Genetic platelet disorders are an expanding group of platelet abnormalities caused by single gene mutations. The clinical manifestations are usually mucocutaneous bleeding and range from moderate post-traumatic bleeding to spontaneous life-threatening hemorrhage. Patients may have low-to-normal platelet counts depending on the specific defect. Several defects also cause associated syndromes.
If platelet count low: immune thrombocytopenia, thrombotic thrombocytopenic purpura, if platelet count normal: use of antiplatelet agents
The most well-characterized syndromes are Glanzmann thrombasthenia (GT) and Bernard-Soulier (BS) syndrome, resulting from mutations of alphaIIbbeta3 (ITGA2B and ITGB3) and the GPIb-IX-V complex (GP1BA, GP1BB, and GP9), respectively. These are the primary surface receptors mediating aggregation and adhesion, respectively.
Platelet type, pseudo von Willebrand disease (VWD) results from a mutation in GP1b alpha (GP1BA), causing increased binding and clearance of von Willebrand factor.
Other known surface receptors defects: mutations in alpha2beta1 (ITGA2 and ITGB1) and GPVI (GP6), cause reduced collagen adhesion; P2Y12 (P2RY12) mutations cause abnormal secretion and response to ADP.
Wiskott-Aldrich syndrome (WAS) results from mutation of WAS. Microthrombocytopenia with abnormal platelet function in the setting of global immune dysfunction, X-linked thrombocytopenia (XLT) is a milder form.
Defects in protein trafficking and granule formation
Alpha-granule defects—Gray platelet syndrome caused by mutations in NBEAL2 (localized to 3p21.1-3p22.1), and Quebec platelet syndrome caused by tandem duplication of the urokinase plasminogen activator gene (PLAU)
Delta-granule defects—Hermansky-Pudlak syndrome: many genes identified so far (HSPS1, HPS3, HPS4, HPS5, HPS6, HPS7, HSP8, HSP9, AP3B1, DTNBP1, BLOC1S3, BLOC1S4, BLOC1S5, and BLOC1S6)
Scott syndrome results from defective regulation of phosphatidylserine on the platelet surface due to mutation of transmembrane protein 16F (TMEM16F), official gene name is ANO6 (anoctamin 6)
Defects in transcription factors FOXA2, HOXA11, GATA1, FLI1, RUNX1 cause familial thrombocytopenia and platelet dysfunction along with skeletal, immune, and other organ system defects.
Defects in platelet production: congenital amegakaryocytic thrombocytopenia (CAMT)—caused by mutations in thrombopoietin receptor gene (MPL); thrombocytopenia absent radius (TAR), caused by a mutation in RBM8A with a minimally deleted 200-kb region at chromosome band 1q21.1 that is necessary but not sufficient to cause TAR; MHY9 mutations result in defective myosin function, thrombocytopenia, and giant platelets.
Majority of known mutations are autosomal dominant inheritance. GT, BS, CAMT, and TAR are autosomal recessive. WAS and GATA-I are X-linked.
Not reported for known mutations.
Hemostatic challenges, such as menstruation, childbirth, and surgery, may unveil or worsen bleeding symptoms. Heat or humidity and illness may also affect bleeding symptoms.
Many genes or single-nucleotide polymorphism (SNP) associations have been reported, correlating to platelet count (ATXN2, NAA25, C12orf51, and PTPN11), platelet function (GP6, PEAR1, ADRA2A, PIK3CG, JMJD1C, MRVI1, and SHH), platelet lifespan (BCLXL), and other parameters. However, thus far no clinically relevant association has been identified.
Polymorphisms of cytochrome p450 gene CYP2C19 and COX-1 gene PTGS1 modulate platelet response to clopidogrel and aspirin, respectively. However, no clinical relevance has been demonstrated.
Diagnostic Criteria and Clinical Characteristics
Diagnostic evaluation should include at least one of the following (see Fig. 39-1 algorithm):
Complete blood count and peripheral smear review of all cell lines
Examination of platelet morphology
Platelet aggregation studies
Detailed family bleeding history
Detailed medication history