Glanzmann thrombasthenia: genetic basis and clinical correlates

Abstract

G lanzmann 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 studies confirm the diagnosis. Management of bleeding is based on a combination of hemostatic agents including recombinant activated factor VII with or without platelet transfusions and antifibrinolytic agents. Refractory bleeding and platelet alloimmunization are common complications. 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 multidisciplinary care.

Thrombocytopathies: Not Just Aggregation Defects—The Clinical Relevance of Procoagulant Platelets

“…Typical bleeding manifestations are purpura, gum bleeding and menorrhagia, while gastrointestinal or central nervous system bleeding are less frequently reported [ 95 ]; bleeding after trauma or surgery might be severe [ 93 , 96 , 97 ]. Most patients are diagnosed in childhood, but heterozygous patients can reach adulthood being asymptomatic [ 93 ]; in general, the bleeding tendency in GT decreases with age [ 98 ].…”

“…Since a functional GPIIb/IIIa is required for efficient dense-granules release, in GT platelets an abnormal release might also be observed [ 104 , 105 ]. Laboratory findings include a normal platelet count, size and granularity, but a prolonged bleeding time [ 35 , 98 ]. PFA-100/200 assay shows a very prolonged closure time (>300 s), which is compatible with GT, but not specific [ 36 , 98 ].…”

“…Laboratory findings include a normal platelet count, size and granularity, but a prolonged bleeding time [ 35 , 98 ]. PFA-100/200 assay shows a very prolonged closure time (>300 s), which is compatible with GT, but not specific [ 36 , 98 ]. LTA is considered the gold standard method for the clinical diagnosis of GT [ 98 ].…”

Inherited platelet diseases with normal platelet count: phenotypes, genotypes and diagnostic strategy

“…Of the disorders covered by this review, GT is the most frequent and widely screened disease. 12 , 15 Genotyping has now identified several hundred disease-causing mutations in a constantly changing spectrum, so the classification of patients into type I and type II subgroups based on residual platelet IIb3 content should be updated to take into account mutation analysis. 18 , 19 From 2001, the year in which P2RY12 was first characterized, 10 newly identified genes include FERMT3 , ANO6 , RASGRP2 and EPHB2 thereby expanding the gene repertoire for IPD.…”

“…Procedures range from local measures to the use of platelet transfusions or recombinant activated FVII to stop major bleeding as well as the establishment of and adherence to standardized protocols for prophylaxis prior to surgery or childbirth. 15 , 91-93 A special case is type I GT in which the absence of IIb3 can lead to the formation of isoantibodies, making patients refractory to normal platelets.…”