| VOLUME 20, NUMBER 6 |
NOVEMBER/DECEMBER 2007 |
CLINICAL CASE REPORT 297
Renal thrombotic microangiopathy and cerebral venous
thrombosis in a young man
P. P. VARMA, H. KHURANA, A. K. HOODA, V. MARWAHA, S. BADWALABSTRACT
We report a patient of primary catastrophic
antiphospholipid syndrome who presented with rapidly
progressive renal failure and seizures. He was detected to
have thrombotic microangio-pathy on kidney biopsy and deep
cerebral venous thrombosis. The patient was successfully
managed with anticoagulants, steroids, plasmapheresis and
cyclophosphamide.
Natl Med J India 2007;20:297ê9
INTRODUCTION
Antiphospholipid syndrome (APS), also known
as Hughes syndrome, is a prothrombotic state with an incidence
of 2%–5% in the general population. It is characterized by
arterial or venous thrombosis, recurrent foetal loss and
laboratory evidence of antiphospholipid (anticardiolipin)
antibodies (APLA) or lupus anticoagulant (LAC). APS is
classified into ‘primary’ when no underlying cause is
identified, and ‘secondary’ when it is associated with an
underlying cause, e.g. systemic lupus erythematosus (SLE),
drugs, infections or malignancy.1
The descriptive adjective ‘catastrophic’
was added to APS in 1992 by Asherson2,3
to highlight an accelerated form of this syndrome that caused
multiorgan failure. Patients with catastrophic APS (CAPS) have
clinical evidence of multiple organ involvement developing
over a very short period of time, histopathological evidence
of multiple small vessel occlusions, and laboratory evidence
of APLA, usually in a high titre. Renal thrombotic
microangiopathy and cerebral venous thrombosis have been
rarely reported in APS. We report here a patient of CAPS with
thrombotic microangiopathy of the kidneys and cerebral venous
thrombosis. To the best of our knowledge, no case with this
profile and outcome has been reported in the literature.
THE CASE
A 26-year-old man, non-smoker and with no history of
hypertension or diabetes, presented with painless progressive
swelling of both lower limbs and dull, throbbing headache for
1 week. He also had breathlessness on exertion and a weight
gain of 6 kg during this period. There was no history of
fever, decrease in urine output, facial puffiness, sore throat, drug intake, oral ulcers,
malar rash or photosensitivity.
On examination, his body mass index was
21.45 kg/m2 and he was afebrile with a
pulse rate of 106 per minute, blood pressure of 200/130 mmHg
and respiratory rate of 18 per minute. He had pallor and
bilateral pitting pedal oedema. Systemic examination was
normal.
Investigations revealed a haemoglobin value
of 7.1 g/dl with normal total, differential and platelet
counts; peripheral blood smear showed dimorphic anaemia with
presence of schistocytes; erythrocyte sedimentation rate was
68 mm after the 1st hour (Westergren) and C-reactive protein
was 12 mg/dl. Urine examination revealed 2+ proteinuria, 2–4
white blood cells, 6–8 red blood cells and granular casts. The
24-hour urinary protein was 783 mg. His blood urea nitrogen
was 78 mg/dl, serum creatinine 9 mg/dl, serum total protein
4.8 g/dl and serum albumin 2.6 g/dl. Liver function tests,
serum electrolytes, coagulation profile, chest X-ray and
electrocardiogram were normal. Ultra-sound of the abdomen
showed bilateral normal-size kidneys (right 9.7 cm and left
10.1 cm) with normal echogenicity.
In view of the normal-size kidneys,
progressively rising creatinine and hypertension, a clinical
diagnosis of rapidly progressive renal failure (RPRF) was
made. Over the next 2 days after hospitalization he became
oliguric and on day 3 he developed recurrent generalized
tonic–clonic seizures. Neurological examination showed post-ictal
stupor with no focal neurological deficit or signs of
meningeal irritation. He had a persistently high blood
pressure (210/130 mmHg) and required 7 antihypertensive drugs
in addition to nitroglycerine infusion. Non-contrast CT scan
of the head showed haemorrhages in both occipital lobes and
the left parietal lobe. MR venogram of the brain showed
multiple haemorrhages in the same areas and central venous
thrombosis (CVT) of the deep veins including inferior sagittal
sinus and transverse sinus (Fig. 1).
In view of RPRF and CVT, the possibility of thrombotic
microangiopathy was considered. The collagen profile including
anti-streptolysin O (ASO), antinuclear antibody (ANA), dsDNA,
cytoplasmic and perinuclear staining antineutrophil
cytoplasmic antibody (ANCA) were negative while complement
levels were low (C3 0.96 and C4 0.22) and cryoglobulins were
detected. LAC and APLA were positive on 2 occasions. Viral
markers including
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Fig 1. Initial MR venogram of the
brain (left) showing absence of inferior sagittal and
transverse sinuses, and follow up MR venogram after
treatment (right) showing recanalization of the
transverse sinus (arrow)
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anti-HCV, HBsAg and HIV were negative.
Coagulation parameters revealed deranged prothrombin time of
18 seconds against a control of 12.8 seconds and activated
partial thromboplastin time of 52 seconds against a control of
35 seconds. Renal biopsy showed glomeruli with fibrin thrombi
and fibrinoid necrosis in the hilar arterioles suggestive of
thrombotic microangiopathy (Figs 2 and 3).
Based on the above findings of involvement of 2 organ
systems over a short period of time with positive APLA and
LAC, a diagnosis of ‘probable CAPS’ was made. He was treated
with
0.5 g of methylprednisolone for 3 days along with low
molecular weight heparin (Enoxaparin 40 mg subcutaneously
twice a day). Oral anticoagulation with acitrom was started a
week later and heparin was discontinued once the target
international normalized ratio (INR) of 2.5 was achieved. Oral
steroids were continued at a dose of 0.5 mg/kg/day in addition
to antihypertensives and
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Fig 2. Photomicrograph
showing fibrinoid necrosis in the hilar arteriole (H&E
´200) |
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Fig 3. Photomicrograph showing microthrombi in the
glomeruli (Massons trichrome stain, ´200)
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anticonvulsants. Since the renal functions
showed no improvement over the next 3 weeks, he had daily
plasmapheresis for 7 days and was pulsed with intravenous
cyclophosphamide. He remained dependent on dialysis for the
next 6 weeks during which he was continued on oral steroids,
oral anticoagulants and monthly cyclo-phosphamide pulses. He
started showing gradual improvement 10 weeks after onset—his
urine output started increasing, blood pressure control became
easier, creatinine showed a decline and he became dialysis
independent 11 weeks after onset of illness.
Examination at the last follow up 6 months after onset of
illness showed no pallor or oedema, a blood pressure of 140/80
mmHg and no neurological deficit. His serum creatinine was 3
mg/dl and he was on oral anticoagulants and 3 antihypertensive
drugs. Follow up MR venogram of the brain showed a patent deep
cerebral venous system (Fig. 1).
DISCUSSION
APS is not an uncommon condition but CAPS develops in <1% of
these patients and has a mortality of 50%.4
Till date, 250 patients of CAPS have been reported, of whom
41% were associated with primary APS. Patients may develop
CAPS de novo, without any previous history of
thrombosis.
Asherson classified CAPS into ‘Definite CAPS’ when there
was evidence of involvement of 3 or more organs, systems or
tissues simultaneously or in less than a week and ‘Probable
CAPS’ when only 2 organs, systems or tissues are involved in
the presence of APLA and histopathological evidence of small
vessel occlusion in at least 1 organ or tissue.5
Some of the features of CAPS––thrombotic
microangiopathy, haemolytic anaemia, thrombocytopenia, and
involvement of the central nervous and renal systems also
occur in haemolytic uraemic syndrome—thrombotic cytopaenic
purpura (HUS–TTP) syndrome, malignant hypertension,
heparin-induced thrombocytopenia and the haemolytic anaemia,
elevated liver enzymes and low platelet count (HELLP)
syndrome.6 The
histological features common to all these conditions include a
gamut of lesions involving the glomeruli and blood vessels.
The arteriolar changes are primarily arteriolar narrowing due
to swelling of endothelial cells and subendothelial space
along with infiltration of the arteriolar wall by fibrin (fibrinoid
necrosis). The term fibrinoid necrosis is probably a misnomer
as there is no true necrosis but the lesions are related to
increased vascular permeability and non-specific trapping of
plasma proteins including fibrin in the vascular wall, seen
most commonly in the hilum of the glomerulus. As the lesion
progresses the microthrombi merge with the arteriolar wall and
it is often difficult to distinguish between the microthrombi
and fibrinoid necrosis.7
Management of CAPS is challenging and
an algorithm for treatment has been proposed by Asherson.5
The proposed first-line therapy is with intravenous heparin
followed by oral anticoagulants. Corticosteroids, plasma
exchange and intravenous immunoglobulins are second-line
measures. Plasma exchange improves the outcome by removing IgG
aCL and b2-GPI
as well as cytokines such as interleukin (IL)-1, IL-6, tumour
necrosis factor (TNF)-a
and complement. The third-line therapy comprises
cyclophosphamide and newer experimental agents such as
rituximab, prostacyclines, ancrod and defibrotide.8
Cyclophospha-mide has been used in the treatment of both
primary anti-phospholipid antibody syndrome (P-CAPS) as well
as SLE-associated CAPS (SLE–CAPS). A meta-analysis by
Bayraktar et al. suggests that cyclophosphamide leads
to a worse outcome in patients with P-CAPS but it is
associated with improved survival in patients with SLE–CAPS.9
As our patient did not respond to anticoagulants and steroids
for 3 weeks, plasmapheresis and cyclophosphamide were added
and the response became apparent only after 10 weeks of
initiation of treatment. Even in the meta-analysis quoted
earlier, 19 patients with P-CAPS had been treated with
cyclophosphamide and these patients had a higher mean number
of organs involved than those who had not received
cyclophosphamide, which could be a factor responsible for a
worse outcome in this group of patients.
The description of our patient fits into ‘probable CAPS’ as
there was definite evidence of involvement of 2 systems
(kidney and brain) along with other criteria mentioned above.
Asherson in a series of 1000 patients with APS reported renal
manifestations (glomerular thrombosis, renal infarction, renal
artery thrombosis and renal vein thrombosis) in only 27
patients and CVT in only 7 patients.4 To
the best of our knowledge, no case with a combination of these
systems is described in the literature.
The peculiar features in our patient were severe
hypertension at presentation, which is unusual in CAPS, and
the late response to therapy. This case illustrates that
addition of second- or third-line therapy should be considered
when the response to first-line therapy is not apparent and
that the response may be delayed.
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Asherson RA. The catastrophic
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Piette JC, Cervera R, Levy RA, Nasonov
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Espinosa G, Bucciarelli S, Cervera R,
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Luszik Z, Silva FG. Haemolytic uremic
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Philadelphia:Lippincott Raven; 1998:1004–48.
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Cervera R, Asherson RA, Font J.
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Bayraktar UD, Erkan D, Bucciarelli S,
Espinosa G, Asherson R. The clinical spectrum of
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presence of lupus. J Rheumatol 2007;34:346–52.
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Army Hospital (Research and Referral),
Delhi Cantt,
New Delhi 110010, India
P. P. Varma,
A. K. Hooda
Department of Nephrology
H. Khurana
Department of Medicine
V. Marwaha
Department of Rheumatology
S. Badwal
Department of Pathology
Correspondence to A. K. HOODA;
ashokhooda@hotmail.com |
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