Factor H interferes with the adhesion of sickle red cells to vascular endothelium: a novel disease-modulating molecule.

Sickle cell disease is an autosomal recessive genetic red cell disorder with a worldwide distribution. Growing evidence suggests a possible involvement of complement activation in the severity of clinical complications of sickle cell disease. In this study we found activation of the alternative complement pathway with microvascular deposition of C5b-9 on skin biopsies from patients with sickle cell disease. There was also deposition of C3b on sickle red cell membranes, which is promoted locally by the exposure of phosphatidylserine. In addition, we showed for the first time a peculiar "stop-and-go" motion of sickle cell red blood cells on tumor factor-α-activated vascular endothelial surfaces. Using the C3b/iC3b binding plasma protein factor Has an inhibitor of C3b cell-cell interactions, we found that factor H and its domains 19-20 prevent the adhesion of sickle red cells to the endothelium, normalizing speed transition times of red cells. We documented that factor H acts by preventing the adhesion of sickle red cells to P-selectin and/or the Mac-1 receptor (CD11b/CD18), supporting the activation of the alternative pathway of complement as an additional mechanism in the pathogenesis of acute sickle cell related vaso-occlusive crises. Our data provide a rationale for further investigation of the potential contribution of factor H and other modulators of the alternative complement pathway with potential implications for the treatment of sickle cell disease.

Autologus stem cell transplatation as a care option in elderly patients. A review.

The ageing population and the increase in life expectancy have put new social and health questions into the public health agenda of western countries. Hematological cancer incidence peaks in older population as a logical consequence of a longer lifespan promoting prolonged exposure to carcinogens and accumulation of genetic alterations. Hematological cancer represents a major cause of mortality in this age group despite recent progress observed in the management of cancer in the general population. Autologous stem cell transplantation (ASCT) represents a therapeutic option in the treatment of a large proportion of lymphomas and multiple myeloma, but their role in the onco-geriatric setting remains an open question, due to the presence of chronic disease. Ageing is characterized by progressive decrements in physiologic reserves and abilities to compensate for physical and/or functional limitations, which increase the risk of developing morbidity and disability. These events explains the extreme diversity of ageing individuals in terms of clinical and functional status. As a consequence, life expectancy in the elderly is influenced not only by the neoplastic diseases itself but also by the various co-morbidities common to this age group. The management of elderly people with hematological diseases potentially curative, should therefore combine both geriatric and tumor assessments. Among the elderly patients identified as being candidates for AHSCT, after the mobilization of progenitor cells from the bone marrow into the peripheral blood, the aphaeresis procedure is the most common method for collecting an adequate number of stem cells. The proper selection of patients may greatly improve the results and the toxicity related to cancer treatment in the elderly. We recommend the adoption of some form of geriatric assessment in the evaluation of any patient who is 70 years and older, this review intends to offer an overview of the state of art in ASCT in elderly patients.

Altered von Willebrand factor subunit proteolysis and multimer processing associated with the Cys2362Phe mutation in the B2 domain.

The normal von Willebrand factor (vWF) multimer pattern results from the ADAMTS-13 cleavage of the Tyr 1605-Met 1606 bond in the A2 domain of vWF. We identified a patient with severe von Willebrand disease (vWD) homozygously carrying a Cys to Phe mutation in position 2362 of vWF with markedly altered vWF multimers and an abnormal proteolytic pattern. The proband's phenotype was characterized by a marked drop in plasma vWF antigen and ristocetin cofactor activity, and a less pronounced decrease in FVIII. The vWF multimers lacked any triplet structure, replaced by single bands with an atypical mobility, surrounded by a smear, and abnormally large vWF multimers. Analysis of the plasma vWF subunit's composition revealed the 225 kDa mature form and a single 205 kDa fragment, but not the 176 kDa and 140 kDa fragments resulting from cleavage by ADAMTS-13. The 205 kDa fragment was distinctly visible, along with the normal vWF cleavage products, in the patient's parents who were heterozygous for the Cys2362Phe mutation. Their vWF levels were mildly decreased and vWF multimers were organized in triplets, but also demonstrated abnormally large forms and smearing. Our findings indicate that a proper conformation of the B2 domain, which depends on critical Cys residues, may be required for the normal proteolytic processing of vWF multimers.