Keywords
HELLP syndrome - hemolytic uremic syndrome - thrombotic microangiopathies
Palavras-chave
síndrome HELLP - síndrome hemolítica-urêmica - microangiopatias trombóticas
Introduction
Thrombotic microangiopathies are characterized by endothelial cell dysfunction, microvascular
thrombosis, platelet consumption and reduced tissue perfusion.[1]
[2] As blood flows through partially constricted microvessels, hemolysis occurs.[2] In pregnancy, its most common form is the hemolysis, elevated liver enzymes, low
platelets (HELLP) syndrome.[1]
[2]
[3] Its pathogenesis is not established, and hypotheses include alteration in the maternal-fetal
immune balance, or placenta instigated liver-targeted acute inflammatory condition,
or a severe form of preeclampsia.[2] The microvascular injury in HELLP syndrome is systemic, but mainly affects the liver.[1]
[2]
[3]
Hemolytic uremic syndrome (HUS) is another life-threatening thrombotic microangiopathy
characterized by hemolytic anemia, thrombocytopenia and acute kidney injury.[4] Hypertension can occur due to the activation of the renin-angiotensin system associated
with renal ischemia.[4] Shiga toxin-producing Escherichia coli (STEC) is responsible for the typical form
of the disease.[4] It infects humans after the ingestion of contaminated food or water. Abdominal pain
and hemorrhagic diarrhea develop within 3–7 days, and up to 10% of the infected patients
(usually serotype O157) develop HUS 4–10 days after the onset of diarrhea. The microvascular
injury is mediated by the Shiga toxin, and mainly affects the kidney.[1]
[2] Non-STEC-HUS, or atypical HUS (aHUS), can have multiple etiologies associated with
the dysregulation of the complement activation.[2] At the onset, it is difficult to distinguish HUS/aHUS from thrombotic thrombocytopenic
purpura (TTP), a thrombotic microangiopathy associated with markedly reduced activity
of von Willebrand factor-cleaving metalloprotease (ADAMTS13).[2]
[4]
The authors report a case where both typical HUS and HELLP syndromes were diagnosed,
elucidating the clinical challenge associated with this differential diagnosis.
Case Presentation
A 42-year-old pregnant patient (after in vitro fertilization), gravida 3 para 0, without
significant medical or surgical history, was admitted at 20 weeks of gestation for
severe abdominal pain and bloody diarrhea that started after ingesting vegetables
grown in a family farm. Beside slight uterine contractions, no other symptoms/signs
were present. On blood tests, only a slight leukocytosis (14,800/mm3) and a high C-reactive protein (3.3 mg/dl) were noted. Since the abdominal ultrasound
suggested appendicitis, a laparoscopic appendectomy was performed. The histological
examination did not confirm the diagnosis. The patient, asymptomatic, was discharged
the next day.
Four days later, she was reevaluated for sudden onset of peripheral and periorbital
edema and oliguria, with normal blood pressure (BP). Laboratory tests ([Table 1], line1) were consistent with microangiopathic hemolytic anemia, thrombocytopenia
and acute kidney injury. There was also microscopic hematuria and proteinuria, and
a mild elevation of the aspartate aminotransferase (AST) and the alanine aminotransferase
(ALT). Surgical complications were excluded. An obstetric ultrasound scan excluded
signs of fetal distress, malformations or abnormalities. She was admitted for suspected
typical HUS to the intensive care unit (ICU), where plasmapheresis was immediately
started after red blood cell transfusion. Stool and blood samples were negative, but
STEC serotype O157:H7 was identified in the urine culture. Plasma exchange therapy
was performed daily for 4 days. Thereafter, it was performed according to the platelet
count and the lactate dehydrogenase (LDH) level. The replacement fluid was 100% fresh
frozen plasma (FFP) in the first two sessions and later, 50% albumin solution/50%
FFP. Continuous hemodiafiltration was performed to avoid fluid overload (the volume
balance was zero during the treatment). Anticoagulation was performed with heparin
in the priming of the filter and by continuous infusion during the replacement. After
an initial worsening of the acute kidney injury (creatinine 2.5 mg/dl, max), the tests
started to improve ([Table 1], line 2).
Table 1
Summary of patient's blood and urine test results throughout the progression of the
disease
|
Hemogl.
(g/dL)
|
Platelets
(/mm3)
|
Creatin.
(mg/dL)
|
AST/ALT
(UI/I)
|
LDH
(UI/I)
|
Haptoglobin levels
|
Blood smear
|
Proteinuria
|
|
At onset
(20 wks)
|
7.8
|
58,000
|
1.9
|
85/59
|
680
|
undetectable
|
schistocytes
|
Minor degree (+)
|
|
One week after initial plasma exchange therapy
(21 wks)
|
9.8
|
155,000
|
2.0
|
36/39
|
257
|
normal range
|
-
|
-
|
|
After hypertension onset
(23 wks)
|
8.5
|
50,000
|
2.0
|
37/29
|
246
|
undetectable
|
-
|
7,600 mg/24h
|
|
At the threshold of fetal viability
(24 wks)
|
10.2
|
73,000
|
1.5
|
57/32
|
620
|
undetectable
|
schistocytes
|
14 186 mg/24h
|
|
At pulmonary edema onset
(25 wks)
|
8.9
|
69,000
|
1.5
|
41/71
|
685
|
undetectable
|
-
|
-
|
|
Two weeks after delivery
|
8.5
|
266,000
|
0.6
|
16/19
|
196
|
normal range
|
normal
|
187 mg/24h
|
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; Creatin.,
creatinine; Hemogl., hemoglobin; LDH, lactate dehydrogenase; wks, weeks.
The patient developed hypertension (>160/110 mm Hg) 12 days after admission, requiring
diuretic and antihypertensive therapies. The laboratory tests ([Table 1], line 3) were consistent with the recurrence of hemolysis and thrombocytopenia,
mild elevation of transaminases and nephrotic range proteinuria. Complement activity
and complement proteins were within the normal range, and the auto-antibodies were
negative. Later, ADAMTS13 assessment was normal. Hemolytic uremic syndrome with superimposed
preeclampsia and HELLP syndrome were considered on the differential diagnosis.
The patient refused to terminate the pregnancy. After the red blood cell transfusion
and hypertension control, the tests were stable, and she was transferred to a tertiary-care
hospital at 24 weeks of gestation ([Table 1], line 4). A course of betamethasone was administered for fetal lung maturity. An
ultrasound scan revealed fetal growth restriction with normal umbilical artery Doppler
velocimetry and amniotic fluid index.
At 25 weeks of gestation, she suffered a sudden relapse of microangiopathic hemolysis
([Table 1], line 5) and developed severe hypertension (200/120 mm Hg) and acute pulmonary edema
refractory to therapy, suggesting severe preeclampsia and HELLP syndrome. After discussion
with the parents, delivery of the fetus was decided upon. While on parenteral magnesium
sulfate therapy, an emergency cesarean section was performed. The neonate (600 g,
Apgar scores 4–7-7) was admitted at the neonatal ICU, but died the next day.
After the delivery, and without specific therapy, there was remission of the hemolysis,
thrombocytopenia, proteinuria and the renal and hepatic injuries ([Table 1], line 6). The patient was discharged two weeks later on antihypertensive therapy,
and no further recurrences have been diagnosed.
Discussion
Both HUS and HELLP syndromes are characterized by hemolysis and thrombocytopenia,
with or without hypertension or proteinuria.[3]
[4]
[5] Nonetheless, HELLP syndrome is far more frequent than HUS. Preeclampsia complicates
3–5% of pregnancies, and HELLP syndrome develops in 4–14% of women with severe preeclampsia.[2] On the other hand, diagnosis of HUS/TTP during pregnancy or postpartum is very rare,
probably 1 case in 100,000 pregnancies.[1] Furthermore, STEC-HUS represents only 5–10% of the HUS cases in adults, compared
with > 90% of HUS in children.[4]
Although both are thrombotic microangiopathies, the microvascular injury in the HELLP
syndrome affects mostly the liver, while the kidney is the organ most affected in
the HUS.[1]
[2]
[4]
[5] Hence, transaminases are significantly elevated in the HELLP syndrome, but only
mildly elevated in the HUS.[3]
[4]
[5] In contrast, significant acute kidney injury is infrequently encountered in patients
with HELLP syndrome,[2] but it is an important feature in the clinical course of HUS.[1]
[4]
Hemolytic uremic syndrome / thrombotic thrombocytopenic purpura should be suspected
when hemolysis and thrombocytopenia are diagnosed during pregnancy in the presence
of a normotensive pregnant woman, or when associated with hypertension and/or proteinuria
before 24 weeks of gestation, or when the renal injury is worse than the liver injury.[1]
[5] Whenever the patient presents with hemorrhagic diarrhea, STEC-HUS should be considered
.[4] In the case reported, the onset of the disease resembled the pathophysiology of
STEC-HUS, with hemorrhagic diarrhea preceding hemolytic anemia, thrombocytopenia and
acute kidney injury. In the absence of hypertension and severe liver injury, and presenting
before 24 weeks of gestation, the diagnosis, although rare, appeared clear. During
the diarrheic period, it is important to keep in mind that increased leucocyte count
in the blood and increased serum C-reactive protein are risk factors for developing
HUS after STEC infection,[4] as occurred in this case.
Plasma exchange is the first line treatment for aHUS. Conversely, it has no beneficial
effect to reduce nephropathy in STEC-HUS.[4] Being difficult to distinguish typical HUS/aHUS/TTP at the onset, plasmapheresis
without delay is suggested for most adult patients.[4] While waiting for culture results, plasmapheresis was, therefore, instituted in
our patient. The isolation of STEC serotype O157:H7 further corroborated the initial
diagnosis, although it was isolated in the urine but not in the stool culture.
Later development of severe hypertension and nephrotic range proteinuria, associated
with the recurrence of hemolytic anemia and thrombocytopenia, led to an even greater
diagnosis challenge. Within the hypertensive disorders of pregnancy.[3] HELLP syndrome has been categorized as a complicated form of severe preeclampsia.[2] Although hypertension can also occur in the HUS, this usually happens during the
acute phase of the disease, and does not occur with nephrotic proteinuria.[4] Complete remission of the hemolysis, thrombocytopenia, proteinuria and the renal
and hepatic injuries without a specific therapy after delivery corroborates the diagnosis
of HELLP syndrome.[1]
[2]
[5] To our knowledge, there are no other reports of HELLP superimposed on HUS.
There are no systematic reviews or randomized trials on HUS during pregnancy, probably
due to its rarity. Stella et al[5] reported a series of 14 cases of TTP/HUS in pregnancy or postpartum encountered
in 4 tertiary-care centers over 8 years, which highlights the difficult differential
diagnosis with HELLP. All the patients diagnosed with TTP/HUS before 24 weeks of gestation
(n = 6) survived: 3 had term live births, 1 had a missed abortion, and 2 had intrauterine
fetal death. On the case here reported, the pregnancy was continued for 5 weeks after
the diagnosis of typical HUS, beyond the threshold of fetal viability. Despite this
accomplishment, unfortunately, the neonate died.
The differential diagnosis also considered unusual HELLP syndrome postponed by plasma
exchange therapy. A few studies investigated the role of plasma exchange in HELLP
syndrome, and found that it can be an effective treatment for patients with persistent
HELLP syndrome after delivery.[6]
[7] After therapeutic plasma exchange, LDH and AST levels decrease, and platelets count
increases. The mechanism of action is still controversial. In theory, plasmapheresis
removes from circulation aggregating, procoagulant and vasoactive factors released
from activated platelets and endothelial cells, leading to renal and hepatic function
improvement.
This case reinforces the difficulty in diagnosing HUS during pregnancy, considering
that several clinical and laboratory findings overlap with the far more frequent HELLP
syndrome. Hemolysis, elevated liver enzymes, low platelets syndrome superimposed upon
STEC-HUS is a unique feature of this case that can impact future research.
