Rheumatology 2001;40:585±587
Paediatric Rheumatology/Series Editor: P. Woo
Diffuse muscular haemorrhage as presenting
sign of juvenile systemic lupus erythematosus
and lupus anticoagulant hypoprothrombinaemia
syndrome
J. R. Yacobovich, Y. Uziel, Z. Friedman1, J. Radnay1 and
B. Wolach
Department of Pediatrics and 1Coagulation±Hematology Laboratory,
Sapir Medical Center, Kfar Saba, Israel
Abstract
Lupus anticoagulants are closely related to systemic lupus erythemathosus (SLE) and to
thrombotic events. We describe a 12 year-old girl with a bilateral intramuscular haemorrhage of
the gastrocnemius muscles as her main initial presentation of juvenile SLE. Laboratory work-up
revealed lupus anticoagulant-hypoprothrombinaemia syndrome (LAHS) with very low levels of
factor II due to autoantibodies. She showed a good initial clinical and laboratory response to
prednisone therapy, however steroid dependency developed. To the best of our knowledge, this is
the ®rst case reported of juvenile SLE presenting with LAHS.
KEY WORDS: Systemic lupus erythematosus, Lupus anticoagulant±hypoprothrombinaemia
syndrome, Paediatric, Haemorrhage.
Lupus anticoagulants (LA) are closely associated with
systemic lupus erythematosus (SLE) and have recently
been accepted by the American College of Rheumatology as a criterion for SLE w1x. Usually, antibodies to
phospholipid proteins (APLA) cause hypercoagulability, resulting in thrombotic events; however, sporadic
cases of bleeding diatheses have been described in the
presence of APLA associated with antibodies to coagulation factors. In particular, anti-factor II (FII) antibodies
have been reported as a rare cause of bleeding in lupus
patients w2±4x.
and hepatomegaly were detected. Swelling, redness,
warmth and extreme tenderness were noted in both
legs, more on the left, from the distal thighs and through
the calves. There was no evidence of arthritis. Also
noted was oozing of blood from venipuncture sites.
Laboratory investigations revealed a very high
erythrocyte sedimentation rate, anaemia and markedly
prolonged prothrombin time (PT) and activated partial
thromboplastin time (aPTT) (Table 1). Evaluation of
clotting factors revealed FII less than 5% (normal range
50±110%) and low levels of factors IX (17%) and XI
(29%). We found a neutralizing antiprothrombin antibody in 50 : 50 mixing studies, a phenomenon that has
been described only rarely w5x. The addition of 50%
healthy plasma to the patient's plasma did not restore
the clotting time. Further studies showed Coombs'
positive anaemia, markedly reduced complement levels,
the presence of antinuclear antibodies (ANA) (Table 1)
and negativity for anti-double-stranded DNA antibodies. Investigations of related factors of hypercoagulability, including protein C, protein S, anti-thrombin
III, activated protein C resistance (APCR) and the
FII mutation had negative results. An extensive infectious disease workup ruled out adenovirus, hepatitis A, B
and C, cytomegalovirus, Epstein±Barr virus, coxsackievirus and other enteroviruses.
Sonographic studies of both calves ruled out vein
thrombosis and Baker's cyst but detected increased
Case report
A 12-yr-old, previously healthy Yemenite±Jewish girl
developed painful swelling of her right leg, extending
from the popliteal fossa to the ankle. Ten days later she
was immobilized by similar but more severe symptoms
appearing in her left leg. Additionally, gingival bleeding
was noted, as well as the appearance of spontaneous
bruising on her arms and legs. The family history
revealed two paternal aunts with SLE.
On admission she was bedridden, suffering extreme
pain. Paleness, multiple ecchymoses on the extremities,
Submitted 19 April 2000; revised version accepted 14 December 2000.
Correspondence to: Y. Uziel, Pediatric Rheumatology, Sapir
Medical Center, 44281 Kfar Saba, Israel.
585
ß 2001 British Society for Rheumatology
586
J. R. Yacobovich et al.
echogenicity in the gastrocnemius muscles, consisting
of thickening and discontinuity of the muscle ®bres.
Magnetic resonance imaging of both calves demonstrated a resolving haemorrhage in the right gastrocnemius and a more recent diffuse haemorrhage in the
contralateral muscle (Fig. 1).
Because our adolescent girl demonstrated Coombs'
positive anaemia, positive ANA, low complement levels,
LA with evidence of an anti-prothrombin antibody, and
a strong positive family history, we proposed a diagnosis
of suspected juvenile SLE.
The patient was treated with oral prednisone (2 mgukg
per day in two divided doses) and physical therapy; a
signi®cant improvement was observed within 10 days
and clotting function tests normalized. After 1 month of
treatment the patient was completely asymptomatic, and
(a)
(b)
FIG. 1. MRI sagittal image of T1 (a) and T2 (b) sequences showing hyperintense area in the gastrocnemius muscle of the left leg,
demonstrating recent diffuse haemorrhage.
TABLE 1. Disease course, laboratory values and treatment
Months after onset
0
Laboratory values
Erythrocyte sedimentation rate (mmuh)
White blood cells (109ul)
Haemoglobin (gudl)
Coombs' test
Platelet (109ul)
International ratio
Prothrombin time (s)
Lupus anticoagulant: (normal range 021.2)
Russel Viper Venom Test (normal range 021.2)
FII (%)
anticardiolipin antibodies: IgG phospholipid (normally <23)
IgM phospholipid (normally <11)
ANA
C3 mg% (normally >90)
C4 mg% (normally >16)
Treatment
Prednisone (mguday)
HCQ (mguday)
130
5.4
8.3
4+
282
2.5
68
1.2
2.7
5
26.2
Neg
1u160
35
<5
60
0.25
1.5
3
3.5
6
30
9.5
9.6
1+
490
1.4
42
1.2
2.4
20
7.0
12.4
Neg
218
0.9
27
1.3
1.9
25
5.1
11.6
23
4.76
12.2
1u40
76
9
218
0.9
26
1.6
2.1
92
16.6
11.7
1u40
105
16
226
23.4
Neg
1u160
52
5
30
6.4
13.3
Neg
277
1.3
33
1.1
2.3
31
21.7
20
10
20
33
1.7
1.5
50
Neg
1u40
50
8
12.5
200
9
1.5
1.7
32
21.6
12
55
3.81
11.5
Neg
238
1.08
36
42
70
12
7.8
1u40
76
7
5
200
0
200
Juvenile SLE and intramuscular haemorrhage
a tapering-off schedule of prednisone was implemented.
Three months later, while the patient was on lowdose prednisone (<0.5 mgukg per day), mild bruising
reappeared accompanied by a slightly prolonged PT
and decreased FII levels (Table 1). Clinical and laboratory signs resolved after increasing the prednisone dose
and the addition of hydroxychloroquine (HCQ).
During the follow-up period of 1-yr, the patient
remained asymptomatic, off prednisone and on HCQ.
The FII level remained between 40 and 50%.
Discussion
Rare case reports of bleeding diatheses associated with
LA prompted studies to further the understanding of
their mode of action. Hypoprothrombinaemia was
found in conjunction with circulating anticoagulants in
patients with a tendency to bleed. The condition was
termed lupus anticoagulant±hypoprothrombinaemia
syndrome (LAHS). Further investigation revealed antiprothrombin antibodies, usually non-neutralizing, that
reacted with epitopes on the carboxy-terminal portion of
the FII molecule.
Paediatric cases of LAHS have been documented
w2±4, 6, 7x. Such cases can be divided into two major
categories: those with an underlying systemic disease
(usually SLE) and those with transient LAHS, which is
often related to a preceding viral disease, particularly
adenovirus w8x. In most of these patients the clinical and
laboratory manifestations resolved spontaneously. The
majority of reported cases of LAHS, however, were in
children with SLE and not among the postviral disease
group w4x. The SLE patients needed increased corticosteroid doses to ameliorate the clinical haemorrhage
symptoms and to normalize clotting abnormalities
w2±6x. Azathioprine and intravenous immunoglobulins
have been used occasionally as steroid-sparing agents
w3, 4, 9x.
Prompt and close follow-up is needed in these patients
in order to keep the delicate balance between bleeding
and clotting. The low concentration of FII probably
protects the patients from the thrombotic events associated with APLA. When the level of FII is increased,
indicating lower levels of anti-prothrombin antibodies,
the risk of thrombosis due to the presence of APLA
587
is increased w10x. We elected to add HCQ as additive anti-in¯ammatory and possibly thromboembolic
prophylaxis.
In summary, our patient presented a case of paediatric LAHS as the ®rst manifestation of juvenile SLE.
Close follow-up is indicated in order to maintain the
delicate balance between the haemorrhagic and thrombophilic tendencies, along with periodic screening for
additional manifestations of SLE.
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