Circulating erythrocyte-derived microparticles are associated with coagulation activation in sickle cell disease

Abstract

Background: Sickle cell disease is characterized by a hypercoagulable state as a result of multiple factors, including chronic hemolysis and circulating cell-derived microparticles. There is still no consensus on the cellular origin of such microparticles and the exact mechanism by which they may enhance coagulation activation in sickle cell disease.

Design and methods: In the present study, we analyzed the origin of circulating microparticles and their procoagulant phenotype during painful crises and steady state in 25 consecutive patients with sickle cell disease.

Results: The majority of microparticles originated from platelets (GPIIIa,CD61) and erythrocytes (glycophorin A,CD235), and their numbers did not differ significantly between crisis and steady state. Erythrocyte-derived microparticles strongly correlated with plasma levels of markers of hemolysis, i.e. hemoglobin (r=-0.58, p<0.001) and lactate dehydrogenase (r=0.59, p<0.001), von Willebrand factor as a marker of platelet/endothelial activation (r=0.44, p<0.001), and D-dimer and prothrombin fragment F1+2 (r=0.52, p<0.001 and r=0.59, p<0.001, respectively) as markers of fibrinolysis and coagulation activation. Thrombin generation depended on the total number of microparticles (r=0.63, p<0.001). Anti-human factor XI inhibited thrombin generation by about 50% (p<0.001), whereas anti-human factor VII was ineffective (p>0.05). The extent of factor XI inhibition was associated with erythrocyte-derived microparticles (r=0.50, p=0.023).

Conclusions: We conclude that the procoagulant state in sickle cell disease is partially explained by the factor XI-dependent procoagulant properties of circulating erythrocyte-derived microparticles.

Figures

Figure 1.

Correlations between glycophorin A+ microparticles (GlycoA+ MPs) and blood parameters. Correlations between glycophorin A+ microparticles and markers of in vivo endothelial activation (vWF-Ag), fibrinolysis (D-dimer), and coagulation activation (F1+2). Y- and X-axes are logarithmic. **p<0.005.

Figure 2.

Thrombin generation. The gray (normal) bar shows the median (error bar: 75th quartile) of thrombin generation expressed as AUC after reconstitution of microparticles isolated from patient’s blood to defibrinated and microparticle-free normal pool plasma. The “aTFPI”, “aXI” and the “aVII” bars show the effects of the indicated antibodies on microparticle-induced thrombin generation.

Figure 3.

The effect of glycophorin A+ microparticles (GlycoA+ MP) and anti-human factor XI on thrombin generation. Correlation between the total number of glycophorin A+ microparticles and the extent of inhibition of thrombin generation by anti-human factor XI (r=0.55 p=0.002). Y- and X-axes are logarithmic.