American Journal of Emergency Medicine xxx (2016) xxx–xxx
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American Journal of Emergency Medicine
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Case Report
Late postpartum HELLP syndrome over 10 days after delivery
Abstract
Most cases of postpartum HELLP syndrome develop within 48 hours
after delivery; however, there is no reliable knowledge how long the
postpartum HELLP can delay to onset. We report postpartum HELLP
syndrome developed 10 or more days after delivery. The patient was a
healthy 25-year-old woman. She gave birth to a healthy boy at 40
weeks of gestation by spontaneous delivery. Blood pressure was within
the reference range. Spike fever developed at 2 and 5 days after delivery,
and she was readmitted at 10 days after delivery. On this admission, no
abnormality was detected. However, marked anemia, liver disorder, and
thrombocytopenia developed at 13 days, and she was transferred to the
emergency and critical care center. Recombinant thrombomodulin was
administered, and symptoms started to improve after approximately 5
days. This case may have been postpartum HELLP syndrome which de-
veloped over 10 days after delivery. As shown by this case, there may be
cases developing delayed, for which careful follow-up is necessary.
HELLP syndrome develops in pregnant and postpartum women, and it
manifests 3 signs: hemolysis, elevated liver enzymes, and low platelets.
The cause and essence of the pathology are still unclear, but it is consid-
ered that activation of coagulation by vascular endothelial disorder is
the main pathology causing hemolysis and thrombocytopenia [1]. As
the liver appears to be the main site of this process, it is considered that
downstream liver cells become ischemic and mainly cause liver disorder.
Most cases of HELLP syndrome develop before delivery, but the inci-
dence in the postpartum period is also high, and 20% to 30% of HELLP
syndrome cases develop in the postpartum period [2,3]. Postpartum
HELLP syndrome generally develops early after delivery, and most
cases develop within 48 hours [4]. HELLP syndrome rarely develops
more than 48 hours after delivery, but there is no reliable knowledge
how long the postpartum HELLP can delay to onset. Therefore, there
was no consensus how long to pay attention to postpartum HELLP syn-
drome after delivery [4].
Herein, we present a case of postpartum HELLP syndrome which
may have developed over 10 days after delivery.
The patient was an originally healthy 25-year-old woman with grav-
ida 6, para 6. Mild anemia developed during the sixth pregnancy, and she
was medicated with an oral iron preparation, which maintained hemo-
globin (Hb) at approximately 10 g/dL. She did not have hypertension
or proteinuria. Blood type was B+, and irregular antibody was negative.
She gave birth to a healthy boy weighing 3546 g by spontaneous delivery
at 40 weeks and 3 days of gestation. Blood pressure was within the refer-
ence range during pregnancy and days around delivery. Atonic bleeding
occurred during delivery and Hb decreased to 6 g/dL. The patient was
treated only with intravenous injection of an iron preparation and
followed because the general condition was favorable. Fever at 38°C de-
veloped 2 days after delivery, but the patient was discharged 5 days after
0735-6757/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Nakamura K, et al, Late postpartum HELLP syndrome over 10 days after delivery, Am J Emerg Med (2016), http://
dx.doi.org/10.1016/j.ajem.2016.05.050
delivery because the general condition was favorable and no abnormality
was detected on blood testing. After discharge, spike fever greater than
38°C developed, and the patient was readmitted to the same hospital
for fever and malaise 10 days after delivery. On blood testing on this ad-
mission, Hb was 6.1 g/dL; platelet count, 20.9 × 104/μL; and C-reactive
protein, 2.99 mg/dL; but no other abnormality including liver disorder
was detected. No drug including antibiotics was given. Fever repeated
thereafter, and marked anemia, liver disorder, and thrombocytopenia
were detected on blood testing at 13 days after delivery. No headache,
abdominal pain, diarrhea, nausea, or vomiting was noted. Thus, the pa-
tient was transferred to the Department of Emergency and Critical Care
Medicine of Hitachi General Hospital. On examination, the body temper-
ature was 38.6°C; blood pressure, 120/65 mm Hg; heart rate, 125 beats
per minute (sinus tachycardia); and respiratory rate, 40 per minute.
The consciousness level was clear, and the patient could walk. The face
was pale, and the bulbar conjunctiva showed jaundice. The abdomen
was flat and soft without tenderness. Neurologic findings were normal
without visual abnormality. Blood testing on admission showed worsen
anemia, thrombopenia, liver function abnormality, coagulation abnor-
mality (white blood cell was 5100/μL; red blood cell, 273 × 104/μL; Hb,
5.1 g/dL; mean corpuscular volume, 74.3 fL; mean corpuscular hemoglo-
bin concentration, 30.5%; platelet count, 6.4 × 104/μL; total bilirubin, 6.48
mg/dL; indirect bilirubin, 2.65 mg/dL; glutamate oxaloacetate transami-
nase (GOT), 99 U/L; glutamate pyruvate transaminase (GPT), 81 U/L; lac-
tase dehydrogenase (LDH), 770 U/L; γ-glutamyl trans peptitase (γGTP),
317 U/L; choline esterase, 151 U/L; alkaline phosphatase (ALP),
1839 U/L; blood urea nitrogen, 8.7 mg/dL; Creatinin, 0.5 mg/dL; Na,
129 mEq/L; K, 3.4 mEq/L; Cl, 92 mEq/L; C-reactive protein, 8.3 mg/dL;
haptoglobin, 20 mg/dL; prothrombin time, 74%; activated partial
thromboplastin time, 36.2 seconds; fibrinogen, 474 mg/dL; fibrin degra-
dation products (FDP), 22.2 μg/mL; D-dimer, 13.2 μg/mL). Marked hepa-
tomegaly and splenomegaly were observed on computed tomography
and ultrasonography. To exclude autoimmune diseases, hepatitis virus
infection, hemolytic-uremic syndrome, thrombotic thrombocytopenic
purpura, prothrombin gene 20210a mutation [5], and other diseases,
tests of viruses including various hepatitis viruses and autoimmunity
were performed, but no abnormality was detected. ADAMTS-13 inhibi-
tor was negative, ADAMTS-13 activity was 61%, von Willebrand factor
activity was 270%, and there was no finding to be mentioned on bone
marrow testing or chromosomal abnormality. The diagnosis was class
1 HELLP syndrome based on the Mississippi-Triple Class System [6];
therefore, she was admitted to an intensive care unit, treated with 19
200 U/d recombinant thrombomodulin (rTM), and followed. The clini-
cal course is shown in the Table. Four units of red blood cells was trans-
fused at day 2 after admission. Fever decreased from approximately day
5 after admission, and the general condition was also improved. Recom-
binant thrombomodulin was administered until day 6, and the patient
2 K. Nakamura et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx
Table
Clinical course
Day 1 2 3 4 5 6 7 8
Max temperature (°C) 40.9 39.9 39.1 40 38.5 37.2 36.8 37
Hb (g/dL) 5 4.5 7.4 6.1 6 5.7 6.3 7.3
GOT (U/L) 99 70 65 56 43 56 65 71
LDH (U/L) 770 695 743 675 644 607 593 503
Platelet (×104/μL) 6.4 5 4.5 4.7 5.6 6.6 7.9 20
was discharged from intensive care unit and then discharged from hos-
pital by walking on day 9. On outpatient follow-up after 1 month, both
thrombocytopenia and liver disorder were improved, and the laboratory
test values and ultrasound findings became within the reference ranges.
A case of delayed-onset postpartum HELLP syndrome was presented.
Fever developed 2 and 5 days after delivery and thereafter, but no hemo-
lytic anemia, liver disorder, or thrombocytopenia was noted at 10 days,
suggesting that HELLP syndrome developed between 10 days after deliv-
ery and day 13 after admission to our hospital, being very late onset.
There are no standard diagnostic criteria of HELLP syndrome, but the
Tennessee system classification proposed by Sibai et al is generally used
and frequently used in Japan, in which cases meeting the following con-
ditions related to pregnancy/delivery are regarded as HELLP syndrome:
(1) hemolysis in peripheral blood smear (red blood cell fragments), an
increase in indirect bilirubin, a decrease in haptoglobin (b25 mg/dL);
(2) a decrease in the platelet count: 100 000/mm3 or lower; (3) liver
function: LDH greater than 6001 U/L, aspartate aminotransferase great-
er than 0 IU/L, total bilirubin greater than 1.2 mg/dL [2]. The present pa-
tient met all these conditions. In addition, this case was class 1 HELLP,
representing a severe condition, based on the Mississippi-Triple Class
System [6]. HELLP syndrome frequently complicates pregnancy-
induced hypertension, but approximately 20% of HELLP cases are not
complicated by hypertension [7]. Because it is considered that vascular
endothelial disorder similar to that in thrombotic microangiopathy is
the main pathology of HELLP syndrome, hemolytic-uremic syndrome
and thrombotic thrombocytopenic purpura are often considered to be
differentiated. Because no ADAMTS-13 activity reduction, inhibitor neg-
ativity, renal disorder, or diarrhea was observed, suggesting that it is ap-
propriate to consider that this case was HELLP syndrome.
Most cases of postpartum HELLP syndrome develop within 48 hours
after delivery [4], but Sibai et al [2] reported that the most delayed onset
time was 7 days in a study with 442 cases of HELLP syndrome. Unfortu-
nately, the details of this most delayed case were not described in their
report. Various epidemiological studies on HELLP syndrome have been
performed, but to our knowledge, no study analyzed the most delayed
onset time after delivery. There is no consensus viewpoint regarding
the possible most delayed onset time of postpartum HELLP syndrome,
and the onset time is described as within 48 hours in many reviews
[4,6]. To our knowledge, the most delayed onset time of postpartum
HELLP syndrome was 7 days after delivery reported by Sibai et al. It
may be worth mentioning that some cases develop more than 10 days
after delivery through the course observed in the present patient, and
sufficient follow-up after delivery may be necessary.
This patient was treated with rTM alone, and symptoms remitted
smoothly. Recombinant thrombomodulin is a therapeutic drug with an
anticoagulant action used to treat disseminated intravascular coagulopa-
thy (DIC). Thrombomodulin is an integral membrane type 1 glycoprotein
expressed on the luminal surface of vascular endothelial cells. Its binding
to endogenous thrombin activates protein C [8], inducing its anticoagu-
lant action. Other actions other than the anticoagulant action have also
been reported: adsorption of high morbidity group box 1 and anti-
inflammatory action, such as binding to lipopolysaccharide [9]. Recombi-
nant thrombomodulin is a drug expected to physiologically remit vascular
endothelial disorder [10,11]. Reportedly, 21% to 55% of HELLP syndrome
cases are accompanied by vascular endothelial disorder-induced DIC
[12], and there are also other case reports in which rTM was effective to
Please cite this article as: Nakamura K, et al, Late postpartum HELLP syndrome over 10 days after delivery, Am J Emerg Med (2016), http://
dx.doi.org/10.1016/j.ajem.2016.05.050
treat HELLP syndrome [13]. Because HELLP syndrome may spontaneously
remit, it was unclear whether rTM was effective for HELLP syndrome in
9 our patient. However, rTM is theoretically effective for vascular endothe-
36.9
lial disorder, and it may be a treatment option for such a severe HELLP
7.4 syndrome as the Mississippi-Triple Class 1 or 2.
52 A case of delayed postpartum HELLP syndrome which developed 10
444 or more days after delivery was presented. Many cases of postpartum
25.8
HELLP syndrome develop early after delivery, and most cases occur
within 48 hours, but there are rare late-onset cases, including those de-
veloping more than 10 days after delivery, to which attention should be
paid. Recombinant thrombomodulin may be a treatment option for
HELLP syndrome.
Disclosure
We have no conflict of interest.
Kensuke Nakamura MD, PhD
Department of Emergency and Critical Care Medicine
Hitachi General Hospital, Hitachi, Ibaraki 317-0077, Japan
Corresponding author. Tel.: +81 294 23 1111; fax: +81 294 23 8317
E-mail address: mamashockpapashock@yahoo.co.jp
Ryota Inokuchi MD, PhD
Department of Emergency and General Medicine
JR General Hospital, Sibuya-ku, Tokyo 151-8528, Japan
E-mail address: intensivecareunits@gmail.com
Tomohiro Sonoo MD
Department of Emergency and Critical Care Medicine
Hitachi General Hospital, Hitachi, Ibaraki 317-0077, Japan
E-mail address: sonopy77@gmail.com
Takahiro Hiruma MD, PhD
Department of Emergency and Critical Care Medicine
The University of Tokyo Hospital, Bunkyo, Tokyo 113-8655, Japan
E-mail address: hirupiru@yahoo.co.jp
Kurato Tokunaga MD
Department of Emergency and Critical Care Medicine
Hitachi General Hospital, Hitachi, Ibaraki 317-0077, Japan
E-mail address: livefreedays@yahoo.co.jp
Kent Doi MD, PhD
Department of Emergency and Critical Care Medicine
The University of Tokyo Hospital, Bunkyo, Tokyo 113-8655, Japan
E-mail address: kdoi-tky@umin.ac.jp
http://dx.doi.org/10.1016/j.ajem.2016.05.050
References
[1] D'Anna R. The HELLP syndrome. Notes on its pathogenesis and treatment. Minerva
Ginecol 1996;48(4):147–54.
[2] Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA. Maternal mor-
bidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and
low platelets (HELLP syndrome). Am J Obstet Gynecol 1993;169(4):1000–6.
[3] Miranda ML, Vallejo-Vaz AJ, Cerrillo L, Marenco ML, Villar J, Stiefel P. The HELLP syn-
drome (hemolysis, elevated liver enzymes and low platelets): clinical characteristics
and maternal-fetal outcome in 172 patients. Pregnancy Hypertens 2011;1(2):164–9.
[4] Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and man-
agement. A review. BMC Pregnancy Childbirth 2009;9:8.
[5] Asherson RA, Schamroth-Rapaport N, Skudowitz B, Singh S, Marx D, Miesbach W.
Recurrent deep vein thrombosis, ovarian carcinoma and antibodies to mitochondria
M5 in a patient with asymptomatic primary “plus” antiphospholipid syndrome: an
unusual combination. Clin Exp Rheumatol 2007;25(6):890–5.
[6] Martin JN, Rose CH, Briery CM. Understanding and managing HELLP syndrome: the
integral role of aggressive glucocorticoids for mother and child. Am J Obstet Gynecol
2006;195(4):914–34.
 K. Nakamura et al. / American Journal of Emergency Medicine xxx (2016) xxx–xxx 3

[7] Sibai BM. Diagnosis, controversies, and management of the syndrome of hemolysis, el-
evated liver enzymes, and low platelet count. Obstet Gynecol 2004;103(5 Pt 1):981–91.
[8] Van de Wouwer M, Collen D, Conway EM. Thrombomodulin-protein C-EPCR sys-
tem: integrated to regulate coagulation and inflammation. Arterioscler Thromb
Vasc Biol 2004;24(8):1374–83.
[9] Ito T, Kawahara K, Okamoto K, et al. Proteolytic cleavage of high mobility group box
1 protein by thrombin-thrombomodulin complexes. Arterioscler Thromb Vasc Biol
2008;28(10):1825–30.
[10] Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human
activated protein C for severe sepsis. N Engl J Med 2001;344(10):699–709.
[11] Ebisawa K, Fukuda T, Inokuchi R, Nakamura K. Recombinant thrombomodulin
monotherapy for secondary thrombotic thrombocytopenic purpura. Am J Emerg
Med 2015;33(4):599.e1-e3.
[12] Van Dam PA, Renier M, Baekelandt M, Buytaert P, Uyttenbroeck F. Disseminated
intravascular coagulation and the syndrome of hemolysis, elevated liver
enzymes, and low platelets in severe preeclampsia. Obstet Gynecol 1989;73(1):
97–102.
[13] Ikezoe T, Ikenoue N, Uchikawa N, Kojima S, Fukaya T, Yokoyama A. Use of recombi-
nant human soluble thrombomodulin in the management of HELLP syndrome com-
plicated by DIC. Thromb Res 2010;126(3):e238–40.

Please cite this article as: Nakamura K, et al, Late postpartum HELLP syndrome over 10 days after delivery, Am J Emerg Med (2016), http://
dx.doi.org/10.1016/j.ajem.2016.05.050