villard.qxp 14/3/08 16:26 Page 24
Coagulation Disorders Platelet Disorders
bleeding, including intracranical haemorrhage (ICH) and gastrointestinal • if platelets appear very large (the size of red cells or even larger), this
(GI) bleeding. However, these patients tend to improve their platelet is compatible with Bernard-Soulier syndrome or the MYH9 defects;
counts with time. The dogma is that these patients will achieve normal • the presence of very small platelets is most consistent with
platelet counts within one year of birth. However, milder Wiskott–Aldrich syndrome, whether the complete syndrome or the
thrombocytopenia often persists and platelet levels may fall again during XLT form; and
adulthood. Signalling via the thrombopoietin receptor is abnormal, but • platelet clumping may suggest von Willebrand type IIb, although
the defect in the signalling pathway has not been defined. pseudothrombocytopenia would need to be excluded either by using
citrate as the anticoagulant or by making smears directly from a drop
Patients with velocardiofacial (VCF) syndrome and DiGeorge syndrome, of blood.
marked by cardiac abnormalities, parathyroid and thymus insufficiencies,
cognitive/learning impairment and facial dysmorphology (VCF only) have Microscopic examination of blood smears with May–Grünwald–Giemsa
deletions within human chromosome 22q11 and are collectively referred staining can also reveal light-blue leukocyte inclusions called Döhle-like
to as cardiac abnormality, T cell deficit, cleft palate and hypocalcaemia bodies in the cytoplasm of neutrophils, suggesting May–Hegglin
due to Chr22 deletion (‘CATCH22’) patients.
8
syndrome. In fact, while the NMMHC-IIA is homogeneously distributed
within granulocyte cytoplasm, it always presents a spotty distribution in
Patients with either Wiskott–Aldrich syndrome (WAS) or the MYH9-related diseases, and inclusion leukocytes correspond to these
X-linked thrombocytopenia (XLT) form of WAS usually have marked or spots. Immunocytochemical studies with antibodies directed against
severe thrombocytopenia and platelets that are smaller NMMHC-IIA represent a more sensitive method of detecting the irregular
than normal.
9
In addition to severe thrombocytopenia, WAS is a distribution of myosin.
11
A grey (uncoloured) appearance will signal the
significant congenital immunodeficiency syndrome that includes an Grey platelet syndrome, where thrombocytopenia is associated with a
inability to produce antipolysaccharide antibodies, resulting in a lack of α-granules.
predilection to pneumococcal sepsis. Eczema is common and
newborns and very young infants may present with a milk allergy and Other Abnormalities Suggesting
haematochezia. However, it is important to note that frequent Congenital Thrombocytopenia
infections may overlap with immune thrombocytopenias secondary to There are other clinical characteristics for recognising inherited
hypogammaglobulinaemia.
10
thrombocytopenia, but they are non-specific and have little predictive
value. Bleeding is not an important criterion as a large group of
High-tone hearing loss, renal failure and cataracts are suggestive of individuals with inherited thrombocytopenia may never have clinically
myosin heavy chain 9 (MYH9)-related macrothrombocytopenia significant spontaneous bleeding and will be identified during routine
syndromes.
11
Syndromes in this category include the May–Hegglin blood tests with mild/moderate thrombocytopenia (e.g. >20,000/µl).
anomaly, Fechtner syndrome, Sebastian syndrome and Epstein syndrome. However, any discordance between the severity and frequency of
The gene mutated in all four of these autosomal dominant bleeding and a relatively high platelet count is probably suggestive of a
macrothrombocytopenias was mapped to the chromosome 22q12–13, congenital functional defect. In the same way, when there is doubt as to
and has recently been identified as MYH9, encoding the non-muscle the reality of the immune mechanism, the determination of the platelet
myosin heavy-chain IIA (NMMHC-IIA). lifespan by isotopic study can help the clinician. Classically, reduced
platelet lifespan is suggestive of ITP. Nevertheless, it has recently been
Assessment of the Platelet Size on Peripheral Blood Smear shown in an animal model that deletion of the Bcl-x gene, involved in
As many of the CTPs have abnormal platelet morphology, careful apoptosis, induces a shortened platelet lifespan.
12
examination of the peripheral blood smear should be performed for all
patients with newly diagnosed thrombocytopenia. Newer automatic Conclusion
blood cell analysers are superior to the previous generation in their Despite careful clinical and biological analysis, we have to admit that a
recognition of platelets; nevertheless, the larger platelets are not substantial number of patients will not fit into any of the disorders
recognised, so the mean platelet volume obtained in standard described. In these cases it is reasonable to refer these patients to a
laboratories does not reflect the whole platelet population. The visual haematologist specialised in inherited platelet disorders. Future research will
inspection of the smear remains the ‘gold standard’ for platelet size in be focused on the analysis of the megakaryocyte lineage in these patients.
clinical practice. The recognition of giant platelets or microthrombocytes In the same way, the focus will now turn towards new rational therapies, for
helps to narrow the diagnostic possibilities. For example: example the use of new agonists of the thrombopoietin receptor. ■
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4. Loh ML, Rubnitz JE, TEL/AML1-positive paediatric leukaemia: 8. Ryan AK, Goodship JA, Wilson DI, et al., Spectrum of clinical represent a variable expression of a single illness, Medicine,
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Hematol, 2002;9345–52. deletions: a European collaborative study, J Med Genet, 12. Mason KD, Carpinelli MR, Fletcher JI, et al., Programmed
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24 EUROPEAN HAEMATOLOGY 2007
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