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Coagulation Disorders Platelet Disorders
When Should Congenital Inherited Thrombocytopenia Be Suspected?
a report by
JF Viallard and P Nurden
French National Reference Centre for Inherited Platelet Diseases
In the case of an isolated chronic thrombocytopenia in an adult, the A family history of leukaemia suggests a familial thrombocytopenia–
diagnostic procedure is well established. First, several causes must be leukaemia (Tel-AML1) syndrome. It is important to indentify this as it is
ruled out. These include: the thrombocytopenia most often linked to malignancy.
4
Approximately
half of patients go on to develop a malignancy, two-thirds of which
• false thrombocytopenia diagnosis caused by platelet aggregation and are myeloid leukaemias and one-third of which are solid tumours.
clumping in the presence of ethylenediaminetetraacetic acid (EDTA) Recently, mutations in the AML1 (Runx1 or CBFA2) gene have been
anticoagulant; identified in affected members of families with autosomal dominant
• haematological malignancy and myelodysplastic syndromes; thrombocytopenia and abnormal platelet functions. AML1 encodes a
• viral infections (particularly HIV infection); transcription factor that is widely expressed in multiple haematopoietic
• autoimmune diseases such as systemic lupus erythematosus (SLE) lineages and that regulates the expression of a variety of haematopoietic
and/or antiphospholipid syndrome; genes. AML1 is particularly critical for megakaryopoiesis and is a frequent
• disseminated intravascular coagulopathy; target for chromosomal translocation in human leukaemia. Many of the
• thrombotic thrombocytopenic purpura; and patients affected, usually by point mutations in one allele, are
• splenic sequestration. predisposed to the development of acute myeloid leukaemia in adult life.
5
When these causes have been excluded, an antibody-mediated Response to Idiopathic Thrombocytopenic
mechanism is usually suspected and a diagnosis of immune Purpura Treatments
thrombocytopenic purpura (ITP) proposed. However, since Nurden and Another suggestive indicator for CTP is the ‘failure’ to respond to
Caen first identified the molecular defect in patients with ITP-specific therapy. This includes not only the use of intravenous
Bernard–Soulier syndrome in 1975,
1
the genetic causes of a growing immunoglobulins (IVIgs), steroids or other immune-modulating therapies
number of congenital thrombocytopenias (CTPs) have been elucidated, such as azathioprine, cyclophosphamide and rituximab, but also
a number of cases of CTP have been misdiagnosed as ITP and the splenectomy. While the lack of response in patients with CTP to these
patients have been subjected to splenectomy and/or cyclophosphamide, treatments is a universally accepted criterion based on anecdotal
among other inappropriate therapies. experience, an exact definition of lack of response has not been
established. For example, how much does the platelet count have to
Recent developments, especially in the identification of molecular increase by after treatment with IVIg to diagnose ITP and exclude CTP?
defects, have highlighted the characteristic features of congenital cases Arbitrarily, a peak platelet response to treatment >30,000/µl increase
of non-immune thrombocytopenia and improved our ability to identify from baseline would suggest that the case in question is not CTP.
them.
2
However, the specialised testing needed to diagnose platelet Conversely, a <10,000/µl peak increase is compatible with CTP, although
disorders is often restricted to specialised centres. The challenge for the it is just as compatible with a diagnosis of ‘refractory’ ITP.
6
Numbers in
physician is to identify patients who will benefit from specific between might favour ITP, but are even more ambiguous.
investigation procedures. The aim of this article is to assist clinicians in
distinguishing between genetic and immune thrombocytopenia. There A confusing feature is that some patients with CTP (with Wiskott–Aldrich
are at least four criteria that suggest CTP. The first is a family history of syndrome, for example) respond to corticosteroids, IVIg and/or
thrombocytopenia; the second, the absence of an increase in the platelet splenectomy either because there is an immunological component to the
count in response to ITP treatments; the third, the presence of special thrombocytopenia or because impeding the clearance mechanism for
associated features; and the fourth, an abnormal platelet size assessed by aberrant platelets helps to offset impaired platelet production. As
examination of a peripheral blood smear. ‘spontaneous’ fluctuation in the platelet count may occur (for example as
a result of a viral infection), the assessment of two treatment responses
Familial History of Thrombocytopenia is probably more helpful as a diagnostic criterion.
While non-specific, the most obvious feature suggesting CTP is the
presence of a family history of thrombocytopenia. This should Associated Features
immediately raise suspicion of CTP rather than ITP, especially if more than Some features, when identified in patients with persistent
two family members are involved and/or the family members are closely thrombocytopenia, suggest specific types of CTP. For example, bilateral
related. Nevertheless, a family history of ITP has also been reported in radial aplasia (often associated with other orthopaedic abnormalities of
familial autoimmune disease in which the family history may be more the ulna and knees) is suggestive of thrombocytopenia with absent radii
consistent with SLE.
3
(TAR) syndrome.
7
Patients with TAR have a high incidence of serious
© TOUCH BRIEFINGS 2007 23
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