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BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is applied in patients with respiratory or cardiopulmonary failure, but bleeding is a frequent complication contributing to the high mortality rates in this patient collective. A major factor predisposing patients to bleeding events is an acquired von Willebrand syndrome (aVWS). So far, specific treatment options for this phenomenon are lacking. In hereditary von Willebrand disease (VWD), treatment with recombinant or plasma-derived von Willebrand factor (rVWF or pVWF) is common practice. Closure time measured by the Platelet Function Analyser-200 (PFA-200) is an established assay to detect defects in primary hemostasis and the method is useful to monitor the effect of hemostatic therapy. The aim of this study was to assess the effect of recombinant (rVWF) vs. plasma-derived von Willebrand factor (pVWF) on closure times measured by PFA in blood obtained from ECMO patients with aVWS. METHODS: Blood was sampled from thirteen patients receiving extracorporeal membrane oxygenation and three patients with hereditary VWD. Diagnosis of aVWS was made by conventional coagulation parameters and by multimeric structure analysis. PFA analysis of blood spiked with rVWF or pVWF was performed. RESULTS: Thirteen patients receiving ECMO were recruited. Ten patients survived and three patients suffered major bleeding complications. PFA closure times in ECMO patients with aVWS spiked with rVWF were significantly shorter at all concentrations than with pVWF (e.g., rVWF vs. pVWF: 1 U/ml: 150.4 ± 21.7 s vs. 263.8 ± 11.7 s; 4 U/ml: 97.8 ± 9.8 s vs. 195.8 ± 15.4 s, p<0.001). PFA closure times were also significantly shorter in three patients with hereditary VWD treated with rVWF compared to pVWF (e.g., 1 U/ml rVWF vs. pVWF: 73.7±1.33 s vs. 231.3±43.4 s, p<0.01) CONCLUSION: In summary, this study shows that rVWF compared to pVWF more effectively reduced PFA closures times in blood samples of ECMO patients with aVWS. Higher doses of VWF are needed to normalize PFA closure time in blood samples of patients with ECMO-induced aVWS compared to hereditary VWD. These data support the use of PFA-200 to monitor hemostatic effects in a future clinical trial involving ECMO patients with aVWS.
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Acquired hemophilia A (AHA) is due to autoantibodies against coagulation factor VIII (FVIII) and most often presents with unexpected bleeding. In contrast to congenital hemophilia, the patient's residual FVIII activity does not seem to correlate with the risk of bleeding as suggested from previous studies. Risk factors for bleeding have not been described. We used data from the prospective GTH-AH 01/2010 study to assess the risk of bleeding and the efficacy of hemostatic therapy. FVIII activity was measured at baseline and weekly thereafter. Bleeding events were assessed by treating physicians. A total of 289 bleeds were recorded in 102 patients. There were 141 new bleeds observed starting after day 1 in 59% of the patients, with a mean rate of 0.13 bleed per patient-week in weeks 1 to 12, or 0.27 bleed per patient-week before achieving partial remission. Weekly measured FVIII activity was significantly associated with the bleeding rate, but only achieving FVIII activity ≥50% abolished the risk of bleeding. A good World Health Organization performance status assessed at baseline (score 0 vs higher) was associated with a lower bleeding rate. Hemostatic treatment was reportedly effective in 96% of bleeds. Thus, the risk of new bleeds after a first diagnosis of AHA remains high until partial remission is achieved, and weekly measured FVIII activity may aid in assessing the individual risk of bleeding. These results will help to define future strategies for prophylaxis of bleeding in AHA.
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Autoanticorpos/sangue , Inibidores dos Fatores de Coagulação Sanguínea/sangue , Fator VIII , Hemofilia A , Hemorragia , Hemostáticos/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Fator VIII/antagonistas & inibidores , Fator VIII/metabolismo , Feminino , Hemofilia A/sangue , Hemofilia A/tratamento farmacológico , Hemofilia A/epidemiologia , Hemorragia/sangue , Hemorragia/tratamento farmacológico , Hemorragia/epidemiologia , Hemostáticos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: We conducted a multicenter evaluation of a new one-stage factor VIII (FVIII) assay (Roche Diagnostics), intended for the quantitative assessment of FVIII activity. We evaluated the analytical performance of the FVIII assay on the cobas t 711 analyzer. METHODS: Experiments performed at three laboratories used 3.2% citrated residual or commercially purchased plasma samples. Five human plasma pools and two controls were used to determine assay within-run and within-laboratory precision, and total reproducibility; coefficients of variation (CVs) and/or standard deviations (SDs) were calculated. Lot-to-lot variability and method comparison (vs Coagulation FVIII Deficient Plasma/Dade Actin FS Activated PTT reagent/Standard Human Plasma Calibrator on the Sysmex CS-5100 analyzer; Siemens Healthineers) were evaluated by Passing-Bablok and Deming regression, respectively, and Pearson's r calculated. Assay-specific reference range was determined using 199 fresh plasma samples from healthy adults, not receiving anticoagulants. RESULTS: Across sites, SDs for repeatability were 0.016-0.046 for samples with ≤1.0 international units (IU)/dL FVIII activity; CVs were 0.9%-3.8% for samples with >1.0 IU/dl activity. Among samples with mean FVIII activity 0.344-133 IU/dl, good intermediate precision (SD 0.020 for samples with 0.344 IU/dl activity; CV 1.8%-4.7%) and good total reproducibility (CV 2.0%-13.3%) were observed. The FVIII assay showed excellent lot-to-lot variability (Pearson's r = .999) and good correlation with the comparator assay (Pearson's r = .993-.996). The reference range for FVIII activity was 82.2-218.0 IU/dl. CONCLUSION: The one-stage FVIII assay demonstrated robust analytical performance on the cobas t 711 analyzer, supporting its use in routine laboratory practice.
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Fator VIII , Hemofilia A , Adulto , Testes de Coagulação Sanguínea , Hemofilia A/diagnóstico , Humanos , Valores de Referência , Reprodutibilidade dos TestesRESUMO
Dabigatran is a direct thrombin inhibitor and a non-vitamin-K-antagonizing oral anticoagulant, approved for the prevention of stroke and systemic embolization in atrial fibrillation. Idarucizumab is a humanized monoclonal antibody that was recently approved for antagonizing the anticoagulant effects of dabigatran. Here, we report the use of idarucizumab in four acute stroke patients treated with dabigatran in order to enable intravenous thrombolysis in three patients and emergent trepanation in one patient with space occupying subdural hematoma. Since experience on the optimal management of acute stroke patients under medication with dabigatran and on the use of idarucizumab is currently limited, we propose an approach for laboratory testing and fast administration of intravenous thrombolysis and neurosurgery based on our experience.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Dabigatrana/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Antitrombinas/uso terapêutico , Interações Medicamentosas , Hematoma Subdural , Humanos , Acidente Vascular Cerebral/cirurgia , Terapia Trombolítica , TrepanaçãoRESUMO
Acquired hemophilia A (AHA) is caused by autoantibodies against factor VIII (FVIII). Immunosuppressive treatment (IST) results in remission of disease in 60% to 80% of patients over a period of days to months. IST is associated with frequent adverse events, including infections as a leading cause of death. Predictors of time to remission could help guide IST intensity but have not been established. We analyzed prognostic factors in 102 prospectively enrolled patients treated with a uniform IST protocol. Partial remission (PR; defined as no active bleeding, FVIII restored >50 IU/dL, hemostatic treatment stopped >24 hours) was achieved by 83% of patients after a median of 31 days (range 7-362). Patients with baseline FVIII <1 IU/dL achieved PR less often and later (77%, 43 days) than patients with ≥1 IU/dL (89%, 24 days). After adjustment for other baseline characteristics, low FVIII remained associated with a lower rate of PR (hazard ratio 0.52, 95% confidence interval 0.33-0.81, P < .01). In contrast, PR achieved on steroids alone within ≤21 days was more common in patients with FVIII ≥1 IU/dL and inhibitor concentration <20 BU/mL (odds ratio 11.2, P < .0001). Low FVIII was also associated with a lower rate of complete remission and decreased survival. In conclusion, presenting FVIII and inhibitor concentration are potentially useful to tailor IST in AHA.
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Hemofilia A , Imunossupressores/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/efeitos adversos , Fator VIII/análise , Fator VIII/imunologia , Feminino , Hemofilia A/diagnóstico , Hemofilia A/mortalidade , Hemofilia A/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Indução de Remissão , Análise de Sobrevida , Resultado do TratamentoRESUMO
Background: The Heartmate 3 (HM 3) is a left ventricular assist device featuring less shear stress, milder acquired von Willebrand syndrome, and fewer bleeding incidences than its predecessor the Heartmate II (HM II). The novel surface coating of the HM 3 suggests less contact activation of plasmatic coagulation. We hypothesized that patients with HM 3 exhibit fewer aberrations in their thrombin potential than patients with HM II. We compared these results with the thrombin potential of patients with heart transplantation (HTX). Methods: Thrombin generation in plasma samples of patients with HM II (n = 16), HM 3 (n = 20), and HTX (n = 13) was analyzed 3 days after implantation/transplantation and after long-term support (3-24 months) with HM II (n = 16) or HM 3 (n = 12) using calibrated automated thrombography. Heparin in postoperative samples was antagonized with polybrene. Results: Three days postoperatively HM II patients exhibited a lower endogenous thrombin potential (ETP) than HM 3 and HTX patients (HM II: 947 ± 291 nM*min; HM 3: 1231 ± 176 nM*min; HTX: 1376 ± 162 nM*min, p < 0.001) and a lower velocity index of thrombin generation (HM II: 18.74 ± 10.90 nM/min; HM 3: 32.41 ± 9.51 nM/min; HTX: 37.65 ± 9.41 nM/min, p < 0.01). Subtle differences in the thrombin generation profiles remained in HM II and HM 3 patients under long-term support (Velocity Index: HM II: 38.70 ± 28.46 nM/min; HM 3: 73.32 ± 32.83 nM/min, p < 0.05). Prothrombin fragments 1 + 2 were higher in HM II than in HM 3 patients (HM II: 377.7 ± 208.4 pM; HM 3: 202.1 ± 87.7 pM, p < 0.05) and correlated inversely with the ETP (r = -0.584, p < 0.05). Conclusion: We observed a more aberrant thrombin generation in HM II than in HM 3 despite comparable anticoagulation and routine parameters. A trend toward lower values was still observable in HM 3 compared to HTX patients. Calibrated automated thrombography may be a good tool to monitor the coagulation state of these patients and guide anticoagulation in the future.
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Patients with ventricular assist devices (VADs) and extracorporeal membrane oxygenation (ECMO) suffer from an increased risk for thromboembolic events as well as for hemorrhages. High shear stress in the mechanical device results in acquired von Willebrand syndrome (AVWS), characterized by a loss of high-molecular-weight multimers of von Willebrand factor (VWF) leading to an increased bleeding risk. Onset of AVWS occurs within hours, persists during the whole period of mechanical support, and subsides rapidly after explantation. Patients with the older HeartMate II exhibit more severe AVWS than those with the newer HeartMate III, thanks to lower shear stress in the latter. All ECMO and VAD patients exhibit thrombocytopathia and often thrombocytopenia which further increases the bleeding risk. Etiological models for AVWS are increased cleavage by the metalloproteinase ADAMSTS13, mechanical destruction of VWF, and shear-induced VWF binding to platelets. Platelet secretion defects may be caused by transient platelet activation leading to degranulation. AVWS can be diagnosed by detection of VWF multimers using gel-electrophoresis and functional assays of varying sensitivity (VWF ristocetin cofactor activity, VWF activity, VWF collagen binding). Platelet dysfunction is monitored using light transmission aggregometry and secretion defects are detectable using flow cytometry. Modest use of anticoagulants and a target-controlled therapy based on VWF parameters and other coagulation and platelet parameters are shown to be beneficial in this patient group. Persistent hemorrhages may be controlled with tranexamic acid and platelet concentrates. Prompt weaning from the device, when indicated, is the best therapeutic option to prevent recurrent bleeding.
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Transtornos Plaquetários/sangue , Oxigenação por Membrana Extracorpórea/métodos , Doenças de von Willebrand/complicações , Doenças de von Willebrand/terapia , Feminino , Humanos , MasculinoRESUMO
Acquired haemophilia is an autoimmune disorder characterised by autoantibody formation against coagulation factor VIII. Immunosuppressive treatments including steroids, cytotoxic drugs, rituximab or combinations thereof have been used to eradicate autoantibodies. Very few prospective studies exist evaluating the use of these treatments. Here, we performed a survey among 73 physicians from 57 haemophilia treatment centres in order to describe current practice patterns and critical issues for future research in acquired haemophilia. The results demonstrate a high diversity of first- and second-line treatments. Factors influencing treatment decision were underlying disorder, severity of bleeding and inhibitor titre. Frequently used first-line treatments were steroids plus cyclophosphamide (44%) and steroids alone (11%). Second-line treatment was most often rituximab (30%), with or without steroids and/or cyclophosphamide. Most participants indicated to change from first- to second-line treatment after 4 weeks in case of failure to obtain partial remission (31%), continued bleeding (40%) or continued severe bleeding requiring bypass treatment (59%). Immunoadsorption was preferred for first- and second-line treatment by 10% and 9% of participants, respectively. These results highlight critical issues in the field. Open questions and directions for future research are discussed.
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Hemofilia A/tratamento farmacológico , Imunossupressores/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Áustria , Autoanticorpos/sangue , Ciclofosfamida/uso terapêutico , Coleta de Dados , Alemanha , Hemofilia A/etiologia , Humanos , Técnicas de Imunoadsorção , Padrões de Prática Médica , Indução de Remissão , Rituximab , Esteroides/uso terapêutico , Suíça , Falha de TratamentoRESUMO
The use of plants as production platforms for pharmaceutical proteins has been on the rise for the past two decades. The first marketed plant-made pharmaceutical, taliglucerase alfa against Gaucher's disease produced in carrot cells by Pfizer/Protalix Biotherapeutics, was approved by the US Food and Drug Administration (FDA) in 2012. The advantages of plant systems are low cost and highly scalable biomass production compared to the fermentation systems, safety compared with other expression systems, as plant-based systems do not produce endotoxins, and the ability to perform complex eukaryotic post-translational modifications, e.g., N-glycosylation that can be further engineered to achieve humanized N-glycan structures. Although bleeding disorders affect only a small portion of the world population, costs of clotting factor concentrates impose a high financial burden on patients and healthcare systems. The majority of patients, â¼75% in the case of hemophilia, have no access to an adequate treatment. The necessity of large-scale and less expensive production of human blood coagulation factors, particularly factors associated with rare bleeding disorders, may be an important area for plant-based systems, as coagulation factors do not fit into the industry-favored production models. In this review, we explore previous studies on recombinant production of coagulation Factor II, VIII, IX, and XIII in different plant species. Production of bioactive FII and FIX in plants was not achieved yet due to complex post-translational modifications, including vitamin K-dependent γ-carboxylation and propeptide removal. Although plant-made FVIII and FXIII showed specific activities, there are no follow-up studies like pre-clinical/clinical trials. Significant progress has been achieved in oral delivery of bioencapsulated FVIII and FIX to induce immune tolerance in murine models of hemophilia A and B, resp. Potential strategies to overcome bottlenecks in the production systems are also addressed in this review.
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OBJECTIVE: Outcomes after ventricular assist device (VAD) implantation have significantly improved during the last decade. However, bleeding episodes remain a serious complication of VAD support. This cannot be explained by the individual anticoagulation regimen alone in several cases, but may be symptomatic of acquired von Willebrand disease (VWD). The leading finding in acquired VWD (AVWD) is the loss of large multimers which results in diminished binding to collagen and to the platelets. We, therefore, analysed patients with two VAD types for laboratory parameters of VWD and compared them with patients after heart transplantation (HTX). MATERIALS AND METHODS: Seven patients with a HeartMate II left-ventricular assist device and five patients who received a Thoratec biventricular assist device were included in this study. Eight HTX recipients served as controls. Analysis included international normalized ratio (INR), partial thromboplastin time (PTT), platelet count, von Willebrand factor (VWF) antigen, collagen binding capacity, ristocetin cofactor activity, the ratios of the latter two to the VWF antigen and presence of large VWF multimers. RESULTS: The VAD and HTX groups did not differ with regard to age or time-point of analysis after surgery. INR and number of platelets were comparable in both groups, PTT was prolonged in VAD patients. Both VAD and HTX patients had elevated but comparable amounts of VWF antigen. However, large multimers were missing in all of 10 tested VAD patients. In contrast, five of six tested HTX recipients displayed normal multimer pattern. Indeed, collagen binding capacity and ristocetin cofactor activity (which measures binding of VWF to platelets) were lower in VAD patients compared to HTX recipients. Impaired coagulation associated with VADs was also reflected by the diminished ratios of collagen binding capacity and ristocetin cofactor activity to VWF antigen. A pathologic collagen binding ratio was found in all 10 tested VAD patients and one of the eight HTX patients, a reduced ristocetin cofactor activity ratio in 10 of 12 VAD and one of eight HTX patients. CONCLUSION: Non-surgical postoperative bleeding after VAD implantation could be explained by an AVWD. Several pharmacologic treatment options (tranexamic acid, desmopressin, VWF-factor VIII concentrate, recombinant factor VIIa) may arise from our data. Improved VAD design could prevent this problem in the future.
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Coração Auxiliar/efeitos adversos , Hemorragia/etiologia , Desenho de Prótese , Disfunção Ventricular/cirurgia , Doenças de von Willebrand/complicações , Fator de von Willebrand/metabolismo , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Disfunção Ventricular/complicaçõesRESUMO
INTRODUCTION: New laboratory methods to measure haemostatic function require careful assessment before routine use. We evaluated the analytical performance of four new coagulation assays for the measurement of fibrinogen by Clauss assay, prothrombin time-derived fibrinogen, thrombin time and D-dimer levels. METHODS: The four assays were evaluated on the cobas t 711 and cobas t 511 analysers at four centres in Europe. Analytical performance and method comparisons with other commercially available assays were performed according to Clinical and Laboratory Standards Institute guidelines (EP09-A3, EP05-A3) using residual anonymized human sodium citrate (3.2% [0.109M]) plasma samples. Lot-to-lot variability and the equivalency of each assay on the cobas t 711 and cobas t 511 analysers were also assessed. RESULTS: Overall, coefficients of variance were ≤4.1% and ≤8.6% for within-run precision and total reproducibility, respectively. Method comparison experiments showed good or acceptable agreement for each assay compared with their respective comparator method, and equivalency was demonstrated for the two cobas t platforms (Pearson's correlation coefficient ≥0.991). A high level of consistency was observed between lots for all four assays (Pearson's correlation coefficient ≥0.994). CONCLUSION: This multicentre study demonstrates excellent analytical performance for four new coagulation assays on the cobas t 711 and cobas t 511 analysers.
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Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Tempo de Protrombina/métodos , Kit de Reagentes para Diagnóstico , Feminino , Humanos , Masculino , Tempo de Tromboplastina Parcial/métodosRESUMO
BACKGROUND: The number of implanted ventricular assist devices (VADs) has increased significantly recently. Bleeding, the most frequent complication, cannot be solely attributed to anticoagulation therapy. Acquired von Willebrand syndrome (AVWS) caused by increased shear stress is frequent in VAD patients and can increase the bleeding risk. The HeartMate III (HM III) is a novel left VAD featuring potential improvements over the HeartMate II. METHODS AND RESULTS: In this study, we investigated the prevalence and onset of AVWS in 198 VAD patients. To our knowledge, this is the largest cohort of VAD patients whose longitudinal data on AVWS have been collected. We also analyzed whether AVWS is less severe in HM III patients than in HeartMate II patients. Because platelet dysfunction can raise the bleeding risk, we investigated platelet function in a subset of patients. In total, 198 VAD patients and 60 patients with heart transplants as controls were included in this study. The ratio of von Willebrand factor collagen binding capacity to von Willebrand factor:antigen, multimer analyses, and platelet function (especially secretion of α- and δ-granules) were investigated. All 198 VAD patients developed AVWS. As soon as the VAD was explanted, the AVWS disappeared within hours. AVWS was less severe in the HM III patients than in the HeartMate II patients. The HM III patients had fewer bleeding symptoms. In addition, VAD patients exhibited a platelet α- and δ-granule secretion defect. CONCLUSIONS: AVWS develops in VAD patients and may increase the bleeding risk. The HM III device causes less severe AVWS. Platelet secretion defects should be investigated in VAD patients because they also raise the bleeding risk. CLINICAL TRIAL REGISTRATION: https://www.drks.de/drks_web. Unique identifier: DRKS00000649.
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Plaquetas/metabolismo , Insuficiência Cardíaca/terapia , Coração Auxiliar/efeitos adversos , Hemorragia/epidemiologia , Função Ventricular Esquerda , Doenças de von Willebrand/epidemiologia , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Alemanha/epidemiologia , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/fisiopatologia , Hemorragia/sangue , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Testes de Função Plaquetária , Prevalência , Fatores de Risco , Via Secretória , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Doenças de von Willebrand/sangueRESUMO
INTRODUCTION: New methods for coagulation tests require careful assessment before routine use. We evaluated the analytical performance of five new coagulation assays for measuring prothrombin time (PT) and activated partial thromboplastin time (aPTT). METHODS: PT Rec, PT Owren, aPTT, aPTT Lupus and aPTT Screen assays (Roche Diagnostics) were evaluated on cobas t 711 and cobas t 511 analysers (Roche Diagnostics) at four European centres. Analytical performance and method comparisons with relevant commercially available assays were performed to Clinical Laboratory Standards Institute guidelines using residual anonymized samples. Lot-to-lot comparison and equivalency of the cobas t analysers were also assessed; reference ranges were determined using samples from apparently healthy volunteers. RESULTS: Overall, coefficients of variation were ≤1.3% for within-run precision and ≤6.3% for total reproducibility across all sites. Deming regression analyses showed good agreement between each assay (cobas t 711) and respective comparator method (Pearson's r: 0.964-0.999, n > 120 samples/assay/site). Passing-Bablok regression analyses demonstrated equivalence of the two cobas t platforms for use with each assay (Pearson's r ≥ 0.995). Lot-to-lot consistency was high for all assays and comparisons (Pearson's r ≥ 0.998). Reference ranges (2.5th-97.5th percentiles; n = 200 samples/assay) in seconds were 8.4-10.6 (PT Rec), 18.2-27.2 (PT Owren), 23.6-30.6 (aPTT), 24.1-31.7 (aPTT Lupus) and 23.9-33.2 (aPTT Screen). CONCLUSION: Based on the excellent analytical performance and good agreement with relevant comparator methods, the five coagulation assays on the novel cobas t 711 and cobas t 511 analysers are suitable for routine use in core laboratories.
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Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Tempo de Protrombina/métodos , Kit de Reagentes para Diagnóstico , Feminino , Humanos , Masculino , Tempo de Tromboplastina Parcial/métodosRESUMO
Women with a history of venous thromboembolism (VTE), thrombophilia or both may be at increased risk of thrombosis during pregnancy, but the optimal management strategy is not well defined in clinical guidelines because of limited trial data. A strategy of risk assessment and heparin prophylaxis was evaluated in pregnant women at increased risk of VTE. In a prospective trial (Efficacy of Thromboprophylaxis as an Intervention during. Gravidity [EThIG]), 810 pregnant women were assigned to one of three management strategies according to pre-defined risk factors related to history of VTE and thrombophilic profile. Low-risk women (group I), received 50-100 IU dalteparin/kg body weight/day for 14 days postpartum, or earlier when additional risk factors occurred. Women at high (group II) or very high risk (group III) received dalteparin from enrollment until six weeks postpartum (50-100 IU and 100-200 IU/kg/day, respectively). Objectively confirmed, symptomatic VTE occurred in 5/810 women (0.6%; 95% confidence interval [CI], 0.2 to 1.5%) (group I, 0 of 225; II, 3/469; III, 2/116). The rate of serious bleeding was 3.0% (95 % CI, 1.9 to 4.4%); 1.1% (95 % CI, 0.5 to 2.2%) was possibly dalteparin-related. There was no evidence of heparin-induced thrombocytopenia, one case of osteoporosis, and rates of miscarriage and stillbirth were similar to previous, retrospective studies. Risk-stratified heparin prophylaxis was associated with a low incidence of symptomaticVTE and few clinically important adverse events. Antepartum heparin prophylaxis is, therefore, warranted in pregnant women with idiopathic thrombosis or symptomatic thrombophilia.
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Anticoagulantes/uso terapêutico , Dalteparina/uso terapêutico , Seleção de Pacientes , Complicações Cardiovasculares na Gravidez/prevenção & controle , Trombofilia/complicações , Tromboembolia Venosa/prevenção & controle , Adulto , Anticoagulantes/administração & dosagem , Anticoagulantes/efeitos adversos , Dalteparina/administração & dosagem , Dalteparina/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Alemanha/epidemiologia , Hemorragia/induzido quimicamente , Humanos , Incidência , Injeções Subcutâneas , Gravidez , Complicações Cardiovasculares na Gravidez/epidemiologia , Complicações Cardiovasculares na Gravidez/etiologia , Resultado da Gravidez , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Prevenção Secundária , Trombofilia/tratamento farmacológico , Resultado do Tratamento , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologiaRESUMO
Objectives: Impaired binding of Von Willebrand factor (VWF) to platelets and to collagen due to acquired Von Willebrand syndrome (AVWS) is associated with support from a ventricular assist device (VAD) and can contribute to bleeding tendencies in patients with VADs. The onset of AVWS has been shown to occur immediately after VAD implantation. Our aim was to determine long-term data on AVWS in VAD patients. Methods: We analysed 278 data sets of 74 patients on HeartMate II (HMII) support for 3-80 months after implantation (11.2 ± 12.1, median 6.3 months.). Ristocetin cofactor activity (VWF:RCo), collagen binding capacity (VWF:CB), VWF antigen (VWF:Ag) and the ratios of VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag were determined. Further, the presence of high molecular weight (HMW) multimers of VWF was investigated. Results: Abnormally low values of VWF:RCo/VWF:Ag and VWF:CB/VWF:Ag were found in 69% and 97% of blood samples, respectively. Only ten of 181 multimer analyses showed a normal pattern, and HMW multimers were present in both specimens in only one of the 74 patients. No significant changes in these parameters were observed over time. The VWF:CB/VWF:Ag ratio correlated with the multimer patterns, whereas the VWF:RCo/VWF:Ag ratio seemed to be less sensitive for AVWS. Conclusions: Our data indicate that AVWS is a typical phenomenon in patients with VAD support and that there are no time-dependent changes in these parameters apparent in most patients on long-term support with HMII.
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Coração Auxiliar/efeitos adversos , Doenças de von Willebrand/etiologia , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Colágeno/sangue , Feminino , Seguimentos , Hemorragia/sangue , Hemorragia/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto Jovem , Doenças de von Willebrand/sangue , Fator de von Willebrand/metabolismoRESUMO
OBJECTIVE: To report a case of a patient with multiple cerebral cavernous malformations (CCM). OBSERVATION: A 22year old man with mild von Willebrand disease presented with two occipital CCM, one of them with acute hemorrhage. Genetic testing for CCM1-3 did not reveal a mutation. Over a period of 54months, the patient suffered 26 new CCM hemorrhages despite multiple treatment attempts including thalidomide, simvastatin and hemostatic factors. Only after initiation of propranolol, which has already been successfully used in three children with giant cerebral cavernoma, the occurrence of new CCM with hemorrhages was completely stopped already at dose of 30mg daily - now for a period of 26months and without any other medications. CONCLUSION: This case suggests a protective role for propranolol in preventing the occurrence of new cerebral cavernoma with hemorrhages in adults with multiple CCM.
Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Propranolol/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Progressão da Doença , Seguimentos , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Masculino , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND/OBJECTIVES: Novel (or non-vitamin K antagonist) oral anti-coagulants (NOACs) are antagonists of coagulation factors (F) Xa (rivaroxaban) or IIa (dabigatran), and their non-inferiority compared with vitamin K antagonists has been demonstrated in patients with non-valvular atrial fibrillation. However, it is still not fully understood if and how dabigatran and rivaroxaban impact platelet function. This observational study aimed to assess platelet function in patients receiving dabigatran or rivaroxaban. METHODS/RESULTS: This was a single centre, observational study quantifying platelet aggregation in 90 patients treated with NOACs by multiple electrode aggregometry. The thrombin receptor activating peptide (TRAP)-induced platelet aggregation was significantly higher in 35 patients receiving dabigatran (d) compared with control (c) patients (d 108±31 vs. c 85±30arbitrary units [AU]∗min, p<0.001). Patients receiving rivaroxaban (r) showed no differences compared with the control group (r 88±32 vs. c 85±30AU∗min, p=0.335). In intraindividual time courses of 16 patients, a significantly higher aggregation was found after the administration of dabigatran (before vs. after; 83±29 vs. 100±31AU∗min, p=0.009). CONCLUSION: In this observational study, the TRAP-induced platelet aggregation was enhanced in cardiovascular patients receiving dabigatran. This might be explained by a change in the expression profile of thrombin receptors on the surface of platelets. Rivaroxaban had no influence on platelet aggregation.
Assuntos
Antitrombinas/uso terapêutico , Fibrilação Atrial/tratamento farmacológico , Plaquetas/efeitos dos fármacos , Dabigatrana/uso terapêutico , Agregação Plaquetária/efeitos dos fármacos , Receptores de Trombina/metabolismo , Rivaroxabana/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/farmacologia , Dabigatrana/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/tratamento farmacológico , Rivaroxabana/farmacologia , Trombose Venosa/tratamento farmacológicoRESUMO
OBJECTIVES: Neuron-specific enolase (NSE) is used as a diagnostic tool in neuropathies, cerebral diseases or traumata and for some tumours. Furthermore, it is also expressed by erythrocytes and platelets and has been linked to haemolysis ex vivo as a laboratory issue. Chronic haemolysis is frequently associated with mechanical circulatory support by ventricular assist device (VAD) or total artificial heart (TAH). Therefore, we compared NSE with indicators of haemolysis in VAD and TAH patients. METHODS: We included 599 data sets of 97 patients who underwent VAD or TAH implantation. NSE, haptoglobin (HAPT), haemopexin (HPX), free haemoglobin (frHB), lactate dehydrogenase activity (LDH), platelet counts and total bilirubin (TBIL) in plasma were analysed. Further, all major cerebral events were assessed. RESULTS: NSE correlated to frHB (rs = 0.553) and to LDH (rs = 0.695). An inverse correlation was found with HAPT (rs = -0.484) and HPX (rs = -0.398). Thirty-two patients suffered neurological events. Within the time frame of 1 day before to 4 days after a neurological event, correlations of NSE to HAPT (rs = -0.540) and HPX (rs = -0.611) in negative and to frHB (rs = 0.757), LDH (rs = 0.862) and TBIL (rs = 0.549) in positive direction were established (all P < 0.05). Furthermore, haemolysis was graded into three groups for severe, moderate or no or only slight haemolysis. NSE values differed correspondingly between these groups (P < 0.001). CONCLUSION: NSE correlates to laboratory parameters indicative of haemolysis in VAD and TAH patients. Our data suggest an influence of intravascular haemolysis on NSE. Therefore, the parameter should be used with caution when it is used to assess cerebral damage.
Assuntos
Coração Artificial/efeitos adversos , Hemólise/fisiologia , Fosfopiruvato Hidratase/sangue , Bilirrubina/sangue , Haptoglobinas/análise , Hemoglobinas/análise , Hemopexina/análise , Humanos , L-Lactato Desidrogenase/sangue , Contagem de Plaquetas , Estudos RetrospectivosRESUMO
OBJECTIVES: Unexplained bleeding events are a severe complication in patients with left ventricular assist devices (LVADs). Platelet dysfunction and acquired von Willebrand syndrome (AVWS) may contribute to bleeding tendencies. Yet, comprehensive data with respect to platelet function and AVWS in LVAD patients in terms of bleeding events are scarce. METHODS: Thirty-nine HeartMate II patients were included in this study. Data of at least two time points were available for each patient. Platelet function was analysed via light transmission aggregometry in 19 patients without LVAD, 28 in early (≤14 days) and 30 in late postimplantation states (≥30 days). Von Willebrand factor (VWF) antigen, VWF collagen binding capacity and VWF multimeric analyses were performed in 26 patients without LVAD, 39 in early and 33 in late postimplantation states to diagnose AVWS. Bleeding complications were recorded for 39 patients in the early and 33 in the late postoperative period. RESULTS: Platelet dysfunction was detectable in 18 of 19 without LVAD and in all patients following LVAD implantation. Platelet aggregation values did not change over time (without-early, P = 0.27, n = 14; early-late, P = 0.17, n = 21). AVWS was not diagnosed in patients without LVAD, except for one. On LVAD, 33 of 39 patients had AVWS in the early and all in the late period (n = 33). Bleeding events occurred in 44% of patients in the early and in 64% of patients in the late period. CONCLUSIONS: According to our data, platelet aggregation is often impaired in LVAD patients even without an implanted LVAD. Additionally, appearance of AVWS seems to be closely linked to LVAD implantation.