Procoagulant properties of microparticles released from red blood cells in paroxysmal nocturnal haemoglobinuria

Abstract

SummaryThrombosis in paroxysmal nocturnal haemoglobinuria (PNH) has been suggested to be due to several pathophysiological states: a suppressed fibrinolytic system, increased leucocyte‐derived tissue factor, complement (C′)‐mediated damage to platelets and endothelia, or increased platelet‐ and endothelium‐derived microparticles (MPs). Because haemolytic attack is often accompanied by thrombosis in PNH, we studied the role of C′‐induced release of MPs in the thrombogenesis of PNH. C′ activation induced procoagulant alteration in PNH red blood cells (RBC), when assessed by thrombin generation in the presence of C′‐activated PNH RBC, which was abolished by their subsequent treatment with annexin V. Significant amounts of procoagulant MPs, measured by phosphatidylserine‐binding prothrombinase activity, were released from PNH RBC in association with the formation of C5b‐9, but not significantly before C5b‐8. Generation of procoagulant, annexin V‐binding, MPs from C′‐activated RBC was studied also by flow cytometry. While phorbol 12‐myristate 13‐acetate, an activator of protein kinase C (PKC), induced the release of MPs from normal RBC as well as PNH RBC, C′‐induced release of MPs from PNH RBC was Ca2+‐independent and not associated with the activation of PKC, calpain or caspase. Procoagulant properties of MPs released from PNH RBC could contribute to the thrombogenesis of PNH.

Microparticles Provide a Novel Biomarker To Predict Severe Clinical Outcomes of Dengue Virus Infection

“…During their life span, RBCs lose approximately 20% of their hemoglobin content through vesicle formation (71). Stored RBCs also lose their membrane integrity, thereby resulting in hemolysis and RMP generation that may contribute to complications associated with transfusion (66,72,73). Additionally, RMP formation could be triggered with different types of stimuli, such as shear stress, complement attack via the insertion of the terminal complement C5b-9 in the membrane of RBCs, oxidative stress, and proapoptotic stimulations (74)(75)(76).…”

“…Increased RMP levels have been documented in different pathological conditions, including sickle cell disease (77), hereditary hemolytic anemia (78), paroxysmal nocturnal hemoglobinuria (73), atherosclerosis (79), and malaria (9,80). RMPs might also be involved in immunomodulation by inhibiting macrophage release of proinflammatory cytokines (81) or, conversely, acting as potent stimulators of cells of the innate immune system (82).…”

The prothrombotic state in paroxysmal nocturnal hemoglobinuria: a multifaceted source

“…51 Erythrocytes have been reported to produce microparticles as a result of MAC-induced apoptosis. 52 Some microparticles observed in PNH have indeed been confirmed to originate from erythrocytes; however, Hugel et al reported that this was not 'to a significant extent' while 'very high levels' of microparticles of platelet origin were detected. 15 Two studies have concluded that the level of erythrocyte microparticles produced in PNH patients was similar to healthy controls; 15,53 hence, it is possible that the contribution of erythrocyte microparticles to the prothrombotic state in PNH is only minimal.…”

Red Blood Cell Microparticles: Clinical Relevance

“…In paroxysmal nocturnal hemoglobinuria, the increase of EMPs or the proportion of different types of MPs is controversial [30][31][32]. Nevertheless, complement activation generates EMPs from glycosylphosphatidylinositol-deficient RBCs in a calcium-independent manner, and enhances their procoagulant activity in vitro [32,33], proving that they may play a pathogenic role in the thrombotic profile of hemoglobinuria patients.…”