Genetic and molecular evidence for complement dysregulation in patients with HELLP syndrome
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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 216-1499] 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.
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.
Keywords: Complement system proteins; Genetic variants; HELLP syndrome; Haemostasis;
Pregnancy.
Reference
Bazzan, M., Todros, T., Tedeschi, S., Ardissino, G., Cardaropoli, S., Stella, S., ... & Cugno, M. (2020). Genetic and molecular evidence for complement dysregulation in patients with HELLP syndrome. Thrombosis Research, 196, 167-174.
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