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W2022204812 abstract "Primary or essential thrombocythaemia (ET) is a rare chronic myeloproliferative disorder characterized by an elevated platelet count, haemorrhage and thrombosis. Little is known about its characteristics in children or the role played by genetic factors. With the widespread use of automated blood cell counters, elevated platelet counts are sometimes found coincidentally in asymptomatic young patients who meet the diagnostic criteria of ET. The clinical manifestation and natural history of the disease in children, especially in those in whom ET is found coincidentally, are not known. The appropriate management and ideal timing of therapeutic intervention therefore remain open to debate. This review summarizes the clinical and laboratory characteristics and management of ET in children, based on a review of 40 paediatric cases reported in the English literature up to September 1998 (1; 5; 10; 11; 19; 22; 24; 27; 32; 34; 37; 40; 42; 43; 47; 48; 49; 50; 55; 59; 61; 62; 66; 68; 75; 80; 82), and on experience with the disease at our institution (two patients; 18). The review discusses the similarities and differences of the disease in adults and children, and its familial occurrence. The unique features of familial thrombocytosis (FT) are described. Thrombocytosis is found relatively frequently in the paediatric population and, as Table I indicates, is usually secondary (30; 76). In contrast, ET is rare in children. Although the precise incidence of ET is unknown, the identification of asymptomatic cases that are coincidental with the increased use of automated blood cell counting suggests that it is more common than previously thought. The ages of the reported children ranged from 6 weeks to 18 years (median 11 years), and the male to female ratio was 19:23. ET is closely related to other chronic myeloproliferative disorders, such as agnogenic myeloid metaplasia with myelofibrosis, polycythaemia vera, and chronic myeloid leukaemia. It can either be a polyclonal (29) or monoclonal disease, originating in a pluripotent stem cell (23; 29). Most adult patients have a normal marrow cell karyotype, but abnormal cytogenetics have been reported, such as del(21q) (81) and t(9,22) (53). Cytogenetic studies were available in 25/42 paediatric cases; all results were normal. In ET the high platelet count derives from increased production of megakaryocytes. This is evident in marrow biopsies and in clonogenic studies in which there is an increase in megakaryocytic colony formation, sometimes accompanied by an increased production of granulocyte-macrophage, erythroid and mixed colonies (26). The abnormal proliferative properties of the stem cells in this disease are also demonstrated by autonomous megakaryocyte and erythroid colony formation in in vitro cultures, noted in over 80% of the patients (38). Reticulated platelets, measured by flow cytometry with monoclonal phycoerythrin-conjugated glycoprotein Ib antibodies and thiazole orange, were counted in our two patients (18); both had high values (56% and 65%; normal 5–12%), a finding that is consistent with abnormally high platelet production or may represent short platelet survival (77). Overexpression of thrombopoietin in mice has recently been shown to induce thrombocytosis (12). However, this does not seem to be the mechanism responsible for the increased production of platelets in ET. Thrombopoietin concentrations in peripheral blood and bone marrow as well as thrombopoietin mRNA in marrow stromal cells from patients with ET were found to be comparable to those of normal control subjects (33). In patients with non-familial ET, thrombopoietin transcript and protein concentrations are low in CD34+ cells, megakaryocytes and in supernatants from in vitro cultures of blood or marrow CD34(+) cells (71). Moreover, a neutralizing antibody against thrombopoietin does not alter autonomous megakaryocyte growth (71). Thrombopoietin levels tested in three reported paediatric ET cases by biological assay using mice were normal (19; 40). In our two patients thrombopoietin levels were determined by enzyme-linked immunosorbent assay using polyclonal rabbit antibodies for both capture and signal (Amgen, Thousand Oaks, Calif., U.S.A.). In both patients, levels were < 100 pg/ml (the lower limit of this assay's sensitivity), levels that are consistent with normal negative feedback but that might also be due to increased uptake by excess platelets (25). Therefore excessive proliferation and autonomous growth of megakaryocytes in ET are unlikely to be related to overstimulation by thrombopoietin. Abnormalities in the thrombopoietin receptor also do not seem to be the cause, since no mutation/deletion in the thrombopoietin receptor gene has been found (44; 71). In addition, immunoblotting with anti-phosphotyrosine antibody showed no aberrant protein-tyrosine phosphorylation in platelets of ET patients before treatment with thrombopoietin, and the levels of thrombopoietin-induced protein-tyrosine phosphorylation, including thrombopoietin receptor-tyrosyl phosphorylation, roughly paralleled those of thrombopoietin receptor expression (36). Further, 71) showed an absence of constitutive activation of signal transducers and activators of transcription (STATs) in autonomously growing adult patient megakaryocytes: STATs 3 and 5 were activated only by addition of thrombopoietin to these megakaryocytes, suggesting that the thrombopoietin-mediated signalling pathway was not constitutively activated in platelets of ET patients. These findings suggest that, at least in adults with non-familial ET, excessive proliferation and autonomous growth of megakaryocytes is not related to abnormalities in the thrombopoietin receptor or its signalling pathways. Several reports of a high frequency of complications in young adults (48; 55) have prompted some physicians to recommend treatment for any patient (including children) with a platelet count > 600–1000 × 109/l, whether symptomatic or not (21; 48; 55). Other studies, however, suggest that young patients are at lower risk of thrombosis (34; 41; 51). Of 42 paediatric patients, 18 (43%) experienced symptoms related to their disease, either at diagnosis or afterwards, including eight (19%) who had severe bleeding or thrombotic events. This complication rate is comparable to that found in some adult series (56; 73) but differs from conclusions drawn from small series comprising children or young adults (34; 41; 51). A literature review cannot accurately determine the risk of thrombosis or bleeding in ET in childhood, because a tendency to report more severe cases might cause selection bias. We can conclude, however, that ET in children is not entirely benign. Of 42 children with ET, 18 experienced symptoms. Four had major bleeding episodes: gastrointestinal, haemoptysis and post-surgical haemorrhages requiring blood transfusions (59; 49; 24; 5). Another six had minor to moderate bleeding: bruising, epistaxis or bleeding after tonsillectomy that was excessive but did not require transfusion. Four patients suffered severe arterial thrombotic events involving the middle cerebral and coronary arteries (68; 55; 48; 37). Two had severe venous thrombosis, involving the mesenteric, hepatic and portal veins and a cerebral venous sinus (55; 47). An additional two had recurrent severe headaches, parasthesias of the extremities, and erythromelalgia (32; 10). No patient had combined bleeding and thrombotic events. On physical examination, splenomegaly was the most common physical finding (44%); hepatomegaly was present in 22% of cases. Patients who are asymptomatic at diagnosis may manifest symptoms related to their disease later. On follow-up ranging from 9 months to 10 years (mean 48 months), six of the 30 initially asymptomatic patients developed symptoms: severe thrombosis (one), major bleeding (one), epistaxis (one), bruising (two) and severe headaches (one) (34; 55; 49; 10; 47; 42). Adult patients with ET have an approximately 2–5% risk of developing acute myeloblastic leukaemia (9; 58; 63). This is also true for children. Two of the 42 reported paediatric patients with ET (5%) developed acute myeloblastic leukaemia after 3 and 6.5 years of follow-up, at the ages of 15 and 20 years, respectively (59; 24). Because of major bleeding, both had received therapy before transformation occurred; one was treated with radioactive phosphorus, the other with thiotepa and busulphan. Two other patients developed massive splenomegaly with a leuco-erythroblastic blood film 3 and 11 years after being diagnosed with ET (42; 1). Bone marrow biopsy confirmed transition to idiopathic myelofibrosis. Four patients (9.5%) died of complications related to ET. Both patients with malignant myeloid transformation died shortly after the diagnosis of acute myeloblastic leukaemia was made. Two others died of severe thrombotic events; one of coronary artery thrombosis, the other from multiple venous thromboses (55). Most children with ET (62%) had persistent platelet counts > 1000 × 109/l; seven of them had intermittent counts > 2000 × 109/l. Various combinations of abnormalities in platelet morphology have been reported, giant forms being the most common (76%). Other abnormalities included bizarre shapes, abnormal clumping, small forms, megakaryocyte fragments, and hypogranularity. Mean platelet volume was low in half of the cases. In some cases mean platelet volume was still low despite the presence of occasional circulating giant platelets. Ultrastructural abnormalities of platelets included a decrease in number and abnormal morphology of pseudopods and α-granules, as well as abnormal tubular and open canalicular systems (Kapoor et al, 1998; 5; 18). Prolonged bleeding, prothrombin and partial thromboplastin times, and low fibrinogen, can be found in children with ET but are relatively rare (< 20%). Various abnormalities on platelet aggregation tests were observed in 71% of the 25 cases in which they were evaluated, most often in response to ADP and epinephrine, less frequently to collagen, ristocetin and arachidonate. A borderline decrease in von Willebrand factor and ristocetin cofactor was found in one of our two patients, and high molecular weight von Willebrand factor multimers were decreased in both. Glycoprotein (Gp) expression on platelets was measured in our two patients by flow cytometry, using fluorescein isothiocyanate-conjugated monoclonal antibodies reactive with the glycoproteins and adjusted to platelet size; both had low expression of GpIb–IX and GpIIb–IIIa and high GpIV. Leucocyte alkaline phosphatase assays were performed in 20 patients, four of whom had a low score. Three of the children with low scores were members of the same family (22). However, low scores were not found in all familial cases studied; five of the 13 patients with normal scores on this assay came from three families. Bone marrow is frequently hypercellular (13/17 reported cases) with an abundance of megakaryocytes (25/26 reported cases). Abnormalities of megakaryocytes have been reported including hyperlobulation, dysplasia as well as unusually large and early forms (10/15 reported cases). No increase in myeloblast counts or fibrosis were reported at diagnosis. Reticulin is usually slightly increased (4/5 reported cases). Children can be diagnosed during investigation for symptoms related to ET, on family screening, or on a blood test done for unrelated reasons. Thrombocytosis was a coincidental finding in 17 of the reported cases; six of them became symptomatic later. An additional 13 children were diagnosed during family studies (after another family member was found to be affected); none became symptomatic on follow-up. The remaining 12 patients were diagnosed on the basis of thrombotic or bleeding events. The diagnostic criteria set by the Polycythemia Vera Study Group (57) include a platelet count > 600 × 109/l, absence of conditions associated with reactive thrombocytosis, normal iron stores, normal red cell mass, and absence of the Philadelphia chromosome. In addition, collagen fibrosis should either be absent or, in the absence of both splenomegaly and leuco-erythroblastosis, restricted to less than one-third the cross-sectional area of the biopsy. According to these criteria, ET is diagnosed chiefly through exclusion. The presence of elevated erythrocyte sedimentation rate, fibrinogen, C-reactive protein, von Willebrand factor or interleukin-6 are more compatible with the diagnosis of reactive thrombocytosis. Findings positively supporting a diagnosis of ET include high platelet distribution width, circulating giant platelets, splenomegaly, spontaneous in vitro megakaryocytic or erythroid colony growth, and the occurrence of thrombotic events. The relationship between anaemia and childhood ET deserves special attention in any discussion of the diagnostic dilemmas of ET. Five of the reported children with the disease had a low haemoglobin concentration for their age (9.7–11.6 g/dl) but still displayed typical features of ET. Because anaemia from nutritional causes or gastrointestinal loss/malabsorption is common in children, and because patients with ET can develop anaemia, usually from blood loss from the gastrointestinal tract (77), thrombocytosis should not be assumed to be secondary. Indeed, three of the children reported above had major bleeding events (haemoptysis, upper gastrointestinal and post-tonsillectomy bleeding), one had bruising, and one had thrombotic but not bleeding episodes. Since ET is rare in children, it is important that a comprehensive approach to diagnosis be taken. This includes measures to exclude a laboratory error and transient thrombocytosis. A thorough clinical assessment should be conducted, along with laboratory tests when necessary, to elicit evidence of peripheral, abdominal cardiac or cerebral ischaemia, or venous thrombosis at the time of diagnosis or previously. Exclusion of secondary or other causes of thrombocytosis (Table I) should include determination of erythrocyte sedimentation rate, plasma fibrinogen level, a complete blood count with differential, peripheral blood smear, serum ferritin level and determination of bone marrow iron stores, cytogenetic studies, and concomitant abnormalities in other marrow lineages. Supportive evidence should be sought, including bone marrow biopsy and aspirate to determine cellularity, megakaryocyte number and morphology, fibrosis and reticulin deposits. Addition tests include prothrombin time, partial thromboplastin time, mean platelet volume, platelet morphology, leucocyte alkaline phosphatase, vitamin B12, platelet aggregation studies, von Willebrand factor antigen and multimers, ristocetin-cofactor activity, thrombopoietin levels, in vitro colony growth, and ultrasonographic examination of spleen, liver and large vessels. In all cases of affected children, family screening is recommended, including a history of vascular events, platelet counts, and leucocyte alkaline phosphatase of the parents and siblings. The role of platelet glycoprotein quantitation, platelet electron microscopy, determination of the percentage of reticulated platelets, all require further study. The frequency of haematological evaluation for early detection of patients who need therapy or those who undergo conversion to other myeloproliferative disorders also needs to be clarified. As previously discussed, ET in children is not always a benign entity; the crucial question is how to identify patients who are at high risk of complications and need treatment. Most laboratory tests are of little help in predicting the clinical course of ET (4; 54). Occasional studies in adults (21), however, have shown a correlation between increased risk of haemorrhage if the platelet count is > 2000 × 109/l. We divided the 42 paediatric ET cases into symptomatic and asymptomatic groups and searched for differentiating factors. We found that symptomatic paediatric patients had significantly higher mean platelet counts than those who were asymptomatic (2419 v 904 × 109/l, P < 0.001). The difference was still significant when familial cases were excluded (2285 v 1343 × 109/l, P = 0.01). No significant difference was found between the two groups in age at diagnosis, gender, splenomegaly, hepatomegaly, platelet morphology and function, leucocyte alkaline phosphatase score, vitamin B12 levels, bone marrow cellularity, and number and morphology of megakaryocytes. Although one has to be cautious about analysing groups of patients identified by a literature search because of its built-in bias, platelet counts may be important in predicting complications. It is noteworthy that three children with platelet counts of < 1000 × 109/l experienced thrombotic events (68; 55). This occurrence illustrates the role of structural or functional platelet abnormalities in the pathophysiology of vascular complications, in addition to the numerical factor or the existence of other concomitant hypercoagulability factors. In children with ET, laboratory evidence of a haemorrhagic tendency included prolonged prothrombin time, prolonged partial thromboplastin time, low fibrinogen, abnormal platelet aggregation, pseudo-von Willebrand's disease type IIa, and decreased GpIb–IX and GpIIb–IIIa expression. On the other hand, some adult patients have been shown to have laboratory evidence of a thrombotic tendency apart from thrombocytosis, including platelet hyperaggregability or spontaneous aggregation (14; 31). Evidence of platelet aggregation abnormalities in asymptomatic patients with risk factors for thrombosis might support treatment. The need to screen patients with ET for hypercoagulability states should be clarified, with tests for activated factor V resistance, prothrombin 20210 variant, homocysteinaemia, and deficiencies of protein C, S and anti-thrombin III. Little information is available on the coexistence of ET with inherited thrombophilic states in children. Some preliminary studies reported a reduction in the concentration of natural anticoagulants such as protein C, S and antithrombin in adult patients with ET (8). Results of such tests in children can further support a decision to commence treatment. Therapeutic intervention in patients with ET has been described as a ‘compromise between accepting the risk of potentially serious drug toxicity and the necessity of preventing thrombohaemorrhagic complications’ (51). The consensus of several studies (13; 21; 34; 73) is that patients who had one or more thrombotic events should be treated because of an increased risk of recurrence that may be prevented by lowering the platelet count. Treatment of asymptomatic adult patients remains problematic. Estimates of the risk of major thrombotic or haemorrhagic events in these patients range as high as 20% (13; 16; 21; 73). In patients < 18 years old the incidence of complications and the indications for treatment are less certain. The platelet count below which the risk of complications is negligible is unknown; nor has the benefit of lowering the platelet count to under 600 × 109/l been established, especially in young patients. Furthermore, concern exists about the leukaemogenic potential of current drugs. Patients with polycythaemia vera treated with radioactive phosphorus or alkylating agents have an increased risk of developing acute leukaemia that ranges from 1% to 14% (6; 35). Use of these agents in myeloproliferative disorders has therefore been significantly reduced over the past decade. Hydroxyurea has been shown to reduce the platelet count as well as the risk of thrombotic events in patients with ET (15; 28). Several studies have reported that the use of hydroxyurea does not lead to an increased risk of acute leukaemia in patients with myeloproliferative disorders (39; 58). Therefore hydroxyurea has been the major myelosuppressive agent used for treatment of ET in adults and children (15; 28; 73). However, recent studies (70; 78) have suggested that use of this agent confers a small leukaemogenic risk (approximately 3.5%) above the innate tendency for transformation to acute myeloid leukaemia. It is noteworthy that none of the paediatric patients treated with hydroxyurea underwent malignant transformation. Antiplatelet agents such as low-dose acetylsalicylic acid or dipyridamole have proved efficacious in preventing recurrence of thrombosis in the acral, coronary and cerebral arterial circulations in patients with ET (28; 51), and have been recommended as initial therapy in patients with minor benign problems. However, acetylsalicylic acid prolongs the bleeding time in patients with myeloproliferative disorders (3) and may occasionally lead to serious haemorrhagic complications (72). Therefore it might be unsafe to put asymptomatic patients on preventive anti-platelet agents before knowing which of them have a higher propensity to thrombosis than to bleeding. Interferon-α therapy is effective and should be considered under certain circumstances (60). However, its cost, availability in injectable form only and potential toxicity prevent its use as an initial therapy. Side-effects include flu-like syndrome, neuropsychiatric symptoms, autoimmune phenomena and cytopenia (64; 60). In addition, its long-term toxicity is unknown. Anagrelide has a high specificity toward megakaryocytes (2) and effectively controls extreme thrombocytosis in adults (2; 65; 69) and children (10; 32; 47; 55). It is an orally administered agent and has negligible carcinogenic effects (69). Most of its side-effects are related to vasodilatory or positive inotropic activity (2; 65; 69). In view of its efficacy and the infrequency of serious side-effects, anagrelide might well be considered as first-line therapy in the future, when its long-term efficacy and safety have been confirmed. Several therapeutic modalities in various combinations were used in 17 children with ET, including acetylsalicylic acid, radioactive phosphorus, busulphan, melphalan, chlorambucil, hydroxyurea, thiotepa, anagrelide and plateletpheresis. Indications for treatment included thrombotic events, major bleeding, minor bleeding, or merely high platelet counts. Interestingly, three symptomatic patients were not treated: one with coronary and cerebral thrombosis, one with major bleeding after tonsillectomy, and one with bruising (Spach et al, 1962; 34; 49). All three are long-term survivors and remain well despite persistently high platelet counts. In 16/17 treated patients the platelet count declined during treatment. However, rebound elevation occurred once the medication was discontinued, except in one patient treated with busulphan for 12 months who has had normal platelet counts during a follow-up period of 9 years (61). Both patients who developed myeloid leukaemia were among the 10 patients treated with myelosuppressive drugs. Familial thrombocytosis (FT) in adults is rare (19). However, a review of paediatric cases with ET revealed an unexpectedly high proportion of familial cases of thrombocytosis. Eight families accounted for 17 patients (55% of 31 with available family history or 40% of all 42 cases). In all eight families the disease occurred in at least two successive generations, which suggests an autosomal dominant inheritance. Further, analysis of familial versus non-familial cases revealed important differences (Table II). Familial cases had significantly lower mean platelet counts (P = 0.0003), lower incidence (though not statistically significant) of hepatosplenomegaly, and no thrombotic complications (P = 0.01). No familial case converted to leukaemia or myelofibrosis. It is unclear from the literature whether FT is a separate entity with its own pathogenesis, course and outcome. Malignant transformation was reported once, in a 63-year-old patient with FT (66), and thrombohaemorrhagic complications have been described (11; 19; 22; 43; 62; 66; 75; 80). However, children with FT seem to have a more benign course than ET patients in non-familial cases, which suggests that FT is a separate form of primary thrombocytosis. The one-base deletion mutation of the 5′-untranslated region of the thrombopoietin gene recently reported in two families with primary thrombocytosis (45; 79) supports this conclusion. In vitro studies showed that the identified mutation was an activating mutation causing increased thrombopoietin production and thus high serum thrombopoietin levels. However, this mechanism is probably not involved in the pathogenesis of all cases of FT. For example, two of the paediatric patients in whom thrombopoietin was checked and found normal were members of one family (19), and in at least one family with FT in which it was studied, neither mutations in the thrombopoietin receptor gene nor abnormalities in c-mpl mRNA expression were found (46). Therefore familial thrombocytosis may be due to a variety of mechanisms. Since the disease occurs most often in late middle age and the elderly, ET in pregnancy is rare. Also, among 74 women younger than 50 years followed by 7) only 18 became pregnant. When the disease affects women during pregnancy, multiple placental infarctions, presumably caused by platelet thrombi, may result in placental insufficiency. In the series of 7), spontaneous abortion, mostly in the first trimester, occurred in 14 (45%) of 31 pregnancies. Other pregnancy-related complications are less common, and include intrauterine fetal death, abruptio placentae, intrauterine growth retardation, and premature delivery (7; 20; 52; 67; 74). Besides adverse pregnancy outcome, maternal complications can also occur, and range as high as 70%; including haemorrhagic and thrombotic events. The possibility of placental and maternal thrombosis during pregnancy encouraged many physicians to recommend treatment aimed at lowering the platelet count. Treatments used during pregnancy include acetylsalicylic acid, dipyridamole, heparin, plateletpheresis and interferon-α (7; 20; 52; 67). No congenital anomalies were directly attributed to ET in pregnancy. A rare case of aplasia cutis congenita in an infant born to a mother with ET was reported (17), but it seemed to be unrelated to ET, since other aetiologies were more likely. Unlike observations reported in small series, the present review, which is based on 42 reported paediatric cases with ET, found that many patients developed severe vascular complications. However, the proportion of newly diagnosed asymptomatic patients who will develop complications and the time frame involved remains unknown. Although symptomatic patients in the current series had significantly higher platelet counts than asymptomatic patients, there is still no test available that can provide an accurate prognosis and predict the need for therapy. Because children with ET treated with leukaemogenic agents can develop leukaemia, myelosuppressive drugs should be used only as a last resort. At present, hydroxyurea is the most commonly used drug in myeloproliferative disorders and has relatively few side-effects. In future, anagrelide may be proved safer and as effective as hydroxyurea, and might be considered as first-line therapy for children with ET in whom treatment is indicated. In contrast to reports of adults, familial occurrence is common among children with primary thrombocytosis. The significantly lower platelet counts, lower incidence of hepatosplenomegaly, and absence of thrombosis suggest that FT is a unique form of primary thrombocytosis that follows a more benign course than ET. This paper was prepared with the assistance of Editorial Services, The Hospital for Sick Children, Toronto, Ontario." @default.
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W2022204812 title "Essential thrombocythaemia in children" @default.
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