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Medicine Jun 2018Thrombosis is the most common complication of thrombocytosis, which can be particularly damaging to reattached digits. We present a guideline about digital replantation...
INTRODUCTION
Thrombosis is the most common complication of thrombocytosis, which can be particularly damaging to reattached digits. We present a guideline about digital replantation when thrombocytosis is expected.
CASE PRESENTATION
We report a case of an 18-year-old man who sustained a traumatic amputation of two fingers and splenic rupture in a traffic accident. He underwent digital replantation the day after splenectomy when life-threatening conditions had been managed. The platelet count increased to over 1,300,000/mm and post-splenectomy reactive thrombocytosis was diagnosed. Hydroxyurea and anagrelide were administered to control the platelet count after consultation with a hematologist. The reattached fingers survived without any complication.
CONCLUSION
In patients with digital amputation, replantation can be attempted, even when thrombocytosis is expected, when requested by the patient. Furthermore, the platelet count should be actively controlled with medication to improve the survival rate of the reattached finger.
Topics: Adolescent; Amputation, Traumatic; Finger Injuries; Fingers; Humans; Hydroxyurea; Male; Platelet Count; Quinazolines; Replantation; Splenectomy; Splenic Rupture; Thrombocytosis
PubMed: 29851840
DOI: 10.1097/MD.0000000000010951 -
Case Reports in Dermatological Medicine 2018Hydroxycarbamide (HC) is the first-line treatment for certain myeloproliferative neoplasms, such as polycythemia vera and essential thrombocytosis (ET). In a subset of...
Hydroxycarbamide (HC) is the first-line treatment for certain myeloproliferative neoplasms, such as polycythemia vera and essential thrombocytosis (ET). In a subset of these patients long-term treatment with HC can result in the development of confluent actinic keratoses (AK) followed by invasive keratinocytic carcinomas ("squamous dysplasia"), preferentially on sun-exposed skin. Discontinuation or dose reduction of HC may result in partial improvement. A 59-year-old farmer after 14 years on HC (2 gr/d) and acetylsalicylic acid (100 mg/d) for ET, was referred for numerous, hyperkeratotic AK on face, scalp, and hands that could not be controlled with repeated ( = 15) cryosurgery sessions in the previous 3 years. Acitretin (0.32 mg/kg daily) and topical treatments (cryosurgery with ingenol mebutate) were initiated with only marginal improvement after 3 months. Acitretin dose was doubled and HC was switched to anagrelide (0.5 mg twice daily). Within a month the AK load regressed significantly and, at 3 months follow-up, complete clinical remission was achieved and acitretin was discontinued. Twenty months later the patient is clear from AK. In conclusion, the impressive and sustainable AK remission under anagrelide draws attention to a possible role of the phosphodiesterase 3 pathway, the major pharmacological target of anagrelide, as a potential therapeutic target for keratinocytic cancers.
PubMed: 29780645
DOI: 10.1155/2018/2874012 -
British Journal of Haematology Jun 2018Somatic mutations in the calreticulin (CALR) gene have been found in most patients with JAK2- and MPL-unmutated Philadelphia chromosome-negative myeloproliferative...
Somatic mutations in the calreticulin (CALR) gene have been found in most patients with JAK2- and MPL-unmutated Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). It has recently been shown that mutant CALR constitutively activates the thrombopoietin receptor MPL and, thus, plays a causal role in the development of MPNs. However, the roles of mutant CALR in human haematopoietic cell differentiation remain predominantly elusive. To examine the impact of the 5-base insertion mutant CALR gene (Ins5) on haematopoietic cell differentiation, we generated induced pluripotent stem cells from an essential thrombocythaemia (ET) patient harbouring a CALR-Ins5 mutation and from a healthy individual (WT). Megakaryopoiesis was more prominent in Ins5-haematopoietic progenitor cells (Ins5-HPCs) than in WT-HPCs, implying that the system recapitulates megakaryocytosis observed in the bone marrow of CALR-mutant ET patients. Ins5-HPCs exhibited elevated expression levels of GATA1 and GATA2, suggesting a premature commitment to megakaryocytic differentiation in progenitor cells. We also demonstrated that 3-hydroxy anagrelide markedly perturbed megakaryopoiesis, but not erythropoiesis. Collectively, we established an in vitro model system that recapitulates megakaryopoiesis caused by mutant CALR. This system can be used to validate therapeutic compounds for MPN patients harbouring CALR mutations and in detailed studies on mutant CALR in human haematological cell differentiation.
Topics: Calreticulin; Cell Differentiation; Female; GATA1 Transcription Factor; GATA2 Transcription Factor; Hematopoietic Stem Cells; Humans; Induced Pluripotent Stem Cells; Male; Megakaryocytes; Mutation; Myelopoiesis
PubMed: 29741776
DOI: 10.1111/bjh.15266 -
BMJ Case Reports Feb 2018Anagrelide is a phosphodiesterase-3 inhibitor used in the treatment of essential thrombocythaemia. Cardiovascular side effects such as ventricular tachycardia and...
Anagrelide is a phosphodiesterase-3 inhibitor used in the treatment of essential thrombocythaemia. Cardiovascular side effects such as ventricular tachycardia and cardiomyopathy are rare but potentially fatal and should be made known to patients before starting the medication. It usually arises within the first 6 months after initiation of therapy and may be dose related. The elderly population are particularly susceptible. These cardiotoxicities result from an increase in cyclic AMP that induces positive inotropic and chronotropic effects and are often reversible with cessation of use. We report a case of a 78-year-old woman with essential thrombocythaemia and recently started on anagrelide who presented with syncope and multiple bruises and facial trauma and found to have developed ventricular tachyarrhythmia.
Topics: Age Factors; Aged; Electrocardiography; Female; Humans; Hydroxyurea; Platelet Aggregation Inhibitors; Quinazolines; Risk Factors; Tachycardia, Ventricular; Thrombocythemia, Essential
PubMed: 29437800
DOI: 10.1136/bcr-2017-220723 -
Medicine Nov 2017Primary myelofibrosis is encountered with the myeloproliferative diseases and is the least prevalent among women of childbearing age. The prognosis is guided by... (Review)
Review
RATIONALE
Primary myelofibrosis is encountered with the myeloproliferative diseases and is the least prevalent among women of childbearing age. The prognosis is guided by pancytopenia, leukemic transformation and thrombosis which are the dominant complications.
PATIENT CONCERNS
Data regarding protocol management during pregnancy in the context of myelofibrosis are insufficient. Fewer than ten cases have been described until now and half of this cases have resulted in fetal death due to placental infarction during the second and third trimesters.
DIAGNOSES
We present the case of a 34-year-old pregnant woman diagnosed with Jak 2- negative primary myelofibrosis. Personal history did not include miscarriage or stillbirth.
INTERVENTIONS
The patient was previously treated with anagrelide hydrochloride, which was interrupted at 6 weeks of gestation when the pregnancy was confirmed. It was replaced with Interferon-a 3 MU/day. Because of severe thrombocytosis, administration of aspirin 150 mg/day was recommended.
OUTCOMES
The pregnancy was uneventful. The patient was hospitalized at 33 weeks of gestation because of moderate vaginal bleeding and high risk of preterm birth. After a specialized hematological investigation, the treatment with aspirin was replaced with low-molecular-weight heparin 0.6 ml per day. This combined treatment assisted in the natural tendency to lower platelet counts during pregnancy and resulted in stabilization of the hematological status. At 38 weeks of gestation the patient delivered a healthy baby boy via cesarean. He weight 2850 grams and his Apgar score was 9. Anticoagulant and interferon treatments were continued post-partum under hematologist surveillance.
LESSONS
This case was rare and complex. Because it was related to pregnancy it required continuos collaboration and supervision between obstetrician and hematologist.
Topics: Adult; Aspirin; Cesarean Section; Drug Therapy, Combination; Female; Fibrinolytic Agents; Heparin, Low-Molecular-Weight; Humans; Live Birth; Pregnancy; Pregnancy Complications; Primary Myelofibrosis; Treatment Outcome
PubMed: 29145319
DOI: 10.1097/MD.0000000000008735 -
Haematologica Jan 2018Evaluation of Anagrelide (Xagrid) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk...
Treatment of essential thrombocythemia in Europe: a prospective long-term observational study of 3649 high-risk patients in the Evaluation of Anagrelide Efficacy and Long-term Safety study.
Evaluation of Anagrelide (Xagrid) Efficacy and Long-term Safety, a phase IV, prospective, non-interventional study performed in 13 European countries enrolled high-risk essential thrombocythemia patients treated with cytoreductive therapy. The primary objectives were safety and pregnancy outcomes. Of 3721 registered patients, 3649 received cytoreductive therapy. At registration, 3611 were receiving: anagrelide (Xagrid) (n=804), other cytoreductive therapy (n=2666), or anagrelide + other cytoreductive therapy (n=141). The median age was 56 70 years for anagrelide other cytoreductive therapy. Event rates (patients with events/100 patient-years) were 1.62 2.06 for total thrombosis and 0.15 0.53 for venous thrombosis. Anagrelide was more commonly associated with hemorrhage (0.89 0.43), especially with anti-aggregatory therapy (1.35 0.33) and myelofibrosis (1.04 0.30). Other cytoreductive therapies were more associated with acute leukemia (0.28 0.07) and other malignancies (1.29 0.44). multivariate analyses identified increased risk for thrombosis with prior thrombohemorrhagic events, age ≥65, cardiovascular risk factors, or hypertension. Risk factors for transformation were prior thrombohemorrhagic events, age ≥65, time since diagnosis, and platelet count increase. Safety analysis reflected published data, and no new safety concerns for anagrelide were found. Live births occurred in 41/54 pregnancies (76%).
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Biomarkers; Cell Transformation, Neoplastic; Disease Management; Disease Progression; Europe; Female; Humans; Male; Middle Aged; Mortality; Pregnancy; Pregnancy Complications, Hematologic; Prospective Studies; Quinazolines; Risk Assessment; Thrombocythemia, Essential; Treatment Outcome; Young Adult
PubMed: 29079600
DOI: 10.3324/haematol.2017.174672 -
Pharmacological Research Feb 2018Exaggerated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as... (Review)
Review
Exaggerated Janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling is key to the pathogenesis of pro-inflammatory disorders, such as rheumatoid arthritis and cardiovascular diseases. Mutational activation of JAKs is also responsible for several haematological malignancies, including myeloproliferative neoplasms and acute lymphoblastic leukaemia. Accumulating evidence links adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), an energy sensor and regulator of organismal and cellular metabolism, with the suppression of immune and inflammatory processes. Recent studies have shown that activation of AMPK can limit JAK-STAT-dependent signalling pathways via several mechanisms. These novel findings support AMPK activation as a strategy for management of an array of disorders characterised by hyper-activation of the JAK-STAT pathway. This review discusses the pivotal role of JAK-STAT signalling in a range of disorders and how both established clinically used and novel AMPK activators might be used to treat these conditions.
Topics: AMP-Activated Protein Kinases; Animals; Humans; Inflammation; Interleukin-6; Janus Kinases; STAT Transcription Factors; Signal Transduction
PubMed: 29037480
DOI: 10.1016/j.phrs.2017.10.001 -
Leukemia Feb 2018The multistep process of TP53 mutation expansion during myeloproliferative neoplasm (MPN) transformation into acute myeloid leukemia (AML) has been documented...
The multistep process of TP53 mutation expansion during myeloproliferative neoplasm (MPN) transformation into acute myeloid leukemia (AML) has been documented retrospectively. It is currently unknown how common TP53 mutations with low variant allele frequency (VAF) are, whether they are linked to hydroxyurea (HU) cytoreduction, and what disease progression risk they carry. Using ultra-deep next-generation sequencing, we examined 254 MPN patients treated with HU, interferon alpha-2a or anagrelide and 85 untreated patients. We found TP53 mutations in 50 cases (0.2-16.3% VAF), regardless of disease subtype, driver gene status and cytoreduction. Both therapy and TP53 mutations were strongly associated with older age. Over-time analysis showed that the mutations may be undetectable at diagnosis and slowly increase during disease course. Although three patients with TP53 mutations progressed to TP53-mutated or TP53-wild-type AML, we did not observe a significant age-independent impact on overall survival during the follow-up. Further, we showed that complete p53 inactivation alone led to neither blast transformation nor HU resistance. Altogether, we revealed patient's age as the strongest factor affecting low-burden TP53 mutation incidence in MPN and found no significant age-independent association between TP53 mutations and hydroxyurea. Mutations may persist at low levels for years without an immediate risk of progression.
Topics: Adult; Aged; Aged, 80 and over; Alleles; Disease Progression; Female; Gene Frequency; High-Throughput Nucleotide Sequencing; Humans; Hydroxyurea; Janus Kinase 2; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Retrospective Studies; Tumor Suppressor Protein p53; Young Adult
PubMed: 28744014
DOI: 10.1038/leu.2017.230 -
Cancer Medicine Jun 2017Aim of this study is to explore the role of different treatments on the development of secondary malignancies (SMs) in a large cohort of essential thrombocythemia (ET)...
Aim of this study is to explore the role of different treatments on the development of secondary malignancies (SMs) in a large cohort of essential thrombocythemia (ET) patients. We report the experience of a regional cooperative group in a real-life cohort of 1026 patients with ET. We divided our population into five different groups: group 0, no treatment; group 1, hydroxyurea (HU); group 2, alkylating agents (ALK); group 3, ALK + HU sequentially or in combination; and group 4, anagrelide (ANA) and/or α-interferon (IFN) only. Patients from groups 1, 2, and 3 could also have been treated either with ANA and/or IFN in their medical history, considering these drugs not to have an additional cytotoxic potential. In all, 63 of the 1026 patients (6%) developed 64 SM during the follow-up, after a median time of 50 months (range: 2-158) from diagnosis. In univariate analysis, a statistically significant difference was found only for gender (P = 0.035) and age (P = 0.0001). In multivariate analysis, a statistically significant difference was maintained for both gender and age (gender HR1.7 [CI 95% 1.037-2.818] P = 0.035; age HR 4.190 [CI 95% 2.308-7.607] P = 0.0001). The impact of different treatments on SMs development was not statistically significant. In our series of 1026 ET patients, diagnosed and followed during a 30-year period, the different therapies administered, comprising HU and ALK, do not appear to have impacted on the development of SM. A similar rate of SMs was observed also in untreated patients. The only two variables which showed a statistical significance were male gender and age >60 years.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Fibrinolytic Agents; Humans; Hydroxyurea; Interferon-alpha; Male; Middle Aged; Neoplasms, Second Primary; Quinazolines; Thrombocythemia, Essential; Young Adult
PubMed: 28544749
DOI: 10.1002/cam4.1081