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1.
Se Pu ; 41(2): 107-121, 2023 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-36725707

RESUMO

Heparin (Hp) is the most widely used anticoagulant drug in the clinics, with an annual global output of over 10 billion dollars. Hp, a member of the glycosaminoglycans (GAGs), is prepared from porcine intestinal mucosa via extraction, separation, and purification. Hp is a linear polysaccharide with repeating disaccharide units. Low-molecular-weight heparins (LMWHs) are depolymerized from Hp via chemical or enzymatic degradation. Compared with Hp, LMWHs exhibit less bleeding side effect, milder immunogenicity, and higher bioavailability when injected subcutaneously. In general, Hps, including LMWHs, are high complex drugs with large molecular weights (MWs), inhomogeneous MW distributions, and structural heterogeneity, including different degrees and locations of sulfonation, and unique residues generated from different production processes. Thus, developing efficient analytical methods to elucidate the structures of Hps and characterize or quantitate their properties is extremely challenging. Unfortunately, this problem limits their quality control, production optimization, clinical safety monitoring, and new applications. Research has constantly sought to elucidate the complicated structures of Hp drugs. Among the structural analysis and quality control methods of Hp currently available, chromatographic methods are the most widely studied and used. However, no literature thoroughly summarizes the specific applications of chromatographic methods in the structural analysis, manufacturing process, and quality control of Hp drugs. This paper systematically organizes and describes recent research progresses of the chromatographic methods used to analyze Hp drugs, including the identification and composition of monosaccharides, disaccharides, oligosaccharides, and polysaccharides. The applications, innovations, and limitations of these chromatographic methods are also summarized in this review. The insights obtained in this study will help production and quality control personnel, as well as drug researchers, obtain a deeper understanding of the complex structures of Hp drugs. This paper also provides a comprehensive reference for the structural analysis and quality control of Hps, proposes ideas for the development of new quality control methods, and lays a strong foundation for the in-depth structural elucidation of Hp drugs.


Assuntos
Heparina de Baixo Peso Molecular , Heparina , Animais , Suínos , Anticoagulantes , Cromatografia , Heparina Liase/metabolismo , Dissacarídeos
2.
Medicine (Baltimore) ; 102(4): e32817, 2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36705388

RESUMO

RATIONALE: Venovenous extracorporeal membrane oxygenation (ECMO) is recommended for the treatment of critically ill patients with acute respiratory distress syndrome due to coronavirus disease 2019 (COVID-19). However, ECMO management can cause both bleeding and thrombotic complications. There are insufficient coagulofibrinolytic data for appropriate ECMO management in patients with COVID-19. PATIENT CONCERNS: A 48-year-old man with severe COVID-19-acute respiratory distress syndrome underwent long-term venovenous ECMO management for 48 days. Refractory oronasal bleeding developed on day 13, so the administration of unfractionated heparin was ceased for 29 days. DIAGNOSIS: The patient showed dynamic coagulofibrinolytic responses associated with ECMO management, as shown by fibrin/fibrinogen degradation products, soluble fibrin, thrombin-antithrombin complex, and plasmin-α2-plasmin inhibitor complex elevations, suggesting the development of ECMO-induced coagulopathy. INTERVENTIONS: We assessed coagulofibrinolytic markers to decide the appropriate timing for controlling excessive activation of coagulation by exchanging ECMO circuits. Moreover, viscoelastic hemostatic assays were used for adequate transfusion of blood products. OUTCOMES: Safe long-term ECMO management was completed, which was withdrawn on day 48. The patient was weaned off mechanical ventilation on day 57 and was transferred to another hospital for rehabilitation. LESSONS: Monitoring the coagulofibrinolytic status using markers and viscoelastic hemostatic assays may be effective for safe long-term ECMO management even without anticoagulant therapy.


Assuntos
COVID-19 , Oxigenação por Membrana Extracorpórea , Hemostáticos , Síndrome do Desconforto Respiratório , Humanos , Masculino , Pessoa de Meia-Idade , Anticoagulantes , COVID-19/complicações , COVID-19/terapia , Oxigenação por Membrana Extracorpórea/efeitos adversos , Produtos de Degradação da Fibrina e do Fibrinogênio , Hemorragia/etiologia , Heparina , Síndrome do Desconforto Respiratório/etiologia , Síndrome do Desconforto Respiratório/terapia
3.
Clin Appl Thromb Hemost ; 29: 10760296221129591, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36700247

RESUMO

Introduction: Cerebral venous thrombosis (CVT) is a life-threatening neurological condition. There is limited evidence for the use of direct oral anticoagulants (DOAC) for long-term anticoagulation in this patient population. We report a case series of patients treated with apixaban and their clinical course. Methods: This was a retrospective cohort study. Patients diagnosed with CVT in a defined time period at our institution were screened for long-term anticoagulation and patients who were treated with apixaban were included in this study. Results: A total of nine patients were included in this study. The mean age was 36 years and 56% of the patients included were women. All received initial anticoagulation with unfractionated heparin (UFH) infusion for at least twenty-four hours, except for one patient who had anti-thrombin III deficiency and was treated with argatroban infusion. For long-term anticoagulation, 56% of patients received apixaban 10 mg twice daily for the first five to seven days followed by 5 mg twice daily, while the remaining 44% were transitioned from IV anticoagulation to apixaban 5 mg twice daily. There were no adverse events reported, except for one patient who developed anemia after 7 months of treatment and required a blood transfusion. Complete recanalization was achieved in 78% while 22% had partial recanalization. Follow-up time ranged from six to twenty-three months. Conclusion: The use of apixaban for long-term anticoagulation in CVT resulted in recanalization in all of the patients in this case series without any major side effects. This case series adds to the emerging studies demonstrating the utility of apixaban for CVT.


Assuntos
Trombose Intracraniana , Trombose Venosa , Humanos , Feminino , Adulto , Masculino , Heparina , Anticoagulantes , Estudos Retrospectivos , Trombose Intracraniana/diagnóstico , Trombose Venosa/epidemiologia
4.
PLoS One ; 18(1): e0280069, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36634087

RESUMO

BACKGROUND: Surface compatibility with blood is critical both for scientific investigations on hemostasis and clinical applications. Regarding in vitro and ex vivo investigations, minimal alteration in physiological hemostasis is of particular importance to draw reliable conclusions on the human coagulation system. At the same time, artificial coagulation activation must be avoided, which is relevant for the patient, for example to prevent stent graft occlusion. The aim was to evaluate the advantages and disadvantages of antithrombotic and antifouling surface coatings in the context of their suitability for ex vivo incubation and the study of coagulation properties. METHODS: We investigated the impact of different protocols for surface coating of synthetic material and different anticoagulants on hemostasis and platelet activation in ex vivo human whole blood. Blood samples from healthy donors were incubated in coated microtubes on a rotating wheel at 37°C. Two protocols for surface coating were analyzed for hemostatic parameters and metabolic status, a heparin-based coating (CHC, Corline Heparin Conjugate) without further anticoagulation and a passivating coating (MPC, 2-methacryloyloxethyl phosphorylcholine) with added anticoagulants (enoxaparin, ENOX; or fondaparinux, FPX). Employing the MPC-based coating, the anticoagulants enoxaparin and fondaparinux were compared regarding their differential effects on plasmatic coagulation by thrombelastometry and on platelet activation by flowcytometry and platelet function assays. RESULTS: Using the CHC coating, significant coagulation cascade activation was observed, whereas parameters remained mostly unchanged with MPC-based protocols. Extended incubation caused significantly elevated levels of the soluble membrane attack complex. Neither ENOX nor FPX caused a relevant impairment of platelet function or activation capacity and thrombelastometric parameters remained unchanged with both protocols. For translational purposes, we additionally modeled endotoxemia with the MPC-based protocols by incubating with lipopolysaccharide plus/minus thrombin. While coagulation parameters remained unchanged, elevated Interleukin 8 and Matrix Metalloproteinase 9 demonstrated preserved immune cell responsiveness. CONCLUSIONS: The MPC-based protocols demonstrated better hemocompatibility compared to CHC, and ENOX and FPX proved useful for additional anticoagulation. Furthermore, this simple-to-use whole blood model may be useful for experimental analyses of the early coagulatory and immunological response without decalcification.


Assuntos
Anticoagulantes , Enoxaparina , Humanos , Anticoagulantes/farmacologia , Fondaparinux , Hemostasia , Heparina , Inflamação
5.
BMC Nephrol ; 24(1): 12, 2023 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-36642717

RESUMO

BACKGROUND: Unfractionated heparin sodium and nafamostat mesylate have long been used as anticoagulants in continuous kidney replacement therapy (CKRT) where citrate is unavailable. This study aimed to determine whether heparin or nafamostat mesylate used during CKRT was associated with a longer filter life. METHODS: In this single-centre observational study, we included adult patients who required CKRT and used heparin or nafamostat mesylate for their first CKRT in the intensive care unit from September 1, 2013, to December 31, 2020. The primary outcome was filter life (from the start to the end of using the first filter). We used propensity score matching to adjust for the imbalance in patients' characteristics and laboratory data at the start of CKRT and compared the outcomes between the two groups. We also performed restricted mean survival time analysis to compare the filter survival times. RESULTS: We included 286 patients, 157 patients on heparin and 129 patients on nafamostat mesylate. After propensity score matching, the mean filter life with heparin was 1.58 days (N = 91, Standard deviation [SD], 1.52) and with nafamostat mesylate was 1.06 days (N = 91, SD, 0.94, p = 0.006). Multivariable regression analysis adjusted for confounding factors supported that heparin was associated with a longer filter life compared with nafamostat mesylate (regression coefficient, days, 0.52 [95% CI, 0.15, 0.89]). The between group difference of the restricted mean filter survival time in the matched cohort was 0.29 (95% CI, 0.07-0.50, p = 0.008). CONCLUSION: Compared to nafamostat mesylate, heparin was associated with one-third to one-half a day longer filter life. TRIAL REGISTRATION: Not applicable.


Assuntos
Injúria Renal Aguda , Terapia de Substituição Renal Contínua , Adulto , Humanos , Heparina/uso terapêutico , Anticoagulantes/uso terapêutico , Coagulação Sanguínea , Ácido Cítrico/uso terapêutico , Injúria Renal Aguda/terapia , Terapia de Substituição Renal
6.
Theriogenology ; 198: 231-240, 2023 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-36621132

RESUMO

Guinea pig in vitro fertilization (IVF) are poorly developed due to the limited accessibility to oocytes and the lack of an efficient method of sperm capacitation. Thus, we aimed to evaluate different capacitation protocols that we validated through sperm analysis and using heterologous (He) IVF with zona-intact bovine oocytes. Spermatozoa of guinea pigs were collected and processed separately by 4 different protocols: A) Spermatozoa were obtained by flushing the lumen of one cauda epididymis and incubated in a minimal culture medium (MCM); B) One epididymis was placed in a prewarmed of M2 medium and gently minced with fine scissors. Spermatozoa were incubated in a modified human tubal fluid medium (HTF). In both protocols, the spermatozoa were capacitated at 37 °C under an atmosphere of 5% CO2 for 2 h. In the protocols C and D, the spermatozoa were collected by flushing the lumen of the cauda epididymis and selected by commercial density gradient Bovipure® (Nidacon Laboratories AB, Göthenborg, Sweden), according to the manufacturer's instructions. Then for Protocol C) spermatozoa were incubated in MCM medium supplemented with 10 mg/mL heparin (MCM-Hep); while for Protocol D) spermatozoa were incubated in FERT medium supplemented 10 mg/mL heparin (FERT-Hep). Incubation of C and D protocols were performed at 38.5 °C under an atmosphere of 5% CO2 for 2 h. Capacitation protocols C and D showed a higher percentage of viability, total and hyperactive-like motility, and acrosome reaction compared to protocols A and B. For this reason, protocols C and D were used for further He-IVF analysis. Guinea pig sperm and matured zona-intact bovine oocytes were co-incubated at 5% CO2 and 38.5 °C. Sperm-oocyte interaction was assessed at 2.5 h post-insemination (hpi) and pronuclear formation (PrF) were evaluated at 18, 20, 22, 24 and 26 hpi, while the cleavage rate was evaluated at 48 hpi. In protocol D, PrF was significantly higher than in protocol C (P ≤ 0.05) at every time point evaluated. Also, the cleavage rate at 48 hpi was higher (P ≤ 0.05) in He-IVF protocol D (69.8 ± 1.7%) compared to He-IVF protocol C (49.1 ± 1.1%). In conclusion, we determined the most adequate sperm capacitation conditions for guinea pig that allow zona-intact bovine oocyte penetration and lead to hybrid embryo formation, suggesting that these conditions could be optimal to develop IVF in guinea pigs.


Assuntos
Dióxido de Carbono , Zona Pelúcida , Humanos , Cobaias , Animais , Masculino , Bovinos , Sêmen , Espermatozoides , Interações Espermatozoide-Óvulo , Fertilização In Vitro/veterinária , Capacitação Espermática , Heparina
7.
J Thromb Haemost ; 21(1): 101-116, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36695374

RESUMO

BACKGROUND: Platelet endothelial aggregation receptor 1 (PEAR1) is a single-transmembrane orphan receptor primarily expressed on platelets and endothelial cells. Genetic variants of PEAR1 have repeatedly and independently been identified to be associated with cardiovascular diseases, including coronary artery disease. OBJECTIVES: We have identified sulfated fucoidans and their mimetics as ligands for PEAR1 and proposed that its endogenous ligand is a sulfated proteoglycan. The aim of this study was to test this hypothesis. METHODS: A heparin proteoglycan-mimetic (HPGM) was created by linking unfractionated heparin (UFH) to albumin. The ability of the HPGM, UFH and selectively desulfated heparins to stimulate platelet aggregation and protein phosphorylation was investigated. Nanobodies against the 12th to 13th epidermal growth factor-like repeat of PEAR1 and phosphoinositide 3-kinase (PI3K) isoform-selective inhibitors were tested for the inhibition of platelet activation. RESULTS: We show that HPGM, heparin conjugated to an albumin protein core, stimulates aggregation and phosphorylation of PEAR1 in washed platelets. Platelet aggregation was abolished by an anti-PEAR1 nanobody, Nb138. UFH stimulated platelet aggregation in washed platelets, but desulfated UFH did not. Furthermore, HPGM, but not UFH, stimulated maximal aggregation in platelet-rich plasma. However, both HPGM and UFH increased integrin αIIbß3 activation in whole blood. By using PI3K isoform-selective inhibitors, we show that PEAR1 activates PI3Kß, leading to Akt phosphorylation. CONCLUSION: Our findings reveal that PEAR1 is a receptor for heparin and HPGM and that PI3Kß is a key signaling molecule downstream of PEAR1 in platelets. These findings may have important implications for our understanding of the role of PEAR1 in cardiovascular disease.


Assuntos
Heparina , Fosfatidilinositol 3-Quinases , Humanos , Heparina/farmacologia , Heparina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Células Endoteliais/metabolismo , Receptores de Superfície Celular/metabolismo , Plaquetas/metabolismo , Agregação Plaquetária , Proteoglicanas/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Ligantes , Albuminas
8.
Methods Mol Biol ; 2619: 249-256, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36662475

RESUMO

Heparin/heparan sulfate (HP/HS) is a class of acidic polysaccharides with many potential medical applications, especially HP, and its derivatives, low molecular weight heparins (LMWHs), have been widely used as anticoagulants to treat thrombosis for decades. However, the complex structure endows HP/HS a variety of biological functions and hinders the structural and functional studies of HP/HS. Heparinases derived from bacteria are useful tools for the structural studies of HP/HS as well as the preparation of LMWHs. The enzymatic method for the structural analysis of HP/HS chains is easy to operate, requires less samples, and is low cost. Here, we describe an enzymatic approach to investigate the primary sequences of the HP/HS oligosaccharides using a recently discovered exotype heparinase.


Assuntos
Heparina , Heparitina Sulfato , Heparina/química , Heparitina Sulfato/química , Heparina Liase , Anticoagulantes , Oligossacarídeos/química
9.
Biomolecules ; 13(1)2023 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-36671483

RESUMO

Vascular endothelial growth factor-A (VEGF-A), a secreted homodimeric glycoprotein, is a critical regulator of angiogenesis in normal and pathological states. The binding of heparin (HE) to VEGF165 (the major form of VEGF-A) modulates the angiogenesis-related cascade, but the mechanism of the observed changes at the structural level is still insufficiently explored. In the present study, we examined the effect of HE on the structural and physicochemical properties of recombinant human VEGF165 (rhVEGF165). The HE binding results in an increase of hydrophobic surface exposure in rhVEGF165 without changes in its secondary structure. Differential scanning calorimetry measurements for intact and HE-bound rhVEGF165 reveals the absence of any pronounced thermally induced transitions in the protein in the temperature range from 20 to 100 °C. The apolar area increase during the heparin binding explains the pronounced HE-induced oligomerization/aggregation of rhVEGF165, as studied by chemical glutaraldehyde cross-linking and dynamic light scattering. Molecular modeling and docking techniques were used to model the full structure of dimeric VEGF165 and to reveal putative molecular mechanisms underlying the function of the VEGF165/HE system. In general, the results obtained can be a basis for explaining the modulating effect of HE on the biological activity of VEGF-A.


Assuntos
Receptores de Fatores de Crescimento do Endotélio Vascular , Fator A de Crescimento do Endotélio Vascular , Humanos , Heparina/química , Fatores de Crescimento do Endotélio Vascular
10.
J Cardiovasc Pharmacol Ther ; 28: 10742484221145010, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36594404

RESUMO

Fondaparinux sodium is a chemically synthesized selective factor Xa inhibitor approved for the prevention and treatment of venous thromboembolic events, that is, deep vein thrombosis, pulmonary embolism, and superficial vein thrombosis, in acutely ill (including those affected by COVID-19 or cancer patients) and those undergoing surgeries. Since its approval in 2002, the efficacy and safety of fondaparinux is well demonstrated by many clinical studies, establishing the value of fondaparinux in clinical practice. Some of the advantages with fondaparinux are its chemical nature of synthesis, minimal risk of contamination, 100% absolute bioavailability subcutaneously, instant onset of action, a long half-life, direct renal excretion, fewer adverse reactions when compared with direct oral anticoagulants, and being an ideal alternative in conditions where oral anticoagulants are not approved for use or in patients intolerant to low molecular weight heparins (LMWH). In the last decade, the real-world use of fondaparinux has been explored in other conditions such as acute coronary syndromes, bariatric surgery, in patients developing vaccine-induced immune thrombotic thrombocytopenia (VITT) and in pregnant women with heparin-induced thrombocytopenia (HIT), or those intolerant to LMWH. The emerging data from these studies have culminated in recent updates in the guidelines that recommend the use of fondaparinux under various conditions. This paper aims to review the recent data and the subsequent updates in the recommendations of various guidelines on the use of fondaparinux sodium.


Assuntos
COVID-19 , Trombose , Trombose Venosa , Gravidez , Humanos , Feminino , Fondaparinux/efeitos adversos , Heparina de Baixo Peso Molecular/efeitos adversos , Polissacarídeos/efeitos adversos , Anticoagulantes/efeitos adversos , Trombose/tratamento farmacológico , Trombose/prevenção & controle , Trombose Venosa/tratamento farmacológico , Heparina
11.
J Mater Chem B ; 11(5): 1079-1089, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36625414

RESUMO

It is challenging to stop bleeding effectively in patients treated with heparin which leads to enhanced risk of uncontrolled bleeding during operation. Herein, we report an easy-to-use and heparin-tolerant hemostatic agent based on a thrombin-like cysteine enzyme (papain), which catalyzes the hydrolysis of fibrinogen and cross-linking of fibrin clots. A papain-based hemostat with increased procoagulant activity is developed through immobilizing papain on the cellulose carrier, which displays short clotting time in both normal and heparinized plasmas. The excellent hemostatic performance of the papain-based hemostat is further confirmed with reduced hemostatic time and limited blood loss in a mouse tail amputation model, rabbit auricular artery injury model and rat liver injury model, in which a natural coagulation system fails to function on account of heparin. This bio-hemostat has great potential to reverse the effect of heparin and stop topical hemorrhage rapidly in surgical procedures.


Assuntos
Hemostáticos , Heparina , Camundongos , Ratos , Animais , Coelhos , Heparina/farmacologia , Cisteína/farmacologia , Papaína/farmacologia , Hemostáticos/farmacologia , Coagulação Sanguínea , Hemorragia , Modelos Animais de Doenças
12.
Int J Mol Sci ; 24(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36675176

RESUMO

Heparin, a class of glycosaminoglycans (GAGs), is widely used to induce sperm capacitation and fertilization. How heparin induces sperm capacitation remains unclear. Olfactory receptors (ORs) which are G protein-coupled receptors, have been proposed to be involved in sperm capacitation. However, the interaction between ORs and odor molecules and the molecular mechanism of ORs mediating sperm capacitation are still unclear. The present study aimed to explore the underlying interaction and mechanism between heparin and ORs in carrying out the boar sperm capacitation. The results showed that olfactory receptor 2C1 (OR2C1) is a compulsory unit which regulates the sperm capacitation by recognizing and binding with heparin, as determined by Dual-Glo Luciferase Assay and molecular docking. In addition, molecular dynamics (MD) simulation indicated that OR2C1 binds with heparin via a hydrophobic cavity comprises of Arg3, Ala6, Thr7, Asn171, Arg172, Arg173, and Pro287. Furthermore, we demonstrated that knocking down OR2C1 significantly inhibits sperm capacitation. In conclusion, we highlighted a novel olfactory receptor, OR2C1, in boar sperm and disclosed the potential binding of heparin to Pro287, a conserved residue in the transmembrane helices region 7 (TMH7). Our findings will benefit the further understanding of ORs involved in sperm capacitation and fertilization.


Assuntos
Heparina , Receptores Odorantes , Capacitação Espermática , Animais , Masculino , Heparina/farmacologia , Heparina/metabolismo , Simulação de Acoplamento Molecular , Receptores Odorantes/genética , Receptores Odorantes/metabolismo , Sêmen/metabolismo , Capacitação Espermática/genética , Capacitação Espermática/fisiologia , Espermatozoides/metabolismo , Suínos
13.
Int J Mol Sci ; 24(2)2023 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-36675182

RESUMO

Chemokines are critically involved in controlling directed leukocyte migration. Spatiotemporal secretion together with local retention processes establish and maintain local chemokine gradients that guide directional cell migration. Extracellular matrix proteins, particularly glycosaminoglycans (GAGs), locally retain chemokines through electrochemical interactions. The two chemokines CCL19 and CCL21 guide CCR7-expressing leukocytes, such as antigen-bearing dendritic cells and T lymphocytes, to draining lymph nodes to initiate adaptive immune responses. CCL21-in contrast to CCL19-is characterized by a unique extended C-terminus composed of highly charged residues to facilitate interactions with GAGs. Notably, both chemokines can trigger common, but also ligand-biased signaling through the same receptor. The underlying molecular mechanism of ligand-biased CCR7 signaling is poorly understood. Using a series of naturally occurring chemokine variants in combination with newly designed site-specific chemokine mutants, we herein assessed CCR7 signaling, as well as GAG interactions. We demonstrate that the charged chemokine C-terminus does not fully confer CCL21-biased CCR7 signaling. Besides the positively charged C-terminus, CCL21 also possesses specific BBXB motifs comprising basic amino acids. We show that CCL21 variants where individual BBXB motifs are mutated retain their capability to trigger G-protein-dependent CCR7 signaling, but lose their ability to interact with heparin. Moreover, we show that heparin specifically interacts with CCL21, but not with CCL19, and thereby competes with ligand-binding to CCR7 and prevents signaling. Hence, we provide evidence that soluble heparin, but not the other GAGs, complexes with CCL21 to define CCR7 signaling in a ligand-dependent manner.


Assuntos
Movimento Celular , Quimiocina CCL21 , Heparina , Leucócitos , Receptores CCR7 , Movimento Celular/imunologia , Quimiocina CCL21/imunologia , Glicosaminoglicanos , Heparina/farmacologia , Ligantes , Receptores CCR7/imunologia , Leucócitos/efeitos dos fármacos , Leucócitos/imunologia
14.
J Med Case Rep ; 17(1): 11, 2023 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-36631902

RESUMO

BACKGROUND: Pulmonary vein thrombosis (PVT) is rarely associated with malignancies. Leiomyosarcoma, a malignant tumor originating from smooth muscles, has never been reported as the etiology of PVT. CASE PRESENTATION: In this case report, we described a 43-year-old Kurdish woman with a known case of leiomyosarcoma who presented with hemoptysis, dyspnea, and pleuritic chest pain. Chest computed tomography (CT) angiography revealed a thrombus in the left infero-posterior pulmonary vein. She was successfully treated with unfractionated heparin administered intravenously followed by orally administered warfarin. At the end of the article, we describe and compare other reports of malignancy-related PVT. CONCLUSIONS: While malignancies are not a common cause of PVT, both primary lung tumors and metastatic cancers could be associated with PVT. Delay in diagnosis may lead to serious complications and even death. Therefore, clinicians should be aware of the possibility of the development of PVT in different malignancies for appropriate diagnosis and treatment.


Assuntos
Leiomiossarcoma , Neoplasias Pélvicas , Veias Pulmonares , Neoplasias Uterinas , Trombose Venosa , Feminino , Humanos , Adulto , Heparina , Anticoagulantes/uso terapêutico , Leiomiossarcoma/complicações , Leiomiossarcoma/diagnóstico por imagem , Veias Pulmonares/diagnóstico por imagem , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/tratamento farmacológico , Trombose Venosa/etiologia , Neoplasias Uterinas/complicações , Neoplasias Uterinas/diagnóstico por imagem
15.
Zhonghua Yi Xue Za Zhi ; 103(0): 1-7, 2023 Jan 10.
Artigo em Chinês | MEDLINE | ID: mdl-36634914

RESUMO

Heparin resistance is becoming a hot issue of clinical concern. In critically ill patients, heparin resistance can lead to failure of anticoagulation therapy or increase the risk of major bleeding. Prompt recognition of heparin resistance can help to precisely adjust heparin dosage and avoid deterioration and adverse events. Heparin resistance can be mechanistically classified into the antithrombin-mediated and the non-antithrombin-mediated. Common etiologies include heparin-induced thrombocytopenia, severe infections such as severe COVID-19, treatment with extracorporeal circulation or extracorporeal membrane oxygenation (ECMO), and use of factor Xa reversal agents; heparin resistance is now often identified by the concordance of activated partial thromboplastin time (APTT) ratio with anti-FXa. Common clinical management strategies include antithrombin supplementation and replacement of anticoagulant drugs (e.g., direct thrombin inhibitors), but their safety and efficacy still need to be further validated.


Assuntos
COVID-19 , Heparina , Humanos , Heparina/uso terapêutico , Heparina/efeitos adversos , Anticoagulantes/uso terapêutico , Antitrombinas , Tempo de Tromboplastina Parcial , Estudos Retrospectivos
16.
BMC Pharmacol Toxicol ; 24(1): 2, 2023 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-36639796

RESUMO

INTRODUCTION: The literature recommends against the use of fondaparinux in patients with kidney failure and dialysis as it may, with repeated dosing, accumulate and put patients at risk of bleeding. The management of patients with thrombosis in the presence of heparin-induced thrombocytopenia HIT requires the introduction of an alternative anticoagulant like bivalirudin or argatroban. When these drugs are not available, fondaparinux, remains the only alternative. In similar scenarios, there are few studies addressing how to administer it.  METHODS: We developed a protocol for fondaparinux in patients with renal failure where pharmacokinetic parameters are altered, and levels changed only after hemodialysis or in cases of residual renal activity. Patients received a full first dose except for high risk of bleeding. We targeted a peak anti-factor Xa activity level of 0.6-1.3 units/ml and changed the subsequent dose accordingly. Furthermore, we monitored the patients for signs of bleeding, a drop in hemoglobin level, or clinical signs of thrombosis.  DISCUSSION: We described 10 patients with kidney failure and suspected HIT taking fondaparinux. All the patients achieved therapeutic anti-factor Xa activity levels. However, one developed new-onset venous thromboembolism (VTE) despite therapeutic anti-factor Xa levels. Another patient experienced a bleeding episode. We believe that these two patients developed complications due to their medical conditions rather than the use of fondaparinux. CONCLUSION: Fondaparinux can be safely used in kidney failure using our protocol. However, despite its safety profile and relative success, this case series was small. More robust studies need to be conducted prior to drawing conclusions.


New Fondaparinux Protocol to Reduce the Risk of Blood Thickening and Blood Clots Formation in Adults with Kidney Disease and Heparin-induced Thrombocytopenia (drop in platelets after the use of heparin): A Test Study.Fondaparinux is a drug used to treat patients suffering from thrombosis (clot in blood) and prevent vessels occlusions. When patients have kidney disease, the ideal treatment for thrombosis would be heparin; and, in case of Heparin Induced Thrombocytopenia (HIT), an unexpected drop in platelets after the use of heparin, the ideal treatment would be argatroban or bivalirudin. Fondaparinux can be used for HIT. However, studies recommend against its use in kidney disease as it might accumulate and cause bleeding.We were put in a challenging situation where we had patients with life-threatening thrombosis, kidney disease, HIT and unavailability of both argatroban and bivalirudin. Our only option was fondaparinux. We had to devise a safe and efficient protocol. The starting dose was the one used had the patient had a normal kidney function. Then, anti-Factor Xa activity was regularly measured with the target level 0.6-1.3units/ml 4 h after a dose. The dose was individualized, changed based on the Factor Xa activity result, the risk of bleeding or thrombosis, the overall kidney function and the need for dialysis.Our protocol was tested on 10 patients. All our patients could reach the target and safe Factor Xa activity. We had 2 exceptions. The first had a clotting event despite having therapeutic Factor Xa activity and the second was a very sick cancer patient who was bleeding despite skipping many doses of fondaparinux. We consider that these 2 cases developed complications due to their medical conditions rather than the use of fondaparinux.We concluded that fondaparinux can be safely used in patients with kidney disease, granted that Factor Xa activity is measured, the risk of bleeding is weighed to the risk of thrombosis and the dose is individualized. However, our sample size is small and further studies with a larger number of patients are needed to draw a conclusion.


Assuntos
Anticoagulantes , Fondaparinux , Insuficiência Renal , Trombocitopenia , Trombose , Adulto , Humanos , Anticoagulantes/uso terapêutico , Fondaparinux/uso terapêutico , Hemorragia/induzido quimicamente , Heparina/efeitos adversos , Insuficiência Renal/tratamento farmacológico , Estudos Retrospectivos , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico , Trombose/tratamento farmacológico
17.
J Pediatr Hematol Oncol Nurs ; 40(1): 24-33, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-35611518

RESUMO

Background: Children and adolescents with cancer often undergo aggressive treatment and receive supportive care requiring a long-term tunneled central venous catheter (TCVC). Regular flushing promotes TCVC patency when not in use (i.e., noninfusing). However, TCVC flushing guidelines and the current practice of daily flushing are not based on high-quality evidence. Few studies have compared the effect of less frequent flushing on TCVC patency. The purpose of this study was to evaluate the feasibility of a three times weekly heparin flushing intervention, as compared to daily heparin flushing, in children and adolescents and young adults (AYAs) with noninfusing TCVCs. Methods: Twenty children and AYAs were randomized to one of two groups, standard of care (SOC) (i.e., daily heparin flushing) or intervention (three times weekly heparin flushing) for 8 weeks. Feasibility data (recruitment, retention, acceptability, TCVC patency, and complications) were analyzed descriptively. Results: Twenty of 22 eligible patients were enrolled in the study (90% recruitment rate). Four participants discontinued the study early due to TCVC removal (20% attrition rate). One participant in each group had their TCVC removed due to a central line-associated bloodstream infection, one SOC group participant had their TCVC removed due to damage, and one intervention group participant had their TCVC removed due to discontinuation of treatment. No participants were withdrawn for safety concerns or because they did not find the protocol acceptable. Conclusions: It is feasible to conduct a large-scale randomized controlled trial to investigate a three times weekly heparin flushing intervention in children and AYAs with TCVCs.


Assuntos
Cateterismo Venoso Central , Cateteres Venosos Centrais , Neoplasias , Criança , Humanos , Adolescente , Adulto Jovem , Cateteres Venosos Centrais/efeitos adversos , Heparina/efeitos adversos , Cateterismo Venoso Central/efeitos adversos , Projetos Piloto , Neoplasias/complicações
18.
Biochem Biophys Res Commun ; 642: 154-161, 2023 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-36580826

RESUMO

The physicochemical properties of biomaterials influence cell adhesion, shape, and polarization of macrophages. In this study, we aimed to evaluate the polarization of macrophages in terms of the regulation of cell adhesion and how synthetic mimics for heparin and poly(sodium-4-styrenesulfonate) can regulate macrophage polarization by modulating cell shape, focal adhesion, cell traction force, and intracellular tension. Our initial findings showed that macrophages cultured with heparin-mimicking polymer-based hydrogel matrix showed reduced expression of cell adhesion markers such as integrins, vinculin, RhoA, and ROCK1/2 and reduced cell shape, elongation, cell-matrix traction force, and intracellular tension. Furthermore, we observed a significant decrease in cell adhesion in cells cultured on the hydrogel, resulting in the promotion of M1 polarization. These findings offer insights into the important roles of cell-matrix interactions in macrophage polarization and offer a platform for heparin-mimicking polymer-based hydrogel matrices to induce M1 polarization by inducing cell adhesion without classical activators.


Assuntos
Hidrogéis , Polímeros , Adesão Celular , Heparina/farmacologia , Heparina/metabolismo , Macrófagos/metabolismo , Polímeros/farmacologia , Polímeros/metabolismo , Materiais Biomiméticos
19.
Clin Chem Lab Med ; 61(1): 55-66, 2023 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-36069790

RESUMO

OBJECTIVES: Quantitative protein mass-spectrometry (QPMS) in blood depends on tryptic digestion of proteins and subsequent measurement of representing peptides. Whether serum and plasma can be used interchangeably and whether in-vitro anticoagulants affect the recovery is unknown. In our laboratory serum samples are the preferred matrix for QPMS measurement of multiple apolipoproteins. In this study, we investigated the effect of different matrices on apolipoprotein quantification by mass spectrometry. METHODS: Blood samples were collected from 44 healthy donors in Beckton Dickinson blood tubes simultaneously for serum (with/without gel) and plasma (heparin, citrate or EDTA). Nine apolipoproteins were quantified according to standard operating procedure using value-assigned native serum calibrators for quantitation. Tryptic digestion kinetics were investigated in the different matrices by following formation of peptides for each apolipoprotein in time, up to 22 h. RESULTS: In citrate plasma recovery of apolipoproteins showed an overall reduction with a bias of -14.6%. For heparin plasma only -0.3% bias was found compared to serum, whereas for EDTA-plasma reduction was more pronounced (-5.3% bias) and variable with >14% reduction for peptides of apoA-I, A-II and C-III. Digestion kinetics revealed that especially slow forming peptides showed reduced formation in EDTA-plasma. CONCLUSIONS: Plasma anticoagulants affect QPMS test results. Heparin plasma showed comparable results to serum. Reduced concentrations in citrate plasma can be explained by dilution, whereas reduced recovery in EDTA-plasma is dependent on altered proteolytic digestion efficiency. The results highlight the importance of a standardized pre-analytical phase for accurate QPMS applications in clinical chemistry.


Assuntos
Heparina , Fase Pré-Analítica , Humanos , Ácido Edético , Espectrometria de Massas , Anticoagulantes , Ácido Cítrico , Citratos
20.
FASEB J ; 37(1): e22717, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36563024

RESUMO

Bone morphogenetic proteins (BMP) are powerful regulators of cellular processes such as proliferation, differentiation, and apoptosis. However, the specific molecular requirements controlling the bioavailability of BMPs in the extracellular matrix (ECM) are not yet fully understood. Our previous work showed that BMPs are targeted to the ECM as growth factor-prodomain (GF-PD) complexes (CPLXs) via specific interactions of their PDs. We showed that BMP-7 PD binding to the extracellular microfibril component fibrillin-1 renders the CPLXs from an open, bioactive V-shape into a closed, latent ring shape. Here, we show that specific PD interactions with heparin/heparan sulfate glycosaminoglycans (GAGs) allow to target and spatially concentrate BMP-7 and BMP-9 CPLXs in bioactive V-shape conformation. However, targeting to GAGs may be BMP specific, since BMP-10 GF and CPLX do not interact with heparin. Bioactivity assays on solid phase in combination with interaction studies showed that the BMP-7 PD protects the BMP-7 GF from inactivation by heparin. By using transmission electron microscopy, molecular docking, and site-directed mutagenesis, we determined the BMP-7 PD-binding site for heparin. Further, fine-mapping of the fibrillin-1-binding site within the BMP-7 PD and molecular modeling showed that both binding sites are mutually exclusive in the open V- versus closed ring-shape conformation. Together, our data suggest that targeting exquisite BMP PD-binding sites by extracellular protein and GAG scaffolds integrates BMP GF bioavailability in a contextual manner in development, postnatal life, and connective tissue disease.


Assuntos
Proteína Morfogenética Óssea 7 , Glicosaminoglicanos , Proteína Morfogenética Óssea 7/metabolismo , Heparina/metabolismo , Fibrilina-1/metabolismo , Simulação de Acoplamento Molecular , Proteínas Morfogenéticas Ósseas/metabolismo , Heparitina Sulfato/metabolismo , Ligação Proteica , Proteína Morfogenética Óssea 2/metabolismo
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