Patrizia Rampazzo

Accuracy of a portable prothrombin time monitor (Coagucheck) in patients on chronic oral anticoagulant therapy: a prospective multicenter study.

A portable prothrombin time (PT) monitor allows patients on oral anticoagulant therapy (OAT) to measure their PT at home. The purpose of the study was to evaluate the accuracy and precision of a portable PT monitor (Coagucheck, Roche Diagnostics, Mannheim, Germany) as compared with laboratory methods. The prospective study was conducted in four centers of the Italian Federation of Anticoagulation Clinics. A one-month instruction phase was followed by a six-month surveillance phase. Seventy-eight subjects on stable OAT (48 men, 30 women, age range: 18-75) were selected on a volunteer basis. Dual measurements of INR values were performed in each subject both from finger capillary blood by the monitor and from venous blood by the Anticoagulation Clinic laboratory in three instruction sessions. The mean difference (bias) of the monitor INR results when compared with the average of laboratory INR and monitor INR results was -0.025 (limits of agreement-LA: -0.84/+0.81 INR units). The mean bias was -0.0675 (LA: -0.37/+0.23), +0.018 (LA: -0.39/+0.35), and +0.039 (LA: -0.49/+0.55), respectively, for INR values lower than 2.0, between 2.0 and 3.0, and greater than 3.0. The overall precision coefficient of monitor INR was 0.370, while it was 0.23, 0.46, 0.29, and 0.21, respectively, in Centers 1, 2, 3, and 4. The overall variation coefficient was 6.5% while it was 3.7%, 8.5%, 4.7%, and 4.9%, respectively, in Centers 1, 2, 3, and 4. Coagucheck has an acceptable level of accuracy for INR values in the range between 2.0 and 3.0. A wide variation in monitor performance was found among centers.

[Anti-β2 Glycoprotein I—β2 Glycoprotein I] immune complexes in patients with antiphospholipid syndrome and other autoimmune diseases

Antiphospholipid syndrome (APS) is defined by the presence of aPL antibodies in patients with thromboembolic phenomena. Some antiphospholipid (aPL) antibodies, such as those directed against β2-glycoprotein I (β2GPI), are associated with thromboembolism, possess Lupus Anticoagulant (LA) activity and recognize their target antigen only when bound to specific surfaces or to phospholipids (PL). To ascertain whether both free and antibody-bound β2GPI circulate in APS, we set up an ELISA to detect [IgG anti-β2GPI–β2GPI] immune complexes. In this system, rabbit anti-human β2GPI antibodies were adsorbed onto plastic plates, incubated with patient plasma, and bound complexes were detected by means of alkaline phosphatase-labeled goat anti-human IgG; each assay was stopped when positive controls consisting of in vitro generated immune complexes reached an Optical Density (OD) of 0.5 at 405 nm. Plasma from 16 patients with APS showed a mean OD405 of 0.291 (range 0.115–0.558), not statistically different from the mean obtained for 15 age-and sex-matched healthy volunteers (mean OD405 = 0.169, range 0.066–0.264). Surprisingly, levels of immune complexes in 14 patients with other autoimmune diseases and no circulating anti-β2GPI antibodies were statistically higher (mean OD405 = 0.552, range 0.204–0.991) than those of healthy subjects and patients with APS. These data indicate that while autoantibodies to β2GPI are mainly unbound in plasma of patients with APS, they are complexed with their antigen in patients with other autoimmune diseases, possibly reflecting a higher binding affinity.

Coagulation Activation in Children with Sickle Cell Disease Is Associated with Cerebral Small Vessel Vasculopathy

Background Thrombotic complications in Sickle Cell Disease (SCD) arise since infancy, but the role of the coagulation system in children has been poorly explored. To determine its role in the development of clinical complications in childhood we measured coagulation and endothelial parameters in children with SCD at steady state. Methods Markers of thrombin generation, fibrin dissolution and endothelial activation were evaluated in 38 children with SS-Sβ°, 6 with SC disease and 50 age and blood group matched controls. Coagulation variables were correlated with markers of hemolysis and inflammation, with the presence of cerebral and lung vasculopathy and with the frequency of clinical complications. Results SS-Sβ° patients presented higher levels of factor VIII, von Willebrand factor antigen (VWF:Ag) and collagen binding activity, tissue plasminogen activator antigen (t-PA:Ag), D-dimer, p-selectin, prothrombin fragment1+2 (F1+2) and lower ADAMTS-13:activity/VWF:Ag (p<0.05) compared to controls and SC patients. In SS-Sβ° patients coagulation variables correlated positively with markers of inflammation, hemolysis, and negatively with HbF (p<0.05). Patients with cerebral silent infarcts showed significant decrease in t-PA:Ag and ADAMTS-13 Antigen and a tendency toward higher D-dimer, F1+2, TAT compared to patients without them. D-dimer was associated with a six fold increased risk of cerebral silent infarcts. No correlation was found between coagulation activation and large vessel vasculopathy or other clinical events except for decreased t-PA:Ag in patients with tricuspid Rigurgitant Velocity >2.5m/sec. Conclusions SS-Sβ° disease is associated with extensive activation of the coagulation system at steady state since young age. ADAMTS-13 and t-PA:Ag are involved in the development of cerebral silent infarcts.

Comprehensive care for sickle cell disease immigrant patients: a reproducible model achieving high adherence to minimum standards of care.

Comprehensive care and advances in clinical investigations have reduced morbidity and mortality in sickle cell disease (SCD), but only a minority of children with SCD has access to comprehensive care. In Europe the majority of patients with SCD are immigrants who present barriers in accessing the health system; therefore, new evidence‐based models of comprehensive care are needed to ensure that all SCD patients receive high‐quality care, overcoming patient‐ and health system‐related barriers. We wanted to verify if addressing the specific needs of immigrant patients contributes to improving adherence.

Intellectual function evaluation of first generation immigrant children with sickle cell disease: the role of language and sociodemographic factors

BackgroundSickle Cell Disease (SCD) is the most common genetic disease worldwide. Neurological events are among the most worrisome clinical complications of SCD and are frequently accompanied by cognitive impairment. Intellectual function in SCD may vary according to genetic and environmental factors. Immigrant children with SCD are increasing at a global level and display specific health care needs. The aim of our multicenter study was to describe the intellectual function of first generation African immigrants with SCD and the influence of sociodemographic factors on its characteristics.MethodsThe Wechsler Intelligence Scales were administered to evaluate broad intellectual functions in children with SCD and in age-matched healthy siblings. Patients’ clinical, socio-demographic, Magnetic Resonance Imaging (MRI) and Angiography (MRA) data were correlated to intellectual function scores.Results68 children, mean age 8.95 years were evaluated. 72% spoke three languages, 21% two. FSIQ was <75 in 25% of the children. Mean VIQ was lower than PIQ in 75%. Mean verbal subtest scores were lower than performance scores. Female gender, number of languages spoken at home and mother’s employment were associated with single subtest performances (p < 0.05). MRA was abnormal in 73.4% and MRI in 35.9%. No significant correlation was established between silent lesions and intellectual function, even if patients with lesions performed worse. Fifteen siblings performed better than patients on cognitive domains, including language (p < 0.05).ConclusionsImmigrant bilingual children with SCD seem to display a rate of cognitive impairment similar to their monolingual counterparts but a more pronounced and precocious onset of language difficulties. Adjunctive tests need to be considered in this group of patients to better define their specific deficits.

Comparison between routine laboratory prothrombin time measurements and fingerstick determinations using a near-patient testing device (Pro-Time).

Oral anticoagulant (OA) treatment is saving lives by reducing mortality and morbid1. Materials and Methods ity associated with thrombosis-related clinical events [1]. The number of patients treated 1.1. Patients is rapidly increasing, and monitoring OA treatment is an emerging health/social problem [2]. During 15 working days, 150 patients referred to Near-patient testing devices are increasingly our Center for a periodic checkup of OA treatment proposed, and home-monitoring offers an attracwere evaluated. They were in stable OA therapy, tive alternative to testing in the clinic. However, with at least three preceding international normalstudies designed to validate the adequacy of such ized ratios (INRs) in the therapeutic range. Both devices are mandatory prior to their general applivenous and capillary blood samples were drawn cation. by qualified personnel. Each session included two The adequacy of self-testing devices was first plasma samples from healthy subjects. reported by Lucas et al. [3]. Subsequently, many The Pro Timet Microcoagulation System is a studies reported the reliability of various devices hand-held portable device that can be used by eiin comparison to standard prothrombin time (PT) ther battery or electrical power supply. This instrudeterminations [4–8]. ment gives PT determinations on capillary blood In this study we have compared the reliability samples obtained by using a disposable device of Pro Timet, a new microcoagulation device (In(Tenderlettt Plus) for fingerstick incision, blood ternational Technidyne Corporation, Edison, NJ, collection, and application of the sample to a test USA), with the PT determination system routinely cuvette. Each test cuvette has five reaction channels containing lyophilized human recombinant thromboplastin with an international sensitivity Abbreviations: OA, oral anticoagulant; PT, prothrombin time; index (ISI) of around 1.0. INR, international normalized ratio. When the blood sample is applied and the quality Corresponding author: Vittorio Pengo, Department of Clinical and Experimental Medicine, University of Padova School of Medcontrol results are within the expected ranges, the icine, Thrombosis Centre, “Ex Busonera” Hospital, via Gattamelinstrument displays the PT result in INR and secata, 64, I-35128 Padova, Italy. Tel.: 139 (49) 821 5658. Fax: 139 (49) 875 4179. E-mail: ,pengo@ux1.unipd.it.. onds. If the test has not been performed correctly,

Initiation of Warfarin Treatment in Outpatients with Nonrheumatic Atrial Fibrillation: A Scheme for Early Indication of Maintenance Dose

Eighty-four outpatients with nonrheumatic atrial fibrillation starting oral anticoagulant treatment were adminis tered warfarin (10 mg/day) for the first 2 days of treatment. Prothrombin time, expressed as International Normalized Ratio (INR), was measured on day 3 and plotted against the weekly warfarin maintenance dose, defined as the dose able to maintain INR between 2.0 and 3.0 (therapeutic range) on three consecu tive occasions, 1 week apart. The data fit a regression line (r = 0.74, p < .0001) that we use to estimate the weekly maintenance dose of other patients.

Cognitive evoked potentials and neural networks are abnormal in children with sickle cell disease and not related to the degree of anaemia, pain and silent infarcts

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Cognition and the Default Mode Network in Children with Sickle Cell Disease: A Resting State Functional MRI Study.

Cerebrovascular complications are frequent events in children with sickle cell disease, yet routinely used techniques such as Transcranial Doppler (TCD), Magnetic Resonance (MRI) and Angiography (MRA), insufficiently explain the cause of poor cognitive performances. Forty children with SS-Sβ° (mean age 8 years) underwent neurocognitive evaluation and comprehensive brain imaging assessment with TCD, MRI, MRA, Resting State (RS) Functional MRI with evaluation of the Default Mode Network (DMN). Sixteen healthy age-matched controls underwent MRI, MRA and RS functional MRI.Children with SCD display increased brain connectivity in the DMN even in the absence of alterations in standard imaging techniques. Patients with low neurocognitive scores presented higher brain connectivity compared to children without cognitive impairment or controls, suggesting an initial compensatory mechanism to maintain performances. In our cohort steady state haemoglobin level was not related to increased brain connectivity, but SatO2<97% was. Our findings provide novel evidence that SCD is characterized by a selective disruption of connectivity among relevant regions of the brain, potentially leading to reduced cognition and altered functional brain dynamics. RS functional MRI could be used as a useful tool to evaluate cognition and cerebral damage in SCD in longitudinal trials.

Longitudinal evaluation of cerebral white matter hyperintensities lesion volume in children with sickle cell disease

We read with great interest the paper by van der Land et al (2016) regarding risk factors of cerebral white matter hyperintensities (WMHs) in children with sickle cell disease (SCD). In their cross sectional analysis (40 SS-Sb° patients, mean age 12 1 years), the authors identified male gender as a risk factor for WMH appearance, the association of low fetal haemoglobin (HbF) with large lesion volume and low ADAMTS13 levels to be associated with low cerebral blood flow. They concluded by suggesting that low HbF levels and endothelial dysfunction may be involved in the pathogenesis of WMHs in patients with SCD and that WMH volume could be an interesting biomarker for disease progression in future therapeutic trials for SCD. We agree with both of these conclusions by the authors. Indeed, we had already shown a negative correlation between lesion volume and both tissue plasminogen activator value ( 0 42, P 0 019) and ADAMTS13 antigen level ( 0 39, P 0 03) in patients with SS-Sb° SCD, unveiling the possible role of endothelial dysfunction on the volume of silent infarcts (Colombatti et al, 2013). In addition, a few cross-sectional studies have shown the correlation between WMHs and cognitive dysfunction, providing some evidence that the course of silent infarcts (SI) might severely impact on the quality of life of SCD children (van der Land et al, 2015). Nonetheless, no longitudinal study directly quantified the evolution of WMHs volume in SCD and little information is available regarding the timing of their appearance in SCD patients. We retrospectively evaluated WMH volume in 61 children with SS-Sb°. Since 2009, magnetic resonance imaging (MRI) scans have been performed routinely at our centre as part of SCD clinical care every two years, starting as soon as sedation is no longer necessary, generally at 5 years of age. MRIs are performed before 5 years of age whena Transcranial Doppler scan (TCD) cannot be performed, or following an indeterminate (poor window) or conditional/abnormal TCD, or according to clinical indication. MRI is also performed as part of pre-bone marrow transplantation evaluation. All MRIs were performed at steady state with a previously described protocol (Montanaro et al, 2013). The white matter lesion volume was measured by manually drawing all lesions on each fluid attenuation inversion recovery (FLAIR) image; the global lesion volume was obtained by using the following formula: X lesions ðslice thicknessþ interslice-gapÞ