Long-term follow-up of antiphospholipid syndrome: real-life experience from a single center.

OBJECTIVE: The objective of this paper is to assess the prevalence of the main clinical manifestations and laboratory features at disease onset and during the ensuing 10 years of a large cohort of patients with antiphospholipid syndrome (APS) from a single center. METHODS: The study included all consecutive APS patients followed longitudinally in our center from 2003 to 2013. Descriptive statistics for demographics, clinical and laboratory features and mortality were performed. RESULTS: A total of 160 patients were included. Most of them, 128 (78.8%), were women and the mean (SD) age at diagnosis was 39.1 (14.0) years. The majority of them, 104 (65.0%), had primary APS, 36 (22.5%) had APS associated with systemic lupus erythematous, and 20 (12.5%) had APS associated with other autoimmune disease. During the study period, thrombotic events occurred in 27 (16.9%) patients, the most common being strokes, nonbacterial thrombotic endocarditis and deep venous thrombosis. Regarding obstetric morbidity, 18 women (14.3%) became pregnant and 90% of pregnancies succeeded in having live births. The most common obstetric complication was early pregnancy loss (15% of pregnancies). Prematurity (11.1% of live births) and intrauterine growth restriction (5.6% of live births) were the most frequent fetal morbidities. Ten (6.3%) patients died and the most frequent causes of death were severe thrombosis, hemorrhage, and cancer. Three (0.9%) cases of catastrophic APS occurred. The survival probability at 10 years was 93.8%. CONCLUSIONS: Patients with APS develop significant morbidity and mortality despite current treatment. It is imperative to identify prognostic factors and therapeutic measures to prevent these complications.

Lack of grading agreement among international hemostasis external quality assessment programs.

: Laboratory quality programs rely on internal quality control and external quality assessment (EQA). EQA programs provide unknown specimens for the laboratory to test. The laboratory's result is compared with other (peer) laboratories performing the same test. EQA programs assign target values using a variety of methods statistical tools and performance assessment of 'pass' or 'fail' is made. EQA provider members of the international organization, external quality assurance in thrombosis and hemostasis, took part in a study to compare outcome of performance analysis using the same data set of laboratory results. Eleven EQA organizations using eight different analytical approaches participated. Data for a normal and prolonged activated partial thromboplastin time (aPTT) and a normal and reduced factor VIII (FVIII) from 218 laboratories were sent to the EQA providers who analyzed the data set using their method of evaluation for aPTT and FVIII, determining the performance for each laboratory record in the data set. Providers also summarized their statistical approach to assignment of target values and laboratory performance. Each laboratory record in the data set was graded pass/fail by all EQA providers for each of the four analytes. There was a lack of agreement of pass/fail grading among EQA programs. Discordance in the grading was 17.9 and 11% of normal and prolonged aPTT results, respectively, and 20.2 and 17.4% of normal and reduced FVIII results, respectively. All EQA programs in this study employed statistical methods compliant with the International Standardization Organization (ISO), ISO 13528, yet the evaluation of laboratory results for all four analytes showed remarkable grading discordance.

Time to change the classical vision of coagulation in liver disease: from the balance disequilibrium to systems biology network modeling.

The longstanding dogma that patients with liver disease have a hemostasis related bleeding tendency is neglected from the last 10 years however, despite this tremendous change of paradigm no longer progress had been made in this field. A mathematical model is a description of a system using mathematical concepts and language. Mathematical models are able to analyze large amount of data and they can make predictions about behavior. Mathematical models are used in the social sciences, engineering as well as in medicine. Blood coagulation in patients with liver disease is difficult to predict due to its network complexity and moreover, due to all factors that potentially can impact hemostasis in this patient population outside of the coagulation itself, as portal hypertension, endothelial dysfunction and renal injury, between others. Although ambitious and extremely complex, the aforementioned approach requires a substantial investment of multidisciplinary human and technologic resources, this holistic overview is the closest to the real situation. The ability of the mathematical modeling to predict bleeding and thrombotic complications in patients with liver disease deserves to be investigated.

Identification of new markers of recurrence in patients with unprovoked deep vein thrombosis by gene expression profiling: the retro study.

OBJECTIVE: The aim of this study was to assess differences in the gene expression profile of peripheral blood cells between patients with early recurrent thrombosis vs. patients without recurrent events after withdrawal of anticoagulant therapy for a first episode of unprovoked deep vein thrombosis (uDVT), to identify novel predictors of recurrence. METHODS: In the discovery population (N = 32), a microarray RNA assay followed by RT-PCR confirmation were performed. In the validation population (N = 44) a multiple RT-PCR-based strategy was applied to assess genes differentially expressed in the discovery population. RESULTS: The sex-adjusted Linear Model for Microarray Data analysis showed 102 genes differentially expressed (P < 0.01) in the discovery population. Nineteen of them underwent further confirmation in the validation population. The gene encoding for Acyl-CoA Synthetase Family Member 2 (ACSF2) was underexpressed in recurrent DVT patients in both, the discovery (P = 0.007) and validation populations (P = 0.004). In the receiver operator characteristic (ROC) analysis, the areas under the curve of ACSF2 expression were 0.77 and 0.80, respectively. CONCLUSIONS: For the first time an association between ACSF2 expression and the risk of recurrent DVT is suggested. Should this association be confirmed in larger prospective studies, ACSF2 could become useful for the selection of patients requiring extended anticoagulant therapy.

El autocontrol de la terapia con cumarínicos es más eficiente que dabigatrán para prevenir ictus en fibrilación auricular no valvular en España. Respuesta / Self-management of vitamin K antagonists is more cost-effective than dabigatran for stroke prevention in non-valvular atrial fibrillation in Spain. Response

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Assessment of anti-prothrombin antibodies in thrombosis complicating inflammatory bowel diseases.

PURPOSE: In inflammatory bowel diseases (IBD), risk of thrombosis and production of antibodies are increased. In autoimmune and inflammatory disorders, a role of anti-prothrombin (aPT) antibodies in developing thrombosis has been hypothesised. The aim of the study is to evaluate the prevalence of aPT antibodies in IBD patients, with and without thrombosis. METHODS: Thirty-three IBD patients with thrombosis, 33 IBD patients without thrombosis matched for sex, age, diagnosis and disease activity and 66 sex- and age-matched healthy controls were enrolled. Thrombosis was considered recent when blood sample was obtained within 3 months from the event. RESULTS: Prevalence of aPT antibodies in thrombotic IBD patients (3/33, 9.1 %), non-thrombotic IBD patients (4/33, 12.1 %) and in healthy subjects (3/66, 4.5 %) did not result significantly different (p = 0.377). The prevalence of aPT antibodies was more frequent in ulcerative colitis (6/32, 18.7 %) than in Crohn's disease (1/34, 2.9 %) and healthy controls (p = 0.022). Among thrombotic IBD patients, the prevalence of aPT antibodies was higher in those with recent (2/9, 22.2 %) than in those with previous thrombosis (1/24, 4.2 %) (p = 0.103). All thrombotic IBD patients with aPT antibodies were affected by ulcerative colitis with previous history of deep venous thrombosis. CONCLUSIONS: aPT antibodies do not appear to play a relevant role in thrombosis complicating IBD course. A possible association in ulcerative colitis patients with DVT could not be excluded.

Análisis coste-efectividad de dabigatrán para la prevención de ictus y embolia sistémica en fibrilación auricular no valvular en España / Cost-effectiveness of dabigatran for stroke prevention in non-valvular atrial fibrillation in Spain

Introducción y objetivos. Análisis coste-efectividad de dabigatrán para la prevención de ictus y embolia sistémica por fibrilación auricular no valvular en España, según la perspectiva del Sistema Nacional de Salud. Métodos. Adaptación de un modelo de Markov secuencial que simula la historia natural de la enfermedad para una cohorte de 10.000 pacientes con fibrilación auricular no valvular a lo largo de su vida. Los comparadores son warfarina en un primer escenario y el patrón de prescripción habitual (el 60% con antagonistas de la vitamina K, el 30% con ácido acetilsalicílico y el 10% no tratados) en el segundo. Se realizaron análisis de sensibilidad determinístico y probabilístico. Resultados. En ambos escenarios dabigatrán disminuyó los eventos sufridos y consiguió ganancias en cantidad y calidad de vida. La razón coste-efectividad incremental de dabigatrán comparado con warfarina fue de 17.581 euros/año de vida ajustado por calidad ganado y de 14.118 euros/año de vida ajustado por calidad ganado respecto al patrón de prescripción habitual. Se demostró eficiencia en subgrupos. Incorporando los costes sociales al análisis, dabigatrán es una estrategia dominante (más efectiva y de menor coste). El modelo demostró ser robusto. Conclusiones. Desde la perspectiva del Sistema Nacional de Salud, dabigatrán resulta una estrategia eficiente para la prevención de ictus en pacientes con fibrilación auricular no valvular en comparación con warfarina y con el patrón de prescripción habitual; en ambas comparaciones realizadas, los valores de la razón coste-efectividad incremental estuvieron por debajo del umbral de 30.000 euros/año de vida ajustado por calidad. Desde la perspectiva de la sociedad, dabigatrán sería además una estrategia dominante que aporta más efectividad y menores costes que las dos alternativas (AU)

Introduction and objectives. Assessment of the cost-effectiveness of dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Spain, from the perspective of the National Health System. Methods. Adaptation of a Markov chain model that simulates the natural history of the disease over the lifetime of a cohort of 10 000 patients with non-valvular atrial fibrillation. Model comparators were warfarin in a first scenario, and a real world prescribing pattern in a second scenario, in which 60% of the patients were treated with vitamin K antagonists, 30% with acetylsalicylic acid, and 10% received no treatment. Deterministic and probabilistic sensitivity analyses were performed. Results. Dabigatran reduced the occurrence of clinical events in both scenarios, providing gains in quantity and quality of life. The incremental cost-effectiveness ratio for dabigatran compared to warfarin was 17581 euros/quality-adjusted life year gained and 14118 euros/quality-adjusted life year gained when compared to the real world prescribing pattern. Efficiency in subgroups was demonstrated. When the social costs were incorporated into the analysis, dabigatran was found to be a dominant strategy (ie, more effective and less costly). The model proved to be robust. Conclusions. From the perspective of the Spanish National Health System, dabigatran is an efficient strategy for the prevention of stroke in patients with non-valvular atrial fibrillation compared to warfarin and to the real-world prescribing pattern; incremental cost-effectiveness ratios were below the 30 000 euros/quality-adjusted life year threshold in both scenarios. Dabigatran would also be a dominant strategy from the societal perspective, providing society with a more effective therapy at a lower cost compared to the other 2 alternatives (AU)

Cost-effectiveness of dabigatran for stroke prevention in non-valvular atrial fibrillation in Spain.

INTRODUCTION AND OBJECTIVES: Assessment of the cost-effectiveness of dabigatran for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Spain, from the perspective of the National Health System. METHODS: Adaptation of a Markov chain model that simulates the natural history of the disease over the lifetime of a cohort of 10,000 patients with non-valvular atrial fibrillation. Model comparators were warfarin in a first scenario, and a real world prescribing pattern in a second scenario, in which 60% of the patients were treated with vitamin K antagonists, 30% with acetylsalicylic acid, and 10% received no treatment. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Dabigatran reduced the occurrence of clinical events in both scenarios, providing gains in quantity and quality of life. The incremental cost-effectiveness ratio for dabigatran compared to warfarin was 17,581 euros/quality-adjusted life year gained and 14,118 euros/quality-adjusted life year gained when compared to the real world prescribing pattern. Efficiency in subgroups was demonstrated. When the social costs were incorporated into the analysis, dabigatran was found to be a dominant strategy (ie, more effective and less costly). The model proved to be robust. CONCLUSIONS: From the perspective of the Spanish National Health System, dabigatran is an efficient strategy for the prevention of stroke in patients with non-valvular atrial fibrillation compared to warfarin and to the real-world prescribing pattern; incremental cost-effectiveness ratios were below the 30,000 euros/quality-adjusted life year threshold in both scenarios. Dabigatran would also be a dominant strategy from the societal perspective, providing society with a more effective therapy at a lower cost compared to the other 2 alternatives. Full English text available from:www.revespcardiol.org.

La mutación R92Q del gen TNFRSF1A se asocia con manifestaciones extra-intestinales en la enfermedad de Crohn / The TNFRSF1A gene R92Q mutation is associated with extra-intestinal manifestations of Crohn’s disease

It has been suggested that the R92Q mutation of the tumour necrosis factor receptor superfamily 1A (TNFRS1A) gene may be implicated in different inflammatory disorders. The aim of this study was to establish the role of this mutation as a determinant of Crohn`s disease (CD) susceptibility and/or clinical phenotype. One hundred and sixty-five CD patients and 203 healthy controls were prospectively included. The frequency of individuals carrying the R92Q mutation was similar between CD patients (4.24 percent) and controls (4.43 percent) (OR: 0.95; 95 percent CI = 0.34-2.62). In the genotype-phenotype evaluation, the univariate analysis showed that extra-intestinal manifestations were positively associated with the presence of R92Q mutation (p = 0.025; OR: 5.56; 95 percent CI = 1.04-29.6). In the multivariate analysis, presence of R92Q mutation was independently associated to extra-intestinal manifestations of CD, specially cutaneous manifestations (p = 0.02; OR: 5.17, 95 percent CI = 1.07-24.8). The R92Q mutation of TNFRSF1A gene is not a determinant of CD susceptibility, but contributes to the appearance of extra-intestinal manifestations of the disease.

Se ha sugerido que la mutación R92Q del gen de la super-familia del receptor del factor de necrosis tumoral 1A (TNFRS1A) podría estar relacionada con diversos trastornos inflamatorios. El objetivo de este estudio fue determinar el papel de esta mutación como factor determinante de la susceptibilidad y/o fenotipo clínico de la enfermedad de Crohn (EC). Ciento sesenta y cinco pacientes con EC y 203 controles sanos fueron incluidos de manera prospectiva. La frecuencia de individuos portadores de la mutación R92Q fue similar entre los pacientes con EC (4,24 por ciento) y los controles (4,43 por ciento) (OR: 0,95; 95 por ciento IC = 0,34-2,62). En la evaluación genotipo-fenotipo, el análisis univariado indicó que las manifestaciones extra-intestinales estaban relacionadas con la presencia de la mutación R92Q (p = 0,025; OR: 5,56; 95 por ciento IC = 1,04-29,6). En el análisis multivariado, la presencia de la mutación R92Q estuvo relacionada de manera independiente con las manifestaciones extra-intestinales de la EC, especialmente manifestaciones cutáneas (p = 0,02; OR: 5,17, 95 por ciento IC = 1,07-24,8). La mutación R92Q del gen TNFRSF1A no es un factor determinante de susceptibilidad a EC, pero contribuye a la aparición de manifestaciones extra-intestinales de la enfermedad.

Solid cancer, antiphospholipid antibodies, and venous thromboembolism.

The pathogenic role of antiphospholipid antibodies (aPL) in the development of venous thromboembolism (VTE) in patients with malignancies has not been established. From May 2006 to April 2008, 258 consecutive patients with solid-organ malignancies who developed VTE (VTE+) were recruited. A group of 142 patients matched for age, sex and tumor type cancer patients without VTE (VTE-) and an age-and-sex matched group of 258 healthy subjects were also included. A second blood sample was taken in positive aPL patients at least 12 weeks later. Twenty-one (8.1%) VTE+ patients, 2 (1.4%) VTE- patients (p=0.006) and 2 (0.8%) healthy subjects (p<0.001) were positive for aPL. Persistent aPL positivity was observed in only 4 out of 15 available VTE+ patients. No differences in demographic characteristics, clinical pattern and outcome were observed in VTE+ patients according to aPL status. The low prevalence and transience of aPL positivity in patients with solid-organ malignancies with VTE argues against a pathogenic role in the development of thrombosis in this setting. The published evidence of the relationship between cancer, aPL, and thrombosis is reviewed.

[Morbidity and mortality in patients treated with oral anticoagulants]. / Morbilidad y mortalidad en pacientes con tratamiento anticoagulante oral.

INTRODUCTION AND OBJECTIVES: The number of patients receiving oral anticoagulant therapy has increased markedly in recent years, with the consequence that monitoring must be decentralized. The aim of this study was to provide reference values for the quality of care in patients receiving oral anticoagulants at large specialized Spanish centers for use in future comparative analyses. METHODS: The records of 20,347 outpatients who were receiving oral anticoagulants between January and December 2003 at four large Spanish centers were assessed. Databases at the four hospitals were searched for severe adverse events. RESULTS: In total, 211,987 regular check-ups were carried out, 72.7% of which gave international normalized ratios (INRs) within the range 2-4. Overall, 2369 hemorrhagic events were observed, 190 (8%) of which were severe, with 20 deaths (0.1 per 100 patient-years). In addition, there were 299 thromboembolic events, with 11 deaths (0.05 per 100 patient-years). The frequency of these events was greater in patients with a cardiac prosthesis, who required more intense anticoagulation. The incidence of death with different diagnoses was also greater in anticoagulated patients with a cardiac prosthesis, and the highest probability of death (1 in 3) was associated with episodes of cerebral hemorrhage. The incidence of hemorrhage increased as the INR increased. In contrast, thrombotic events occurred principally when the INR was below 2, and were not observed with INRs over 6. CONCLUSIONS: The incidence of adverse events in patients receiving oral anticoagulant therapy at large Spanish centers was similar to that observed in other European countries.

Morbilidad y mortalidad en pacientes con tratamiento anticoagulante oral / Morbidity and mortality in patients treated with oral anticoagulants

Introducción y objetivos. El número de pacientes en tratamiento anticoagulante oral (TAO) ha crecido notablemente en los últimos años y ha demandado un proceso de descentralización de los controles. El objetivo de este estudio es tener una referencia de los índices de calidad de la población en TAO seguida en grandes unidades especializadas de España que permita un análisis comparativo futuro. Métodos. Se valoraron desde enero a diciembre de 2003 las fichas de los 20.347 pacientes en TAO controlados en 4 grandes unidades del país. Se buscó efectos adversos severos en los ficheros informatizados de los 4 hospitales. Resultados. Se realizaron 211.987 controles, y el 72,7% está dentro de un rango de 2-4. Se detectaron en total 2.369 eventos hemorrágicos, 190 (8%) graves, con 20 fallecimientos (0,1/100 pacientes/año). Hubo 299 episodios tromboembólicos con 11 fallecimientos (0,05/100 pacientes/año). La frecuencia de estos eventos fue mayor en aquellos enfermos con prótesis cardiacas, que precisaban una mayor intensidad de anticoagulación. La incidencia de fallecimientos por diagnósticos fue también mayor en pacientes anticoagulados por prótesis cardiacas y la mayor probabilidad de muerte (1 de cada 3 pacientes) se asoció a episodios de hemorragia cerebral. La incidencia de hemorragia se incrementó en función de la prolongación del INR, mientras que los eventos trombóticos aparecieron especialmente con INR < 2, y no se detectaron con INR > 6. Conclusiones. La incidencia de efectos adversos que afectan a los pacientes en TAO controlados en grandes unidades del país es similar a las reconocidas en otros países occidentales (AU)

Introduction and objectives. The number of patients receiving oral anticoagulant therapy has increased markedly in recent years, with the consequence that monitoring must be decentralized. The aim of this study was to provide reference values for the quality of care in patients receiving oral anticoagulants at large specialized Spanish centers for use in future comparative analyses. Methods. The records of 20,347 outpatients who were receiving oral anticoagulants between January and December 2003 at four large Spanish centers were assessed. Databases at the four hospitals were searched for severe adverse events. Results. In total, 211,987 regular check-ups were carried out, 72.7% of which gave international normalized ratios (INRs) within the range 2­4. Overall, 2369 hemorrhagic events were observed, 190 (8%) of which were severe, with 20 deaths (0.1 per 100 patient­years). In addition, there were 299 thromboembolic events, with 11 deaths (0.05 per 100 patient­years). The frequency of these events was greater in patients with a cardiac prosthesis, who required more intense anticoagulation. The incidence of death with different diagnoses was also greater in anticoagulated patients with a cardiac prosthesis, and the highest probability of death (1 in 3) was associated with episodes of cerebral hemorrhage. The incidence of hemorrhage increased as the INR increased. In contrast, thrombotic events occurred principally when the INR was below 2, and were not observed with INRs over 6. Conclusions. The incidence of adverse events in patients receiving oral anticoagulant therapy at large Spanish centers was similar to that observed in other European countries (AU)

Severe valvular regurgitation and antiphospholipid antibodies in systemic lupus erythematosus: a prospective, long-term, followup study.

OBJECTIVE: To assess whether the presence of antiphospholipid antibodies is related to the incidence and progression of severe valvular dysfunction and the need for valve replacement in patients with systemic lupus erythematosus (SLE). METHODS: In this prospective, long-term followup study, the initial echocardiographic findings in a cohort of 61 consecutive SLE patients were compared with those of 40 matched controls. All patients were serially evaluated for 14 +/- 3 years and had a followup echocardiogram 8 +/- 3 years after the initial evaluation. Serial determinations of anticardiolipin antibodies and lupus anticoagulant were performed in all cases. RESULTS: The number of SLE patients with valvular abnormalities increased from 39% to 73% between the initial and the followup echocardiography, but only 7 patients (12%) developed severe valvular regurgitation. Severe valvular regurgitation was significantly associated with the presence of high levels of IgG anticardiolipin antibodies (P = 0.001). The combined incidence of stroke, peripheral embolism, need for valve surgery, and death was 86% in patients with severe valvular regurgitation, compared with 25% in those without (P = 0.003). CONCLUSION: In SLE patients, the presence of high levels of IgG anticardiolipin antibodies is associated with the development of severe valvular regurgitation and with a high incidence of thromboembolic events and the need for valvular surgery.

Steady plasma concentration of unfractionated heparin reduces infarct volume and prevents inflammatory damage after transient focal cerebral ischemia in the rat.

Unfractionated heparin (UH) decreases the extent of infarction after transient focal brain ischemia in the rat and abridges neuroinflammatory damage in patients with acute stroke. This study was aimed at assessing whether controlled and steady heparinemia in plasma can reduce infarct volume and exert neuroprotective effects after ischemia. Infarct volume was measured at 24 and 7 days following a 1-hr intraluminal middle cerebral artery (MCA) occlusion in rats treated with UH or with vehicle. After testing several UH administration protocols, we choose to give a bolus of 200 U/kg, which was started 3 hr after the occlusion, followed by a 24-hr intraperitoneal perfusion of 70 U/kg/hr, which maintained a 24-hr steady plasma heparinemia (0.3-0.6 U/ml) and caused no CNS or systemic bleeding. In addition, plasma IL-10 concentration was measured by ELISA, endothelial VCAM-1 expression was evaluated by i.v. injection of a (125)I-labeled monoclonal antibody against VCAM-1, and brain hemeoxygenase-1 (HO-1) expression was determined by Western blot. UH-treated rats showed smaller infarctions than rats treated with vehicle, as well as higher IL-10 plasma levels and HO-1 brain expression and lower endothelial VCAM-1 induction. The study shows that a stable plasma concentration of UH given at nonhemorrhagic doses reduces infarct volume after ischemia-reperfusion in the rat. It also shows that UH prevented the induction of cell adhesion molecules in the cerebral vasculature and increased the expression of molecules with antiinflammatory and prosurvival properties. These findings support further testing of the clinical value of parenteral, adjusted, high-dose UH in patients with acute stroke.