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Diagnosis of essential thrombocythaemia (ET) is challenging in patients lacking JAK2/CALR/MPL mutations. In a retrospective evaluation of 320 patients with 'triple-negative thrombocytosis', we assessed utility of bone marrow histology (90.9% of patients) and myeloid gene panel (MGP, 55.6%). Supportive histology ('myeloproliferative neoplasm-definite/probable', 36.8%) was associated with higher platelet counts and varied between centres. 14.6% MGP revealed significant variants: 3.4% JAK2/CALR/MPL and 11.2% other myeloid genes. Final clinical diagnosis was strongly predicted by histology, not MGP. 23.7% received cytoreduction (17.6% under 60 years). Real-world 'triple-negative' ET diagnosis currently depends heavily on histology; we advocate caution in MGP-negative cases and that specific guidelines are needed., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)

Disease Overview: Atypical chronic myeloid leukemia (aCML) and myelodysplastic/myeloproliferative (MDS/MPN) neoplasms, not otherwise specified (NOS), are MDS/MPN overlap neoplasms characterized by leukocytosis, in the absence of monocytosis and eosinophilia, with <20% blasts in the blood and bone marrow., Diagnosis: aCML, previously known as aCML, BCR::ABL1 negative, was renamed as aCML by the ICC classification, and as MDS/MPN with neutrophilia by the 5th edition of the WHO classification. This entity is characterized by dysplastic neutrophilia with immature myeloid cells comprising ≥10% of the white blood cell count, with prominent dysgranulopoiesis. MDS/MPN-NOS consists of MDS/MPN overlap neoplasms not meeting criteria for defined categories such as chronic myelomonocytic leukemia (CMML), MDS/MPN-ring sideroblasts-thrombocytosis (MDS/MPN-RS-T), and aCML., Mutations and Karyotype: Cytogenetic abnormalities are seen in 40-50% of patients in both categories. In aCML, somatic mutations commonly encountered include ASXL1, SETBP1, ETNK1, and EZH2 whereas MDS/MPN-NOS can be further stratified by mutational profiles into CMML-like, MDS/MPN-RS-T-like, aCML-like, TP35-mutated, and "others", respectively., Risk Stratification: The Mayo Clinic aCML model stratifies patients based on age >67 years, hemoglobin <10 g/dl, and the presence of TET2 mutations into low-risk (0-1 points) and high-risk (>2 points) groups, with median survivals of 18 and 7 months, respectively. MDS/MPN-NOS patients have traditionally been risk stratified using MDS risk models such as IPSS and IPSS-R., Treatment: Leukocytosis and anemia are managed like lower risk MPN and MDS. DNMT inhibitors have been used in both entities with suboptimal response rates. Allogeneic stem cell transplant remains the only curative strategy but is associated with high morbidity and mortality., (© 2023 Wiley Periodicals LLC.)

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 <14 years, 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., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

In myeloproliferative neoplasms (MPN), JAK2V617F allele burden measurement has an impact on prognosis that helps in patient monitoring. Less is known about its usefulness in CALR-mutated cases. Additional mutations found by next-generation sequencing have also shown an impact on prognosis that may drive therapeutic choices, especially in myelofibrosis, but few studies focused on CALR-mutated patients. We performed a molecular evaluation combining next-generation sequencing with a myeloid panel and CALR allele burden measurement at diagnosis and during follow-up in a cohort of 45 patients with CALR-mutated essential thrombocythaemia. The bone marrow histology was also blindly reviewed in order to apply the WHO2016 classification. The most frequently mutated gene was TET2 (11/21 mutations). CALR type 1-like patients appear to have a more complex molecular landscape. We found an association between disease progression and CALR allele burden increase during follow-up, independently of additional mutations and WHO2016-reviewed diagnosis. Patients with disease progression at the time of follow-up showed a significant increase in CALR allele burden (+16·7%, P = 0·005) whereas patients without disease progression had a stable allele burden (+3·7%, P = 0·194). This result argues for clinical interest in CALR allele burden monitoring., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

Disease Overview: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T)., Diagnosis: MDS-RS is a lower-risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥ 15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes., Mutations and Karyotype: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations. Cytogenetic abnormalities are uncommon in both., Risk Stratification: Most patients with MDS-RS-SLD are stratified into lower-risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic transformation., Treatment: Anemia and iron overload are complications seen in both and are managed similar to lower-risk MDS and MPN. The advent of luspatercept, a first-in-class erythroid maturation agent will tremendously boost the ability to manage anemia. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains uncertain., (© 2019 Wiley Periodicals, Inc.)

Disease Overview: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS), now classified under myelodysplastic syndromes with RS (MDS-RS) and RARS with thrombocytosis (RARS-T); now called myelodysplastic/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T)., Diagnosis: MDS-RS is a lower risk MDS, with single or multilineage dysplasia (SLD/MLD), <5% bone marrow (BM) blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥ 450 × 10(9)/L and large atypical megakaryocytes (similar to BCR-ABL1 negative MPN)., Mutations and Karyotype: Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F, ASXL1, DNMT3A, SETBP1, and TET2 mutations; with ASXL1/SETBP1 mutations adversely impacting survival. Cytogenetic abnormalities are uncommon in both diseases., Risk Stratification: Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-International Prognostic Scoring System (R-IPSS). Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia. Both diseases have a low risk of leukemic TREATMENT: Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain., (© 2017 Wiley Periodicals, Inc.)

Refractory anemia with ring sideroblasts and thrombocytosis (RARS-T) shares overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). RARS-T is characterized by SF3B1 and JAK2 mutations and prognosis is considered to be better than MDS but not as good as MPN. The objective of the study was to identify predictors of survival in RARS-T. We analyzed clinical and laboratory variables in 82 patients and applied a 27-gene NGS assay to 48 marrow samples obtained at diagnosis. 94% of patients had ≥1 mutations; common mutations being: SF3B1 85%, JAK2V617F 33%, ASXL1 29%, DNMT3A 13%, SETBP1 13% and TET2 10%. In a multivariable survival analysis (n = 82), anemia (P = 0.02) [HB< 10 gm/dl: HR 2.3, 95% CI 1.2-4.6] and abnormal karyotype (P =.01) [HR 6.1, 95% CI 2.7-13.8] were independently prognostic for inferior survival. In patients with NGS information (n = 48), univariate analysis showed association between poor survival and presence of SETBP1 (P = 0.04) or ASXL1 (P = 0.08) mutations whereas the absence of these mutations (ASXL1wt/SETBP1wt) was favorable (P = 0.04); the number of concurrent mutations did not provide additional prognostication (P = 0.3). We developed a HR-weighted prognostic model, with 2 points for an abnormal karyotype, 1 point for either ASXL1 and/or SETBP1 mutations, and 1 point for a HB level < 10 gm/dl, which effectively stratified patients into three risk categories; low (0 points), intermediate (1 point) and high (≥2 points), with median survivals of 80, 42 and 11 months respectively (P = 0.01). In summary, we confirm the unique mutational landscape in RARS-T and provide a novel mutation-enhanced prognostic model., (© 2016 Wiley Periodicals, Inc.)

Disease Overview: Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include refractory anemia with ring sideroblasts (RARS) and RARS with thrombocytosis (RARS-T)., Diagnosis: RARS is a lower risk myelodysplastic syndrome (MDS) with dysplasia limited to the erythroid lineage, <5% bone marrow (BM) blasts and ≥15% BM RS. RARS-T is a provisional entity in the MDS/MPN (myeloproliferative neoplasm) overlap syndromes, with diagnostic features of RARS, along with a platelet count ≥450 × 10(9)/L and large atypical megakaryocytes similar to those observed in BCR-ABL1 negative MPN. Mutations and Karyotype: Mutations in the SF3B1 gene are seen in ≥80% of patients with RARS and RARS-T, and strongly correlate with the presence of BM RS; RARS-T patients have additional mutations such as, JAK2V617F (∼60%), MPL (<5%), and CALR (<5%). Cytogenetic abnormalities are uncommon in both RARS and RARS-T., Risk Stratification: Most patients with RARS are stratified into lower risk groups by the International Prognostic Scoring System (IPSS) for MDS and the revised IPSS. Disease outcome in RARS-T is better than that of RARS, but worse than that of essential thrombocytosis. Both RARS and RARS-T have a low risk of leukemic transformation., Treatment: Anemia and iron overload are complications in both diseases and are managed similar to lower risk MDS. Aspirin therapy is reasonable in RARS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs is uncertain. Case reports of RARS-T therapy with lenalidomide warrant additional studies., (© 2015 Wiley Periodicals, Inc.)

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., (© 2011 Blackwell Publishing Ltd.)

Familial and acquired erythrocytosis and thrombocytosis are characterized by myeloid lineage hyperproliferation, which is either single or multi-lineage in origin. The single lineage disorders exhibit Mendelian inheritance with polyclonal hematopoiesis and often arise from a single genetic defect. In contrast, the multi-lineage disorders exhibit complex patterns of inheritance with multi-genetic origins and clonal hematopoiesis. They have the potential to acquire JAK2 somatic mutations, but this is not the primary event. Identification of the disease-causing genes will enable better classification of familial and acquired erythrocytosis and thrombocytosis. Furthermore, it will provide an insight into the mechanisms regulating myeloid cell proliferation.

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.

Familial chronic myeloproliferative disorders are defined when in the same pedigree at least two relatives have a chronic myeloproliferative disorder (CMD) as polycythemia vera (PV), essential thrombocythemia (ET) or primary myelofibrosis (PMF). This condition should be distinguished from inherited disorders with Mendelian transmission and single haematopoietic lineage proliferation, named hereditary erythrocytosis and thrombocytosis. The recently discovered mutations in patients with CMD (V617F and exon 12 of JAK2 gene, MPL gene), and those identified in hereditary erythrocytosis and in hereditary thrombocytosis have improved our ability to discriminate these conditions. In familial CMD, the JAK2 mutations are acquired and occur as secondary genetic events. As both mutations of the JAK2 gene have been reported in the same pedigree, a genetic predisposition to the acquisition of the JAK2 mutations is supposed to be inherited. The prevalence of familial cases within CMD is at least 7.6%. The inheritance pattern of familial CMD is consistent with an autosomal dominant trait with decreased penetrance. The clinical presentation at diagnosis of patients with familial CMD does not differ from that of patients with sporadic CMD. In addition, patients with familial CMD develop the same type of complications (thrombosis and haemorrhage) and disease evolution (post-PV myelofibrosis, post-ET myelofibrosis and leukaemia) observed in patients with sporadic CMD. The 10-year survival is 83% for patients with familial PV, 100% for those with familial ET, and 30% for those with familial PMF. The aim of this review is to focus the state of the art of familial CMD and to offer an overview of inherited conditions causing erythrocytosis and thrombocytosis., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

MPLW515L/K and JAK2V617F can co-exist in myelofibrosis with myeloid metaplasia (MMM). The chronology of clonal emergence was studied in three such cases using serially stored bone marrow. At diagnosis, a major MPL515 mutant clone was accompanied by a minor JAK2V617F clone in all three instances. At 25 time points over a period of 4-8 years, allele burden fluctuated but remained high for MPLW515L/K and low for JAK2V617F. We conclude that MPLW515L/K and JAK2V617F are both early events in MMM and allele burden, rather than the mere presence of these mutations, might be relevant to phenotypic variation in myeloproliferative disorders.

Hereditary thrombocythaemia (HT) is an inherited autosomal dominant disorder. Recent studies reported six different mutations, four within the thrombopoietin (TPO) gene and two within c-Mpl (TPO receptor) gene in six unrelated families with HT. This study investigated the molecular basis of hereditary thrombocythaemia in an Israeli-Jewish family. We screened the genes for TPO and c-Mpl by amplification and sequencing of all the corresponding exons including exon/intron boundaries and promoters. In addition, plasma levels of TPO and erythropoietin (EPO) were measured. No abnormality in the TPO/c-Mpl genes has been identified in affected HT family members. Plasma TPO and EPO levels were found to be normal/low or normal respectively in the individuals affected. In conclusion, lack of a molecular lesion within either TPO or cMpl genes indicate that HT may be caused by factors other than TPO-cMpl axis in this family.

A 52-year-old man developed essential thrombocythemia (ET) with JAK2 V617F mutation after orthotopic liver transplantation (OLT). Retrospective analysis showed that, despite a low platelet count, the JAK2 mutation was already found at presentation 14 months before OLT. The high platelet count that would have been typical of ET might be masked by the cirrhosis-related hypersplenism. Thrombocythemia became obvious after OLT. The patient subsequently developed blastic transformation 12 months afterward, a process probably accelerated by the immunosuppression required for the OLT., ((c) 2006 Wiley-Liss, Inc.)

An association between an activating JAK2 mutation (JAK2(V617F)) and BCR/ABL-negative myeloproliferative disorders was recently reported in multiple simultaneous publications. In the current study, mutation analysis for JAK2(V617F) was performed in peripheral blood mononuclear cells (PBMC) from 157 patients with myelofibrosis with myeloid metaplasia (MMM) including 117 with agnogenic (AMM), 22 with postpolycythaemic (PPMM), and 18 with post-thrombocythaemic (PTMM) myeloid metaplasia. The detection rate for JAK2(V617F) was significantly higher in PPMM (91%; homozygous in 18%) compared with either AMM (45.3%; homozygous in 2.6%) or PTMM (38.9%; homozygous in 11.1%). Concomitant analysis in granulocytes (n=57) and CD34(+) cells (n=25) disclosed a higher incidence of homozygous JAK2(V617F) mutation but the overall mutation rate was similar to that obtained from PBMC. JAK2(V617F) was not detected in DNA derived from T cells (n=19). In AMM, the presence of JAK2(V617F) was associated with an older age at diagnosis and a history of thrombosis or pruritus. Multivariate analysis identified only age and the Dupriez prognostic score as independent prognostic factors; JAK2(V617F) had no prognostic significance. In conclusion, JAK2(V617F) is a myeloid lineage-specific event, its incidence in MMM is significantly higher with an antecedent history of polycythaemia vera (PV), and its presence in AMM does not affect prognosis but is associated with PV-characteristic clinical features.

Familial thrombocytosis (FT) is an inherited disorder with clinical presentations similar to essential thrombocytosis (ET). In several pedigrees, overproduction of thrombopoietin (TPO) has been shown to be responsible for the disease. We report herein three cases of thrombocytosis in three successive generations. All cases had increased serum TPO levels. Sequence analysis of TPO gene and transmembrane domain of c-MPL, known as the TPO receptor, revealed no mutations. Platelet c-MPL expression was similar or slightly increased as compared to normal volunteers. These data suggest that altered regulation of the TPO gene might be involved in the pathogenesis of FT., (Copyright 2004 Wiley-Liss, Inc.)

Most cases of urticaria pigmentosa are confined to the skin, but visceral involvement and/or haematological abnormalities have been observed. It is still a matter of debate whether all forms of mastocytosis are true neoplasias or reactive hyperplasias. Familial inheritance of urticaria pigmentosa is rare. We report on a fraternal set with urticaria pigmentosa as part of a systemic mastocytosis. The first patient additionally revealed persistent thrombocytosis and splenomegaly. His brother developed urticaria pigmentosa, intermittent diarrhoea, hepatomegaly and asthma bronchiale associated with trisomy 21 (Down's syndrome). The association of mastocytosis with thrombocytosis has seldom been described. In our patient it preceded the development of systemic mastocytosis. The association with Down's syndrome has not been reported until now.

In this paper are presented four cases, with unusual chromosomal abnormalities, identified at the first presentation, among over 100 patients with myeloid and lymphoid acute and chronic leukemias cytogenetically investigated. The complexity and nature of cytogenetic abnormalities was in direct relationship with the disease evolution. The first case, a 22 years old man with acute lymphoblastic leukemia type L3, exhibited many structural changes in bone marrow cells with diploid number of chromosomes: del(3)(q26); del (5)(p13); t(8;14) (q24;q32); del(9)(p11q11);inv(15)(p12qter). The second case, a 62 years old woman, diagnosed as poorly differentiated acute leukemia, refractory to treatment, showed hiperdiploidy (48-54 chromosomes) and 3-4 markers derived from chromosomes 5 and 12. The third case, a young man of 27 years old, diagnosed as acute myeloid leukemia, apart of Philadelphia chromosome, presented trisomy 16, both in diploid and aneuploid cells. None of these three patients did respond to any medical therapy. Their rapid death was a powerful proof of the correlation between the complexity of genome changes and disease aggressiveness. In the fourth case, a constitutional translocation t(3;5)(q26.3;q21) identified in a 72 years old woman with essential thrombocythemia, appeared not to be involved in the etiology of the disease. In this case, the treatment with hydroxyurea was successful and the disease evolution was favourable. In conclusion, we appreciate that in the three cases of myeloid and lymphoid leukemias it was a direct relationship between the complexity of genomic changes and the aggressiveness of the disease.

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.

Hereditary thrombocythaemia (HT) is an autosomal dominant disorder with clinical presentation and complications resembling sporadic essential thrombocythaemia (ET). Mutations in the thrombopoietin (TPO) gene causing overproduction of TPO and elevated TPO serum levels have been found previously in three families with HT. Here, we present evidence for genetic heterogeneity by demonstrating that HT in a Spanish and a US family is caused by genes other than TPO. Affected family members in both families had normal TPO serum levels. Genetic linkage analysis with TPO microsatellite markers excluded TPO as the disease gene in the Spanish HT family, and sequencing of the TPO gene revealed no mutations in the propositus of the US family. To test a role for MPL, the gene for the TPO receptor, we identified three single nucleotide polymorphisms (SNP) and a novel polymorphic CA microsatellite marker. By linkage analysis, we excluded MPL as the cause of HT in the Spanish family. Interestingly, mapping of the CA microsatellite marker to a region 40.5 kb upstream of MPL revealed the presence of sequences from the TIE gene, which encodes a tyrosine kinase receptor expressed on megakaryocytes and endothelial cells. Thus, MPL and TIE are in close physical proximity, and the CA microsatellite described here will be a useful genetic marker for both genes.

Hereditary thrombocythaemia (HT) with clinical features very similar to essential thrombocythaemia (ET) has been found to be transmitted as an autosomal dominant trait in several families. Here we studied the pathogenesis of HT in a previously described Japanese kindred. We found markedly elevated thrombopoietin (TPO) serum levels in all affected individuals and identified a novel point mutation in the TPO gene, a G --> T transversion at position 516 of the TPO mRNA (G516T) that co-segregated with the HT phenotype in all affected family members. This mutation is located in the 5'-untranslated region (5'-UTR) of the TPO mRNA and when assayed in reticulocyte lysates, improved translational efficiency of in vitro transcribed TPO mRNA. Cell lines transfected with the mutant TPO cDNA secreted up to 8-fold more TPO protein than cells transfected with the normal cDNA. We provide a molecular model of how the mutation partially disables the physiologic repression of TPO translation and thereby causes thrombocytosis. This is the third family in which HT has been caused by the loss of translational inhibition of TPO mRNA.

The underlying molecular basis for familial thrombocythaemia (FT). an extremely rare form of primary thrombocythaemia which occurs in an autosomal dominant manner, is currently unknown. We have investigated a family with FT and clarified whether we could detect alteration(s) in the genes coding for c-mpl and its ligand, thrombopoietin (TPO). There was no difference in platelet c-mpl mRNA expression levels between the affected and non-affected individuals in the family. Nucleotide sequence analysis of the c-mpl cDNA for the proband revealed no abnormality. We identified an intragenic tetranucleotide short tandem repeat system in the TPO gene and found non-linkage between the TPO locus and the FT phenotype. We conclude that genes for c-mpl and TPO are not responsible for thrombocythaemia in our FT family.

Familial thrombocytosis (FT) is a hereditary disorder probably involving the regulation of megakaryopoiesis. This report is the first documented case of FT in infancy. The clinical course was complicated by a leukaemoid reaction which lasted for several months, in combination with failure to thrive and hepatosplenomegaly. At the age of 5 years the patient, with the exception of thrombocytosis, is healthy and without medication.

Thirty-nine Chinese patients presenting as essential thrombocythemia (ET) were analyzed retrospectively. The median age at presentation was 69 years and the M:F ratio was 1.35:1. At diagnosis, 33 cases (84%) were asymptomatic and the diagnosis was made incidentally, while 3 cases (8%) presented with small vessel, and 2 cases (5%) with large vessel, thrombosis. One patient (3%) presented with minor bleeding. The platelet count ranged from 0.9-34 x 10(12)/l. Of 12 karyotypes done, 2 cases were abnormal, both showing the Philadelphia (Ph) chromosome. First-line therapy was radiophosphorus (32P) in 3 cases, melphalan in 20 cases, and hydroxyurea in 12 cases; 4 cases did not receive specific therapy. During the follow-up (mean = 4 years), no thrombotic or bleeding episodes were observed. One patient with the Ph chromosome underwent blastic transformation. These results indicate that bleeding and thrombosis occur significantly less in Chinese patients than in Western patients. The Ph chromosome appears to be a bad prognostic indicator. Because of the very low incidence of complications and good prognosis, the authors believe that cytoreductive therapy is best achieved by the use of hydroxyurea instead of alkylating agents or radiophorphours, as the latter agents are potentially leukemogenic.

Four cases of thrombocytosis in three successive generations of a family are described. High peripheral platelet count was found incidentally in the proband with cutaneous malignant lymphoma. Bone marrow examination showed megakaryocytic hyperplasia. Neither Philadelphia chromosome nor chimaeric bcr/abl junction was detected in marrow cells. In this family, thrombocytosis was thought to be transmitted by an autosomal dominant mode of inheritance.

Routine blood examination of a 27-year-old female revealed a platelet count of 2000 X 10(9)/l. Bone marrow cells showed the Philadelphia chromosome which was one product of a complex rearrangement of chromosomes 9, 22 and X. Her platelet count was lowered by plateletphoresis and chemotherapy. She remains in good health 19 months later, but her thrombocythaemia is considered to be an early manifestation of chronic myeloid leukaemia.

We studied 5 patients with essential thrombocythemia utilizing glucose-6-phosphate dehydrogenase (G-6-PD) enzyme as a cell marker for determining clonality. One of the patients was found to be heterozygous for isoenzymes B and A in the nonhaemopoietic tissues such as fibroblasts, but manifested only isoenzyme type B in the erythrocytes, neutrophils, and platelets. Our studies support the concept that essential thrombocythemia is a clonal disorder arising in a multipotent stem cell.