Thrombosis in paroxysmal nocturnal hemoglobinuria

Abstract

The most frequent and feared complication of paroxysmal nocturnal hemoglobinuria (PNH) is thrombosis. Recent research has demonstrated that the complement and coagulation systems are closely integrated with each influencing the activity of the other to the extent that thrombin itself has recently been shown to activate the alternative pathway of complement. This may explain some of the complexity of the thrombosis in PNH. In this review, the recent changes in our understanding of the pathophysiology of thrombosis in PNH, as well as the treatment of thrombosis, will be discussed. Mechanisms explored include platelet activation, toxicity of free hemoglobin, nitric oxide depletion, absence of other glycosylphosphatidylinositol-linked proteins such as urokinase-type plasminogen activator receptor and endothelial dysfunction. Complement inhibition with eculizumab has a dramatic effect in PNH and has a major impact in the prevention of thrombosis as well as its management in this disease.

The prothrombotic state in paroxysmal nocturnal hemoglobinuria: a multifaceted source

“…23 The subsequent excess of hemoglobin leads to the visible hemoglobinuria, while the depletion of NO, a potent vasodilator, results in vasoconstriction, decreased regional blood flow and muscular contraction, causing chest and abdominal pain, amongst other symptoms. 3 Moyo et al reported significant differences in the proportion of PNH cells in patients with symptoms of abdominal pain, hemoglobinuria and esophageal spasm (causing chest pain and dysphagia). The mean proportion of PNH granulocytes in patients with these symptoms was at least twice that of patients who did not possess these clinical manifestations.…”

“…5 Thrombosis can occur at any site, with deep vein thrombosis, pulmonary embolism, myocardial infarction or cerebral vascular attack all commonly observed complications. 25 There appears to be an increased incidence of thrombosis at atypical sites, such as the hepatic vein resulting in Budd-Chiari syndrome, occurring in 40-44% of PNH patients, in addition to thrombosis in the vasculature of the central nervous system, mesenteric, dermal veins and the cavernous sinus. 26 The proportion of PNH cells and clone size has also been associated with thrombotic complications.…”

“…83,84 The membrane attacks complex formation on the surface of monocytes and neutrophils and is also thought to contribute to the procoagulant state in PNH. 3,23 Complement-induced cell activation results in the expression of tissue factor as well as plasminogen activator inhibitor 1, contributing to thrombus Multifaceted prothrombotic state in PNH haematologica | 2018; 103 (1)formation while impairing fibrinolysis (discussed below). 86 Proteinase 3 (PR3), an enzyme thought to reduce thrombin-induced platelet activation binds to the GPI-anchored co-factor NB1 (CD177) expressed on neutrophils.…”

“…2 Despite such a large role in the burden of the disease, the mechanism behind the development of thrombosis is poorly understood, highlighting the importance of thrombosis management in PNH patients and elucidating more information regarding the nature of the thrombotic event. 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.…”

“…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.…”