Glanzmann thrombasthenia

Abstract

Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding syndrome affecting the megakaryocyte lineage and characterized by lack of platelet aggregation. The molecular basis is linked to quantitative and/or qualitative abnormalities of alphaIIb beta3 integrin. This receptor mediates the binding of adhesive proteins that attach aggregating platelets and ensure thrombus formation at sites of injury in blood vessels. GT is associated with clinical variability: some patients have only minimal bruising while others have frequent, severe and potentially fatal hemorrhages. The site of bleeding in GT is clearly defined: purpura, epistaxis, gingival hemorrhage, and menorrhagia are nearly constant features; gastrointestinal bleeding and hematuria are less common. In most cases, bleeding symptoms manifest rapidly after birth, even if GT is occasionally only diagnosed in later life. Diagnosis should be suspected in patients with mucocutaneous bleeding with absent platelet aggregation in response to all physiologic stimuli, and a normal platelet count and morphology. Platelet alphaIIb beta3 deficiency or nonfunction should always be confirmed, for example by flow cytometry. In order to avoid platelet alloimmunisation, therapeutic management must include, if possible, local hemostatic procedures and/or desmopressin (DDAVP) administration. Transfusion of HLA-compatible platelet concentrates may be necessary if these measures are ineffective, or to prevent bleeding during surgery. Administration of recombinant factor VIIa is an increasingly used therapeutic alternative. GT can be a severe hemorrhagic disease, however the prognosis is excellent with careful supportive care.

Figure 1

Schematic representation of the structure of the GPIIb (αIIb) gene (ITGA2B) together with a representative spectrum of the types of genetic abnormalities that give rise to Glanzmann thrombasthenia (GT). The defects responsible for variant forms of the disease are in blue type, those which are prevalent in ethnic groups are in green. Asterisks indicate the number of times that the same genetic defect has been described in apparently unrelated families. For a continually updated list of defects please consult the ISTH database . UTR: untranslated region, del = deletion, ins = insertion, inv = inversion, term = premature termination, stop = stop codon. For simplicity, the initial genetic defect is highlighted. Frameshifts and aberrant splicing are not always noted.

Figure 2

Schematic representation of the structure of the GPIIIa (β3) gene (ITGB3) together with a representative spectrum of the types of genetic abnormalities that give rise to Glanzmann thrombasthenia (GT). Note that abnormalities are abundant in both αIIb and β3 genes and that no parts of either gene appear to be exempt. For further information see the legend to Figure 1.