Fibrinolytic response to venous occlusion in patients with homozygous sickle cell disease

Abstract

The fibrinolytic potential was evaluated in 37 patients with homozygous sickle cell disease and compared to a control group of 30 age- and sex-matched healthy volunteers. In all individuals, the euglobulin clot lysis time and plasma antigen levels of t-Pa and PAI-1 were measured before and after venous occlusion (v.o) for 10 min. The global fibrinolytic activity was normal in 4 patients (good responders to v.o), while it was decreased in 33 patients (poor responders to v.o). Among the latter, 22 patients had significantly increased baseline levels of PAI-1 Ag (82.6 +/- 27.5 ng/ml, p < 0.001) and a normal release of t-Pa Ag after v.o. In contrast, 11 patients had basal values of PAI-1 Ag comparable to those in controls with a defective release of t-Pa Ag after v.o (11.4 +/- 5.2 ng/ml, p < 0.01). These data provide evidence for reduced fibrinolytic capacity resulting from either increased basal levels of PAI-1 or defective release of t-PA.

Placenta Growth Factor (PlGF), a Novel Inducer of Plasminogen Activator Inhibitor-1 (PAI-1) in Sickle Cell Disease (SCD)

“…These data suggest that PAI-1 levels correlated to sickle gene dosage or severity. Our data showing that MNC of SCD patients at steady state had increased levels of PAI-1 and that PAI-1 was induced by PlGF in HPMVEC are novel; our observation that PlGF is also elevated in SCD patients is consistent with previous studies (10,11).…”

“…Circulating levels of tPA in Berkeley SS and knock-in SS mice were significantly lower than corresponding controls (supplemental Fig. S1D), consistent with reports of lower tPA plasma levels in patients with SCD (10,11). To assess whether PlGF affected tPA levels, we stimulated primary HPMVEC with PlGF and measured release of tPA in the medium.…”

“…However, no further increases in PAI-1 levels were seen during vaso-occlusive crises, although D-dimers were elevated further during vaso-occlusive events. In a separate study, the same group (11) showed that two-thirds of sickle cell disease patients showed a poor tPA response to vaso-occlusion. Indeed, our data in two strains of sickle mice are consistent with their results of lower tPA levels in SCD.…”

“…The factors that elevate PAI-1 in SCD (10,11) are unknown. In this study, we observed increased PAI-1 expression in pulmonary endothelial cells and macrophages of sickle mice and identified the molecular mechanisms of PlGF-mediated PAI-1 induction in primary HPMVEC.…”

“…SCD patients have increased levels of activated coagulation factors and decreased levels of anticoagulant proteins, including an abnormal fibrinolytic system (8,9). Elevated plasma levels of circulating tissue factor (4) and PAI-1 have been reported at steady state and are further increased during sickle vaso-occlusive crises (10,11). A prothrombotic state predisposes patients to pulmonary hypertension and stroke, two devastating complications of SCD (12).…”