RESUMEN
Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological condition. Initial treatment involves plasma exchange (PLEX), corticosteroids, caplacizumab and rituximab. In relapsed and refractory cases despite initial treatments, further immune-modulating therapy includes the proteasome inhibitor, bortezomib. Evidence for bortezomib in this setting is limited to case reports and case series. We report our experience and perform a systematic review of the literature. We identified 21 publications with 28 unique patients in addition to our cohort of eight patients treated with bortezomib. The median age of patients was 44 years (IQR: 27-53) and 69% female. They were usually in an initial, refractory presentation of iTTP where they had received PLEX, corticosteroids, rituximab and another line of therapy. After bortezomib administration, 72% of patients had a complete response, with 85% maintaining a durable response without relapse at the last follow-up.
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Púrpura Trombocitopénica Idiopática , Púrpura Trombocitopénica Trombótica , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Bortezomib , Rituximab , Estudios Retrospectivos , Púrpura Trombocitopénica Idiopática/terapia , Corticoesteroides , Intercambio Plasmático , Proteína ADAMTS13RESUMEN
The efficacy and structural evolution of Mo-doped titania nanoparticles (MTNPs) as advanced photocatalysts for degrading methyl blue (MB) are investigated by X-ray absorption spectroscopy (XAS). The 3 wt % MTNP, characterized by uniform size and anatase structure, exhibits higher efficiency. The spectral analyses unveiled structural variations in the TiO6 octahedral structure and revealed an active site of the distorted square pyramidal structure symmetry (C4v). The in situ XAS spectra illustrate that MTNPs, particularly at 3 wt % doping, effectively enhanced the hole carriers in Ti 3d orbitals with a charge transfer to Mo 4d orbitals and impeded electron-hole pair merging, significantly enhancing the photodegradation under light illumination. This study deepens our understanding of the crucial role of Mo doping in optimizing TiO2 nanoparticle performance for efficient environmental remediation, showcasing the potential of MTNPs as sustainable photocatalytic materials.
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[Figure: see text].
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Síndrome Antifosfolípido/metabolismo , Proteínas Relacionadas con Receptor de LDL/metabolismo , Preeclampsia/metabolismo , Proteína Fosfatasa 2/metabolismo , Trofoblastos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Anticuerpos Antifosfolípidos/sangre , Síndrome Antifosfolípido/complicaciones , Proteínas Reguladoras de la Apoptosis/metabolismo , Línea Celular , Femenino , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Ratones , Ratones Endogámicos C57BL , Preeclampsia/etiología , EmbarazoRESUMEN
Acquired von Willebrand syndrome (AVWS) is a rare hematologic disorder characterized by quantitative or qualitative defects of von Willebrand factor (vWF), a protein crucial for normal hemostasis. AVWS has been described in association with several pathologic entities with varied mechanisms. Among these, lymphoproliferative disorders are the most common, with monoclonal gammopathy of undetermined significance (MGUS) being the most frequently reported. AVWS in this setting is commonly associated with the development of bleeding that is clinically challenging to manage due to accelerated clearance of vWF, limiting the utility of many conventional treatment modalities such as DDAVP or vWF/FVIII. We report a case of a 43-year-old male who was sent to our institution for new-onset easy bruising and laboratories concerning for von Willebrand disease (vWD). Further diagnostic workup revealed evidence of an IgG monoclonal gammopathy and findings suggestive of vWF inhibition. Ultimately, he was found to have monoclonal gammopathy of clinical significance (MGCS)-associated AVWS refractory to conventional treatment but responsive to lenalidomide and dexamethasone. This case suggests that lenalidomide may be suitable for patients with AVWS secondary to MGCS.
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Gammopatía Monoclonal de Relevancia Indeterminada , Paraproteinemias , Enfermedades de von Willebrand , Masculino , Humanos , Adulto , Enfermedades de von Willebrand/complicaciones , Enfermedades de von Willebrand/tratamiento farmacológico , Gammopatía Monoclonal de Relevancia Indeterminada/complicaciones , Gammopatía Monoclonal de Relevancia Indeterminada/tratamiento farmacológico , Factor de von Willebrand/metabolismo , Lenalidomida/uso terapéutico , Paraproteinemias/complicaciones , Paraproteinemias/tratamiento farmacológico , Paraproteinemias/diagnósticoRESUMEN
BACKGROUND: Acquired Hemophilia A (AHA) is a rare autoimmune disorder associated with the development of autoantibodies against factor VIII (FVIII). Although obtaining hemostatic control through the use of recombinant factor VIIa, activated prothrombin complex concentrate and recombinant porcine FVIII are cornerstones in the clinical management of AHA, these therapies have several disadvantages, including a higher risk for the development of thromboembolic events, unpredictable efficacy and short half-lives. While emicizumab has been FDA licensed for use in bleeding prophylaxis for patients with Congenital Hemophilia A (CHA) with and without inhibitors, it has not been approved for use in AHA, with only a few reports describing its use in this context. CASE REPORT: We report our experience with the use of emicizumab in an 83-year old male with AHA, complicated by the onset of atrial fibrillation following admission, drug-induced thrombocytopenia, infectious complications, and the identification of a low-grade lymphoproliferative disorder, in which emicizumab prophylaxis was used for bleeding prophylaxis in the context of persistently elevated inhibitor titers without evidence of thrombotic events or thrombotic microangiopathy.
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Anticuerpos Biespecíficos , Hemofilia A , Hemostáticos , Masculino , Porcinos , Animales , Hemofilia A/tratamiento farmacológico , Factor VIII/uso terapéutico , Anticuerpos Biespecíficos/farmacología , Anticuerpos Biespecíficos/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Hemorragia/tratamiento farmacológico , Hemorragia/prevención & control , Hemostáticos/uso terapéuticoRESUMEN
In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of ß2 glycoprotein I promotes thrombosis, and preclinical studies indicate that this is due to endothelial nitric oxide synthase (eNOS) antagonism via apolipoprotein E receptor 2 (apoER2)-dependent processes. How apoER2 molecularly links these events is unknown. Here, we show that, in endothelial cells, the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase 2A (PP2A). Disabled-2 (Dab2) recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1. Concurrently, Src homology domain-containing transforming protein 1 (SHC1) recruits the PP2A scaffolding subunit to the proline-rich apoER2 C terminus along with 2 distinct regulatory PP2A subunits that mediate inhibitory dephosphorylation of Akt and eNOS. In mice, the coupling of these processes in endothelium is demonstrated to underlie aPL-invoked thrombosis. By elucidating these intricacies in the pathogenesis of APS-related thrombosis, numerous potential new therapeutic targets have been identified.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Anticuerpos Antifosfolípidos/inmunología , Autoanticuerpos/inmunología , Endotelio/metabolismo , Proteínas Relacionadas con Receptor de LDL/metabolismo , Proteína Fosfatasa 2/metabolismo , Proteína Transformadora 1 que Contiene Dominios de Homología 2 de Src/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis , Células Endoteliales/metabolismo , Endotelio/inmunología , Endotelio Vascular/metabolismo , Humanos , Masculino , Ratones , Modelos Biológicos , Complejos Multiproteicos , Óxido Nítrico Sintasa de Tipo III/antagonistas & inhibidores , Óxido Nítrico Sintasa de Tipo III/metabolismo , Trombosis/etiología , Trombosis/metabolismo , Trombosis/patologíaRESUMEN
The standard dose of rituximab used in B-cell hematological malignancies, 375 mg/m2 weekly, may be excessive for autoimmune conditions. Successful use of a low, fixed dose of 100-200 mg of rituximab, weekly for 4 weeks, has been reported in the literature in the treatment of autoimmune thrombotic thrombocytopenic purpura (aTTP). We retrospectively analyzed our rituximab data in aTTP over a 13-year-period for 39 patients, with the aim of comparing response and outcomes with a standard lymphoma-dose course versus a low fixed 100 mg-dose course. Compared to the standard dose (17 patients, 17 courses of 4 infusions), our patients who received a low dose (8 patients, 9 courses of 4 infusions) had a possibly lower baseline risk but did achieve a similar time to remission and number of plasma exchange procedures to remission. Preemptive low-dose courses for ADAMTS13 activity <50 % during remission (6 patients, 10 courses of 4 infusions) achieved a median peak ADAMTS13 activity of 99 %, in a median of 1 month, with no clinical relapses. Our results provide additional evidence for the efficacy of low-dose rituximab, with the benefit of much lower cost, less infusion time, and theoretically lower risk of toxicity.
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Antineoplásicos Inmunológicos/uso terapéutico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Rituximab/uso terapéutico , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Rituximab/farmacología , Adulto JovenRESUMEN
BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.).
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Factor IX/genética , Terapia Genética , Vectores Genéticos/administración & dosificación , Hemofilia B/terapia , Adulto , Alanina Transaminasa/sangre , Dependovirus/genética , Factor IX/metabolismo , Estudios de Seguimiento , Expresión Génica , Terapia Genética/efectos adversos , Hemofilia B/sangre , Hemofilia B/genética , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Transgenes , Adulto JovenRESUMEN
Von Willebrand disease (VWD) is the most common congenital bleeding disorder and is due to quantitative or qualitative defects of von Willebrand factor (VWF). Acquired defects of VWF, termed acquired von Willebrand syndrome (AVWS), are due to a host of different mechanisms. Autoantibody-mediated AVWS may be associated with lymphoproliferative or immunological disorders, such as systemic lupus erythematosus (SLE). A large majority of AVWS cases are type 1 or type 2A-like and patients tend to have a mild to moderate bleeding tendency. We report a case of severe autoimmune AVWS in a woman with SLE who presented with clinical and laboratory features of type 3 VWD (undetectable VWF antigen, ristocetin cofactor activity, and VWF multimers). A mixing study demonstrated an inhibitor to VWF (6BU/mL). Her bleeds were managed with antifibrinolytics, recombinant activated factor VII, and activated prothrombin complex concentrate. She was initially treated with steroids and intravenous immunoglobulin therapy. However, her bleeding symptoms continued until she was treated with rituximab, and her VWF parameters normalized. She relapsed two years later due to non-compliance with her immunosuppressive medications and expired another two years later secondary to complications of sepsis and uremic pericarditis. This case emphasizes the importance of aggressive initial therapy of SLE to reduce secondary complications, frequent patient monitoring, and continued treatment of the underlying autoimmune disorder in patients with AVWS.
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Enfermedades Autoinmunes/diagnóstico , Enfermedades de von Willebrand/diagnóstico , Adulto , Enfermedades Autoinmunes/mortalidad , Enfermedades Autoinmunes/patología , Femenino , Humanos , Análisis de Supervivencia , Adulto Joven , Enfermedades de von Willebrand/mortalidad , Enfermedades de von Willebrand/patologíaRESUMEN
Atypical hemolytic uremic syndrome (aHUS) is a rare genetic disorder caused by defective complement regulation resulting in thrombotic microangiopathy (TMA). Patients can present as children or adults. The syndrome consists of hemolytic anemia with schistocytosis, thrombocytopenia, significant renal damage, and/or other organ system dysfunction(s). Patients with aHUS may succumb to the complications of the disease with the very first manifestation; surviving patients often suffer from progressive organ dysfunction with significant morbidity and mortality despite plasma infusion or plasma exchange. Eculizumab, a humanized monoclonal antibody to C5, was approved for treatment of aHUS in 2011. This is an expensive but highly effective therapy changing the lives and improving the outcome of patients with aHUS. Making timely and accurate diagnosis of aHUS can be life-saving if eculizumab treatment is begun promptly. Finding a genetic mutation in a complement regulatory protein is diagnostic with the appropriate clinical syndrome, but at least 30 % of patients do not have defined or reported mutations. Thus the diagnosis rests on the clinical acumen of the physician. However, the clinical manifestations of aHUS are shared by other etiologies of thrombotic microangiopathy. While laboratory finding of undetectable ADAMTS13 activity defines TTP, distinguishing aHUS from the other causes of TMA remains an art. In addition, aHUS can be unmasked by conditions with enhanced complement activation, such as systemic lupus erythematosus, pregnancy, malignant hypertension, and hematopoietic stem cell transplantation. Thus if TMA occurs in the setting of enhanced complement activation, one must consider aHUS as an underlying etiology, especially if treatment of the condition does not resolve the TMA.
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BACKGROUND: Due to the convenience afforded by the lack of required laboratory monitoring, direct oral anticoagulants (DOACs) are increasingly used as alternatives to Vitamin-K antagonists for certain medical conditions. However, there are circumstances in which assessment of DOAC plasma concentrations may be helpful in guiding clinical decisions, including patients presenting with either bleeding or thrombosis, or patients requiring urgent invasive procedures. Evaluating the anticoagulant effects of DOACs is often difficult because of the limited availability of DOAC-specific assays in most laboratories. OBJECTIVE: To evaluate the correlation between ex vivo plasma concentrations of rivaroxaban and a chromogenic anti-Xa assay for low-molecular-weight heparin (LMWH) routinely used in our coagulation laboratory. MATERIALS AND METHODS: Twenty-nine blood samples from 20 patients anticoagulated with rivaroxaban (dose; 10-20 mg/day) were evaluated using an anti-Xa assay for LMWH and results were correlated with rivaroxaban plasma concentrations using a rivaroxaban specific assay. RESULTS: A linear dose-dependent relationship was demonstrated between plasma concentrations of rivaroxaban and the chromogenic anti-Xa assay for LMWH (R2 = 0.92). PT and PTT demonstrated poor correlations (R2 = 0.03; and R2 = 0.01, respectively) with rivaroxaban plasma concentrations. CONCLUSION: Findings from this study suggest that if specific assays for rivaroxaban are unavailable, then the chromogenic anti-Xa assay for LMWH may be useful for assessing the anticoagulant effects of rivaroxaban.
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Inhibidores del Factor Xa/farmacocinética , Factor Xa/metabolismo , Heparina de Bajo-Peso-Molecular/farmacología , Rivaroxabán/farmacocinética , Administración Oral , Pruebas de Coagulación Sanguínea/métodos , Inhibidores del Factor Xa/administración & dosificación , Femenino , Humanos , Masculino , Rivaroxabán/administración & dosificaciónAsunto(s)
Endotelio Vascular/fisiología , Infarto del Miocardio/sangre , Accidente Cerebrovascular/sangre , Trombosis/sangre , Anticoagulantes/uso terapéutico , Coagulación Sanguínea/genética , Proteínas del Sistema Complemento/metabolismo , Interacción Gen-Ambiente , Estudio de Asociación del Genoma Completo , Hemostasis , Humanos , Infarto del Miocardio/genética , Infarto del Miocardio/prevención & control , Inhibidores de Agregación Plaquetaria/uso terapéutico , Guías de Práctica Clínica como Asunto , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/prevención & control , Trombofilia/genética , Trombosis/genéticaRESUMEN
BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder characterized by a severe deficiency of ADAMTS13 activity. Although therapeutic plasma exchange (PLEX) is the standard of care, 30% to 50% patients develop exacerbation or relapse, requiring immunomodulatory agents. Of these agents, glucocorticoids, rituximab, and cyclosporine A are the most frequently used. CASE REPORT: We report a case of chronic relapsing TTP in a patient who had eight relapses over a 14-year period. After her seventh relapse, the patient demonstrated only partial response to glucocorticoids, two courses of rituximab, and cyclophosphamide. The eighth relapse occurred 58 days after her last PLEX and subsequent to this she received a course of bortezomib (Velcade, Millennium Pharmaceuticals, Inc.). After treatment with bortezomib the patient demonstrated a complete response with a progressive increase in ADAMTS13 activity from less than 5% to 22% accompanied by undetectable inhibitor, and she has remained PLEX free for more than 169 days. CONCLUSION: Bortezomib may serve as an adjunct treatment in patients with acquired TTP who exhibit an incomplete response or are refractory to conventional management.
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Ácidos Borónicos/uso terapéutico , Inmunosupresores/uso terapéutico , Púrpura Trombocitopénica Trombótica/tratamiento farmacológico , Pirazinas/uso terapéutico , Proteínas ADAM/sangre , Proteínas ADAM/inmunología , Proteína ADAMTS13 , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Ácidos Borónicos/efectos adversos , Bortezomib , Ciclofosfamida/uso terapéutico , Resistencia a Medicamentos , Femenino , Glucocorticoides/uso terapéutico , Humanos , Huésped Inmunocomprometido , Inmunosupresores/efectos adversos , Persona de Mediana Edad , Púrpura Trombocitopénica Trombótica/terapia , Pirazinas/efectos adversos , Recurrencia , Inducción de Remisión , Rituximab , Infecciones Estafilocócicas/etiologíaRESUMEN
The clinical presentation of thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies (TMAs) can often be similar. The role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in diagnosing TTP is accepted by most researchers but continues to be debated in a few studies. We report the experience of our single-centre academic institution, where ADAMTS13 is used to diagnose TTP and guide plasma exchange (PLEX). Patients presenting to our institution with thrombotic microangiopathy (60 patients) between January 2006 and December 2012 were divided into two groups based on ADAMTS13 activity and clinical history. Patients with ADAMTS13 activity <10% were included in the TTP (n = 30) cohort while patients with activity >11% were classified as 'other microangiopathies' (TMA, n = 30). PLEX was only initiated in patients with a high likelihood of TTP and discontinued when the baseline ADAMTS13 activity was >11%. Patients with severe ADAMTS13 deficiency (TTP group) showed significant presenting differences: lower platelet counts, less renal dysfunction, higher presence of neurological abnormalities, and greater haemolysis markers as compared to non-deficient patients (TMA group). Most importantly, patients without severe ADAMTS13 deficiency were safely managed without increased mortality despite receiving no PLEX or discontinuing PLEX after a short course (upon availability of ADAMTS13 results). In conclusion, ADAMTS13 can be used to diagnose TTP and guide appropriate PLEX therapy.
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Proteínas ADAM/deficiencia , Púrpura Trombocitopénica Trombótica/diagnóstico , Microangiopatías Trombóticas/diagnóstico , Proteína ADAMTS13 , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Niño , Diagnóstico Diferencial , Manejo de la Enfermedad , Femenino , Humanos , Masculino , Metaloendopeptidasas/deficiencia , Persona de Mediana Edad , Intercambio Plasmático/métodos , Púrpura Trombocitopénica Trombótica/enzimología , Púrpura Trombocitopénica Trombótica/terapia , Estudios Retrospectivos , Rituximab , Microangiopatías Trombóticas/enzimología , Microangiopatías Trombóticas/terapia , Adulto JovenAsunto(s)
Anticoagulantes/efectos adversos , Heparina/efectos adversos , Intestino Delgado/cirugía , Trombocitopenia/inducido químicamente , Trombosis de la Vena/cirugía , Anticoagulantes/uso terapéutico , Humanos , Intestino Delgado/irrigación sanguínea , Isquemia/cirugía , Masculino , Arteria Mesentérica Superior , Oclusión Vascular Mesentérica/cirugía , Persona de Mediana EdadRESUMEN
In recent years, a variety of emerging online media, such as TikTok, Kuaishou, YouTube and other short video application platforms, have appeared. The problem of short video addiction has become an issue to education experts and the general public, as students' excessive use of short video has become increasingly serious with many hidden concerns to the students' learning effectiveness. In addition, to meet the growing demand for innovative design talents worldwide, the Taiwan government has been committed to promoting policies related to the cultivation of innovative and creative talents nowadays, particularly for innovative design profession students who often use the Internet and short videos for learning. Therefore, the study aims to use questionnaires to understand the habits and addiction of the innovative design profession students in using short videos, and to further investigate the relation of short video addiction to the students' creative self-efficacy (CSE) and career interests. A total of 561 valid questionnaires were collected after eliminating invalid questionnaires and reliability analysis. Structural equation modeling and model validation were conducted afterwards. The results showed that short video addiction had a negative effect on CSE; CSE had a positive effect on career interests; and CSE had an indirect effect between short video addiction and career interests.
RESUMEN
Hemophilia-A (HA) is caused by heterogeneous loss-of-function factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that impair intrinsic-pathway-mediated coagulation-amplification. The standard-of-care for severe-HA-patients is regular infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called "FVIII-inhibitors (FEIs)" and become refractory. We used the PATH study and ImmunoChip to scan immune-mediated-disease (IMD)-genes for novel and/or replicated genomic-sequence-variations associated with baseline-FEI-status while accounting for non-independence of data due to genetic-relatedness and F8-mutational-heterogeneity. The baseline-FEI-status of 450 North American PATH subjects-206 with black-African-ancestry and 244 with white-European-ancestry-was the dependent variable. The F8-mutation-data and a genetic-relatedness matrix were incorporated into a binary linear-mixed model of genetic association with baseline-FEI-status. We adopted a gene-centric-association-strategy to scan, as candidates, pleiotropic-IMD-genes implicated in the development of either ³2 autoimmune-/autoinflammatory-disorders (AADs) or ³1 AAD and FEIs. Baseline-FEI-status was significantly associated with SNPs assigned to NOS2A (rs117382854; p=3.2E-6) and B3GNT2 (rs10176009; p=5.1E-6), which have functions in anti-microbial-/-tumoral-immunity. Among IMD-genes implicated in FEI-risk previously, we identified strong associations with CTLA4 assigned SNPs (p=2.2E-5). The F8-mutation-effect underlies ~15% of the total heritability for baseline-FEI-status. Additive genetic heritability and SNPs in IMD-genes account for >50% of the patient-specific variability in baseline-FEI-status. Race is a significant determinant independent of F8-mutation-effects and non-F8-genetics.