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1.
Clin Appl Thromb Hemost ; 27: 1076029621992128, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33539188

RESUMO

Hyperferritinemia is associated with poor outcomes in critically ill patients with sepsis, hemophagocytic lymphohistiocytosis (HLH), macrophage activation syndromes (MAS) and coronavirus disease 19 (COVID-19). Autopsies of hyperferritinemic patients that succumbed to either sepsis, HLH, MAS or COVID-19 have revealed disseminated microvascular thromboses with von Willebrand factor (VWF)-, platelets-, and/or fibrin-rich microthrombi. It is unknown whether high plasma ferritin concentration actively promotes microvascular thrombosis, or merely serves as a prognostic biomarker in these patients. Here, we show that secretion of VWF from human umbilical vein endothelial cells (HUVEC) is significantly enhanced by 100,000 ng/ml of recombinant ferritin heavy chain protein (FHC). Ferritin fraction that was isolated by size exclusion chromatography from the plasma of critically ill HLH patients promoted VWF secretion from HUVEC, compared to similar fraction from non-critically ill control plasma. Furthermore, recombinant FHC moderately suppressed the activity of VWF cleaving metalloprotease ADAMTS-13. These observations suggest that a state of marked hyperferritinemia could promote thrombosis and organ injury by inducing endothelial VWF secretion and reducing the ADAMTS-13 activity.


Assuntos
Proteína ADAMTS13/metabolismo , /complicações , Ferritinas/metabolismo , /complicações , Fator de von Willebrand/metabolismo , Proteína ADAMTS13/antagonistas & inibidores , Estado Terminal , Ferritinas/sangue , Células Endoteliais da Veia Umbilical Humana , Humanos , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/complicações , Oxirredutases/sangue , Oxirredutases/metabolismo , Proteínas Recombinantes/sangue , Proteínas Recombinantes/metabolismo , Trombose/sangue , Trombose/etiologia
2.
Ann Hematol ; 100(2): 375-382, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33404693

RESUMO

Sickle cell disease (SCD) comprises a group of genetic disorders characterized by the presence of the hemoglobin (Hb) S in homozygosis or in heterozygosis with some other Hb variant or in interaction with thalassemia. SCD is characterized by a very complex pathophysiology, which determines a wide variability of clinical manifestations, including a chronic state of hypercoagulability responsible for the increased risk of thromboembolic events. ADAMTS13 and von Willebrand factor (VWF) play an important role in arterial and venous thrombosis. Thus, the aim of this study was to understand how the ADAMTS13-VWF axis behaves in sickle cell disease, as well as whether there is an association of these markers with the use of hydroxyurea (HU). This is a cross-sectional study conducted with 40 patients diagnosed with SCD and 40 healthy individuals. The analysis of the ADAMTS13-VWF axis was comparatively performed between groups of patients and controls and, afterwards, between patients with SCD who were users and non-users of HU. ADAMTS13 activity, ADAMTS13 activity/VWF:Ag, and ADAMTS13:Ag/VWF:Ag ratios were significantly lower and VWF:Ag levels significantly higher in SCD patients when compared to the controls. There was no statistically significant difference in ADAMTS13:Ag and VWF collagen binding (VWF:CB) levels between the groups evaluated. Among the categories of HU use, there was no statistically significant difference in any of the evaluated markers. As a conclusion, we could observe that the ADAMTS13-VWF axis is altered in SCD when compared to healthy individuals and that there is no association between these markers and the use of HU.


Assuntos
Proteína ADAMTS13/sangue , Anemia Falciforme/sangue , Fator de von Willebrand/metabolismo , Adolescente , Adulto , Anemia Falciforme/complicações , Anemia Falciforme/tratamento farmacológico , Estudos Transversais , Feminino , Humanos , Hidroxiureia/administração & dosagem , Masculino , Trombose Venosa/sangue , Trombose Venosa/etiologia
6.
Front Immunol ; 11: 610696, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33343584

RESUMO

Both neutrophil extracellular traps (NETs) and von Willebrand factor (VWF) are essential for thrombosis and inflammation. During these processes, a complex series of events, including endothelial activation, NET formation, VWF secretion, and blood cell adhesion, aggregation and activation, occurs in an ordered manner in the vasculature. The adhesive activity of VWF multimers is regulated by a specific metalloprotease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Increasing evidence indicates that the interaction between NETs and VWF contributes to arterial and venous thrombosis as well as inflammation. Furthermore, contents released from activated neutrophils or NETs induce the reduction of ADAMTS13 activity, which may occur in both thrombotic microangiopathies (TMAs) and acute ischemic stroke (AIS). Recently, NET is considered as a driver of endothelial damage and immunothrombosis in COVID-19. In addition, the levels of VWF and ADAMTS13 can predict the mortality of COVID-19. In this review, we summarize the biological characteristics and interactions of NETs, VWF, and ADAMTS13, and discuss their roles in TMAs, AIS, and COVID-19. Targeting the NET-VWF axis may be a novel therapeutic strategy for inflammation-associated TMAs, AIS, and COVID-19.


Assuntos
Proteína ADAMTS13/imunologia , Armadilhas Extracelulares/imunologia , Trombose/imunologia , Fator de von Willebrand/imunologia , Doença Aguda , Isquemia Encefálica/imunologia , Isquemia Encefálica/patologia , Isquemia Encefálica/virologia , Humanos , Acidente Vascular Cerebral/imunologia , Acidente Vascular Cerebral/patologia , Acidente Vascular Cerebral/virologia , Trombose/patologia , Trombose/virologia , Microangiopatias Trombóticas/imunologia , Microangiopatias Trombóticas/patologia , Microangiopatias Trombóticas/virologia
7.
Cell Commun Signal ; 18(1): 190, 2020 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-33357215

RESUMO

The rapid ability of SARS-CoV-2 to spread among humans, along with the clinical complications of coronavirus disease 2019-COVID-19, have represented a significant challenge to the health management systems worldwide. The acute inflammation and coagulation abnormalities appear as the main causes for thousands of deaths worldwide. The intense inflammatory response could be involved with the formation of thrombi. For instance, the presence of uncleaved large multimers of von Willebrand (vWF), due to low ADAMTS13 activity in plasma could be explained by the inhibitory action of pro-inflammatory molecules such as IL-1ß and C reactive protein. In addition, the damage to endothelial cells after viral infection and/or activation of endothelium by pro-inflammatory cytokines, such as IL-1ß, IL-6, IFN-γ, IL-8, and TNF-α induces platelets and monocyte aggregation in the vascular wall and expression of tissue factor (TF). The TF expression may culminate in the formation of thrombi, and activation of cascade by the extrinsic pathway by association with factor VII. In this scenario, the phosphatidylserine-PtdSer exposure on the outer leaflet of the cell membrane as consequence of viral infection emerges as another possible underlying mechanism to acute immune inflammatory response and activation of coagulation cascade. The PtdSer exposure may be an important mechanism related to ADAM17-mediated ACE2, TNF-α, EGFR and IL-6R shedding, and the activation of TF on the surface of infected endothelial cells. In this review, we address the underlying mechanisms involved in the pathophysiology of inflammation and coagulation abnormalities. Moreover, we introduce key biochemical and pathophysiological concepts that support the possible participation of PtdSer exposure on the outer side of the SARS-CoV-2 infected cells membrane, in the pathophysiology of COVID-19. Video Abstract.


Assuntos
/genética , Inflamação/genética , Fosfatidilserinas/genética , Trombose/genética , Proteína ADAM17/genética , Proteína ADAMTS13/genética , /patologia , Células Endoteliais/virologia , Humanos , Inflamação/complicações , Inflamação/virologia , Fosfatidilserinas/metabolismo , Receptores de Interleucina-6/genética , Trombose/patologia , Trombose/virologia , Fator de von Willebrand/genética
9.
Int J Hematol ; 112(6): 764-772, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32856231

RESUMO

Immune thrombotic thrombocytopenic purpura (iTTP) is caused by ADAMTS13 deficiency due to anti-ADAMTS13 autoantibodies. Rituximab, an anti-CD20 monoclonal antibody, is often used to suppress these autoantibodies. This retrospective study, conducted in an iTTP cohort in Japan, evaluated the long-term efficacy of rituximab as off-label treatment for refractory or relapsed cases. A total of 252 iTTP patients with severe ADAMTS13 deficiency (< 10%) and its inhibitor were enrolled, and 169 episodes in 156 patients were analyzed. Sixty-five episodes with relapse or resistance to conventional treatment were treated with rituximab, while 104 episodes received conventional treatment only. The rituximab group had a significantly higher inhibitor titer than the rituximab-untreated group. During the median follow-up period of 3.9 years, there were 8 relapses in the rituximab group and 17 relapses in the rituximab-untreated group. The median time to relapse in the rituximab group (2.9 years) was significantly longer than that in the rituximab-untreated group (1.2 years). Relapse-free survival at 2 years was significantly higher in the rituximab group than in the rituximab-untreated group. The incidence of relapse at 5 years did not differ between the 2 groups. Rituximab reduced the risk of relapse in refractory or relapsed iTTP patients for 2 years.


Assuntos
Uso Off-Label , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Rituximab/uso terapêutico , Proteína ADAMTS13/deficiência , Proteína ADAMTS13/imunologia , Adulto , Idoso , Autoanticorpos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/mortalidade , Recidiva , Estudos Retrospectivos , Prevenção Secundária , Fatores de Tempo , Resultado do Tratamento
14.
Am J Hematol ; 95(8): 953-959, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32350923

RESUMO

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a life-threatening immune-mediated thrombotic microangiopathy. Daily therapeutic plasma exchange (TPE) and the optimized use of rituximab have strikingly improved the outcome of this disease, however the rate of disease recurrence remains high. Specific predictors of relapse in patients in remission can be relevant for an optimal patient management. In this study, we aimed to identify predictive variables of disease relapse in a multicenter cohort of 74 out of 153 iTTP patients. They were tested at different time points during remission for the levels of ADAMTS-13 activity and autoantibody, and did not receive pre-emptive treatment for ADAMTS-13 activity deficiency during remission. The results showed that the association of ADAMTS13 activity ≤20% with a high anti-ADAMTS-13 titer at remission, and the time to response to first line treatment ≥13 days, were independent predictive factors of disease relapse. In addition, the use of rituximab in patients with exacerbation or refractoriness to TPE was significantly associated with reduced relapse rate. By Cox regression analysis, patients with ADAMTS-13 activity ≤20% plus anti-ADAMTS13 antibody titer ≥15 U/mL at remission had an increased risk of relapse (HR 1.98, CI 95% 1.087-3.614; P < .02). These findings may help to outline more personalized therapeutic strategies in order to provide faster and sustained responses to first-line iTTP treatment and prevent relapses in these patients.


Assuntos
Proteína ADAMTS13/sangue , Autoanticorpos/sangue , Púrpura Trombocitopênica Trombótica/terapia , Feminino , Humanos , Masculino , Púrpura Trombocitopênica Trombótica/patologia , Recidiva
15.
PLoS One ; 15(5): e0232637, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32365113

RESUMO

ADAMTS13 regulates the hemostatic activity of von Willebrand factor (VWF). Determined by static assays, proteolytic activity <10IU/dL in patient plasma, in absence of ADAMTS13 autoantibodies, indicates Upshaw-Schulman syndrome (USS); the congenital form of Thrombotic Thrombocytopenic Purpura (TTP). We have recently functionally characterized sixteen USS-associated ADAMTS13 missense variants under static conditions. Here, we used two assays under shear flow conditions to analyze the activity of those seven mutants with sufficiently high residual secretion plus two newly identified variants. One assay determines cleavage of VWF strings bound to the surface of endothelial cells. The other, light transmission aggregometry-based assay, mimics degradation of VWF-platelet complexes, which are likely to be present in the circulation during TTP bouts. We found that 100 ng/ml of all variants were able to cleave about 80-90% of VWF strings even though 5 out of 9 exhibited activity ≤1% in the state-of-the-art static assay at the same concentration. These data indicate underestimation of ADAMTS13 activity by the used static assay. In simulated circulation, two variants, with missense mutations in the vicinity of the catalytic domain, exhibited only minor residual activity while all other variants were able to effectively break down VWF-platelet complexes. In both assays, significant proteolytic activity could be observed down to 100 ng/ml ADAMTS13. It is thus intriguing to postulate that most variants would have ample activity if secretion of 10% of normal plasma levels could be achieved.


Assuntos
Proteína ADAMTS13/genética , Variação Genética , Mutação de Sentido Incorreto , Púrpura Trombocitopênica Trombótica/congênito , Púrpura Trombocitopênica Trombótica/genética , Plaquetas/metabolismo , Domínio Catalítico , Códon sem Sentido , Células Endoteliais/metabolismo , Células HEK293 , Hemostasia , Humanos , Agregação Plaquetária , Proteínas Recombinantes/genética , Resistência ao Cisalhamento , Fatores de Tempo , Fator de von Willebrand
16.
Intern Med ; 59(10): 1315-1321, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32418955

RESUMO

We herein report a patient with mixed connective tissue disease (MCTD) who had been stable for years but suddenly developed thrombotic thrombocytopenic purpura (TTP). The patient showed a clinical pentad of signs of TTP, low activity of ADAMTS13, and positivity of anti-ADAMTS13 antibodies. She did not respond to plasma exchange or steroid therapy and died five days after admission. An autopsy revealed microthrombi in the brain, heart, kidney, adrenal glands, esophageal submucosa, and bone marrow as well as diffuse alveolar hemorrhaging. Physicians should bear in mind that TTP can occur in MCTD patients regardless of disease activity.


Assuntos
Doença Mista do Tecido Conjuntivo/complicações , Púrpura Trombocitopênica Trombótica/complicações , Proteína ADAMTS13/imunologia , Corticosteroides/uso terapêutico , Autoanticorpos/sangue , Autopsia , Evolução Fatal , Feminino , Humanos , Masculino , Troca Plasmática , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/imunologia
17.
Zhonghua Xue Ye Xue Za Zhi ; 41(3): 216-221, 2020 Mar 14.
Artigo em Chinês | MEDLINE | ID: mdl-32311891

RESUMO

Objective: To analyze the clinical characteristics, treatment and prognosis of patients with thrombotic thrombocytopenic purpura (TTP) . Methods: 83 patients with TTP from May 1998 to May 2019 were analyzed retrospectively. Results: Among the 83 patients, there were 27 males and 56 females, with a median age of 39 (10-68) years. 41 cases (49.4%) showed pentalogy syndrome and 79 cases (95.2%) showed triad syndrome. 78.0% (46/59) of the patients had a PLASMIC score of 6 or higher. TTP gene mutations was detected in 5 of 10 patients. The activity of von Willebrand factor-cleaving protease (ADAMTS13) , which was detected in 10 patients before plasma exchange (PEX) , was less than 10% in 9 patients. 83 patients were treated with PEX/plasma infusion and glucocorticoid, 35 of which were treated combined with rituximab and/or immunosuppressant. The median follow-up was 34 (1-167) months, the effective rate was 81.9%, the remission rate was 63.9%, the relapse rate was (35.7 ±7.1) %, and the 3-year overall survival (OS) rate was (78.6 ±4.6) %. The effective rate (72.9%vs 94.3%, P=0.019) and OS rate[ (63.8±7.5) %vs (94.3±3.9) %, χ(2)=8.450, P=0.004] in the group treated with PEX/PI and glucocorticoid alone were lower than those in the group treated combined with rituximab and/or immunosuppressant. COX multivariate analysis showed that age (HR=1.111, 95%CI 1.044-1.184, P=0.001) and alanine transaminase (ALT) /aspartate aminotransferase (AST) (HR=1.353, 95%CI 1.072-1.708, P=0.011) were independent risk factors for OS. Conclusion: Most patients with TTP have triad syndrome, accompanied by a decrease in ADAMTS13 activity. Plasma infusion and glucocorticoid combined with rituximab, immunosuppressive therapy could improve overall survival. The prognosis of patients with older age and high ALT/AST ratio is poor.


Assuntos
Púrpura Trombocitopênica Trombótica , Proteínas ADAM , Proteína ADAMTS13 , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Troca Plasmática , Estudos Retrospectivos , Rituximab , Adulto Jovem
18.
Semin Thromb Hemost ; 46(3): 289-301, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32259874

RESUMO

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and potentially lethal disease characterized by fragmentary hemolysis, moderate-to-severe thrombocytopenia, end-organ dysfunction, and severely reduced ADAMTS13 levels (< 10%). Survival in iTTP has improved significantly since the introduction of plasma exchange as standard therapy combined with immune suppression to address the underlying pathophysiology. A host of challenges remain including prompt recognition of the disease, treatment of the end-organ effects of the disease, improving the early mortality rate, significantly reducing the relapse rate as well as addressing refractory disease. Discussed in this narrative review of iTTP are the recent measures aimed at addressing these issues, including improvements in clinical prediction models, postremission maintenance approaches with early retreatment as well as the development of novel therapies.


Assuntos
Proteína ADAMTS13/metabolismo , Púrpura Trombocitopênica Trombótica/diagnóstico , Púrpura Trombocitopênica Trombótica/terapia , Adulto , Humanos , Adulto Jovem
19.
Vox Sang ; 115(5): 433-442, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32227485

RESUMO

BACKGROUND: A pre-plasma exchange ADAMTS13 measurement differentiates thrombotic thrombocytopenic purpura (TTP) from other forms of thrombotic microangiopathy (TMA). Given that many hospitals do not perform the ADAMTS13 assay in-house and that the turnaround time (TAT) differs among reference laboratories, we performed an analysis investigating the potential impact of a delay in obtaining the results on the healthcare system. METHODS: An economic model was developed to estimate the impact of a delay in obtaining the pretreatment ADAMTS13 results on patients admitted with TMA with cost (US dollars) as the primary outcome. Incremental cost-effectiveness ratio (ICER) as a composite outcome was calculated from both cost and life days [LDs], an effectiveness surrogate marker. Model parameters were gathered from the medical literature, except for the institutional cost of the ADAMTS13 test. RESULTS: In patients with TMA, during the 6-day study period, the incremental cost to the healthcare system ranged from approximately $4155 to $5123 for every 1-day delay in obtaining the pre-exchange ADAMTS13 results with virtually no change in the effectiveness marker. The ICER composite outcome established the cost-effectiveness of having a fast TAT for pre-exchange ADAMTS13 results. Probabilistic sensitivity analyses also confirmed the robustness of the model. CONCLUSIONS: In patients with clinical presentations of TMAs, having a rapid TAT for pre-exchange ADAMTS13 measurement appeared to be cost-effective. If testing cannot be performed in-house, then our findings support the necessity of contracting with a reference laboratory that can reliably provide the result, preferably within 1 day of admission.


Assuntos
Proteína ADAMTS13/análise , Análise Custo-Benefício , Modelos Econômicos , Púrpura Trombocitopênica Trombótica/terapia , Biomarcadores/análise , Diagnóstico Diferencial , Hospitalização , Humanos , Púrpura Trombocitopênica Trombótica/diagnóstico , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/terapia
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