Patients with early aplasia are more likely to have frameshift or nonsense mutations and a complete loss of c-MPL. Missense mutations with residual c-MPL are often associated with a slower progression of the disease. (iii) Defects of the cytoskeleton and macrothrombocytopenia. MYH9-related diseases, affecting nonmuscle myosin heavy-chain IIA (myosin-IIA) show phenotypic variations associating macrothrombocytopenia with various combinations of Döhle-like bodies in leukocytes, nephritis, sensorineural hearing loss and cataracts [24]. Platelets are sometimes giant with ultrastructural modifications

that extend to MKs. Amino acid substitutions in the head domain with Ca2 + -ATPase activity are more likely see more associated with deafness and renal disease, while those affecting the rod or tail domain more frequently are restricted to a hematological consequence. Decreased myosin light chain phosphorylation and myosin-IIA function in MKs may affect MK migration and disturb the timing and extent of proplatelet formation. Macrothrombocytopenia may also occur in patients with mutations in FLNA encoding filamin A [25]. These mutations give multiple defects including periventricular nodular heterotopia, an X-linked dominant disease. Filamin A is a cytoskeletal attachment site for GPIbα thereby underlining the importance of the VWF–GPIb–filamin A axis in MK

development including the macrothrombocytopenia associated with the Bolzano GPIbα mutation. (iv) Wiskott–Aldrich syndrome (WAS). This X-linked disease combines microthrombocytopenia with

eczema, recurrent infections HIF activation due to immune deficiency Megestrol Acetate and a high incidence of autoimmunity and malignancy [reviewed in Ref. 2]. WAS platelets aggregate poorly and have a low granule number. Mutations in exons 1 and 2 can give hereditary X-linked thrombocytopenia, a milder form of the disease without infections, probably due to a high prevalence of missense mutations and residual protein. WASP is a key regulator of actin polymerization in hematopoietic cells; its deficiency induces premature proplatelet formation as a lack of actin-rich podosomes slows down MK migration to the vascular sinus. (v) Other causes. Severe autosomal dominant thrombocytopenia with normal sized platelets is given by mutations in the 5′-untranslated region of ANKRD26, a gene involved in mitochondrial metabolism [26]. Diagnosis of a suspected IPD starts with the case history and physical examination of the patient [1,3–5]. IPDs mostly manifest early in life with bleeding immediately after injury, primarily in skin (petechiae), from mucous membranes and the nose. Some patients develop life-threatening blood loss in the gastrointestinal or genitourinary tracts while intracranial haemorrhaging can occur. Bleeding score questionnaires are useful to evaluate mild bleeding symptoms, particularly in children that have yet to be hemostatically challenged.