Giuseppe Lassandro

Carotenoids and Cardiovascular Risk

Fruits and vegetables (typically associated with the Mediterranean diet) are very rich in carotenoids, i.e. fat-soluble pigments really important in human life. Structurally, carotenoids consists of eleven (beta-carotene, zeaxanthin, lycopene) or ten (alpha-carotene, lutein) conjugated double bonds, responsible for their antioxidant capability in agreement with their substituents. Low-Density Lipoprotein (LDL) particles oxidation process is the one of the most important first steps of atherosclerotic disease and, consequentially, the first pathogenetical step of cerebro- and cardiovascular events like myocardial infarction and stroke, which are the first cause of death in industrialized countries. Reactive oxygen species (ROS) also seem to be the target of Carotenoids main action, by scavenging singlet oxygen (1O2) and free radicals. Literature data showed that ROS increase atherosclerotic individual burden. The carotenoids scavenging action could reduce atherosclerosis progression partly due to such a decrease in ROS concentrations. Many studied demonstrated such a reduction by analyzing the relationship between carotenoids and Intima-Media Thickness of common carotid artery wall (CCA-IMT), [a well established marker of atherosclerosis evolution] reduction. Aim of this review is to evaluate actual knowledge about the importance of carotenoids molecules in slowing down the starting and the progression of atherosclerotic plaque, and to consider their implementation in everyones diet as a tool to obtain a sharp decrease of LDL oxidation and their possible effect on endothelial function.

Reduced interleukin-5 production by peripheral CD4+ T cells in common variable immunodeficiency patients.

We evaluated the capacity of peripheral CD4+ T helper cells in four Common Variable Immunodeficiency (CVI) patients to secrete interleukin-4 (IL-4) and IL-5. While in control CD4+ T cells, stimulated via CD3 and cultured in presence of IL-2 or IL-15, a 10 fold increased production of IL-5 (146 ± 30; 142 ± 25 pg/ml) was found, a 4 fold increment of this cytokine was, instead, detected in 3 out of 4 CVI patients (34 ± 13; 39 ± 12 pg/ml) (p < 0.05). In conclusion, the reduction of IL-5, involved in the late regulation of B cell differentiation into Ig-secreting plasma cells, may contribute to the defective antibody production in CVI patients.

Issues in pediatric haemophilia care

The hemophilias are the most common X-linked inherited bleeding disorders. The challenges in children are different from that in adults and, If not properly managed, can lead to chronic disease and lifelong disabilities. Currently, inhibitors are the most severe complication and prophylaxis is emerging as the optimal preventive care strategy. Quality of life has become in the western countries the primary objective of the process of providing care, thus all the strategies (psychotherapy, physiotherapy, community life), not just the infusion of the missing factor, should be activated for the patient and family to give them the perception of being healthy.

A Practical Approach to the Use of Low Molecular Weight Heparins in VTE Treatment and Prophylaxis in Children and Newborns

Low-molecular weight heparins are currently the most commonly used anticoagulants in children and newborns. However, since thrombotic complications rarely occur outside large childrens hospitals, physicians often encounter some practical problems in managing these treatments when a pediatric thrombosis specialist is not available. The drug of choice is enoxaparin, due to its favorable FXa/FIIa ratio and the availability of pharmacokinetic and pharmacodynamic data. The treatment of acute thrombosis should be started with two daily injections but when compliance is an issue, a single daily administration schedule could be chosen for secondary prophylaxis ensuring careful measurement of the post 24-hour anti-FXa activity. Furthermore, a subcutaneous device may be a useful tool and a topical dermal anesthetic could be effective in controlling pain without affecting anti-FXa levels. In neonate and toddlers, where mini doses are frequently needed, the dead space of syringes and needles could represent an issue and therefore the use of insulin syringes without dead space is advisable, while a dilution of the drug is useful with other syringes. This article derives from a nonsystematic review of the available literature, with special attention to recent international guidelines and expert recommendations, combined to authors’ clinical practice in large tertiary pediatric hospitals and will provide concise and practical information for the use of low-molecular weight heparin in childhood and infancy in a sort of “answering frequently asked questions.”

High serum sclerostin levels in children with haemophilia A.

Keywords: sclerostin; haemophilia A; bone mineral density; receptor activator of nuclear factor-κB ligand; osteoprotegerin; DKK1

Health economic models in hemophilia A and utility assumptions from a clinician's perspective

The clinical benefits of prophylaxis in patients with hemophilia are well‐established and include the following: reduced bleeding episodes, prevention of joint damage, decreased inhibitor development, and improved health‐related quality of life. However, the cost‐effectiveness of prophylaxis is still not clear.

Autoimmune haematological disorders in two Italian children with Kabuki Syndrome

Kabuki syndrome (also called Niikawa-Kuroki syndrome) is a rare genetic disease described for the first time in Japan, characterised by anomalies in multiple organ systems and often associated with autoimmune disorders and impaired immune response. We herein report the clinical history, the therapeutic approach and the outcome of two children with Kabuki syndrome who developed autoimmune haematological disorders (haemolytic anaemia and immune thrombocytopenia). Factors regarding differential diagnosis and interventions in better management of this syndrome and its complications are discussed. This is the first report of Italian children with autoimmune haematological disorders complicating Kabuki syndrome.

Innovative use of recombinant activated factor VII during physical rehabilitation in an Italian child with Glanzmann's thromboasthenia.

In 1918 Eduard Glanzmann described a series of patients with normal platelet count but prolonged bleeding time and modified clot retraction. This rare, recessively inherited platelet disorder was named Glanzmann’s thromboasthenia (GT). It has a high expression in certain ethnic groups, such as Iraqi Jews, Iranians, Arabs, French Gypsies and Indians, in which consanguineous marriages are common. The disease is due to the absence or decrease in the expression of the platelet glycoprotein (GP) IIb/IIIa membrane complex1,2. GPIIb and GPIIIa are present in the platelet membrane as heterodimeric molecules and the GPIIb/IIIa or αIIbβ3 complex represents a member of the ubiquitous integrin family of cell surface receptors. GT is usually considered the most frequent inherited integrin disorder3. Bleeding manifestations in this autosomal recessive disorder occur in patients who are homozygous or compound heterozygous for GPIIb/IIIa mutations. GPIIb/IIIa complex is involved in platelet aggregation, resulting from the binding of fibrinogen to this glycoprotein complex on activated platelets2–4. The diagnostic features of GT consist of absent platelet aggregation in response to all physiological stimuli and abnormal clot retraction, in presence of normal ristocetin-induced agglutination, platelet count and morphology. Platelet αIIbβ3 deficiency should always be confirmed in newly diagnosed patients by monoclonal antibodies and flow cytometry analysis3. Clinical manifestations seen in childhood include easy bruising, epistaxis, gingival bleeding, menorrhagia and less frequently gastrointestinal bleeding, haematuria, haemarthrosis, muscle haematoma and nervous system haemorrhages2. Bleeding complications are also frequent after dental extraction, surgery and giving birth. The bleeding tendency in GT patients is highly variable: some patients remain asymptomatic, whereas others experience severe bleeding episodes. Treatment measures for mild bleeding are local pressure through nasal packing with gelatine sponge for epistaxis, local haemostatics such as fibrin glue and topical thrombin, as well as the use of anti-fibrinolytic agents. The standard therapy for severe bleeding is platelet transfusion. However, repeated transfusions may result in the development of antibodies against GPIIb/IIIa and/or human leucocyte antigens (HLA), resulting in refractoriness to further platelet transfusions. Moreover, transfusions are not always readily available and the use of blood products is associated with the risk of infections and allergic reactions. An alternative effective agent is, therefore, needed for the management of GT patients, particularly those who are refractory to platelet transfusion5,6. Recombinant human activated factor VIIa (rFVIIa) is structurally similar to the coagulation factor VIIa derived from human plasma. It is produced by expressing the cloned gene for human factor VII in baby hamster kidney cells without the use of human serum or other human proteins7. Factor VIIa exerts its haemostatic effect only after interaction with the tissue factor, usually at the site of injury. In the presence of platelet disorders, a tissue factor-dependent mechanism operates to generate thrombin for initial platelet activation with exposure of coagulant surfaces. However, the impaired platelet activation hampers the amplification phase and thrombin generation is not sufficient for fibrin formation. High doses of rFVIIa activate platelets and mediate increased thrombin generation, which is important for further activation, adhesion and aggregation of platelets as well as the formation of fibrin to improve the haemostatic process. The use of rFVIIa (Novoseven®, Bagsvaerd, Denmark) has been approved in many countries including North America, Europe, Australia and Japan for the treatment of bleeding in patients with haemophilia A or B with inhibitor antibodies, as well as acquired haemophilia. The efficacy of rFVIIa has also been documented in patients with GT and its use has been approved by the European Medical Evaluation Agency (EMEA) for the management of bleeding in GT patients with anti-platelet antibodies and a history of platelet refractoriness, as well as in patients with FVII deficiency8. Haemarthrosis is extremely rare in GT patients. The clinical and pathophysiological features of joint bleeding have been extensively investigated in haemophilic patients. Recurrent haemorrhages can result in synovial hypertrophy, followed by haemosiderin deposition, which increase the risk of synovitis. The inflamed synovium is even more prone to haemorrhage. Cartilage and subchondral bone destruction is thought to be either a consequence of the catabolic activity of the inflamed synovium and/or to be caused by the direct toxic effects of blood breakdown products themselves. The latter mechanism results in loss of joint space, subchondral bone irregularity, erosions, and subchondral cyst formation. These changes ultimately lead to severe functional impairment (haemophilic arthropathy)9. Here we report the case of an Italian 11-year old male GT patient with traumatic ankle haemarthrosis who was treated with a novel regimen of rFVIIa, in order to prevent joint damage.

Hemarthrosis due to a rare cause of hemorrhagic diathesis: Ehlers-Danlos syndrome.

The authors report a case of hemarthrosis complicated by severe anemia related to a congenital connective tissue disease: Ehlers-Danlos syndrome. A boy fell down and suffered tumefaction of both knees with bilateral rupture of the rotula tendon. He underwent surgical reinsertion of each tendon on the rotula. He later showed an unexpected ongoing hematic effusion, with severe anemia. He was screened for coagulation disorders with no results. On taking a more detailed history and investigating the patients phenotypical features, the authors diagnosed Ehlers-Danlos syndrome, hypermobile variant. The hemarthrosis and anemia were thus concluded to be consequences of excessive tissue fragility due to a congenital connective tissue disease.

Current Management of the Hemophilic Child: A Demanding Interlocutor. Quality of Life and Adequate Cost-Efficacy Analysis

Hemophilias are the most known inherited bleeding disorders. The challenges in the management of hemophilic children are different from those in adults: prophylaxis regimen removed the hallmark of crippling disease with lifelong disabilities; individualized regimens are being implemented in order to overcome venous access problems. Presently, at least in high-income countries, advances in treatment of hemophilia resulted in continuous improvement of the patients’ quality of life and life expectancy. Inhibitors remain the most severe complication of hemophilia therapy. The treatment’ compliance is the key to achieve a successful management. The patient, his family, the medical and psychological team are the players of a comprehensive care system. The current management of hemophilic children is the example of huge resource investments enabling long-term benefits in particular quality of life as a primary objective of the healthcare process.