýznamnými sítnicovými změnami (p < 0,05). Závěry: Struktura retinálních změn u pacientů s COVID-19 koreluje se závažností klinického průběhu onemocnění a metabolických změn pacientů. Metabolické změny korelují se změnami sítnice a mohou mít prediktivní význam v prevenci celkových cévních komplikací spojených s onemocněním COVID-19.

Aims: To study the relationship between the severity of COVID-induced metabolic changes and the structure and frequency of retinal chan- ges, according to funduscopy data in patients with different clinical courses of COVID-19. Materials and methods: 117 patients with COVID-19 were examined. While examining patients, severity of the course of COVID-19, the expressiveness of changes in the metabolic status were determined; fundus image registration was performed with portable fundus cameras Pictor Plus Fundus Camera and VistaView (Volk Optical). Results: As a result of the research, retinal changes were found in 49 (41.9 %) patients with COVID-19. In 8 (16.3 %) cases, clinically significant (vitreous hemorrhage, prethrombosis of the central retinal vein or branches of the central retinal vein, thrombosis of the central retinal vein or branches of the central retinal vein) COVID-induced retinal and ophthalmological changes were observed, which caused a decrease in visual acuity. In 41 (83.7 %) cases, clinically insignificant changes (cotton wool spots, narrowed retinal vessels, intraretinal and petechial hemorrhages, tortuosity and dilatation of retinal venules) COVID-induced retinal changes were observed. Clinically significant retinal changes occur in patients with a statistically significantly higher level of D-dimer and a greater percentage of lung parenchyma lesion than in the group of patients with clinically insignificant retinal changes (p < 0.05). Conclusions: The structure of retinal changes in patients with COVID-19 correlates with the severity of the clinical course of the disease and changes in the metabolic status of patients. Metabolic changes are correlated with retinal changes and can be predictive for preventing general vascular complications in COVID-19.

• MeSH
• COVID-19 * complications   virology   MeSH
• Fibrin Fibrinogen Degradation Products analysis   MeSH
• Humans MeSH
• Metabolic Diseases diagnosis   classification   virology   MeSH
• Retina * pathology   virology   MeSH
• Retinal Vessels pathology   virology   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Clinical Study MeSH

BACKGROUND: Dabigatran directly inhibits thrombin and is used in primary and secondary stroke prevention in individuals with nonvalvular atrial fibrillation. The prodrug dabigatran etexilate is absorbed by enteral P-glycoprotein (ABCB1) and then activated by hepatic and intestinal carboxylesterases (CES1) to produce active metabolites. Variations in dabigatran metabolism because of genetics may affect concentration levels and clinical outcomes. STUDY QUESTION: We conducted a study to assess how polymorphisms in the CES1 (rs2244613) and ABCB1 (rs4148738) genes affect the through plasma level (c min ) of dabigatran and its correlation to clinical outcomes. STUDY DESIGN: Retrospective multicentric study of consecutive patients on dabigatran therapy. Examination of CES1 rs2244613 and ABCB1 rs4148738 polymorphisms, c min 12 hours after administration, clinical follow-up (ischemic stroke, major or clinically relevant hemorrhage, myocardial infarction, other thromboembolism, and death). MEASURES AND OUTCOMES: A total of 432 patients received treatment for an average of 19.78 months (SD of 20.165). The sex distribution of the patients was 56.5% male, and the average age was 67.56 years (SD of 14.7). The ABCB1 variant genotype was present in 67.8% of patients, whereas 37.5% carried the CES1 polymorphism. RESULTS: Compared with wild-type patients, patients with the CES1 variant had significantly lower dabigatran plasma levels (with a mean difference of 16.986; 95% confidence interval, 5.794-28.178 ng/mL, P = 0.003). We also found a significant risk of major bleeding in patients carrying the ABCB1 rs4148738 allele (hazard ratio = 1.99, confidence interval 95% 1.10 to 3.59, P = 0.024). CONCLUSIONS: The CES1 variant genotype rs2244613 is closely linked with reduced c min of dabigatran. Carriers of the ABCB1 rs4148738 polymorphism exhibit a tendency toward higher plasma levels of dabigatran, which leads to a significantly increased risk of bleeding.

• MeSH
• Antithrombins * adverse effects   blood   pharmacokinetics   administration & dosage   MeSH
• Dabigatran * adverse effects   pharmacokinetics   blood   administration & dosage   MeSH
• Atrial Fibrillation drug therapy   genetics   complications   blood   MeSH
• Ischemic Stroke * prevention & control   genetics   blood   MeSH
• Polymorphism, Single Nucleotide MeSH
• Carboxylic Ester Hydrolases * genetics   blood   MeSH
• Hemorrhage * chemically induced   blood   MeSH
• Middle Aged MeSH
• Humans MeSH
• ATP Binding Cassette Transporter, Subfamily B * genetics   MeSH
• Retrospective Studies MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH