Hereditary macrothrombocyte disorders as known inherited macrothrombocytopenia (IMTP) are gaining greater recognition through advanced genetic and molecular studies. It is a heterogenous group of rare bleeding disorders characterized by abnormally giant platelets, thrombocytopenia, mild to moderate bleeding phenotypes, and/or positive family history and/or syndromic findings. The main characteristic features of macrothrombocytopenia are reduced platelet count (<150,000/µL) and significantly enlarged platelets (mean platelet volume (MPV) >12fL). Up to now, more than 30 genes linked to IMTP have been identified in nearly half of the patients with syndromic and non-syndromic IMTP. All inheritance patterns, including autosomal dominant, recessive, and sex-linked, have been described; however, nearly 50% of affected patients have unidentified genetic mutations or molecular abnormalities. The early and late stages of megakaryopoiesis and subsequent proplatelet formation and functional platelet are regulated by a large number of genes. Defects in these genes result in the dysfunction of several steps in megakaryopoiesis, proplatelet formation, and mature platelet. Many patients with non-syndromic IMTP are either asymptomatic or have minor bleeding manifestations and,detected incidentally with platelet count and morphology evaluation; however, patients with syndromic IMTP may be early diagnosed by specific clinical findings in addition to macrothrombocytopenia. Physicians should suspect IMTP if the following clinical and laboratory findings are present:

• a

  Hearing loss, cataracts, impaired renal function, elevated hepatic enzymes and Döhle-like bodies in neutrophil for non-muscle myosin heavy chain (MYH)-9 related disease,

• b

  Splenomegaly, bone marrow fibrosis, pale platelet and elevated serum levels of vitamin B12 for gray platelet syndrome,

• c

  Cardiac abnormalities, dysmorphic face, digital abnormalities and mental retardation for Paris Trousseau thrombocytopenia/Jacobsen syndrome,

• d

  Craniofacial defects, cardiac abnormalities, mental retardation, hypotonia, thymic aplasia, immune deficiency for DiGeorge syndrome/Velocardiofacial syndrome,

• e

  Xanthomas, premature atherosclerosis, arthritis, hemolytic anemia with stomatocytes, elevated plasma phytosterols for sitosterolemia.

No definitive guidelines are available for managing asymptomatic or mildly symptomatic patients with IMTP; however, platelet transfusion, antifibrinolytic therapy, and recombinant factor VIIa are usually recommended for those with severe bleeding manifestations or prior to surgery. Recently, it has been reported that thrombopoietin-receptor agonists can be used in some patients with MYH9 related disorders. The International Society of Thrombosis and Haemostasis’ scientific subcommittee on platelet physiology has published guidelines for diagnosing IMTP. In this approach, personal and family history, and physical examination are the key, followed by i) investigation of platelet count and morphology, ii) evaluation of platelet function by light transmission aggregometry, and iii) a panel of tests to assess granule contents and platelet surface markers by electron microscopy and flow cytometry studies. Further, next-generation sequencing has greatly expanded the molecular repertoire of IMTP, thus enabling the identification of new disorders.

Laboratory findings2,5,14,15

• a

  Abnormal complete blood count parameters, including platelet count and MPV may be detected incidentally in many cases. Platelet count below 150,000/µL and significantly increased platelet size (MPV >12 fL) are pathognomonic findings.

• b

  Abnormal platelet morphology may be observed in peripheral blood smear. In patients with IMTP, on average, 20% of platelets are large (>4µm diameter), and 12% are giant (>8 µm diameter) (normal platelets size are between 1.5 µm and 3 µm in diameter). As well, vacuolated platelets for GATA1 related disease, giant platelets for MYH9 related disease, biallelic Bernard Soulier syndrome (BSS) (GP1bα, GP1bβ and GP9-moderate to severe phenotype), GPS, FLNA related and TUBB1 related disease, large platelet for monoallelic BSS (GP1bα-mild phenotype), Paris-Trousseau/Jacobsen syndrome, GATA1 related-, ITGA2B- and ITGB3 related-disorders are diagnostic signs in peripheral blood smear.

• c

  Abnormal platelet function by light transmission aggregometry may be observed in patients with BSS (e.g., Ristosetin induced platelet aggregation response is absent).

• d

  Immunofluorescence testing with antibody against non-muscle myosin heavy chain reveals a spotty abnormal distribution of these molecules in patients with MYH9 disorders.

• e

  Flow cytometry reveals lack of GP1bα, GP1bβ and GP IX receptor in patients with BSS.

• f

  Two-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the surface radio iodinated platelet glycoproteins results show the absence of GPIb which identifies BSS.

• g

  Electron microscopy reveals abnormal ultrastructure of platelets (e.g., lack of alpha granules and inclusions in MYH9 disorders, giant fused alpha granules in Paris-Trousseau syndrome).

• h

  The next-generation sequencing technology has enabled comprehensive genetic testing using broad diagnostic panels for IMTP related disorders. Recent studies using whole-exome sequencing and whole-genome sequencing have greatly contributed to the early recognition of IMTP related genes and the detection of pathogenic variants within these genes.

v.Treatment: No definitive guidelines are available for managing asymptomatic or mildly symptomatic patients with IMTP; however, platelet transfusion, antifibrinolytic therapy, and recombinant FVIIa are usually recommended for those with severe bleeding manifestations.5,15 Recently, it has been reported that TPO-receptor agonists can be used in some patients with MYH9 related disorders.5

Conclusion: The International Society of Thrombosis and Haemostasis’ scientific subcommittee on platelet physiology has published guidelines for diagnosing IMTP. In this approach, personal and family history, and physical examination are the key, followed by i) investigation of platelet count and morphology, ii) evaluation of platelet function by light transmission aggregometry, and iii) a panel of tests to assess granule contents and platelet surface markers by electron microscopy and flow cytometry studies. Further, next-generation sequencing has greatly expanded the molecular repertoire of IMTP, thus enabling the identification of new disorders.