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2.
Platelets ; : 1-4, 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33349108

RESUMO

The frequent finding of thrombocytopenia in patients with severe SARS-CoV-2 infection (COVID-19) and previous evidence that several viruses enter platelets suggest that SARS-CoV-2 might be internalized by platelets of COVID-19. Aim of our study was to assess the presence of SARS-CoV-2 RNA in platelets from hospitalized patients with aconfirmed diagnosis of COVID-19. RNA was extracted from platelets, leukocytes and serum from 24 COVID-19 patients and 3 healthy controls, real-time PCR and ddPCR for viral genes were carried out. SARS-CoV-2 RNA was not detected in any of the samples analyzed nor in healthy controls, by either RT-PCR or ddPCR, while RNA samples from nasopharyngeal swabs of COVID-19 patients were correctly identified. Viral RNA was not detected independently of viral load, of positive nasopharyngeal swabs, or viremia, the last detected in only one patient (4.1%). SARS-CoV-2 entry in platelets is not acommon phenomenon in COVID-19 patients, differently from other viral infections.

3.
Blood ; 136(17): 1956-1967, 2020 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-32693407

RESUMO

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease.

4.
Int J Hematol ; 112(5): 725-727, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32557126

RESUMO

Chemotherapy is the mainstay of treatment for advanced pancreatic cancer however, due to possible myelotoxicity, it is used with caution in patients with thrombocytopenia, especially when severe. TPO-receptor agonists have been employed for chemotherapy-induced thrombocytopenia, however treatment with TPO-receptor agonists to allow chemotherapy in patients with inherited thrombocytopenia has not been reported so far. We report the first successful use of eltrombopag to prevent chemotherapy-induced thrombocytopenia in a patient with MHY9-related disorder and pancreatic cancer. Treatment with eltrombopag allowed to attain a safe and stable platelet count for several months sufficient to permit chemotherapy and to allow the patient to undergo endoscopic placement of a biliary stent with no bleeding complications.


Assuntos
Benzoatos/uso terapêutico , Hidrazinas/uso terapêutico , Cadeias Pesadas de Miosina , Neoplasias Pancreáticas/tratamento farmacológico , Pirazóis/uso terapêutico , Trombocitopenia/tratamento farmacológico , Trombocitopenia/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzoatos/farmacologia , Perda Sanguínea Cirúrgica/prevenção & controle , Endoscopia do Sistema Digestório , Feminino , Humanos , Hidrazinas/farmacologia , Neoplasias Pancreáticas/cirurgia , Contagem de Plaquetas , Pirazóis/farmacologia , Receptores de Trombopoetina/agonistas , Trombocitopenia/sangue , Trombocitopenia/congênito
5.
Platelets ; : 1-4, 2020 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-32200672

RESUMO

Gastrointestinal angiodysplasia (GIA) is the most common cause of occult gastrointestinal bleeding (GIB) requiring often hospitalization and transfusions, especially in patients with hemorrhagic disorders. Thalidomide, impairing neo-angiogenesis, has been successfully used in the management of bleeding in patients with GIA and in particular in patients with inherited bleeding disorders. Only one case of short-term treatment with thalidomide in a patient with Glanzmann thrombasthenia (GT) and recurrent GIB due to GIA has been reported so far.We report the case of a woman with GT developing high frequency recurrent GIB due to GIA requiring repeated blood and platelet transfusions, who was treated with thalidomide obtaining a striking and stable reduction of GIB and of the requirement of platelet and blood transfusions for over 5 years. Moreover, we raise the suspicion that the association between GT and GIA may not be fortuitous.

6.
Haematologica ; 105(7): 1948-1956, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31558677

RESUMO

Major surgery is associated with an increased risk of venous thromboembolism (VTE), thus the application of mechanical or pharmacologic prophylaxis is recommended. The incidence of VTE in patients with inherited platelet disorders (IPD) undergoing surgical procedures is unknown and no information on the current use and safety of thromboprophylaxis, particularly of low-molecular-weight-heparin in these patients is available. Here we explored the approach to thromboprophylaxis and thrombotic outcomes in IPD patients undergoing surgery at VTE-risk participating in the multicenter SPATA study. We evaluated 210 surgical procedures carried out in 155 patients with well-defined forms of IPD (VTE-risk: 31% high, 28.6% intermediate, 25.2% low, 15.2% very low). The use of thromboprophylaxis was low (23.3% of procedures), with higher prevalence in orthopedic and gynecological surgeries, and was related to VTE-risk. The most frequently employed thromboprophylaxis was mechanical and appeared to be effective, as no patients developed thrombosis, including patients belonging to the highest VTE-risk classes. Low-molecular-weight-heparin use was low (10.5%) and it did not influence the incidence of post-surgical bleeding or of antihemorrhagic prohemostatic interventions use. Two thromboembolic events were registered, both occurring after high VTE-risk procedures in patients who did not receive thromboprophylaxis (4.7%). Our findings suggest that VTE incidence is low in patients with IPD undergoing surgery at VTE-risk and that it is predicted by the Caprini score. Mechanical thromboprophylaxis may be of benefit in patients with IPD undergoing invasive procedures at VTE-risk and low-molecular-weight-heparin should be considered for major surgery.

7.
Hum Mutat ; 41(1): 277-290, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31562665

RESUMO

The heterogeneous manifestations of MYH9-related disorder (MYH9-RD), characterized by macrothrombocytopenia, Döhle-like inclusion bodies in leukocytes, bleeding of variable severity with, in some cases, ear, eye, kidney, and liver involvement, make the diagnosis for these patients still challenging in clinical practice. We collected phenotypic data and analyzed the genetic variants in more than 3,000 patients with a bleeding or platelet disorder. Patients were enrolled in the BRIDGE-BPD and ThromboGenomics Projects and their samples processed by high throughput sequencing (HTS). We identified 50 patients with a rare variant in MYH9. All patients had macrothrombocytes and all except two had thrombocytopenia. Some degree of bleeding diathesis was reported in 41 of the 50 patients. Eleven patients presented hearing impairment, three renal failure and two elevated liver enzymes. Among the 28 rare variants identified in MYH9, 12 were novel. HTS was instrumental in diagnosing 23 patients (46%). Our results confirm the clinical heterogeneity of MYH9-RD and show that, in the presence of an unclassified platelet disorder with macrothrombocytes, MYH9-RD should always be considered. A HTS-based strategy is a reliable method to reach a conclusive diagnosis of MYH9-RD in clinical practice.

8.
J Thromb Haemost ; 18(3): 732-739, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31750621

RESUMO

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.

9.
Thromb Res ; 181 Suppl 1: S54-S59, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31477229

RESUMO

Inherited platelet disorders (IPD) are a heterogeneous group of hemorrhagic diseases affecting both men and women, but usually associated with more evident bleeding symptoms in women due to the exposure to sexspecific hemostatic challenges, like menstruation and delivery. Indeed, up to 50% of women presenting with menorrhagia are diagnosed an IPD, moreover women with IPD can have ovulation-associated bleeding events and are at higher risk of endometriosis. Large retrospective studies have shown that women with IPD have a significantly increased risk of post-partum hemorrhage, predicted by a high bleeding score at previous history and by a platelet count below 50X109/L. In addition, in patients with IPD, female sex was associated with a higher frequency of excessive bleeding after surgery, even when excluding gynecological procedures. In conclusion, IPD may represent a serious problem for women's health, and their diagnosis and appropriate management is crucial to ensure female patients a good quality of life.


Assuntos
Transtornos Plaquetários/genética , Feminino , Humanos
11.
Open Forum Infect Dis ; 6(4): ofz112, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30968058

RESUMO

Background: Experimental CCR5 antagonism with maraviroc in atherosclerosis-prone mice and preliminary data in humans suggest an anti-atherosclerotic effect of the drug. We assessed the impact of maraviroc treatment in persons living with HIV on subclinical indicators of atherosclerosis. Methods: Persons living with HIV on effective antiretroviral therapy (ART) including only protease inhibitors were recruited if they had a Framingham risk score >20% and brachial flow-mediated dilation (bFMD) <4%, as indices of high cardiovascular risk. Maraviroc (300 mg per os for 24 weeks) was administered, in addition to ongoing ART, to all patients using a crossover design. Brachial FMD, carotid-femoral pulse wave velocity (cfPWV), and carotid intima-media thickness (cIMT) were measured as markers of atherosclerosis. Vascular competence-as expressed by the ratio of circulating endothelial microparticles (EMPs) to endothelial progenitor cells (EPCs)-and markers of systemic inflammation and monocyte and platelet activation were assessed. Results: Maraviroc treatment significantly improved bFMD, cfPWV, and cIMT by 66%, 11%, and 13%, respectively (P = .002, P = .022, P = .038, respectively). We also found a beneficial effect of maraviroc on the EMP/EPC ratio (P < .001) and platelet/leucocyte aggregates (P = .013). No significant changes in markers of systemic inflammation, monocyte activation, and microbial translocation were observed. Conclusions: Maraviroc led to significant improvements in several markers for cardiovascular risk, endothelial dysfunction, arterial stiffness, and early carotid atherosclerosis, which was accompanied by an increase of vascular competence, without seeming to affect systemic inflammation. Our data support the need for larger studies to test for any effects of maraviroc on preventing atherosclerosis-driven pathologies.

12.
Haematologica ; 104(7): 1473-1481, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30655369

RESUMO

Platelet-type von Willebrand disease is an inherited platelet disorder characterized by thrombocytopenia with large platelets caused by gain-of-function variants in GP1BA leading to enhanced GPIbα-von Willebrand factor (vWF) interaction. GPIbα and vWF play a role in megakaryocytopoiesis, thus we aimed to investigate megakaryocyte differentiation and proplatelet-formation in platelet-type von Willebrand disease using megakaryocytes from a patient carrying the Met239Val variant and from mice carrying the Gly233Val variant. Platelet-type von Willebrand disease megakaryocytes bound vWF at an early differentiation stage and generated proplatelets with a decreased number of enlarged tips compared to control megakaryocytes. Moreover, they formed proplatelets upon contact with collagen, differently from normal megakaryocytes. Similarly, collagen triggered megakaryocytes showed defective activation of the RhoA-MLC2 axis, which prevents proplatelet formation, and increased phosphorylation of Lyn, which acts as a negative regulator of GPVI signaling, thus preventing ectopic proplatelet-formation on collagen. Consistently, human and murine bone marrow contained an increased number of extravascular platelets compared to controls. In addition, platelet survival of mutant mice was shortened compared to control mice, and the administration of desmopressin, raising circulating vWF, caused a marked drop in platelet count. Taken together, these results show for the first time that thrombocytopenia in platelet-type von Willebrand disease is due to the combination of different pathogenic mechanisms, i.e. the formation of a reduced number of platelets by megakaryocytes, the ectopic release of platelets in the bone marrow, and the increased clearance of platelet/vWF complexes.


Assuntos
Plaquetas/patologia , Megacariócitos/patologia , Mutação , Complexo Glicoproteico GPIb-IX de Plaquetas/metabolismo , Trombocitopenia/fisiopatologia , Doenças de von Willebrand/patologia , Fator de von Willebrand/metabolismo , Animais , Plaquetas/metabolismo , Estudos de Casos e Controles , Movimento Celular , Humanos , Megacariócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Complexo Glicoproteico GPIb-IX de Plaquetas/genética , Trombocitopenia/metabolismo , Trombopoese , Doenças de von Willebrand/metabolismo , Fator de von Willebrand/genética
13.
Expert Rev Hematol ; 12(1): 29-46, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30571151

RESUMO

INTRODUCTION: Hemorrhagic diseases associated with platelet dysfunction include inherited platelet function disorders (IPFD) and a large number of non-hereditary conditions, defined as acquired platelet function disorders (APFD). Their identification requires a careful clinical evaluation and a rational use of diagnostic laboratory assays. Areas covered: Here we describe the laboratory techniques currently available for the assessment of platelet function, including new and experimental laboratory assays, and their alterations in platelet function disorders. Although useful and very widely used in diagnostics, none of them replicates thoroughly the in vivo setting. Expert commentary: The goals of platelet function testing are to provide a rapid and precise diagnosis to every patient bleeding due to a platelet disorder, to assess the individual bleeding risk and potentially to monitor the efficacy of prohemostatic interventions. Most of the tests currently available do not fulfill these needs due to lack of standardization, complexity, and inability to reproduce the multiple reactions involved in the role of platelets in primary hemostasis. These goals can in perspective be achieved by a continuous effort to standardize, improve and expand platelet function assays, by the generation of standardized diagnostic algorithms and, for IPFD, by the implementation of next-generation sequencing-based methods in the diagnostic practice.


Assuntos
Transtornos Plaquetários/diagnóstico , Plaquetas/metabolismo , Testes de Função Plaquetária/métodos , Humanos
14.
Blood ; 132(24): 2532-2534, 2018 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-30545893

Assuntos
Trombose , Hemorragia , Humanos
16.
Blood ; 131(3): 353-364, 2018 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-29158361

RESUMO

Chemerin is a chemoattractant and adipokine that circulates in blood as inactive prochemerin (chem163S). Chem163S is activated by a series of C-terminal proteolytic cleavages resulting in diverse chemerin forms with different levels of activity. We screened a panel of proteases in the coagulation, fibrinolytic, and inflammatory cascades to identify those that process prochemerin in plasma. Factor XIa (FXIa) cleaved chem163S, generating a novel chemerin form, chem162R, as an intermediate product, and chem158K, as the final product. Processing at Arg162 was not required for cleavage at Lys158 or regulation of chemerin bioactivity. Contact phase activation of human platelet-poor plasma by kaolin led to cleavage of chem163S, which was undetectable in FXI-depleted plasma and markedly enhanced in platelet-rich plasma (PRP). Contact phase activation by polyphosphate in PRP resulted in 75% cleavage of chem163S. This cleavage was partially inhibited by hirudin, which blocks thrombin activation of FXI. After activation of plasma, levels of the most potent form of chemerin, chem157S, as well as inactive chem155A, increased. Plasma levels of chem163S in FXI-deficient patients were significantly higher compared with a matched control group (91 ± 10 ng/mL vs 58 ± 3 ng/mL, n = 8; P < .01) and inversely correlated with the plasma FXI levels. Thus FXIa, generated on contact phase activation, cleaves chem163S to generate chem158K, which can be further processed to the most active chemerin form, providing a molecular link between coagulation and inflammation.


Assuntos
Coagulação Sanguínea , Quimiocinas/metabolismo , Fator XIa/metabolismo , Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Sequência de Aminoácidos , Arginina/metabolismo , Plaquetas/metabolismo , Micropartículas Derivadas de Células/metabolismo , Quimiocinas/sangue , Quimiocinas/química , Humanos , Hidrólise , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/química , Cinética , Peptídeos/química , Peptídeos/metabolismo , Fosfolipídeos/metabolismo , Isoformas de Proteínas/sangue
18.
Haematologica ; 102(7): 1192-1203, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28385783

RESUMO

Excessive bleeding at surgery is a feared complication in patients with inherited platelet disorders. However, very few studies have evaluated the frequency of surgical bleeding in these hemorrhagic disorders. We performed a worldwide, multicentric, retrospective study to assess the bleeding complications of surgery, the preventive and therapeutic approaches adopted, and their efficacy in patients with inherited platelet disorders: the Surgery in Platelet disorders And Therapeutic Approach (SPATA) study. We rated the outcome of 829 surgical procedures carried out in 423 patients with well-defined forms of inherited platelet disorders: 238 inherited platelet function disorders and 185 inherited platelet number disorders. Frequency of surgical bleeding was high in patients with inherited platelet disorders (19.7%), with a significantly higher bleeding incidence in inherited platelet function disorders (24.8%) than in inherited platelet number disorders (13.4%). The frequency of bleeding varied according to the type of inherited platelet disorder, with biallelic Bernard Soulier syndrome having the highest occurrence (44.4%). Frequency of bleeding was predicted by a pre-operative World Health Organization bleeding score of 2 or higher. Some types of surgery were associated with a higher bleeding incidence, like cardiovascular and urological surgery. The use of pre-operative pro-hemostatic treatments was associated with a lower bleeding frequency in patients with inherited platelet function disorders but not in inherited platelet number disorders. Desmopressin, alone or with antifibrinolytic agents, was the preventive treatment associated with the lowest bleedings. Platelet transfusions were used more frequently in patients at higher bleeding risk. Surgical bleeding risk in inherited platelet disorders is substantial, especially in inherited platelet function disorders, and bleeding history, type of disorder, type of surgery and female sex are associated with higher bleeding frequency. Prophylactic pre-operative pro-hemostatic treatments appear to be required and are associated with a lower bleeding incidence.


Assuntos
Transtornos Plaquetários/congênito , Transtornos Plaquetários/complicações , Hemorragia/etiologia , Hemorragia/prevenção & controle , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Transtornos Plaquetários/diagnóstico , Criança , Pré-Escolar , Feminino , Hemorragia/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados da Assistência ao Paciente , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/prevenção & controle , Pré-Medicação/métodos , Medição de Risco , Fatores de Risco , Procedimentos Cirúrgicos Operatórios/métodos , Resultado do Tratamento , Adulto Jovem
19.
Blood ; 129(7): 883-895, 2017 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-28034890

RESUMO

Platelets contain and release several matrix metalloproteinases (MMPs). Among these, active MMP-2 enhances platelet aggregation by favoring the activation of phosphatidylinositol 3- kinase (PI3K) and contributes to arterial thrombosis. The platelet surface target of MMP-2 and the mechanism through which it primes platelets to respond to subsequent stimuli are still unknown. We show that active MMP-2 enhances platelet activation induced by weak stimuli by cleaving PAR1 at a noncanonical extracellular site different from the thrombin-cleavage site and thus initiates biased receptor signaling, triggering only some of the signaling pathways normally activated by full PAR1 agonism. The novel PAR1-tethered ligand exposed by MMP-2 stimulates PAR1-dependent Gq and G12/13 pathway activation, triggering p38-MAPK phosphorylation, Ca+2 fluxes, and PI3K activation, but not Gi signaling; this is insufficient to cause platelet aggregation, but it is enough to predispose platelets to fully respond to Gi-activating stimuli. Integrin αIIbß3 is a necessary cofactor for PAR1 cleavage by MMP-2 by binding the MMP-2 hemopexin domain, thus favoring the interaction of the enzyme with PAR1. Our studies unravel a novel mechanism regulating platelet activation that involves the binding of MMP-2 to integrin αIIbß3 and the subsequent cleavage of PAR1 by active MMP-2 at a noncanonical site, exposing a previously undescribed tethered ligand that triggers biased G-protein agonism and thus predisposes platelets to full activation by other stimuli. These results identify the MMP-2-αIIbß3-PAR1 interaction as a potential target for the prevention of arterial thrombosis.


Assuntos
Plaquetas/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Ativação Plaquetária , Receptor PAR-1/metabolismo , Transdução de Sinais , Animais , Plaquetas/citologia , Células CHO , Cricetulus , Humanos , Camundongos , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Mapas de Interação de Proteínas
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