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Journal of Hematology Jun 2021Essential thrombocythemia (ET) is one of the "classic" Philadelphia chromosome negative (Ph-) myeloproliferative neoplasms characterized by sustained thrombocytosis,...
BACKGROUND
Essential thrombocythemia (ET) is one of the "classic" Philadelphia chromosome negative (Ph-) myeloproliferative neoplasms characterized by sustained thrombocytosis, increased megakaryopoiesis and high risk of vascular complications. ET is very rare in childhood. The annual incidence is approximately 1 per 10,000,000 in children less than 14 years, and about 60 times lower than adults. The genetic landscape and clonal features in childhood ET has not been well defined. There is no evidence-based guidance on the diagnosis of childhood ET.
METHODS
Medical records of 28 pediatric patients (age ≤ 14 years at diagnosis) with ET were reviewed and evaluated to characterize the different mutation profiles and to evaluate the treatment modalities used and the potential long-term outcome.
RESULTS
More than half of the patients were found to have positive history of parental consanguinity (57.1%) whereas positive family history was documented for more than a quarter of our patients (28.6%). Janus kinase 2 gene () V617F mutation was positive in two of 26 patients (7.7%). Myeloproliferative leukemia virus oncogene () exon 10 and calreticulin () mutations were tested in eight patients, which were negative for all of them. Treatment included low-dose aspirin (LDA) in seven patients (50%), combination of LDA with hydroxyurea in three patients (21.4%), hydroxyurea in two patients (14.3%), combination of platelets apheresis with LDA and anagrelide in one patient each (7.1%). During the treatment, two patients experienced stroke (7.1%), one patient developed Budd-Chiari syndrome (3.6%) and one patient developed azoospermia (3.6%).
CONCLUSIONS
The incidence of ET in children is extremely low in Saudi Arabia. Most of the children with ET were asymptomatic, and thrombocytosis was often discovered incidentally. V617F mutation has no known impact on the prognosis or on the outcome of the disease in the pediatric age group that is in contrast to the adult ET. Children less than 1 year are at high risk for complications particularly during acute precipitating infectious episode. The potential complications and clinical course of pediatric ET are unpredictable.
PubMed: 34267847
DOI: 10.14740/jh822 -
Pharmacology 2021
Topics: Humans; Hydroxyurea; Kidney Function Tests; Myeloproliferative Disorders; Platelet Aggregation Inhibitors; Quinazolines; Thrombocythemia, Essential
PubMed: 34139702
DOI: 10.1159/000516894 -
Cureus Mar 2021Treatment modalities for polycythemia vera (PV) have evolved over time. Phlebotomy and low-dose aspirin suffice in low-risk patients, but cytoreductive therapies are... (Review)
Review
Treatment modalities for polycythemia vera (PV) have evolved over time. Phlebotomy and low-dose aspirin suffice in low-risk patients, but cytoreductive therapies are indicated in all high-risk patients (age ≥ 65 years or those with a history of PV-related thrombotic event) and may be considered for low-risk patients with progressively increasing splenomegaly, progressively increasing leucocyte and platelet counts, and for those who do not tolerate phlebotomy. Hydroxyurea/hydroxycarbamide or interferons can be used as first-line drugs. Hydroxyurea may not be tolerated by some patients, and it also carries risk of myelosuppression. Interferon alfa is especially useful for PV symptoms, and the newer preparation, ropeginterferon alfa-2b, has lesser incidence of flu-like reactions. Ruxolitinib reduces the JAK2V617F mutation burden and is used as a second-line drug. Anagrelide reduces platelet production and can be used in conjunction with hydroxyurea in patients with excessive thrombocytosis. The alkylating agent, busulfan, can also be used as a last resort in patients with a limited life expectancy. Prospective future treatments include givinostat, a histone deacetylase inhibitor, and idasanutlin, a murine double minute 2 antagonist.
PubMed: 33936902
DOI: 10.7759/cureus.14193 -
Clinical Case Reports Apr 2021Long-term use of hydroxyurea can cause leg ulcers which usually do not heal unless the drug is discontinued. Patients should be counseled regarding alternative lines of...
Long-term use of hydroxyurea can cause leg ulcers which usually do not heal unless the drug is discontinued. Patients should be counseled regarding alternative lines of treatment like anagrelide and pegylated-interferon.
PubMed: 33936725
DOI: 10.1002/ccr3.3991 -
Annals of Hematology Jul 2021Secondary thrombocytosis is a frequent secondary finding in childhood infection and inflammation. Primary hereditary thrombocytosis may be caused by germline mutations... (Review)
Review
Secondary thrombocytosis is a frequent secondary finding in childhood infection and inflammation. Primary hereditary thrombocytosis may be caused by germline mutations within the genes encoding key regulators of thrombopoiesis, i.e., thrombopoietin (THPO) and its receptor c-MPL (MPL) or the receptor's effector kinase Januskinase2 (JAK2). Furthermore, somatic mutations in JAK2, MPL, and in the gene-encoding calreticulin (CALR) have been described to act as driver mutations within the so-called Philadelphia-negative myeloproliferative neoplasms (MPNs), namely essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF). Increasing knowledge on the molecular mechanisms and on the clinical complications of these diseases is reflected by the WHO diagnostic criteria and European LeukemiaNet (ELN) recommendations on the management of adult MPN. However, data on childhood thrombocytosis are rare, and no consensus guidelines for pediatric thrombocytosis exist. Current literature has highlighted differences in the epidemiology and molecular pathogenesis of childhood thrombocytosis as compared to adults. Furthermore, age-dependent complications and pharmacological specificities suggest that recommendations tailored to the pediatric population are necessary in clinical practice. Here we summarize literature on classification, diagnostics, and clinical management of childhood thrombocytosis.
Topics: Adolescent; Adult; Age of Onset; Algorithms; Anticoagulants; Calreticulin; Child; Disease Management; Female; Germ-Line Mutation; Humans; Hydroxyurea; Interferon-alpha; Janus Kinase 2; Male; Myelodysplastic-Myeloproliferative Diseases; Platelet Count; Quinazolines; Receptors, Thrombopoietin; Severity of Illness Index; Thrombocythemia, Essential; Thrombocytosis; Thrombophilia
PubMed: 33712866
DOI: 10.1007/s00277-021-04485-0 -
Pharmacology 2021When choosing a cytoreduction method for patients suffering from essential thrombocythemia (ET), it is important to know the safety profile of the medicine used. Few...
BACKGROUND AND PURPOSE
When choosing a cytoreduction method for patients suffering from essential thrombocythemia (ET), it is important to know the safety profile of the medicine used. Few articles have been published about the effects of hydroxycarbamide (hydroxyurea, HU) and anagrelide (ANA) on renal function in ET patients. This study is the largest analysis of nephrotoxicity of cytoreductive drugs used in ET therapy so far, which additionally includes risk factors for the progression of kidney disease and coexisting genetic mutation.
EXPERIMENTAL APPROACH
The retrospective study included 310 patients diagnosed with ET. Demographic data, comorbidities, Cr, and estimated glomerular filtration rate (eGFR) were all taken into account prior to diagnosis and after 6 months of HU and ANA treatment.
KEY RESULTS
A statistically significant difference was found between Cr and eGFR levels at baseline and after 6 months of treatment (p < 0.001). The applied treatment (HU and ANA) had the greatest impact on kidney function. ANA significantly increased the risk of worsening renal function in contrary to hydroxycarbamide after 6 months of treatment (eGFR change: median +1 mL/min/1.73 m2 [interquartile range (IQR) (-4)-(+7)] in the HU group vss. median -13 mL/min/1.73 m2 [IQR (-18)-(-6)] in the ANA group, odds ratio [OR] 7.92 95% confidence interval [95% CI] [4.17-15.08], p < 0.001). Lowering of eGFR <60 mL/min/1.73 m2 occurred in 31 patients (31.0%) from the ANA group and 10 people (4.8%) treated with HU (p = 0.000). In 1 patient from the ANA group, >50% decrease in eGFR was observed. The chance for an increase in Cr levels was higher in people with pre-existing arterial hypertension (OR 1.92 CI = 95% [1.21-3.05], p = 0.006). Sex, type of mutation found (JAK2 V617F or CALR), and previous renal impairment did not affect renal function after 6 months of treatment. In addition, there was no difference in the efficacy of ET treatment between HU and ANA (p = 0.998).
CONCLUSIONS AND IMPLICATIONS
The observations indicate that ANA should be used in patients with ET with great caution and taking into account the risk of worsened kidney function.
Topics: Aged; Calreticulin; Creatinine; Disease Progression; Female; Humans; Hydroxyurea; Janus Kinase 2; Kidney Diseases; Male; Middle Aged; Mutation; Platelet Aggregation Inhibitors; Quinazolines; Retrospective Studies; Risk Factors; Thrombocythemia, Essential; Treatment Outcome
PubMed: 33691325
DOI: 10.1159/000513377 -
Intestinal Research Oct 2021Hydroxyurea is an antimetabolite drug that is commonly used in many hematological disorders. Ulcer formation in the gastrointestinal tract is a rare phenomenon...
Hydroxyurea is an antimetabolite drug that is commonly used in many hematological disorders. Ulcer formation in the gastrointestinal tract is a rare phenomenon associated with this drug. We report a case of a 73-year-old woman who was found to have an isolated ileocecal valve ulcer while on hydroxyurea 1 g daily for essential thrombocythemia. A comprehensive evaluation ruled out all other causes. The cytoreductive therapy was switched to anagrelide and the endoscopic evaluation 6 months later showed complete healing of the ulcer. However, the hydroxyurea was resumed due to increasing platelet counts and intolerance to dose increments of the anagrelide. Subsequently, the patient was found to have a recurrence of the ulcer. Apart from oral ulcers, there have also been reports of ulcers involving the small bowel and the colon associated with the use of hydroxyurea. The pathophysiology of the non-oral gastrointestinal ulceration in relation to this drug is unclear. Withdrawal of the drug typically leads to complete resolution. Increasing awareness of the rare association between the use of hydroxyurea and nonoral gastrointestinal ulcers is essential for early detection to prevent related complications.
PubMed: 33249801
DOI: 10.5217/ir.2020.00099 -
Wiener Klinische Wochenschrift Jan 2021According to the World Health Organization (WHO) classification, essential (primary) thrombocythemia (ET) is one of several Bcr-Abl negative chronic myeloproliferative...
According to the World Health Organization (WHO) classification, essential (primary) thrombocythemia (ET) is one of several Bcr-Abl negative chronic myeloproliferative neoplasms (MPN). The classical term MPN covers the subcategories of MPN: ET, polycythemia vera (PV), primary myelofibrosis (PMF), and prefibrotic PMF (pPMF). ET is marked by clonal proliferation of hematopoietic stem cells, leading to a chronic overproduction of platelets. At the molecular level a JAK2 (Janus Kinase 2), calreticulin, or MPL mutation is found in the majority of patients. Typical ongoing complications of the disease include thrombosis and hemorrhage. Primary and secondary prevention of these complications can be achieved with platelet function inhibitors and various cytoreductive drugs including anagrelide, hydroxyurea and interferon. After a long follow up, in a minority of ET patients the disease transforms into post-ET myelofibrosis or secondary leukemia. Overall, life expectancy with ET is only slightly decreased.
Topics: Austria; Humans; Mutation; Myeloproliferative Disorders; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential
PubMed: 33215234
DOI: 10.1007/s00508-020-01761-3 -
International Heart Journal Nov 2020Essential thrombocythemia (ET) is a Philadelphia chromosome-negative myeloproliferative disorder that is characterized by the overproduction of platelets and a marked...
Essential thrombocythemia (ET) is a Philadelphia chromosome-negative myeloproliferative disorder that is characterized by the overproduction of platelets and a marked increase in the numbers of mature megakaryocytes present in the bone marrow. Thrombohemorrhagic disorders are major morbidities of ET, especially those with mutations in the gene encoding Janus kinase 2 (JAK2). In this study, we report the case of an 18-year-old patient with ET carrying JAK2 mutation who developed acute ST-elevation myocardial infarction (STEMI) 5 months after a commencement of anagrelide. Coronary endothelial dysfunction confirmed by positive acetylcholine provocation test lasted a year after the occurrence of STEMI. Furthermore, intracoronary imaging using optical coherence tomography demonstrated non-atheromatous intimal fibrosis possibly due to chronic endothelial damage. The coronary pathologies reflected chronic change potentially associated with properties of ET and JAK2 mutation in addition to hyperviscosity. These observations suggest that the side effect of anagrelide in our patient was considered causative, while underlying chronic endothelial dysfunction and adverse endothelial remodeling may be predisposing factors to his fatal cardiovascular events.
Topics: Acetylcholine; Adolescent; Coronary Angiography; Coronary Vessels; Echocardiography; Endothelium, Vascular; Fibrinolytic Agents; Fibrosis; Heart Function Tests; Humans; Janus Kinase 2; Magnetic Resonance Imaging; Male; Nitroglycerin; Percutaneous Coronary Intervention; Quinazolines; Radionuclide Imaging; ST Elevation Myocardial Infarction; Thrombectomy; Thrombocythemia, Essential; Tomography, Optical Coherence; Tunica Intima; Vasodilator Agents
PubMed: 33191357
DOI: 10.1536/ihj.20-377 -
Thrombosis and Haemostasis May 2021Hemorrhage is a well-known complication of essential thrombocythemia (ET) and polycythemia vera (PV), but evidence-based data on its management and prevention are... (Review)
Review
Hemorrhage is a well-known complication of essential thrombocythemia (ET) and polycythemia vera (PV), but evidence-based data on its management and prevention are lacking to help inform clinicians. In this review, appropriate published data from the past 15 years regarding bleeding epidemiology, classification, location, and risk factors are presented and discussed. Research was conducted using the Medline database. The bleeding classifications were heterogeneous among the collected studies. The median incidences of bleeding and major bleeding were 4.6 and 0.79% patients/year, in ET patients and 6.5 and 1.05% patients/year in PV patients, respectively. The most frequent location was the gastrointestinal tract. Bleeding accounted for up to 13.7% of deaths, and cerebral bleeding was the main cause of lethal hemorrhage. Thirty-nine potential risk factors were analyzed at least once, but the results were discrepant. Among them, age >60 years, bleeding history, splenomegaly, myeloproliferative neoplasm subtype, and platelet count should deserve more attention in future studies. Among the treatments, aspirin seemed to be problematic for young patients with ET (especially -mutated ET patients) and anagrelide was also identified as a bleeding inducer, especially when associated with aspirin. Future studies should analyze bleeding risk factors in more homogeneous populations and with common bleeding classifications. More tools are needed to help clinicians manage the increased risk of potentially lethal bleeding events in these diseases.
Topics: Age Factors; Hemorrhage; Humans; Platelet Count; Polycythemia Vera; Risk Factors; Thrombocythemia, Essential
PubMed: 33186994
DOI: 10.1055/s-0040-1720979