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1.
Subcell Biochem ; 94: 437-464, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189311

RESUMO

Von Willebrand factor (VWF) and coagulation factor VIII (FVIII) circulate as a complex in plasma and have a major role in the hemostatic system. VWF has a dual role in hemostasis. It promotes platelet adhesion by anchoring the platelets to the subendothelial matrix of damaged vessels and it protects FVIII from proteolytic degradation. Moreover, VWF is an acute phase protein that has multiple roles in vascular inflammation and is massively secreted from Weibel-Palade bodies upon endothelial cell activation. Activated FVIII on the other hand, together with coagulation factor IX forms the tenase complex, an essential feature of the propagation phase of coagulation on the surface of activated platelets. VWF deficiency, either quantitative or qualitative, results in von Willebrand disease (VWD), the most common bleeding disorder. The deficiency of FVIII is responsible for Hemophilia A, an X-linked bleeding disorder. Here, we provide an overview on the role of the VWF-FVIII interaction in vascular physiology.


Assuntos
Fenômenos Fisiológicos Cardiovasculares , Fator VIII/metabolismo , Fator de von Willebrand/metabolismo , Fator VIII/química , Hemofilia A/metabolismo , Humanos , Doenças de von Willebrand/metabolismo , Fator de von Willebrand/química
2.
Cancer Sci ; 110(11): 3424-3433, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31495050

RESUMO

Tongue squamous cell carcinoma (TSCC) has a poor prognosis due to its early metastasis through blood and lymphatic vessels. We undertook a systematic review to investigate the prognostic significance of blood microvessel density (MVD) and lymphatic vessel density (LVD) in TSCC patients. We carried out a systematic search in Ovid Medline, Scopus, and Cochrane libraries. All studies that evaluated the prognostic significance of MVD/LVD markers in TSCC were systematically retrieved. Our results showed that MVD/LVD markers, CD31, CD34, CD105, factor VIII, lymphatic vessel endothelial hyaluronan receptor-1, and D2-40 were evaluated in TSCC patients until 28 June 2018. Six out of 13 studies reported markers that were associated with poor prognosis in TSCC. Two out of three studies suggested that a high number of D2-40+ vessels predicated low overall survival (OS); the third study reported that the ratio of D2-40+ over factor VIII+ vessels is associated with low OS. Most of the other markers had controversial results for prognostication. We found higher expression of MVD/LVD markers were commonly, but not always, associated with shorter survival in TSCC patients. It is therefore not currently possible to recommend implementation of these markers as reliable prognosticators in clinical practice. More studies (especially for D2-40) with larger patient cohorts are needed.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Vasos Linfáticos/metabolismo , Microvasos/metabolismo , Neoplasias da Língua/metabolismo , Anticorpos Monoclonais Murinos/metabolismo , Antígenos CD34/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Endoglina/metabolismo , Fator VIII/metabolismo , Humanos , Receptores de Hialuronatos/metabolismo , Linfangiogênese , Neovascularização Patológica , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Prognóstico , Neoplasias da Língua/mortalidade , Neoplasias da Língua/patologia , Proteínas de Transporte Vesicular/metabolismo
3.
J Pediatr Orthop ; 39(9): 479-486, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31503237

RESUMO

BACKGROUND: Although physeal fractures and physeal bars can result in significant clinical consequences to growth and development of the injured physis, little orthopaedic research has focused upon this topic. Our objective was to extend a previously developed rat model to examine the immunohistochemical features following surgical application of techniques disrupting the physis. METHODS: Physes were surgically disrupted using fracture (control), epiphyseal scrape (ES), or epiphyseal drill (ED). After 1, 3, 6, 10, or 21 days, animals were euthanized, sites processed for histology and immunohistochemical localization of vascular endothelial growth factor (VEGF), Factor VIII, Sox-9, PTHrP (parathyroid hormone-related protein) and PTHrP-R (parathyroid hormone-related protein receptor) in resting, proliferative, and hypertrophic physeal zones. Incidence of physeal bars, vertical septa and islands within the metaphysis was quantified. Semiquantitative analysis of immunohistochemistry was performed. RESULTS: Physeal bars, vertical septa, and displaced cartilage islands were present each of the surgical treatments. Fisher's exact test showed a statistically significant increase in the presence of physeal bars (P=0.002) and vertical septa (P=0.012) in the ED group at 10 and 21 days. Analysis of VEGF showed significant differences among the surgical treatments involving the resting zone, and the proliferative zone for days 1, 6, and 21 (P≤0.02) with greater mean scores present in the fracture (control) group, followed by the ED group; the lowest scores were present in the ES group. PTHrP-R immunolocalization showed significant differences among treatments in the hypertrophic zone at days 6 and 21 (P=0.022 and 0.044, respectively). CONCLUSIONS: On the basis of the type of surgical treatment, results show significant differences in the presence of VEGF (reflecting the vascular bed) in the resting and proliferating zones at days 1, 6, and 21. VEGF localization was less abundant in the ED group (which had more physeal bars), suggesting that lack of vascular ingrowth plays a role in physeal bar formation. CLINICAL RELEVANCE: Basic science data presented here provide insight into the importance of the various regions of the physis and its repair and continued growth after physeal fracture. We suggest that a better understanding of the cellular basis of physeal arrest following physeal fracture may have future relevance for the development of treatments to prevent or correct arrest.


Assuntos
Lâmina de Crescimento/metabolismo , Fraturas Salter-Harris/metabolismo , Técnicas de Ablação , Animais , Epífises/lesões , Epífises/metabolismo , Fator VIII/metabolismo , Lâmina de Crescimento/cirurgia , Imuno-Histoquímica , Proteína Relacionada ao Hormônio Paratireóideo/metabolismo , Ratos , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Fatores de Transcrição SOX9/metabolismo , Fraturas Salter-Harris/cirurgia , Fator A de Crescimento do Endotélio Vascular/metabolismo
4.
Blood Coagul Fibrinolysis ; 30(1S Suppl 1): S4-S6, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31517708

RESUMO

: In persons with hemophilia, the severity and spontaneity of bleeding episodes depends on the degree of factor deficiency present in the patients. Severe hemophilia is classically characterized by a factor VIII (FVIII) or factor IX (FIX) coagulant activity below 1% of normal (spontaneous and severe bleeds). Moderate hemophilia is associated with factor activity between 1 and 5% of normal (milder spontaneous and traumatic bleeds). Finally, mild hemophilia has factor activity in excess of 5% of normal (traumatic bleeds in general). Nonetheless, this classification is rather simplistic. It is a known fact that there are subjects with identical clotting factor levels who have different bleeding phenotypes. We will analyze different factors to justify this.


Assuntos
Fator IX/análise , Fator VIII/análise , Hemofilia A/sangue , Coagulação Sanguínea , Fator IX/metabolismo , Fator VIII/metabolismo , Hemofilia A/metabolismo , Hemorragia/sangue , Hemorragia/metabolismo , Humanos
5.
Int J Lab Hematol ; 41(5): 679-683, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31421012

RESUMO

INTRODUCTION: The measurements of clotting factor activities are usually performed using a one-stage clotting assay (OSA) or chromogenic substrate assay (CSA). Advances in automated coagulation analysers have led to the utilization of stored calibration curves. There are sometimes substantial intervals between test calibration and analysis of samples. Variability in results can be influenced by calibrant and methodology. Several guidelines recommend calibration and patient samples be performed together in parallel; this incurs costs, but reliance on a stored calibration curve may lead to inaccuracy of results over time. METHODS: We evaluated inclusion of a live truncated (3 point) calibration curve using calibrator plasma alongside test samples and compared results calculated against the stored calibration curves and live truncated calibration to assess the impact on precision and accuracy. The feasibility of this was tested on two hospital sites in the UK; OSA and CSA were performed on Sysmex CS5100 using Actin FS, SynthASil, Innovin, Biophen chromogenic VIII and Rossix chromogenic IX. RESULTS: Results of two batches of IQC were compared for FII, FV, FVII, FX, FIX:C, FXI, FXII and OSA FVIII (FVIII:C1) and CSA FVIII:C (FVIII:CR) and FXI:C. By utilizing a live truncated calibration, precision improved with the most striking examples: FXII %CV 23.1% to 3.1% (site A) FXI 7.3% to 2.4% (site B). The improvement in other clotting factors was more modest. CONCLUSION: To the best of our knowledge, this is the first study that demonstrates that the use of a live truncated calibration curve will improve precision and accuracy.


Assuntos
Fatores de Coagulação Sanguínea/análise , Testes de Coagulação Sanguínea/instrumentação , Testes de Coagulação Sanguínea/métodos , Coagulação Sanguínea , Calibragem/normas , Fatores de Coagulação Sanguínea/metabolismo , Testes de Coagulação Sanguínea/economia , Compostos Cromogênicos , Análise Custo-Benefício , Fator VIII/análise , Fator VIII/metabolismo , Humanos , Proteínas Recombinantes/análise , Proteínas Recombinantes/metabolismo , Padrões de Referência , Reprodutibilidade dos Testes , Tromboplastina/análise , Tromboplastina/metabolismo
6.
J Pharm Biomed Anal ; 175: 112781, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31398627

RESUMO

Patients with hemophilia A are currently diagnosed and monitored by measuring the activity of coagulation factor VIII (FVIII) in plasma mostly with the one-stage clotting assay (OSA). Although the OSA is routinely available in many clinical laboratories, it has in some circumstances relatively low sensitivity and specificity. Therefore, the FVIII activity as a biomarker does not always correlate with the bleeding phenotype. Therefore, we have developed a liquid chromatography tandem mass spectrometry method to quantify the concentration of coagulation FVIII in plasma which would allow us to investigate the relation between FVIII plasma concentration, FVIII activity and bleeding tendency in future studies. LC-MS/MS method was set up by firstly dissociation Von Willebrand factor (VWF) from coagulation factor VIII by triggering the coagulation cascade to occur thus generating active factor VIII (FVIIIa). FVIIIa was then selectively extracted by means of immunoaffinity interaction using anti-FVIII camelid nanobody, after which FVIIIa was eluted, heat denatured and trypsin digested. Finally, a FVIII specific peptide was used as a surrogate for quantification by mass spectrometry. Critical method parameters such as antibody amount, incubation time, sample volume and type of streptavidin 96 well plate were optimized. The method was validated according to European Medicines Agency (EMA) guidelines where an LLOQ of 1 ng/mL was obtained using 50 µL of citrate plasma sample. Within-run and between-run accuracy and precision for quality control (QC) samples, LLOQ (1 ng/mL), QC Low (5 ng/mL), QC Med (150 ng/mL), QC High (300 ng/mL) were within the threshold of 15% relative standard deviation (RSD) and Bias. The selective immunoaffinity method which was used in combination with a highly sensitive mass spectrometer allowed for an unpresented LLOQ of 1 ng/mL utilizing 50 µL plasma sample. This method will be used to investigate the beneficial value of FVIII plasma concentration which may be used in conjunction with FVIII activity for patient diagnosis and dosage optimization.


Assuntos
Anticorpos/química , Camelídeos Americanos/metabolismo , Fator VIII/química , Fator VIII/metabolismo , Plasma/química , Animais , Cromatografia Líquida/métodos , Hemofilia A/sangue , Humanos , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos , Fator de von Willebrand/química
7.
World Neurosurg ; 130: 335-338, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31326638

RESUMO

BACKGROUND: Association of moyamoya disease (MMD) with von Willebrand disease (vWD) is extremely rare. CASE DESCRIPTION: We first report a 27-year-old female case of MMD concurrent with vWD type 1, which presented as hemorrhagic stroke. The patient underwent a revascularization surgery with perioperative replacement therapy of von Willebrand factor and coagulation factor VIII. No hemorrhagic complications occurred. CONCLUSIONS: The patient overcame postoperative transient neurological events and fully recovered. We discuss appropriate perioperative supplementation of coagulation factors for a revascularization surgery for MMD with vWD.


Assuntos
Hemorragia/cirurgia , Doença de Moyamoya/cirurgia , Doença de von Willebrand Tipo 1/cirurgia , Adulto , Fator VIII/metabolismo , Feminino , Hemorragia/diagnóstico , Hemorragia/etiologia , Humanos , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/etiologia , Doença de von Willebrand Tipo 1/complicações , Doença de von Willebrand Tipo 1/diagnóstico , Fator de von Willebrand/metabolismo
8.
Transfus Apher Sci ; 58(4): 447-448, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31320278

RESUMO

Acquired hemophilia A, due to spontaneous autoantibody against FVIII, is a rare hemorrhagic disorder with an incidence of about 1 per million population per year. If unrecognized and untreated, it is associated with a high morbidly and mortality rate of 8-12%. Autoantibody against coagulation factor VIII neutralizes procoagulant activity. We report herein is such a rare case of acquired hemophilia in a patient with CLL.


Assuntos
Autoanticorpos/sangue , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator VIII/antagonistas & inibidores , Hemofilia A/sangue , Leucemia Linfocítica Crônica de Células B/sangue , Idoso , Fator VIII/metabolismo , Feminino , Humanos
9.
Haemophilia ; 25(5): 893-901, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31294905

RESUMO

AIM: N8-GP (turoctocog alfa pegol) is a glycoPEGylated, extended half-life human recombinant factor VIII (FVIII) shown to be an efficacious treatment for patients with haemophilia A. Accurate monitoring of replacement therapy helps ensure proper dosing, leading to better patient care. The objective of this field study was to evaluate the accuracy and intra- and inter-laboratory variabilities of N8-GP and rAHF (Advate® ) FVIII activity (FVIII:C) measurements in clinical laboratories using their routine methods and reagents. METHODS: Laboratories measured plasma samples spiked with 0.03, 0.2, 0.6 and 0.9 IU/mL N8-GP or rAHF. Samples were blinded, and laboratories were instructed to perform evaluations using their routine FVIII activity assays and calibrators. RESULTS: Of the 67 participating laboratories from 25 countries, 60 used a one-stage assay, 36 used a chromogenic assay, and 29 used both one-stage and chromogenic assays. Participating laboratories used nine different activated partial thromboplastin time (aPTT) reagents, the most common being SynthASil® and Actin® FS. Most aPTT reagents recovered N8-GP close to target. Three silica-based aPTT reagents (APTT-SP, TriniCLOT™ and STA® PTT-Automate) underestimated N8-GP, recovering 40%-83% of target concentration. For chromogenic assays, N8-GP and rAHF recoveries were comparable at all concentrations, with overall mean recoveries for both products close to 130%. Assay variability was similar for both assay types and both products; inter-laboratory variability was greater than intra-laboratory variability and highest at 0.03 IU/mL. CONCLUSIONS: Most clinical laboratories accurately measured N8-GP and rAHF when using their in-house one-stage or chromogenic FVIII:C assays. However, three silica-based aPTT reagents underestimated N8-GP recovery.


Assuntos
Fator VIII/metabolismo , Hemostasia/fisiologia , Testes de Coagulação Sanguínea/métodos , Humanos , Laboratórios
10.
Int J Lab Hematol ; 41(5): 664-670, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31271527

RESUMO

INTRODUCTION: Chromogenic substrate assay (CSA) reagents Revohem™ FVIII and Revohem™ FIX are now available as in vitro diagnostic reagents for autoanalysers in Japan. In this study, we evaluated the performance of these reagents in the CS-5100 automated coagulation analyser. METHODS: We assessed within-run and between-day imprecision, on-board stability and frozen-storage stability of Revohem FVIII and FIX. Sensitivity to lupus anticoagulant (LA) was examined using LA-positive patient plasma. Correlations were analysed using plasma samples from normal individuals and patients with haemophilia A (HA) or B (HB) or von Willebrand disease (VWD). RESULTS: Imprecision was <2% for Revohem FVIII and <6.5% for Revohem FIX. On-board storage of Revohem FVIII resulted in a <10% decrease in FVIII levels from baseline at 24 hours, whereas Revohem FIX showed a >10% decrease at 8 hours. Revohem FVIII showed good stability while frozen for 22 days. Although Revohem FIX showed degradation due to freeze-thawing, a new calibration improved stability up to 22 days. Interference from LA was not observed with Revohem FVIII or FIX. The FVIII CSA-CSA correlation was excellent in normal (r = 0.9924), HA (r = 0.9945) and VWD (r = 0.9914). The FVIII CSA-OSA correlation was good in normal (r = 0.8468) and excellent in HA (r = 0.975) and VWD (r = 0.9936). The FIX CSA-OSA correlation was fair in normal (r = 0.4791) and excellent in HB (r = 0.9501). CONCLUSION: Revohem FVIII and FIX both showed excellent performance in the CS-5100 analyser. These reagents could be useful in routine laboratory testing for diagnosing and treating haemophilia.


Assuntos
Automação Laboratorial/instrumentação , Testes de Coagulação Sanguínea/instrumentação , Compostos Cromogênicos/metabolismo , Fator IX/metabolismo , Fator VIII/metabolismo , Automação Laboratorial/métodos , Testes de Coagulação Sanguínea/métodos , Hemofilia A/sangue , Hemofilia A/diagnóstico , Hemofilia A/metabolismo , Hemofilia B/sangue , Hemofilia B/diagnóstico , Hemofilia B/metabolismo , Humanos , Inibidor de Coagulação do Lúpus/sangue , Inibidor de Coagulação do Lúpus/metabolismo , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Doenças de von Willebrand/sangue , Doenças de von Willebrand/diagnóstico , Doenças de von Willebrand/metabolismo
11.
Blood Transfus ; 17(3): 223-228, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31246563

RESUMO

One of the most serious complications of the treatment of severe haemophilia A is the development of alloantibodies against exogenous factor VIII (FVIII). Inhibitors render factor replacement therapy ineffective, exposing patients to a remarkably high risk of morbidity and mortality. Besides the well-known bypassing agents (i.e. activated prothrombin complex concentrate and recombinant activated factor VII) used to treat or prevent bleeding in haemophilia patients with inhibitors, there is growing interest in newer haemostatic therapies that are not based on the replacement of the deficient FVIII. This review will focus on the most interesting among these innovative therapies, emicizumab, and will provide an update on its current stage of clinical development.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator VIII , Fator VIIa/uso terapêutico , Hemofilia A , Isoanticorpos/sangue , Fator VIII/antagonistas & inibidores , Fator VIII/metabolismo , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Humanos , Proteínas Recombinantes/uso terapêutico
12.
Thromb Haemost ; 119(9): 1384-1393, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31203578

RESUMO

Hemophilia A (HA) is an X-linked hereditary bleeding disorder caused by deficiency of coagulation factor (F) VIII activity. One of the greatest complications in the treatment of HA is the development of neutralizing alloantibodies, known as FVIII inhibitors. HA patients who develop FVIII inhibitors have limited treatment options available to them and experience greater disease- and treatment-related burdens than HA patients without FVIII inhibitors. Emicizumab, a recently approved bispecific monoclonal antibody, mimics the function of FVIIIa by bridging FIXa and FX to restore effective hemostasis. Although emicizumab and FVIII show some functional similarities, several key differences influence the results of standard laboratory assays when conducted in the presence of emicizumab, and can result in a misleading interpretation of coagulation assays in emicizumab-treated patients. Here, we discuss current laboratory monitoring methods, including activated partial thromboplastin time, FVIII one-stage clotting assays, FVIII chromogenic assays, and global coagulations assays; address why these conventional methods may be inappropriate for monitoring of HA patients receiving emicizumab; and suggest alternative methods applicable to monitoring HA treatment in an evolving treatment landscape.


Assuntos
Anticorpos Biespecíficos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Técnicas de Laboratório Clínico/métodos , Fator VIII/metabolismo , Hemofilia A/diagnóstico , Coagulação Sanguínea , Testes de Coagulação Sanguínea , Compostos Cromogênicos , Fator VIII/genética , Hemofilia A/tratamento farmacológico , Hemostasia , Humanos , Tempo de Tromboplastina Parcial
13.
Int J Lab Hematol ; 41(4): 572-577, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31149782

RESUMO

INTRODUCTION: The formation of neutralizing antibodies (FVIII inhibitors) in haemophilia A patients is an immune response to the deficient factor. This process is multifactorial and includes environmental and genetic factors. Some genetic markers that play a decisive role in the immune response have been identified as risk factors for inhibitor development. OBJECTIVE: Our aim was to investigate the association between polymorphisms in several genes involved in the regulation of the immune response and inhibitor development in patients with haemophilia A in North China. METHODS: We analysed eight SNPs (MAPK9 rs4147385, CSF1R rs17725712, CD44 rs927335, STAT4 rs7574865, IKZF1 rs4917014, ETS1 rs6590330, BANK1 rs17266594 and rs10516487) by Snapshot SNP genotyping assays in 100 haemophilia A patients, including 29 with inhibitors and 71 without inhibitors. RESULTS: Our results demonstrated that the rs17725712 A allele and the AA homozygous genotype of CSF1R were more frequent in patients with inhibitors. The rs4147385 G allele in MAPK9 was also more frequent in the inhibitor cohort. CONCLUSION: We confirmed an association of CSF1R rs17725712 and MAPK9 rs4147385 with inhibitor development in haemophilia A patients in North China.


Assuntos
Alelos , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator VIII/antagonistas & inibidores , Proteína Quinase 9 Ativada por Mitógeno/genética , Polimorfismo de Nucleotídeo Único , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Anticorpos Neutralizantes/sangue , Grupo com Ancestrais do Continente Asiático , Autoanticorpos/sangue , China , Fator VIII/genética , Fator VIII/metabolismo , Hemofilia A/sangue , Hemofilia A/genética , Humanos , Masculino
14.
Thromb Haemost ; 119(9): 1489-1497, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31230343

RESUMO

BACKGROUND: We aimed to identify risk factors for residual pulmonary vascular obstruction after a first unprovoked pulmonary embolism (PE). METHODS: Analyses were based on data from the double-blind randomized "PADIS-PE" trial that included 371 patients with a first unprovoked PE initially treated during 6 uninterrupted months; all patients underwent baseline ventilation-perfusion lung scanning at inclusion (i.e., after 6 months of anticoagulation). Each patient's pulmonary vascular obstruction indexes (PVOIs) at PE diagnosis and at inclusion were centrally assessed. RESULTS: Among the 371 included patients, residual PVOI was available in 356 patients, and 150 (42.1%) patients had PVOI ≥ 5%. At multivariable analysis, age > 65 years (odds ratio [OR], 2.81, 95% confidence interval [CI], 1.58-5.00), PVOI ≥ 25% at PE diagnosis (OR, 3.53, 95% CI, 1.94-6.41), elevated factor VIII (OR, 3.89, 95% CI, 1.41-10.8), and chronic respiratory disease (OR, 2.18, 95% CI, 1.11-4.26) were independent predictors for residual PVOI ≥ 5%. Patients with ≥ 1 of these factors represented 94.5% (123 patients) of all patients with residual PVOI ≥ 5%. CONCLUSION: Six months after a first unprovoked PE, age > 65 years, PVOI ≥ 25% at PE diagnosis, elevated factor VIII, or chronic respiratory disease were found to be independent predictors for residual pulmonary vascular obstruction. CLINICAL TRIALS REGISTRATION: URL: http://www.controlled-trials.com. Unique identifier: NCT00740883.


Assuntos
Fatores Etários , Embolia Pulmonar/diagnóstico , Estenose de Veia Pulmonar/diagnóstico , Método Duplo-Cego , Fator VIII/metabolismo , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Valor Preditivo dos Testes , Prognóstico , Embolia Pulmonar/epidemiologia , Risco , Sensibilidade e Especificidade , Estenose de Veia Pulmonar/epidemiologia
15.
Acta Haematol ; 142(2): 71-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31085919

RESUMO

INTRODUCTION: Women with von Willebrand disease (VWD) are at a higher risk of bleeding, which might affect the health of mother and child during pregnancy and the intra- and postpartum periods. This retrospective cohort study evaluates changes in the coagulation parameters von Willebrand factor antigen (VWF:Ag), von Willebrand ristocetin cofactor (VWF:RCo), and Factor VIII activity (FVIII:C) during pregnancy in patients with VWD. In total, 44 pregnancies of 38 patients were assessed (VWD type 1 n = 32, type 2A n = 3, type 2B n = 1, type 2 subtype unidentified n = 2). The patients' median age at childbirth was 32 years (range 22-40). RESULTS: A significant increase in coagulation parameters was found in patients with VWD type 1 (VWF:Ag, VWF:RCo, and FVIII:C p = 0.000). In the third trimester, VWF:Ag and FVIII:C normalized in all patients with VWD type 1; in 3 patients VWF:RCo remained below the normal range. Patients with VWD type 2 showed a significant increase of VWF:Ag (p = 0.003) and FVIII:C (p = 0.011), and a non-significant increase of VWF:RCo (p = 0.097). In 4 of 9 pregnancies of patients with VWD type 2, all surveyed coagulation parameters normalized until the third trimester. CONCLUSION: For the majority of the observed patients, the von Willebrand parameters increased during pregnancy.


Assuntos
Coagulação Sanguínea , Fator VIII/metabolismo , Complicações Hematológicas na Gravidez/sangue , Terceiro Trimestre da Gravidez/sangue , Doenças de von Willebrand/sangue , Fator de von Willebrand/metabolismo , Adulto , Feminino , Humanos , Gravidez , Estudos Retrospectivos
16.
Haemophilia ; 25(3): 527-534, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31050100

RESUMO

INTRODUCTION: Acquired haemophilia A (AHA) is a rare autoimmune bleeding disorder caused by the presence of autoantibodies against coagulation factor VIII (FVIII). The mortality rate remains high. International recommendations define complete remission as undetectable inhibitor (<0.6 Bethesda Units [BU]) and normal FVIII activity (FVIII:C) that persists after immunosuppressive therapy stopped. For patients achieving remission, the risk of relapse reaches 20%. The risk factors for this relapse are not well known. AIM: In this study, we examined the accuracy of the FVIII/W ratio (FVIII:C/von Willebrand Factor Antigen (VWF:Ag) ratio) to predict relapse in 64 consecutive patients with AHA. RESULTS: In this cohort, all patients had a very low FVIII/W ratio at the time of diagnosis, and this value progressively increased in the first weeks of immunosuppressive treatment. In our study, 9/55 (14%) did not achieve complete remission. Twenty-seven patients were followed long enough (more than a year) to show that in the 22 patients who did not relapse, the FVIII/W ratio remained durably normalized. By contrast, in the five patients who relapsed during follow-up, we noted either no normalization of the FVIII/W ratio, or a secondary decrease to an abnormal value of <0.7 after initial normalization. In all patients who relapsed, the ratio was the first abnormal biological result to be observed, always preceding changes in the activated partial thromboplastin time (aPTT), FVIII:C and anti-FVIII reappearance. CONCLUSION: These data suggest that the FVIII/W ratio could be considered a sensitive biological marker to predict recovery and/or relapse in AHA.


Assuntos
Fator VIII/metabolismo , Hemofilia A/sangue , Hemofilia A/diagnóstico , Fator de von Willebrand/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Estudos Retrospectivos
17.
Haemophilia ; 25(3): e153-e158, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30993836

RESUMO

INTRODUCTION: BAY 81-8973 (Kovaltry® ) is a full-length, unmodified recombinant human factor VIII approved in China for prophylaxis and on-demand treatment in patients with haemophilia A. Limited access to FVIII prophylaxis in China has historically led to this population being undertreated. This subanalysis of LEOPOLD II investigated whether the efficacy and safety of BAY 81-8973 varied between Chinese and non-Chinese patients. AIM: To evaluate BAY 81-8973 efficacy and safety in Chinese patients. METHODS: LEOPOLD II enrolled males aged 12-65 years with severe haemophilia A who were receiving on-demand treatment. Patients were randomly assigned to receive BAY 81-8973 as low-dose prophylaxis (20-30 IU/kg twice-weekly), high-dose prophylaxis (30-40 IU/kg 3 times weekly) or on-demand for 1 year. RESULTS: Data were available from 23 Chinese and 57 non-Chinese patients; Chinese patients had a higher prestudy bleeding rate and were more likely to have target joints than non-Chinese patients. 74% of patients were assigned to prophylaxis. Annualized bleeding rates (ABRs) in Chinese and non-Chinese patients receiving prophylaxis were significantly lower compared to patients treated on-demand. Median ABRs for all bleeds in the last 6 months of the study were 2.0 and 1.0 for Chinese and non-Chinese patients, respectively, in the combined prophylaxis groups, and 61.3 and 58.5 in the on-demand group. A treatment-related adverse event occurred in 1 Chinese patient; no patients developed FVIII inhibitors. CONCLUSION: BAY 81-8973 prophylaxis was efficacious and well tolerated in Chinese patients with severe haemophilia A, with ABRs comparable to those in non-Chinese patients receiving prophylaxis.


Assuntos
Fator VIII/efeitos adversos , Fator VIII/uso terapêutico , Hemofilia A/tratamento farmacológico , Segurança , Adolescente , Adulto , Criança , China , Fator VIII/metabolismo , Fator VIII/farmacocinética , Hemofilia A/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
18.
Drug Des Devel Ther ; 13: 941-948, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30962676

RESUMO

Background: BAY 81-8973 (Kovaltry) is an unmodified full-length recombinant factor VIII (rFVIII) for treatment of hemophilia A. The BAY 81-8973 manufacturing process results in a product of enhanced purity with a consistently high degree of branching and sialylation of N-linked glycans. This study evaluated whether a relationship exists between N-linked glycosylation patterns of BAY 81-8973 and two other rFVIII (sucrose-formulated rFVIII [rFVIII-FS; Kogenate FS]) and antihemophilic factor (recombinant) plasma/albumin-free method (rAHF-PFM; Advate) and their pharmacokinetic (PK) characteristics. Materials and methods: N-linked glycans or terminal carbohydrates were enzymatically removed from immobilized BAY 81-8973, rFVIII-FS, and rAHF-PFM proteins and analyzed using high-performance liquid chromatography to determine the percentage of individual N-linked glycan structures and degree of sialylation of each structure. PK data were available from two separate phase 1 crossover studies in which the PK profile of BAY 81-8973 was compared with that of rFVIII-FS (n=26) and rAHF-PFM (n=18) in patients with severe hemophilia A who received a single 50 IU/kg dose of each product. Results: BAY 81-8973 and rFVIII-FS had increased N-linked glycan branching with higher levels of sialylation compared with rAHF-PFM. Levels of trisialylated glycans were 29.0% for BAY 81-8973 vs 11.5% for rFVIII-FS and 4.8%-5.5% for rAHF-PFM; tetrasialylated glycans were 12.0% vs 2.8% and 0.6%, respectively. Degree of sialylation was 96% for BAY 81-8973, 94% for rFVIII-FS, and 78%-81% for rAHF-PFM. Based on chromogenic assay results from the single-dose phase 1 PK studies, BAY 81-8973 half-life was 15% longer than that for rFVIII-FS and 16% longer than rAHF-PFM. Conclusion: Increased N-glycan branching and sialylation were seen for BAY 81-8973 vs rFVIII-FS and rAHF-PFM. Improved PK for BAY 81-8973 relative to rFVIII-FS and rAHF-PFM as seen in single-dose crossover PK studies might be related to this greater level of branching and sialylation, which can prolong the time BAY 81-8973 remains in the circulation.


Assuntos
Fator VIII/farmacocinética , Polissacarídeos/metabolismo , Ácidos Siálicos/metabolismo , Sacarose/farmacocinética , Adolescente , Adulto , Idoso , Criança , Estudos Cross-Over , Fator VIII/administração & dosagem , Fator VIII/metabolismo , Feminino , Glicosilação , Humanos , Masculino , Pessoa de Meia-Idade , Polissacarídeos/análise , Sacarose/administração & dosagem , Sacarose/metabolismo , Adulto Jovem
19.
Transfusion ; 59(S2): 1560-1567, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30980741

RESUMO

BACKGROUND: Cryoprecipitate's shelf life is limited due to concerns over decreased clotting factor activity and contamination with extended storage. Hemostatic characteristics of thawed cryoprecipitate stored up to 35 days at refrigerated and room temperatures were assessed. STUDY DESIGN AND METHODS: Pooled cryoprecipitate was thawed and aliquoted for storage at 1-6°C or 21-24°C. Samples were tested immediately after thawing and at 4 h, 24 h, 72 h, and weekly for 35 days. At each time point fibrinogen, factor VIII (FVIII), and von Willebrand factor (vWF) were assessed. Thrombin generation and rotational thromboelastometry (ROTEM) were also performed. Further, packed red cells, platelet concentrates, frozen plasma, and stored cryoprecipitate were combined (1:1:1:1) to simulate massive transfusion and analyzed by ROTEM. Day 35 samples were cultured for bacterial contamination. RESULTS: Precipitation was observed in refrigerated samples; however, these aggregates were easily resuspended upon warming in a 37°C water bath. No significant changes were observed in fibrinogen concentration or ROTEM at either temperature. FVIII and vWF declined significantly during storage. vWF, clot time, and thrombin generation were significantly better preserved with refrigeration. With simulated massive transfusion, fibrinogen function remained at or above the established range for whole blood at both storage temperatures. Bacterial contamination was not observed in cold stored or room temperature cryoprecipitate. CONCLUSION: The fibrinogen concentration and function of cryoprecipitate at extended storage durations are adequate for fibrinogen replacement in critical bleeding. These results support extension of the shelf life of cryoprecipitate when used for fibrinogen replacement.


Assuntos
Criopreservação , Fator VIII/metabolismo , Fibrinogênio/metabolismo , Hemostáticos/metabolismo , Transfusão de Sangue , Humanos , Tromboelastografia , Trombina/metabolismo , Fatores de Tempo , Fator de von Willebrand/metabolismo
20.
Thromb Haemost ; 119(6): 906-915, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30934104

RESUMO

Factor XIIIa (fXIIIa) is a transglutaminase that plays a crucial role in fibrin clot stabilization and regulation of fibrinolysis. It is known to bind to procoagulant platelets. In contrast, the zymogen fXIII interaction with platelets is not well characterized. We investigated the interaction of zymogen fXIII with activated platelet subpopulations. Confocal microscopy and flow cytometry using fluorescently labelled factors and antibodies. Phosphatidylserine (PS)-positive activated platelets bound 700 to 800 molecules/cell of fXIII at 100 nM, while both PS-negative activated platelets and resting platelets bound 200 to 400 molecules/cell. The binding was reversible, calcium-independent and linear within the fXIII concentration range of up to 1,000 nM. fXIII predominantly bound to the caps of procoagulant platelets and co-localized with fibrinogen. Exogenous fibrinogen promoted fXIII binding by activated PS-negative platelets; this effect was abolished by the integrin αIIbß3 antagonist monafram. The fXIII binding was 1.5- to 3-fold decreased for platelets from four patients with grey platelet syndrome, and was variable for platelets from six patients with Glanzmann's thrombasthenia. Strong platelet stimulation, fibrinogen and αIIbß3 play essential roles in fXIII binding, without any of them fXIII does not bind to platelets. The preferential binding in the cap-like structures might be important for increasing local fXIII concentration in platelet thrombi.


Assuntos
Afibrinogenemia/metabolismo , Plaquetas/fisiologia , Fator VIII/metabolismo , Fibrinogênio/metabolismo , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/metabolismo , Trombastenia/metabolismo , Afibrinogenemia/genética , Coagulação Sanguínea , Precursores Enzimáticos , Fibrinólise , Humanos , Ativação Plaquetária , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/genética , Ligação Proteica
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