Peter A. Castaldi

The neurotoxicity of high-dose cytosine arabinoside is age-related

Fifteen patients with acute myeloid leukaemia were given a total of 17 courses of high‐dose cytosine arabinoside (Ara‐C). The median age of the patients was 37 years. Four patients developed severe irreversible neurotoxicity, three developed mild to moderate, reversible neurotoxicity, whereas eight patients had no toxicity. Of five patients over the age of 55 years given high dose Ara‐C, four developed severe, irreversible neurotoxicity, but there were no severe episodes in nine patients aged 55 years or less. (P < 0.01). At a dose of 3 g/m2 given intravenously every 12 hours for 3 days, three cases of severe irreversible neurotoxicity were noted in elderly patients. Neurotoxicity at this total dose has previously been considered unusual. Administration of high dose Ara‐C at total doses of 18 g/m2 and over carries a risk of severe irreversible cerebellar toxicity that increases with age.

Heparin-induced thrombocytopenia: effects of rabbit IgG, and its Fab and FC fragments on antibody-heparin-platelet interaction.

The mechanism whereby the antibody interacts with platelets and heparin is still unclear. Two mechanisms have been proposed previously. In this study, purified rabbit IgG and its Fab and Fc fragments were used to differentiate the two possible mechanisms

The Interaction of von Willebrand Factor and the Platelet Glycoprotein Ib-IX Complex

The interaction between blood platelets and the vessel wall represents the initial event in the haemostatic response to vessel injury. At a molecular level, this interaction involves the platelet membrane glycoprotein (GP) Ib-IX complex, von Willebrand factor (vWF) and a component (s) of the subendothelial matrix. In recent years, the primary sequences of both the vWF molecule and the three chains comprising the GP Ib-IX complex, i.e., GP Ib(α), GP Ib(β) and GP IX, have been determined, providing further insight into the structure-function relationships of these molecules. As a result, much recent investigation has been directed towards identifying small amino acid sequences in the primary chains of both GP Ib(α) and vWF which define the adhesive interaction. This review summarises current data concerning structure-function analysis of vWF and the GP Ib-IX complex and the putative identification of ligand- and receptor-binding domains involved in the interaction of vWF with the GP Ib-IX complex.

4 Bernard-Soulier syndrome

Summary Bernard-Soulier syndrome (BSS) is a rare autosomal bleeding disorder characterized clinically by prolonged skin bleeding time, normal clot retraction and thrombocytopenia with large and morphologically abnormal platelets, and biochemically by the absence of platelet membrane glycoproteins (GP)Ib, V and IX. GP Ib and GPIX exist in the platelet membrane as a heterodimer complex which acts as the major receptor mediating platelet adhesion to blood vessel subendothelium. Studies with BSS platelets have proved particularly rewarding in the investigation of the GPIb-IX complex as a multifunctional receptor protein. The transmembrane complex contains binding domains for von Willebrand factor, thrombin, fibrin and quinine/quinidine drug-dependent antibodies as well as an attachment site on the cytoplasmic side of the membrane for a platelet cytoskeleton. In addition, the internal segment of the β-chain of GP Ib contains a cyclic AMP-dependent protein kinase-associated phosphorylation site which appears to regulate platelet reactivity. Limited proteolytic cleavage of the complex, in particular the GP Ib α -chain, has allowed immunological and functional characterization of three distinct domains; a 45 kDa segment at the N-terminal end of the α-chain of GP Ib, which contains binding sites for von Willebrand factor and thrombin, a 90 kDa highly glycosylated region of GP Ib α and a membrane-associated region consisting of the remnant of GP Ib α disulphide-linked to GP Ib β and non-covalently-complexed with GP IX. This membrane-associated region contains the antigenic epitope(s) for quinine/quinidine drug-dependent antibodies. It is highly probable that the future study of platelets from patients with the Bernard-Soulier syndrome will further clarify the role of the GP Ib-IX complex in platelet physiology.