Journal of Infection (2006) 52, e87–e91

www.elsevierhealth.com/journals/jinf

CASE REPORT

An unusual transitory increase of lupus
anticoagulant in dengue virus infection
complicated with cerebral ischaemia
Wei-Hsi Chen*
Stroke Biology Research Laboratory, Department of Neurology, Chang Gung Memorial Hospital,
123 Ta Pei Road, Niao Sung Hsiang, Kaohsiung 833, Taiwan, ROC
Accepted 8 June 2005
Available online 19 July 2005

KEYWORDS
Lupus anticoagulant;
Dengue virus;
Cerebral ischaemia;
Coagulopathy

Summary
Dengue is a common mosquito-transmitted viral disease prevalent at
many undeveloped and developing countries. Although, neurological complication
and hemostatic disturbance are common in dengue virus infection, cerebral
ischaemia is barely mentioned. A 61-year-old woman experienced an acute onset
of right hemiparesis in her early course of dengue virus type II infection. Extensive
laboratory investigation revealed an increase of lupus anticoagulant activity and a
prolonged activated partial thromboplastin time that were normalized in the
convalescent stage. Her human leucocyte antigens were A2, A11, B8, Cw7, DR4 and
DR9. This patient highlights the co-operation between transient activation of
humoral immunity and preferential immunogenetic for coagulopathic thrombosis in
specific viral disease.
Q 2005 The British Infection Society. Published by Elsevier Ltd. All rights reserved.

Introduction
Dengue is a common mosquito-transmitted viral
disease prevalent in Latin American, the Pacific
islands and continental Asia. Annually, there are an
estimated 50–100 million cases of dengue fever, and
250 000–500 000 cases of dengue haemorrhagic
fever throughout the world. Human infection with
dengue virus shows different clinical courses,
ranging from asymptomatology, dengue fever,
dengue haemorrhagic fever to dengue shock syndrome. Neurological complications, including
* Tel.: C886 7 731 7123x3399; fax: C886 7 311 2516.
E-mail address: e49130@ms14.hinet.net.

encephalitis, meningitis, encephalopathy, myelitis,
polyradiculitis and seizure, are common in
advanced stage.1 Isolated facial palsy or neuropathy may occasionally occur in dengue fever.
Dengue has not been an endemic disease in
Taiwan in the past. It was not until after June, 2002
that a serious outbreak of dengue occurred in
Taiwan, similar to Latin America in the same year.
There were 5388 persons seropositive for dengue
fever, and 242 for dengue haemorrhagic fever or
shock syndrome. Among this population, 5287
persons with dengue fever and 241 with dengue
haemorrhagic fever or shock syndrome resided in
Southern Taiwan. A total of 21 persons died. Most of
the patients were infected by the dengue II virus,

0163-4453/$30.00 Q 2005 The British Infection Society. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.jinf.2005.06.003

e88

W.-H. Chen

while the dengue IV virus was only recovered in a
minority of subjects. During that period, a dengueseropositive woman presented with stroke symptom in her early course of infection. This unusual
presentation was associated with a transitory
increase of lupus anticoagulant (LAC) activity that
has not been described previously.

Case history
A 61-year-old woman caught sorethroat and asthenia when dengue fever was endemic in South
Taiwan at 2002. On the following morning, a sudden
onset of left side weakness developed while she was
watching video at home. She could still elevate her
left arm and leg, talk coherently and walk
independently except unsteadiness. Chillness,
fever and arthralgia developed at noon. She arrived
at our emergency service at the evening. She
denied having major medical disease, recent
craniofacial trauma, surgery, blood transfusion,
migraine or illicit drug usage.
On admission, her blood pressure was
136/87 mmHg, pulse rate 78 beats/min, respiratory
rate 13 breaths/min and body temperature 37.8 8C.
There was no ecchymosis, cutaneous lesion, joint
swelling, oral ulcer or lymphadenopathy. Neurological examination revealed mild central facial
weakness, hemiparesis and dorsiflexed plantar
reflex at left side. Cerebral ischaemia at the right
hemisphere was considered. Hematology, biochemistry, serology, lipids profile, hepatitis B and C
markers, and urinalysis were normal, except
leucopenia
(3500/mm 3 ;
normal:
5000–
3
10 000/mm ), thrombocytopenia (70 000/mm 3;
normal: 150 000–350 000/mm3), and an elevation
of aspartate aminotransferase (245 IU/ml; normal:
!45 IU/l), glutamine aminotransferase (210 IU/ml;
normal: !45 IU/l) and C-reactive protein (6.3 mg/dl;
normal: !5 mg/dl). Diffuse-weighted, apparent diffusion coefficient and T2-weighted magnetic resonance imaging showed a high intensity at the right
corona radiate, compatible with an acute infarct
(Fig. 1). Carotid duplex and transcranial Doppler did
not reveal abnormal finding. Liver sonography did not
show cirrhosis or active lesion. The stroke risk factor
survey2–4 revealed a prolongation of activated partial
thromboplastin time (1.40-fold of control) and mixing
test (1.36-fold of control after mixing) (aPTT Stago)
and a positive LAC activity (1.5-fold increase;
normal!1.2-fold increase) (dilute Russell’s Viper
Venom test, LA Screen/LA Confirm, Gradipore Ltd,
Australia). The anti-cardiolipin IgG-antibody, antibeta2-glycoprotein I IgG-antibody (Varelisa test-kit,

Figure 1 The magnetic resonance imaging showed a
diffuse-weighted (A, arrow) and FLAIR-weighted (B,
arrow) lesion compatible with an acute infarct at the
right corona radiata.

Pharmacia&Upjohn, Germany), thrombin time,
factor II activity, protein C, protein S, anti-thrombin
III, homocysteine, cryoglobulin and cryofibrinogen
were within reference range. The anti-nuclear
factor, antibodies to extractable nuclear antigens,
ds-DNA, Coombs’ test, Venereal Disease Research
Laboratory and Treponema pallidum haemagglutination test were negative. Human leucocyte antigens
were A2, A11, B8, Cw7, DR4 and DR9.
The serum capture IgM/IgG ratio, measured by the
modified capture ELISA,5 was 5.0 for dengue II virus.
The NS1 serology-specific antibody to dengue virus
type II was absent.6 The one-step SYBR Green I-based
RT-PCR assay7 confirmed the dengue virus II in this
patient. Three weeks later, the serum capture
IgM/IgG ratio was turned to 1.7 and NS1 serologyspecific antibody to dengue virus type II increased
to 1.5. These findings supported a primary dengue
virus type II infection basing on (1) the capture IgM/
IgG ratio was R1.2 in acute phase; (2) a negative
NS1-specific IgG antibody response in sera during
acute phase but a positive serotype specificity in
convalescent stage or O9 days after illness onset.
In addition, the IgM antibody to Japanese encephalitis virus, adenovirus, enterovirus 70, parvovirus
B19, cytomegalovirus, Epstein–Barr virus, varicella
zoster virus and herpes simplex virus type I and II,
and Mycoplasma pneumoniae were absent, and the
IgG antibody to these pathogens did not increase in
the convalescent stage. The HIV test and hepatitis
virology markers were negative. Dengue fever with
cerebral ischaemia was established.
During hospitalization, a favorable improvement was ensued. Her activated partial thromboplastin time, mixing test, LAC activity, platelet
count, leucocyte count and hepatic enzymes were
normal at 1, 3, 6 and 12 months after onset,
respectively.

Dengue and cerebral ischaemia

Discussion
Hemostatic disturbance displays an important
cause for cerebral ischaemia in infection.8 Dengue
virus modifies hemostasis in two separate but interrelated ways: A direct action on the cells involved in
hemostasis such as the platelets and endothelial
cells, and an immunological and inflammatory
reaction.9,10 These actions are steered by dengue
fever itself, or indirectly by cytokines and chemokines released from mononuclear phagocytotic
cells activated by the dengue virus. There are two
polar results; the first and most common is
consumptive coagulopathy, thrombocytopenia,
thrombocytic dysfunction, and an inhibition of
plasminogen activator inhibitor 1 or an overexpression of tissue plasminogen activator leading to
haemorrhage, and the second one is a generation of
soluble adhesive molecules, anti-platelet antibodies and anti-endothelial cell antibodies rendering procoagulation. Generally, consumptive
coagulopathy and thrombocytopenia11 are predominant in dengue virus infection and, in addition to
fibrinolysis,12 are pronounced in advanced stages of
the disease,13 and that explains the high prevalence
of haemorrhagic diathesis in complicated dengue
virus infection.
LAC prolongs the phospholipid-dependent clotting reactions by forming a bivalent antigen–
antibody complex with an increased affinity for
phospholipids which competes with coagulation
factors for the same catalytic surface. A generation
of prothrombotic lupus anticoagulant has been
reported in association with a few microbials to
date that include HIV,14,15 hepatitis C virus,14,15
hepatitis B virus, Epstein–Barr virus, varicella zoster
virus, parvovirus B19,16 T. pallidum, Mycobacterium leprosy, M. pneumoniae, streptococcal viridans, Coxiella burnetii and Bartonella henselae
(Table 1). An abnormal increase of anti-phospholipid antibodies has been mentioned in flaviviral
infection: LAC and anti-cardiolipin antibody in
hepatitis C and B virus, and anti-beta2-glycoprotein
I antibody in Japanese encephalitis virus.17 A
concomitant prolongation of aPTT and a diluted
Russell’s Viper Venom test without a clotting factor

e89
deficiency supported a perturbation of phospholipids/cofactor in this patient.
The modern concept for anti-phospholipid antibody generation is an activation of the humoral
reaction by a neoepitopic complex formed by a
binding of the domain antigen of cofactor protein
with anionic/neutral phospholipids that are translocated from the inner to the outer leaflet during
apoptosis. A molecular mimicry promises a
microbial peptide sequence to masquerade the
domain antigen of cofactor protein for phospholipid
binding. For example, in beta2-glycoprotein I, a
molecular mimicry is seen between domain V and
the GDKV peptide (G264DKVSFFCKNKEKKC) in cytomegalovirus, and hexapeptide T133LRVYK in domain
III and T2687LRVLE in the structural protein of
Japanese encephalitis virus. Immunization of either
GDKV or and T133LRVYK is able to generate antibeta2-glycoprotein I antibody. Annexin V, and
especially beta2-glycoprotein I and prothrombin,
are cofactor proteins for LAC generation. In
previous studies, an administration of TIFI, a 19
amino acid peptide (TIFILFCCSKEKRKKKQAAT)
derived from cytomegalovirus, induces LAC and
anti-beta2-glycoprotein I antibody generation.18
The Swiss protein database was used to compare
the sequence of TIFI, dengue virus, prothrombin
and beta2-glycoprotein I. A high homology is seen
among K10EKRKKK in TIFI and E132KTKK in nonstructural protein 2 in dengue virus type II,
K467LKKPVA, E49EVRK and R608LKK in prothrombin,
and 301KNKEKK and 283QEKFK in beta2-glycoprotein I
(Table 2). This result may support a molecular
mimicry between prothrombin or beta2-glycoprotein I and dengue virus type II for LAC
generation.
HLA is important for antigenic presentation in
anti-phospholipid antibody generation. The DR53 is
the modulator for anti-beta2-glycoprotein antibody
generation in the anti-phospholipid antibody syndrome.19 Regard to LAC, a relatively high frequency
of DR4 or DQ1 is found in the primary antiphospholipid antibody syndrome and DR7 or Bw44
in the chloropromazine-related subjects.20 In this
patient, DR4 was found. This finding strengthens
the predisposing proviso of a specific human

Table 1

Microbials that associate with lupus anticoagulant positivity

Bacterium
Virus

Streptococcal viridans, Coxiella burnetii
HIV, hepatitis B virus, hepatitis C virus, Epstein–
Barr virus
Treponema pallidum
Mycobacterium leprosy

Spirochete
Others

Bartonella henselae
Varicella zoster virus, adenovirus, parvovirus
B19, cytomegalovirus
Mycoplasma pneumoniae

e90
Table 2

W.-H. Chen
The homology of sequences among TIFI, dengue virus, prothrombin and beta2-glycoprotein I

TIFI sequence

T

I

F

I

L

F

C

C

S

K
132

Dengue virus NS2

E
*
E
467

Prothrombin
49

E

*
E

K
*
K
*
K
V
608

Beta2-glycoprotein I

301

283

leucocyte antigen genotype for LAC generation in
infection.
A mimetic microbial sequence, and a perfect cooperation among antigen presenting macrophages,
specific HLA, autoreactive T and B cells, and
downstream messager cytokines all influence LAC
generation. These intricate cascades may explain
why a great variation of LAC generation occurs in
response to infection and other stimuli. Nevertheless, an abnormally increase of LAC in this
patient further strengths the critical role of antiphospholipid antibodies in antibody-mediated
thrombosis in infection. A transitory increase
renders difficulty for confirmative diagnosis. An
elucidation of the interaction between the
microbial structure and immunobiology may provide valuable pharmacological information and a
preventive strategy in dealing with infectionrelated cerebral ischaemia.

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