RESUMEN
INTRODUCTION: Chronic insufficiency alters homeostasis, in part due to endothelial inflammation. Plasminogen activator inhibitor-1 (PAI-1) is increased in renal disease, contributing to vascular damage. We assessed PAI-1 activity and PAI-1 4G/5G polymorphism in hemodialysis (HD) subjects and any association between thrombotic vascular access (VA) events and PAI-1 polymorphism. METHODS: Prospective, observational study in 36 HD patients: mean age: 66.6 +/- 12.5 yr, males n=26 (72%), time on HD: 28.71 +/- 22.45 months. Vascular accesses: 10 polytetrafluoroethylene grafts (PTFEG), 22 arteriovenous fistulae (AVF), four dual lumen catheters (CAT). Control group (CG): 40 subjects; mean age: 60.0 +/- 15 yrs, males n=30 (75%). Group A (GA): thrombotic events (n=12), and group B (GB): No events (n=24). Groups were no different according to age (69.2 +/- 9.12 vs. 65.3 +/- 14.5 yrs), gender (males: 7; 58.3% vs. 18; 81.8%), time on HD (26.1 +/- 14.7 vs. 30.1 +/- 38.7 months), causes of renal failure. Time to follow-up for access thrombosis: 12 months. RESULTS: PAI-1 levels in HD: 7.21 +/- 2.13 vs. CG: 0.42 +/- 0.27 U/ml (p<0.0001). PAI-1 4G/5G polymorphic variant distribution in HD: 5G/5G: 6 (17%), 4G/5G: 23 (64%); 4G/4G: 7 (19%) and in CG: 5G/5G: 14 (35%); 4G/5G: 18 (45%); 4G/4G: 8 (20%). C-reactive protein (CRP) in HD: 24.5 +/- 15.2 mg/L vs. in CG 2.3 +/- 0.2 mg/L (p<0.0001). PAI-1 4G/5G variants: GA: 5G/5G: 3; 4G/5G: 8; 4G/4G: 1; GB: 5G/5G: 3; 4G/5G: 15; 4G/4G: 6. Thrombosis occurred in 8/10 patients (80%) with PTFEG, 3/22 (9%) in AVF, and 1/4 (25%) in CAT. Among the eight PTFEG patients with thrombosis, seven were PAI 4G/5G. CONCLUSIONS: PAI-1 levels were elevated in HD patients, independent of their polymorphic variants, 4G/5G being the most prevalent variant. Our data suggest that in patients with PTFEG the 4G/5G variant might be associated with an increased thrombosis risk.
Asunto(s)
Derivación Arteriovenosa Quirúrgica , Oclusión de Injerto Vascular/genética , Inhibidor 1 de Activador Plasminogénico/genética , Polimorfismo Genético , Diálisis Renal , Trombosis/genética , Anciano , Prótesis Vascular , Proteína C-Reactiva/metabolismo , Distribución de Chi-Cuadrado , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inhibidor 1 de Activador Plasminogénico/sangre , Politetrafluoroetileno , Estudios Prospectivos , Estadísticas no ParamétricasRESUMEN
The fibrinolytic system contains a proenzyme plasminogen (Plg) which is converted to plasmin (Plm) by the action of Plg activators. Physiological Plg activators are: tissue-type plasminogen activator (t-PA) and urokinase-type plasminogen activator. Plg was shown to be further cleaved by leukocyte elastase producing several fragments, one of which is called mini-plasminogen (mini-Plg) or neo-plasminogen Val442. In this paper we studied whether mini-Plg is able to produce clot lysis when it is activated by rt-PA in purified systems and in Plg depleted normal plasma. We found that mini-Plg clot lysis time was longer than that of Plg. Clot lysis times were 2.3 minutes +/- 0.06 for Plg and 9.8 minutes +/- 0.1 for mini-Plg. Mini-Plg is less efficient than Plg in producing clot lysis at all studied concentrations (0.1-1.2 microM). In Plg depleted normal human plasma mini-Plg is unable to produce complete clot lysis in presence of rt-PA. Although mini-Plg can be activated to mini-Plm by rt-PA, these results show that the activation process is insufficient to produce an efficient clot lysis.
Asunto(s)
Fibrinólisis/efectos de los fármacos , Fibrinólisis/fisiología , Fragmentos de Péptidos/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Plasminógeno/efectos de los fármacos , Plasminógeno/metabolismo , Activador de Tejido Plasminógeno/farmacología , Fibrina/metabolismo , Fibrina/farmacología , Fibrinolisina/metabolismo , Humanos , Técnicas In Vitro , Proteínas Recombinantes/farmacología , Activador de Tejido Plasminógeno/metabolismoRESUMEN
BACKGROUND: Hyperhomocysteinemia is a risk factor for thrombosis, a frequent complication of vascular access (VA) in hemodialysis (HD). The enzyme methylenetetrahydrofolate reductase (MTHFR) is necessary for the remethylation of homocysteine (Hcy) to methionine. It has been postulated that patients homozygous and, to a lesser extent, heterozygous for the C677T thermolabile variant of this enzyme present a reduced catalytic activity, with secondary increases in plasmatic Hcy levels (normal: 10 +/- 5 micromol/L) and an elevated risk of vascular thromboses. METHODS: Sixty-two patients on chronic HD were divided into two groups: group A (n = 23, 37.1%) was normal for the enzyme (CC); group B (n = 39, 62.9%) was heterozygous (CT). Both groups were not different according to age, sex, time on HD, hematocrits (Hct), baseline levels of Hcy, folic acid and vitamin B12. After the 1st HD session patients were started on folic acid 10 mg/day and 500 microg/week of intravenous (i.v.) methylcobalamin. RESULTS: Two years later, thrombotic events were not different between the two groups. Group A = 5 (21.7%) vs. group B = 12 (30.7%), Hcy levels were significantly different between final and baseline measurements (group A 21.5 +/- 5.2 vs. 16.6 +/- 3.9 micromol/L, p = 0.02; group B 22.1 +/- 8.9 vs. 16.1 +/- 3.9 micromol/L, p = 0.008), folic acid (group A 22.1 vs. 346.9 ng/ml, range (r) =166-527, p < 0.001; group B 19.2 vs. 218.5 ng/ml, r = 138-298, p < 0.001) and vitamin B12 (group A 1489 vs. 3192.3 pg/ml, r = 1494-4890, p = 0.01; group B 1086 vs. 1513.8 pg/ml, r = 1092-1934, p = 0.02). CONCLUSIONS: HD patients heterozygous for the C677T variant of the enzyme MTHFR can present a similar risk of thrombotic events in arteriovenous fistulae (AVF) compared to patients normal for the enzyme at a 1-yr follow-up. These results could be explained by an adequate control of Hcy levels after folic acid and methylcobalamin replacement therapy.