A CASE OF HELLP SYNDROME

Case Report

A CASE OF HELLP SYNDROME:

AN IMMUNO-LOGICAL APPROACH
Heggermont WA1, Verhelst C2, De Wilde K2, De Paepe M2, Lacquet F3, Vonck A2
1

Algemene Inwendige Geneeskunde, UZ Leuven Gasthuisberg, Leuven, 2Dienst Nefrologie,

Laboratorium Klinische Biologie, AZ Sint-Blasius, Dendermonde, Belgium

Correspondence and offprint requests to: Dr. Ward A. Heggermont, E-mail: ward.heggermont@med.
kuleuven.be

ABSTRACT
We report on a 27-year-old woman who developed
severe arterial hypertension on a background of general
malaise within 48hours after vaginal delivery, suggesting
severe acute-onset pre-eclampsia. Concomitant biochemical observations of haemolysis, elevated liver tests and
low platelets lead to the diagnosis of (post-partum) HELLP
syndrome. Our patient was transferred immediately to the
intensive care unit (ICU), where she underwent plasmapheresis in combination with intravenous glucocorticoids,
nicardipine and labetalol. Our patient recovered fully after
three plasmapheresis sessions. Genetic testing of mutations responsible for complement deficits was negative.
Key words: HELLP syndrome, atypical HUS, complement system,
thrombotic microangiopathy

INTRODUCTION
In this brief case report, we discuss the immunological
characteristics of HELLP syndrome, the pathophysiological
similarities between HELLP and atypical haemolytic uraemic
syndrome (aHUS), and the possible immunogenetic abnormalities in the complement cascade underlying the symptomatology of these two disorders. In particular the importance of genetic screening and the eventual consequences
for a next pregnancy are emphasized.

CASE REPORT
A 27-year-old woman, without previous medical record,
gave birth to a healthy daughter of 2070grams with an
Apgar-score of 6 (after 1 minute) and 8 (after 5 minutes).

doi: 10.2143/ACB.67.5.2062695

Vaginal delivery at 37 weeks was induced with ocytocin (Syntocinon) because of intra-uterine growth restriction (IUGR).
Although regularly checked at routine pregnancy controls,
there was no documentation of proteinuria or arterial hypertension during pregnancy. Within the first 48hours after
delivery however, our patients arterial blood pressure was
rising firmly with peak values of 220/160mmHg, suggesting
severe acute-onset pre-eclampsia. Immediately, intravenous
administration of nicardipine (Rydene), labetalol (Trandate)
and magnesium sulphate was initiated. Patient was subsequently transferred to the intensive care unit (ICU), where
continuous invasive blood pressure controls showed no
improvement within the first 6hours after onset. At the same
time, blood sampling showed slightly elevated transaminases (alanine transaminase 46 IU/L, aspartate transaminase
52IU/L). Blood platelet count was slightly below normal levels, more precisely 13610/L. Moreover, free haptoglobin
levels were immeasurably low, a typical sign of haemolysis.
An optical analysis of a peripheral blood smear showed 8
schistocytes per microscopic field, which is moderately elevated. Within 48hours after delivery, taken into account all
these clinical and laboratory findings, the diagnosis of HELLP
syndrome seemed obvious. However, also a lupus flare, TTP,
and HUS remained possible. New biochemical analyses however, performed 4 and 8hours after the first blood sample,
showed an extreme worsening of haemolysis with an
unmeasurable haptoglobin, lactate dehydrogenase of more
than 1000 IU/L, a blood platelet count of only 7410/L
and relatively unchanged transaminase levels. Plasmapheresis with a specific human plasma solution (Octaplas) was
initiated. Intravenous glucocorticoids were administered
(methylprednisolon 0.5mg/kg body weight once daily) and
meanwhile, nicardipin (Rydene) as antihypertensive agent
was administered. After three plasmapheresis sessions within
four days, biochemical and clinical improvement was seen:
blood pressure lowered to normal levels, there was a complete recovery of blood platelet count and liver tests, and all
markers of haemolysis returned to normal values (table 1).

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A CASE OF HELLP SYNDROME

Table 1: Evolution of maternal biometry and biochemical parameters during pregnancy and during HELLP-event
(S.I. units; reference values according to particular laboratory; ND=no data at given timepoint)
parameter

unit

reference
values

d-112

d-56

d-28

d-14

delivery
(d0)

d+1

d+2

d+7

d+11

blood pressure

mmHg

heart rate

bpm

<140/80

140/40

130/70

130/70

120/60

165/70

182/90

220/160

146/70

126/70

60-100

72

73

81

84

86

92

112

72

bodyweight

kg

78

ND

75

76

77

ND

ND

ND

ND

hemoglobin

g/dL

70

12-14

ND

ND

ND

ND

11,6

13,2

12,1

12,7

12,8

blood platelets

x103/mm3

150-450

ND

ND

ND

ND

136

78

74

241

242

uric acid

mg/dL

2,4-5,7

ND

ND

ND

ND

6,48

ND

ND

7,44

ND

ALT

IU/L

<31

ND

ND

ND

ND

ND

46

52

42

13

haptoglobin

mg/dL

30-200

ND

ND

ND

ND

ND

41

<3

73

128

(TTP) categorized as a thrombotic microangiopathy (TMA)

with characteristic microvascular endothelial activation, cell
injury and thrombosis.

HELLP VERSUS AHUS: TWO MANIFESTATIONS

OF THE SAME CONDITION?

Figure 1: Peripheral blood smear of our patient (fragmentocytes are

marked by arrows).

There was no need for platelet or erythrocyte transfusions.

The patient developed a lower urinary tract infection with
Escherichia coli, which was subsequently treated with ciprofloxacine orally, 250mg twice daily during a 5 days period.
Seven days after onset of symptoms, our patient was dismissed from ICU and transferred to the gynaecology department for further recovery. She was treated with oral nifedipine (Adalat) and ciprofloxacine (Ciproxine). Eleven days
after delivery, the mother and her baby left the hospital in
good condition.

BACKGROUND
The HELLP syndrome is a serious complication in pregnancy, characterized by haemolysis, elevated liver enzymes
and low platelet count occurring in 0.5 to 0.9% of all pregnancies and in 10-20% of cases with severe pre-eclampsia. HELLP
syndrome mostly occurs in the third trimester, although a 5%
to 8% of cases occur within 72hours after delivery. Nowadays,
HELLP syndrome is considered a multisystemic disorder of
which the aetiopathological background is not completely
understood. However, it is parallel to haemolytic uraemic
syndrome (HUS) and thrombotic thrombocytopenic purpura

Acta Clinica Belgica, 2012; 67-5

The pathogenesis of HELLP syndrome is uncompletely

understood. One hypothesis is an alteration in the maternalfoetal immune balance inducing platelet aggregation,
endothelial dysfunction and arterial hypertension. Trophoblast invasion (which invariably brings the foetus in contact
with the immunocompetent maternal cells) and/or increased
platelet plasminogen activation may play a role. Some believe
that the HELLP syndrome is a placenta-instigated, liver-targeted acute inflammatory condition. Moreover, controversy
surrounds the issue of HELLP being a separate disorder or a
severe form of pre-eclampsia. Haemolytic uremic syndrome
(HUS) is a triad of microangiopathic haemolytic anaemia
(MAHA), thrombocytopenia and renal impairment. There are
two subtypes of HUS: diarrhoeal-associated/epidemic HUS
(D+ HUS) and non-diarrhoeal/atypical HUS (D- or aHUS).
Focusing on the last subtype, recent advances have shown
that aHUS is a disease of excessive complement activation on
host tissue, particularly along the renal glomerular and arteriolar endothelial and basement membranes. Fifty percent of
reported aHUS cases involve mutations in complement genes
that control the regulation or activation of the alternative
complement pathway. Interestingly, whereas the main
endothelial damage in aHUS is found in the kidney; the HELLP
syndrome is characterised by severe damage of liver endothelium. These findings put together, an interesting hypothesis
states that aHUS and HELLP could be two manifestations of
the same disorder (complement dysregulation) with the kidney (in aHUS) and the liver (in HELLP syndrome) as target
organs for inflammation.

COMPLEMENT AND THE HELLP SYNDROME:

AN IMMUNO-LOGICAL APPROACH
In recent literature, a few case reports exist of patients
developing HELLP during or just after pregnancy, of whom
mutations in the complement system have been described

A CASE OF HELLP SYNDROME

aposteriori. However, more extensive evidence supports a

role for the complement system in pre-eclampsia and HELLP.
Elevated levels of the AP complement activation fragment Bb
in the first 20 weeks of pregnancy, and increased levels of the
anaphylatoxin C5a and terminal C5b-9 were independently
associated with pre-eclampsia later in pregnancy. A key
observation in murine models is that inhibition of the complement system protects against tissue damage and that loss
of complement regulatory activity enhances damage. Apparentely, if inadequately controlled, complement activation
occurs in aHUS and possibly HELLP. The complement system
contributes to thrombosis by (a) directly enhancing blood
clotting properties, (b) changes in endothelial function that
augment the clotting properties of blood, (c) indirect augmentation of the thrombogenic properties of blood. A disruption of the endothelial cell lining by mechanical or chemical stimuli may activate the complement system and clotting.
The focal nature of haemostatic control and thus the thrombotic tendency of each organ varies depending on the distribution of the anticoagulant and procoagulant factors
throughout its vascular tree. This uneven distribution of such
factors in the coagulation system perhaps explains the tissuespecificity of the kidney for aHUS and the liver for HELLP.
Reduced control of complement activation is thought to be
responsible for the damage of the renal endothelium in
aHUS. Whether these mechanisms apply to the liver injury
seen in the HELLP syndrome remains to be established.

Table 2: ADAMTS13 levels, thrombophilic factors,

complement factors and specific complementdirected antibodies, and auto-immune antibodies
during HELLP episode (S.I. units, reference values
according to particular laboratory)
parameter

result

unit

reference
values

fibrinogen

169,9

mg/dL

180-350

fibronectin

not tested

ADAMTS13

40%

40-100

cardiolipin IgG

0,8

U/mL

<7

aPC resistance

2,72

A.U.

2,1-3,1

protein C

160

70-150

protein S

52

70-150

sanguinity

O Rh-

direct Coombs test

negative

negative

indirect Coombs test

negative

negative

<6.0

mol/L

<6.0

lupus anticoagulans

negative

negative

ANF

negative

negative

ANCA

negative

negative

complement mutations
factor H
factor I
MCP (CD46)
C3

negative
negative
negative
negative

negative
negative
negative
negative

factor H auto-Ab

negative

negative

homocystein

IMPLICATIONS FOR A NEXT PREGNANCY

Women with a history of HELLP syndrome carry an
increased risk of at least 20% (range 5-52%) that some form
of gestational hypertension will recur in a subsequent gestation. Whereas thrombophilia screening is accepted for
patients with prior-severe, acute onset pre-eclampsia, one
should always consider screening of a number of particular
mutations in certain subunits of the complement system, and
its regulatory proteome. The latter was done in our case:
genetic screening for complement mutations was however
negative (table 2).

CONCLUSION
Complement is a central mechanism contributing to
aHUS and possibly to HELLP. Although the cause of tissue
injury in these diseases is multifactorial, excessive activation
or defective regulation of the complement system is important in the aetiopathogenesis. The susceptibility of the renal
endothelium in aHUS and the hepatic vessels in HELLP to
damage, and tendency to excessive complement activation,
suggest unique predisposing features and responses to

injury. Depending on the triggering stimuli and the vascular

bed involved, aHUS of HELLP syndrome may develop. Therefore, one should always consider screening of a number of
particular mutations in certain subunits of the complement
system, certainly in patients with prior-severe, acute onset
pre-eclampsia.

CONFLICT OF INTEREST: None declared.

REFERENCES
1. Haram K, Svendsen E, Abilgaard U. The HELLP syndrome: clinical issues and management. A review. BMC Pregnancy and Childbirth 2009; 9(8): 1-15.
2. Fang CJ, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in understanding of pathogenesis of aHUS and HELLP. BJH 2008; 143: 336-348.
3. Mihu D, Costin N, Mihaela Mihu C, Seicean A, Ciortea R. HELLP syndrome amultisystemic disorder. J Gastrointestin Liver Dis 2007; 16(4): 419-424.
4. Lynch AM, Murphy JR, Byers T et al. Alternative complement pathway activation
fragment Bb in early pregnancy as a predictor of preeclampsia. Am J Obst Gyn
2008; 198: 385 e1-e9.
5. Girard G, Yarilin D, Thurman JM,Holers VM, Salmon JE. Complement activation
induces dysregulation of angiogenic factors and causes fetal rejection and
growth restriction. Journal of Experimental Medicine 2006; 203: 2165-2175.

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