Human immunodeficiency virus-associated thrombotic microangiopathies: clinical characteristics and outcome according to ADAMTS13 activity.

Human immunodeficiency virus (HIV) infection is a risk factor for thrombotic microangiopathy (TMA). We sought whether a severe deficiency in ADAMTS13, the enzyme specifically involved in the cleavage of von Willebrand factor, was associated with specific presenting features and outcome in HIV-associated TMA. In this prospective, multicentre, case-control study, 29 patients of 236 in the French Network on TMA had an HIV-associated TMA. Seventeen patients with severe ADAMTS13 deficiency (ADAMTS13 <5% HIV(+) group) were compared to 12 patients with a detectable ADAMTS13 activity (ADAMTS13 >or=5% HIV(+) group). HIV(+) patients were also compared to 62 patients with idiopathic TMA, either with (45 patients, ADAMTS13 <5% idiopathic group) or without (17 patients, ADAMTS13 >or=5% idiopathic group) severe ADAMTS13 deficiency. ADAMTS13 <5% HIV(+) patients had less AIDS-related complications than ADAMTS13 >or=5% HIV(+) patients (23.5% versus 91.6%, respectively, P = 0.0005) and their median CD4(+) T cell count was higher (P = 0.05). TMA-associated death rate was higher in ADAMTS13 >or=5% HIV(+) patients than in ADAMTS13 <5% HIV(+) patients (50% versus 11.7%, respectively, P = 0.04). In ADAMTS13 <5% patients, TMA-associated death rate was comparable between HIV(+) and idiopathic patients (15.5% in idiopathic patients, P-value was non-significant). By contrast, TMA-associated death rate in ADAMTS13 >or=5% HIV(+) patients was higher than in idiopathic patients (11.7% in idiopathic patients, P = 0.04). In conclusion, HIV-associated TMA with severe ADAMTS13 deficiency have less AIDS-related complications and a higher CD4(+) T cell count. TMA prognosis is better and comparable to this of idiopathic forms.

Prognostic value of inhibitory anti-ADAMTS13 antibodies in adult-acquired thrombotic thrombocytopenic purpura.

In order to assess the prognostic value of inhibitory anti-ADAMTS13 antibodies in thrombotic thrombocytopenic purpura (TTP), we performed a multicentre prospective study of 33 adult patients with idiopathic acquired TTP. Patients were treated with high-dose plasma infusion and therapeutic plasma exchange. Patients without (group 1, n = 12) and with (group 2, n = 21) detectable inhibitory anti-ADAMTS13 antibodies were compared for clinical presentation, treatment and outcome. Both groups were comparable for clinical presentation. All patients in group 1 achieved a sustained complete remission within a median of 7 d [95% confidence interval (CI), 4-18], which required a median plasma volume of 235 ml/kg (range, 131-1251). In group 2, 17 patients achieved a durable complete remission within a median of 23 d (95% CI, 11-32) (P = 0.001). Median plasma volume was 718 ml/kg (range, 219-3107) (P = 0.02). In group 2, there was a trend for more episodes of flare-up than in group 1 (13 vs. 3, respectively, P = 0.07). Four patients, all from group 2, died (P = not significant). The relapse rate was comparable between both groups. We suggest that TTP with detectable inhibitory anti-ADAMTS13 antibodies displays a worse prognosis, relative to a delayed platelet count recovery, a higher plasma volume requirement to achieve complete remission, and a trend for more frequent episodes of flare-up.

The granulocyte colony-stimulating factor receptor supports erythroid differentiation in the absence of the erythropoietin receptor or Stat5.

To evaluate the functional conservation of signal transduction mechanisms between haematopoietic receptors and to characterize the molecules activated in this phenomenon, we introduced granulocyte colony-stimulating factor receptor (G-CSFR) cDNA into mouse fetal liver cells using a retroviral vector. In semi-solid medium assays, G-CSFR-infected cells gave rise to all types of colonies [granulocyte-macrophage (GM), megakaryocyte (MK) and mixed lineage (GEMM) colony-forming units (CFU) and erythroid burst-forming units (BFU-E)] in the presence of G-CSF alone. The direct effect of G-CSF on erythroid differentiation of G-CSFR-transduced erythroid progenitors was demonstrated by the development of erythroid colonies using G-CSFR-expressing Lin- cells cloned at one cell per well in liquid culture in the presence of G-CSF. Interestingly, while Stat5, but not Stat3, was activated in erythroid cells in response to erythropoietin (EPO), both were activated in erythroid and granulocytic cells stimulated by G-CSF. Furthermore, G-CSF induced the growth of erythroid colonies from G-CSFR-expressing fetal liver cells from EPO receptor-/- (EPO-R-/-) or Stat5a-/- Stat5b-/- mice, demonstrating that erythroid differentiation can occur in the absence of EPO-R or Stat5. These data show that forced expression of G-CSFR allows G-CSF-dependent multilineage proliferation and differentiation of haematopoietic progenitors and rescues EPO-R-/- erythroid cells. While G-CSF induces Stat5 activation in G-CSFR-expressing erythroid cells, this activation is not necessary for the terminal erythroid differentiation induced by G-CSF.