RESUMO
Congenital factor VII (FVII) deficiency, the most frequent among the recessively inherited disorders of blood coagulation, is characterized by a wide range of symptoms, from mild mucosal bleeds to life-threatening intracranial hemorrhage. Complete FVII deficiency may cause perinatal lethality. Clinically relevant thresholds of plasma levels are still uncertain, and modest differences in low FVII levels are associated with large differences in clinical phenotypes. Activated FVII (FVIIa) expresses its physiological protease activity only in a complex with tissue factor (TF), which triggers clotting at a very low concentration. Knowledge of the FVIIa-TF complex helps to interpret the clinical findings associated with low FVII activity as compared with other rare bleeding disorders and permits effective management, including prophylaxis, with recombinant FVIIa, which, however, displays a short half-life. Newly devised substitutive and nonsubstitutive treatments, characterized by extended half-life properties, may further improve the quality of life of patients. Genetic diagnosis has been performed in thousands of patients with FVII deficiency, and among the heterogeneous F7 mutations, mostly missense changes, several recurrent variants show geographical distribution and identity by descent. In the general population, common F7 polymorphisms explain a large proportion of FVII level variance in plasma through FVII-lowering effects. Their combination with pathogenic variants may impact on the frequent detection of FVII coagulant levels lower than normal, as well as on mild bleeding conditions. In the twenties of this century, 70 years after the first report of FVII deficiency, more than 200 studies/reports about FVII/FVII deficiency have been published, with thousands of FVII-deficient patients characterized all over the world.
RESUMO
Activated factor VII (FVIIa), the first protease of clotting, expresses its physiological procoagulant potential only after complexing with tissue factor (TF) exposed to blood. Deep knowledge of the FVIIa-TF complex and F7 gene helps to understand the Janus-faced clinical findings associated to low or elevated FVII activity (FVIIc). Congenital FVII deficiency, the most frequent among the recessively inherited bleeding disorders, is caused by heterogeneous mutations in the F7 gene. Complete FVII deficiency causes perinatal lethality. A wide range of bleeding symptoms, from life-threatening intracranial hemorrhage to mild mucosal bleeding, is observed in patients with apparently modest differences in FVIIc levels. Though clinically relevant FVIIc threshold levels are still uncertain, effective management, including prophylaxis, has been devised, substantially improving the quality of life of patients. The exposure of TF in diseased arteries fostered investigation on the role of FVII in cardiovascular disease. FVIIc levels were found to be predictors of cardiovascular death and to be markedly associated to F7 gene variation. These genotype-phenotype relationships are among the most extensively investigated in humans. Genome-wide analyses extended association to numerous loci that, together with F7, explain >50% of FVII level plasma variance. However, the ability of F7 variation to predict thrombosis was not consistently evidenced in the numerous population studies. Main aims of this review are to highlight i) the biological and clinical information that distinguishes FVII deficiency from the other clotting disorders and ii) the impact exerted by genetically predicted FVII level variation on bleeding as well as on the thrombotic states.
Assuntos
Deficiência do Fator VII , Trombose , Fator VII/genética , Deficiência do Fator VII/diagnóstico , Deficiência do Fator VII/genética , Feminino , Estudo de Associação Genômica Ampla , Hemostasia , Humanos , Gravidez , Qualidade de Vida , Trombose/genéticaRESUMO
Perioperative bleeding is a major concern in patients with factor VII (FVII) deficiency. Evaluating data of 95 FVII-deficient patients undergoing 110 surgical procedures (61 major, 49 minor), we assessed the impact of type of surgery, bleeding phenotype and FVII coagulant activity (FVII:C) levels on perioperative replacement therapy (RT). Compared to those with higher FVII:C levels, patients with <3% FVII:C received a higher number of RT doses (8 vs. 2, P = 0·003) for a longer RT duration (3 days vs. 1 day, P = 0·001), with no difference in RT dose. Similarly, patients with a history of major bleeds received a higher number of RT doses (8·5 vs. 2-3, P = 0·013) for a longer RT duration (2 days vs. 1 day, P = 0·005) as compared to those with a history of minor bleeds or to asymptomatic patients. No difference in RT was found among major and minor surgical procedures. Overall, multivariate analysis showed that history of major bleeding was the only independent predictor of number of RT doses (ß = 0·352, P = 0·001) and RT duration (ß = 0·405, P = 0·018). Overall, a ≈20 µg/kg perioperative RT was efficacious in 95·5% of cases. The infusion should be repeated ≈8 times in high-risk subsets (i.e. patients with a history of major bleeding).
Assuntos
Deficiência do Fator VII/diagnóstico , Deficiência do Fator VII/cirurgia , Adolescente , Adulto , Tomada de Decisão Clínica , Terapia Combinada , Gerenciamento Clínico , Fator VII/administração & dosagem , Deficiência do Fator VII/epidemiologia , Feminino , Hemorragia/etiologia , Hemorragia/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Procedimentos Cirúrgicos Operatórios/métodos , Avaliação de Sintomas , Resultado do Tratamento , Adulto JovemRESUMO
In women of fertile age, iron loss consequent to excessive menstrual discharge is by far the most frequent cause of iron-deficient anemia. However, the relationship between menstrual discharge and iron loss is poorly understood. In this prospective study, total menstrual and iron losses were assayed in a large cohort of non-anemic women and women with excessive menstrual blood losses (menorrhagia) in order to provide data useful for intervention. One hundred and five Caucasian women aged 20-45 years were recruited. Blood cell count and serum ferritin (SF) levels were determined in each case before menses. Menstrual fluid losses (MFL) were determined using a standardized pads' weight method. Hematin concentration was assayed by a variant of the Alkaline Hematin Method from which iron concentration was calculated. Mean SF levels were 36.2 (range 8.6-100) ng/ml in healthy women and 6.4 (range 5-14) ng/ml in patients with menorrhagia. Median values of iron lost/cycle were 0.87 mg in healthy women and 5.2 mg in patients with menorrhagia (ranges 0.102-2.569 and 1.634-8.665 mg, respectively, p < 0.001). In women with menorrhagia, iron lost/cycle strongly correlated (0.789, p < 0.001) with MFL. In conclusion, healthy women with normal menses lose, on average, 1 mg iron/cycle. Average iron losses in patients with menorrhagia are, at least in our cohort, on average, five-to-six times higher than normal. Most women with menorrhagia had totally depleted iron stores. Indirect, quantitative evaluation of iron lost with menses may be useful to assess the risk of developing iron-deficient anemia in individual patients.
Assuntos
Anemia Ferropriva/sangue , Eritropoese/fisiologia , Ferro/sangue , Menorragia/sangue , Menstruação/sangue , Adulto , Anemia Ferropriva/diagnóstico , Anemia Ferropriva/epidemiologia , Feminino , Humanos , Menorragia/diagnóstico , Menorragia/epidemiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
Changes at the invariable donor splice site +1 guanine, relatively frequent in human genetic disease, are predicted to abrogate correct splicing, and thus are classified as null mutations. However, their ability to direct residual expression, which might have pathophysiological implications in several diseases, has been poorly investigated. As a model to address this issue, we studied the IVS6+1G>T mutation found in patients with severe deficiency of the protease triggering coagulation, factor VII (FVII), whose absence is considered lethal. In expression studies, the IVS6+1G>T induced exon 6 skipping and frame-shift, and prevented synthesis of correct FVII transcripts detectable by radioactive/fluorescent labelling or real-time RT-PCR. Intriguingly, the mutation induced the activation of a cryptic donor splice site in exon 6 and production of an in-frame 30bp deleted transcript (8 ± 2%). Expression of this cDNA variant, lacking 10 residues in the activation domain, resulted in secretion of trace amounts (0.2 ± 0.04%) of protein with appreciable specific activity (48 ± 16% of wt-FVII). Altogether these data indicate that the IVS6+1G>T mutation is compatible with the synthesis of functional FVII molecules (~0.01% of normal, 1pM), which could trigger coagulation. The low but detectable thrombin generation (352 ± 55nM) measured in plasma from an IVS6+1G>T homozygote was consistent with a minimal initiation of the enzymatic cascade. In conclusion, we provide experimental clues for traces of FVII expression, which might have reverted an otherwise perinatally lethal genetic condition.
Assuntos
Processamento Alternativo/genética , Deficiência do Fator VII/genética , Fator VII/genética , Mutação Puntual/genética , Sítios de Splice de RNA/genética , Coagulação Sanguínea/genética , Criança , DNA Complementar/genética , DNA Complementar/metabolismo , Éxons/genética , Fator VII/análise , Feminino , Mutação da Fase de Leitura/genética , Genes Letais , Homozigoto , Humanos , Masculino , Splicing de RNA/genética , Trombina/análise , Trombina/genética , Adulto JovemRESUMO
Because of the very short half-life of factor VII, prophylaxis in factor VII deficiency is considered a difficult endeavor. The clinical efficacy and safety of prophylactic regimens, and indications for their use, were evaluated in factor VII-deficient patients in the Seven Treatment Evaluation Registry. Prophylaxis data (38 courses) were analyzed from 34 patients with severe factor VII deficiency (<1-45 years of age, 21 female). Severest phenotypes (central nervous system, gastrointestinal, joint bleeding episodes) were highly prevalent. Twenty-one patients received recombinant activated factor VII (24 courses), four received plasma-derived factor VII, and ten received fresh frozen plasma. Prophylactic schedules clustered into "frequent" courses (three times weekly, n=23) and "infrequent" courses (≤ 2 times weekly, n=15). Excluding courses for menorrhagia, "frequent" and "infrequent" courses produced 18/23 (78%) and 5/12 (41%) "excellent" outcomes, respectively; relative risk, 1.88; 95% confidence interval, 0.93-3.79; P=0.079. Long term prophylaxis lasted from 1 to >10 years. No thrombosis or new inhibitors occurred. In conclusion, a subset of patients with factor VII deficiency needed prophylaxis because of severe bleeding. Recombinant activated factor VII schedules based on "frequent" administrations (three times weekly) and a 90 µg/kg total weekly dose were effective. These data provide a rationale for long-term, safe prophylaxis in factor VII deficiency.
Assuntos
Deficiência do Fator VII/prevenção & controle , Fator VII/uso terapêutico , Fator VIIa/uso terapêutico , Plasma , Adolescente , Adulto , Criança , Pré-Escolar , Fator VIIa/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Sistema de Registros/estatística & dados numéricos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
We report 2 asymptomatic homozygotes for the nonsense p.R462X mutation affecting the carboxy-terminus of coagulation factor VII (FVII, 466 aminoacids). FVII levels of 3-5% and 2.7 ± 0.4% were found in prothrombin time-based and activated factor X (FXa) generation assays with human thromboplastins. Noticeably, FVII antigen levels were barely detectable (0.7 ± 0.2%) which suggested a gain-of-function effect. This effect was more pronounced with bovine thromboplastin (4.8 ± 0.9%) and disappeared with rabbit thromboplastin (0.7 ± 0.2%). This suggests that the mutation influences tissue factor/FVII interactions. Whereas the recombinant rFVII-462X variant confirmed an increase in specific activity (~400%), a panel of nonsense (p.P466X, p.F465X, p.P464X, p.A463X) and missense (p.R462A, p.R462Q, p.R462W) mutations of the FVII carboxy-terminus resulted in reduced secretion but normal specific activity. These data provide evidence for counteracting pleiotropic effects of the p.R462X mutation, which explains the asymptomatic FVII deficiency, and contributes to our understanding of the role of the highly variable carboxy-terminus of coagulation serine proteases.
Assuntos
Coagulação Sanguínea/genética , Códon sem Sentido/genética , Deficiência do Fator VII/genética , Deficiência do Fator VII/metabolismo , Fator VII/genética , Fator VII/metabolismo , Animais , Bovinos , Criança , Ensaio de Imunoadsorção Enzimática , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese Sítio-Dirigida , Tempo de Protrombina , Coelhos , Tromboplastina/metabolismoRESUMO
Excessive bleeding represents a major complication of surgical interventions and its control is especially relevant in patients with Congenital Bleeding Disorders (CBD). In factor VII (FVII) deficiency, scanty data on surgery is available to guide treatment strategies. The STER (Seven Treatment Evaluation Registry) is a multi-centre, prospective, observational, web-based study protocol providing the frame for a structured and detailed data collection. Inhibitor occurrence was checked in a centralized fashion. Forty-one surgical operations (24 'major' and 17 'minor') were performed in 34 subjects with a carefully characterized FVII deficiency under the coverage of recombinant activated Factor VII (rFVIIa). Bleeding occurred during three major interventions of orthopaedic surgery, but rFVIIa was given at very low dose in each case. An antibody to FVII was observed in one patient who underwent a multiple dental extraction. No thromboses were reported during the 30-d follow up period. Replacement therapy with rFVIIa proved effective when suitable doses were used, which, during the period of maximum bleeding risk (the day of operation), were calculated (Receiver Operated Characteristic analysis) to be of at least 13 µg/kg/body weight per single dose and no less than three administrations. This indication is important especially in the case of major surgery.
Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Coagulantes/uso terapêutico , Deficiência do Fator VII/tratamento farmacológico , Fator VIIa/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Avaliação de Medicamentos/métodos , Métodos Epidemiológicos , Deficiência do Fator VII/complicações , Feminino , Hemostasia Cirúrgica/métodos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Proteínas Recombinantes/uso terapêutico , Resultado do TratamentoRESUMO
The safest duration of anticoagulation after idiopathic deep vein thrombosis (DVT) is unknown. We conducted a prospective study to assess the optimal duration of vitamin K antagonist (VKA) therapy considering the risk of recurrence of thrombosis according to residual vein thrombosis (RVT). Patients with a first unprovoked DVT were evaluated for the presence of RVT after 3 months of VKA administration; those without RVT suspended VKA, while those with RVT continued oral anticoagulation for up to 2 years. Recurrent thrombosis and/or bleeding events were recorded during treatment (RVT group) and 1 year after VKA withdrawal (both groups). Among 409 patients evaluated for unprovoked DVT, 33.2% (136 of 409 patients) did not have RVT and VKA was stopped. The remaining 273 (66.8%) patients with RVT received anticoagulants for an additional 21 months; during this period of treatment, recurrent venous thromboembolism and major bleeding occurred in 4.7% and 1.1% of patients, respectively. After VKA suspension, the rates of recurrent thrombotic events were 1.4% and 10.4% in the no-RVT and RVT groups, respectively (relative risk = 7.4; 95% confidence interval = 4.9-9.9). These results indicate that in patients without RVT, a short period of treatment with a VKA is sufficient; in those with persistent RVT, treatment extended to 2 years substantially reduces, but does not eliminate, the risk of recurrent thrombosis.
Assuntos
Acenocumarol/administração & dosagem , Anticoagulantes/administração & dosagem , Extremidade Inferior/patologia , Tromboembolia Venosa/tratamento farmacológico , Trombose Venosa/tratamento farmacológico , Varfarina/administração & dosagem , Acenocumarol/efeitos adversos , Acenocumarol/uso terapêutico , Adulto , Idoso , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Esquema de Medicação , Feminino , Hemorragia , Humanos , Extremidade Inferior/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Fatores de Risco , Ultrassonografia , Tromboembolia Venosa/diagnóstico por imagem , Tromboembolia Venosa/patologia , Tromboembolia Venosa/prevenção & controle , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/patologia , Vitamina K/antagonistas & inibidores , Vitamina K/metabolismo , Varfarina/efeitos adversos , Varfarina/uso terapêuticoRESUMO
Residual vein thrombosis (RVT) indicates a prothrombotic state and is useful for evaluating the optimal duration of oral anticoagulant treatment (OAT). Patients with a first episode of deep vein thrombosis, treated with OAT for 3 months, were managed according to RVT findings. Those with RVT were randomized to either stop or continue anticoagulants for 9 additional months, whereas in those without RVT, OAT was stopped. Outcomes were recurrent venous thromboembolism and/or major bleeding. Residual thrombosis was detected in 180 (69.8%) of 258 patients; recurrent events occurred in 27.2% of those who discontinued (25/92; 15.2% person-years) and 19.3% of those who continued OAT (17/88; 10.1% person-years). The relative adjusted hazard ratio (HR) was 1.58 (95% confidence interval [CI], 0.85-2.93; P = .145). Of the 78 (30.2%) patients without RVT, only 1 (1.3%; 0.63% person-years) had a recurrence. The adjusted HR of patients with RVT versus those without was 24.9 (95% CI, 3.4-183.6; P = .002). One major bleeding event (1.1%; 0.53% person-years) occurred in patients who stopped and 2 occurred (2.3%; 1.1% person-years) in those who continued OAT. Absence of RVT identifies a group of patients at very low risk for recurrent thrombosis who can safely stop OAT. This trial was registered at http://www.ClinicalTrials.gov as no. NCT00438230.
Assuntos
Anticoagulantes/administração & dosagem , Trombose Venosa/tratamento farmacológico , Adulto , Idoso , Esquema de Medicação , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Prevenção Secundária , Resultado do Tratamento , Ultrassonografia , Trombose Venosa/complicações , Trombose Venosa/diagnóstico por imagemRESUMO
The complex formed between the procoagulant serine protease activated factor VII (FVII) and the membrane protein tissue factor, exposed on the vascular lumen upon injury, triggers the initiation of blood clotting. This review describes the clinical picture of FVII deficiency and provides information on diagnosis and management of the disease. FVII deficiency, the most common among the rare congenital coagulation disorders, is transmitted with autosomal recessive inheritance. Clinical phenotypes range from asymptomatic condition, even in homozygotes, to severe disease characterized by life-threatening and disabling symptoms (central nervous system and gastrointestinal bleeding and hemarthrosis), with early age of presentation and the need for prophylaxis. In females, menorrhagia is prevalent and affects two thirds of the patients of fertile age. Although FVII gene mutations are extremely heterogeneous, several recurrent mutations have been reported, a few of them relatively frequent. The study of genotype-phenotype relationships indicates that modifier (environmental and/or inherited) components modulate expressivity of FVII deficiency, as reflected by patients with identical FVII mutations and discordant clinical phenotypes. Several treatment options are available for FVII deficiency: the most effective are plasma-derived FVII concentrates and recombinant activated FVII (rFVIIa). Treatment-related side effects are rare.
Assuntos
Deficiência do Fator VII/genética , Fator VII/genética , Trombose Venosa/etiologia , Fatores de Coagulação Sanguínea/uso terapêutico , Deficiência do Fator VII/sangue , Fator VIIa/fisiologia , Fator VIIa/uso terapêutico , Feminino , Genótipo , Humanos , Recém-Nascido , Masculino , Menorragia/etiologia , Menorragia/genética , Menorragia/terapia , Tempo de Tromboplastina Parcial , Fenótipo , Gravidez , Diagnóstico Pré-Natal , Tempo de Protrombina , Proteínas Recombinantes/uso terapêuticoRESUMO
The discovery of the Janus kinase 2 Val617Phe mutation has brought new insights into the development of myeloproliferative disorders; however, the pathogenesis of essential thrombocythemia and its related thrombotic complications has not been completely understood. Although the Janus kinase 2 Val617Phe mutation confirms the initially suspected clonal character of the disease, factors influencing clonal transformation and expansion in the bone marrow have not been fully detected. Furthermore, patients affected by essential thrombocythemia who are carriers of the Janus kinase 2 Val617Phe mutation show a higher incidence of venous thromboembolism both before, and at the time of diagnosis, compared with noncarriers, and recent evidence of splanchnic and cerebral vein thrombosis in carriers of the Janus kinase 2 Val617Phe mutation has been reported. The intake of oral contraceptives is a strong and independent risk factor for venous thromboembolism. In addition, in-vitro tests showed both an altered primary haemostatic plug formation and enhanced platelet aggregation in patients taking such drugs. Little is known, though, about the influence of steroid hormones on both megakaryopoiesis and platelet function in patients with the Janus kinase 2 Val617Phe mutation. Herewith, we report the case of a 30-year-old woman who took a third generation oral contraceptive for 5 months and developed an essential thrombocythemia with spleno-portal axis and superior mesenteric vein thrombosis. She was found to carry the kinase gene Janus kinase 2 mutation.
Assuntos
Anticoncepcionais Orais Hormonais/administração & dosagem , Janus Quinase 2/genética , Veias Mesentéricas , Mutação de Sentido Incorreto , Trombocitopenia/genética , Trombose/genética , Adulto , Feminino , Humanos , Janus Quinase 2/metabolismo , Circulação Esplâncnica , Trombocitopenia/enzimologia , Trombose/enzimologiaRESUMO
We evaluated a simplified algorithm for safely postponing diagnostic imaging for pulmonary embolism (PE). At the index visit, patients were identified as being at high or low risk of PE; the former received full dosage low molecular weight heparin while the latter were left untreated until performance of diagnostic imaging (max 72 hours). During this period, no thromboembolic events occurred in low-risk patients (0/211, 0.% [upper 95% CI 0.9%]); only one event occurred in those at high-risk (1/125, 0.8% [upper 95% CI, 1.2]). Our study demonstrates that diagnostic imaging for PE can be safely deferred for up to 3 days.
Assuntos
Algoritmos , Embolia Pulmonar/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticoagulantes/uso terapêutico , Diagnóstico Precoce , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Embolia Pulmonar/tratamento farmacológico , Risco , Tromboembolia/prevenção & controle , Trombofilia/complicações , Trombofilia/diagnóstico , Fatores de Tempo , Tomografia Computadorizada Espiral , Resultado do Tratamento , Trombose Venosa/prevenção & controle , Relação Ventilação-PerfusãoRESUMO
The intake of steroid hormone contraceptives is a strong and independent risk factor for venous thromboembolism. Several studies have assessed an increased risk of venous thromboembolism in women using oral contraceptives who are carriers of the G20210A mutation in the prothrombin gene. Most trials evaluating the thrombotic risk of oral contraceptives are based on combined oral preparations, but only a few focus on progestogen-only oral preparations. Results from such studies are conflicting and globally assess the thrombotic risk, ranging from modest to slightly increased. Furthermore, little is known about the relationship between the C677T mutation in the methylenetetrahydrofolate reductase gene and the progestogen-based preparations. Herewith we report the case of a 49-year-old woman with a complex genetic thrombosis risk factor who had taken oral progesterone for 15 months without any complication, but then experienced severe left upper extremity deep vein thrombosis 2 months after the drug suspension.
Assuntos
Anticoncepcionais Orais Hormonais/efeitos adversos , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Mutação Puntual , Progesterona/efeitos adversos , Trombose Venosa/induzido quimicamente , Trombose Venosa/genética , Anticoncepcionais Orais Hormonais/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Progesterona/administração & dosagem , Protrombina/genética , Fatores de Risco , Fatores de Tempo , Extremidade Superior/irrigação sanguínea , Trombose Venosa/enzimologiaRESUMO
Factor VII deficiency is the most common among rare inherited autosomal recessive bleeding disorders, and is a chameleon disease due to the lack of a direct correlation between plasma levels of coagulation Factor VII and bleeding manifestations. Clinical phenotypes range from asymptomatic condition-even in homozygous subjects-to severe life-threatening bleedings (central nervous system, gastrointestinal bleeding). Prediction of bleeding risk is thus based on multiple parameters that challenge disease management. Spontaneous or surgical bleedings require accurate treatment schedules, and patients at high risk of severe hemorrhages may need prophylaxis from childhood onwards. The aim of the current review is to depict an updated summary of clinical phenotype, laboratory diagnosis, and treatment of inherited Factor VII deficiency.
RESUMO
Congenital factor VII (FVII) deficiency is a consequence of a genetic polymorphism that can produce a wide spectrum of disease severity. Mildly affected patients may experience increased bleeding after surgery, trauma or mucosal bleeding, while spontaneous and life-threatening bleeding occurs in patients who are severely affected. Replacement therapy is the mainstay of treatment for patients with FVII deficiency. This has traditionally been achieved using fresh frozen plasma (FFP), prothrombin complex concentrates (PCCs), or plasma-derived FVII concentrates. However, recombinant activated FVII is now widely used for therapy in these patients. As cases of FVII deficiency tend to be encountered infrequently in most centers, no consolidated evidence-based therapeutic regimens have evolved and the side effects of the available treatments have not been comprehensively evaluated. Consequently, an online registry, the Seven Treatment Evaluation Registry (STER) has been set up. This is a prospective study that aims to evaluate the efficacy and safety of the different therapeutic options with which FVII-deficient patients may be treated. Recruitment of patients into the study is currently underway.
Assuntos
Fatores de Coagulação Sanguínea/uso terapêutico , Transfusão de Componentes Sanguíneos , Deficiência do Fator VII/terapia , Fator VIIa/uso terapêutico , Plasma , Sistema de Registros , Perda Sanguínea Cirúrgica/prevenção & controle , Estudos de Avaliação como Assunto , Deficiência do Fator VII/classificação , Deficiência do Fator VII/complicações , HumanosAssuntos
Fator IX , Fator VIII , Hemofilia A , Hemofilia B , Fator IX/administração & dosagem , Fator IX/economia , Fator VIII/administração & dosagem , Fator VIII/economia , Feminino , Hemofilia A/economia , Hemofilia A/prevenção & controle , Hemofilia B/economia , Hemofilia B/prevenção & controle , Humanos , Itália , Masculino , Inquéritos e QuestionáriosRESUMO
To investigate the relationship between clinical phenotype, clotting activity (FVIIc) and FVII genotype, a multi-center study of factor VII (FVII) congenital deficiency with centralized genotyping and specific functional assays was carried out. FVII mutations characterized in patients (n=313) were extremely heterogeneous (103 different, 22 novel). Clinical phenotypes ranged from asymptomatic condition, including 15 homozygotes and 14 double heterozygotes, to patients with a severe disease characterized by life-threatening and disabling symptoms (CNS, GI bleeding and hemarthrosis) strongly associated with an early age of presentation. Based on type and number of symptoms we classified 90 'severe' (median FVIIc 1.4%, IQR [Interquartile Range] 0.9-3.8), 83 'moderate' (FVIIc 3%, IQR 1-21.7), and 140 'mild' bleeders (FVIIc 14%, IQR 3-31). The significantly different FVIIc levels, and the decreasing prevalence of homozygotes or double heterozygotes among severe (98%), moderate (84%) and mild (56%) bleeders, further support our classification. The excess of females among moderate bleeders (female/male ratio = 2.6) is attributable to menorrhagia. There was no evidence for modulation of clinical features by frequent functional polymorphisms. Homozygotes for the same mutation (Ala294Val; 11125delC) with similar FVIIc and FXa generation levels, showed striking differences in clinical phenotypes. Our study depicts the ample clinical picture of this rare disorder, proposes a severity classification and provides arguments for the early management of the disease in the severe cases. Genotype-phenotype relationships indicate the presence of major environmental and/or extragenic components modulating expressivity of FVII deficiency.
Assuntos
Deficiência do Fator VII/epidemiologia , Deficiência do Fator VII/genética , Fator VII/genética , Variação Genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Deficiência do Fator VII/congênito , Fator Xa/metabolismo , Feminino , Genótipo , Hemorragia , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação , Fenótipo , Fatores SexuaisRESUMO
BACKGROUND: Treatment of patients with suspected deep vein thrombosis (DVT) or pulmonary embolism (PE) is problematic if diagnostic imaging is not immediately available. Pretest clinical probability (PCP) and D-dimer assessment can be used to identify patients for whom empirical protective anticoagulation is indicated. To evaluate whether PCP and D-dimer assessment, together with the use of low-molecular-weight heparins (LMWHs), allow objective appraisal of DVT and PE to be deferred for up to 72 hours, patients with suspected DVT and PE were prospectively examined. METHODS: Patients identified with a high PCP or a moderate PCP with positive D-dimer test results received a protective full-dose treatment of LMWH; the remaining patients were discharged without anticoagulant administration. However, all patients were scheduled to undergo objective tests for DVT or PE within 72 hours. Standard antithrombotic therapy was administered when deferred diagnostic tests confirmed venous thromboembolism. RESULTS: In total, 409 consecutive patients with suspected DVT and 124 with suspected PE were included in this study. A total of 23.8% (95% confidence interval [CI], 20.3%-27.3%) of patients had confirmed venous thromboembolism. At the short-term follow-up (72 hours), only a single thromboembolic event (0.2%; upper 95% CI, 0.6%) had occurred, whereas at the 3-month follow-up, 5 events (1.2%; 95% CI, 0.2%-2.1%) had occurred in patients in whom diagnosis of DVT or PE had previously been ruled out. None of the patients had major bleeding events. Ninety percent of patients were treated as outpatients. CONCLUSION: Our study demonstrates that this approach allows the safe deferral of diagnostic procedures for DVT and PE for up to 72 hours.