RESUMEN
Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.
Asunto(s)
Resistencia a la Enfermedad/genética , Estudio de Asociación del Genoma Completo , Infecciones por VIH/genética , Hemofilia A/genética , Adulto , Variaciones en el Número de Copia de ADN , Epistasis Genética , Factor VIII/uso terapéutico , Femenino , Eliminación de Gen , Predisposición Genética a la Enfermedad , Seropositividad para VIH/genética , Heterocigoto , Homocigoto , Humanos , Modelos Logísticos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Fenotipo , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Receptores CCR5/genética , Receptores CCR5/metabolismoRESUMEN
Frequent arterial and venous thromboembolism in patients with congenital afibrinogenaemia (CA) is neither understood nor is a safe and effective treatment established. It was our objective to report on the clinical observations and laboratory data contributing to the understanding of the frequency, physiopathology, prognosis and treatment of CA. We observed the long-term clinical course and laboratory data in a cohort of four patients with CA and thromboembolic complications, and conducted a systematic review retrieving all available data. Four patients with CA developed recurrent and extensive arterial and venous thromboembolism (TE) from an age of 25-51 years. In two patients, a treatment strategy targeting at maintaining constantly measurable fibrinogen (Fbg) levels (≥0.5 g/l) either by regular Fbg replacement or by orthotopic liver transplantation resulted in long-term remissions. Radiological imaging documented resolved arterial thrombi after 6-12 months. In contrast, recurrent thromboembolic events were observed in two other patients with infrequent Fbg replacement. A systematic review of the literature revealed 48 reports of TE in patients with CA (median age at first event 31 years), and a favourable outcome in most patients with frequent application of Fbg, aimed at constantly measurable trough levels. Present data suggests that patients with CA are at high risk of arterial and venous thromboembolic events, probably caused by thrombin excess owing to lack of thrombin scavenging by Fbg/fibrin. Regular low-dose Fbg replacement might be a safe and effective treatment option in patients with CA and thromboembolic complications.
Asunto(s)
Afibrinogenemia/complicaciones , Tromboembolia Venosa/complicaciones , Adulto , Afibrinogenemia/congénito , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
The efficacy and tolerability of a pasteurised human fibrinogen concentrate were assessed in an open, multi-centre, non-controlled retrospective study in patients with congenital fibrinogen deficiency. Haemostatic efficacy was assessed by laboratory investigation and clinical observation. The study included 12 patients (afibrinogenaemia, n = 8; hypofibrinogenaemia, n = 3; dysfibrinogenaemia combined with hypofibrinogenaemia, n = 1). Fibrinogen substitution was indicated: to stop an ongoing bleed; as prophylaxis before surgery; or for routine prophylaxis to prevent spontaneous bleeding. In total, 151 fibrinogen infusions were recorded. The median single dosage was 63.5mg/kg body weight for bleeding events or surgery and 76.9 mg/kg for prophylaxis. The median total dose per event for bleeding events or surgery was 105.6 mg/kg. Fibrinogen was administered in 26 bleeding episodes; 11 surgical operations; and 89 prophylactic infusions, of which 86 were received by one patient. The median response (n = 8) was 1.5 mg/dl per substituted mg of fibrinogen per kg body weight (0.8-2.3). The median in vivo recovery (n = 8) was 59.8% (32.5-93.9). Clinical efficacy was very good in all events with the exception of one surgical procedure, where it was moderate. No intercurrent bleeding occurred during prophylaxis. All but one infusion was well tolerated; the patient, who was administered 86 prophylactic infusions, experienced an anaphylactic reaction after the 56th infusion. In addition, one patient developed deep vein thrombosis and non-fatal pulmonary embolism with treatment for osteosynthesis after collum femoris fracture. Fibrinogen substitution could not be excluded as a contributing factor in this high-risk patient. Substitution with pasteurised human fibrinogen concentrate in patients with congenital fibrinogen deficiencies is efficient and generally well tolerated.
Asunto(s)
Afibrinogenemia/terapia , Transfusión de Componentes Sanguíneos , Fibrinógeno/administración & dosificación , Preservación Biológica , Afibrinogenemia/congénito , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
The main pharmacokinetic characteristics of a plasma-derived, pasteurised fibrinogen concentrate were assessed in an open, multicentre, non-controlled study in five patients with congenital afibrinogenaemia or severe congenital hypofibrinogenaemia. Plasma samples were assayed for fibrinogen content in laboratories of the participating clinical centres (CCs) and additionally in a central laboratory at Aventis Behring (ABL). The values of the pharmacokinetic variables, using the fibrinogen determination at ABL, yielded a somewhat shorter terminal half-life compared with that determined at the CCs, with median (range) values of 2.7 days (2.5-3.7 days) versus 3.6 days (3.0-5.3 days), respectively. Fibrinogen clearance rate was clearly lower at the ABL with values of 0.91 ml/h/kg (0.84-1.22 ml/h/kg) compared with 1.65 ml/h/kg (0.82-2.55 ml/h/kg) at the CCs. The distribution volume at steady state (V-ss) of 89 ml/kg (81-116 ml/kg) was also smaller at the ABL than at the CCs (101 ml/kg [84-139 ml/kg]). Response, in vivo recovery and area under the curve did not differ noticeably between the laboratories. The normalisation or near normalisation of pre-infusion pathological coagulation tests indicated a good haemostatic efficacy of the tested fibrinogen concentrate, which was also generally well tolerated and not associated with any serious adverse reactions.
Asunto(s)
Transfusión de Componentes Sanguíneos , Fibrinógeno/farmacocinética , Preservación Biológica , Adulto , Afibrinogenemia/terapia , Femenino , Fibrinógeno/administración & dosificación , Humanos , MasculinoRESUMEN
Joint hemorrhages are very common in patients with severe hemophilia. Inhibitors in patients with hemophilia are allo-antibodies that neutralize the activity of the clotting factor. After total knee replacement, rare intra-articular bleeding complications might occur that do not respond to clotting factor replacement. We report a 40-year-old male with severe hemophilia A and high responding inhibitors presenting with recurrent knee joint hemorrhage after bilateral knee prosthetic surgery despite adequate clotting factor treatment. There were two episodes of marked postoperative hemarthrosis requiring extensive use of substitution therapy. Eleven days postoperatively, there was further hemorrhage into the right knee. Digital subtraction angiography diagnosed a complicating pseudoaneurysm of the inferior lateral geniculate artery and embolization was successfully performed. Because clotting factor replacement therapy has proved to be excessively expensive and prolonged, especially in patients with inhibitors, we recommend the use of cost-effective early angiographic embolization.