Persistent thrombocytopenia predicts poor long-term survival in patients with antiphospholipid syndrome: a 38-year follow-up study.

OBJECTIVES: To investigate the impact of thrombocytopenia on survival in patients with APS. METHODS: Thrombocytopenia and other predictors of outcome were retrospectively evaluated in an aPL-positive and APS cohort with 38-year follow-up (1980-2018). Thrombocytopenia was defined as <150 × 109 platelets/l. Hazard ratios (HR) of mortality were calculated using Cox-regression models. RESULTS: Among 114 patients, 64% had primary APS, 25% secondary APS and 10% asymptomatic aPL. Mean follow-up was 19 (range 5-38) years. ANA [hazard ratio (HR) 1.8, 95% CI 0.8, 3.6, P = 0.10], arterial thrombotic events (HR 7.0, 95% CI 1.4, 3.5, P = 0.016), myocardial infarction (HR 8.3, 95% CI 1.1, 59, P = 0.03), intracardiac thrombosis (HR 17, 95% CI 1, 279, P = 0.04) and thrombocytopenia (HR 2.9, 95% CI 1.4, 6.1, P = 0.004) were risk factors for all-cause mortality, but in multivariate analysis only thrombocytopenia (HR 2.7, 95% CI 1.3, 6.0, P = 0.01) remained significant. Persistent (HR 4.4, 95% CI 2.1, 9.2, P = 0.001) and low-moderate thrombocytopenia (HR 2.8, 95% CI 1.2, 6.4, P = 0.01) were associated with a significant increase in mortality compared with acute (HR 1.6, 95% CI 0.5, 5.3, P = 0.40) and severe (HR 2.1, 95% CI 0.5, 9.2, P = 0.30) forms. APS patients with vs without thrombocytopenia were more frequently male (58 vs 24%, P = 0.001) with arterial thrombosis (55 vs 32%, P = 0.04), LA positivity (100 vs 87%, P = 0.04), type I aPL profile (89% vs 71%, P = 0.05) and anticoagulant treatment (89 vs 63%, P = 0.01). Thrombosis caused 13% of deaths in thrombocytopenic patients and 1% in those without (P = 0.01). CONCLUSION: Thrombocytopenia is an aPL-related manifestation that identifies patients with severe disease phenotype and high thrombotic risk. Persistent low-moderate thrombocytopenia is associated with a reduced long-term survival.

Autoantibodies to types I and IV collagen and heart valve disease in systemic lupus erythematosus/antiphospholipid syndrome.

Introduction/objectives autoantibodies to types I and IV collagen have been described in rheumatic fever and infective endocarditis. We tried to elucidate if an autoimmune response against collagens I and IV exists, associated with heart valve disease in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). A cohort of 172 patients with SLE (n = 79), primary APS (PAPS, n = 83), and secondary APS (n = 10) were assessed for valvulopathy by transthoracic echocardiograms. Autoantibodies to types I and IV collagen were assessed in patients and 50 controls, setting autoantibody positivity at two standard deviations above the mean antibody level of controls. Positive anticollagen IV antibody rate was significantly higher in SLE patients (17.7%) in respect to the rest of groups (PAPS 2.4%, controls 2%; P = 0.001). Percentage of positive autoantibodies to collagen I was similar in SLE and APS cohort of patients with and without valvular disease (48.4 vs 51.6%, respectively; P = 0.45). Percentage of positive autoantibodies to collagen IV was increased but not significantly in SLE and APS cohort of patients with respect to those without valvular disease (62.5 vs 37.5%, respectively; P = 0.08). Mean (standard deviation) levels of positive anticollagen I and IV antibodies did not differ between patients with and without valvular disease (85.6 ± 55 vs 81 ± 85 U/ml, respectively; P = 0.86 for anticollagen I) (0.05 ± 0.02 vs 0.12 ± 0.16 U/ml, respectively; P = 0.34 for anticollagen IV). Our data indicate a lack of association of autoantibodies to types I and IV collagen with heart valve disease in SLE and APS.

Cardiac manifestations other than valvulopathy in antiphospholipid syndrome: long-time echocardiography follow-up study.

AIM: Non-valvular cardiac disease in the antiphospholipid syndrome (APS) has been scanty studied. We wanted to assess the prevalence and evolution of left myocardial disease, pulmonary hypertension and intracardiac thrombi in a cohort of APS patients. METHOD: A total of 53 patients with APS, either primary (n = 34, 64%) or associated to lupus (n = 19, 36%) and 20 controls were included. Initial transthoracic echocardiography assessment was performed in patients at diagnosis, with echocardiography controls performed along mean follow-up of 12 years. Prevalence of myocardial disease in APS cohort was assessed taking into account primary risk factors (hemodynamically significant valvular disease, systemic hypertension, diabetes, alcoholism, myocardial infarction or myocarditis), the same as for pulmonary hypertension (severe left ventricular dysfunction or chronic lung disease). RESULTS: Left myocardial disease had a prevalence of 3.8% (2/53 patients), not different from controls (P = 0.12). Both patients had diastolic dysfunction grade I that maintained stability throughout echocardiographic follow-up period. Pulmonary hypertension had a prevalence of 11.3% (6/53 patients), not different from controls (P = 0.12); all cases were related to pulmonary embolism. Patients diagnosed with pulmonary hypertension in baseline maintained stable pressures throughout follow-up in the absence of new thrombosis. Intracardiac thrombi had a prevalence of 1.8% (1/53 patients), not different from controls (P = 0.4), without changes along echocardiographic follow-up. CONCLUSION: Pulmonary hypertension is the most prevalent non-valvular cardiac manifestation in APS, with an evolution associated with thromboembolic disease, while left myocardial disease and intracardiac thrombi would be rare manifestations in APS.

Idiopathic retroperitoneal fibrosis: a clinicopathological study in 24 Spanish cases.

Idiopathic retroperitoneal fibrosis (IRPF) is a rare condition of unknown aetiology characterized by chronic non-specific inflammation of the retroperitoneum. The aim of this study is to describe, for the first time, the features of Spanish patients with IRPF. In this retrospective study, a clinical description was performed to examine the histopathological features, radiologic findings, laboratory data and treatment of a cohort of 24 IRPF Spanish patients who were admitted to Vall d'Hebron Hospital in Barcelona (Spain) between 1982 and 2009. Patients with secondary retroperitoneal fibrosis were excluded. Nineteen patients (79.1 %) were male, whereas 5 were female. The mean age at diagnosis was 51.8 ± 16.4 years. Pain (79.1 %) and hydronephrosis (70.8 %) were the most common clinical manifestations. Abdominal computed tomography and ultrasonography were performed on all cases. Acute-phase reactants were elevated in most patients. Thirteen surgical biopsies were performed, and all were consistent with retroperitoneal fibrosis. Steroid therapy was given in 19 cases, and eight patients (42.1 %) required urethral catheterisation. Chronic renal failure (CRF) rate after 2 years of follow-up was 42.8 %, more frequently in patients with higher serum creatinine at diagnosis. IRPF in Spain is a rare condition affecting mainly middle-aged males, with pain and hydronephrosis as the most frequent manifestations. Steroids are the mainstay treatment, and CRF is the main sequel. An earlier diagnosis and uniform treatment protocols could prompt lower CRF rates.

Protein Z levels and anti-protein Z antibodies in patients with arterial and venous thrombosis.

INTRODUCTION: The thrombotic risk associated with protein Z (PZ) deficiency is unclear. Anti-protein Z (anti-PZ) has been described as a risk factor in unexplained embryo demise. The aim of our study was to evaluate a possible PZ deficiency and presence of anti-PZ antibodies on thrombotic diseases. MATERIAL AND METHODS: We performed a case-control study on 114 patients with preexisting arterial or venous thrombosis (50 and 64, respectively). Thrombosis was studied based on etiology (creating factor risk subgroups) and on specific thrombotic disease. RESULTS: PZ levels of patients were significantly lower compared to controls (1709+-761.3 ng/mL vs. 2437+-964.7 ng/mL P=0.001). The high arterial risk factor subgroup showed the lowest PZ level (1267.5+-609 ng/mL) whereas the rest of arterial and venous etiological subgroups presented similar PZ levels. Patients with peripheral artery disease had the lowest PZ level (1022+-966 ng/mL). The rest of arterial and venous thrombotic diseases presented similar PZ levels. A significant increased risk for arterial and venous thrombosis for the lowest (<1685 ng/mL) quartile of PZ has been founded (OR:52, P=0.001 and OR:18, P=0.007, respectively). Anti-PZ antibodies were negative in the majority of patients, although mean anti-PZ IgG antibody levels in the arterial thrombosis group were significantly higher compared to venous thrombosis and control groups (P=0.05 and P=0.005, respectively). CONCLUSIONS: The results suggest that both arterial and venous thrombotic events are related to low PZ levels and that low PZ concentrations are associated with thrombosis in our study. In arterial thrombosis our findings strengthen previous studies that related low PZ levels to atherosclerotic disease. Anti-PZ antibodies do not seem to play a potent role in thrombosis.

Anticoagulante Lúpico: Sensibilidad de 19 reactivos comerciales de tiempo de tromboplastina parcial activado / Lupus Anticoagulant: Sensitivity of 19 commercial activated partial thromboplastin time reagents

El Anticoagulante Lúpico (AL) constituye una familia de inmunoglobulinas que interfieren las pruebas de coagulación dependientes de fosfolípidos. Hay una gran variedad de pruebas que permiten detectar y confirmar la presencia de AL en el plasma de un paciente. Sin embargo, el tiempo de tromboplastina parcial activado (TTPA) sigue siendo una de las pruebas más utilizadas para la detección de dicho inhibidor. Teniendo en cuenta la importancia clínica de su diagnóstico de laboratorio, se dicidió estudiar la sensibilidad, para detectar AL, de 19 reactivos comerciales de TTPA. Se obtuvieron varias conclusiones importantes: No se encontró relación entre sensibilidad y tamaño de los liposomas; tampoco con la uniformidad de los mismos. La fuente de fosfolípido y el tipo de activador no son suficientes para explicar las diferencias en sensibilidad de los reactivos. Finalmente, se encontró una correlación negativa entre la sensibilidad y la concentración total de fosfolípido del reactivo. A menor concentración de fosfolípido, mayor sensibilidad.

Lupus anticoagulants (LA) are immunoglobulins which interfere in in vitro phospholipid-dependent coagulation tests. Various methods have been proposed; however, activated partial thromboplastin time (APTT) is the most used screening test for lupus anticoagulant. Previous studies have shown that sensitivity to the lupus anticoagulant defect varies considerably with different APTT reagents. In view of the undoubted clinical importance of lupus anticoagulants, the sensitivity of 19 commercial APTT reagents has been evaluated. The study raises several important conclusions: No difference was found in sensitivity associated with a narrower distribution of liposomes' diameter, considering the latter as a marker of uniformity in phospholipid distribution. The source of the platelet substitute and the nature of the contact phase activator are unlikely to determine such varied sensitivity. Finally, a significant negative correlation between APTT sensitivity and total phospholipid concentration was found. The lower the phospholipid concentration, the higher the APTT sensitivity to AL.

Transforming growth factor-12 polymorphism and systemic lupus erythematosus.

OBJECTIVE: To determine whether transforming growth factor-beta2 (TGF-beta2) gene polymorphism is associated with systemic lupus erythematosus (SLE) susceptibility. TGF-beta is a multifunctional family of cytokines important in tissue repair, inflammation and immunoregulation. SLE is thought to be a T cell dependent autoimmune disorder with T cell dysfunction. Due to its known suppressive effects on interleukin 2 dependent T cell growth, TGF-beta2 is considered to be a candidate SLE susceptibility gene. Furthermore, SLE has been linked with a region to which the TGF-beta2 gene has been mapped. METHODS: Association studies were performed in 3 case-control populations, from Spain. Turkey, and UK, using a TGF-beta2 5'-untranslated region (5'-UTR) 4 base pair (bp) insertion polymorphism. Genotyping was performed using fluorescent labeled polymerase chain reaction product sizing. Results. No significant differences were detected in TGF-beta2 5'-UTR polymorphism allele frequencies between SLE patients and matched controls in the 3 populations studied. CONCLUSION: The 4 bp insertion polymorphism within the TGF-beta2 gene does not appear to be associated with SLE. However, this does not rule out the possible involvement of TGF-beta2 in the disease pathogenesis.