Familial Thrombocytosis Research Articles

Essential Thrombocythemia in Children and Adolescents.

Simple SummaryAmong chronic Ph-negative myeloproliferative neoplasms, essential thrombocythemia is found in children with low but increasing incidence. The diagnostic and clinical features do not completely overlap with ET of adult age. A significant number of cases, in fact, do not meet the criteria of clonality, and many cases require extensive clinical evaluation to exclude secondary, reactive forms. Therefore, histological analysis of bone marrow biopsy is necessary, and its use should be enforced. The clinical course appears to be more benign, at least within the first decades of observation, with the incidence of thrombotic events being much lower than in adults (4 % vs. 30%). Hemorrhages are mostly irrelevant. Therefore, the management should be carefully adapted to the individual patient, balancing the risk of future complications with long-term collateral effects of any drug. This review analyzes the peculiarities of the disease facing similarities and differences with adult scenarios.This paper reviews the features of pediatric essential thrombocythemia (ET). ET is a rare disease in children, challenging pediatric and adult hematologists alike. The current WHO classification acknowledges classical Philadelphia-negative MPNs and defines diagnostic criteria, mainly encompassing adult cases. The presence of one of three driver mutations (JAK2V617F, CALR, and MPL mutations) represent the proof of clonality typical of ET. Pediatric ET cases are thus usually confronted by adult approaches. These can fit only some patients, because only 25–40% of cases present one of the driver mutations. The diagnosis of hereditary, familial thrombocytosis and the exclusion of reactive/secondary thrombocytosis must be part of the diagnostic process in children and can clarify most of the negative cases. Still, many children present a clinical, histological picture of ET, with a molecular triple wild-type status. Moreover, prognosis seems more benign, at least within the first few decades of follow-up. Thrombotic events are rare, and only minor hemorrhages are ordinarily observed. As per the management, the need to control symptoms must be balanced with the collateral effects of lifelong drug therapy. We conclude that these differences concert a compelling case for a very careful therapeutic approach and advocate for the importance of further cooperative studies.

Clinical course of myeloproliferative leukaemia virus oncogene (MPL) mutation-associated familial thrombocytosis: a review of 64 paediatric and adult patients.

Familial thrombocytosis (FT) is a rare hereditary haematological disorder characterised by increased platelet count, usually caused by germ-line mutations in thrombopoietin (THPO), myeloproliferative leukaemia virus oncogene (MPL) or Janus kinase 2 (JAK2) genes, and can be associated with increased risk of thrombosis. We aimed to determine the yield of diagnostic tests, assess treatment received and describe the clinical course of MPL-associated FT. We retrospectively reviewed all paediatric and adult haematology patients diagnosed with MPL-related FT, who were seen in our clinics from March 2013 to February 2021. Of 64 eligible patients, 26 (41%) were aged <14years, while the remaining 38 (59%) patients were adults. The median (interquartile range) age at diagnosis was 20(33·5)years. In all, 26 tribes were represented in this cohort of 64 patients, out of which 31 (48%) patients belonged to two tribes. A total of 60 patients (94%) had thrombocytosis on blood count. Additional genetic tests, including myelodysplastic syndrome (MDS) gene panel, Philadelphia gene breakpoint cluster region-Abelson (BCR-ABL) and JAK2, were carried out for 52 patients and only one patient was positive for JAK2 mutation. In all, 21 (33%) patients were prescribed aspirin and seven (11%) were prescribed hydroxyurea. Overall, 63 (98%) patients did not develop any thrombotic or haemorrhagic event. There was no significant association of MPL-mutated FT with thrombosis or haemorrhage.

The MPL mutation.

Myeloproliferative neoplasms (MPN) patients share driver mutations in JAK2, MPL or CALR genes leading to the activation of the thrombopoietin receptor (TPOR) and downstream signaling pathways. JAK2 mutation drives all the three major entities of MPN (Polycythemia Vera, Essential Thrombocythemia and Primary Myelofibrosis) through the constitutive activation of TPOR, erythropoietin (EPOR) and colony stimulating factor 3 receptor (CSF3R) signaling. MPL is a proto-oncogene encoding for TPOR, the hematopoietic growth factor receptor of myeloid stem cells. MPL mutants induce the stable dimerization of TPOR that in turn activate JAK2 and the thrombopoietin pathway. The thrombopoietin pathway plays an important role in the development of megakaryocytes and platelets as well as the self-renewal of hematopoietic stem cells. Little wonder therefore that mutations of MPL result in thrombocytosis, leading to an abnormal MPL trafficking or receptor activation. Finally, some extremely rare germline genetic variants in MPL can induce MPN-like hereditary disease. Against this molecular background, TPOR is a key actor in the MPN development and MPL mutations are of major relevance to fully elucidate the molecular mechanisms underlying the clinical manifestations of MPN and to arrange novel therapeutic strategies aiming to disrupt the dysegulated signaling cascade. This chapter will focus on the role MPL in the pathogenesis of MPN and in familial thrombocytosis and will review these different subtypes of somatic and germline genetic variants by dissecting how they impact clinical phenotype.

Do we need antiplatelet therapy in thrombocytosis? Pro

SummaryThrombocytosis (defined as platelets &gt;450 × 109/l) has several aetiologies. After having excluded spurious thrombocytosis (e. g., due to microspherocytes, schistocytes, cryoglobulins, or bacteria), the differential diagnosis of true thrombocytosis encompasses secondary causes (as diverse as inflammation, infection, malignancy, iron deficiency, or asplenia), primary hereditary (rare forms of familial thrombocytosis) and primary acquired entities (either in the context of a myelodys-plastic syndrome or more frequently a myeloproliferative neoplasia). This manuscript addresses the following aspects: 1) diagnostic approach to thrombocytosis; 2) various mechanisms leading to a high platelet count; 3) potential of some of these mechanisms to modulate platelet function, producing hyper-reactive platelets and thus exerting a direct impact on the thrombotic risk; 4) indication of anti-thrombotic treatment in patients with thrombocytosis. There is a single prospective randomized clinical trial showing the benefit of acetyl-salicylic acid in polycythaemia vera. For other types of primary thrombocytosis and for secondary forms, treatment decisions have to be individualized according to the patient thrombotic and bleeding risks, taking into account the mechanism causing thrombocytosis. This manuscript discusses experimental and clinical data suggesting that besides patients with essential thrombocythaemia and other forms of primary thrombocytosis also those with thrombocytosis in the context of chronic inflammation, malignancy, or exposure to high altitude might benefit from anti-platelet treatment.

JAK2 mutations to the fore in hereditary thrombocythemia.

Acquired mutations of the gene that encodes the intracellular signalling molecule JAK2 are the most frequently observed disease-driving events of the common myeloproliferative neoplasms. A number of germline JAK2 mutations have recently been described in several kindred with the rare disease of hereditary thrombocythemia, also known as familial thrombocythemia or familial thrombocytosis. These inherited mutations are all located within the pseudo-kinase and kinase domains of JAK2 and have been shown to directly contribute to the thrombocythemic phenotype. Molecular characterisation of the resulting, aberrant signalling signatures may provide insights into genotype-phenotype relationships of both hereditary thrombocythemia and the common myeloproliferative neoplasms.

Advances in understanding the pathogenesis of familial thrombocythaemia

Familial thrombocytosis can be divided into two broad categories. The first includes inherited syndromes that affect only the megakaryocytic lineage with Mendelian inheritance, high penetrance and polyclonal haematopoiesis. The second category includes inherited predisposition to true Philadelphia-negative myeloproliferative neoplasms (MPN) and is characterized by low penetrance, clonal haematopoiesis and presence of somatic mutations such as JAK2 V617F. It must be underlined that these two categories represent two well separate entities, with different patterns of proliferation and different transmission modalities. This review will focus on the molecular pathogenesis of hereditary thrombocytosis, underlining those clinical pictures that are specifically associated with mutations in the genes of thrombopoietin or in its receptor. Moreover, we propose an approach for the diagnosis and therapy of these syndromes.

Molecular characterization of chronic myeloproliferative neoplasias in México

By using novel molecular markers, it is possible to gain information on both the classification and the pathophysiology of the chronic myeloproliferative neoplasia (MPN). In a group of 36 Mexican mestizo patients with MPN, we studied five molecular markers: The BCR/ABL1 fusion gene, the JAK2 V617F mutation, the JAK2 exon 12 mutations, the MPL W515L mutation and the MPL W515K mutation; 17 patients with essential thrombocythemia (ET), eight with polycythemia vera (PV), four with primary mielofibrosis (MF), five with undifferentiated MPN, one with primary erythrocytosis and one with familial thrombocytosis. Patients with the BCR/ABL1 fusion gene were excluded. Twelve individuals with the JAK2 V617F mutation were found; 11 of them had been clinically classified as PV and one had been classified as MF. One patient with the MPL W515L was identified with a clinical picture of ET. No individuals with either the MPL W515K mutation or the JAK2 exon 12 mutations were identified. Of the 17 individuals with ET, six (35%) had the JAK2 V617F mutation and one (6%) was found to have the MPL W515L mutation. Of the eight individuals with PV, five displayed the JAK2 V617F mutation, whereas of the four patients with MF, one had the JAK2 V617F mutation. The most consistent relationship was that between PV and the JAK2 V617F mutation (p=0·08). In the diagnosis and classification of the MPN, in addition to the newly identified molecular markers, clinical and laboratory data are still very important.

Hereditary thrombocytosis caused by MPLSer505Asn is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis

Background The MPL(Ser505Asn) mutation has been reported to be a cause of hereditary thrombocythemia. Recently, we detected this mutation in a large proportion of children with familial thrombocythemia, suggesting that in Italy the incidence of MPL(Ser505Asn) mutation could be underestimated. We extended the search for this mutation to all patients with essential thrombocythemia who had a positive family history for thrombocytosis or essential thrombocythemia. We identified eight Italian families positive for the MPL(Ser505Asn) mutation. Clinical and hematologic data were available for members of seven families, including 21 patients with a proven mutation and 20 relatives with thrombocytosis. Fifteen major thrombotic episodes, nine of which were fatal, were recorded among 41 patients. The thrombotic manifestation was 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 one case. Almost all patients over 20 years old had splenomegaly and bone marrow fibrosis, while these were rarely observed in patients under 20 years old, suggesting that these manifestations are associated with aging. Finally, the life expectancy of family members with thrombocytosis was significantly shorter than that of members without thrombocytosis (P=0.003). Conclusions Patients with familial thrombocytosis caused by a MPL(Ser505Asn) mutation have a high risk of thrombosis and, with aging, develop splenomegaly and bone marrow fibrosis, significantly affecting their life expectancy.

Familial thrombocytosis caused by the novel germ‐line mutation p.Pro106Leu in the MPL gene

Familial thrombosis (FT) has been described as a rare autosomal-dominant disorder, mostly caused by activating mutations of the thrombopoietin gene (THPO). Other cases of FT have been linked to one of two different germline mutations in the myeloproliferative leukaemia virus oncogene gene (MPL), which codes for the thrombopoietin receptor MPL. We studied an Arab family with two siblings with severe thrombocytosis by linkage analysis and obtained evidence for linkage to MPL. Sequencing revealed homozygosity for the novel MPL germline mutation p.Pro106Leu (c.317C > T) in the two siblings. Subsequently, homozygosity for p.Pro106Leu was identified in six further FT patients from three other Arab families. Of 18 heterozygous carriers, 14 had normal platelet counts, while four had mild thrombocytosis. Strong support for association of the novel MPL mutation p.Pro106Leu with development of familial thrombocytosis has been obtained. Overall, p.Pro106Leu was absent on 386 alleles of 193 healthy German controls and present on 14 of 426 alleles (3.3%) of 213 unrelated Arabs, which was statistically significantly different (P < 0.001, Fisher's exact test). We assume that p.Pro106Leu is a frequent MPL mutation in the Arab population, leading to severe thrombocytosis in homozygotes and occasionally to mild thrombocytosis in heterozygotes. In the families described the mode of inheritance could be regarded as autosomal-recessive with possible mild heterozygote manifestation rather than autosomal-dominant with high penetrance as usually seen in FT.

A Basic Classification and a Comprehensive Examination of Pediatric Myeloproliferative Syndromes

Myeloproliferative syndromes (MPSs) are clonal stem cell disorders resulting in excessive proliferation of one or more cell lineages. Since MPSs in children occur much less commonly than adults, one can argue that the biology and the categories of the various pediatric MPSs seem to be different from adults. Furthermore, confusion exists between pediatric MPS and other overlapping conditions, such as myelodysplastic syndrome. The authors' objectives were to develop a classification system with a list of disorders relevant to children and to characterize pediatric cases of MPS that were devised according to this classification. Based on the predominant proliferating cell lineage, the authors established a classification system for childhood MPS. Primary MPS was classified into granulocytic proliferation--chronic myelogenous leukemia (CML); monocytic--juvenile myelomonocytic leukemia (JMML); megakaryocytic--essential thrombocythemia (ET), familial thrombocytosis, transient myeloproliferative disorder of Down syndrome (TMD); erythrocytic--polycythemia vera, familial erythrocytosis; fibroblastic--idiopathic myelofibrosis (IMF); eosinophilic--idiopathic hypereosinophilic syndrome (IHES); and mast cells--mastocytosis. Secondary MPS was classified as non-clonal proliferation (eg, infections, drugs, toxins, autoimmune, non-hematologic neoplasm, and trauma), and these were excluded from the study. Next, the classification system was applied to the patient population at the authors' institution. One hundred two cases with primary MPS were identified between 1970 and 2001. Patients were evaluated for clinical manifestations, blood and bone marrow parameters, cytogenetics, and survival following different treatment modalities. Significant proportions of cases of childhood MPS (60%) were unique to the pediatric population and not seen in adults. The most common disorders were JMML (n = 31), TMD of Down syndrome (n = 30), and CML (n = 30); the other disorders were rare: four cases of ET, two of IMF, two of IHES, two of mastocytosis, and one primary erythrocytosis. In contrast to adults, MPS in children is more frequently treated with hematopoietic stem cell transplantation (HSCT), the only available curative option for most of these diseases. HSCT was particularly successful in the more recent cases due to more advanced techniques for HSCT. The authors found that all the cases could be easily classified. MPS in children is different from adult-type MPS in terms of biology, categories, classification, and prognosis.

Thrombocytosis and thrombocythemia

Thrombocytosis is caused by three major pathophysiological mechanisms: (1) reactive or secondary thrombocytosis; (2) familial thrombocytosis; and (3) clonal thrombocytosis, including essential thrombocythemia and related myeloproliferative disorders. Recent work has begun to elucidate the abnormal megakaryocytopoiesis of essential thrombocythemia, which is associated with paradoxically elevated plasma levels of thrombopoietin. The clonal nature of all cases of essential thrombocythemia has been challenged. Thrombotic complications are the major causes of morbidity and mortality in this disease. Indications for platelet cytoreduction and antiplatelet therapy, as well as complications of treatment, are being clarified.

Familial thrombocytosis as a recessive, possibly X-linked trait in an Arab family.

Familial thrombocytosis (FT) has previously been described as an autosomal-dominant disorder with manifestations similar to those of sporadic essential thrombocythaemia. We studied an Arab family consisting of four brothers, aged 4-8 years, who had either sustained markedly elevated (> 1000 x 109/l) or moderately elevated (> 500 x 109/l) platelet counts, two healthy sisters and their parents who had normal platelet counts. The four brothers with FT had normal plasma thrombopoietin levels and are currently not presenting with any thrombotic or haemorrhagic complications. Mutation analysis at the thrombopoietin gene (THPO) of the affected family members failed to detect the intron 3 G-->C splice mutation that had been described as causing FT. In addition, segregation analysis using a polymorphic CA marker revealed completely discordant THPO alleles among the affected brothers. We postulate the existence of a new locus for FT whereby the disease is transmitted as a recessive, possibly X-linked trait.

Translational pathophysiology: a novel molecular mechanism of human disease

In higher eukaryotes, the expression of about 1 gene in 10 is strongly regulated at the level of messenger RNA (mRNA) translation into protein. Negative regulatory effects are often mediated by the 5′-untranslated region (5′-UTR) and rely on the fact that the 40S ribosomal subunit first binds to the cap structure at the 5′-end of mRNA and then scans for the first AUG codon. Self-complementary sequences can form stable stem-loop structures that interfere with the assembly of the preinitiation complex and/or ribosomal scanning. These stem loops can be further stabilized by the interaction with RNA-binding proteins, as in the case of ferritin. The presence of AUG codons located upstream of the physiological start site can inhibit translation by causing premature initiation and thereby preventing the ribosome from reaching the physiological start codon, as in the case of thrombopoietin (TPO). Recently, mutations that cause disease through increased or decreased efficiency of mRNA translation have been discovered, defining translational pathophysiology as a novel mechanism of human disease. Hereditary hyperferritinemia/cataract syndrome arises from various point mutations or deletions within a protein-binding sequence in the 5′-UTR of the L-ferritin mRNA. Each unique mutation confers a characteristic degree of hyperferritinemia and severity of cataract in affected individuals. Hereditary thrombocythemia (sometimes called familial essential thrombocythemia or familial thrombocytosis) can be caused by mutations in upstream AUG codons in the 5′-UTR of the TPO mRNA that normally function as translational repressors. Their inactivation leads to excessive production of TPO and elevated platelet counts. Finally, predisposition to melanoma may originate from mutations that create translational repressors in the 5′-UTR of the cyclin-dependent kinase inhibitor–2A gene.

Benign familial microcytic thrombocytosis with autosomal dominant transmission.

Familial thrombocytosis is an extremely rare disorder, so far reported in only a handful of families. In the majority of cases the characteristics were of essential thrombocythemia. Most patients presented with a platelet count above 800,000/mm3, were diagnosed as having a myeloproliferative disease, and some required chemotherapy. We describe a benign form of familial thrombocytosis with autosomal dominant inheritance in five healthy members of three generations of a family, all of whom had moderate thrombocytosis within the range 422,000-662,000/mm3, characterized by low mean platelet volume. A careful medical history and a 5-year follow up of the subjects did not reveal any untoward clinical development. This variant of familial thrombocytosis is therefore of a benign nature. Possible mechanisms linking thrombocytosis with platelet microcytosis in this family are discussed.

Benign familial thrombocytosis

A 13-year-old girl was found to have a platelet count in excess of 4 million/microliters while being evaluated for a minor bleeding episode. Her father and two sisters also had thrombocytosis. All four affected patients were asymptomatic and had no clinical or laboratory evidence of a myeloproliferative disorder other than an elevated platelet count. This represents the second reported instance of benign familial thrombocytosis.