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Abstract

The plasma levels of soluble urokinase-type plasminogen activator receptor (uPAR; CD87) measured by enzyme-linked immunosorbent assay were higher in patients with paroxysmal nocturnal hemoglobinuria (PNH) (5.8 +/- 4.7 ng/ml, mean +/- S.D., n = 9) than in normal donors (2.0 +/- 0.8 ng/ml, mean +/- S.D., n = 15). The high level of soluble uPAR in PNH plasma competed with the membrane uPAR expressed by normal blood neutrophils for binding to urokinase-type plasminogen activator (uPA). We also found that uPA complexed with soluble uPAR was partly resistant to inactivation by plasminogen activator inhibitors in the plasma, although uPA was inactivated similarly by plasma containing high and low levels of uPAR. PNH-affected blood cells are deficient in urokinase-type PAR, a glycosyl-phosphatidylinositol (GPI)-anchored protein. The deficiency of uPAR on PNH-affected leukocytes and the increased soluble uPAR in the PNH plasma may synergistically contribute to the development of thrombosis in PNH by inhibiting the cell-associated fibrinolytic activity.

Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents

“…In PNH, microvesicles are known to be released upon hemolysis and complement activation from RBCs (Hugel et al 1999), WBCs (monocytes) and platelets (Wiedmer et al 1993; Simak et al 2004), and even from the endothelium; their procoagulant action is commonly accepted, but their specific role in the pathophysiology of thromboembolisms in PNH still needs to be documented. An additional mechanism of thrombophilia in PNH might be the impairment of the fibrinolytic system, due to the lack of membrane-bound urokinase-type plasminogen activator receptor (uPAR), which is GPI-linked, and to the excess of its soluble form (Ninomiya et al 1997; Sloand et al 2006). Finally, thrombophilia in PNH may arise from the build-up of cell-free plasma hemoglobin due to hemolysis (Olsen et al 1996; Schafer et al 2004).…”

Increased soluble urokinase plasminogen activator receptor (suPAR) is associated with thrombosis and inhibition of plasmin generation in paroxysmal nocturnal hemoglobinuria (PNH) patients

“…uPAR which is expressed on the membranes of activated normal leukocytes and is believed to play a role in fibrinolysis by promoting the conversion of urokinase to its active form. Increased levels of suPAR lacking the GPI-anchor have been described in plasma and serum from patients with PNH 17;18 as well as in patients with certain types of malignancy 19 .…”

“…While some studies report suPAR to be effective in promoting fibrinolysis under certain conditions in vitro 20;21 , in media containing physiological concentrations of albumin, fibrinolysis is inhibited 22;23 . Membrane uPAR may also support fibinolysis mechanically by bringing plasminogen and urokinase into close proximity on the membrane 24, 25 .…”

Splenectomy for Massive Splenic Infarction Unmasks Paroxysmal Nocturnal Hemoglobinuria

“…The CD59 and CD55 deficiency of PNH platelets followed by increased thrombin production [5], the activated platelets [6]which are more sensitive to aggregation by thrombin and several perturbations of the fibrinolytic system [7, 8]have been suggested as possible causes of the thrombophilic status. Although the presence of activated platelets in PNH patients could result in arterial thromboses such events are rare and the reason for their rarity remains unclear.…”