Genetic and molecular evidence for complement dysregulation in patients with HELLP syndrome

Background: HELLP (Hemolysis, elevated liver enzymes and low platelets) syndrome is a severe and acute pregnancy-related disorder that occurs in approximately 2.5 per 1000 deliveries and represents a major cause of maternal and perinatal morbidity and mortality. This syndrome has been suggested to be a microangiopathy and delivery is the only effective treatment. Objectives: The aim of this study was to investigate the pathophysiology of HELLP syndrome by simultaneously exploring complement, haemostasis, autoimmunity and inflammation in relation to the clinical outcome. Methods: We investigated 19 HELLP patients at the time of diagnosis and 3 months after delivery, for complement function, haemostasis and inflammation with immunoenzymatic methods. Complement-related gene variants were also analyzed by next generation sequencing and multiplex ligation-dependent probe amplification. Nineteen age-matched healthy pregnant women served as controls. Results: At diagnosis, HELLP patients, compared to controls, showed significantly higher plasma levels of SC5b-9 (median 710 ng/ml [range 216\u20131499] vs 253 ng/ml [19\u2013371], P < 0.0001) and of C5a (20.8 ng/ml [5.6\u201327.5] vs 12.7 ng/ml [3.2\u201324.6]; P = 0.004), which decreased three months after delivery (SC5b9: 190 ng/ml [83\u2013446] vs 160 ng/ml [107\u2013219]; C5a: 9.28 ng/ml [2.3\u201321.6] vs 10.7 ng/ml [2.5\u201321.2]). A significantly higher frequency of genetic variants involving complement regulatory genes was also observed (52.6% vs 15.8%; P = 0.016). Moreover, at HELLP diagnosis, patients showed increased coagulation markers (fragment F1 + 2 and D-dimer; P = 0.0001) while both patients and controls had high thrombin-generation potential that decreased after delivery. Conclusions: In the pathophysiology of HELLP syndrome, complement dysregulation, in addition to coagulation activation, is involved and may represent a potential target for treatment with the aim of delaying delivery