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1.
Am J Obstet Gynecol ; 2024 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-38582292

RESUMEN

BACKGROUND: Gestational diabetes mellitus is associated with obstetrical and long-term cardiovascular complications. Although platelet hyperresponsiveness in type-2 diabetes mellitus has been well characterized and has been shown to play a crucial role in cardiovascular complications, this aspect has been little studied in gestational diabetes mellitus. OBJECTIVE: We aimed to evaluate platelet reactivity, in vivo platelet activation, and endothelial function in gestational diabetes mellitus in comparison with normal pregnancy. STUDY DESIGN: This was a prospective, case-control study of 23 women with gestational diabetes mellitus and 23 healthy pregnant women who were studied at 26 to 28 and 34 to 36 weeks of gestation and at 8 weeks postpartum. Platelet reactivity and in vivo platelet activation, including light transmission aggregometry, PFA-100, platelet activation antigen expression, platelet adhesion under flow, platelet nitric oxide and reactive oxygen species production, and endothelial dysfunction markers, were assessed. RESULTS: The study of platelet function showed a condition of platelet hyperreactivity in cases with gestational diabetes mellitus when compared with healthy pregnant women at enrollment, which was further enhanced at the end of pregnancy and tended to decrease 2 months after delivery, although it still remained higher in gestational diabetes mellitus. In vivo platelet activation was also evident in gestational diabetes mellitus, especially at the end of pregnancy, in part persisting up to 8 weeks after delivery. Finally, women with gestational diabetes mellitus showed defective platelet nitric oxide production and endothelial dysfunction when compared with healthy pregnancies. CONCLUSION: Our data showed that gestational diabetes mellitus generates a condition of platelet hyperreactivity that in part persists up to 2 months after delivery. Impaired platelet sensitivity to nitric oxide and reduced platelet and endothelial nitric oxide production may contribute to the platelet hyperreactivity condition. Platelet hyperreactivity may play a role in the long-term cardiovascular complications of gestational diabetes mellitus women.

2.
Br J Haematol ; 201(5): 851-856, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36883298

RESUMEN

The effectiveness of vaccination against SARS-CoV-2 in preventing COVID-19 or in reducing severe illness in subjects hospitalized for COVID-19 despite vaccination has been unequivocally shown. However, no studies so far have assessed if subjects who get COVID-19 despite vaccination are protected from SARS-CoV-2-induced platelet, neutrophil and endothelial activation, biomarkers associated with thrombosis and worse outcome. In this pilot study, we show that previous vaccination blunts COVID-19-associated platelet activation, assessed by circulating platelet-derived microvesicles and soluble P-selectin, and neutrophil activation, assessed by circulating neutrophil extracellular trap (NET) biomarkers and matrix metalloproteinase-9, and reduces COVID-19-associated thrombotic events, hospitalization in intensive-care units and death.


Asunto(s)
COVID-19 , Trombosis , Humanos , COVID-19/prevención & control , COVID-19/complicaciones , SARS-CoV-2 , Activación Neutrófila , Proyectos Piloto , Trombosis/complicaciones , Biomarcadores , Activación Plaquetaria , Vacunación
3.
Haematologica ; 107(7): 1643-1654, 2022 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-34407603

RESUMEN

Platelet-type von Willebrand disease (PT-VWD) is an inherited platelet disorder. It is characterized by macrothrombocytopenia and mucocutaneous bleeding, of variable severity, due to gain-of-function variants of GP1BA conferring to glycoprotein Ibα (GPIbα) enhanced affinity for von Willebrand factor (VWF). The bleeding tendency is conventionally attributed to thrombocytopenia and large VWF-multimer depletion. However, while some indications suggest that platelet dysfunction may contribute to the bleeding phenotype, no information on its characteristics and causes are available. The aim of the present study was to characterize platelet dysfunction in PT-VWD and shed light on its mechanism. Platelets from a PT-VWD patient carrying the p.M239V variant, and from PT-VWD mice carrying the p.G233V variant, showed a remarkable platelet function defect, with impaired aggregation, defective granule secretion and reduced adhesion under static and flow conditions. VWFbinding to GPIbα is known to trigger intracellular signaling involving Src-family kinases (SFK). We found that constitutive phosphorylation of the platelet SFK Lyn induces a negative-feedback loop downregulating platelet activation through phosphorylation of PECAM1 on Tyr686 and that this is triggered by the constitutive binding of VWF to GPIbα. These data show, for the first time, that the abnormal triggering of inhibitory signals mediated by Lyn and PECAM1 may lead to platelet dysfunction. In conclusion, our study unravels the mechanism of platelet dysfunction in PT-VWD caused by deranged inhibitory signaling. This is triggered by the constitutive binding of VWF to GPIbα which may significantly contribute to the bleeding phenotype of these patients.


Asunto(s)
Trombocitopenia , Enfermedades de von Willebrand , Animales , Plaquetas/metabolismo , Hemorragia/genética , Ratones , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/metabolismo , Complejo GPIb-IX de Glicoproteína Plaquetaria/genética , Complejo GPIb-IX de Glicoproteína Plaquetaria/metabolismo , Trombocitopenia/genética , Trombocitopenia/metabolismo , Enfermedades de von Willebrand/genética , Enfermedades de von Willebrand/metabolismo , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismo
4.
Haematologica ; 107(5): 1072-1085, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-34233447

RESUMEN

GATA2 is a transcription factor with key roles in hematopoiesis. Germline GATA2 gene variants have been associated with several inherited and acquired hematologic disorders, including myelodysplastic syndromes. Among the spectrum of GATA2 deficiency- associated manifestations thrombosis has been reported in 25% of patients, but the mechanisms are unknown. GATA2 was shown to be involved in endothelial nitric oxide synthase (eNOS) regulation and vascular development. We assessed eNOS expression and angiogenesis in patients with GATA2 deficiency. Platelets and blood outgrowth endothelial cells (BOEC) from GATA2 variant carriers showed impaired NO production and reduction of eNOS mRNA and protein expression and of eNOS activity. GATA2 binding to the eNOS gene was impaired in BOEC from GATA2-deficient patients, differently from control BOEC. GATA2 deficiency BOEC showed also defective angiogenesis, which was completely restored by treatment with the NO-donor Snitroso- N-acetylpenicillamine (SNAP). Atorvastatin, but not resveratrol, largely restored eNOS expression, NO biosynthesis and neoangiogenesis in GATA2-deficient BOEC by a mechanism involving increased expression of the eNOS transcription factor AP-1/c-JUN, replacing GATA2 when the latter is inactive. Our results unravel a possible thrombogenic mechanism of GATA2 mutations, definitely establish the regulation of eNOS by GATA2 in endothelial cells and show that endothelial angiogenesis is strictly dependent on the eNOS/NO axis. Given the ability of atorvastatin to restore NO production and angiogenesis by GATA2-deficient endothelial cells, the preventive effect of atorvastatin on thrombotic events and possibly on other clinical manifestations of the syndrome related to deranged angiogenesis should be explored in patients with GATA2 deficiency in an ad hoc designed clinical trial.


Asunto(s)
Deficiencia GATA2 , Óxido Nítrico Sintasa de Tipo III , Atorvastatina/farmacología , Células Endoteliales/metabolismo , Endotelio Vascular/metabolismo , Factor de Transcripción GATA2/genética , Células Germinativas/metabolismo , Humanos , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa/metabolismo , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Óxido Nítrico Sintasa de Tipo III/farmacología , Factor de Transcripción AP-1/genética , Factor de Transcripción AP-1/metabolismo , Regulación hacia Arriba
5.
Haematologica ; 107(6): 1374-1383, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35142150

RESUMEN

Deep vein thrombosis results from the cooperative action of leukocytes, platelets, and endothelial cells. The proline-rich tyrosine kinase Pyk2 regulates platelet activation and supports arterial thrombosis. In this study, we combined pharmacological and genetic approaches to unravel the role of Pyk2 in venous thrombosis. We found that mice lacking Pyk2 almost completely failed to develop deep venous thrombi upon partial ligation of the inferior vena cava. Pyk2-deficient platelets displayed impaired exposure of phosphatidylserine and tissue factor expression by endothelial cells and monocytes was completely prevented by inhibition of Pyk2. In human umbilical vein endothelial cells (HUVEC), inhibition of Pyk2 hampered IL-1b-induced expression of VCAM and P-selectin, and von Willebrand factor release. Pyk2-deficient platelets showed defective adhesion on von Willebrand factor and reduced ability to bind activated HUVEC under flow. Moreover, inhibition of Pyk2 in HUVEC strongly reduced platelet adhesion. Similarly, Pyk2-deficient neutrophils were unable to efficiently roll and adhere to immobilized endothelial cells under venous flow conditions. Moreover, platelets and neutrophils from Pyk2- knockout mice showed defective ability to form heterogeneous aggregates upon stimulation, while platelet monocyte interaction occurred normally. Consequently, platelet neutrophil aggregates, abundant in blood of wild-type mice upon inferior vena cava ligation, were virtually undetectable in Pyk2-knockout mice. Finally, we found that expression of Pyk2 was required for NETosis induced by activated platelets. Altogether our results demonstrate a critical role of Pyk2 in the regulation of the coordinated thromboinflammatory responses of endothelial cells, leukocytes and platelets leading to venous thrombosis. Pyk2 may represent a novel promising target in the treatment of deep vein thrombosis.


Asunto(s)
Quinasa 2 de Adhesión Focal/metabolismo , Trombosis de la Vena , Animales , Plaquetas/metabolismo , Células Endoteliales/metabolismo , Quinasa 2 de Adhesión Focal/genética , Humanos , Ratones , Fosforilación , Prolina/metabolismo , Trombosis de la Vena/genética , Trombosis de la Vena/metabolismo , Factor de von Willebrand/metabolismo
6.
J Infect Dis ; 223(6): 933-944, 2021 03 29.
Artículo en Inglés | MEDLINE | ID: mdl-33280009

RESUMEN

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection is associated with hypercoagulability, which predisposes to venous thromboembolism (VTE). We analyzed platelet and neutrophil activation in patients with coronavirus disease 2019 (COVID-19) and their association with VTE. METHODS: Hospitalized patients with COVID-19 and age- and sex-matched healthy controls were studied. Platelet and leukocyte activation, neutrophil extracellular traps (NETs), and matrix metalloproteinase 9, a neutrophil-released enzyme, were measured. Four patients were restudied after recovery. The activating effect of plasma from patients with COVID-19 on control platelets and leukocytes and the inhibiting activity of common antithrombotic agents on it were studied. RESULTS: A total of 36 patients with COVID-19 and 31 healthy controls were studied; VTE developed in 8 of 36 patients with COVID-19 (22.2%). Platelets and neutrophils were activated in patients with COVID-19. NET, but not platelet activation, biomarkers correlated with disease severity and were associated with thrombosis. Plasmatic matrix metalloproteinase 9 was significantly increased in patients with COVID-19. Platelet and neutrophil activation markers, but less so NETs, normalized after recovery. In vitro, plasma from patients with COVID-19 triggered platelet and neutrophil activation and NET formation, the latter blocked by therapeutic-dose low-molecular-weight heparin, but not by aspirin or dypiridamole. CONCLUSIONS: Platelet and neutrophil activation are key features of patients with COVID-19. NET biomarkers may help to predict clinical worsening and VTE and may guide low-molecular-weight heparin treatment.


Asunto(s)
COVID-19/sangre , COVID-19/inmunología , Trombosis/sangre , Trombosis/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Plaquetas/inmunología , COVID-19/virología , Trampas Extracelulares , Femenino , Heparina de Bajo-Peso-Molecular/sangre , Humanos , Masculino , Metaloproteinasa 9 de la Matriz/sangre , Persona de Mediana Edad , Activación Neutrófila , Neutrófilos/inmunología , Activación Plaquetaria , SARS-CoV-2/aislamiento & purificación , Trombosis/virología , Tromboembolia Venosa/sangre , Tromboembolia Venosa/inmunología , Tromboembolia Venosa/virología
7.
Circulation ; 142(7): 621-642, 2020 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-32546049

RESUMEN

BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 µm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 µm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.


Asunto(s)
Arteria Carótida Común/diagnóstico por imagen , Grosor Intima-Media Carotídeo , Factores de Riesgo de Enfermedad Cardiaca , Infarto del Miocardio/diagnóstico por imagen , Accidente Cerebrovascular/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto
8.
Vasc Med ; 26(4): 394-400, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33845700

RESUMEN

Endothelial dysfunction, evaluated by flow-mediated dilatation (FMD), predicts adverse cardiovascular events in patients with intermittent claudication (IC). IC is an example of repeated ischemia/reperfusion injury that may contribute to the progression of vascular disease by worsening endothelial function, a trigger for acute cardiovascular events. The predictive value of effort-induced endothelial dysfunction for cardiovascular events in patients with IC has not been studied previously. The objective of this study was to assess whether exercise-induced endothelial dysfunction is predictive of adverse cardiovascular outcome in IC. In 44 patients with IC, we measured brachial artery FMD by B-mode ultrasonography at rest and 10 minutes after a maximal treadmill exercise. Treadmill exercise halved the FMD (from 3.5 ± 0.6% to 1.45 ± 0.46%, p < 0.05). After a follow-up period of 85 (72-98) months, a total of 20 major cardiovascular events occurred. In a multivariate analysis, a post-exercise reduction of brachial FMD > 1.3% was predictive for cardiovascular events. Maximal exercise-induced endothelial dysfunction is predictive of cardiovascular events in patients with IC.


Asunto(s)
Endotelio Vascular , Claudicación Intermitente , Arteria Braquial/diagnóstico por imagen , Humanos , Claudicación Intermitente/diagnóstico , Isquemia , Factores de Tiempo , Vasodilatación , Caminata
9.
Nanomedicine ; 24: 102103, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31669421

RESUMEN

Matrix metalloproteinase-2 (MMP-2) is an endopeptidase involved in cardiovascular disease and cancer. To date, no highly selective MMP-2 inhibitors have been identified for potential use in humans. Aim of our work was to apply the nanobody technology to the generation of highly selective inhibitors of human MMP-2 and to assess their effects on platelet function and their applicability as conjugated nanobodies. We constructed a nanobody library after immunising an alpaca with human active MMP-2 and identified, after phage display and screening, one MMP-2 inhibitory nanobody (VHH-29), able to hinder the effects of MMP-2 on platelet activation, and one nanobody not inhibiting MMP-2 activity (VHH-136) which, chemically conjugated to a fluorescent probe, allowed the detection of human MMP-2 by flow-cytometry and immune-cytochemistry. In conclusion, we have generated and characterized two new nanotechnological molecular tools for human MMP-2 which represent promising agents for the study of MMP-2 in cardiovascular pathophysiology.


Asunto(s)
Citometría de Flujo , Metaloproteinasa 2 de la Matriz/inmunología , Biblioteca de Péptidos , Anticuerpos de Dominio Único , Ensayo de Inmunoadsorción Enzimática , Células HEK293 , Humanos , Anticuerpos de Dominio Único/química , Anticuerpos de Dominio Único/inmunología
10.
Blood ; 125(4): 697-705, 2015 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-25480660

RESUMEN

Nitric oxide (NO) exerts vasodilatatory, antiplatelet, antioxidant, and antiproliferative effects. Endothelium-derived NO has been shown to be of crucial importance in cardiovascular protection, whereas evidence that NO is synthesized by platelets and regulates platelet function is still controversial. By using a sensitive and specific fluorescent probe, 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate (DAF-FM), we visualized NO production in individual platelets undergoing adhesion on a collagen substrate under flow conditions. NO production, monitored in real time, was dependent on the shear rates applied, increasing with the raising of the shear rates. Furthermore, NO production increased in the presence of l-arginine (nitric-oxide synthase [NOS] substrate), and it decreased in the presence of L-NG-monomethyl arginine (L-NMMA) (NOS inhibitor) but not of D-NG-monomethyl arginine (D-NMMA) (L-NMMA-inactive enantiomer). Platelet deposition, measured with mepacrine-labeled platelets, was inversely related to NO production. A correlation was evident between Ca(++) elevation and NO production, suggesting that platelet NO formation is triggered by intracytoplasmic Ca(++) elevation. Simultaneous measurement of NO and Ca(++) indicated that NO production in individual platelets is preceded by Ca(++) elevations, with a lag phase of 33 ± 9.5 s. Our studies provide the first direct demonstration of platelet NO production triggered by the interaction with an activating surface under flow and suggest that intraplatelet Ca(++) elevation elicits the production of NO which, in turn, modulates thrombus size.


Asunto(s)
Plaquetas/metabolismo , Óxido Nítrico/metabolismo , Adhesividad Plaquetaria/fisiología , Animales , Velocidad del Flujo Sanguíneo , Plaquetas/citología , Calcio/metabolismo , Colágeno/farmacología , Inhibidores Enzimáticos/farmacología , Fluoresceínas/farmacocinética , Masculino , Ratones , Ratones Noqueados , Adhesividad Plaquetaria/efectos de los fármacos , Quinacrina/farmacología , omega-N-Metilarginina/farmacología
11.
Clin Chem Lab Med ; 54(1): 97-103, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26087065

RESUMEN

BACKGROUND: Subconjunctival hemorrage (SCH) is a frequent, mild bleeding manifestation and a common cause of consultation. Hemostatic alterations are possible causes of SCH but their role and prevalence is unknown. We assessed the prevalence of hemostatic abnormalities in patients with spontaneous, recurrent SCH to clarify the role of the hemostasis laboratory in this clinical setting. METHODS: A total of 105 SCH patients (21-78 years, 65 females) with no identifiable cause (hypertension-trauma-conjunctivitis) or concomitant treatments (NSAIDs- aspirin-oral anticoagulants-antiplatelet agents) and 53 age and sex-matched healthy controls (HCs) (22-72 years, 29 females) were evaluated for skin bleeding time, PFA-100®, blood clotting screening, platelet count, light transmission aggregomery, VWF:Ag, VWF:RCo, RIPA, FVIII activity, FXIII antigen and activity and ISTH Bleeding Severity Score (BSS). RESULTS: Prevalence of hemostatic abnormalities was not higher in the SCH population than in HCs BSS was 0.83 (95% CI 0.62-1.06) in SCH and 0.66 (0.37-0.95) in HC (p=NS). Type I Von Willebrand disease was diagnosed in one SCH and none HC patients, a prevalence not significantly different (p=NS by χ2). CONCLUSIONS: The prevalence of hemostatic alterations in patients with recurrent, spontaneous SCH is not different from the general population; hemostatic screening or second level tests are of no use in patients with recurrent SCH and no other bleedings.


Asunto(s)
Hemorragia del Ojo/tratamiento farmacológico , Hemorragia del Ojo/epidemiología , Hemostáticos/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Hemorragia del Ojo/diagnóstico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Recurrencia , Adulto Joven
12.
Sci Rep ; 14(1): 14516, 2024 06 24.
Artículo en Inglés | MEDLINE | ID: mdl-38914608

RESUMEN

Some previous observations suggest that a low platelet count is associated with an increased risk of adverse outcomes in patients with acute coronary syndromes (ACS). However, most of the data come from post-hoc analyses of randomized controlled trials and from studies including thrombocytopenia developed during hospital stay. Our aim was to assess the impact of low platelet count at admission on cardiovascular outcomes and treatment approach in patients hospitalized for ACS in a current real-life setting in Italy. Patients admitted to Italian coronary care units for ACS were enrolled in the START-ANTIPLATELET registry. Baseline clinical characteristics and treatment at discharge were recorded. Patients were followed-up at 6 months, 1 year and yearly thereafter. Low platelet count was defined as a count at admission < 150 > 100 k/µl or < 100 k/µL. Among 1894 enrolled patients, 157 (8.3%) had a platelet count < 150 > 100 k/µl and 30 (1.6%) < 100 k/µl. The median follow-up was 12.3 months (0.4-50.1). patients with low platelets were older (72 ± 10.4 vs 66 ± 12.4 years, p = 0.006), more frequently males (82.9 vs 72.1%, p = 0.001), hypertensive (90.0% vs 70.4%, p = 0.03), with non-valvular atrial fibrillation (NVAF) (17.1 vs 8.6%, p = 0.02), and peripheral arterial disease (11.5 vs 6.2% p = 0.01) and/or had a previous myocardial infarction (40 vs 18.7%, p = 0.008) and/or a PCI (14.6 vs 7.8%, p = 0.001) than patients with normal platelets. A slightly, but significantly, lower percentage of thrombocytopenic patients were treated with primary PCI (78.1 vs 84.4%, p = 0.04) and they were more frequently discharged on aspirin plus clopidogrel rather than aspirin plus newer P2Y12 antagonists (51.9 vs 65.4%, p = 0.01). MACE-free survival was significantly shorter in thrombocytopenic patients compared to patients with normal platelets (< 150 > 100 k/µl: 37.6 vs 41.8 months, p = 0.002; HR = 2.7, 95% CIs 1.4-5.2; < 100 k/µl: 31.7 vs 41.8 months, p = 0.01; HR = 6.5, 95% CIs 1.5-29.1). At multivariate analysis, low platelet count, age at enrollment, low glomerular filtration rate, low ejection fraction, a previous ischemic stroke and NVAF were independent predictors of MACE. A low platelet count at admission identifies a subgroup of ACS patients with a significantly increased risk of MACE and these patients should be managed with special care to prevent excess adverse outcomes.


Asunto(s)
Síndrome Coronario Agudo , Inhibidores de Agregación Plaquetaria , Sistema de Registros , Humanos , Síndrome Coronario Agudo/tratamiento farmacológico , Síndrome Coronario Agudo/sangre , Masculino , Femenino , Anciano , Recuento de Plaquetas , Inhibidores de Agregación Plaquetaria/uso terapéutico , Inhibidores de Agregación Plaquetaria/efectos adversos , Persona de Mediana Edad , Anciano de 80 o más Años , Resultado del Tratamiento , Italia/epidemiología , Admisión del Paciente
13.
Res Pract Thromb Haemost ; 8(1): 102305, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-38292347

RESUMEN

Background: In hemophilia and von Willebrand disease, the degree of alteration of laboratory assays correlates with bleeding manifestations. Few studies have assessed the predictive value for bleeding of laboratory assays in patients with inherited platelet function disorders (IPFDs). Objectives: To assess whether there is an association between platelet function assay results and bleeding history, as evaluated by the International Society on Thrombosis and Haemostasis (ISTH) bleeding assessment tool (BAT). Methods: Centers participating in the international ISTH-BAT validation study were asked to provide results of the diagnostic assays employed for the patients they enrolled, and the association with the individual patients' bleeding score (BS) was assessed. Results: Sixty-eight patients with 14 different IPFDs were included. Maximal amplitude of platelet aggregation was significantly lower in patients with a pathologic BS and correlated inversely with the BS, a finding largely driven by the subgroup of patients with Glanzmann thrombasthenia and CalDAG-GEFI deficiency; after their exclusion, TRAP-induced aggregation remained significantly lower in patients with a pathologic BS. Bleeding time was significantly more prolonged in patients with a high BS than in those with a normal BS (27.1 ± 6.2 minutes vs 15.1 ± 10.6 minutes; P < .01). Reduced α-granule content was significantly more common among patients with a pathologic BS than among those with a normal BS (80% vs 20%; P < .05). Receiver operating characteristic curve analysis revealed a significant discriminative ability of all the aforementioned tests for pathologic BS (P < .001), also after exclusion of patients with Glanzmann thrombasthenia and CalDAG-GEFI deficiency. Conclusion: This study shows that altered platelet laboratory assay results are associated with an abnormal ISTH-BAT BS in IPFD.

15.
Eur Heart J ; 32(3): 316-25, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-21036774

RESUMEN

AIMS: To investigate whether selected matrix metalloproteinases (MMPs) are released in the coronary circulation of patients with acute coronary syndrome (ACS), whether this release is related to platelet activation, and whether it contributes to sustained platelet activation. METHODS AND RESULTS: Blood from the aorta (Ao) and the coronary sinus (Cs) was obtained from 21 controls (non-cardiac chest pain), 24 stable angina (SA), and 30 ACS patients, before performing percutaneous transluminal coronary angioplasty. Selected MMPs, some platelet activation- and atheroma-related markers, and the platelet activation-potentiating activity of plasma were measured. Total MMP-2, active MMP-2, and MMP-9 were released in the coronary circulation of patients with ACS, but not of those with SA or controls. Similarly, transcoronary gradients of ß-thromboglobulin (ß-TG) and platelet factor 4, two platelet-specific proteins, and of soluble CD40L and secretory phospholipase A2 (sPLA2), markers of inflammation and platelet activation, were higher in ACS patients than in the other groups. In contrast, plasma monocyte chemoattractant protein-1, a platelet-unrelated marker of atherogenesis, was not increased in the Cs compared with Ao in any of the groups. Transcoronary gradients of both ß-TG and sPLA2 correlated with those of total and active MMP-2 in ACS, but not in controls or SA. Plasma from the Cs of ACS patients potentiated platelet activation, an effect suppressed by the specific MMP-2-inhibitor, tissue inhibitor of MMP-2 (TIMP-2). CONCLUSION: Matrix metalloproteinase-2 is released in the coronary circulation of ACS patients, derives in part from activated platelets, and may contribute to sustained intracoronary platelet activation.


Asunto(s)
Síndrome Coronario Agudo/enzimología , Plaquetas/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Activación Plaquetaria/fisiología , Análisis de Varianza , Estudios de Casos y Controles , Quimiocina CCL2/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosfolipasas A2 Secretoras/metabolismo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo
16.
Blood Adv ; 6(7): 2236-2246, 2022 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-34619770

RESUMEN

Gain-of-function (GOF) variants in GP1BA cause platelet-type von Willebrand disease (PT-VWD), a rare inherited autosomal dominant bleeding disorder characterized by enhanced platelet GPIbα to von Willebrand factor (VWF) interaction, and thrombocytopenia. To date, only 6 variants causing PT-VWD have been described, 5 in the C-terminal disulfide loop of the VWF-binding domain of GPIbα and 1 in the macroglycopeptide. GOF GP1BA variants generate a high-affinity conformation of the C-terminal disulfide loop with a consequent allosteric conformational change on another region of GPIbα, the leucine-rich-repeat (LRR) domain. We identified a novel GP1BA variant (p.Arg127Gln) affecting the LRR5 domain of GPIbα in a boy with easy bruising and laboratory test results suggestive of PT-VWD. We thus aimed to investigate the impact of the p.Arg127Gln variant on GPIbα affinity for VWF and GPIbα structure. Chinese hamster ovary cells expressing p.Arg127Gln GPIbα showed increased binding of VWF induced by ristocetin and enhanced tethering on immobilized VWF as compared with cells expressing wild-type GPIbα. Surface plasmon resonance confirmed that p.Arg127Gln enhances the binding affinity of GPIbα for VWF. Hydrogen-deuterium exchange mass spectrometry showed that p.Arg127Gln of LRR, while having little effect on the dynamics of the LRR locally, enhances the conformational dynamics of the GPIbα C-terminal disulfide loop structure. Our data demonstrate for the first time that GOF variants outside the GPIbα C-terminal disulfide loop may be pathogenic and that aminoacidic changes in the LRR may cause allosterically conformational changes in the C-terminal disulfide loop of GPIbα, inducing a conformation with high affinity for VWF.


Asunto(s)
Enfermedades de von Willebrand , Factor de von Willebrand , Animales , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Complejo GPIb-IX de Glicoproteína Plaquetaria , Unión Proteica , Factor de von Willebrand/metabolismo
17.
Am J Physiol Heart Circ Physiol ; 300(6): H2072-9, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21378140

RESUMEN

Activated platelets express CD40L on their plasma membrane and release the soluble fragment sCD40L. The interaction between platelet surface CD40L and endothelial cell CD40 leads to the activation of endothelium contributing to atherothrombosis. Few studies have directly demonstrated an increased expression of platelet CD40L in conditions of in vivo platelet activation in humans, and no data are available on its relevance for endothelial activation. We aimed to assess whether platelets activated in vivo at a localized site of vascular injury in humans express CD40L and release sCD40L, whether the level of platelet CD40L expression attained in vivo is sufficient to induce endothelial activation, and whether platelet CD40L expression is inhibited by aspirin intake. We used the skin-bleeding-time test as a model to study the interaction between platelets and a damaged vessel wall by measuring CD40L in the blood emerging from a skin wound in vivo in healthy volunteers. In some experiments, shed blood was analyzed before and 1 h after the intake of 500 mg of aspirin. Platelets from the bleeding-time blood express CD40L and release soluble sCD40L, in a time-dependent way. In vivo platelet CD40L expression was mild but sufficient to induce VCAM-1 expression and IL-8 secretion in coincubation experiments with cultured human endothelial cells. Moreover, platelets recovered from the bleeding-time blood activated endothelial cells; an anti-CD40L antibody blocked this effect. On the contrary, the amount of sCD40L released by activated platelets at a localized site of vascular injury did not reach the concentrations required to induce endothelial cell activation. Soluble monocyte chemoattractant protein-1, a marker of endothelium activation, was increased in shed blood and correlated with platelet CD40L expression. Aspirin intake did not inhibit CD40L expression by platelets in vivo. We concluded that CD40L expressed by platelets in vivo in humans upon contact with a damaged vessel wall activates endothelium; aspirin treatment does not inhibit this mechanism.


Asunto(s)
Aspirina/farmacología , Plaquetas/citología , Plaquetas/metabolismo , Ligando de CD40/metabolismo , Comunicación Celular/fisiología , Endotelio Vascular/citología , Endotelio Vascular/lesiones , Adulto , Aspirina/uso terapéutico , Aterosclerosis/fisiopatología , Aterosclerosis/prevención & control , Plaquetas/efectos de los fármacos , Células Cultivadas , Quimiocina CCL2/metabolismo , Endotelio Vascular/fisiopatología , Femenino , Humanos , Inflamación/fisiopatología , Interleucina-8/metabolismo , Masculino , Persona de Mediana Edad , Modelos Cardiovasculares , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Piel/lesiones , Molécula 1 de Adhesión Celular Vascular/metabolismo
18.
J Thromb Haemost ; 19(5): 1364-1371, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33880867

RESUMEN

BACKGROUND: The ISTH Bleeding Assessment Tool (ISTH-BAT) has been validated for clinical screening of suspected von Willebrand disease (VWD) and for bleeding prediction. Recently it has been validated for subjects with inherited platelet disorders (IPD) (BAT-VAL study). OBJECTIVES: To determine whether the ISTH-BAT bleeding score (BS) predicts subsequent bleeding events requiring treatment in IPD patients. METHODS: Patients with IPD, type 1 VWD (VWD-1) and age- and sex-matched healthy controls enrolled in the BAT-VAL study were prospectively followed-up for 2 years and bleeding episodes requiring treatment were recorded. RESULTS: Of the 1098 subjects initially enrolled, 955 were followed-up and 124 suffered hemorrhages during follow-up, 60% of whom had inherited platelet function disorders (IPFD). Total number of events was significantly higher in IPFD (n = 235) than VWD-1 (n = 52) or inherited thrombocytopenia (IT; n = 20). Events requiring transfusions were 66% in IPFD, 5.7% in VWD-1, and 3% in IT. Baseline BS was significantly higher in IPFD patients with a bleeding event at follow-up than in those without (p < .01) and the percentage of subjects suffering a bleeding event increased proportionally to baseline BS quartile. A significant association between the BS and the chance of suffering severe bleeding was found in the overall, IPFD, and VWD-1 populations. Similar results were obtained for the pediatric population. CONCLUSIONS: Inherited platelet function disorder patients with high BS at enrollment are more likely to suffer from bleeding events requiring treatment at follow-up. Moreover, the higher the baseline BS quartile the greater the incidence of subsequent events, suggesting that independently from diagnosis a high BS is associated with a greater risk of subsequent hemorrhage.


Asunto(s)
Trastornos de las Plaquetas Sanguíneas , Enfermedades de von Willebrand , Trastornos de las Plaquetas Sanguíneas/diagnóstico , Trastornos de las Plaquetas Sanguíneas/genética , Niño , Comunicación , Hemorragia/diagnóstico , Humanos , Pruebas de Función Plaquetaria , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/genética , Factor de von Willebrand
19.
PLoS One ; 15(4): e0231927, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32343751

RESUMEN

Metabolic Syndrome (MS) is characterized by a low-grade inflammatory state causing an alteration of non-invasive indexes derived from blood count, namely monocyte-to-HDL ratio (MHR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR). We analyse a population of 771 subjects (394 controls and 377 MS patients) to evaluate the best predictive index of MS. The diagnosis of MS was made according to the 2006 criteria of the International Diabetes Federation (IDF). We performed ROC curve analyses to evaluate the best predictor index of MS. MHR cut-off value was used to classify the population in two different groups and to create the outcome variable of the Recursive Partitioning and Amalgamation (RECPAM) analysis. This method is a tree-structured approach that defines "risk profiles" for each group of dichotomous variables. We showed that MHR index is significantly linked to body mass index (BMI), waist circumference, creatinine, C-reactive protein (CRP), Erythrocyte Sedimentation Rate (ESR). ROC curve defined an MHR cut-off value of 6.4, which was able to identify two patient groups with significant differences in waist circumference, blood pressure, creatinine, estimated glomerular filtration rate and fasting plasma glucose. RECPAM analysis demonstrated that gender, BMI categorization and hyperglycaemia were the most important risk determinants of increased MHR index that can be considered bona fide a useful and easily obtainable tool to suggest the presence of peculiar metabolic features that predict MS.


Asunto(s)
Glucemia/análisis , Índice de Masa Corporal , Lipoproteínas HDL/sangre , Síndrome Metabólico/patología , Monocitos/citología , Adulto , Anciano , Área Bajo la Curva , Sedimentación Sanguínea , Proteína C-Reactiva/análisis , Estudios de Casos y Controles , Femenino , Humanos , Modelos Logísticos , Masculino , Síndrome Metabólico/sangre , Síndrome Metabólico/metabolismo , Persona de Mediana Edad , Curva ROC , Factores Sexuales , Fumadores , Circunferencia de la Cintura
20.
J Thromb Haemost ; 18(3): 732-739, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31750621

RESUMEN

BACKGROUND: Careful assessment of bleeding history is the first step in the evaluation of patients with mild/moderate bleeding disorders, and the use of a bleeding assessment tool (BAT) is strongly encouraged. Although a few studies have assessed the utility of the ISTH-BAT in patients with inherited platelet function disorders (IPFD) none of them was sufficiently large to draw conclusions and/or included appropriate control groups. OBJECTIVES: The aim of the present study was to test the utility of the ISTH-BAT in a large cohort of patients with a well-defined diagnosis of inherited platelets disorder in comparison with two parallel cohorts, one of patients with type-1 von Willebrand disease (VWD-1) and one of healthy controls (HC). PATIENTS/METHODS: We enrolled 1098 subjects, 482 of whom had inherited platelet disorders (196 IPFD and 286 inherited platelet number disorders [IT]) from 17 countries. RESULTS: IPFD patients had significantly higher bleeding score (BS; median 9) than VWD-1 patients (median 5), a higher number of hemorrhagic symptoms (4 versus 3), and higher percentage of patients with clinically relevant symptoms (score > 2). The ISTH-BAT showed excellent discrimination power between IPFD and HC (0.9 < area under the curve [AUC] < 1), moderate (0.7 < AUC < 0.9) between IPFD and VWD-1 and between IPFD and inherited thrombocytopenia (IT), while it was inaccurate (AUC ≤ 0.7) in discriminating IT from HC. CONCLUSIONS: The ISTH-BAT allows to efficiently discriminate IPFD from HC, while it has lower accuracy in distinguishing IPFD from VWD-1. Therefore, the ISTH-BAT appears useful for identifying subjects requiring laboratory evaluation for a suspected IPFD once VWD is preliminarily excluded.


Asunto(s)
Trastornos de las Plaquetas Sanguíneas , Enfermedades de von Willebrand , Trastornos de las Plaquetas Sanguíneas/diagnóstico , Trastornos de las Plaquetas Sanguíneas/genética , Comunicación , Hemorragia/diagnóstico , Humanos , Pruebas de Función Plaquetaria , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/genética
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