The first THPO and MPL gene mutations were discovered in 1998 (Wiestner et al, 1998) and 2004 (Ding et al, 2004), respectively, but – due to their rarity – their clinical correlates have been better elucidated only over the last 2 years. Before the description of THPO mutations, several cases of ‘familial thrombocytosis’ or ‘familial thrombocythaemia’ were reported and patients were generally referred to as asymptomatic (Williams & Shahidi, 1991; Kikuchi et al, 1995; Cohen et al, 1997) or, at most, as suffering from minor haemorrhages (Schlemper et al, 1994). Thereafter, studies designed to expand into the molecular pathogenesis of hereditary thrombocytosis, investigated very small numbers of patients and did not detail neither clinical findings nor follow up data of affected members and of unaffected relatives. Subjects with hereditary thrombocytosis were mostly referred to haematologists for suspected MPN and– whenever investigated – the bone marrow histology was seemingly indistinguishable from that typical for ET. Nevertheless, in contrast to patients with ET, who have frequent vascular complications and possible evolution in fibrosis or acute leukaemia, patients with hereditary forms due to THPO mutations were regarded as asymptomatic (Kikuchi et al, 1995; Jorgensen et al, 1998; Kondo et al, 1998) and vascular complications were not reported in family members carrying the MPL-S505N mutation (Ding et al, 2004). As a result, the notion that hereditary thrombocytosis are benign diseases became widely accepted, having a vascular risk significantly lower than ET and rarely associated with mild splenomegaly (Dror & Blanchette, 1999; Skoda & Prchal, 2005). Overall, it appeared evident that subjects with hereditary thrombocytosis were significantly younger at diagnosis than patients with ET (Fernandez-Robles et al, 1990; Dror & Blanchette, 1999), thus demanding a specific diagnostic approach (Dame & Sutor, 2005; Teofili et al, 2007b, 2008). Liu et al (2008) identified in a Polish family with hereditary thrombocytosis the identical mutation previously described in a Dutch family (Wiestner et al, 1998). Overall, the authors evaluated 23 affected members belonging to the Polish and to the Dutch families carrying the same kind of THPO mutation, and compared them to a cohort of 107 patients with sporadic ET. This was the first study on hereditary thrombocytosis where haematological and clinical data were recorded on a sizeable number of patients. Surprisingly, all complications investigated, including venous thrombotic events, major vasomotor events, arterio-vascular events and haemorrhage occurred at comparable rates in both patients with THPO mutation and with ET. Stroke was the cause of death in two patients with THPO mutation aged over 70 years, but transient ischaemic attack (two patients, one on hydroxycarbamide treatment), deep venous thrombosis (one case) and miscarriage (one case) were reported also in patients aged less than 50 years. Furthermore, the authors reported that symptoms due to the impaired microcirculation, such as Raynaud phenomenon and erythromelalgia, responded well to aspirin and did not require cytoreductive treatment. Moreover, as investigated according to standard criteria for grading of marrow fibrosis (Thiele et al, 2005), no progression to myelofibrosis was observed in patients without cytoreductive treatment. In particular, the bone marrow histology of these patients is reminiscent of a chronic myeloproliferative disorder, with the increase and clustering of megakaryocytes, marrow hypercellularity and occasional mild increase in reticulin fibres. In addition, minimal or mild splenomegaly was documented in about one third of patients. Indeed, this study highlighted for the first time that persons with THPO mutation have an increased thrombotic risk, and, importantly, raised the issue of an appropriate therapeutic approach. Actually, the absence of JAK2 mutation in about half of the cases of ET leads to the fact that many patients with hereditary thrombocytosis are diagnosed and treated as having ET. This issue appears even more important if we consider that patients with hereditary thrombocytosis often undergo haematological investigation at a very young age. By investigating the presence of molecular markers of MPN in a series of 29 children with ET, we found the MPL-S505N mutation in 9 of 11 children with familial recurrence of thrombocytosis (Teofili et al, 2007a). The patients belonged to four unrelated families, suggesting a high frequency of the defect in the general Italian population. This finding prompted us to extended the search for this mutation to all patients with ET who had familial background of thrombocytosis or ET. We identified four additional families carrying the MPL-S505N mutation and, overall, detected the mutation in 21 patients: among them, 6 had received therapy with hydroxycarbamide or interferon for a pre-existing diagnosis of ET (Teofili et al, 2008). Haematological findings and clinical follow up of these patients and of 20 relatives with referred thrombocytosis were recorded. A high incidence of major thrombosis was documented (15 episodes; 9 casualties, including stroke in four cases, myocardial infarction in seven cases, fetal loss in two cases, deep vein thrombosis of the leg in one case and Budd-Chiari syndrome in a young female patient). Interestingly, except for two patients aged 76 and 80 years who experienced stroke during the follow up (both were on therapy with aspirin and hydroxycarbamide), all thromboses occurred before the diagnosis, in the absence of any antiplatelet therapy. During follow-up, many patients exhibited an increase of spleen size and a progressive bone marrow fibrosis, as evaluated by the standardized scoring system (Thiele et al, 2005). The histological picture was characterized in young patients by hypercellular bone marrow and in adult and elderly patients by overt bone marrow fibrosis, paralleled by the progressive decrease of platelet count and of haemoglobin level. Overall, we showed that the life expectancy of family members with thrombocytosis was significantly shorter than that of relatives without thrombocytosis, because they had an increased thrombotic risk and developed, with ageing, a clinical picture very similar to primary myelofibrosis. This observation is not so surprising if we consider that, in the field of MPN, ET patients positive for MPL-W515L/K exhibit bone marrow fibrosis and anaemia more frequently than those with wild type MPL (Beer et al, 2008; Vannucchi et al, 2008). However, Eyster et al (1986) had already described a family (five members over two generations) with elevated platelet counts; interestingly, two of the affected adults had suffered myocardial infarctions when aged 52 and 57 years, respectively, while two children were asymptomatic. Furthermore, the blood smear examination documented teardrop poikilocytosis in all three adult family members but not in children, suggesting that haematological findings could be affected by age (Eyster et al, 1986). Indeed, this description is highly evocative for an underlying MPL-S505N mutation. In respect to MPL-K39N and MPL-P106L polymorphisms, no thrombotic accidents were reported among the heterozygous carriers (Moliterno et al, 2004; El-Harith et al, 2009). Nevertheless, only analysis on larger samples of individuals belonging to specific ethnic groups will clarify if they might have a clinical impact in homozygotes or in heterozygous individuals exposed to thrombosis predisposing conditions.