RESUMEN
Von Willebrand disease (VWD) is the most common congenital bleeding disorder, with a clinical presentation of mucocutaneous and surgical bleeding varying from mild to severe. It is inherited in an autosomal dominant or autosomal recessive manner. The disease is caused by quantitative or qualitative deficiency of the von Willebrand factor (VWF) and is classified as type 1, 2 (2A, 2B, 2M, 2N), and 3. Although type 1 VWD is the most common form of VWD, the f ormal cutoff for diagnosis remains a subject of debate. In our paper, we present results of studies regarding the clinical and laboratory importance of a new type of bleeding disorder called low VWF. The new guidelines for VWD diagnosis and management suggested that patients with historically type 1 VWD should be divided into 2 subsets: type 1 VWD with a VWF antigen level (VWF:Ag) of less than 30 IU/dl or less than 40 IU/dl, in which about 80% of patients exhibited VWF gene mutations, and low VWF with a VWF:Ag level of 30 to 50 IU/dl or 40 to 50 IU/dl, in which the causative mutation is detected in merely 40% of patients and in most families, inheritance is not dependent on the locus of VWF on chromosome 12. Previously, moderately reduced VWF levels (30-50 IU/dl) were considered a risk factor for bleeding, but not a true bleeding disorder, and this condition was named low VWF. Recently, it was documented in a large group of patients with type 1 VWD and low VWF that bleeding score does not correlate with VWF:Ag and bleeding symptoms in type 1 VWD (<30 IU/dl) and low VWF can change from infrequent and moderate to severe bleeds. Because the plasma concentration of VWF depends on many physiological and pathological factors that may mask the diagnosis of VWD, separation of the group of patients with low VWF (30-50 IU/dl) from those with type 1 VWD may delay or prevent them from receiving appropriate treatment. Diagnosis of VWD in each case, particularly those with a slight decrease in VWF (30-50 IU/dl), should be based primarily on the clinical manifestations and family history of hemorrhagic diathesis.
Asunto(s)
Manejo de la Enfermedad , Enfermedades de von Willebrand/diagnóstico , Femenino , Humanos , Masculino , Mutación , Enfermedad de von Willebrand Tipo 1/diagnóstico , Enfermedad de von Willebrand Tipo 1/tratamiento farmacológico , Enfermedad de von Willebrand Tipo 1/epidemiología , Enfermedad de von Willebrand Tipo 1/genética , Enfermedades de von Willebrand/tratamiento farmacológico , Enfermedades de von Willebrand/epidemiología , Enfermedades de von Willebrand/genética , Factor de von Willebrand/genéticaRESUMEN
Porphyrias are diverse disorders that arise from various inherited enzyme defects in the heme biosynthesis pathway, except for porphyria cutanea tarda (PCT), in which the enzyme deficiency in most cases is acquired. The biosynthetic blocks resulting from the defective enzymes are largely expressed either in the liver or bone marrow, the sites where the majority of heme is produced. Although the pathophysiologic mechanisms of the clinical manifestations of the porphyrias are not fully understood, two cardinal features prevail: skin photosensitivity and neurologic symptoms of intermittent autonomic neuropathy, acute neurovisceral attacks, and disorders of the nervous system. The primary diagnosis of the proband is based on biochemical testing, which is not always able to identify acute porphyrias, especially in asymptomatic family carriers when heme precursors and porphyrins excretion is normal, low-normal and high-reduced values of enzyme activity overlap, and hematological diseases responsible for abnormal blood cells distribution coexist. Molecular analysis of gene mutations responsible for each type of porphyria is the best diagnostic approach for symptomatic as well as presymptomatic gene carriers.
Asunto(s)
Enzimas/metabolismo , Hemo/biosíntesis , Porfirias/enzimología , Animales , Enzimas/genética , Regulación Enzimológica de la Expresión Génica , Predisposición Genética a la Enfermedad , Herencia , Humanos , Mutación , Linaje , Fenotipo , Porfirias/epidemiología , Porfirias/genética , Porfirias/fisiopatología , PronósticoRESUMEN
BACKGROUND: Acute intermittent porphyria (AIP) is an metabolic disorder characterized by a partial deficiency of the porphobilinogen deaminase, the enzyme of heme biosynthesis. The metabolic defect in AIP involves an approximately half-normal activity of porphobilinogen deaminase (PBGD, EC 4.3.1.8), the enzyme catalyzing condensation of four porphobilinogen molecules to hydroxymethylbilane. Due to tissue-specific alternative transcript splicing, the PBGD gene mutations within the range of exons 3-15 may lead to classical AIP involving erythrocytes and all the other tissues. Mutations within intron and exon 1 may result in the so-called non-erythroid AIP in which the PBGD activity is normal in erythrocytes and diminished in other tissues. OBJECTIVES: The aim of the present study was to characterise molecular errors in the PBGD gene in Polish patients with non-erythroid AIP and to evaluate the efficacy of the DNA sequencing method in the early diagnosis of this disorder. MATERIAL AND METHODS: Twenty five members of nine non-erythroid AIP families were assessed. In each of them DNA sequencing was performed using the Big Dye Terminator Cycle Sequencing Kit v.1.1 on the Hitachi 3730 Analyzer (Applied Biosystem, USA). RESULTS: Four mutations were detected in intron 1 of the PBGD gene, including one unreported novel mutation, 33+(4-12) del AGTGCTGAG, of an unknown biological mechanism, and three previously described mutations, i.e. 33+1 G > A, 33+2 T > C, 33+5 G > C, responsible for abnormal transcript splicing in the area of exon 1. Of 14 asymptomatic members of proband families in 6 subjects were diagnosed with AIP, and in 8 the AIP was excluded based on the DNA sequencing method. CONCLUSIONS: DNA sequencing based analysis is the only reliable method for correct diagnosis of asymptomatic non-erythroid AIP patients with normal urinary excretion of heme precursors. The mutations found in Polish patients with non-erythroid AIP represented those of splice defect and resulted in abnormal exon 1 splicing.
Asunto(s)
Empalme Alternativo , Eritrocitos/enzimología , Hidroximetilbilano Sintasa/genética , Mutación , Porfiria Intermitente Aguda/genética , Enfermedad Aguda , Adolescente , Adulto , Enfermedades Asintomáticas , Niño , Eritrocitos/patología , Exones , Femenino , Humanos , Hidroximetilbilano Sintasa/metabolismo , Intrones , Masculino , Persona de Mediana Edad , Linaje , Polonia , Porfiria Intermitente Aguda/diagnóstico , Porfiria Intermitente Aguda/enzimología , Porfiria Intermitente Aguda/patología , Análisis de Secuencia de ADNRESUMEN
Inherited factor VII (FVII) deficiency is a rare autosomal recessive hemorrhagic disorder. The major clinical symptoms include: bleeding from the oral cavity, epistaxis, menorrhagia, spontaneous hemarthros, bleeding to the gastrointestinal tract and central nervous system, and perioperative bleeding. The aim of this study was to present our experience in preventing bleeding and hemorrhagic disorders in surgical patients with inherited FVII deficiency by using recombinant activated FVIIa (rFVIIa), and with prothrombin complex concentrates (PCCs). In 2002-2011, 17 patients with inherited FVII deficiency underwent surgery. Thirteen patients had isolated FVII deficiency below 10%, and four patients 10-25. To prevent bleeding and hemorrhagic complications, we administered small single doses of rFVIIa (Novo-Seven) at 12-h intervals to 15 patients on surgery day and on day 1 following surgery, then every 24âh; PCCs were administered (Prothromplex, Beriplex) to two patients. No symptoms of bleeding, hemorrhagic or thromboembolic complications were observed in the perioperative and 1-month observation period in surgical patients treated with rFVIIa. One patient treated with PCC (Prothromplex) developed distal deep vein thrombosis on postoperative day 7. The results suggest that small, single, every 12-h doses of rFVIIa (NovoSeven) and in next days after surgery one time every 24âh are well tolerated and effective for prevention of thromboembolic, bleeding and hemorrhagic complications in FVII-deficient patients. Antithrombotic prophylaxis with low-molecular-weight heparin should be applied in patients using PCCs.
Asunto(s)
Factores de Coagulación Sanguínea/uso terapéutico , Pérdida de Sangre Quirúrgica/prevención & control , Procedimientos Quirúrgicos Electivos , Deficiencia del Factor VII/complicaciones , Factor VIIa/uso terapéutico , Hemorragia Posoperatoria/prevención & control , Adulto , Anciano , Factores de Coagulación Sanguínea/administración & dosificación , Pruebas de Coagulación Sanguínea , Deficiencia del Factor VII/tratamiento farmacológico , Factor VIIa/administración & dosificación , Femenino , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Cuidados Posoperatorios , Medicación Preanestésica , Cuidados Preoperatorios , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/uso terapéutico , Adulto JovenRESUMEN
Acquired von Willebrand syndrome (AVWS) is an acquired bleeding disorder with clinical and laboratory features similar to those of the inherited form of the disease. AVWS is reported in many disorders, most frequently in myeloproliferative neoplasms and in, among others, essential thrombocythemia (ET). Interestingly, ET is associated with both the thrombotic and haemorrhagic complications, which occur in 20 % and 5-30 % of patients, respectively. The present report concerns a 38-year-old man, suffering from ET, who presented with two episodes of post-arthroscopic joint bleeding after synovectomy required for the treatment of synovial hypertrophy and chronic left knee joint synovitis. We discuss the current diagnostic approaches, as well as the risk factors predisposing to bleeding and its management, in patients with essential thrombocythemia.
Asunto(s)
Artroscopía/efectos adversos , Hemorragia/etiología , Janus Quinasa 2/genética , Sinovitis/cirugía , Trombocitemia Esencial/complicaciones , Enfermedades de von Willebrand/complicaciones , Adulto , Hemorragia/diagnóstico , Hemorragia/genética , Humanos , Articulación de la Rodilla/cirugía , Masculino , Recuento de Plaquetas , Mutación Puntual , Sinovitis/complicaciones , Sinovitis/diagnóstico , Sinovitis/genética , Trombocitemia Esencial/diagnóstico , Trombocitemia Esencial/genética , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/genética , Factor de von Willebrand/análisisRESUMEN
The aim of the study was to determine the prevalence rate for inherited thrombophilia (IT) in patients with chronic (CVU) and recurrent venous leg ulceration. We also investigated and evaluated the severity of the clinical pattern of CVU in patients with and without IT. We examined 110 patients with CVU (the study group) and 110 healthy subjects (the control group). We prepared a questionnaire to be completed by each study participant. Ultrasound Doppler color imaging or/and duplex ultrasonography was performed to evaluate the efficiency of the venous system. The ankle-brachial index was calculated to determine the efficiency of the arterial system. We examined both groups for the presence of IT. IT was diagnosed in 30% of study group and in 1.8% of control group. Our diagnoses of deep vein thrombosis (DVT) were based on medical interviews, physical examinations, and an ultrasonography of the venous system and concerned 64 study group patients (58.2%), 35 of whom (31.8%) experienced recurrent DVT. Proximal and/or distal DVT was determined in an interview and/or by an ultrasonography performed for all patients with CVU and IT. In 94% of these patients, DVT was recurrent, and in 88% of patients with CVU and IT, we observed recurrent DVT and CVU. It recurred more often and persisted longer when compared to patients with CVU and no IT, despite similar management. No differences were observed in ulcer size, localization, or pain level related to ulceration between patients with CVU and IT and those with CVU and no IT.
Asunto(s)
Trombofilia/complicaciones , Trombofilia/genética , Úlcera Varicosa/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Pruebas de Coagulación Sanguínea , Enfermedad Crónica , Europa (Continente)/epidemiología , Femenino , Humanos , Pierna/irrigación sanguínea , Masculino , Persona de Mediana Edad , Prevalencia , Recurrencia , Trombofilia/diagnóstico , Trombofilia/epidemiología , Ultrasonografía Doppler Dúplex , Úlcera Varicosa/genética , Várices/diagnóstico por imagen , Tromboembolia Venosa/complicaciones , Tromboembolia Venosa/diagnóstico por imagenRESUMEN
The recently discovered JAK2 V617F point mutation, found in 50-60% of ET patients, has been reported to be associated with a higher risk of thrombotic events. In this study, we explored if JAK2 V617F mutation, or coexisting thrombophilic and hemostatic risk factors, contributed to these complications. We examined 32 patients with ET, and looked for pathogenetic JAK2 V617F mutation and prothrombotic genes mutations: factor V Leiden, prothrombin and MTHFR. We also evaluated plasma levels of fibrinogen, factors VIII and XII, AT, protein C, protein S and serum level of homocysteine. Urokinase concentration was assessed in patients' plasma as well as platelet lysates. There was no difference in the number of thrombotic complications between ET patients with and without JAK2 mutation. However, we found a number of thrombophilic and hemostatic risk factors that could contribute to thrombotic complications in ET patients.
Asunto(s)
Hemostasis/genética , Janus Quinasa 2/genética , Mutación Puntual/genética , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/enzimología , Trombofilia/complicaciones , Trombofilia/enzimología , Factores de Coagulación Sanguínea , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Hemorragia/complicaciones , Hemorragia/enzimología , Hemorragia/genética , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Trombocitemia Esencial/genética , Trombofilia/genéticaRESUMEN
BACKGROUND: High molecular weight von Willebrand factor (vWF) multimers (HMWM) are often deficient in patients with severe aortic stenosis (AS) owing to shear stress-enhanced proteolysis of vWF. It has also been reported that AS is associated with increased activation of blood coagulation. OBJECTIVE: To investigate whether patients with AS with a deficiency in vWF HMWM have enhanced thrombin generation and platelet activation in vivo. DESIGN: Based on the analysis of vWF HMWM performed using immunolocalisation, 11 subjects with vWF HMWM deficiency (low %HMWM group) were identified and compared with 42 patients with AS with a normal distribution of vWF HMWM (normal %HMWM group). Plasma thrombin markers thrombin-antithrombin complexes (TAT) and prothrombin factor 1+2 (F1.2) plus platelet activation markers soluble CD40 ligand (sCD40L), ß-thromboglobulin and P-selectin were also measured. PATIENTS: 48 consecutive patients with severe AS and five with moderate AS, free of angiographically-proven coronary artery disease and clinically overt bleeding, were studied. RESULTS: Patients in the low %HMWM group had 34.8% higher maximal transvalvular gradient (p = 0.0003) and 44.8% higher mean gradient (p = 0.0002) than those in the normal %HMWM group. Thrombin formation was enhanced in the low %HMWM group (F1.2, 284.5 ± 63.7 vs 216.9 ± 62.5 pmol/l, p = 0.004; thrombin-antithrombin, 4.89 ± 1.3 vs 4.06 ± 0.9 µg/l, p = 0.02) and both markers showed inverse correlations with the percentage of vWF HMWM (r = -0.59, p = 0.002; r = -0.42, p = 0.03, respectively). In the low %HMWM group sCD40L (279.4 ± 60.7 vs 221.4 ± 41.7 pmol/l, p = 0.003) and ß-thromboglobulin (73.1 ± 9.2 vs 64.5 ± 8.5 IU/ml, p = 0.04), but not P-selectin, were also higher than in the remaining patients with AS. CONCLUSION: Patients with advanced AS deficient in vWF HMWM are characterised by enhanced thrombin formation and platelet activation. This observation indicates the ambivalent impact of high shear stress in AS on haemostasis and might help explain two aspects of AS-Heyde syndrome and increased risk of thromboembolism.
Asunto(s)
Estenosis de la Válvula Aórtica/sangre , Coagulación Sanguínea/fisiología , Activación Plaquetaria/fisiología , Trombina/análisis , Enfermedades de von Willebrand/sangre , Factor de von Willebrand/análisis , Anciano , Estenosis de la Válvula Aórtica/diagnóstico , Densitometría , Progresión de la Enfermedad , Ecocardiografía Doppler , Electroforesis , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Peso Molecular , Pronóstico , Índice de Severidad de la Enfermedad , Trombina/metabolismo , Enfermedades de von Willebrand/diagnóstico , Enfermedades de von Willebrand/etiología , Factor de von Willebrand/metabolismoRESUMEN
The aim of the study is to present our own perioperative bridging therapy with low molecular weight heparin (LMWH) for surgical patients with thrombophilia on long-term acenokumarol therapy [oral anticoagulant (OAC)]. In some European countries, the drug used in secondary antithrombotic prophylaxis is acenokumarol. Forty-two patients with inherited thrombophilia and 21 with antiphospholipid syndrome underwent surgery. All patients were on long-term OAC. This OAC was interrupted 2 days before elective surgery and since that day half of the individual therapeutic dose of LMWH was administered. On day of surgery, the LMWH therapeutic dose was divided into two parts. Starting with day 2 after surgery, the patient was again given half of the individual dose of LMWH every 24 h. On day 4, OAC was additionally included. Both drugs were administered until stabilization of international normalized ratio (INR) values within the therapeutic target for 2 consecutive days. LMWH was then interrupted, whereas OAC continued. No symptoms or episodes of venous thromboembolism were observed. No intraoperative or postoperative hemorrhagic complications were reported. The results suggest that our perioperative bridging therapy is safe and effective for prevention of thromboembolic and hemorrhagic complications.
Asunto(s)
Acenocumarol/uso terapéutico , Anticoagulantes/uso terapéutico , Síndrome Antifosfolípido/complicaciones , Heparina de Bajo-Peso-Molecular/uso terapéutico , Complicaciones Posoperatorias/prevención & control , Tromboembolia/prevención & control , Acenocumarol/administración & dosificación , Adulto , Anciano , Anticoagulantes/administración & dosificación , Femenino , Heparina de Bajo-Peso-Molecular/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Tromboembolia/complicacionesRESUMEN
Polymorphic configurations of the coagulation factor VII gene (F7) are associated with plasma levels of FVII antigen (FVII:Ag) and FVII coagulant activity (FVII:C). Our aim was to determine whether F7 polymorphisms influence risk of ischemic stroke in young adults. One hundred and fifty survivors of ischemic stroke before the age of 45 and an equal number of age and sex-matched controls were genotyped for five F7 polymorphisms: the -A670C transversion, -323 decanucleotide insertion (P + 10), the number (which varies between five and eight) of a 37 base pair repeat polymorphisms in intron 7 (IVS7), amino acid substitution R353Q, and +154AA insertion. 353Q, P + 10 and +154AA were demonstrated to associate with significantly decreased plasma FVII:Ag, whereas -670C and IVS7 seven or higher were associated with a tendency towards increased plasma FVII:Ag. The former three polymorphisms were significantly more common in control individuals than in patients, whereas the latter two were significantly more common in patients than in control individuals. The multiple logistic regression analysis revealed that two F7 polymorphisms, -670C and IVS7 seven or higher, are independent risk factors for ischemic stroke in young adult patients.
Asunto(s)
Factor VII/genética , Polimorfismo Genético/genética , Accidente Cerebrovascular/genética , Adulto , Femenino , Humanos , Masculino , Adulto JovenAsunto(s)
Estenosis de la Válvula Aórtica/cirugía , Hemorragia Gastrointestinal/etiología , Implantación de Prótesis de Válvulas Cardíacas , Factor de von Willebrand/metabolismo , Anciano , Estenosis de la Válvula Aórtica/sangre , Estenosis de la Válvula Aórtica/complicaciones , Bioprótesis , Pruebas de Coagulación Sanguínea , Femenino , Hemorragia Gastrointestinal/sangre , Hemorragia Gastrointestinal/cirugía , Prótesis Valvulares Cardíacas , Implantación de Prótesis de Válvulas Cardíacas/instrumentación , Humanos , Peso Molecular , Pruebas de Función Plaquetaria , Multimerización de Proteína , Factores de Riesgo , Índice de Severidad de la Enfermedad , Síndrome , Resultado del Tratamiento , Enfermedades de von Willebrand/sangre , Enfermedades de von Willebrand/complicacionesRESUMEN
Congenital combined coagulation factor V and coagulation factor VIII deficiency (F5F8D) is a rare bleeding disorder due to mutations in the LMAN1 or MCFD2 genes. Here we report the first Polish family with F5F8 deficiency due to a mutation in the MCFD2 gene. The proposita suffered from mild bleeding including epistaxis, menorrhagia, bleeding after dental extraction, and bruising after minor traumas. The F5F8 deficiency was diagnosed due to an excessive postpartum bleeding at the age of 31. Analysis of further family members revealed a second affected individual. Sequencing of the MCFD2 gene and its flanking regions in both patients demonstrated a novel homozygous missense mutation within the second elongation factor hand domain resulting in a substitution of tyrosine by asparagine at amino acid position 135 (p.Tyr135Asn). This variant represents the third missense mutation found in the MCFD2 gene and most likely disrupts the MCFD2-LMAN1 interaction, thus leading to the disease phenotype.