Blood
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Thrombophilia screening is controversial. In a retrospective family cohort, where probands had thrombosis and a thrombophilic defect, 2479 relatives were tested for thrombophilia. In antithrombin-, protein C-, and protein S-deficient relatives, annual incidences of venous thrombosis were 1.77% (95% CI, 1.14-2.60), 1.52% (95% CI, 1.06-2.11), and 1.90% (95% CI, 1.32-2.64), respectively, at a median age of 29 years and a positive family history of more than 20% symptomatic relatives. ⋯ Cumulative recurrence rates in relatives with antithrombin, protein C, or protein S deficiency were 19% at 2 years, 40% at 5 years, and 55% at 10 years. In relatives with FV Leiden, prothrombin 20210G>A, or high levels FVIII, these were 7%, 11%, and 25%, respectively. Considering its clinical implications, thrombophilia testing should address hereditary deficiencies of antithrombin, protein C, and protein S in patients with first venous thrombosis at young age and/or a strong family history of venous thrombosis.
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In paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have investigated by flow cytometry the binding of complement fraction 3 (C3) on RBCs from PNH patients before and during eculizumab treatment. ⋯ The proportion of C3(+) RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab. In 3 patients in whom (51)Cr labeling of RBCs was carried out while on eculizumab, we have demonstrated reduced RBC half-life in vivo, with excess (51)Cr uptake in spleen and in liver. Binding of C3 by PNH RBCs may constitute an additional disease mechanism in PNH, strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis.
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Nonrandom X-chromosome inactivation (XCI), also known as skewing, has been documented in the blood cells of a significant proportion of normal aging women by the use of methylation-based assays at the polymorphic human androgen receptor locus (HUMARA). Recent data obtained with a new transcription-based XCI determination method, termed suppressive polymerase chain reaction (PCR), has shed controversy over the validity of XCI ratio results obtained with HUMARA. ⋯ The 3 methods yielded similar skewing incidences (42%, 38%, and 40%, respectively), and highly concordant XCI ratios. This confirms that the skewing of XCI ratio seen in blood cells of aging women is a bona fide and robust biologic phenomenon.
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Hepcidin, a key regulator of iron metabolism, is a small antimicrobial peptide produced by the liver that regulates intestinal iron absorption and iron recycling by macrophages. Hepcidin is stimulated when iron stores increase and during inflammation and, conversely, is inhibited by hypoxia and augmented erythropoiesis. In many pathologic situations, such as in the anemia of chronic disease (ACD) and iron-loading anemias, several of these factors may be present concomitantly and may generate opposing signaling to regulate hepcidin expression. ⋯ These effects are mediated through down-regulation of phosphorylation of Stat3 triggered by LPS and of Smad1/5/8 induced by iron. In conclusion, hepcidin expression levels in the presence of opposing signaling are determined by the strength of the individual stimuli rather than by an absolute hierarchy among signaling pathways. Our findings also suggest that erythropoietic drive can inhibit both inflammatory and iron-sensing pathways, at least in part, via the suppression of STAT3 and SMAD4 signaling in vivo.
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Engagement of endothelial protein C receptor (EPCR) by activated protein C (aPC) decreases expression of endothelial adhesion molecules implicated in tumor-endothelium interactions. We examined the role of the aPC/EPCR pathway on tumor migration and metastasis. In vitro, B16-F10 melanoma cells showed decreased adhesion to and transmigration through endothelium treated with recombinant human aPC (rhaPC). ⋯ Strikingly, rhaPC treatment resulted in a 44% reduction in lung metastases. This was associated with decreased lung P-selectin and TNF-alpha mRNA levels. These findings support an important role for the aPC/EPCR pathway in reducing metastasis via inhibition of tumor cell adhesion and transmigration.