Thrombotic thrombocytopenic purpura (TTP) is well
described in adults, but there are scattered case reports and case
series in children(1,2). Recent improvements in the understanding of the
fundamental lesion in TTP have led to dramatic improvements in its
diagnosis and treatment(3). We report a case in a child who responded to
aggressive therapy and briefly review the current literature on TTP.
Case Report
A 6-year-old boy presented with pro-gressive pallor
for one month. His hemoglobin (Hb) was 5 g/dL, reticulocyte count was
2.5% and serum creatinine was 2.5 mg/dL. He received two blood
transfusions. After the second transfusion he became disoriented and was
referred to our hospital. At admission, he was febrile, his heart rate
was 110/min and his blood pressure was 110/70 mm Hg. He had a few
petechiae; his respiratory, cardiovascular and abdominal examination was
normal. His higher mental functions were grossly abnormal with
fluctuating consciousness, but his cranial nerve examination, motor and
sensory system examination were within normal limits. Total leucocyte
count was 7700/cu mm and platelet count was 30,000/cu mm. Peripheral
smear showed schistio- cytes, suggesting microangiopathic hemolytic
anemia (MAHA). Serum lactate dehydro-genase (LDH) was 782 units, serum
creati-nine was 2.9 mg/dL, total serum bilrubin was 4.0 mg/dL with a
direct of 0.75. Prothrombin time was 28s against a control of 12s, PTT
was 32s (control 14s) and fibrin degradation product (FDP) was 40U. Our
initial clinical diagnosis was incompatible blood transfusion reaction
with disseminated intravascular coagulation. Other post infec-tious
causes like dengue and leptospirosis were ruled out by serology. Over
the next few hours of admission, he developed nasal, oral and IV site
bleeds, hematemesis, melena, and pulmonary hemorrhage. He received
several units of fresh frozen plasma, platelet concentrates and fresh
whole blood. His platelet counts decreased further and he continued to
bleed profusely though PT, PTT became normal. He was electively
ventilated. We reviewed our diagnosis. In view of micro-angiopathic
hemolytic anemia, thrombocytopenia, diffuse CNS dysfunction and PT, PTT
which was easily corrected, a diagnosis of TTP was considered. High dose
steroids and plasma-pheresis was started. Over the next 10 days with
five sittings of plasmapheresis, his bleeding gradually decreased, his
platelet counts rose to1.8 lakh/cu mm. He was weaned off from
ventilator. After 3 days he had a relapse. He developed a massive left
thalamic bleed with intraventricular extension with bilateral posterior
territory infarction with tentorial herniation. His platelet count at
this time was 19,000 and his PT was 52/12. Neurosurgical opinion was
taken and he was treated conservatively with elective hyper-ventilation,
antiedema measures and fresh frozen plasma. IV immunoglobulin was
planned but his platelet counts picked up rapidly to 70,000/cu mm. Over
the next few days, his general and neurological condition improved. He
had a residual right hemiparesis with aphasia. He was slowly weaned off
from ventilator and feeds and physiotherapy were started.
At discharge on day 30 there was no bleeding, power
in right upper and lower limb was grade 2. He was aphasic, platelet
counts were 2.9-lakhs/cu mm. At one month after discharge, power in
right upper and lower limb is grade 4. He can walk with support and
speak 20 words. Higher mental functions have nearly come to normal. His
platelet counts are 1.7 lakhs/cu mm.
Discussion
Our differential diagnosis in this child included TTP
and post transfusion dis-seminated intravascular coagulation. This child
had MAHA and elevated creatinine before transfusion. This could have
been a sub acute onset of TTP(4). When he came to us, all the criteria
for TTP were fulfilled including MAHA, thrombocytopenia, fever, diffuse
neurological deficits, and mild renal involve-ment. TTP and hemolytic
uremic syndrome (HUS) may at times be confused because the clinical
spectrum is over-lapping(1). However, if the neurological symptoms are
over-whelming like in our patient, TTP is diagnosed, but when renal
involvement including oliguria, hypertension and progressive azotemia
are predominant, HUS is diagnosed. Our patient never had oliguria or
hypertension and azotemia resolved in a few days; hence TTP is a more
likely possibility than HUS. Two organs which are absolutely or
relatively spared in TTP/sporadic HUS are the lung and liver
respectively(5). Theoretically, protease levels in blood which are
absent in TTP and present in HUS help in differentiating the two
conditions but this is possible only in few laboratories(3). DIC is
considered whenever PT, PTT, FDP are grossly deranged, whereas in TTP
they are mildly abnormal, easily corrected or normal.
We now briefly review the recent developments in the
pathogenesis of TTP. The disease was first described by Moscowitz in
1924 in a 16-year-old girl who presented with pallor, petechiae, and a
rapidly fatal coma(6). The terminal capillaries and arterioles of this
child were filled with hyaline thrombi without perivascular
inflamation(3). In the 1980’s plasma of patients with chronic relapsing
TTP were found to have large multimers of von Willibrand factor unlike
normal plasma(7). Since then many workers have proved that a
metaloprotease is required to cleave these large multimers of vWF and
this protease is consistently deficient in the plasma of patients with
TTP(8). This deficiency may be a congenitally inherited mutation in the
ADAMTS-13 gene as seen in relapsing TTP or acquired due to the
development of autoantibodies against this vWF cleaving protease.
Conditions and drugs associated with the development of TTP include HIV,
pregnancy, bartonella infection, ticlopidine etc.(3,4). The
clinical pentad of TTP is micro-angiopathic hemolytic anemia,
thrombo-cytopenia, pyrexia, diffuse CNS involve-ment, and azotemia. The
incidence of various symptomatology in TTP include fever (60%), rash,
headache, fatigue, malaise, altered mental status (36%), seizures (16%),
hemi-plegia (12%), paresthesia (4%), abdominal pain (24%), arthralgias.
Treatment of a single acute episode of TTP includes
infusion of large volumes of protease containing plasma products over
days or weeks. Plasmapheresis is useful in removing autoantibodies and
unusually large multimers of vWF. Two randomized control trials have
demonstrated the superiority of plasma exchange over plasma infusion(9).
Replace-ment of the protease in children with chronic relapsing TTP with
only a few units of fresh frozen plasma, cryosupernatant or plasma
treated with solvent or detergent induces a prompt response. Other drugs
used include vincristine and cyclosporine(10). The mortality rate is
approximately 95% for untreated cases and survival rate is 80-90% with
early diagnosis and treatment with plasma-infusion and plasma-exchange.
In a randomized trial, Rock and colleagues reported a mortality rate of
22% among persons who underwent plasma exchange compared with mortality
rate of 83% among patient who underwent plasma-infusion(3). One third of
patients experience a relapse within following 10 years
Contributors: BS carried out clinical work and
drafted the paper. GRP was consultant in charge of the patient,
supervised drafting of the paper and will act as guarantor of the paper,
PS and AM were involved in case management and review of the paper.
Funding: None.
Competing interests: None stated.
