Clinical Rheumatology
https://doi.org/10.1007/s10067-020-05559-6

CASE BASED REVIEW

A maternal death due to the intracerebral hemorrhage caused
by antiphospholipid syndrome: a case report
Bijan Keikhaei 1 & Najmieh Saadati 2 & Mohammad-Reza Mahmoudian-Sani 1 & Mehran Varnaseri 3
Received: 11 May 2020 / Revised: 26 November 2020 / Accepted: 21 December 2020
# International League of Associations for Rheumatology (ILAR) 2021

Abstract
Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by the presence of antiphospholipid antibodies in patients with arterial or venous thrombosis or pregnancy complications. This paper reports a case of a 31-year-old
woman who died after she underwent C-section for intrauterine fetal death (IUFD) at the 25th week of gestation. The patient was
complaining of pelvic pressure, swelling in the lower limbs, and pain in the groin, one big toe, and both wrists. She had low
platelet count, liver abnormalities, and proteinuria. After IUFD, she complained of flank pain and headache. After discharge from
the hospital, the patient had constant headaches and 5 days later woke up with hemiplegia. CT scan showed cerebral hemorrhage
in the right hemisphere and thrombosis in the left hemisphere. The LA and APS tests were positive. The main cause of death was
hemorrhage and infarction in the brain.
Keywords Antiphospholipid syndrome . Beta-2-glycoprotein I . Intracerebral hemorrhage . Lupus anticoagulant

Introduction
One of the rarest pregnancy disorders is intracerebral hemorrhage, which can cause fatal disabilities or death for both
mother and baby [1]. Only 0.002% of women in the general
population experience intracerebral hemorrhage (ICH) at
birth; the incidence rate of ICH is higher after childbirth compared to the prenatal rate [2]. Smoking, chronic high blood
pressure, non-white race, and older maternal age are among
the ICH risk factors. Preeclampsia and eclampsia with a new
onset in most cases can lead to ICH during pregnancy or
prenatal period, particularly in the event of failure to control
acute high blood pressure [3]. The patients with
antiphospholipid syndrome (APS) may have an increased risk

* Najmieh Saadati
nil2f@yahoo.com
1

Thalassemia and Hemoglobinopathy Research Center, Research
Institute of Health, Ahvaz Jundishapur University of Medical
Sciences, Ahvaz, Iran

2

Fertility, Infertility and Perinatology Research Center, Ahvaz
Jundishapur University of Medical Sciences, Ahvaz, Iran

3

Infectious Diseases Department, Razi Hospital, Ahvaz Jundishapur
University of Medical Sciences, Ahvaz, Iran

for the development of ICH (Table 1). APS is a systemic
autoimmune disease. Antiphospholipid antibody synthesis is
mainly initiated in response to infectious agents, but this process is better known for acting against the phospholipidbinding protein β2 glycoprotein I (β2GPI). The issue arises
from the molecular similarity of the structure of some microbes and viruses to the amino acid sequence of β2GPI.
The binding of β2GPI to protein H of Streptococcus pyogenes
has revealed an antigen in β2GPI that is associated with immune stimulation and antibody synthesis [4, 5]. APS is characterized by the presence of antiphospholipid antibodies in
patients with arterial or venous thrombosis or pregnancy complications. Women with this syndrome have a 45–90% risk of
unsuccessful pregnancy, but treatment can reduce this risk by
30%. The hallmarks of this syndrome are fetal death, preterm
delivery, preeclampsia, and recurrent miscarriages in the absence of chromosomal abnormalities. Pregnancy complications may occur in patients with a history of vascular thrombosis or be the first sign of APS. Given the high risk of pregnancy for APS patients, pregnant patients need regular monitoring and follow-up to minimize thrombotic complications.
One of the mechanisms whereby APS causes miscarriage is
the formation of a syncytium between the fetal trophoblast and
the maternal endometrium. In this mechanism, the anionic
phosphatidylserine of the surface of trophoblasts undergoes
a cell surface flip-flop (translocase). Then, β2GPI binds to

Clin Rheumatol
Table 1
Age/sex

previous case reports of APS complicated by ICH
Clinical manifestations

Laboratory studies

Ref

37-year-old Large cerebral hematoma in the left frontoparietal region and other foci of hemorrhage Laboratory studies was positive for LA
man
on the right hemisphere, fragility of the vessels, and/or platelet dysfunction
and a CL antibodies
31-year-old The final diagnosis was catastrophic APS with diffuse alveolar hemorrhage and kidney ANA were positive, a CL antibodies
woman
involvement. The unusual combination of recurrent alveolar hemorrhage and death
were detected in high titers twice
from intracerebral hemorrhage rather than thrombosis in a catastrophic APS patient
36-year-old Sudden onset of left hemiparesis and status epilepticus. CT scan and MRI showed a
Laboratory studies was positive for LA
man
cerebral hematoma located in the right frontoparietal region. Stereotactic biopsy of the
and a CL antibodies
hematoma wall and scalp artery showed no abnormality

the phosphatidylserine and annexin V on the surface of placental trophoblast, attaching it to APA: Anti-β2GPI. By binding to annexin V, this antibody nullifies its shielding effect
against the binding of coagulation factors to
phosphatidylserine, thereby creating a hypercoagulable state
on the surface of the placenta, which can lead to thrombosis
and miscarriage [6, 7].
In the case reports of APS complicated by ICH, the
clinical manifestations are not comparable to our case,
but similar to our laboratory studies, the LA and a CL tests
are positive.

Case presentation
The case presented in this report is a 31-year-old Iranian woman with APS who died after she underwent C-section following the diagnosis of intrauterine fetal death (IUFD) in 25th
week of gestation. The patient did not state the presence of
APS or any other autoimmune condition and did not use anticoagulants or antiplatelets. There was no autoimmune disease or bleeding disorder in her personal or family history.
The patient was admitted to the clinic at a gestational age of
23 weeks complaining of pelvic pressure. The swelling in
lower limbs was so severe that she had to wear shoes two sizes
larger than usual. She also complained of pain in the groin,
one big toe, and both wrists. The fetal heart rate was not
detected, and ultrasound led to the diagnosis of IUFD. The
laboratory tests showed that the mother had low platelet count,
liver abnormalities, and proteinuria. The physician suspected
autoimmune disease, but this doubt was not followed up. To
terminate the pregnancy, initially, oxytocin was injected at a
dose of 20 units/1000 cc, but since it failed to initiate delivery,
syntometrine was injected at a dose of 50 units/500 cc over
3 h. At this stage, the laboratory test results were as follows:
HB: 10.9 (g/dL), PLT: 80,000 (mm3), PT: 12.3 (Sec), PTT:
66.9 (Sec), INR: 1, Protein trace, BS: 87 (mg/dL), BUN: 17
(mg/dL), Cr: 0.9 (mg/dL), SGOT: 42 (U/L), SGPT: 65 (U/L),
and ALKP: 216 (IU/L). During pregnancy, she never had
hypertension, and her only problem was severe progressive
swelling. The patient had a history of rhinoplasty,

[8]
[9]

[10]

adenectomy, and hypothyroidism and was under medication
with levothyroxine. The patient underwent C-section surgery
with spinal anesthesia, and the dead baby was born. After
receiving two units of fresh frozen plasma (FFP), the patient
was transferred to the maternity ward. The next morning, the
patient showed one-sided ecchymosis and swelling in the eye
and nose. The results of an emergency test done at this stage
were as follows: HB: 7.8 (g/dL), PT: 13.3 (Sec), PTT: 60.4
(Sec), SGOT: 33 (U/L), SGPT: 46 (U/L), and PLT: 1,000,000
(mm3).
Considering the low hemoglobin level, the patient received
pack cell and FFP injections. The next day, the patient had a
blood pressure of 140/90 mmHg. On this basis, the patient
was discharged with a prescription for hydrochlorothiazide
tablets. Five days later, the patient admitted to the emergency
Table 2

Results of APS and LA tests

Antiphospholipid antibodies
Anti-dsDNA
ANA
Anti-cardiolipin Ab(IgM)
Anti-cardiolipin Ab(IgG)
β2GPI IgG
Positive antiphospholipid
Lupus anticoagulant testing
Anti-thrombin III
CH50
C4
Anti-CCP
C-ANCA
P-ANAC
FANA
Anti-dsDNA
Anti-SSB/La
Anti-Ro/SSA
ANAscreen
Anti-cardiolipin Ab(IgG)
Anti-cardiolipin Ab(IgM)
HEP-2 substrate
Positive screening for lupus anticoagulants

11.5 IU/mL
Negative
74 GPL U/mL
242 GPL U/mL
113.4 U/mL

130 IU/dL
94 U/mL
15 mg/dl
2.1 IU/mL
0.5 AU/mL
1/1 AU/mL
Negative
23.8 IU/mL
7.7 U
11.5 U
Negative
77.3 GPL U/mL
31.5 MPL U/mL
Negative

Clin Rheumatol

room with hemiplegia on the right side of the body and convulsions. CT scan showed hemorrhage in the right side of the
brain and thrombosis in the left side (Fig. 1). The patient was
admitted to ICU and monitored by a neurologist, who diagnosed intracerebral hemorrhage. At this stage, the results of
laboratory tests were as follows: HB: 11.8 (g/dL), PLT: 159
(mm3), PT: 13.3 (Sec), PTT: 62 (Sec), ESR: 95) mm/h), NA:
149 (mEq/L), K: 3.8 (mEq/L), SGOT: 24 (U/L), SGPT: 24
(U/L), ALKPH: 228 (IU/L), Mg: 1 (mEq/L), BiliT: 4 (mg/dL),
BiliD: 1 (mg/dL), BUN: 17 (mg/dL), Cr: 6 (mg/dL), and pH:
3.9. APS and lupus anticoagulant (LA) tests were positive
(Table 2). To determine LA and APS antibodies, 5 mL of
the patient’s blood was poured into an anticoagulant-free test
tube, and the sample was coagulated for 20 min at room temperature. The blood sample was then centrifuged in the laboratory to separate the serum. The serum antibodies were determined by the ELISA method. Based on the patient’s history
and test results, treatment started with hydroxychloroquine
200 mg HS and continued with dexamethasone TDS.
Because of the cerebral hemorrhage, anticoagulant therapy
was stopped to perform magnetic resonance angiography
(MRA) and magnetic resonance venography (MRV). MRA
findings showed embolic infarction (hemorrhage). MRV
did not provide any valuable data. In the 2nd day of admission to ICU, portable cardiac ultrasound was performed, which showed no sign of thrombosis in the cardiac
and valves. In the 3rd day of admission, the patient had
headache and convulsions in the right limbs then started
having a treatment-resistant tonic-clonic seizure. CT scan
showed more cerebral hemorrhage, which had caused a
brain shift. The patient was treated with ceftriaxone,
clindamycin, methylprednisolone, dexamethasone, heparin, and midazolam. In the 4th day, the pupils became fixed
and stopped reacting to light. In the same day, brain CT
was performed to determine the extent of damage. In the
5th day of admission to ICU, the patient passed away after
50 min of cardiopulmonary resuscitation.
Fig. 1 (a, b). Computed
tomography (CT) scan images
taken at a gestational age of
25 weeks and 2 days (arrows
show the multiple intracerebral
hemorrhages in the right
hemisphere)

Discussion
Several variants of APS are defined comprising primary and
secondary APS concomitant with another autoimmune disease (mainly SLE) and catastrophic APS (CAPS). The
CAPS as a rare life-threatening variant of APS can rapidly
lead to ischemia and failure in multiple organs due to widespread intravascular thrombotic storm in spite of therapeutic
interventions [11]. The CAPS may show itself with gradual
clinical presentations, often confused with other thrombotic
microangiopathies; this needs a high index of clinical suspicion. A precipitating agent such as medication, surgery, or
infection may be detected in most patients with CAPS [12].
The presence of CAPS can be significantly confirmed by the
antiphospholipid antibodies (aPL) positivity. It should be noted that about 50% of CAPS patients had no history of aPL
positivity. Clinically suspected CAPS should be treated
promptly even without aPL confirmation testing [13]. There
are some therapeutic candidates for the CAPS, including intravenous immunoglobulin (IVIG) treatment, cyclophosphamide therapy, plasma exchange, the use of steroids, and
anticoagulation [14]. The progress of obstetric problems in
APS patients is always suspicious of CAPS. CAPS in pregnancy presents a complex clinical scenario both in terms of
diagnosis as well as therapy. The differential diagnosis of
CAPS in pregnancy and puerperium includes thrombotic
thrombocytopenic purpura (TTP), disseminated intravascular
coagulation (DIC), hemolytic-uremic syndrome (HUS),
heparin-induced thrombocytopenia (HIT), and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, all of which can form part of the manifestations of
CAPS [15]. On a rare occurrence, CAPS is concomitant with
hemorrhagic manifestations such as diffuse alveolar hemorrhage (DAH) [16]. CAPS should be considered when dealing
with spontaneous intracerebral bleeds with multisystem dysfunction in the background of coagulation disorders [17].
Lupus anticoagulant-hypoprothrombinemia syndrome

Clin Rheumatol

(LAHPS) is an uncommon medical condition developed by
antiprothrombin antibodies, leading to bleeding. The LAHPS
is predominantly associated with SLE, and sometimes subsequently with drug ingestion, Mycoplasma infections, and viral
prodromes [18]. Unlike APS, the LAHPS is clinically accompanied with disseminated intravascular coagulation (DIC) and
risky hemorrhage [19, 20]. Transient conditions exist for
LAHPS associated with infection and bleeding are seen rarely.
However, lymphoma/SLE-associated LAHPS is more stable,
and bleeding is a common complication [21]. No universal
agreement is currently available on the best therapeutic strategy for the LAHPS. Early indications for treatment are prevention of postoperative bleeding to treat life-threatening
bleeding until the onset of long-term immunosuppression to
remove the inhibitor [20]. Patients with LA who do not have
hemostatic abnormalities such as factor II deficiency, thrombocytopenia, or vascular defects rarely develop hemorrhage.
However, there are several reports of hemorrhage in APS
patients in the absence of known risk factors for this condition,
which indicate that there is an etiological relationship between
LA and certain types of hemorrhage. In the case of this report,
the patient did not have any symptoms of autoimmune disease
or history of hemostatic abnormalities before pregnancy, and
the first manifestation of APS and LA appeared during pregnancy in the form of hemorrhage in the right hemisphere. In
2014, Sun et al. reported a death of a 32-year-old woman due
to systemic venous thrombosis 11 days after she had C-section
delivery. In that case, blood tests showed reduced platelet
count during the 19th week of pregnancy. Also, the results
of test were positive for anti-cardiolipin and anti-β2GPI antibodies at a gestational age of 36 weeks and 2 days. This
patient was diagnosed with APS. The primary causes of death
in this case were cerebral hemorrhage and hepatic infarction
[22]. In 1999 Sakaguchi et al. reported a case of an 18-yearold woman, who was complaining of fever and swelling and
showed LA, prolonged prothrombin time, hemolytic anemia,
negative Coombs test, no antinuclear antibodies, and normal
fibrinogen levels. In this patient, primary APS had caused
renal damage. This case strongly indicates that there is a causal relationship between LA and renal damage in thrombotic
microangiopathy [23]. Çağirici et al. (2012) reported that for a
37-year-old man with ptosis, facial paralysis, right hemiplegia,
and motor aphasia, CT scans and MRIs showed a large cerebral hematoma in the left frontoparietal region and also other
hemorrhage foci in the right half of the brain. In this patient,
IgM anti-cardiolipin antibodies were 16.5 MPL/mL and IgG
anti-cardiolipin antibodies were 21 GPL/mL. This report concluded that antiphospholipid antibodies led to intracerebral
hemorrhage [8]. In 2019, Mazzoccoli et al. described a rare
case of APS in an adult male who had experienced a wide
range of clinical manifestations involving various organs over
a period of 9 years and was not initially diagnosed with APS.
The first clinical symptoms of this patient were dizziness and

syncope. Later, he also had generalized seizures and head
injuries. Thrombocytopenia was detected when the patient
was admitted to a clinic for bilateral epistaxis and fever.
Then, laboratory tests showed acute pancreatitis with elevated
inflammation markers. Although APS is one of the most common causes of thrombocytophilia, unfortunately, it is often not
diagnosed on time. Since undiagnosed patients receive no
treatment to control their condition, they are at great risk of
severe complications and possibly death [24].

Conclusion
In this report, the patient had no symptoms of rheumatic diseases or history of hemostatic abnormalities before pregnancy,
and the first manifestation of APS and LA appeared after Csection in the form of cerebral hemorrhage in the right hemisphere and severe thrombosis in the left hemisphere. IUFD
occurred at the 25th week of gestation, and the patient passed
away 16 days later. The main cause of death was hemorrhage
and infarction in the brain. Considering the potential complications of APS, physicians should take great care to diagnose
this condition as soon as possible to allow for early treatment.
In the case of pregnant women, physicians should strongly
insist on the appropriate treatment to protect the mother as
well as the baby and provide cautionary suggestions and consider the right time to terminate the pregnancy.
Authors’ contributions N.S. contributed to the rationale and patient management, and all authors contributed to the manuscript development,
images, and descriptions.

Compliance with ethical standards
Disclosures None.
Consent for publication The authors have no ethical conflicts to disclose. The authors confirm obtaining written consent from the patient for
publication of the manuscript (including images, case history, and data).

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