RESUMEN
INTRODUCTION: Deficiencies of plasminogen and plasminogen activator inhibitor type 1 (PAI-1) are rare disorders of fibrinolysis. Current laboratory assays for analysis of activity of plasminogen and PAI-1 do not provide an accurate correlation with clinical phenotype. METHODS: The Nijmegen Hemostasis Assay (NHA) was used to simultaneously measure thrombin and plasmin generation in 5 patients with plasminogen deficiency (PLGD) and 10 patients with complete PAI-1 deficiency. Parameters analysed included: lag time ratio, thrombin peak time ratio, thrombin peak height, thrombin potential (AUC), fibrin lysis time, plasmin peak height and plasmin potential. Parameters were expressed as a percentage compared to a reference value of 53 healthy normal controls. RESULTS: Patients with PLGD demonstrated a short lag time and thrombin peak time, with normal thrombin peak height but an increased AUC. Plasmin generation was able to be detected in only one (23% plasminogen activity) of the five PLGD patients. All ten PAI-1 deficient patients demonstrated a short lag and thrombin peak time, low thrombin peak height with normal AUC. Plasmin generation revealed an increased plasmin peak and plasmin potential; interestingly, there was a large variation between individual patients despite all patients having the same homozygous defect. CONCLUSION: Patients with either PLGD or PAI-1 deficiency show distinct abnormalities in plasmin and thrombin generation in the NHA. The differences observed in the propagation phase of thrombin generation may be explained by plasmin generation. These results suggest that disorders of fibrinolysis also influence coagulation and a global assay measuring both activities may better correlate with clinical outcome.
Asunto(s)
Trastornos de las Proteínas de Coagulación/metabolismo , Fibrinolisina/biosíntesis , Trastornos Hemorrágicos/metabolismo , Inhibidor 1 de Activador Plasminogénico/deficiencia , Trombina/biosíntesis , Adulto , Niño , Trastornos de las Proteínas de Coagulación/genética , Femenino , Genotipo , Trastornos Hemorrágicos/genética , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismoRESUMEN
BACKGROUND: Congenital disorders of glycosylation are rare inherited diseases affecting many different proteins. The lack of glycosylation notably affects the hemostatic system and leads to deficiencies of both procoagulant and anticoagulant factors. OBJECTIVE: To assess the hemostatic balance in patients with multiple coagulation disorders by using a thrombin generation assay. METHOD: We performed conventional coagulation assays and a thrombin generation assay on samples from patients with congenital disorder of glycosylation. The thrombin generation assay was performed before and after activation of the protein C system by the addition of soluble thrombomodulin. RESULTS: A total of 35 patients were included: 71% and 57% had low antithrombin and factor XI levels, respectively. Protein C and protein S levels were abnormally low in 29% and 26% of the patients, respectively, whereas only 11% displayed low factor IX levels. Under baseline conditions, the thrombin generation assay revealed a significantly higher endogenous thrombin potential and thrombin peak in patients, relative to controls. After spiking with thrombomodulin, we observed impaired involvement of the protein C system. Hence, 54% of patients displayed a hypercoagulant phenotype in vitro. All the patients with a history of stroke-like episodes or thrombosis displayed this hypercoagulant phenotype. CONCLUSION: A thrombin generation assay revealed a hypercoagulant in vitro phenotype under baseline condition; this was accentuated by impaired involvement of the protein C system. This procoagulant phenotype may thus reflect the risk of severe vascular complications. Further research will have to determine whether the thrombin generation assay is predictive of vascular events.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/sangre , Trastornos de las Proteínas de Coagulación/sangre , Trastornos Congénitos de Glicosilación/sangre , Trombina/metabolismo , Adolescente , Coagulación Sanguínea/genética , Trastornos de la Coagulación Sanguínea Heredados/diagnóstico , Trastornos de la Coagulación Sanguínea Heredados/genética , Niño , Preescolar , Trastornos de las Proteínas de Coagulación/diagnóstico , Trastornos de las Proteínas de Coagulación/genética , Trastornos Congénitos de Glicosilación/diagnóstico , Trastornos Congénitos de Glicosilación/genética , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Paris , Fenotipo , Estudios Retrospectivos , EspañaRESUMEN
Molecular strategies tailored to promote/correct the expression and/or processing of defective coagulation factors would represent innovative therapeutic approaches beyond standard substitutive therapy. Here, we focus on the molecular mechanisms and determinants underlying innovative approaches acting at DNA, mRNA and protein levels in inherited coagulation factor deficiencies, and in particular on: (i) gene editing approaches, which have permitted intervention at the DNA level through the specific recognition, cleavage, repair/correction or activation of target sequences, even in mutated gene contexts; (ii) the rescue of altered pre-mRNA processing through the engineering of key spliceosome components able to promote correct exon recognition and, in turn, the synthesis and secretion of functional factors, as well as the effects on the splicing of missense changes affecting exonic splicing elements; this section includes antisense oligonucleotide- or siRNA-mediated approaches to down-regulate target genes; (iii) the rescue of protein synthesis/function through the induction of ribosome readthrough targeting nonsense variants or the correction of folding defects caused by amino acid substitutions. Overall, these approaches have shown the ability to rescue the expression and/or function of potentially therapeutic levels of coagulation factors in different disease models, thus supporting further studies in the future aimed at evaluating the clinical translatability of these new strategies.
Asunto(s)
Trastornos de las Proteínas de Coagulación/genética , Trastornos de las Proteínas de Coagulación/terapia , Terapia Genética/métodos , Animales , Factores de Coagulación Sanguínea/genética , Sistemas CRISPR-Cas , ADN/genética , Edición Génica/métodos , Humanos , ARN Mensajero/genéticaAsunto(s)
Trastornos de las Proteínas de Coagulación/tratamiento farmacológico , Terapia de Reemplazo Enzimático , Trastornos de la Audición/tratamiento farmacológico , Plasminógeno/uso terapéutico , Neumonía Bacteriana/tratamiento farmacológico , Infecciones por Pseudomonas/tratamiento farmacológico , Adolescente , Trastornos de las Proteínas de Coagulación/genética , Codón de Terminación , Trastornos de la Audición/etiología , Trastornos de la Audición/genética , Humanos , Masculino , Neumonía Bacteriana/etiología , Neumonía Bacteriana/genética , Infecciones por Pseudomonas/etiología , Infecciones por Pseudomonas/genéticaRESUMEN
BACKGROUND: Autosomal recessive bleeding disorders (ARBDs) include deficiencies of clotting factors I, II, V, VII, X, XI, XIII, vitamin K dependent clotting factors, combined factor V & VIII, Von Willebrand Disease (vWD) type 3, Glanzmann's thrombasthenia (GT) and Bernard-Soulier syndrome. Patients with primary bleeding disorders from all the major provincial capitals of Pakistan were screened for ARBDs. Prothrombin (PT), activated partial thromboplastin time (APTT), bleeding time (BT) and fibrinogen levels were measured. Cases with isolated prolonged APTT were tested for factors VIII and IX using factor assays This was followed by FXI:C level assessment in cases with normal FVIII and FIX levels. vWD was screened in patients with low FVIII levels. Factors II, V and X were tested in patients with simultaneous prolongation of PT and APTT. Peripheral blood film examination and platelet aggregation studies were performed to assess platelet disorders. Urea clot solubility testing was done to detect Factor XIII levels where platelet function tests were normal. Descriptive analysis was done using SPSS version 16. RESULTS: Of the 429 suspected bleeding disorder patients, 148 (35%) were diagnosed with hemophilia A and 211 (49.1%) patients had ARBDs. 70 patients (16.3%) remained undiagnosed. Out of 211 patients with ARBD; 95 (33.8%) had vWD type 3. Fibrinogen deficiency was found in 34 patients (12%), GT in 27 (9.6%), factor XIII deficiency in 13 (4.6%), factor VII deficiency in 12 (4.3%), factor V deficiency in 9 (3.2%). Eight patients (2.8%) had vitamin K-dependent clotting factor deficiency, Bernard-Soulier syndrome was diagnosed in seven patients (2.5%), factor X deficiency in 2 (0.7%), factor II deficiency in 2 (0.7%), factor XI deficiency and combined factor V and VIII deficiency in 1 (0.4%) patient each. CONCLUSION: vWD type 3 was the most common ARBD found in our sample of patients in Pakistan, followed by fibrinogen deficiency and GT in respective order.
Asunto(s)
Trastornos de las Proteínas de Coagulación/epidemiología , Trastornos de las Proteínas de Coagulación/genética , Genes Recesivos , Adolescente , Niño , Consanguinidad , Estudios Transversales , Femenino , Humanos , Masculino , Pakistán/epidemiologíaRESUMEN
Recently several variants of clotting factors have shown a peculiar behavior so that they appear as new defects. The factors involved are FII, FV and FIX. Prothrombin deficiency is usually associated with bleeding. Recently a few prothrombin abnormalities involving Arg396 mutations, have been demonstrated to show antithrombin resistance with the consequent appearance of a thrombophilic state and venous thromboses in young age. The same is true for an abnormal FIX (FIX Padua). The thrombotic manifestations in the latter condition are also venous. The abnormal FIX (FIX Padua) is characterized by a great increase in FIX activity whereas FIX antigen is only slightly increased. The condition is due to an Arg338Lys mutation. The increased intrinsic clotting activity of this abnormal FIX is being investigated as a useful therapeutic approach in homophile B patients. Another new clotting disorder is represented by two abnormal FV (FV East Texas and FV Amsterdam). These are characterized by a deletion of part of the B domain of FV resulting in a "short" FV. The condition is characterized by a mild bleeding tendency due to high levels of Tissue Factor pathway inhibitor. The "short" factor V is in fact resistant to the action of Tissue Factor pathway inhibitor which is sharply increased in these patients. These new clotting entities have again demonstrated that the study of patients who show a tendency to venous thrombosis or a mild bleeding condition that cannot be explained on the basis of our current concepts of blood coagulation, may represent "new" coagulation disorders. All persons interested in thrombotic or hemorrhagic disorders should be informed about these new clinical and laboratory conditions.
Asunto(s)
Factores de Coagulación Sanguínea/genética , Factores de Coagulación Sanguínea/metabolismo , Trastornos de las Proteínas de Coagulación , Trastornos de las Proteínas de Coagulación/sangre , Trastornos de las Proteínas de Coagulación/clasificación , Trastornos de las Proteínas de Coagulación/genética , Trastornos de las Proteínas de Coagulación/terapia , HumanosRESUMEN
Rare diseases are defined as life-threatening or chronically debilitating diseases with a prevalence of less than one per 2000 according to the European Union or one per 1250 according to the USA. Congenital rare bleeding disorders RBD are reported in most populations, with incidence varying from 1 in 5000 (Hemophilia A), 1:30,000 (Hemophilia B) to much rarer (1:500,000 for FVII deficiency, 1-3 million for Prothrombin or FXIII deficiency). Acquired Hemophilia A is also a rare bleeding disorder with estimated frequency of 1 in million. Most RBDs are inherited as autosomal recessive (AR); however, heterozygous carriers with varying degrees of corresponding factor deficiency may render an unpredictable propensity for bleeding. In patients with bleeding symptoms, laboratory assessment and especially molecular techniques currently enable accurate diagnosis and may provide tools for prenatal and family counseling. Currently hemostasis control is mainly based upon replacement of the missing coagulation factors (unless presence of inhibitors renders it impossible), however future gene therapy and disruptive, non-replacement alternatives may be promising for patients with RBD.
Asunto(s)
Trastornos de las Proteínas de Coagulación/diagnóstico , Hemorragia/diagnóstico , Enfermedades Raras/diagnóstico , Animales , Coagulación Sanguínea , Factores de Coagulación Sanguínea/uso terapéutico , Trastornos de las Proteínas de Coagulación/sangre , Trastornos de las Proteínas de Coagulación/genética , Trastornos de las Proteínas de Coagulación/terapia , Terapia Genética/métodos , Hemorragia/sangre , Hemorragia/genética , Hemorragia/terapia , Humanos , Enfermedades Raras/sangre , Enfermedades Raras/genética , Enfermedades Raras/terapiaRESUMEN
BACKGROUND: Pseudoxanthoma elasticum (PXE)-like syndrome is characterized by the association of PXE and cutis laxa (CL) features with a deficiency of vitamin K-dependent clotting factors. It was first described in 1971 and was identified as a distinct genetic entity in 2007 with analysis of the GGCX (γ-glutamyl carboxylase) gene, which is involved in congenital deficiency in vitamin K-dependent clotting factors. Here we report a new case of this extremely rare syndrome. PATIENTS AND METHODS: A 23-year-old female patient was seen for the emergence of loose and redundant skin following extensive weight loss. She also presented a deficiency of vitamin K-dependent clotting factors. Physical examination revealed excessive, leathery skin folds in the axillary and neck regions. A skin biopsy revealed polymorphous and fragmented elastic fibers in the reticular dermis. These were mineralized, as was demonstrated by Von Kossa staining. The clinical features of CL associated with the histopathological features of PXE and vitamin K-dependent clotting factor deficiency led us to a diagnosis of PXE-like syndrome. A molecular study of the GGCX gene showed compound heterozygosity. DISCUSSION: The GGCX gene is usually responsible for PXE-like syndrome. GGCX encodes a γ-glutamyl carboxylase necessary for activation of gla-proteins. Gla-proteins are involved both in coagulation factors in the liver and in the prevention of ectopic mineralization of soft tissues. Uncarboxylated forms of gla-proteins in fibroblast would thus enable mineralization and fragmentation of elastic fibers.
Asunto(s)
Ligasas de Carbono-Carbono/deficiencia , Trastornos de las Proteínas de Coagulación/diagnóstico , Cutis Laxo/diagnóstico , Seudoxantoma Elástico/diagnóstico , Biopsia , Ligasas de Carbono-Carbono/genética , Trastornos de las Proteínas de Coagulación/genética , Trastornos de las Proteínas de Coagulación/patología , Cutis Laxo/genética , Cutis Laxo/patología , Femenino , Heterocigoto , Humanos , Mutación Missense , Procesamiento Proteico-Postraduccional , Seudoxantoma Elástico/genética , Seudoxantoma Elástico/patología , Piel/patología , Pérdida de Peso , Adulto JovenAsunto(s)
Trastornos Hemorrágicos , Adulto , Niño , Femenino , Humanos , Masculino , Embarazo , Afibrinogenemia/diagnóstico , Afibrinogenemia/epidemiología , Afibrinogenemia/genética , Afibrinogenemia/terapia , Factores de Coagulación Sanguínea/administración & dosificación , Factores de Coagulación Sanguínea/genética , Factores de Coagulación Sanguínea/uso terapéutico , Pruebas de Coagulación Sanguínea , Trastornos de las Proteínas de Coagulación/diagnóstico , Trastornos de las Proteínas de Coagulación/epidemiología , Trastornos de las Proteínas de Coagulación/genética , Trastornos de las Proteínas de Coagulación/terapia , Manejo de la Enfermedad , Fibrinógeno/genética , Fibrinógeno/uso terapéutico , Hemorragia/prevención & control , Trastornos Hemorrágicos/diagnóstico , Trastornos Hemorrágicos/epidemiología , Trastornos Hemorrágicos/genética , Trastornos Hemorrágicos/terapia , Complicaciones Hematológicas del Embarazo/terapia , Proteínas Recombinantes/uso terapéuticoRESUMEN
BACKGROUND: Dysfibrinogenemia is a rare group of qualitative fibrinogen disorders caused by structural abnormalities in the fibrinogen molecule. The laboratory diagnosis of dysfibrinogenemia is controversial. Fibrinogen Paris V, clinically termed Dusart Syndrome, is a dysfibrinogenemia caused by a single base substitution in the gene coding for the Aα-chain of the fibrinogen molecule. OBJECTIVES: To diagnose the first Scandinavian family with Fibrinogen Paris V affecting several family members; the proband, a seven-year-old boy with cerebral vein thrombosis. METHODS: The diagnosis was established following the ISTH guideline for laboratory testing supplemented with fibrin structure analysis and fibrinogen gene analysis. RESULTS: Prolonged thrombin time and reduced ratio between the functional and the protein concentration of fibrinogen were observed in four family members who also were characterized by significantly reduced fibrin polymerization (p < 0.001), reduced fibrin fibre diameter (p < 0.001), reduced fibrin mass-length ratio (p < 0.001) and significantly reduced t-PA-induced fibrinolysis of the fibrin clots (p < 0.001) when compared to controls. Fibrinogen gene analysis demonstrated that five of the family members carried the Fibrinogen Paris V mutation. All laboratory tests were normal in the family members carrying the wild type of the fibrinogen gene. Four of the affected patients had suffered from thrombotic episodes. A noticeable feature in the present family was the presence of both venous and arterial thrombosis. CONCLUSIONS: Excellent concordance was observed between the screening and confirmatory tests, fibrin structure analysis and fibrinogen gene analysis. Fibrin structure analysis should be considered in the laboratory algorithm for diagnosis of dysfibrinogenemia.
Asunto(s)
Trastornos de las Proteínas de Coagulación/congénito , Trombosis/sangre , Adolescente , Adulto , Estudios de Casos y Controles , Niño , Trastornos de las Proteínas de Coagulación/sangre , Trastornos de las Proteínas de Coagulación/genética , Análisis Mutacional de ADN , Femenino , Fibrina/química , Fibrinógenos Anormales/genética , Fibrinógenos Anormales/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Linaje , Multimerización de Proteína , Países Escandinavos y Nórdicos , Síndrome , Tiempo de Trombina , Trombosis/genética , Adulto Joven , gamma-Glutamiltransferasa/sangreRESUMEN
Hemolytic-uremic syndrome (HUS) is a rare life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, and impaired renal function. A thrombotic microangiopathy underlies the clinical features of HUS. In the majority of cases, HUS follows an infection with toxin-producing bacteria such as verotoxin-producing Escherichia coli. In some cases, HUS is not preceded by a clinically apparent infection, and therefore, is named atypical HUS. The prognosis of atypical HUS is poor. While mortality approaches 25% during the acute phase, end-stage renal disease develops in nearly half of patients within a year. Evidence is accumulating that complement activation through the alternative pathway is at the heart of the pathophysiology leading to atypical HUS. Genetic abnormalities involving complement regulatory proteins and complement components form the molecular basis for complement activation. Since microvascular thrombosis is a quintessential feature of atypical HUS, complements and the coagulation system must work in tandem to give rise to the pathologic alterations observed in this condition. Here, a brief discussion of clinical and morphologic features of atypical HUS is followed by a concise presentation of the complement and coagulation systems. The interplay between complements and the coagulation system is graphically highlighted. Last but not least, conventional and emerging therapies for atypical HUS are outlined.
Asunto(s)
Trastornos de las Proteínas de Coagulación/fisiopatología , Proteínas del Sistema Complemento/metabolismo , Síndrome Hemolítico-Urémico/patología , Síndrome Hemolítico-Urémico/fisiopatología , Síndrome Hemolítico Urémico Atípico , Trastornos de las Proteínas de Coagulación/genética , Trastornos de las Proteínas de Coagulación/metabolismo , Proteínas del Sistema Complemento/genética , Síndrome Hemolítico-Urémico/complicaciones , Síndrome Hemolítico-Urémico/terapia , Humanos , Fallo Renal Crónico/etiología , PronósticoRESUMEN
The investigation of inherited bleeding disorders with routine tests of hemostasis will yield clear diagnostic information in the majority of subjects with an unequivocal history of bleeding and especially in those where the phenotypic severity is severe and where an obvious family history of bleeding is present. Nevertheless, a significant minority of subjects with obvious bleeding symptoms will remain without a definite diagnosis after extensive hemostatic testing. With these facts in mind, the role of molecular testing for inherited disorders of hemostasis now includes the following: confirmation of a phenotypic diagnosis through targeted genetic analysis, the distinction of bleeding phenocopies by molecular analysis, and provision of genetic testing as the investigation of choice in situations such as prenatal diagnosis and detection of the carrier state for inherited bleeding traits. In addition, molecular testing can sometimes be used to provide supplementary knowledge that can be used to enhance clinical care. Finally, the utility of genome-wide approaches to identify novel genetic associations may provide new information to explain the cause of bleeding in the population of bleeders without established diagnoses.
Asunto(s)
Trastornos de las Proteínas de Coagulación/genética , Pruebas Genéticas/métodos , Hemostasis/genética , Técnicas de Diagnóstico Molecular/métodos , Factores de Coagulación Sanguínea/genética , Trastornos de las Proteínas de Coagulación/sangre , Trastornos de las Proteínas de Coagulación/diagnóstico , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas/tendencias , Estudio de Asociación del Genoma Completo/métodos , Humanos , Técnicas de Diagnóstico Molecular/tendencias , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
Rare inherited bleeding disorders include fibrinogen disorders, and deficiencies of factors II (prothrombin), V, VII, X, XI, XIII, and combined V+VIII, and combined vitamin K-dependent factors, with general population prevalence rates between 1/500,000 and 1/2,000,000. These inherited disorders, transmitted as autosomal recessive traits, are characterized by a heterogeneous clinical presentation (asymptomatic, mild, moderate or severe bleeding tendency); this variability is more important for deficiencies with factor levels ranging from 5 to 50%. Individual bleeding risk assessment before an invasive procedure or during peri-partum period remains difficult, although an essential step to decide whether a substitution with clotting factor is necessary or not. Because there is a poor correlation between factor activity levels and the severity of bleeding symptoms, factor correction before an invasive procedure should not be based on factor level only, but physicians must also take into account the patient phenotype as well as the haemorrhagic risk of the procedure.
Asunto(s)
Trastornos de la Coagulación Sanguínea Heredados/genética , Trastornos de las Proteínas de Coagulación/genética , Hemorragia/etiología , Trastornos de la Coagulación Sanguínea Heredados/tratamiento farmacológico , Trastornos de la Coagulación Sanguínea Heredados/epidemiología , Factores de Coagulación Sanguínea/efectos adversos , Factores de Coagulación Sanguínea/análisis , Factores de Coagulación Sanguínea/genética , Factores de Coagulación Sanguínea/uso terapéutico , Trastornos de las Proteínas de Coagulación/tratamiento farmacológico , Trastornos de las Proteínas de Coagulación/epidemiología , Manejo de la Enfermedad , Urgencias Médicas , Femenino , Genes Recesivos , Hemorragia/prevención & control , Humanos , Masculino , Hemorragia Posoperatoria/etiología , Hemorragia Posoperatoria/prevención & control , Hemorragia Posparto/etiología , Hemorragia Posparto/prevención & control , Embarazo , Prevalencia , Medición de Riesgo , Evaluación de Síntomas , Trombosis/inducido químicamenteRESUMEN
OBJECTIVE: Congenital disorders of glycosylation (CDG) are a group of metabolic diseases due to defects in protein and lipid glycosylation. We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome. There was clinical evidence of a muscular dystrophy-dystroglycanopathy syndrome, supported by deficient O-mannosylation by muscle immunohistochemistry. METHODS: Biochemical and molecular methods were combined to pinpoint the defect in the glycosylation pathway in the endoplasmic reticulum. RESULTS: Metabolic investigations revealed CDG-I, pointing to a defect in protein N-glycosylation in the endoplasmic reticulum. Analysis of lipid-linked oligosaccharides in fibroblasts showed accumulation of Dol-PP-GlcNAc(2) -Man(5) . DNA analysis revealed mutations in DPM2, 1 of the subunits of the dolichol-phosphate-mannose (DPM) synthase; the patient in the first family is compound heterozygous for 2 mutations (c.68A>G, predicting a missense mutation p.Y23C and c.4-1G>C, a splice mutation), whereas the patients in the second family are homozygous for the same missense mutation (c.68A>G, p.Y23C). INTERPRETATION: We describe a new CDG, due to a deficiency of DPM2. Hence, mutations have now been described in the genes for the 3 subunits of DPM: DPM1, DPM2, and DPM3, whereby DPM2-CDG links the congenital disorders of glycosylation to the congenital muscular dystrophies.
Asunto(s)
Trastornos Congénitos de Glicosilación/genética , Epilepsia/genética , Manosiltransferasas/genética , Distrofias Musculares/genética , Adolescente , Adulto , Anciano , Niño , Preescolar , Trastornos de las Proteínas de Coagulación/genética , Trastornos Congénitos de Glicosilación/complicaciones , Análisis Mutacional de ADN , Resistencia a Medicamentos , Distroglicanos/metabolismo , Electromiografía , Retículo Endoplásmico , Epilepsia/etiología , Femenino , Fibroblastos/metabolismo , Glicosilación , Humanos , Lactante , Focalización Isoeléctrica , Hepatopatías/complicaciones , Hepatopatías/genética , Masculino , Manosa/metabolismo , Microcefalia/genética , Microcefalia/patología , Persona de Mediana Edad , Datos de Secuencia Molecular , Distrofias Musculares/complicaciones , Mutación/genética , Mutación/fisiología , Mutación Missense/genética , Mutación Missense/fisiología , Embarazo , Trastornos de la Visión/genética , Trastornos de la Visión/patología , Adulto JovenRESUMEN
PURPOSE OF REVIEW: By definition, rare factor deficiencies have a prevalence of less than 200,000 in the US population, or an incidence of less than one in 2000 in Europe. The very small numbers of patients with rare disorders present challenges in diagnosis, evaluation of bleeding risk and treatment. Use of new assays, full genome sequencing, and global clotting assays will significantly improve diagnosis of patients with rare bleeding disorders. RECENT FINDINGS: In addition to new assays available for monitoring patients, new therapy, both recombinant and plasma derived, is now available. Registries and clinical trials have demonstrated decreased bleeding and improved outcomes when patients are treated with these agents. Expanding international registries have been initiated to correlate genotype and bleeding phenotype in conjunction with global assays. SUMMARY: Ongoing research continues to expand our understanding of the pathophysiology of rare factor deficiencies. This work complements medical practice to incorporate early diagnosis and new treatment options for patients, resulting in safer and less sensitizing regimens and much improved clinical outcomes.
Asunto(s)
Factores de Coagulación Sanguínea/uso terapéutico , Trastornos de las Proteínas de Coagulación/terapia , Enfermedades Raras/terapia , Trastornos de las Proteínas de Coagulación/diagnóstico , Trastornos de las Proteínas de Coagulación/genética , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/genéticaRESUMEN
Hemostasis is traditionally defined as a physiological response to blood vessel injury and bleeding, which entails a co-ordinated process involving the blood vessel, platelets, and blood clotting proteins (i.e. coagulation factors). Hemostasis can be divided into primary and secondary components. The former rapidly initiates after endothelial damage and is characterized by vascular contraction, platelet adhesion, and formation of a soft aggregate plug. The latter is initiated following the release of tissue factor and involves a complex sequence of events known as the blood coagulation cascade, encompassing serial steps where each coagulation factor activates another in a chain reaction that culminates in the conversion of fibrinogen to fibrin. Patients carrying abnormalities of the coagulation cascade (i.e. deficiencies of coagulation factors) have an increased bleeding tendency, where the clinical severity is mostly dependent upon the type and the plasma level of the factor affected. These disorders also impose a heavy medical and economic burden on individual patients and society in general. The aim of this article is to provide a general overview on the pathophysiology, clinics, diagnostics, and therapy of inherited disorders of coagulation factors.
Asunto(s)
Trastornos de la Coagulación Sanguínea/genética , Coagulación Sanguínea/fisiología , Trastornos de las Proteínas de Coagulación/genética , Hemofilia A/genética , Hemofilia B/genética , Humanos , Enfermedades de von Willebrand/genéticaRESUMEN
Antithrombin (AT), in the presence of heparin, is able to inhibit the catalytic activity of factor VIIa bound to tissue factor (TF) on cell surfaces. The clinical meaning of FVIIa-AT complexes plasma levels is unknown. It was the objective of this study to evaluate FVIIa-AT complexes in subjects with thrombosis. Factor VIIa-AT complexes plasma levels in 154 patients consecutively referred to our Department with arterial or venous thrombosis and in a group of 154 healthy subjects, were measured. Moreover, FVIIa-AT complexes were determined in: i) n = 53 subjects belonging to 10 families with inherited factor VII deficiency; ii) n = 58 subjects belonging to seven families with AT deficiency; iii) n = 49 patients undergoing oral anticoagulant therapy (OAT). Factor VIIa-AT levels were determined by a specific ELISA kit (R&D, Diagnostica Stago, Gennevilliers, France). Factor VIIa-AT complexes mean plasma levels were lower in patients with either acute arterial (136 +/- 40 pM) or venous (142 +/- 53 pM) thrombosis than subjects with previous thrombosis (arterial 164 +/- 33 pM and venous 172 +/- 61 pM, respectively) and than healthy controls (156 +/- 63 pM). Differences between acute and previous thrombosis, were statistically significant (p < 0.05). Subjects with inherited and acquired (under OAT) factor VII deficiency had statistically significant lower FVIIa-AT complexes plasma levels (80 +/- 23 pM and 55 +/- 22 pM, respectively) than controls (150 +/- 51 pM, p < 0.0001 and 156 +/- 63 pM, p < 0.00001, respectively). Factor VIIa-AT complexes are positively correlated with plasma factor VII/VIIa levels. Further investigations are needed to verify the possible role of higher FVIIa-AT complex plasma levels in predicting hypercoagulable states and thrombosis.
Asunto(s)
Antitrombinas/metabolismo , Trastornos de las Proteínas de Coagulación/metabolismo , Factor VIIa/metabolismo , Complejos Multiproteicos/metabolismo , Trombosis de la Vena/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antitrombinas/genética , Trastornos de las Proteínas de Coagulación/sangre , Trastornos de las Proteínas de Coagulación/genética , Factor V/metabolismo , Factor VIIa/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Unión Proteica , Trombosis de la Vena/sangre , Trombosis de la Vena/genéticaRESUMEN
A severe coagulopathy is a life-threatening complication of acute promyelocytic leukemia (APL) and is ascribable mainly to the excessive levels of tissue factor (TF) in APL cells regulated in response to the promyelocytic leukemia/retinoic acid receptor alpha (PML/RARalpha) fusion protein. The underlying molecular mechanisms for this regulation remain ill-defined. With U937-PR9 cell lines stably expressing luciferase reporter gene under the control of different mutants of the TF promoter, both luciferase and ChIP data allowed the localization of the PML/RARalpha-responsive sequence in a previously undefined region of the TF promoter at position -230 to -242 devoid of known mammalian transcription factor binding sites. Within this sequence a GAGC motif (-235 to -238) was shown to be crucial because deletion or mutation of these nucleotides impaired both PML/RARalpha interaction and promoter transactivation. However, EMSA results showed that PML/RARalpha did not bind to DNA probes encompassing the -230 to -242 sequences, precluding a direct DNA association. Mutational experiments further suggest that the activator protein 1 (AP-1) sites of the TF promoter are dispensable for PML/RARalpha regulation. This study shows that PML/RARalpha transactivates the TF promoter through an indirect interaction with an element composed of a GAGC motif and the flanking nucleotides, independent of AP-1 binding.