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Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):888-894
Glanzmann thrombasthenia: genetic basis and clinical correlates
Juliana Perez Botero,1 Kristy Lee,2 Brian R Branchford,3 Paul F Bray,4 Kathleen Freson,5 Michele P. Lambert,6 Minjie Luo,7 Shruthi Mohan,2 Justyne E. Ross,2 Wolfgang Bergmeier8 and Jorge Di Paola9 on behalf of the ClinGen Platelet Disorder Variant Curation Expert Panel
1Versiti and Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI, USA; 2Department of Genetics, University of North Carolina at Chapel Hill, NC, USA; 3University of Colorado School of Medicine, Department of Pediatrics, Division of Hematology/Oncology/Bone Marrow Transplant, Aurora, CO, USA; 4Molecular Medicine Program, Division of Hematology and Hematologic Malignancies, Department of Medicine, University of Utah, Salt Lake City, UT, USA; 5Center for Molecular and Vascular Biology, University of Leuven, Leuven, Belgium; 6The Children’s Hospital of Philadelphia and Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA, USA; 7Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Perelman School of Medicine, Philadelphia, PA, USA; 8Department of Biochemistry and Biophysics and UNC Blood Research Center, University of North Carolina at Chapel Hill, NC, USA and 9Division of Pediatric Hematology Oncology, Department of Pediatrics, Washington University School of Medicine in St. Louis, MO, USA
ABSTRACT
Glanzmann thrombasthenia (GT) is an autosomal recessive disorder of platelet aggregation caused by quantitative or qualitative defects in integrins αIIb and β3. These integrins are encoded by the ITGA2B and ITGB3 genes and form platelet glycoprotein (GP)IIb/IIIa, which acts as the principal platelet receptor for fibrinogen. Although there is variability in the clinical phenotype, most patients present with severe mucocutaneous bleeding at an early age. A classic pattern of abnormal platelet aggregation, platelet glycoprotein expression and molecular stud- ies confirm the diagnosis. Management of bleeding is based on a combi- nation of hemostatic agents including recombinant activated factor VII with or without platelet transfusions and antifibrinolytic agents. Refractory bleeding and platelet alloimmunization are common complica- tions. In addition, pregnant patients pose unique management challenges. This review highlights clinical and molecular aspects in the approach to patients with GT, with particular emphasis on the significance of multi- disciplinary care.
Introduction
The Swiss pediatrician Eduard Glanzmann was the first to describe in 1918 a type of purpura that presented with normal platelet count and size in patients with absent/decreased clot retraction and prolonged bleeding time.1 In 1962, Caen and Cousin described the lack of platelet aggregation with multiple agonists,2 and a few years later correlated the platelet aggregation result with decreased platelet fibrinogen and a slight reduction in clot retraction in individuals with Glanzmann thrombasthenia (GT).3 The lack of one of the three major platelet surface glyco- proteins in GT was reported by Nurden and Caen in 1974;4 several other scientists subsequently identified this as the glycoprotein (GP) IIb/IIIa complex. Additional studies with more advanced glycoprotein imaging techniques provided evidence for the definition of two disease groups: type I with absent IIb/IIIa expression (<5% of normal) and type II with reduced expression (5-20% of normal GP IIb/IIIa).5 A third type (type III) has normal levels of integrin but the protein is non- functional.
Glanzmann thrombasthenia is considered a rare disease, defined in the United States as those affecting less than 200,000 individuals.6 The exact incidence has been difficult to calculate, but is estimated at one in 1,000,000. With an autosomal recessive inheritance, males and females are affected equally. There is a world-
Correspondence:
JORGE DI PAOLA
dipaolaj@wustl.edu
Received: December 18, 2019. Accepted: February 7, 2020. Pre-published: March 5, 2020.
doi:10.3324/haematol.2018.214239
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