Javier Calvo

Thrombophilic risk factors and homocysteine levels in Behçet’s disease in eastern Spain and their association with thrombotic events

Behçets disease (BD) is a chronic inflammatory disorder in which thrombosis occurs in about 30% of patients. The prothrombotic mechanisms are unknown. Thrombophilic defects and hyperhomocysteinaemia may be involved in the pathogenesis of thrombotic events, although results have been controversial. Moreover, no information is available on this issue for eastern Spain. We studied the prevalence of inherited and acquired thrombophilic risk factors in 79 patients with BD (43 men, 36 women) who had (n = 23) or did not have (n = 56) thrombosis, and in 84 healthy control subjects (42 men, 42 women). Risk factors examined were antithrombin, protein C and protein S levels, factor V Leiden, the prothrombin G20210A mutation, the methylenetetrahydrofolate reductase C677T polymorphism, and acquired thrombophilic risk factors, including anticardiolipin antibodies, lupus anticoagulant, and serum homocysteine levels. There were no differences between patients and controls in any of the parameters studied. When we studied BD patients with and without thrombotic events, the only thrombophilic defect that differed was the prothrombin G20210A mutation: Three out of 23 patients with thrombosis were carriers, compared with none of 56 patients without thrombosis (p = 0.022). Two of the three carriers developed catastrophic or recurrent thrombotic episodes; one was a homozygous carrier of the G20210A prothrombin mutation and the other was doubly heterozygous for the G20210A prothrombin mutation and factor V Leiden. A meta-analysis demonstrated an association of factor V Leiden and prothrombin mutation with thrombosis in BD. When studies from Turkey were excluded from the meta-analysis, only the prothrombin G20210A mutation was associated with thrombosis.

Enfermedad de Behçet: estudio de 74 pacientes

Fundamento y objetivo: La enfermedad de Behcet (EB) es una entidad clinica poco prevalente en Espana. Son escasos los articulos publicados sobre datos epidemiologicos y manifestaciones clinicas en nuestro pais. El objetivo del presente estudio ha sido conocer las caracteristicas de las manifestaciones clinicas de la EB en la Comunidad Valenciana. Pacientes y metodo: Se recogieron datos de los pacientes diagnosticados entre 1990 y 2005 de EB en los Hospitales Universitarios La Fe, General y Doctor Peset de Valencia. Todos los pacientes cumplian los criterios diagnosticos del Grupo de Estudio Internacional para el diagnostico de la EB. Las diferencias entre sexos se analizaron mediante el test de la *2. Resultados: Formaron el grupo de estudio 74 pacientes (40 varones y 34 mujeres). Las manifestaciones clinicas mas frecuentes fueron las aftas orales (98,5%) y genitales (82,4%), seguidas de las cutaneas (64,2%), oculares (42,5%), fiebre (39,4%) y vasculares (28,4%), con predominio de las trombosis venosas sobre las arteriales. Solo las manifestaciones gastrointestinales fueron mas frecuentes en el sexo femenino (p = 0,002). Las alteraciones vasculares y oculares fueron mas graves en los varones. En cuanto a la prevalencia de los factores de riesgo cardiovascular, el 32,4% de los pacientes eran fumadores, un 20,3% presentaba hiperlipemia; un 19%, hipertension; un 13,5%, obesidad, y un 9,5%, diabetes, aunque no se observo asociacion entre estos y los episodios tromboticos ni la uveitis posterior (p > 0,05). Conclusiones: Los resultados obtenidos fueron similares a los de otras areas geograficas. Destacan la mayor frecuencia de manifestaciones digestivas en mujeres y el predominio de los episodios tromboticos venosos sobre los arteriales. Los factores de riesgo cardiovascular no parecen desempenar un papel en el desarrollo de episodios tromboticos ni uveitis posterior en estos pacientes.

RDW in patients with systemic lupus erythematosus. Influence of anaemia and inflammatory markers

Red blood cell distribution width (RDW) is a routine parameter that reflects size variations in erythrocytes. High RDW has been associated with cardiovascular events and inflammatory diseases. However, no studies evaluating the association of RDW with systemic lupus erythematosus (SLE) have been published. We aimed to explore the association of RDW with inflammatory markers in SLE. As SLE is often associated with anaemia, we considered this factor in order to know whether RDW is related with inflammation, anaemia or both in SLE. The study included 105 SLE patients (7 men, 98 women; aged 15-73 years) and 105 controls (9 men, 96 women; aged 18-71 years). Patients were divided according to anaemia status (26 with, 79 without). Biochemical, hematological and inflammatory parameters (C-reactive protein (CRP), fibrinogen and erythrocyte aggregation (EA1)) were analyzed. SLE patients showed increased RDW, CRP and EA1 (p < 0.001), and decreased hemoglobin levels (p < 0.001) when compared with controls. RDW was higher in SLE patients with anaemia (a-SLE) as compared with those without anaemia (na-SLE) (p < 0.01) or controls (p < 0.001). CRP in a-SLE was higher than in controls (p < 0.01) but lower than in na-SLE (p < 0.05). In na-SLE RDW correlated directly with fibrinogen and CRP (p < 0.001), but not in a-SLE. Our results indicate that SLE patients show higher RDW irrespectively of anaemia status, and that RDW is influenced by both anaemia and inflammation, but the influence of anaemia is stronger.

Rheological alterations and thrombotic events in patients with systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is characterised by increased venous and arterial thrombotic risk. Nevertheless, how hemorheological alterations contribute to thrombotic risk remains a question of debate. We aimed to determine the rheological profile in 105 patients with SLE (24 with a thrombotic event) and 105 healthy controls. We determined blood viscosity and erythrocyte aggregation along with plasma lipids and fibrinogen. Although SLE patients showed lower blood viscosity at 230 s(-1) at a native hematocrit when compared with controls (p < 0.001), differences disappeared after adjusting the hematocrit to 45% (p = 0.095). When comparing SLE patients with and without thrombotic events, no differences in any rheological parameter were found (p > 0.05), except in fibrinogen which was higher in patients with thrombosis (p = 0.013). No differences in the rheological parameters were observed when venous and arterial thrombotic events were compared, although a tendency for higher fibrinogen was observed in patients with venous thrombosis (p = 0.053). Only hematocrit, fibrinogen and triglycerides were independent predictors of native blood viscosity in the multivariate regression analysis, even after adjusting for continuous variables and for tobacco and hypertension: beta coefficient: 0.727 p < 0.001; beta coefficient: 0.152 p = 0.003 and beta coefficient: 0.133 p = 0.015, respectively. The logistic regression analysis revealed that neither increased native blood viscosity (BVn > 4.33) nor increased erythrocyte aggregation (EA1 > 7.85) increased thrombotic risk: OR 0.636, CI 0.313-3.12, p = 0.578 and OR 2.01, CI 0.77-5.20, p = 0.152, respectively. However, hyperfibrinogenemia (Fbg > 342 mg/dL) increased thrombotic risk by around three times: OR 3.44 CI 1.32-8.96, p = 0.011. Our results suggest that the role of blood viscosity and erythrocyte aggregation in thrombotic risk in SLE patients fails to demonstrate any association.

Hemorheological profile in primary and secondary Raynaud's phenomenon. Influence of microangiopathy

Raynauds phenomenon (RP) is an episodic peripheral circulatory disorder characterized by local artery spams in subjects exposed to cold or emotional stress. It is not well-established whether RP patients show an altered rheological profile, mostly due to patient classification and clinical severity. We aimed to compare the hemorheological profile in patients with primary and secondary RP with a healthy control group. Eighteen primary RP, 22 secondary RP and 22 healthy controls, were included in the study. RP patients were also divided according to the presence of digital ulcers (7 with, 33 without). Biochemical and hemorheological variables were analyzed, including glucose, triglycerides, total-cholesterol, immunoglobulins, fibrinogen, plasma viscosity, erythrocyte aggregation, erythrocyte deformability and blood viscosity. Age was higher in secondary RP as compared with primary (p = 0.049), while glucose, triglycerides IgA, IgG and plasma viscosity were higher in secondary RP than in healthy subjects (p < 0.05). RP patients with digital ulcers presented higher IgA (p = 0.012), lower erythrocyte aggregation time (p = 0.008) and a trend for higher fibrinogen levels and plasma viscosity (p = 0.064, p = 0.069, respectively). The results of the present study indicate that secondary RP patients show a mild impairment of the rheological profile that aggravates with microangiopathy severity.

Thrombotic events in systemic lupus erythematosus. Its association with acquired and inherited thrombophilic defects

Systemic lupus erythematosus (SLE) is characterised by increased venous and arterial thrombotic risk. Although antiphospholipid antibodies (APAs) have been shown to be related with thrombotic tendency in these patients, in more than 40% of them, thrombosis occurs without the presence of such antibodies. We analysed the association of venous and arterial thrombotic events with acquired (anticardiolipin antibodies (ACAs) and lupus anticoagulant (LA)) and inherited (antithrombin (AT), protein C (PC), protein S (PS) deficiencies, factor V Leiden and the prothrombin G20210A mutation), thrombophilic risk factors in 86 SLE patients and 89 healthy controls. Patients showed a higher significant percentage of ACAs titres IgG>41 GPL u/ml and LA than controls (P=0.009; P<0.001, respectively), although no differences in AT, PC, PS deficiencies, factor V Leiden and prothrombin G20210A mutation was observed (P>0.05). When patients with and without thrombosis were compared, those with thrombosis showed a statistically higher percentage of ACAs IgG>41 GPL u/ml and LA (P=0.048; P=0.001, respectively), OR 4.33; 95% CI 1.01-18.50 and OR 11.57; 95% CI 3.28-40.75, respectively. When venous and arterial thrombotic events were considered separately, the presence of LA constituted a risk factor for arterial thrombosis (P=0.010), OR 11.33; 95% CI 1.86-68.89, as well as for venous thrombosis (P=0.005), OR 10.15; 95% CI 2.12-48.64, while ACAs IgG>41 GPL u/ml on their own, were not associated with arterial or venous thrombosis (P=0.142, P=0.233, respectively). In addition inherited thrombophilic risk factors AT, PC, PS deficiencies, factor V Leiden and PT G20210A mutation do not seem to increase thrombotic risk in SLE patients.

Homocysteine levels in patients with primary and secondary Raynaud's phenomenon. Its association with microangiopathy severity.

The association between hyperhomocysteinemia (HHcy) and Raynauds phenomenon (RP) remains a matter of debate. In 18 primary RP, 23 secondary RP and 41 controls, we investigated homocysteine (Hcy) levels along with biochemical and inflammatory parameters. The Hcy levels in both primary and secondary RP were elevated when compared with controls (p < 0.05 and p < 0.01, respectively). As age was higher in secondary RP as compared with controls (p < 0.01), both primary and secondary RP were age-matched with a corresponding control group, and with Hcy maintaining its statistical significance (p < 0.05). No differences in creatinine, B12 vitamin or folic acid were observed between groups (p > 0.05), or in the prevalence of cardiovascular risk factors (p > 0.05). When patients were classified according to presence or absence of digital ulcers, as a sign of microangiopathy severity, the former showed higher Hcy levels than the latter (p = 0.035). Our results indicate that both primary and secondary RP patients show a mild increase in Hcy levels, which is not related to age, vitamin deficiencies or impaired renal function, but is related to microangiopathy severity. Therefore the association of HHcy and RP suggest that Hcy may contribute to endothelial dysregulation, which characterizes this disease. Specific studies should be designed to elucidate the pathogenesis of HHcy in these patients.

Haemorheological profile in patients with systemic sclerosis

The relationship between rheological alterations and systemic sclerosis (SSc) is not well established. We have determined in 27 patients with SSc (4 male, 21 female ) aged 59 +/- 14 years and in a well matched control group the whole rheological profile, i.e. blood viscosity (BV), plasma viscosity (PV), erythrocyte aggregation (EA), erythrocyte deformability (ED) along with fibrinogen (Fbg), C-reactive protein (CRP), lipids, and erythrocyte indices. Patients show higher Fbg, PV and EA (P<0.01) and lower ED (P<0.01). A negative significant correlation was found between ED and inflammation markers, both CRP (P<0.05) and Fbg (P<0.01), indicating that decreased ED seems to be related to inflammatory changes at microcirculatory levels. In addition, patients with anticentromere antibodies show significantly lower ED than those without (P<0.05). The clinical significance of this observation needs to be clarified, deserving further research.

Psoriasis and hemorheology. Influence of the metabolic syndrome

Psoriasis is a systemic inflammatory disorder with increased cardiovascular risk which has been partly attributed to the increased prevalence of the metabolic syndrome (MS). However, the contribution of rheological alterations to cardiovascular risk has been scarcely investigated. In 91 psoriasis patients and in 101 healthy volunteers, we determined the rheological profile (fibrinogen, blood viscosity and erythrocyte aggregation), along with lipidic and inflammatory parameters. Patients showed statistically higher BMI, waist, triglycerides, insulin, c-reactive protein (CRP), neutrophils, lower HDL-cholesterol and a higher MS prevalence (p<0.05). When subjects with MS were excluded from the study, patients with psoriasis still showed a worse inflammatory, lipidic and rheological profile in the above-mentioned variables compared with controls without MS (p<0.05). The logistic regression analysis revealed that abdominal obesity and fibrinogen>384 mg/dL were independent predictors of psoriasis (OR 3.75 95% CI 1.77-7.94, p<0.001; OR 2.95 95% CI 1.14-7.64, p=0.025), respectively. Patients on biologics, showed less inflammation and a better rheological profile than those not on biological treatment. In conclusion, patients with psoriasis show an altered rheological profile, which may contribute to increased cardiovascular risk. Although the presence of MS worsens this profile, psoriasis per se shows rheological alterations due to both inflammation and altered metabolic parameters. Anti TNF-α treatment markedly improves the rheological profile by mostly decreasing inflammation.