Plasmatic coagulation and fibrinolytic system alterations in PNH

Abstract

Paroxysmal nocturnal haemoglobinuria (PNH) is characterized pathophysiologically by intravascular lysis of blood cells and clinically by thromboembolic events, often atypical in localization. In this study, we examined the plasmatic coagulation system of PNH patients to investigate a potential relation between coagulation alterations and disease intensity (PNH clone size). We found evidence for both an increase in procoagulant and in fibrinolytic activity, resulting in increased fibrin generation and turnover. Whereas a positive association of the procoagulant potential with PNH clone size was notable, fibrinolytic activity showed an inverse association with clone size. As a possible cause, a growing impairment of fibrinolytic activation and/or an increasing displacement of fibrinolytic activity is assumed. These mechanisms are most likely caused by the detachment of the glycosyl-phosphatidyl-inositol-anchored urokinase plasminogen activator receptor from cell surfaces, causing a progressive resistance to fibrinolytic stimuli, together with a probable shift of the fibrinolytic potential from cell surfaces to soluble, circulating complexes, resulting in a cellular fibrinolysis-steal phenomenon. Together, these processes are accused of mediating an increased thrombophilic risk in PNH. As hereditary prothrombogenic defects were found more frequently in patients suffering ischaemic complications, genetic thrombophilia seems to confer an additional thromboembolic risk in PNH, and should therefore be screened for.

The prothrombotic state in paroxysmal nocturnal hemoglobinuria: a multifaceted source

“…16,37,50 Chronic hyperstimulation of the coagulation system was hypothesized to further downregulate the activity of activated platelets. 4,50 This highlights the complex variable nature of thrombosis in PNH, suggesting that platelets post activation possibly have a diminished role in PNH-induced thrombosis in comparison to other thrombotic diseases.…”

“…3,4,66 Urokinase-type plasminogen activator receptor (uPAR) is a GPI-AP, and as such is absent from PNH monocytes and granulocytes. 112 This results in increased plasma levels of free uPAR protein, which is thought to compete with the membrane bound uPA receptor, competitively inhibiting cell-based plasmin generation and therefore contributing to a prothrombotic state in PNH.…”

“…3 Multiple proposed mechanisms behind the increased incidence of thrombosis include a prothrombotic state in conjunction with platelet abnormalities and impaired fibrinolysis. 3,4 The review herein will discuss changes to the hemostatic system in PNH, and highlight areas that require future research in the prothrombotic processes involved in PNH.…”

Loss of expression of neutrophil proteinase-3: a factor contributing to thrombotic risk in paroxysmal nocturnal hemoglobinuria

“…7,8 The size of the PNH clone and thereby the severity of hemolysis are related to the risk of thrombotic complications. 9 For example, in PNH patients with a granulocyte clone size of greater than 50%, the cumulative lifetime risk is 44%, compared to 6% in those with a clone size of less than 50%. 10 While the pathogenesis of the thrombophilia in PNH has not been clarified, a number of potential mechanisms have been proposed, including episodic hemolysis with release of pro-coagulant microparticles, [11][12][13] complementmediated platelet activation, 9,12,14,15 and defective fibrinolytic activity secondary to loss of leukocyte expression of the GPI-linked urokinase-type plasminogen activator receptor (uPAR).…”

“…9 For example, in PNH patients with a granulocyte clone size of greater than 50%, the cumulative lifetime risk is 44%, compared to 6% in those with a clone size of less than 50%. 10 While the pathogenesis of the thrombophilia in PNH has not been clarified, a number of potential mechanisms have been proposed, including episodic hemolysis with release of pro-coagulant microparticles, [11][12][13] complementmediated platelet activation, 9,12,14,15 and defective fibrinolytic activity secondary to loss of leukocyte expression of the GPI-linked urokinase-type plasminogen activator receptor (uPAR). [16][17][18][19][20] However, none of these hypotheses alone adequately explains the marked degree of hemostatic activation that results in a strikingly higher incidence of thromboembolic complications in PNH.…”