Glanzmann’s thrombasthenia (GT; 2017 ICD-10-CM: D69.1) is a rare autosomal recessive platelet function disorder caused by a quantitative or qualitative defect in platelet membrane glycoprotein IIb/IIIa (GPIIb/IIIa; integrin αIIb/β3), which functions as a receptor for fibrinogen, von Willebrand factor, vitronectin and fibronectin. In the absence of GPIIb/IIIa function, patients with GT show defects in platelet aggregation in response to physiological agonists and fibrin clot retraction. Platelet count and appearance in patients with GT are usually normal.1-3
GT was first described by Eduard Glanzmann in 19184, has an incidence of approximately 1 per 1 million births and affects both sexes.1,2 A mutation on chromosome 17 in either ITGA2B, coding for αIIb, or ITGB3, encoding the β3 subunit, can produce a range of phenotypes, depending on the nature of the mutation. A large number of mutations have been described in both genes; these appear to be more common in ITGA2B, however this may be attributable to the complexity of the locus. Reported mutations include missense, nonsense and splice-site mutations, as well as small deletions, insertions and inversions. Certain ethnic groups in which GT is common due to restricted gene pools tend to harbour an identical mutation.1-3
Acquired platelet disorders are common due to platelet-inhibiting medications or underlying morbidities. Acquired GT is the result of autoantibodies that recognise epitopes on GPIIb/IIIa and may also develop in patients with congenital GT as a result of allogeneic platelet transfusions used to treat bleeding episodes.2
The spontaneous mucocutaneous bleeding typical of patients with GT often manifests in early childhood and can be severe or even fatal. GT symptoms commonly include epistaxis, gingival and other mouth bleeding, menorrhagia, post-partum bleeding, easy bruising and subcutaneous or muscular haematomas, purpura and gastrointestinal bleeding. Haemarthrosis and central nervous system bleeding are less common. Surgery, trauma and dental extractions may also induce abnormal bleeding. Although fatal bleeding can occur at any age, the prevalence tends to decrease with age.1-3,5
The bleeding phenotype and severity in affected individuals is heterogeneous, with bleeding tendency changing over the course of a patient's life (usually becoming milder with age), and not always clearly related to mutation or platelet membrane protein levels, suggesting other genetic or environmental contributors. Depending on the genetic lesion, both homozygous and heterozygous mutations may be symptomatic, including those that affect GPIIb/IIIa function, expression, processing or display.1,2
GT severity is classified according to both GPIIb/IIIa production and activity2,5:
Type I GT
Type II GT
|Type III GT (variant)|| |
>20% GPIIb/IIIa, with dysfunctional properties
Due to bleeding severity, even epistaxis or menorrhagia may require platelet transfusions, as does cover for invasive procedures. Depending on the genetic background, exposure to allogeneic platelets may induce human leucocyte antigen (HLA) or GPIIb/IIIa-based autoimmunisation, rendering affected patients refractory to further therapeutic platelet transfusions.1,2
1. Poon MC, Di Minno G, d'Oiron R, Zotz R. New insights into the treatment of Glanzmann thrombasthenia. Transfus Med Rev 2016;30:92-9.
2. Solh T, Botsford A, Solh M. Glanzmann's thrombasthenia: pathogenesis, diagnosis, and current and emerging treatment options. J Blood Med 2015;6:219-27.
3. Nurden AT, Pillois X, Wilcox DA. Glanzmann thrombasthenia: state of the art and future directions. Semin Thromb Hemost 2013;39:642-55.
4. Glanzmann E. Hereditäre hämorrhagische Thrombasthenie. Ein Beitrag zur Pathologie der Blutplättchen. Jb Kinder Heilk 1918;88:1-42 113-41.
5. Sebastiano C, Bromberg M, Breen K, Hurford MT. Glanzmann's thrombasthenia: report of a case and review of the literature. Int J Clin Exp Pathol 2010;3:443-7.