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Experimental Hematology Dec 2001The mechanism for anagrelide's potent platelet lowering activity in human subjects is not well defined. Studies related to anagrelide function have been hampered by its...
OBJECTIVE
The mechanism for anagrelide's potent platelet lowering activity in human subjects is not well defined. Studies related to anagrelide function have been hampered by its lack of activity in nonhuman primates and water insolubility. In an effort to define the mechanism whereby anagrelide exerts its therapeutic effect, we identified a water-soluble metabolite (anagrelide.met). The availability of anagrelide.met allowed, for the first time, parallel in vitro and in vivo animal studies centered on the mechanisms by which anagrelide lowers platelet levels.
MATERIALS AND METHODS
The effects of anagrelide.met on proliferation and maturation of mega-karyocytes (MKs) as well as platelet production were studied both in vitro and in vivo.
RESULTS
Anagrelide.met is capable of blocking in vitro MK migration by 20% to 40%. At 100 ng/mL, anagrelide.met selectively blocked in vitro MK maturation, resulting in a 50% decrease in the total number of CD41a(+) MKs, corresponding with a 30% decrease in MK ploidy by day 10 and a 60% decrease by day 20. Daily intraperitoneal injections of anagrelide.met 100 microg into BALB/c mice was sufficient to significantly decrease platelet counts within 24 to 48 hours, stabilizing to 40 to 50% of normal levels by day 5. This was associated with a 45% decrease in the number of developing MKs and an increase in thrombopoietin levels. Anagrelide.met did not alter WBC counts, hematocrit, or bleeding time, or lead to any apparent signs of toxicity. Furthermore, unlike the parent anagrelide compound, anagrelide.met did not inhibit ADP-induced platelet aggregation even at high concentrations (10 microg/mL).
CONCLUSIONS
We describe a cross-species reactive anagrelide metabolite that selectively inhibits MK maturation and migration, lowering platelet levels without influencing platelet aggregation.
Topics: Acetylcholinesterase; Animals; Antigens, CD34; Biomarkers; Cell Movement; Cells, Cultured; Chemokine CXCL12; Chemokines, CXC; Fetal Blood; Humans; Megakaryocytes; Mice; Mice, Inbred BALB C; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet Count; Ploidies; Quinazolines; Thrombocytopenia
PubMed: 11750100
DOI: 10.1016/s0301-472x(01)00742-1 -
Therapeutic Advances in Neurological... 2022Cerebrovascular events, especially ischemic stroke, are common complications of essential thrombocythemia (ET). Compared to JAK2V617 F mutation, CALR mutation is...
Cerebrovascular events, especially ischemic stroke, are common complications of essential thrombocythemia (ET). Compared to JAK2V617 F mutation, CALR mutation is considered as a lower risk factor of thrombosis in ET. Until now stroke in ET with CALR mutation has rarely been reported. We retrospectively investigated patients diagnosed with stroke and ET in Xijing hospital of Air Force Medical University, from 2015 to 2021. Clinical characteristics (including medical history, physical and auxiliary examination and prognosis) were recorded and associated literature was reviewed. Among the 19 patients diagnosed with both stroke and ET we retrieved, two cases were positive for CALR mutation. In case 1, a 71-year-old man developed the first ischemic event under the treatment of anagrelide, followed by a hemorrhagic stroke after receiving aspirin and clopidogrel for 4 months. Ischemic stroke reccurred and the neurological function deteriorated progressively. In case 2, a 44-year-old man presented with hypoxic-ischemic encephalopathy due to serious myocardial infarction and subsequent brain imaging indicated three times of ischemic stroke events. The patient gradually got improved through cytoreductive and antiplatelet therapy and rehabilitation. Literature review showed that cerebrovascular event is the most serious neurological complication of ET and may be the presenting symptom. Most of reported cases with ET accompanied by stroke were positive for JAK2 V617 F mutation, but with rare CALR mutation. ET with CALR mutation can cause both hemorrhagic and ischemic stroke. Identification of such rare causes of stroke is of great importance to provide precise and individualized prevention and therapy.
PubMed: 35498365
DOI: 10.1177/17562864221092093 -
American Journal of Hematology Jan 2019First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study;... (Comparative Study)
Comparative Study
First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-α, busulfan and anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis-free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7-6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of anagrelide. Whether or not anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Bone Marrow; Disease Progression; Disease-Free Survival; Drug Approval; Female; Fibrosis; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mortality; Platelet Aggregation Inhibitors; Polycythemia Vera; Primary Myelofibrosis; Prognosis; Proportional Hazards Models; Quinazolines; Retrospective Studies; Severity of Illness Index; Thrombocythemia, Essential; Thrombosis; Treatment Outcome; Young Adult
PubMed: 30252953
DOI: 10.1002/ajh.25294 -
Surgical Case Reports Jun 2019Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by thrombocytosis and a propensity for both thrombotic and hemorrhagic events. ET rarely...
BACKGROUND
Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by thrombocytosis and a propensity for both thrombotic and hemorrhagic events. ET rarely occurs simultaneously with colorectal cancer. Here, we report a case of colorectal cancer in an ET patient treated using laparoscopic ileocecal resection.
CASE PRESENTATION
A 40-year-old woman was admitted to our hospital after presenting with liver dysfunction. She had been previously diagnosed with ET; aspirin and anagrelide had been prescribed. Subsequent examination at our hospital revealed cecal cancer. Distant metastasis was absent; laparoscopic ileocecal resection was performed. Anagrelide was discontinued only on the surgery day. She was discharged on the seventh postoperative day without thrombosis or hemorrhage. However, when capecitabine and oxaliplatin were administered as adjuvant chemotherapy with continued anagrelide administration, she experienced hepatic dysfunction and thrombocytopenia; thus, anagrelide was discontinued. Five days later, her platelet count recovered. Subsequently, anagrelide and aspirin administration was resumed, without any adjuvant chemotherapy. Her liver function normalized gradually in 4 months. One-year post operation, she is well without tumor recurrence or new metastasis.
CONCLUSIONS
To our knowledge, this is the first report of laparoscopic colectomy performed on an ET patient receiving anagrelide. Our report shows that complications such as bleeding or thrombosis can be avoided by anagrelide administration. Contrastingly, thrombocytopenia due to anagrelide intake should be considered when chemotherapy that could cause bone marrow suppression is administered.
PubMed: 31227949
DOI: 10.1186/s40792-019-0660-3 -
European Journal of Haematology Aug 2019This study aimed to retrospectively assess the efficacy and safety of anagrelide in cytoreduction therapy-naïve essential thrombocythemia (ET) patients in a real-world...
OBJECTIVE
This study aimed to retrospectively assess the efficacy and safety of anagrelide in cytoreduction therapy-naïve essential thrombocythemia (ET) patients in a real-world setting.
METHOD
Data from 53 ET patients who received anagrelide as a first-line therapy were reviewed for patient characteristics, antiplatelet status, cytoreduction status, therapeutic effects, adverse events, thrombohemorrhagic event development, progression to myelofibrosis or acute leukemia, and cause of death.
RESULTS
The rate of achieving a platelet count of <600 × 10 /L during anagrelide monotherapy was 83.0%. Adverse events occurred in 32 of 53 patients, and tended to be slightly more severe in patients with cardiac failure; however, they were mostly tolerable. The therapeutic effect of anagrelide was consistent, regardless of genetic mutation profiles. The incidence of anemia as an adverse event was significantly higher in the CALR mutation-positive group. Favorable platelet counts were also achieved in patients for whom hydroxyurea was introduced as a replacement for anagrelide or in addition to anagrelide because of unresponsiveness or intolerance to treatment.
CONCLUSION
In Japanese cytoreduction therapy-naïve ET patients, anagrelide administration as a first-line therapy demonstrated favorable effects in reducing platelet counts, and its safety profile that was generally consistent with those in previous reports.
Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Disease Progression; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Mutation; Platelet Aggregation Inhibitors; Platelet Count; Quinazolines; Risk Factors; Thrombocythemia, Essential; Treatment Outcome; Young Adult
PubMed: 31107982
DOI: 10.1111/ejh.13265 -
Blood Jun 2006Recent insights into the molecular mechanisms of polycythemia vera (PV) and essential thrombocythemia (ET) are challenging the traditional diagnostic classification of... (Review)
Review
Recent insights into the molecular mechanisms of polycythemia vera (PV) and essential thrombocythemia (ET) are challenging the traditional diagnostic classification of these myeloproliferative disorders (MPDs). Clonality analysis using X-chromosome inactivation patterns has revealed apparent heterogeneity among the MPDs. The recently discovered single somatic activating point mutation in the JAK2 gene (JAK2-V617F) is found in the great majority of patients with PV, but also in many patients with phenotypically classified ET and other MPDs. In contrast to the acquired MPDs, mutations of the erythropoietin receptor and thrombopoietin receptor have been identified in familial forms of nonclonal erythrocytosis and thrombocytosis, respectively. The mechanisms of major clinical complications of PV and ET remain poorly understood. Quantitative or qualitative abnormalities of red cells and platelets do not provide clear explanations for the thrombotic and bleeding tendency in these MPDs, suggesting the need for entirely new lines of research in this area. Recently reported randomized clinical trials have demonstrated the efficacy and safety of low-dose aspirin in PV, and an excess rate of arterial thrombosis, major bleeding, and myelofibrotic transformation, but decreased venous thrombosis, in patients with ET treated with anagrelide plus aspirin compared to hydroxyurea plus aspirin.
Topics: Erythropoietin; Humans; Janus Kinase 2; Polycythemia Vera; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Thrombocythemia, Essential; Thrombopoietin
PubMed: 16484586
DOI: 10.1182/blood-2005-08-3526 -
Archives of Pathology & Laboratory... Aug 2006Properly managed, the myeloproliferative disorders are generally compatible with prolonged survival. Challenges to the hematologist include knowing when and how best to... (Review)
Review
CONTEXT
Properly managed, the myeloproliferative disorders are generally compatible with prolonged survival. Challenges to the hematologist include knowing when and how best to intervene to prevent and manage complications. The cytoreductive agent of choice for these disorders is currently hydroxyurea, emerging from randomized trials beginning with those of the Polycythemia Vera Study Group.
OBJECTIVE
To examine the roles and shortcomings of interventions (including hydroxyurea, antiplatelet agents, anagrelide, interferon, thalidomide, alkylating agents, cell cytopheresis, erythropoietins, splenectomy, bone marrow transplantation, and imatinib) for myeloproliferative disorders.
DATA SOURCES
This report uses actual case histories to illustrate the roles and shortcomings of these interventions.
CONCLUSIONS
Beyond phlebotomy for polycythemia vera, patients with polycythemia vera and essential thrombocythemia can be stratified by their risk for thrombosis, which guides the institution of cytoreductive therapies. High-risk patients generally benefit from cytoreductive therapy, and hydroxyurea has emerged as the agent of choice, because alkylating agents (and P32) have high leukemogenic potentials. Anagrelide and interferon are second-line agents. The addition of low-dose aspirin is beneficial for most, helping to prevent arterial thrombotic complications. Therapy in any of these disorders should be tailored to the unique characteristics of the individual patient. With myelofibrosis, therapeutic options run the gamut from observation, erythropoietic stimulators, cytotoxic agents, splenectomy, and bone marrow transplantation. Thalidomide and imatinib have shown some utility. Future challenges are the refinement of individualized treatment strategies and the development of targeted therapies based on rapidly expanding understanding of the molecular perturbations in these disorders.
Topics: Adult; Antineoplastic Agents; Female; Humans; Middle Aged; Phlebotomy; Platelet Aggregation Inhibitors; Polycythemia Vera; Primary Myelofibrosis; Thrombocythemia, Essential; Treatment Outcome
PubMed: 16879016
DOI: 10.5858/2006-130-1151-CMOTMD -
Experimental Hematology & Oncology 2018Patients with polycythemia vera (PV) have a higher mortality risk compared with the general population, primarily driven by cardiovascular disease, thrombotic events...
BACKGROUND
Patients with polycythemia vera (PV) have a higher mortality risk compared with the general population, primarily driven by cardiovascular disease, thrombotic events (TEs), and hematologic transformations. The goal of risk-adapted therapy in PV is prevention of TEs. Current treatment recommendations indicate that high-risk patients (aged ≥ 60 years and/or with history of TEs) should be managed with cytoreductive medications, phlebotomy, and low-dose aspirin. This noninterventional study was conducted to describe real-world cytoreductive medication treatment in adult patients with PV, stratified by risk, in the United States.
METHODS
This retrospective analysis used claims data from the Truven Health MarketScan database. Inclusion criteria were ≥ 2 nondiagnostic claims for PV ≥ 30 days apart, age ≥ 18 years, continuous enrollment during the preindex period (January 1 to December 31, 2012), and continuous enrollment or death during the postindex period (January 1, 2013, to December 31, 2014). Assessments included patient demographics, clinical characteristics, and treatment with cytoreductive medications.
RESULTS
A total of 2856 patients were identified for this analysis, including 1823 with high-risk PV and 1033 with low-risk PV. Mean (SD) age was 62.5 (13.5) years, and 65.9% of patients were male. Preindex comorbid conditions of interest were more common in high-risk than low-risk patients, including hypertension (65.0% vs 43.1%), type 2 diabetes (21.7% vs 10.1%), and congestive heart failure (6.6% vs 0.6%). Among patients who received preindex cytoreductive therapy, the most commonly used medications in high-risk (n = 666) and low-risk (n = 160) patients were hydroxyurea (94.7 and 87.5%, respectively), anagrelide (7.4 and 11.9%), and interferon (1.7 and 4.4%). Among patients who initiated cytoreductive therapy postindex, the most commonly used medications in high-risk (n = 100) and low-risk (n = 35) patients were hydroxyurea (97.0 and 91.4%, respectively), anagrelide (4.0 and 2.9%), and interferon (2.0 and 8.6%). Overall, 42.0% of high-risk and 18.9% of low-risk patients received cytoreductive medication during the preindex or postindex periods.
CONCLUSIONS
Despite consistent guideline recommendations for cytoreductive therapy in patients with high-risk PV, this analysis revealed that only a minority of these patients received cytoreductive medication. A notable proportion of high-risk patients with PV would likely benefit from a revised treatment plan that aligns with current guidelines.
PubMed: 30002948
DOI: 10.1186/s40164-018-0107-8 -
Journal of Thrombosis and Haemostasis :... Jun 2015Anagrelide is a cytoreductive agent used to lower platelet counts in essential thrombocythemia. Although the drug has been known to selectively inhibit megakaryopoiesis...
BACKGROUND
Anagrelide is a cytoreductive agent used to lower platelet counts in essential thrombocythemia. Although the drug has been known to selectively inhibit megakaryopoiesis for many years, the molecular mechanism accounting for this activity is still unclear.
OBJECTIVES AND METHODS
To address this issue we have compared the global gene expression profiles of human hematopoietic cells treated ex-vivo with and without anagrelide while growing under megakaryocyte differentiation conditions, using high-density oligonucleotide microarrays. Gene expression data were validated by the quantitative polymerase chain reaction and mined to identify functional subsets and regulatory pathways.
RESULTS
We identified 328 annotated genes differentially regulated by anagrelide, including many genes associated with platelet functions and with the control of gene transcription. Prominent among the latter was TRIB3, whose expression increased in the presence of anagrelide. Pathway analysis revealed that anagrelide up-regulated genes that are under the control of the transcription factor ATF4, a known TRIB3 inducer. Notably, immunoblot analysis demonstrated that anagrelide induced the phosphorylation of eIF2α, which is an upstream regulator of ATF4, and increased ATF4 protein levels. Furthermore, salubrinal, an inhibitor of eIF2α dephosphorylation, increased the expression of ATF4-regulated genes and blocked megakaryocyte growth.
CONCLUSIONS
These findings link signaling through eIF2α/ATF4 to the anti-megakaryopoietic activity of anagrelide and identify new potential modulators of megakaryopoiesis.
Topics: Activating Transcription Factor 4; Cell Cycle Proteins; Cell Proliferation; Cells, Cultured; Computational Biology; Databases, Genetic; Eukaryotic Initiation Factor-2; Gene Expression Profiling; Gene Expression Regulation; Gene Regulatory Networks; Hematologic Agents; Humans; Megakaryocytes; Oligonucleotide Array Sequence Analysis; Phosphorylation; Polymerase Chain Reaction; Protein Serine-Threonine Kinases; Quinazolines; Repressor Proteins; Signal Transduction; Thrombopoiesis; Time Factors
PubMed: 25851510
DOI: 10.1111/jth.12959 -
British Journal of Haematology Oct 1997Anagrelide, an inhibitor of platelet aggregation, decreases the number of platelets in normal subjects and in patients with myeloproliferative disorders. We describe...
Anagrelide, an inhibitor of platelet aggregation, decreases the number of platelets in normal subjects and in patients with myeloproliferative disorders. We describe studies aimed at discovering the general mechanism(s) by which anagrelide acts. We examined three hypotheses: (1) anagrelide shortens platelet survival, (2) anagrelide inhibits the proliferation of megakaryocytic-committed progenitor cells (CFU-M), and (3) anagrelide inhibits maturation of megakaryocytes. We observed that anagrelide did not shorten platelet survival. Proliferation of CFU-M in vivo was not affected by anagrelide, although high concentrations of anagrelide inhibited CFU-M in vitro. In-vivo and in-vitro anagrelide altered the maturation of megakaryocytes, causing a decrease in their size and changing other morphometric features. We conclude that anagrelide decreases the number of platelets primarily by interfering with the maturation of megakaryocytes.
Topics: Adult; Blood Platelets; Cell Division; Cell Survival; Cells, Cultured; Cellular Senescence; Female; Humans; Male; Megakaryocytes; Middle Aged; Platelet Aggregation Inhibitors; Quinazolines; Stem Cells
PubMed: 9359521
DOI: 10.1046/j.1365-2141.1997.3503164.x