Activated platelets in paroxysmal nocturnal haemoglobinuria

Abstract

One of the major causes of morbidity and mortality in paroxysmal nocturnal haemoglobinuria (PNH) is venous thrombosis. We have studied fibrinolysis, coagulation and platelets in 11 patients with PNH in an attempt to identify the possible mechanism(s) of thrombosis in PNH. In this study we did not identify any fibrinolytic defects, evidence of coagulation activation, nor reduction in coagulation inhibitors. In contrast, in this cohort of 11 PNH patients we have identified varying degrees of platelet activation as defined by the surface expression of activation-dependent proteins and the binding of adhesive proteins to the platelet surface. The thrombotic events in PNH usually occur in the venous system. Our studies and previous experimental studies suggest that anti-platelet therapy may be efficacious in reducing the incidence and severity of venous thrombosis in PNH.

Alternative Pathway Activation of Complement by Shiga Toxin Promotes Exuberant C3a Formation That Triggers Microvascular Thrombosis

“…Furthermore, the anaphylatoxin C3a was shown to directly induce aggregation of human platelets and release of serotonin (53). That the mechanisms of thrombosis may be related to C activation has been also suggested by studies in patients with familial or sporadic forms of atypical HUS or paroxysmal nocturnal hemoglobinuria, both characterized by deficiency in C-regulatory molecules, platelet hyperactivity, and thrombosis (33,54).…”

Glycosyl‐phosphatidyl‐inositol‐defective granulocytes from paroxysmal nocturnal haemoglobinuria patients show increased bacterial ingestion but reduced respiratory burst induction

“…The absence of the GPI-linked CD55 and CD59 molecules, that mediate complement inactivation, increases the level of activated complement fractions in PNH. The availability of such activated complement components on the surface of GPI-defective PMN could act as a chronic triggering factor, as described for PNH platelets [6]. The increase of activated C3 molecules, followed by over expression of higher affinity receptors on PNH granulocytes [50], may thus represent a chronic triggering element for the phagocytic process, likely able to mediate an enhanced ingestion ability by GPI À PMN.…”

“…PNH main clinical features are hemolytic anemia, thrombosis, and cytopenia [3,4]. The absence of the GPI-linked molecules CD55 and CD59, physiologically involved in the protection from activated complement fractions, could account for the occurrence of hemolytic anemia [5]; the deficiency of urokinase plasminogen activator re-ceptor might explain thrombophylia [6], while the origin of the underlying bone marrow failure is still unclear [7][8][9]. GPI-defective clonal hematopoieis, together with a residual polyclonal hematopoieis, develops through several lineages and accounts for the mixed (GPI + and GPI À ) phenotype commonly present in the peripheral blood of PNH patients.…”

Hemoglobin interaction with GP1b induces platelet activation and apoptosis: a novel mechanism associated with intravascular hemolysis

“…Reports suggest that intravascular hemolysis and activation of platelets are potential causes of thrombosis in PNH. [15][16][17] The major untoward effect of free Hb on platelet functions is most likely mediated via the scavenging of nitric oxide (NO) by Hb [18][19][20] or the redox effects of Hb. 21 It has been shown that NO inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion via the cyclic guanosine monophosphate (GMP) pathway.…”