RESUMO
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
Intracranial haemorrhage (ICH) is the most serious bleeding symptom in haemophiliacs, resulting in high rates of mortality and disabling sequelae. The Association of Italian Haemophilia Centres carried out a retrospective survey (1987-2008) of ICH occurring in haemophiliacs with the goals to establish: (i) incidence, location of bleeding, death rate and disabling sequels; (ii) risk factors for ICH; and (iii) treatment used during the acute phase of ICH and for recurrence prevention. A total of 112 ICH episodes had occurred in 88 patients (78 haemophilia A, 10 haemophilia B), 24 of whom experienced recurrences. The cumulative hazard of ICH for the whole cohort over the entire follow-up period was 26.7 per 1000 patients, and the annualized rate of ICH was 2.50 events per 1000 patients (95% CI 1.90-3.31). The risk of ICH was higher in the youngest children (24.4 per 1000, 95% CI 12.7-47.0 in the first year of age and 14.9, 95% CI 7.1-31.4 in the second year of age) and then progressively rose again after the age of 40. Univariate, bivariate (age-adjusted) and multivariate analysis investigating the effects of patient characteristics on ICH occurrence showed that haemophilia severity and inhibitor status were strongly associated with ICH [severe vs. mild, HR 3.96 (2.39-6.57); inhibitor vs. non-inhibitor 2.52 (1.46-4.35)]. HCV infection was also associated with the risk of ICH [HR 1.83 (1.25-2.69)]. Therapeutic suggestions based upon our experience to control ICH recurrence are provided.
Assuntos
Hemofilia A/complicações , Hemofilia B/complicações , Hemorragias Intracranianas/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Autoanticorpos/sangue , Fatores de Coagulação Sanguínea/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Hemofilia A/imunologia , Hemofilia B/imunologia , Humanos , Incidência , Lactente , Recém-Nascido , Hemorragias Intracranianas/prevenção & controle , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Fatores de Risco , Inquéritos e Questionários , Adulto JovemRESUMO
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
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
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
Klinefelter's syndrome is the most common cause of primary testicular failure, resulting in impairment of both spermatogenesis and testosterone production. It is a chromosomal disorder characterized by small, firm testes, azoospermia, gynecomastia, varying degrees of eunuchoidism and testosterone deficiency with elevated gonadotropin plasma levels. In Klinefelter's syndrome there is an increase of certain systemic diseases including venous thromboembolism. An increased thromboembolic risk in hypogonadic men has been explained with hypofibrinolysis due to androgen deficiency. Only two cases have been reported about the association between Klinefelter's syndrome and well-known congenital or acquired thrombophilias. We report the case of a 39-year-old patient with Klinefelter's syndrome who underwent severe deep venous thrombosis with pulmonary embolism, in the absence of any circumstantial triggering event. Further examinations also showed a double heterozygosis for G20210A prothrombin and factor V Leiden mutations. This case suggests that the increased thromboembolic risk, reported in Klinefelter's syndrome, can be worsened by the co-existence of one or more well-known thrombophilic conditions, as shown by the relatively young age of the patient. More studies are needed to clearly understand the pathogenesis of venous thromboembolism in males affected by Klinefelter's syndrome.
Assuntos
Fator V/genética , Síndrome de Klinefelter/complicações , Protrombina/genética , Tromboembolia/etiologia , Trombose Venosa/etiologia , Adulto , Heterozigoto , Humanos , Síndrome de Klinefelter/sangue , Masculino , Mutação Puntual , Tromboembolia/genética , Trombofilia/etiologia , Trombofilia/genética , Trombose Venosa/genéticaRESUMO
Hereditary combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX and X as well as natural anticoagulants protein C, protein S and protein Z. The spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases. The bleeding symptoms are often life-threatening, occur both spontaneously and in a surgical setting, and usually involve the skin and mucosae. A range of non-haemostatic symptoms are often present, including developmental and skeletal anomalies. VKCFD is an autosomal recessive disorder caused by mutations in the genes of either gamma-glutamyl carboxylase or vitamin K2,3-epoxide reductase complex. These two proteins are necessary for gamma-carboxylation, a post-synthetic modification that allows coagulation proteins to display their proper function. The developmental and skeletal anomalies seen in VKCFD are the result of defective gamma-carboxylation of a number of non-haemostatic proteins. Diagnostic differentiation from other conditions, both congenital and acquired, is mandatory and genotype analysis is needed to confirm the defect. Vitamin K administration is the mainstay of therapy in VKCFD, with plasma supplementation during surgery or severe bleeding episodes. In addition, prothrombin complex concentrates and combination therapy with recombinant activated FVII and vitamin K supplementation may constitute alternative treatment options. The overall prognosis is good and with the availability of several effective therapeutic options, VKCFD has only a small impact on the quality of life of affected patients.
Assuntos
Transtornos Herdados da Coagulação Sanguínea/fisiopatologia , Fatores de Coagulação Sanguínea/metabolismo , Proteínas Sanguíneas/metabolismo , Proteína C/metabolismo , Proteína S/metabolismo , Deficiência de Vitamina K/congênito , Transtornos Herdados da Coagulação Sanguínea/diagnóstico , Carbono-Carbono Ligases/genética , Carbono-Carbono Ligases/metabolismo , Humanos , Recém-Nascido , Proteínas Recombinantes/uso terapêutico , Vitamina K/uso terapêutico , Deficiência de Vitamina K/genéticaRESUMO
Essential thrombocythemia is a hematological disorder characterized by clonal hemopoiesis in the bone marrow and increased number of circulating platelets. It is usually discovered accidentally at the time of routine blood examinations or can become clinically evident with either thrombotic or hemorrhagic complications. In the present article, we describe the case of a 66-year-old woman with pneumonia due to Pneumocystis carinii, who experienced deep vein thrombosis and pulmonary embolism during hospitalization with a subsequent heparin-induced thrombocytopenia. Bone marrow examination performed after clinical improvement revealed the patient to be affected by essential thrombocythemia.
Assuntos
Anticoagulantes/efeitos adversos , Heparina/efeitos adversos , Embolia Pulmonar/etiologia , Trombocitemia Essencial/diagnóstico , Trombocitopenia/induzido quimicamente , Tromboflebite/etiologia , Idoso , Anticoagulantes/uso terapêutico , Feminino , Fondaparinux , Heparina/uso terapêutico , Humanos , Achados Incidentais , Fator Plaquetário 4/imunologia , Pneumonia por Pneumocystis/complicações , Polissacarídeos/uso terapêutico , Embolia Pulmonar/tratamento farmacológico , Trombocitemia Essencial/complicações , Trombocitopenia/imunologia , Tromboflebite/tratamento farmacológico , Varfarina/uso terapêuticoRESUMO
Combined deficiency of the vitamin K-dependent clotting factors (VKCFD) is a rare bleeding disorder involving defective gamma-carboxylation of coagulation factors II , VII, IX and X as well as natural anticoagulants protein C and protein S. The disease is characterized by a cluster of different, often life threatening, bleeding symptoms occurring both spontaneously and in a surgical setting. In the present paper we describe two different treatment modalities to be used both in a programmed surgical procedure and in an emergency scenario. As this disease is a natural model that resembles oral anticoagulation, our experience discloses a possible rationale in the use of recombinant activated FVII for warfarin reversal.
Assuntos
Transtornos Herdados da Coagulação Sanguínea/complicações , Perda Sanguínea Cirúrgica , Deficiência do Fator VII/genética , Hemostasia Cirúrgica/métodos , Oxigenases de Função Mista/deficiência , Extração Dentária , Adulto , Biópsia , Transtornos Herdados da Coagulação Sanguínea/tratamento farmacológico , Transtornos Herdados da Coagulação Sanguínea/genética , Testes de Coagulação Sanguínea , Fator VII/genética , Deficiência do Fator VII/tratamento farmacológico , Fator VIIa/uso terapêutico , Feminino , Gastroscopia , Homozigoto , Humanos , Oxigenases de Função Mista/genética , Proteínas Recombinantes/uso terapêutico , Vitamina K/uso terapêutico , Vitamina K Epóxido RedutasesRESUMO
Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm characterized by progressive anemia, massive splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis and in about 50% of cases the presence of JAK2V617F mutation. Curative therapy in PMF is currently possible only with allogeneic haematopoietic stem cell transplantation which is, unfortunately, associated with relatively high risks of mortality and morbidity which undermine its broad applications. Non-transplant treatment modalities are used for palliative purposes. Recently, anti-angiogenic drugs such as thalidomide have been used to treat these patients on the basis of the prominent bone marrow angiogenesis. Here, we report the case of a patient suffering from JAK2V617F-positive PMF with marked bone marrow neo-angiogenesis. The patient was treated with thalidomide but after 20 days developed life-threatening toxic epidermal necrolysis (TEN). To the best of our knowledge this is the first case of TEN in a patient with PMF under thalidomide therapy.