Clonal hemopoiesis and risk of thrombosis in young female patients with essential thrombocythemia

OBJECTIVE: Several studies demonstrated a high prevalence of nonrandom X-chromosome inactivation pattern (X-CIP) in essential thrombocythemia (ET). This study explored the incidence of clonal hemopoiesis in myeloid precursors and endogenous erythroid colonies (EECs) in ET patients and its correlation with thrombotic manifestations. MATERIALS AND METHODS: Clonal analysis of hemopoiesis using X-CIP was performed in 40 female patients with ET. Median age was 40.5 years (range 20-64), and median platelet count at testing time was 700 x 10(9)/L (range 220-1300 x 10(9)/L). Patients older than 65 years were excluded to reduce age-related skewing. Clonality was assessed on neutrophils, platelets, EECs, and bone marrow CD34(+) cells. RESULTS: Eight (20%) of 40 patients developed thrombosis mainly at diagnosis. Clonal hemopoiesis was found in 17 (42.5%) patients, 15 (37.5%) had polyclonal hemopoiesis, and 8 (20%) were considered uninterpretable due to constitutive skewing. Clonality was confirmed on purified CD34(+) subpopulations from bone marrow, documenting that clonality does not appear lineage-restricted. There were no statistical differences in age at diagnosis, median platelet count at testing time, and length of follow-up. Thrombotic episodes were significantly more frequent in the monoclonal group (p = 0.04, Fisher exact test). CONCLUSIONS: Young female patients with ET exhibiting a clonal pattern of hemopoiesis by X-CIP analysis are at higher risk for thrombosis. X-CIP analysis may contribute to defining the individual risk leading to appropriate treatment. X-CIP will allow a correct diagnosis in patients with latent myeloproliferative disorders and thrombosis in unusual sites. Clonal hemopoiesis is easily recognized by X-CIP, but its applicability is limited to the female sex and is hampered by the presence of age-related or constitutive skewing.     

Familial essential thrombocythemia

Primary or essential thrombocythemia is rarely observed in childhood, and familial occurrence has been reported only once. In this study, essential thrombocythemia is documented in five members of both sexes from two to 62 years of age in three successive generations. The propositus had a persistent elevation of the platelet count, splenomegaly, a normal hemoglobin level, a normal white blood cell count, and abnormal platelet aggregation. Platelet arachidonic acid metabolites assayed by high-performance liquid chromatography and serum thrombopoietin levels were normal. Megakaryocytes were increased in number and size. Both mature and early immature megakaryocytes, but no atypical megakaryocytes, were identified by surface immunofluorescence. Bone marrow cultures showed normal myeloid and erythroid colony formation, and chromosome studies revealed a normal female karyotype. These findings support the concept that familial essential thrombocythemia is a myeloproliferative disorder that is transmitted by an autosomal dominant mode of inheritance, and that untreated young women and children with essential thrombocythemia have long survival.     

Treatment of essential thrombocythemia

PURPOSE: Essential thrombocythemia (ET) is a myeloproliferative syndrome that rises many therapeutic problems. This affection is rarely life threatening, but hemorrhagic and thrombotic complications must be prevented when possible. The rarity of these complications makes difficult the assessment of treatment efficiency. Few randomised clinical trials were done, and treatment often rests on retrospective studies. The potential toxicity of treatments, their leukemogenicity in particular, rises a decisional problem for young patients. We propose to review available data in order to propose the most rational treatment for each patient. CURRENT KNOWLEDGE AND KEY POINTS: After numerous years when we only disposed of retrospective studies, non-randomised prospective studies or isolated case-reports, two randomised trials allows us to more precisely define ET treatment. The first trial proved the efficiency of the hydroxyurea-aspirin association in the prevention of thrombotic events in high-risk patients. The second trial signalled to our attention the increased risk of bleeding of the association anagrelide-aspirin, with also the possibility of increased appearance of myelofibrosis. FUTURE PROSPECTS AND PROJECTS: New perspectives in the treatment of ET will require to get more insights in the role of hydroxyurea and anagrelide in particular by longer follow-up. But not less important is a better definition of the thrombosis risks (who has to be treated?) and also of the diagnostic groups since ET can, in some particular cases, be misdiagnosed with polycythemia vera or idiopathic myelofibrosis.     

Left main coronary thrombosis with essential thrombocythemia

Essential thrombocythemia is a disorder that causes persistent increase in the platelet count. The disease is associated with an elevated risk of thrombosis. A 71-year-old woman was diagnosed with left main coronary thrombosis after an angiogram due to stable angina. One week before the angiogram was taken the patient had also been diagnosed with essential thrombocythemia. After appropriate medical treatment for 5 days the patient underwent an excimer laser treatment, which failed in dissolving the thrombus. Before the patient underwent coronary surgery, thrombopheresis was performed in order to reduce the platelet count. After a successful coronary operation the patient improved completely.     

Hydroxyurea in old patients with essential thrombocythemia

BACKGROUND AND AIMS: A previous thrombotic event and advanced age are well-known risk factors for thrombosis in essential thrombocythemia (ET). In these patients, therefore, cytotoxic drugs are needed to reduce platelet count. In spite of this convincing idea, in clinical practice, some old patients do not use platelet-reducing drugs, for a variety of causes, and few specific studies in old patients with ET are available. Our retrospective study reports single-center experience in 54 old ET patients with long follow-ups. METHODS: We compared the clinical outcome of 27 ET old patients not taking cytotoxic drugs (group A) with 27 cases treated with hydroxyurea (HU) (group B), evaluating the incidence of thrombosis and thrombosis-free survival. In 16 patients in group A and in 18 in group B, V617FJak2 mutation was sought. About 20% of HU-treated patients developed major side-effects. RESULTS: No significant difference was found in the occurred thrombosis between the 2 groups in either clinical or laboratory features. V617FJak2 was equally common in groups A and B, and in patients with or without thrombosis. CONCLUSIONS: This study is not randomised and includes a small number of patients. However, it shows that it is necessary to identify better patients who really need treatment, as the side-effects of HU are relatively common in old people and their treatment should be discontinued. V617FJak2 does not define the thrombotic risk in old ET patients.     

XYY male with essential thrombocythemia in childhood

We describe a boy with XYY male accompanied with essential thrombocythemia. This is, to our knowledge, the first complete case report of the kind in the pediatric literature. The patient was asymptomatic, but at age 5 his platelet count had increased to 145.5 x 10(4)/microL, and he was diagnosed as having essential thrombocythemia based on the diagnostic criteria of the Polycythemia Vera Study Group. At that time, it was discovered by chromosome analysis of both bone marrow and peripheral blood cells that he was XYY male. At times during the clinical course when his platelet count was 94.1 x 10(4)/microL, his serum thrombopoietin (measured by enzyme-linked immunosorbent assay) was 1.09 fmol/mL, which was normal for his age. Aspirin was administered, and he remained asymptomatic throughout the course. After 2 years, he underwent a spontaneous remission. Because of the small number of reported cases, we have been unable to determine the relation between XYY males and essential thrombocythemia.     

Hypertension complicating essential thrombocythemia

Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by marked thrombocytosis with associated hemorrhagic, thrombotic and embolic complications caused by platelet dysfunction. In this report we describe two cases of ET and moderate to severe hypertension associated with renal artery stenosis and renal microvascular lesions. In both cases treatment of the hematologic disorder resulted in reduction of blood pressure and improvement of clinical symptoms.     

Thrombospondin in essential thrombocythemia

Essential thrombocythemia is a myeloproliferative disorder characterized by frequent bleeding and thrombotic complications. On a molecular level, two abnormalities of platelet thrombospondin have been identified: abnormal glycosylation of the intact 185,000-dalton chain has been detected and a shortened form of the thrombospondin chain is present. We have used two monoclonal antibodies and Lens culinaris lectin to probe the structure of thrombospondin in the platelets from three patients with essential thrombocythemia; one patient with polycythemia vera and two patients with secondary thrombocytosis. The presence of abnormal thrombospondin fragments with molecular weights of 160,000 and 30,000 was detected in the intact platelets and in the supernatant from thrombin-treated platelets, in all of the individuals except one of the secondary thrombocytosis patients. Monoclonal antibody binding studies indicate that both fragments are produced by proteolysis at a single site, which results in the removal of a 30,000- dalton fragment from the NH2-terminal. Lens culinaris lectin-binding studies revealed that some of the carbohydrate moieties of thrombospondin are near this cleavage site. The results are consistent with the hypothesis that the abnormal thrombospondin fragments observed under conditions of increased platelet production are due to increased susceptibility to proteolysis which, in turn, may be due to defective glycosylation.     

An antibody to platelet membrane antigen associated with thrombotic events in essential thrombocythemia

A 71-year-old man with essential thrombocythemia presented with acute onset of thrombosis in his fingers. The platelet count at presentation was 752 x 10(9)/liter, and his PTT was within the normal range. Platelet aggregation was normal in response to ADP, decreased to epinephrine, and absent to collagen, with the patient receiving 1.2 g aspirin/day. Plasma vWF:Ag was 158 U/dl, VIII:C was 150 U/dl, and the vWF:Ag multimer pattern was normal. HLA antibodies were not detected in his serum, and the platelet-associated IgG was normal at 3.9 fg/platelet. Incubation of normal, unactivated platelets with the patient's plasma did not result in agglutination of the platelets. However, a serum antibody reacting against a platelet antigen with an apparent molecular weight of 45,000 could be demonstrated by Western blotting. This antibody also reacted with endothelial cells. The reactive pattern was similar to that of commercially obtained actin; the serum antibody could be removed by preincubation with actin. Platelet-plasmapheresis was carried out daily for 10 days, after which the serum still reacted weakly with the platelet antigen. By day 20, the band could still be identified on the electroblot, but 2 weeks later no band could be seen. Similar assay of sera from six other patients with myeloproliferative disorders and comparable thrombocytosis but without thrombotic manifestations did not show any such reactions. The data suggest a correlation between the presence of an antibody possibly directed against platelet and/or endothelial cell actin and the vascular events in this patient with essential thrombocythemia.     

Hemostatic complications in young patients with essential thrombocythemia

PURPOSE: The purpose of this study was to determine the incidence of hemostastic complications in young patients with essential thrombocythemia (ET). PATIENTS AND METHODS: The clinical course of 44 patients under the age of 45 with the diagnosis of ET was reviewed in a retrospective manner. Patients were collected from three medical centers in the United States and Italy: the Brigham and Women's Hospital and the Harvard Community Health Plan, Boston, Massachusetts, and the Ospedali Riuniti di Bergamo, Bergamo, Italy. RESULTS: The overall incidence of hemorrhage or thrombosis, or both, in this group of patients was 39% (17 of 44), with serious complications occurring in 23% (10 of 44). Two patients died of thrombotic events. Neither the presence of symptoms at diagnosis nor any single laboratory parameter proved predictive of clinical sequelae. Treatment with antiplatelet drugs or platelet-lowering agents was not protective. CONCLUSION: We conclude that ET in young patients may result in serious and life-threatening hemostatic problems and consequently that young age is not a favorable prognostic factor in this disease.     

Pipobroman therapy of essential thrombocythemia

We report our results with pipobroman (PB) therapy in patients with essential thrombocythemia (ET). 21 consecutive untreated patients were treated with PB from 1975 to 1984. PB was given at a dose of 1 mg/kg/d until platelet count dropped below 600 X 10(9)/l. In 18 patients (86%) a hematological remission was obtained. Median duration of induction phase was 49 d. In all cases a maintenance regimen was required at a dose ranging from 0.2 mg/kg/d to 0.5 mg/kg/d, according to platelet number. Follow-up of responder patients ranged from 6 to 108 months (median 17 months). Treatment was well tolerated and we observed only a very moderate and transient hematological toxicity. No patient had relapsed or developed secondary neoplasms at the time of writing. Median survival time of all patients was 24 months (range 10-115).     

Neurological disorders in essential thrombocythemia

Patients with essential thrombocythemia often complain of various subjective neurological symptoms. This prospective study aims to assess their incidence and response to therapy. Among 37 consecutive patients with essential thrombocythemia, 11 presented with neurological symptoms. Among them 4 had thrombotic events, 7 complained of transient or fluctuating subjective symptoms, and one had both. Brain magnetic resonance imagery failed to detect any substratum in patients with subjective symptoms. JAK2V617F mutation was found in 9 of 11 patients with neurological symptoms versus 14 of 26 patients without symptoms. Ten patients received low-dose aspirin for these symptoms: complete resolution was observed in 3, improvement with persisting episodes in 2, and resistance to aspirin in 2 patients, in whom addition of cytoreductive therapy became necessary to resolve those disabling symptoms. In this prospective cohort, 30% of patients with essential thrombocythemia presented neurological symptoms. Aspirin was fully efficient in only 30% of cases. JAK2V617F mutation could be a risk factor for such symptoms.     

Pathogenic markers in essential thrombocythemia

Although long recognized as a clinical entity, the diagnosis of essential thrombocythemia (ET) still relies on the exclusion of reactive conditions and other myeloproliferative disorders. Recent studies have attempted to identify new markers for this disorder and suggest that part of the problem may relate to its heterogeneity. Cytogenetic abnormalities are rare, but analysis using X-chromosome inactivation patterns indicates that nearly 50% of evaluable patients have polyclonal myelopoiesis and this is associated with a lower risk of thrombosis. Reduced and heterogeneous staining of c-Mpl in bone marrow biopsies may help to distinguish ET and a reactive thrombocytosis. Increased expression of PRV-1 (polycythemia ruba vera) in granulocytes may assist in discriminating between polycythemia vera and at least some cases of ET. The contribution of these markers to disease pathogenesis is unknown and prospective studies are needed to evaluate their usefulness for predicting clinical outcome and directing patient therapy.     

Low protein s in essential thrombocythemia with thrombosis

Patients with essential thrombocythemia (ET) are at increased risk for large-vessel and microvascular thrombosis, presumably because of abnormal platelet number and function. To determine if another hemostatic abnormality might contribute to this thrombotic risk, we investigated protein C and protein S and the fibrinolytic system in four patients with ET. The patients segregated into two distinct groups. The first group consisted of two patients with moderate thrombocytosis who were without thrombotic symptoms and who had normal protein S and protein C and normal fibrinolysis. The second group consisted of two patients with mild to moderate thrombocytosis and thrombosis. Both these latter two patients had abnormalities in protein S. The first patient had only 31% free protein S and 67% total protein S, with normal protein C and normal fibrinolysis. Following treatment, vasoocclusive symptoms resolved and platelet count decreased, but protein S remained low (28% free protein S). The second patient in this group had only 35% total protein S at initial study. Other hemostatic abnormalities were also present. Following treatment, symptoms resolved and protein S returned to normal. Based on this limited series, it appears that, in some patients with ET, thrombotic phenomena may be due to the presence of a second hemostatic abnormality in addition to the high platelet count and abnormal platelet function. This abnormality may be acquired as part of the disease process. Some of these abnormalities may be corrected following treatment.