Immature platelet dynamics are associated with clinical outcomes after major trauma.

BACKGROUND: Major trauma results in dramatic changes in platelet behavior. Newly-formed platelets are more reactive than older platelets, but their contributions to hemostasis and thrombosis after severe injury have not been previously evaluated. OBJECTIVES: To determine the relationship between immature platelet metrics and plasma thrombopoietin with clinical outcomes after major injury. METHODS: Prospective observational cohort study of adult trauma patients. Platelet counts and the immature platelet fraction (IPF) were measured at admission, 24 hours, 72 hours and 7 days post-injury. Thromboelastometry was performed at admission. Plasma thrombopoietin, c-Mpl and GPIbα were quantified in a separate cohort. The primary outcome was in-hospital mortality; secondary outcomes were venous thromboembolic events (VTE) and multiple organ dysfunction (MODS). RESULTS: On admission, immature platelet counts (IPC) were significantly lower in non-survivors (n=40) compared to survivors (n=236; 7.3x109/L vs 10.6x109/L, p=0.009), but IPF did not differ. Similarly, impaired platelet function on thromboelastometry was associated with lower admission IPC (9.1x109/L vs 11.9x109/L, p<0.001). However, at later timepoints we observed significantly higher IPF and IPC in patients who developed VTE (21.0x109/L vs 11.1x109/L, p=0.02) and prolonged MODS (20.9 x109/L vs 11x109/L, p=0.003) compared to those who did not develop complications. Plasma thrombopoietin levels at admission were significantly lower in in non-survivors (p<0.001), in patients with MODS (p<0.001) and in those who developed VTE (p=0.04). CONCLUSIONS: Lower levels of immature platelets in the acute phase after major injury are associated with increased mortality, whereas higher immature platelet levels at later timepoints may predispose to thrombosis and multiple organ dysfunction

Platelet transfusions reduce fibrinolysis but do not restore platelet function during trauma hemorrhage

National Institute for Health Research (UK) Program Grant for Applied Research (RP-PG-0407- 10036)

Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review

<p>Abstract</p> <p>Background</p> <p>Dyskeratosis congenita (DC) is a progressive, multi-system, inherited disorder of telomere biology with high risks of morbidity and mortality from bone marrow failure, hematologic malignancy, solid tumors and pulmonary fibrosis. Hematopoietic stem cell transplantation (HSCT) can cure the bone marrow failure, but it does not eliminate the risks of other complications, for which life-long surveillance is required. Pulmonary fibrosis is a progressive and lethal complication of DC.</p> <p>Case presentation</p> <p>In this report, we describe a patient with DC who developed pulmonary fibrosis seven years after HSCT for severe aplastic anemia, and was successfully treated with bilateral lung transplantation. We also performed a systematic literature review to understand the burden of pulmonary disease in patients with DC who did or did not receive an HSCT. Including our patient, we identified 49 DC patients with pulmonary disease (12 after HSCT and 37 without HSCT), and 509 with no reported pulmonary complications.</p> <p>Conclusion</p> <p>Our current case and literature review indicate that pulmonary morbidity is one of the major contributors to poor quality of life and reduced long-term survival in DC. We suggest that lung transplantation be considered for patients with DC who develop pulmonary fibrosis with no concurrent evidence of multi-organ failure.</p

Germline heterozygous DDX41 variants in a subset of familial myelodysplasia and acute myeloid leukemia

The Brazilian National Council for Scientific and Technological Development), Bloodwise, Children with Cancer and MRC (Medical Research Council, UK)

Zebrafish Models for Dyskeratosis Congenita Reveal Critical Roles of p53 Activation Contributing to Hematopoietic Defects through RNA Processing

Dyskeratosis congenita (DC) is a rare bone marrow failure syndrome in which hematopoietic defects are the main cause of mortality. The most studied gene responsible for DC pathogenesis is DKC1 while mutations in several other genes encoding components of the H/ACA RNP telomerase complex, which is involved in ribosomal RNA(rRNA) processing and telomere maintenance, have also been implicated. GAR1/nola1 is one of the four core proteins of the H/ACA RNP complex. Through comparative analysis of morpholino oligonucleotide induced knockdown of dkc1 and a retrovirus insertion induced mutation of GAR1/nola1 in zebrafish, we demonstrate that hematopoietic defects are specifically recapitulated in these models and that these defects are significantly reduced in a p53 null mutant background. We further show that changes in telomerase activity are undetectable at the early stages of DC pathogenesis but rRNA processing is clearly defective. Our data therefore support a model that deficiency in dkc1 and nola1 in the H/ACA RNP complex likely contributes to the hematopoietic phenotype through p53 activation associated with rRNA processing defects rather than telomerase deficiency during the initial stage of DC pathogenesis