The Role of Abnormal Hemostasis and Fibrinolysis in Morbidity and Mortality of Acute Promyelocytic Leukemia.

Despite the improved therapeutic advances in the management of acute promyelocytic leukemia (APL), a significant early mortality during induction, also referred to as early death (ED), remains an obstacle for further improvement in outcome. Hemorrhagic complications are the most common cause of morbidity and mortality. Perturbed hemostatic dysfunction is present as the result of abnormalities in both the coagulation and the fibrinolytic systems. The activation of coagulation is distinct from the classical disseminated intravascular coagulation. Multiple abnormalities in the fibrinolytic system have recently been identified. The most significant change is increased production of tissue plasminogen activator (tPA) and its receptor annexin A2 by the APL promyelocytes. Among the hemorrhagic complications, intracranial hemorrhage predominates. The pathogenesis of this catastrophic event is elucidated by new evidence of adverse effect of tissue plasminogen activator (tPA) on the brain, including both the plasmin-dependent and plasmin-independent pathways. In order to address the hemorrhagic complications, a thorough understanding of the hemostatic dysfunction is essential. In this article, our current concept of the abnormal hemostasis in APL is reviewed. The failure to reduce the early death rate, despite the introduction of effective therapy, will also be discussed.

Microparticle source and tissue factor expression in pregnancy.

Microparticles (MPs) bearing tissue factor (TF) are potent activators of the coagulation system. To investigate whether MPs originating from platelets or trophoblast cells contribute to coagulation changes in pregnancy, we aimed to characterize whether pregnancy, labor, and delivery are associated with changes in the origin and composition of circulating maternal MPs. We performed a prospective cohort study. Blood samples were collected in 20 non-pregnant women, 20 term pregnant women not in labor, and 20 term pregnant women in labor. Two samples were collected in the pregnant groups, the first prior to delivery and the second 1 h after delivery. MPs from platelets and trophoblasts and MPs expressing TF were identified using flow cytometry. Comparisons were made among the non-pregnant and pregnant groups, non-laboring and laboring groups, and predelivery and postdelivery values within the pregnant groups. Pregnancy was not associated with changes in MP origin or number of TF-expressing MPs. Neither labor nor delivery was associated with changes in the percentage of trophoblast-derived MPs in the pregnant groups. The percentage of platelet-derived MPs among laboring women increased after delivery (8.5 vs. 20.5 %, p = 0.02), although there was no difference with delivery in the non-laboring group. TF expression was not associated with delivery in either laboring or non-laboring women. In conclusion, pregnancy was not associated with changes in cell origin of circulating maternal MPs or in the number of TF-expressing MPs. However, labor and delivery appear to be associated with an increase in the number of platelet-derived MPs.

Ticlopidine-, clopidogrel-, and prasugrel-associated thrombotic thrombocytopenic purpura: a 20-year review from the Southern Network on Adverse Reactions (SONAR).

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

Particulate matter-induced lung inflammation increases systemic levels of PAI-1 and activates coagulation through distinct mechanisms.

BACKGROUND: Exposure of human populations to ambient particulate matter (PM) air pollution significantly contributes to the mortality attributable to ischemic cardiovascular events. We reported that mice treated with intratracheally instilled PM develop a prothrombotic state that requires the release of IL-6 by alveolar macrophages. We sought to determine whether exposure of mice to PM increases the levels of PAI-1, a major regulator of thrombolysis, via a similar or distinct mechanism. METHODS AND PRINCIPAL FINDINGS: Adult, male C57BL/6 and IL-6 knock out (IL-6(-/-)) mice were exposed to either concentrated ambient PM less than 2.5 µm (CAPs) or filtered air 8 hours daily for 3 days or were exposed to either urban particulate matter or PBS via intratracheal instillation and examined 24 hours later. Exposure to CAPs or urban PM resulted in the IL-6 dependent activation of coagulation in the lung and systemically. PAI-1 mRNA and protein levels were higher in the lung and adipose tissue of mice treated with CAPs or PM compared with filtered air or PBS controls. The increase in PAI-1 was similar in wild-type and IL-6(-/-) mice but was absent in mice treated with etanercept, a TNF-α inhibitor. Treatment with etanercept did not prevent the PM-induced tendency toward thrombus formation. CONCLUSIONS: Mice exposed to inhaled PM exhibited a TNF-α-dependent increase in PAI-1 and an IL-6-dependent activation of coagulation. These results suggest that multiple mechanisms link PM-induced lung inflammation with the development of a prothrombotic state.

The thrombogenic effect of an inflammatory cytokine on trophoblasts from women with preeclampsia.

OBJECTIVE: This study was undertaken to investigate whether the increased thrombogenic potential of cytotrophoblastic cells of women with preeclampsia can be accounted for by increased rates of apoptosis. STUDY DESIGN: Cytotrophoblasts were isolated from the placenta of (a) nulliparous women without hypertensive disease who were delivered at term and (b) nulliparous women with preeclampsia. The cytotrophoblasts were identified by morphology, and cytokeratin and gonadotropin-releasing hormone positivity. The inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) was added to cytotrophoblasts in vitro and incubated for 24 hours. Tissue factor antigen, activity, and amount of apoptosis were evaluated both before and after TNF-alpha stimulation. RESULTS: TNF-alpha simulation significantly increased tissue factor activity both in the cytotrophoblasts of women with (0.08 +/- 0.04 pmol/min/10 6 cells to 0.53 +/- 0.19 pmol/min/10 6 cells) and without (0.07 +/- 0.04 pmol/min/10 6 cells to 0.30 +/- 0.16 pmol/min/10 6 cells) preeclampsia. TNF-alpha stimulation of the cytotrophoblasts also significantly increased tissue factor antigen in the cytotrophoblasts of both groups of women (3.6 +/- 0.9 fmol/10 6 cells to 34.0 +/- 7.5 fmol/10 6 cells, and 7.5 +/- 1.4 fmol/10 6 cells to 25.4 +/- 2.2 fmol/10 6 cells, respectively). For both tissue factor antigen and activity, the magnitude of increase after stimulation was significantly greater in the preeclamptic cytotrophoblasts. In contrast, both normal and preeclamptic cytotrophoblasts showed similar increases in their apoptotic indices (approximately 2-fold) after induction by TNF-alpha. CONCLUSION: The greater response of tissue factor activity and antigen to TNF-alpha by preeclamptic cytotrophoblasts cannot be accounted for by the increase in apoptosis. These data suggest that preeclamptic cytotrophoblasts are inherently more thrombogenic and more sensitive to TNF-alpha stimulation.