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Key Points

  • Disease summary:

    • 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.

  • Differential diagnosis:

    • If platelet count low: immune thrombocytopenia, thrombotic thrombocytopenic purpura, if platelet count normal: use of antiplatelet agents

  • Monogenic forms:

    • 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.

  • Family history:

    • Majority of known mutations are autosomal dominant inheritance. GT, BS, CAMT, and TAR are autosomal recessive. WAS and GATA-I are X-linked.

  • Twin studies:

    • Not reported for known mutations.

  • Environmental factors:

    • Hemostatic challenges, such as menstruation, childbirth, and surgery, may unveil or worsen bleeding symptoms. Heat or humidity and illness may also affect bleeding symptoms.

  • Genome-wide associations:

    • 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 ...

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