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[This corrects the article DOI: 10.3389/fcell.2023.1115622.].
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BACKGROUND: rVIII-SingleChain is a recombinant factor VIII (FVIII) with increased binding affinity to von Willebrand factor compared with other FVIII products. rVIII-SingleChain is indicated for the treatment and prevention of bleeding episodes in patients with hemophilia A. OBJECTIVES: To collect real-world evidence data from patients treated with rVIII-SingleChain to confirm the efficacy and safety established in the clinical trial program and carry out a population pharmacokinetic (PK) analysis. METHODS: This interim analysis includes data, collected between January 2018 - September 2021, from patients treated with rVIII-SingleChain prophylaxis at French Hemophilia Treatment centers. Data on annualized bleeding rates, dosing frequency, and consumption before and after switching to rVIII-SingleChain were recorded. A population PK analysis was also conducted to estimate PK parameters. RESULTS: Overall, 43 patients switched to prophylaxis with rVIII-SingleChain either from a previous prophylaxis regimen or from on-demand treatment. Following the switch to rVIII-SingleChain, patients maintained excellent bleed control. After switching to rVIII-SingleChain, most patients maintained or reduced their regimen. Interestingly, a majority of patients treated >2 ×/weekly with a standard half-life FVIII reduced both injection frequency and FVIII consumption with rVIII-SingleChain. A PK analysis revealed a lower clearance of rVIII-SingleChain (1.9 vs. 2.1 dL/h) and a longer half-life both in adolescents/adults (n = 28) and pediatric (n = 6) patients (15.5 and 11.9 hours, respectively vs. 14.5 and 10.3 hours) than previously reported. CONCLUSIONS: Patients who switched to rVIII-SingleChain prophylaxis demonstrated excellent bleed control and a reduction in infusion frequency. A population PK analysis revealed improved PK parameters compared with those reported in the clinical trial.
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Hemofilia A , Hemostáticos , Adulto , Adolescente , Humanos , Niño , Hemofilia A/tratamiento farmacológico , Factor VIII/farmacocinética , Factor de von Willebrand/efectos adversos , Hemorragia/inducido químicamente , Hemostáticos/efectos adversos , SemividaRESUMEN
BACKGROUND: The disease-causative variant remains unidentified in approximately 0.5% to 2% of hemophilia B patients using conventional genetic investigations, and F9 deep intronic variations could be responsible for these phenotypes. OBJECTIVES: This study aimed to characterize deep intronic variants in hemophilia B patients for whom genetic investigations failed. METHODS: We performed whole F9 sequencing in 17 genetically unsolved hemophilia B patients. The pathogenic impact of the candidate variants identified was studied using both in silico analysis (MaxEntScan and spliceAI) and minigene assay. RESULTS: In total, 9 candidate variants were identified in 15 patients; 7 were deep intronic substitutions and 2 corresponded to insertions of mobile elements. The most frequent variants found were c.278-1806A>C and the association of c.278-1244A>G and c.392-864T>G, identified in 4 and 6 unrelated individuals, respectively. In silico analysis predicted splicing impact for 4 substitutions (c.278-1806A>C, c.392-864T>G, c.724-2385G>T, c.723+4297T>A). Minigene assay showed a deleterious splicing impact for these 4 substitutions and also for the c.278-1786_278-1785insLINE. In the end, 5 variants were classified as likely pathogenic using the American College of Medical Genetics and Genomics guidelines, and 4 as of unknown significance. Thus, the hemophilia B-causing variant was identified in 13/17 (76%) families. CONCLUSION: We elucidated the causing defect in three-quarters of the families included in this study, and we reported new F9 deep intronic variants that can cause hemophilia B.
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Hemofilia B , Humanos , Hemofilia B/diagnóstico , Hemofilia B/genética , Intrones , Mutación , FenotipoRESUMEN
Background: The theory that D-dimer level might has a predictive or diagnostic role in preeclampsia needs to be explored. Aim of the study was to evaluate the association between serum D-dimer level and the occurrence of placenta-mediated complications (PMC) in a pregnant population at high risk. Methods: A prospective multicenter cohort study including 200 pregnant women was conducted. Results: Serum D-dimer increases throughout pregnancy, with the highest levels at the end of gestation. Serum D-dimer level was similar for women with PMC and with no complication. Serum D-dimer level was not different in women with preeclampsia versus uncomplicated women. Serum D-dimer level was not different in women with early or late preeclampsia versus uncomplicated women. Conclusion: This result suggests that serum D-dimer level was not predictive of the PMC occurrence. This corroborates the fact that the origin of PMC based more on immunity than in hemostasis.
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INTRODUCTION: Data on failure to identify the molecular mechanism underlying FXI deficiency by Sanger analysis and the contribution of gene segment deletions are almost inexistent. AIMS AND METHODS: Prospective and retrospective analysis was conducted on FXI-deficient patients' DNA via Next Generation Sequencing (NGS), or Sanger sequencing and Multiplex Probe Ligation-dependent Assay (MLPA) to detect cryptic causative gene variants or gene segment deletions. RESULTS: Sanger analysis or NGS enabled us to identify six severe and one partial (median activity 41 IU/dl) FXI deficient index cases with deletions encompassing exons 11-15, the whole gene, or both. After Sanger sequencing, retrospective evaluation using MLPA detected seven additional deletion cases in apparently homozygous cases in non-consanguineous families, or in previously unsolved FXI-deficiency cases. Among the 504 index cases with a complete genetic investigation (Sanger/MLPA, or NGS), 23 remained unsolved (no abnormality found [n = 14] or rare intronic variants currently under investigation, [n = 9]). In the 481 solved cases (95% efficiency), we identified F11 gene-deleted patients (14 cases; 2.9%). Among these, whole gene deletion accounted for four heterozygous cases, exons 11-15 deletion for five heterozygous and three homozygous ones, while compound heterozygous deletion and isolated exon 12 deletion accounted for one case each. CONCLUSION: Given the high incidence of deletions in our population (2.9%), MLPA (or NGS with a reliable bioinformatic pipeline) should be systematically performed for unsolved FXI deficiencies or apparently homozygous cases in non-consanguineous families.
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Deficiencia del Factor XI , Humanos , Exones/genética , Heterocigoto , Mutación , Estudios Prospectivos , Estudios Retrospectivos , Deficiencia del Factor XI/genética , Eliminación de SecuenciaRESUMEN
BACKGROUND: Nonacog alfa, a standard half-life recombinant factor IX (FIX), is used as a prophylactic treatment in severe haemophilia B (SHB) patients. Its half-life determined in clinical studies involving a limited sampling (72 h) was shown to be rather short. In our clinical practice, we suspected that its half-life could have been underestimated. OBJECTIVES: We aimed to evaluate nonacog alfa pharmacokinetics in real world clinical practice based on FIX levels in patients receiving prophylaxis. METHODS: We retrospectively collected data on patients with SHB receiving prophylaxis from eight centres across France. The terminal half-life (THL), time to reach 5-2 IU/dl and FIX activity at 48, 72 and 96 h were derived by Bayesian estimations using NONMEM analysis. RESULTS AND CONCLUSIONS: Infusion data (n = 455) were collected from 64 patients with SHB. The median THL measured in 92 pharmacokinetic (PK) studies was 43.4 h. In 26 patients ≤12 years of age, 51 PK studies showed a median time to reach 5 IU/dl of FIX of 70.5 h and a median time to reach 2 IU/dl of 121.5 h. In 38 patients 13-75 years of age, 41 PK studies showed a median time to reach 5 IU/dl of FIX of 92.0 h and a median time to reach 2 IU/dl of 167.5 h. Extending the sampling beyond 72 h makes it possible to observe a plateau, with FIX remaining between 2 and 5 IU/dl for several days and shows that the THL of nonacog alfa might be longer than previously described. ESSENTIALS: Nonacog alfa terminal half-life (THL) in patients receiving regular prophylaxis was evaluated in clinical practice. The median THL was estimated to be 36.9 h for patients aged .8-12 years. The median THL was estimated to be 49.9 h for patients aged 13-75 years. For patients aged ≤12 and >12 years, the median times to reach 5 IU/dl were 70.5 and 92 h, respectively; to reach 3 IU/dl, 95.5 and 131.5 h, respectively; to reach 2 IU/dl, 121.5 and 167.5 h, respectively. We suggest that the half-life of nonacog alfa might be longer than previously described in both younger and older patients.
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Factor IX , Hemofilia B , Adulto , Teorema de Bayes , Factor IX/farmacocinética , Factor IX/uso terapéutico , Semivida , Hemofilia B/tratamiento farmacológico , Humanos , Persona de Mediana Edad , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapéutico , Estudios RetrospectivosRESUMEN
Heparin-induced thrombocytopenia (HIT) is a prothrombotic immune drug reaction caused by platelet-activating antibodies that in most instances recognize platelet factor 4 (PF4)/polyanion complexes. Platelet activation assays (i.e., functional assays) are more specific than immunoassays, since they are able to discern clinically relevant heparin-induced antibodies. All functional assays used for HIT diagnosis share the same principle, as they assess the ability of serum/plasma from suspected HIT patients to activate fresh platelets from healthy donors in the presence of several concentrations of heparin. Depending on the assay, donors' platelets are stimulated either in whole blood (WB), platelet-rich plasma (PRP), or in a buffer medium (washed platelets, WP). In addition, the activation endpoint studied varies from one assay to another: platelet aggregation, membrane expression of markers of platelet activation, release of platelet granules. Tests with WP are more sensitive and serotonin release assay (SRA) is considered to be the current gold standard, but functional assays suffer from certain limitations regarding their sensitivity, specificity, complexity, and/or accessibility. However, the strict adherence to adequate preanalytical conditions, the use of selected platelet donors and the inclusion of positive and negative controls in each run are key points that ensure their performances.
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INTRODUCTION: Severe haemophilia is a rare disease characterised by spontaneous bleeding from early childhood, which may lead to various complications, especially in joints. It is nowadays possible to avoid these complications thanks to substitutive therapies for which the issue of adherence is major. The transition from adolescence to adulthood in young people with severe haemophilia is a critical period as it is associated with a high risk of lack of adherence to healthcare, which might have serious consequences on daily activities and on quality of life. METHODS AND ANALYSIS: We present the protocol for a cross-sectional, observational, multicentric study to assess the differences between adolescents and young adults with severe haemophilia in France through the transition process, especially on adherence to healthcare. This study is based on a mixed methods design, with two complementary and consecutive phases, comparing data from a group of adolescents (aged 14-17 years) with those from a group of young adults (aged 20-29 years). The quantitative phase focuses on the determinants (medical, organisational, sociodemographic and social and psychosocial and behavioural factors) of adherence to healthcare (considered as a marker of the success of transition). The qualitative phase explores participants' views in more depth to explain and refine the results from the quantitative phase. Eligible patients are contacted by the various Haemophilia Treatment Centres participating in the French national registry FranceCoag. ETHICS AND DISSEMINATION: The study was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2016-A01034-47). Study findings will be disseminated to the scientific and medical community in peer-reviewed journals and presented at scientific meetings. Results will be popularised to be communicated via the French association for people with haemophilia to participants and to the general public. TRIAL REGISTRATION NUMBER: NCT02866526; Pre-results.
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Hemofilia A/terapia , Transición a la Atención de Adultos , Cumplimiento y Adherencia al Tratamiento/estadística & datos numéricos , Rendimiento Académico , Adolescente , Adulto , Actitud Frente a la Salud , Estudios Transversales , Relaciones Familiares , Femenino , Francia , Hemofilia A/psicología , Humanos , Masculino , Satisfacción del Paciente , Factores Protectores , Investigación Cualitativa , Calidad de Vida , Factores de Riesgo , Clase Social , Cumplimiento y Adherencia al Tratamiento/psicología , Adulto JovenRESUMEN
[This corrects the article DOI: 10.1371/journal.pone.0173596.].
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The Innovance VWF:Ac test (Siemens) has the particularity to assess the binding capacity of von Willebrand factor (VWF) to recombinant platelet GPIb mutated in the absence of ristocetin. Our study aimed to evaluate and validate according to standard NF EN ISO 15189 the original protocol adaptation on STA-R Evolution series analyser (Diagnostica Stago). We evaluated the performance in terms of imprecision and we validate additional parameters necessary in range B as recommended by the SH GTA 04 (Cofrac). We compared the new assay with the reference assay: ristocetin cofactor activity (VWF:RCo) performed on the BCS-XP analyser by testing retrospectively samples from 82 healthy normal subjects and 61 patients with von Willebrand disease (VWD). This new assay is consistent with objectives set in terms of imprecision with CV around 4%. Excepted limit of quantification higher, additional parameters evaluated in range B have been validated. The Innovance VWF: Ac assay allowed the detection of all deficits of VWF already detected by the VWF:RCo test on the BCS-XP. This adjustment on STA-R analyser therefore has satisfactory analytical performance criteria. Apart from the limit of quantification, this reagent can be used according to the recommendations specified in the original protocol adaptation. Its performance and compatibility with the spot measurement allow the diagnosis and therapeutic monitoring of VWD according to current requirements and guidelines.
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Bioensayo , Enfermedades de von Willebrand/diagnóstico , Factor de von Willebrand/análisis , Automatización de Laboratorios , Bioensayo/instrumentación , Bioensayo/métodos , Bioensayo/normas , Análisis Químico de la Sangre/instrumentación , Análisis Químico de la Sangre/métodos , Análisis Químico de la Sangre/normas , Estudios de Casos y Controles , Contaminación de Equipos , Humanos , Límite de Detección , Reproducibilidad de los Resultados , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI.
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Coagulantes/uso terapéutico , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Trombina/biosíntesis , Factor de von Willebrand/uso terapéutico , Factores de Coagulación Sanguínea/uso terapéutico , Niño , Coagulantes/química , Coagulantes/inmunología , Manejo de la Enfermedad , Combinación de Medicamentos , Mapeo Epitopo , Factor VIII/química , Factor VIII/inmunología , Factor VIIa/uso terapéutico , Hemofilia A/sangre , Hemofilia A/inmunología , Hemofilia A/patología , Humanos , Tolerancia Inmunológica , Masculino , Medicina de Precisión , Proteínas Recombinantes/uso terapéutico , Índice de Severidad de la Enfermedad , Factor de von Willebrand/química , Factor de von Willebrand/inmunologíaRESUMEN
The ristocetin cofactor activity assay (VWF:RCo) is the reference method for assessing von Willebrand factor (VWF) activity but remains difficult to perform, and the coefficient of variation of the method is high (about 20-30%). This study evaluated and compared the performance for measuring the VWF activity of two newly commercialised assays [VWF:Ac Innovance (VWF:Ac) and VWF:RCo Acustar (VWF:RCo Acu)] with the reference VWF:RCo aggregation in 123 pathological plasma samples. The correlation and concordance between both new tests (VWF:RCo-Acu and VWF:Ac) and the reference VWF:RCo were good. The results of the VWF activity to VWF antigen ratio were also comparable whatever the method for the classification of VWF deficiency in all patients. Our results showed that both new tests could replace the "gold standard" VWF:RCo in aggregometry with several benefits: they are fully automated, easier and faster to perform, better adapted to emergency situations if necessary.
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Pruebas de Coagulación Sanguínea/métodos , Enfermedades de von Willebrand/sangre , Factor de von Willebrand/análisis , Factor de von Willebrand/inmunología , Automatización , Coagulación Sanguínea , Calibración , Estudios de Casos y Controles , Colágeno/química , Ensayo de Inmunoadsorción Enzimática , Humanos , Agregación Plaquetaria , Estudios Prospectivos , Valores de Referencia , Reproducibilidad de los Resultados , Ristocetina/sangre , Sensibilidad y Especificidad , Enfermedades de von Willebrand/diagnóstico , Factor de von Willebrand/metabolismoRESUMEN
We report the case of a 13-year-old girl, with a cerebral venous thrombosis treated initially by heparin. In front of this early thrombocytopenia, in spite of the absence of preliminary treatment by heparin, the "heparin-dependent" anti-PF4 antibodies ELISA assay was realized and turned out to be strongly positive. In spite of the negativity of the specific functional tests, the heparinotherapy was substituted by a treatment by danaparoïd of sodium, allowing a clinico-biological improvement. Because of the low score of HIT imputability, we realized a specific antibodies anti-PF4 alone assay which was strongly positive. This specific positivity probably explains the positivity of the antibodies anti PF4 "heparin-dependent" assay. The originality of this case lies in the young age of the patient and in the probably pathogenic character of these unusual antibodies, in addition markers of an auto-immune disease.
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Autoanticuerpos/sangre , Trombosis Intracraneal/complicaciones , Factor Plaquetario 4/inmunología , Tromboflebitis/complicaciones , Adolescente , Anticoagulantes/efectos adversos , Femenino , Heparina/efectos adversos , HumanosRESUMEN
Methods routinely used for investigating the molecular basis of antithrombin (AT) deficiency do not detect large SERPINC1 rearrangements. Between 2000 and 2008, 86 probands suspected of having AT-inherited type I deficiency were screened for SERPINC1 mutations in our laboratory. Mutations causally linked to the deficiency were identified by sequencing analysis in 63 probands. We present here results of multiplex ligation-dependent probe amplification (MLPA) analysis performed in 22 of the 23 remaining probands, in whom sequencing had revealed no mutation. Large deletions, present at the heterozygous state, were detected in 10 patients: whole gene deletions in 5 and partial deletions removing either exon 6 (n = 2), exons 1-2 (n = 1) or exons 5-7 (n = 2) in 5 others. Exon 6 partial deletions are a 2,769-bp deletion and a 1,892-bp deletion associated with a 10-bp insertion, both having 5' and/or 3' breakpoints located within Alu repeat elements. In addition, we identified the 5' breakpoint of a previously reported deletion of exons 1-2 within an extragenic Alu repeat. Distinct mutational mechanisms explaining these Alu sequence-related deletions are proposed. Overall, in this series, large deletions detected by MLPA explain almost half of otherwise unexplained type I AT-inherited deficiency cases.
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Deficiencia de Antitrombina III/genética , Antitrombinas/deficiencia , Antitrombinas/genética , Eliminación de Secuencia , Adolescente , Adulto , Anciano , Antitrombina III , Secuencia de Bases , Análisis Mutacional de ADN/métodos , Exones/genética , Salud de la Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Adulto JovenRESUMEN
OBJECTIVES: Many questions remain regarding the mechanism of perinatal stroke. METHODS: In a series of 100 prospectively enrolled term neonates with symptomatic arterial ischemic stroke, we explored family antecedents, pregnancy and delivery conditions and clinical presenting features and distinguished features of the 50 larger infants with the remainder. Cardiac and cervical arterial imaging were performed in 70 and 51 cases. RESULTS: Previous fetal loss, first pregnancy, primiparity, twin-gestation, cesarean and traumatic delivery, neonatal distress, male sex and premature rupture of membranes were statistically more common than in the general population. Normal pregnancy proportion and mean birthweight were in the normal range, arguing against a vasculo-placental origin in the majority. Furthermore, there was an excess of large babies. The larger infants were more subject to suffer from acute perinatal events, with a trend for an excess of neonatal distress (p=0.065) and for more severe presenting features (p=0.027), while the lighter were more likely to have experienced longstanding obstetrical risk factors such as complicated pregnancy (p=0.047) and tobacco exposure (p=0.028). Cervical MR angiography showed an internal carotid occlusion in two babies, whereas echo-Doppler was always normal; in one case the two methods were discordant. Echocardiography was non-informative. INTERPRETATION: The data from this prospective cohort of neonates with stroke confirm that many obstetrical and perinatal factors are risk determinants. They also suggest that birthweight and gender may be biomarkers of two populations of neonates with different pathological mechanisms. MR angiography appears more sensitive than echo-Doppler for the exploration of the neonatal cervical vasculature.
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Peso al Nacer/fisiología , Isquemia Encefálica/epidemiología , Complicaciones del Embarazo/epidemiología , Accidente Cerebrovascular/epidemiología , Asfixia Neonatal/epidemiología , Biomarcadores , Isquemia Encefálica/diagnóstico , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/patología , Estudios de Cohortes , Femenino , Francia/epidemiología , Edad Gestacional , Humanos , Mortalidad Infantil/tendencias , Recién Nacido , Angiografía por Resonancia Magnética , Masculino , Valor Predictivo de las Pruebas , Embarazo , Factores de Riesgo , Distribución por Sexo , Accidente Cerebrovascular/diagnóstico , UltrasonografíaRESUMEN
The prognosis of patients with myocardial infarction (MI) and normal coronary arteries (NCA) in the presence of an inherited coagulation disorder is unknown. The purpose of this study was to compare the clinical thrombosis outcome of patients with (GpI) or without (GpII), inherited coagulation disorders, who suffered from an acute MI with NCA. Eighty two consecutive patients (mean age 49 +/- 15 years; 29 females) with MI, but NCA, were recruited. Twelve patients (15%) had an inherited coagulation disorder. GpI and GpII were statistically similar regarding age (45 +/- 11 vs 50 +/- 16 years-old), gender (33 vs. 36% female), tobacco consumption (50 vs. 53%), diabetes mellitus (8 vs. 10%), hypertension (25 vs. 17%), obesity (8.3 vs. 14%), family history of coronary heart disease (33 vs. 19%), hypercholesterolemia (50 vs. 21%; p =.08), left ventricular ejection fraction (58 +/- 13 vs. 61 +/- 13%) and spasm (8.3% vs. 17%). All patients were initially treated with antiplatelet agents with the exception of one (8%) in GpI, and 6 (9%) in GpII who were taking oral anticoagulant therapy (ns). The mean follow-up was 57 +/- 26 (range from 2-91 months). During the outcome, 12/78 (15.4%) thrombosis events occurred, including venous thrombosis or pulmonary embolism (1/12 vs. 1/66), reinfarction (2/12 vs. 4/66), and stroke (2/12 vs. 2/66), with two events in one patient (GpI). Kaplan-Meier event-free survival, with combined end-point, defined as venous thrombo-embolic event, reinfarction, or stroke differed between the two groups: 4/12 (33.3%) in GpI and 7/66 (10.6%) in Gp II (p <.02). Patients with MI, NCA and congenital coagulation disorder present a high risk of thrombosis recurrence under antiplatelet agent.
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Trastornos de la Coagulación Sanguínea/complicaciones , Infarto del Miocardio/complicaciones , Adulto , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Estudios de Casos y Controles , Angiografía Coronaria , Salud de la Familia , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Infarto del Miocardio/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Pronóstico , Recurrencia , Factores de Riesgo , Trombosis/etiología , Resultado del TratamientoRESUMEN
Some cases of heparin-induced thrombocytopenia (HIT) have been reported to be associated with antibodies against interleukin-8 (IL-8), a chemokine related to platelet factor 4. We found that sera from 5 HIT patients containing immunoglobulin G (IgG) or IgM antibodies to IL-8, as evidenced using surface plasmon resonance spectroscopy, were able to trigger IL-8-dependent activation of washed platelets, leading to procoagulant activity. This activation occurred at IL-8 concentrations achievable in vivo and was facilitated by heparin (0.1 U/mL). Activation was also induced by affinity-purified anti-IL-8 IgG and involved FcgammaRIIa. In the 2 patients who could be followed up, antibodies were no longer detectable 4 months after heparin withdrawal. One additional patient with paraneoplastic recurrent thrombosis without thrombocytopenia was found to have platelet-activating anti-IL-8 IgM, but in this case heparin was inhibitory. This is another example of potentially pathogenic platelet activation by antibodies.