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Diagnosis and Management of Inherited Platelet Disorders
levels. These can complicate the interpretation of results.
17
Many sophisticated analyses include the study of platelet ultrastructure by
patients with congenital thrombocytopenia are identified only after electron microscopy
2,24
and the evaluation of protein phosphorylations
they have been considered as idiopathic thrombocytopenic purpura by Western blotting.
30
Study of megakaryocytopoiesis in
(ITP) and have received unsuccessful medications including culture starting with peripheral blood CD34+ cells can yield
corticotherapy, intravenous immunoglobulin G (IVIgG) or even information about defects in the formation and liberation of
splenectomy.
18
FT with or without giant platelets can be associated platelets from MKs.
31
Assaying plasma levels of thrombopoietin
with deafness, cataracts, kidney disease, eczema, infections, skeletal (TPO) is important in FT and can reveal an abnormality of the
abnormalities or cardiac disease. c-Mpl receptor.
32
Biological Tests In some diseases, diagnosis is relatively easy. Thus, an absence of
The first task is to perform a complete blood count and a differential aggregation with all physiological agonists, a normal platelet count
smear review. Automated haematology analysers recognise platelets and a normal response of platelets to ristocetin suggest GT.
1,6
by their size, so the presence of enlarged platelets may lead to an Diagnosis is confirmed by flow cytometric analysis of platelet αIIbβ3
underestimation of platelet count. Examining a slide stained with receptors, a particularly useful method for newborns, in whom the
May–Grunwald–Giemsa (MGG) will provide information about quantity of blood available is limited.
28
Thrombocytopenia with giant
platelet size, the presence of agglutinates and the platelet granule platelets and a specific absence of the response to ristocetin
content. This first simple screening can help to classify the patient corresponds to the profile of BSS, a finding confirmed by the absence
within the FT group.
19
or abnormal functioning of the GPIb-IX-V complex.
5
Further screening for a platelet defect is possible with one of the Macrothrombocytopenia and a normal response with ristocetin should
new mechanical devices that substitute for the bleeding time test.
20
be accompanied by MGG staining to look for Döhle bodies in
Here, the Platelet Function Analyzer (PFA-100, Dade Behring, Newark, leukocytes (MYH9-related disease) and also to verify the presence of
US) is the most widely used and is very sensitive for the more severe α-granules (absent in gray platelet syndrome).
19
A simple
platelet defects (especially those involving VWF), although its immunofluorescence test can point to MYH9-related disease.
33
usefulness for patients with mild bleeding syndromes is controversial.
21
Thrombocytopenia associated with small platelets suggests
Mostly, platelet function testing requires a specialised laboratory. Wiskott-Aldrich syndrome (WAS) or the X-linked thrombocytopenia
Platelet aggregation is a crucial test and involves measuring the light (XLT) form if the major clinical signs of WAS, such as infections and
transmittance through citrated platelet-rich plasma (PRP) agitated with eczema, are absent.
34
a soluble agonist.
22,23
Among the stimuli to be tested are ADP,
collagen, arachidonic acid (AA), epinephrine and ristocetin at both In FT it is important to verify the response of platelets to small doses of
high and weak doses. Thrombin-receptor-activating peptide (TRAP) ristocetin. A positive ristocetin-induced platelet aggregation (RIPA) with
is a useful alternative to thrombin in citrated PRP. Quality control is an upregulated interaction between GPIb and VWF is suggestive of type
essential and each laboratory must establish a response range for each 2B VWD or platelet-type VWD.
17,31
Molecular biology is the final step in
agonist in control subjects. establishing diagnosis for patients with rare platelet diseases.
35,36
It
constitutes the only method of identifying abnormalities of
When there is a lack of response to collagen, convulxin, a specific transcription factors and confirming the basis of new diseases.
agonist of GPVI, can be used to examine this receptor.
24
When
the platelet does not respond to AA, specific agonists of Management of a Platelet-based Bleeding Syndrome
the thromboxane A2 receptor such as U46628 are tested. An
abnormal aggregation with some but not all agonists implies Spontaneous Bleeding Syndrome
a defect within the signalling pathways responsible for the A number of factors must be taken into account when managing
transmission of signals from the agonist receptors. The release patients with a severe bleeding diathesis.
1,15
Close attention must be
of secretory pools of nucleotides from dense granules can be paid to children with scattered petechiae and superficial bruising. If
simultaneously measured with a Chronolog Lumi-aggregometer bleeding occurs, the child must immediately go to hospital.
(Chrono-Log Corporation, Havertown, US).
23
Clot retraction is another Local procedures to reduce blood loss need to be discussed with
useful test, while optical evaluation of platelet adhesion to specific experts at specialist centres. If blood loss is significant, transfusion of
substrates is starting to be used.
25
red cell concentrates is advised. Platelet transfusions are required for
extensive blood loss. It is important, if possible, to transfuse platelets
Platelet receptors can be quantified by flow cytometry using panels that have been prepared recently. A problem of platelet transfusion for
of antibodies directed against specific epitopes of the receptors.
26
patients lacking receptors is the development of isoantibodies directed
For the αIIbβ3 complex, monoclonal antibodies recognising against the missing protein.
1,37
The presence of inhibitors may
activation-dependent determinants enable an evaluation of its compromise the efficacy of new transfusions. Nowadays, it is common
functional capacity.
27
Measures of the surface expression to use recombinant FVIIa rather than platelets, especially when
of P-selectin or CD63 provide information about platelet secretion. inhibitors are present.
38,39
P-selectin is associated with the membranes of α-granules
of unstimulated platelets and translocates to the plasma membrane The occurrence of GI angiodysplasia in elderly patients with GT is a
of activated platelets.
28
Procoagulant activity can be measured problem. The clinical course often involves multiple episodes of GI
by assessing annexin-V binding to phosphatidylserine.
29
More bleeding and a resistance to classic treatments (plasma argon
EUROPEAN HAEMATOLOGY 2007 19
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