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

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.

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.

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.

At diagnosis, HELLP patients, compared to controls, showed significantly higher plasma levels of SC5b-9 (median 710 ng/ml [range 216-1499] vs 253 ng/ml [19-371], P < 0.0001) and of C5a (20.8 ng/ml [5.6-27.5] vs 12.7 ng/ml [3.2-24.6]; P = 0.004), which decreased three months after delivery (SC5b9: 190 ng/ml [83-446] vs 160 ng/ml [107-219]; C5a: 9.28 ng/ml [2.3-21.6] vs 10.7 ng/ml [2.5-21.2]). 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.

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.