Immune tolerance by intermittent factor VIII boluses in two high responder hemophilia A patients.
ABSTRACT Immune tolerance (IT) in hemophilia A patients with anti-factor VIII antibodies is generally based on daily factor VIII administrations. Here we report the preliminary results of an immune tolerance regimen based on recombinant high-dose (400 U/kg) factor VIII boluses administered at 48-hour intervals. Two high responder hemophilia A patients aged 2 and 3 years received this treatment without the need of permanent venous access. In both cases the IT regimen caused an anamnestic response of less than three weeks' duration and an antibody reduction to less than 5 Bethesda units was achieved in about 8-10 weeks. In the child with a more prolonged follow-up the inhibitor became undetectable after four months and factor VIII recovery at 6 months was > 85%. This intermittent high-dose regimen seems to be effective in rapidly inducing immune tolerance and seems particularly suitable for very young children in whom it may be useful to avoid the risks and to reduce the psychological burden of permanent venous access.
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ABSTRACT: Adenosine diphosphate (ADP) plays a crucial role in hemostasis and thrombosis, and its receptors are potential targets for antithrombotic drugs. Two G-protein-coupled P2 receptors contribute to platelet aggregation: the P2Y1 receptor initiates aggregation through mobilization of calcium stores, whereas the P2Y12 receptor coupled to adenylyl cyclase inhibition is essential for a full aggregation response to ADP and the stabilization of aggregates. The latter is defective in certain patients with a selective congenital deficiency of aggregation to ADP. It is also the target of the antithrombotic drug clopidogrel and of adenosine triphosphate analogues and other compounds currently under evaluation. In addition, the P2X1 ionotropic receptor is present in platelets, but its role is not yet completely known. Studies in P2Y1-knockout mice and experimental thrombosis models using selective P2Y1 antagonists have shown that the P2Y1 receptor, like the P2Y12 receptor, is a potential target for new antithrombotic drugs.International Journal of Hematology 01/2002; 74(4):375-81. · 1.68 Impact Factor
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ABSTRACT: Atherosclerosis is a focal inflammatory disease of the arterial wall. It starts with the formation of fatty streaks on the arterial wall that evolve to form a raised plaque made of smooth muscle cells (SMCs), and infiltrating leukocytes surrounding a necrotic core. The pathogenesis of the atherosclerotic lesion is incompletely understood, but it is clear that a dysfunction of the endothelium, recruitment and activation of inflammatory cells and SMC proliferation have a pivotal role. Over recent years receptors for extracellular nucleotides, the P2 receptors, have been recognized as fundamental modulators of leukocytes, platelets, SMCs and endothelial cells. P2 receptors mediate chemotaxis, cytokine secretion, NO generation, platelet aggregation and cell proliferation in response to accumulation of nucleotides into the extracellular milieu. Clinical trials have shown the benefit of antagonists of the ADP platelet receptor(s) in the prevention of vascular accidents in patients with atherosclerosis. Therefore, we anticipate that a deeper understanding of the involvement of P2 receptors in atheroma formation will open new avenues for drug design and therapeutic intervention.British Journal of Pharmacology 03/2002; 135(4):831-42. · 5.07 Impact Factor
Article: Mechanisms of platelet aggregation.[Show abstract] [Hide abstract]
ABSTRACT: Platelet aggregation is initiated by receptor activation coupled to intracellular signaling leading to activation of integrin alphaIIbbeta3. Recent advances in the study of platelet receptors for collagen, von Willebrand factor, thrombin, and adenosine diphosphate are providing new insights into the mechanisms of platelet aggregation.Current Opinion in Hematology 10/2001; 8(5):270-6. · 4.11 Impact Factor