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DOI: 10.1097/01.wco.0000073939.19076.78
Abbreviations
FFP
HUS
TTP
VWF
Introduction
Thrombotic thrombocytopenic purpura (TTP) is a
potentially fatal disorder characterized by platelet
aggregates in the microvasculature, resulting in blood
vessel occlusion that gives rise to tissue ischaemia and
end-organ damage. The condition is rare and has a
reported incidence in adults of 3.7 per million [1].
Women are affected more frequently than men, with a
male : female ratio of 1 : 2 [2,3]. The diagnosis of TTP is
usually rst suspected clinically (Table 1). Previously
healthy individuals typically present with thrombocytopenia and microangiopathic haemolysis, in some cases
accompanied by neurological dysfunction, fever, renal
impairment, abdominal pain, chest pain and cardiac
arrythmias. Prompt diagnosis is mandatory so that
emergency treatment can be instituted immediately, as
delay may result in increased rates of treatment failure
and mortality [4].
Clinical types
Several clinical types of TTP are now recognized. The
most common type is acute single-episode TTP, in
which there are no subsequent relapses. More than a
third of patients who survive the initial episode of TTP
will subsequently relapse [5] and are dened as having
intermittent TTP. A small number of patients with
chronic unremitting TTP do not fully recover from their
initial event and have persistent thrombocytopenia and
continuing haemolysis. The rarest type is chronic
relapsing TTP. This is a congenital disorder, usually
presenting in infancy or childhood, and is characterized
by frequent episodes of thrombocytopenia and haemolysis at predictable intervals (approximately every 2130
days). Occasionally the initial episode or relapses are
precipitated by an identiable cause resulting in
secondary TTP. Secondary TTP occurs in association
with pregnancy, drugs (e.g. ticlodipine, clopidogrel, oral
contraception, cyclosporin, mitomycin C and quinine),
autoimmune disorders such as systemic lupus erythematosus, infection (particulary HIV) and post-bone marrow
transplantation.
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Pathophysiology
The formation of platelet aggregates in the microvasculature is implicated in the pathogenesis of classical TTP,
but what triggers this has not been entirely clear. Several
causes have been proposed, including defects of platelets or plasma components and endothelial cell damage.
However, evidence accumulated over recent years
suggests that the abnormal processing of von Willebrand
factor (VWF) multimers plays a central role in the
aetiology of platelet aggregation in TTP.
von Willebrand factor and thrombotic
thrombocytopenic purpura
Treatment
With the exception of two randomized, controlled trials,
one comparing plasma exchange with plasma infusion
[3], and the other comparing fresh frozen plasma (FFP)
with cryosupernatant [31 . .], no randomized clinical trials
ULVWF multimer
in linear form
ULVWF multimer
in globular form
released from
endothelial cells
ADAMTS13
Platelet
ADAMTS13 inactivated
by inhibitory antibody
(a) Normally, after their release from endothelial cells, unusually large von Willebrand factor (ULVWF) multimers are rapidly cleaved by ADAMTS13.
Under conditions of high sheer stress in the arterioles and capillaries, the ULVWF multimers unfold to a linear form exposing their cleavage sites for
ADAMTS13 and binding sites for platelets.
(b) In acquired thrombotic thrombocytopenic purpura, ADAMTS13 is inactivated by IgG autoantibodies. Under conditions of high sheer stress, the
biologically active ULVWF multimers are not cleaved and readily bind platelets and endothelium, resulting in the formation of platelet thrombi and small
vessel occlusion.
Conclusion
Recent advances in the knowledge of the pathological
mechanisms in TTP may help us to make a more rapid
diagnosis of TTP, to formulate prognostic indicators and
to adopt more rational and targeted therapeutic strategies. The development of a simple rapid assay for
ADAMTS13 activity and the degree of any inhibitory
activity that is routinely available will facilitate the
diagnosis of TTP (especially difcult cases), and may
help in predicting relapse and guiding therapy. The
elucidation of the complementary DNA of ADAMTS13
will hopefully lead to the production of recombinant
ADAMTS13, which could be used to treat congenital and
other types of TTP. Recombinant ADAMTS13 would be
potentially safer for patients by minimizing the exposure
and consequent infectious risk of blood components.
These advances need to be associated with improved
therapeutic strategies ultimately to improve the prognosis of this life-threatening disease.
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..
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