Abstract
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder, characterized by complement-mediated intravascular hemolysis and thrombosis. The increased incidence of PNH-driven thrombosis is still poorly understood, but unlike other thrombotic disorders, is thought to largely occur through complement-mediated mechanisms. Treatment with a C5 inhibitor, eculizumab, has been shown to significantly reduce the number of thromboembolic events in these patients. Based on previously described links between changes in fibrin clot structure and thrombosis in other disorders, our aim was to investigate clot structure as a possible mechanism of thrombosis in patients with PNH and the anti-thrombotic effects of eculizumab treatment on clot structure. Clot structure, fibrinogen levels and thrombin generation were examined in plasma samples from 82 patients from the National PNH Service in Leeds, UK. Untreated PNH patients were found to have increased levels of fibrinogen and thrombin generation, with subsequent prothrombotic changes in clot structure. No link was found between increasing disease severity and fibrinogen levels, thrombin generation, clot formation or structure. However, eculizumab treated patients showed decreased fibrinogen levels, thrombin generation and clot density, with increasing time spent on treatment augmenting these antithrombotic effects. These data suggest that PNH patients have a prothrombotic clot phenotype due to increased fibrinogen levels and thrombin generation, and that the antithrombotic effects of eculizumab are, in-part, due to reductions in fibrinogen and thrombin generation with downstream effects on clot structure.
Highlights
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare life-threatening disorder of hematopoietic stem cells, estimated at 0.1-0.2/100 000 persons per year, characterized by increased sensitivity to complement attack with or without intravascular hemolysis.[1]
Untreated PNH patients presented with higher fibrinogen and thrombin generation levels that subsequently lead to faster forming fibrin clots, which were harder to break down when compared to healthy controls
Increases in PNH granulocyte proportion led to increased LDH levels, indicating increased intravascular hemolysis
Summary
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare life-threatening disorder of hematopoietic stem cells, estimated at 0.1-0.2/100 000 persons per year, characterized by increased sensitivity to complement attack with or without intravascular hemolysis.[1] Thrombosis is the most serious complication, and accounts for 40%-67% of deaths in PNH.[2] An acquired mutation in the X-linked phosphatidylinositol glycan class A gene (PIG-A) results in the loss of glycosylphosphatidyinositol (GPI) anchors leading to mature blood cells lacking essential surface proteins. Clot structure was examined in 82 PNH patients to determine if alterations in clot structure may contribute to increased thrombosis risk in PNH, and to explore if treatment with eculizumab normalizes such alterations
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
