Diagnosis Of Essential Thrombocytosis Research Articles

Approach to the Diagnosis and Management of Essential Thrombocytosis in a Resource-Limited Setting

Essential thrombocytosis (ET) is a myeloproliferative neoplasm (together with polycythemia vera, chronic myelogenous leukemia, and primary myelofibrosis) characterized by clonal proliferation of megakaryocytes, usually due to the presence of JAK2, CALR, or MPL mutations. Whereas a bone marrow aspirate and genetic testing for these mutations are necessary for an accurate diagnosis of ET, in resource-limited settings, these are often either inaccessible or limited by prohibitive costs. A nuanced clinical approach is necessary to diagnose and manage ET in these settings. In this study, we present a case of ET diagnosed and managed in a resource-limited rural setting in Kenya with hydroxyurea and aspirin. We highlight the importance of individualized therapeutic targets, the challenges with dose adjustments in the setting of hydroxyurea-induced neutropenia, and how extrapolated data from the use of hydroxyurea elsewhere may help guide such dose adjustments. Finally, we propose a rationalized approach to treating ET in a resource-limited clinical setting.

Splanchnic venous thrombosis and recurrent spontaneous abortion due to latent essential thrombocytosis revealed after 20 years: Case report

A 50-year old housewife presented to our department with recurrent pain and bluish discoloration of bilateral lateral two toes for 1 year. She had multiple thrombotic complications (portal vein thrombosis, small bowel ischemia, and recurrent abortions) at the age of 30 years for which a cause was not identified. She had a long asymptomatic period of 20 years following that and was diagnosed to have essential thrombocytosis (ET) when she was admitted with digital ischemia. She was started on hydroxyurea and aspirin. She had significant improvement in her ischemic symptoms and the platelet counts and white blood counts came down on follow-up. We present a patient with multiple thrombotic complications during the masked phase of ET (with normal platelet counts) which was not reported previously to the best of our knowledge. A very long asymptomatic period of 20 years between the first thrombotic event and the later events revealing the diagnosis of ET is unusual.

Essential thrombocytosis: diagnosis, differential diagnosis, complications and treatment considerations of relevance for acardiologist.

Essential thrombocytosis (ET) is arare haematological malignancy, with an incidence rate of 1.5-2.5/100,000 per year. For many patients with ET the first manifestation of their underlying disease is athrombotic or haemorrhagic complication. Arecent retrospective study revealed an incidence rate of at least 2.1% in people under 40years presenting with an acute coronary syndrome, although the diagnosis was initially missed in all cases. Thus, cardiologists face amuch higher than average incidence rate of ET in their daily practice, but seem insufficiently aware of the disease. The current review summarises symptoms, (differential) diagnosis, complications and treatment considerations of ET of relevance for acardiologist. Typical symptoms, besides thrombosis and haemorrhage, include erythromelalgia and aquagenic pruritus, while platelets > 450 × 109/l are adiagnostic for ET once other myeloproliferative neoplasms, secondary and spurious thrombocytosis have been excluded. With regard to treatment, timing of revascularisation depends on the presence of ischaemia and concurrent platelet counts. In the presence of ischaemia, revascularisation should not be delayed and adequate platelet counts can be achieved by platelet apheresis. In the absence of ischaemia, revascularisation can be delayed until adequate platelet counts have been achieved by cytoreductive therapies. Cardiologists should be aware of/screen for possible ET.

Essential Thrombocytosis in Patients

In patients under <40 years, traditional cardiovascular (CV)-risk factors are a less likely cause of acute coronary syndromes (ACS) compared to older counterparts. To estimate the prevalence of essential thrombocytosis (ET), a hematological disorder and less-prevalent risk factor, in young patients presenting with ACS. We constructed a retrospective database of all patients <40 years (n=271) that had consecutively undergone coronary angiography (CAG) after theirfirstACS within our hospital within the last ten years (2010-2020) and had known thrombocyte counts (n=241). Patients with thrombocytes >450x10*9/L were screened for this hematological disorder. In our database, we identified 15 subjects with thrombocytosis. One was previously known as ET. Of the remaining 14 patients, five were considered reactive/secondary thrombocytosis, and four were lost to follow-up, four were eventually diagnosed with ET, one remains uncertain. The diagnosis was newly established before the initiation of this study in two patients (average delay: six years). Two patients were identified as a result of this study. Conclusion: With a prevalence of at least 2.1%, ET appears not uncommon in patients <40 years with ACS. Moreover, screening patients with ACSandelevated thrombocytes yielded a novel diagnosis of ET in 27% of patients. The diagnosis was initially missed in all cases. Since the timing of revascularization should be adjusted to thrombocyte count/initiation of ET therapy to prevent thrombotic complications, cardiologists should know, recognize and screen for this pathology in ACS-patients, notably in those with absent traditional CV-risk factors: an 'ACS-protocol' aimed at less-prevalent risk factors could support this.

Myeloproliferative neoplasms – a global view

Myeloproliferative neoplasms – a global view

Evaluation of Thromboembolism According to Mutation Status in Patients with Essential Thrombocytosis; Single-Center Experience

ABSTRACT&#x0D; Aim: The presence of Janus kinase 2 (Jak2) mutation in essential thrombocytosis (ET) patients is associated with an increased risk of thrombosis, while the presence of calreticulin (Calr) mutation is associated with a decrease in thrombosis risk. The aim of this study is to compare patients with mutation (Jak2, Calr, myeloproliferative leukemia virus oncogene [Mpl]) and non-mutation (triple-negative) patients in terms of the development of thromboembolism.&#x0D; Methods: 95 patients who were followed up with the diagnosis of ET between 2009 and 2020 were included in this study. The clinical characteristics, laboratory results, and mutation status of the patients were analyzed retrospectively, based on the patients’ files. The patients in mutation positive (Jak2, Calr, Mpl) group a, only jak2 mutation-positive group b, and triple-negative (Jak2, Calr, Mpl negative) group c were compared.&#x0D; Results: The median age of ET patients was 53 years (18-91). The Jak2 mutation was found positive in 42% (n:40) of the patients with ET. 4 patients (4%) were calr mutation-positive, but mpl mutation was not detected. 51 patients (54%) were triple-negative. A total of 22 (23%) patients had a thrombotic event at diagnosis and follow-up. Thrombotic events were detected in 27.5% (11/44) of the patients with positive Jak2 mutation and in 21.5% (11/51) of the patients with triple-negative. No thrombotic event was detected in 4 patients with a positive calr mutation. No statistically significant difference was found for thrombotic events in mutation-positive patients compared with triple-negative patients (p = 0.7). No statistically significant difference was found in terms of white blood cell count, thrombocyte count and spleen size examined at the time of diagnosis. When compared in terms of hemoglobin, age and gender distribution (male / female), the difference was found statistically significant in those with positive mutation (p = 0.001 *, p = 0.001 *, p = 0.03*).&#x0D; Discussion and Conclusion: The results of this study showed that Jak2V617F gene mutation is an important finding for diagnosis and complications in patients with ET, and its presence increases the risk of thrombosis development. The presence of calr mutation reduces the risk of thrombosis and appears at an earlier age than Jak2V617F mutation. Thrombosis risk in triple-negative ET patients is similar to the one in patients with Jak2V617F mutation.

Dural Venous Sinus Thrombosis and Papilledema Related to JAK2 Mutation: A Case Series.

Dural venous sinus thrombosis (DVST) is an important cause of papilledema. Patients diagnosed with DVST should undergo work-up for underlying hypercoagulable state, including genetic causes. One important prothrombotic mutation is in the JAK2 gene, which is a driver of myeloproliferative neoplasms including polycythemia vera (PV). We aimed to determine the prevalence of JAK2 mutation in patients in presenting to neuro-ophthalmology clinic with DVST and papilledema. Retrospective case series of patients seen in a tertiary neuro-ophthalmology practice who presented with papilledema due to DVST and were investigated for presence of JAK2 mutation. Four out of 15 patients with DVST (26%) were found to have JAK2 V617F mutation which led to subsequent diagnosis of PV in 2. One additional patient had a known diagnosis of essential thrombocytosis. We describe the clinical presentation of these four patients with papilledema and JAK2 mutation. A significant proportion of patients with papilledema secondary to DVST will harbor mutations in the JAK2 gene. Clinicians should be aware of this mutation as early testing will facilitate timely diagnosis and treatment of myeloproliferative disease to improve prognosis and reduce risk of recurrent thrombotic events.

Mutation profile in BCR-ABL1-negative myeloproliferative neoplasms: A single-center experience from India

Objective/BackgroundRecurrent somatic mutations in the JAK2, calreticulin (CALR), and the MPL genes are described as drivers of BCR-ABL1-negative myeloproliferative neoplasms (MPN) that includes polycythemia vera (PV), essential thrombocytosis (ET), primary myelofibrosis (PMF), and MPN unclassified (MPN-U). MethodsWe describe the mutation profile and clinical features of MPN cases diagnosed at a tertiary care center. JAK2V617F and MPL (S505/W515) mutations were screened by allele-specific polymerase chain reaction, while CALR exon 9 and JAK2 exon 12 mutations were screened by fragment analysis/Sanger sequencing. Among the 1,570 patients tested for these mutations during the study period, 407 were classified as MPN with a diagnosis of PV, ET, PMF, and MPN-U seen in 30%, 17%, 36%, and 17%, respectively, screened. ResultsSimilar to previous reports from Asian countries, the incidence of PMF was the highest among the classic MPN. JAK2V617F mutation was detected in 90% of PV, 38% of ET, 48% of PMF, and 65% of MPN-U. JAK2 exon 12 mutations were seen in 5.7% of PV and 1.4% of PMF. CALR exon 9 mutations were seen in 33% of ET, 33% of PMF, and 12% of MPN-U. MPL mutations were detected in 2.8%, 2.7%, and 2.9% of ET, PMF, and MPN-U, respectively. Fifteen % of PMF, 26% of ET, and 22% of MPN-U were triple negative. ConclusionThere was a significantly higher incidence of CALR mutation in PMF and ET cases. Our study highlights the challenges in the diagnosis of JAK2-negative PV and the need for harmonization of criteria for the same.

ESSENTIAL THROMBOCYTOSIS IS THE INTERSECTION OF HEMATOLOGY AND CARDIOLOGY. Review

Relevance. Essential thrombocytosis (ET) is a pathology of clonal hematopoietic stem cells, which is manifested by increased platelet formation. This pathology is quite rare and refers to myeloproliferative diseases. It is more common for women in two age groups: 50-70 y.o. and 20-30 y.o.&#x0D; Objective. Evaluate diagnostic criteria, determine the risk of complications and, depending on this, a treatment plan for essential thrombocytosis.&#x0D; Methods. Analysis of scientific publications in PubMed by keywords for the period 2006-2020. Case Comparison.&#x0D; Results. The article discusses the pathogenesis, clinical picture, diagnostic criteria, determining the risk of complications and, depending on this, the treatment plan. ET is characterized with an increase in the number of megakaryocytes (MGKC) in the bone marrow (BM) and morphological changes in platelets, resulting in functional impairment of the latter. ET has long asymptomatic period. Manifestations of the disease are opposite: thrombosis and bleeding. Among multiple vessels that can be impaired, thrombosis of coronary arteries with a myocardial infarction development occurs in 5,3-12% of patients. In this clinical case patients have to be treated according to the guidelines of management of acute coronary syndrome, however they also have to start pathogenetic treatment. The article provides a clinical example illustrating the need for early pre-asymptomatic diagnosis of ET. In this clinical case, modern algorithms for the diagnosis and treatment of such complications of ET as myocardial infarction are considered.&#x0D; Conclusions. From the above we can conclude that early asymptomatic diagnosis of ET is needed for stratification of the risk of thromboembolic complications according to new recommendations with timely startetd pathogenetic therapy.

Quantification of IGF-1 Receptor May be Useful in the Differential Diagnosis of Essential Thrombocytosis from Reactive Thrombocytosis- Suggested to Add IGF-1Receptor Quantification As the Minor Criteria for the Diagnosis of ET

Introduction. The 2016 revision to the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia lists the criteria for the diagnosis of essential thrombocythemia (ET ) as 1) Platelet count more than 450 x 109/L 2) BM biopsy 3) Not meeting WHO criteria for BCR-ABL CML, PV, PMF, myelodysplastic syndromes, or other myeloid neoplasms, 4) Presence of JAK2, CALR, or MPL mutation The minor criteria included Presence of a clonal marker or absence of evidence for reactive thrombocytosis .Among these criteria , the most reliable criteria for diagnosis of ET is the presence of JAK2, CALR, or MPL mutation, these mutually exclusive mutations with respective incidences of 55%, 25%, and 3% , so approximately 17% are so called ET . These 17 % cases will depend on other criterias to make a definite diagnosis as ET. Bone marrow criteria is helpful in some cases but in many cases, the differential from re-active thrombocytosis (RT) could be misleading , So a substantial portion of triple-negative patients with ET have evidence of polyclonal: the use of cytoreductive drugs in these patients is questionable We have recently published using IGF-1R quantification by flow cytometry could be helpful in differentiating polycythemia from secondary polycythemia Now we also found quantification of IGF-1R by flow cytometry to be helpful in the diagnosis of ET from reactive thrombocytosis. Materials and Methods: Nineteen patients with ET (treatment naive), 20 with reactive thrombocytosis (RT) (5 sickle cell disease, 5 arthritis, 5 iron deficiency, 3 metastatic Cancer, 2 with infection, one with bleeding) and 23 normal volunteer controls were studied. Flow cytometry: MNC were isolated from peripheral blood then incubated with fluorophore-conjugated primary antibody or isotype controls for 30 min at room temperature and analyzed by FACS Calibur System (BD Biosciences, San Jose, CA). PE-conjugated antibody against human IGF-1R was purchased from R&D Systems. Results: Untreated ET patients had significantly higher IGF-1R (290.8, 86.83-475.2) than RT patients (127.0, 47.75-177.2),(P =220 means that a patient belongs to ET group, with sensitivity of 47.4% and specificity equal to 94.7%. Conclusion: Quantification of IGF-1 receptor may be useful in the differential diagnosis of Essential thrombocythemia from reactive thrombocytosis, especially in those cases where no driver mutations were detected (triple negative). Disclosures Wang: Celgen: Research Funding.

Tumor Markers in Diagnosis and Follow up of Haematologic Malignancies

Purpose: Τo estimate the incidence of abnormal values of tumor markers CA 15-3, CA125, CA19-9 and CEA at diagnosis and relapse/deterioration or remission of patients with hematological malignancies. Also, correlating them with the burden of disease at diagnosis and relapse/deterioration or remission of the above diseases.Material-methods: Studied 268 patients, aged 16-95 years, who suffered from 14 hematological malignancies: myelodysplastic syndromes (MDS), idiopathic thrombocytosis, polycythemia vera, primary myelofibrosis, chronic myelogenous leukemia (CML), Hodgkin's and Non- Hodgkin's(NHL) lymphomas, chronic lymphocytic leukemia (CLL), multiple myeloma (M.M.), acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), mastocytosis, hairy cell leukemia and hypereosinophilic syndrome. Tumor markers were determined by electrochemiluminescence immunoassay method, based on the principle of double immunofluorescence conducted by analyzer Hitachi Modular E170, subunit Elecsys.Results: Tumor marker CA15-3 showed pathological values at diagnosis of hematological malignancies, except MDS and AML, which correlate with high disease burden at diagnosis of essential thrombocytosis(p <0,05), polycythemia vera(p <0.05) and NHL(p <0,001). Tumor marker CA125 had abnormal values at diagnosis of NHL and M.M, which correlate with high disease burden at diagnosis of NHL(p <0,01). CA19-9 and CEA showed no pathological values at diagnosis of hematological malignancies. CA15-3 showed pathological values at relapse/ deterioration of hematological malignancies, except for AML and ALL. These values correlate with the degree of relapse/deterioration of MDS(p <0,001), idiopathic thrombocytosis(p <0,01), lymphoma Hodgkin’s(p <0,05), NHL(p <0,001) and CLL (p <0,01). CA125 showed pathological values at relapse/deterioration of M.M, NHL and CLL. These values correlate with the degree of relapse/deterioration of NHL(p <0,01) and CLL(p <0,05). CEA had pathological values at relapse/deterioration of M.M. CA19-9 had no significant findings at relapse/deterioration of hematological malignancies. Pathological values of CA15-3 decreased to normal levels during the remission of hematological malignancies, apart from MDS, primary myelofibrosis and AML. Decline of these values correlate with the degree of remission of Hodgkin’s lymphomas(p <0,05), NHL(p <0,001), CLL(p <0,01) and idiopathic thrombocytosis (p <0,01). Pathological values of CA125 decreased to normal levels during the remission of M.M, NHL and CLL. Decline of these values correlate with the degree of remission of NHL(p <0,01) and CLL(p <0,05). CA19-9 and CEA had no significant findings at remission of hematological malignancies.Conclusions: CA15-3 is a surrogate marker at diagnosis of hematological malignancies, other than MDS and AML. It can determine relapse/deterioration or remission in idiopathic thrombocytosis, MDS, NHL, Hodgkin's lymphomas and CLL. CA125 is a surrogate marker at diagnosis of NHL and M.M. It can determine relapse/deterioration or remission in NHL and CLL. CEA can help detect relapse/ deterioration in M.M. CA19-9 has no value in diagnosing and monitoring of hematological malignancies. Further studies in this area will likely bring new knowledge about tumor markers and their utility in current practice. DisclosuresNo relevant conflicts of interest to declare.

Gender Is a Core Modifier of Disease Outcomes and Survival in the MPN

Introduction: Host modifiers contribute to variation in disease pathogenesis and clinical features in the myeloproliferative neoplasms (MPN), essentialthrombocytosis (ET), polycythemia vera (PV), and myelofibrosis (MF).Gender modifies the JAK2 V617F allele burden (women had lower levels and lower annual increases), influences PV gene expression (men had twice as many differentially-regulated genes as women) and influences thrombotic events (a predominance of abdominal vein thrombosis in women). The MPN symptom burden also appears to differ by gender. In this analysis, we describe gender differences in disease presentation and outcome in relation tomutational status. Methods: We analyzed a prospective cohort of 612 PV, ET and MF patients enrolled between 2005 and 2013 to study genomic modifiers of the MPN and disease outcomes. We stratified disease evolution and survival by both gender and mutational status. Results: In this cohort, 26% were newly diagnosed, and 61% were female. The current median follow-up is 8 years (&gt; 4800 patient-years) and 110 have died. Prevalence of Molecular lesions JAK2 V617F was identified in 468/612 MPN patients (76%; 61% female), and comprised the majority of ET (62%; 70% female), PV (99.5%; 59% female), MF (62%; 39% female) and post MPN AML (80.7%; 38% female) patients. CALR mutations were identified in 81/612 MPN patients (13%; 58% female), representing 23% of all ET (59% female), and 21 % of all MF (52% female) and 3.8% of post MPN AML. MPL mutations were identified in 9 MPN patients (1.5%): 7 females with ET, and 2 males with MF. Disease presentation Among JAK2 V617F positive patients, more females presented with ET compared to males (43% vs 29%; p=0.002) and more males presented with MF (21% vs 9%; p=0.001). Gender differences in presentation were less apparent in those with CALR -mutated ET (59% women) and MF (53% women). Disease transformation By gender, among 197 women with an original diagnosis of ET, 62% retained their phenotype, whereas 20%, 17%, and 1.5% evolved to PV, MF, and AML, respectively. Among men with ET, 63% retained their phenotype, while 16%, 20%, and 1.1% evolved to PV, MF, and AML. Among MF patients, regardless of mutational status, 1 (3%) women and 5 (10%) men evolved to AML (p=0.39). With regard to transformations by gender, rates of MF (16% in both) and AML (2.6% and 5.5%p=0.083) were similar between women and men. Among 123 JAK2V617F- positive ET women, during the follow-up period, 66 (54%) retained an ET phenotype, while 32%, 14%, and 0.8% evolved to PV, MF, and AML, respectively. Among 53 JAK2V617F-positive ET men, 54% retained an ET phenotype; 25%, 17%, and 4% evolved to PV, MF, and AML, respectively. Among 141 JAK2V617F-positive PV females, 109 (77%) retained PV, 26 (18%) evolved to MF, and 6 (4%) evolved to AML (1 via MF, 5 PV to AML); among 100 JAK2V617F-positive males, 73% retained a PV phenotype, 20% evolved to MF, and 7% to AML (3 PV to AML, 4 via MF phase). Among JAK2V617F -positive patients with an original MF diagnosis, 1/20 (5%) and 3/31 (10%) women and men evolved to AML (p=NS); 22% vs. 18% of JAK2V617F -positive men versus women evolved to MF or AML (p=0.28). No CALR -mutated ET patient evolved to PV. Of 38 CALR- ET women, 27 (71%) retained their phenotype, 10 evolved to MF (26%), and 1 to AML (3%). Among the 26 CALR -mutated ET men, 81% retained their phenotype, while 19% evolved to MF (no AML transformations). Survival The proportion of deaths differed by gender; of the 612 patients, despite the predominance of females in the cohort, at the time of last follow-up, there were 110 deaths (18%): 50/375 women died, compared to 60/237 men (13% vs. 25%; p value=0.0002). A larger proportion of male deaths were due to MF and MF to AML, but this was not statistically different (male deaths in MF/AML phase: 54/60; (90%); women 38/50 (75%); p=0.0692)). Conclusion: We identified a gender influence on disease distribution at presentation, particularly in the JAK2V617F-positive subset with females presenting more commonly with ET and males more commonly with MF. Despite the predominance of females in this MPN cohort, the distribution of females at presentation and evolution into more indolent phenotypes compared to males and a trend toward lower rates of AML evolution may have accounted for longer disease duration and fewer deaths in females compared to males. This trend in MPN evolution complements a theme of gender differences in symptom burden, clinical consequences, and genomic changes. Disclosures Stein: Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees. Spivak:Incyte: Membership on an entity's Board of Directors or advisory committees. Moliterno:Incyte: Membership on an entity's Board of Directors or advisory committees.

Issues in Categorization and Management of Pediatric Patients with Myeloproliferative Neoplasms

Myeloproliferative Neoplasms (MPN) are well characterized in adults, with symptoms including thrombotic episodes, severe bleeding episodes, splenomegaly, and transformation to AML. Accepted treatment algorithms are available for management and multiple clinical trials are being done in adult patients. Much has been done to understand the pathogenesis in adults, and mutations in JAK2, MPL, and most recently CALR are established as causative lesions in these disorders. In contrast, knowledge of these disorders in children is more rudimentary, with limited information available regarding long-term clinical outcomes in children. Children have a lower frequency of the known mutations; studies to identify alternative driver mutations in children are ongoing.Eight pediatric patients with MPN have been seen at Cornell during their illness. Seven were diagnosed with Essential Thrombocytosis (ET) and the eighth had an initial diagnosis of ET but later was diagnosed with myelofibrosis (MF). One patient did not have bone marrow testing but was diagnosed by her primary hematologist on the basis of extreme thrombocytosis, and JAK2V617F positive testing on peripheral blood when no cause of reactive thrombocytosis was identified. Table 1 summarizes key features of these patients. The average age of diagnosis for these children is 10 years and 3 months. The oldest patient was diagnosed in 2006 and has had the longest consecutive period of thrombocytosis, 8 years.These patients presented with a variety of symptoms, including headache, abdominal pain, fatigue, and bleeding. All the children experienced extreme thrombocytosis (platelet count > 1,000 x 109/L) during their illness. Despite the presence of acquired von Willebrand’s disease in at least three patients, none have experienced severe bleeding symptoms. There have been no reported severe thrombotic episodes, and any evaluations done for complaints of headache, chest pain, or palpitations have shown no CNS infarcts or cardiac abnormalities. One child developed pseudo tumor cerebri with no cerebral venous sinus thrombosis or CNS lesion detected. Four children have been treated with aspirin with no significant bleeding complications. Six of the eight had been treated with cytoreductive therapy (Hydroxyurea) by their primary hematologist at some point in their course, for various findings including extreme thrombocytosis, fatigue, erythromelalgia, and recurrent headache. All showed a good response in platelet count to Hydroxyurea treatment, none developed dose-limiting side effects, and the highest dose that was needed to relieve symptoms at any point was 35mg/kg. Four patients remain on therapy with Hydroxyurea.Genetic sequencing was positive for JAK2V617F in three of eight patients. All of these patients have received Hydroxyurea treatment, and the child with pseudotumor cerebri was JAK2V617F positive. Of the five patients who are negative for JAK2 mutation, four were tested for MPLW515K/L and all are negative. Two of these patients have had sequencing sent for CALR mutations, and one patient is negative for CALR mutation as well (one patient is pending.) Figure 1 summarizes the sequencing completed to date on these patients.This cohort of pediatric patients shows a lower frequency of the known causative mutations than their adult counterparts. There is variation in how these patients were managed by their primary hematologists, likely due to the lack of treatment guidelines in this patient population (Kucine et al, 2014.) With the apparent differences in clinical course and genetic drivers from adults with MPN, there is a clear need for further research on the outcomes and pathogenesis in pediatric patients with MPN. Our group is currently working to answer some of the questions regarding pathogenesis and outcomes in pediatric patients with MPN to allow for individualization of treatment recommendations and family guidance in these children.Table 1Summary of Eight Pediatric MPN PatientsPatientAge at Diagnosis (years)DiagnosisInitial SymptomsA9ETWeakness, ParesthesiasB7ETHeadacheC10ETHeadache, FatigueD7ETHeadacheE8ETBleedingF13MFAbdominal Pain, SplenomegalyG10ETHeadacheH19ETFatigue, Itching [Display omitted] ReferencesKucine N, Chastain KM, Mahler MB, Bussel JB. Primary thrombocytosis in children. Haematologica. 2014;99(4)620-28. DisclosuresOff Label Use: Hydroxyurea use in certain children with MPN is accepted practice but is technically off-label.

Spontaneous Resolution of Extreme Thrombocytosis in 2 Children

Essential thrombocytosis (ET) is rare in children, sometimes difficult to be distinguished from secondary thrombocytosis. This report concerns 2 children with extreme thrombocytosis of 4100 × 109/L and 1644 × 109/L with partial and complete remission at 3 months and 4 years from diagnosis, with a follow-up of 4 and 17 years, respectively, with no cytoreduction therapy. Diagnosis of ET was suggested according to accepted criteria. However, spontaneous remission of the thrombocytosis argues for the diagnosis of secondary thrombocytosis. These patients highlight the complexity of distinguishing childhood ET from secondary thrombocytosis and the need for cautious personalized decision on cytoreduction therapy.

Essential Thrombocytosis and Antiphospholipid Antibody Syndrome Causing Chronic Budd-Chiari Syndrome

Essential thrombocytosis is extremely rare in children. However, when present, it is associated with increased prevalence of antiphospholipid antibodies and thrombo-hemorrhagic complications. The authors report here a child with Budd-Chiari Syndrome resulting from essential thrombocytosis and associated antiphospholipid antibodies. A 13- y-old boy presented with microcytic hypochromic anemia, hepatosplenomegaly and thrombocytosis. CT scan demonstrated calcified thrombus in inferior vena cava (IVC). Diagnosis of essential thrombocytosis was considered in view of persistent thrombocytosis, antiphospholipid antibodies, bone marrow showing increased number, clusters and giant forms of megakaryocytes and IVC thrombosis. He was started on warfarin prophylaxis and did not have thrombotic recurrence on follow up.

Gender Differences In the Prevalence of Thrombosis In the JAK2 V617F-Positive Myeloproliferative Disorders

AbstractAbstract 3080 Introduction:Thrombotic events are prevalent and morbid conditions in essential thrombocytosis (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), but the exact mechanisms aside from hyperviscosity and dysfunctional platelet behavior are largely undefined. Since ET, PV and PMF are chronic, latent disorders of middle and older age, we examined the influence of traditional thrombotic risk factors on the tendency toward thrombotic events. To this end, we retrospectively analyzed a cohort of 270 JAK2 V617F-positive patients from the Johns Hopkins Center for Myeloproliferative Disorders. Methods:Thrombotic events within 5 years preceding or at any time following an official diagnosis of ET (n=59), PV (n=166), or MF (post-ETMF, post-PVMF, and PMF) (n=45) were captured by retrospective review of the medical record; the events were characterized as microvascular or macrovascular, arterial or venous. Traditional thrombotic risk factors were recorded, including hypertension, diabetes, dyslipidemia, and history of smoking) and since there were gender differences in diagnostic class (ET and PV were more common in women), age at diagnosis, smoking history, dyslipidemia, and leukocyte count, these variables were incorporated into a multivariable logistic regression model. Result:Of the entire MPD cohort, 67 patients (25%) had 79 microvascular or macrovascular thrombotic events, including 14 (24%) with ET (18 events), 45 (27%) with PV (51 events), and 8 (18%) with MF (10 events). The thrombosis prevalence did not differ statistically by disease class. However, thrombosis prevalence did differ by gender: women had a higher prevalence of thrombosis compared to men (29% vs. 18%; p=0.035) and the odds ratio remained significant after multivariable adjustment (OR 1.98, p=0.04). There were no gender differences with respect to treatment (aspirin or cytoreductive agents), nor were there differences due to age (median 56 years) or disease duration at the time of thrombosis. The frequency of JAK2 V617F homozygosity also did not differ by gender. In men, 9 of 13 (69%) thrombotic events occurred at diagnosis or in the preceding 5 years; however, in women, thrombotic events during follow-up were as likely since only 20 of 45 (44%) thrombotic events occurred at diagnosis or in the preceding 5 years. Nine patients experienced multiple thrombotic events, of these, 6 were women; in 8 cases, these thrombotic events involved different vascular beds, suggesting a general proclivity for thrombosis. Overall, a dependence between sex and the type of thrombosis could not be identified, possibly due to inadequate power (p=0.36). However, there was an indication of gender differences in some thrombotic subgroups: for example, of 20 abdominal venous thromboses (AVT, including hepatic vein, portal vein, mesenteric vein and splenic vein thrombosis), 16 (80%) occurred in women (p=0.07). AVT was the most common event in PV, occurring in 23% of cases, and of these, 11 of 12 were reported in women. Further, in 7 of these women, an AVT was the presenting manifestation of their MPD. AVT was also the most common type of thrombosis in MF, occurring in 50% of cases; of these, 4 of 5 also occurred in women. In contrast to PV, rather than manifesting at diagnosis, 3 of the 5 events (60%) complicated splenectomy. Neurologic events also appeared to be more frequent in women: 6 of 7 CVA's (86%) occurred in women (p=0.14), and of 11 TIA's, 8 (73%) occurred in women (p=0.4). Conclusion:In this retrospective analysis of 270 cases, thrombotic events were equally prevalent in ET, PV, and MF, though importantly more common in women in this patient cohort. There was also a trend suggesting differences in thrombosis type between women and men, since TIA, CVA, and especially, AVT appeared to be more common in women. Indeed, in women, AVT was often the presenting feature leading to a diagnosis of PV. This study indicates unique disease and gender specific interactions in the generation of thrombosis in the MPD, and suggests that women are paradoxically at higher risk for thrombosis in the MPD. Though a mechanism is not yet defined, this analysis contributes to a growing literature emphasizing gender differences in all three MPD, which already includes differences in the JAK2 V617F allele burden and disease class. Further, this analysis supports the important impact of individual and host variation on the clinical manifestations of the MPD. Disclosures:No relevant conflicts of interest to declare.

JAK2 V617F Mutation Status Predicts Thrombotic Complications, Including Arterial Thrombosis, in Patients with Essential Thrombocytosis (ET).

Background: ET carries a significant risk of thrombotic complications which are difficult to predict, with a past history of thrombosis being the main predictor of subsequent events. The JAK2V617F mutation (JAK2) and spontaneous erythroid colony growth (SEC) have been inconsistently associated with increased thrombosis in these patients. We aimed to assess the predictive value of these assays for the development of thrombotic events post-diagnosis in patients with ET.Methods: A retrospective review of consecutive patients with ET diagnosed according to WHO criteria between January 1998 and August 2006 was performed. Data was abstracted from the medical record regarding baseline demographic characteristic, vascular risk factors, therapy, occurrence of thrombo-haemorrhagic events, and transformation to AML or myelofibrosis. Thrombotic events were defined as arterial or venous events occurring at or 12 months prior to diagnosis (prior thrombosis) and at any time post diagnosis of ET (subsequent thrombosis). Investigators were blinded to JAK2 and SEC results at the time of data collection. SECs were performed at the time of diagnosis in 53 patients. JAK2 analysis was performed by an allele specific PCR method on peripheral whole blood (n=32) or archived bone marrow samples (n=29).Results: 62 patients with ET were identified: median age 60yrs; 53% female; median platelet count at diagnosis 873 × 109/L; 10,8 and 44 being low, intermediate and high clinical risk, respectively. 67% (41/61) had a positive JAK2 test and 47% (25/53) had a positive SEC assay. 8 (13%) and 6 (10%) had a history of prior arterial and venous thrombotic complications. Median follow up was 39 months (range, 1 to 137 months). At diagnosis JAK2 positive patients had higher white cell counts (12.3 vs 8.9 ×109/L, p=0.01) and neutrophil counts (9.1 vs 5.7 ×109/L, p=0.01), and a trend to older age (62 vs 57yrs, p=0.3) and higher haemoglobin (139 vs 133 g/L, p=0.12), but not platelet count (870 vs 892 ×109/L, p=0.8). There was a trend for increased rates of prior thrombosis among JAK2 positive patients (27% vs 5%, p=0.08). Survival was not affected by JAK2 status (5yr OS 71% vs 72%, p=0.7). The presence of the JAK2 mutation predicted for the development of subsequent thrombosis (5yr event rate 32% vs 0%, p=0.01) which persisted when the analysis was stratified for a prior history of thrombosis (p=0.01). Further analysis demonstrated the JAK2 mutation to predict subsequent arterial thrombosis (5yr event rate 22% vs 0%, p=0.05) but not venous thromboembolism (5yr event rate 11% vs 0%, p=0.18). The increased risk of arterial thrombosis in JAK2 positive patients persisted when corrected for a prior history of vascular events (p=0.04). The SEC assay was not found to be predictive of any thrombotic events.Conclusions: Patients with ET who are JAK2 positive are at increased risk of thrombotic complications, particularly arterial thrombosis. This increased risk persists after correction for a history of prior thrombosis.

Incidence of Pulmonary Hypertension in Patients with Chronic Myeloproliferative Disorders.

Background: Increased incidence of cardiac involvement and pulmonary hypertension (PH) has been reported in patients with chronic myeloproliferative disorders (CMPD). Most studies are small and retrospective except one where majority of the patient had essential thrombocytosis (ET).Method: We conducted a study to assess the incidence of PH in patients with CMPD. Patients were excluded if they had secondary cause of PH. Diagnosis of PH was established if right ventricular systolic pressure (RVSP) by transthoracic echocardiography (TTE) and Doppler study was ≥ 35 mmHg. 27 patients with diagnosis of CMPD established by standard criterion were included in the study. 9 patients had ET, 14 had polycythemia vera (PV) and 3 had chronic myeloid leukemia (CML).Results: Diagnosis of PH was established in 14/27 patients. 2 patients were excluded form analysis because of poor ejection fraction on TTE, 1 with PV and 1 with CML, giving final diagnosis of PH in 12/25 (48%) patients. 9 patients were males and 16 were females. Mean age at diagnosis in the entire cohort was 56.2 years and that with and without PH was 54.5 vs. 57.7 years respectively. Mean duration of follow up was 8.7 years and that with and without PH was 7.8 vs. 9.9 years respectively. 7/9 ET, 5/14 PV AND 0/2 CML patients had PH, mostly of mild to moderate severity. All patients were asymptomatic at the time of their last visit within last 2 months.The results are depicted in the table 1.There was no relation of PH to duration of disease, platelet count and hematocrit at diagnosis or during follow up period for the entire group or specific diagnosis of ET or PV. Because of erratic and variable duration of aspirin use by individual patients, we could not determine its significance.Discussion: The results of our study are similar to the study reported by Garypidou et al with regard to ET. However they had only 2 patients with PV and both of them had no evidence of PH. In our study 5/14 PV (36%) patients had PH, indicating PV patients also have significant risk of having PH.Pathogenesis of PH can be reliably related to CMPD because:Cases of secondary PH were excludedTTE excluded cardiac causes of PHIncidence of primary PH is very low (0.2cases/100,000) and usually occurs in 3rd or 4th decade.Moreover autopsy studies have demonstrated the presence of atypical megakaryocytes and thrombotic material in the lung capillaries of pulmonary hypertension patients and CMPD. Increased level of thrombopoietin also has been demonstrated in pulmonary artery of patients with PH. Thus platelets are implicated in pathogenesis of PH in patients with CMPD. Since PH seems to be common in patients with CMPD, more studies are needed to study the long-term impact of PH on survival in these patients. Impact of therapy including platelet lowering agents and ASA on development and progression of PH also needs to be studied.Table 1CMPDTotal No (%)MeanAge at Dx(yrs)Duration of Ds(yrs)Mean Plt at Dx(k/muL)Mean Plt at fu(k/muL)Mean Hct at Dx(%)Mean Hct at fu(%)ET PH +7/9(77.8)56.37.2877.7488.641.136.7ET PH −2/9(22.2)65.08.0698.0492.045.340.0PV PH +5/14(35.7)52.010528.8320.453.943.2PV PH −9/14(64.3)58.710.6511.9316.858.941.9CML PH −2/246.54.0620.5387.536.936.2Dx-diagnosis, Ds-disease, yrs-years, Plt-platelet, fu-follow up, Hct-hematocrit, PH-pulmonary hypertension, +-present, − absent

Creating a National Cohort of Myeloproliferative Disorders Using the Internet: A Feasibility Study.

The Internet is a potentially useful tool for recruiting patients with rare diseases to clinical trials. It facilitates the rapid and efficient recruitment of subjects, allowing patients to participate in minimal risk clinical trials who may not otherwise enroll because of lack of available studies, age, health, or proximity to a major medical center. In this study we recruited patients with the myeloproliferative disorders polycythemia vera (PV), essential thrombocytosis (ET) and agnogenic myeloid metaplasia (AMM) through the aid of an Internet support group. Our goal was to test the feasibility of using an internet-based support group to recruit 600 patients to a national cohort that collected clinical, demographic, and quality of life data as well as blood samples for tissue banking. Information on the trial was emailed to the mailing list and posted on the website of the MPD support group www.mpdinfo.org. Participants emailed the study investigator with their interest in the study, their diagnoses and mailing addresses. Information packets with consent forms, questionnaires, and release of medical records were sent through the U.S. postal service to participants. Once signed informed consents and questionnaires were returned, patients were mailed blood sample kits with pre-paid return postage to obtain blood samples. Patients were eligible if they had a diagnosis of PV, ET or AMM, lived in the United States, were >18 years old, and had not had a stem cell transplant. From January – July 2004, 497 people responded with initial interest. At each stage of the enrollment process there was a decrease in the number of participants: 23 were excluded because they lived outside of the United States. 474 were sent information packets, of which 360 were returned. Of these, 2 patients were excluded because of prior stem cell transplant and 12 opted out of the study. 344 patients consented to having blood samples drawn and 247 of these samples have been received in our tissue bank to date. Thus, the overall retention rate from initial response to receipt of blood sample is 52%. The median age of the cohort is 58 (range 20– 84 years) and the majority (58%) are female, in contrast to recent clinical trials in PV, ET and AMM where the majority of participants are older and male. Similar to recent studies 98% are white; and the median duration of disease for these patients is 63 months (range 3–543). The Internet recruitment method did select for a highly educated and more affluent population than in other series: 60% of participants are college graduates and 47% reported annual incomes >$75,000/year. PV was the most common self reported diagnosis (50%) followed by ET (35%) and then AMM (14%). Of 269 participants on whom we have received medical records thus far, we have been able to verify diagnosis on 136 participants; 53/136 (39%) have PV; 58/136 (42%) have ET; and 25/136 (18%) have AMM or myelofibrosis. Despite provision of a signed medical records releases, HIPAA restrictions have interfered with our ability to obtain medical records in some cases. In conclusion we have found that using the Internet for recruiting participants with rare diseases was efficient and feasible, and has produced a large cohort willing to provide self-reported information, medical records and research specimens. Issues of incomplete data collection, selection bias, and HIPAA restrictions remain barriers to optimal use of the Internet for minimal risk studies.

Aortic Mural Thrombus Embolization: An Unusual Presentation of Essential Thrombocytosis

Hypercoagulable conditions are increasingly recognized as a causative factor in patients with thromboembolic phenomenon. Essential thrombocytosis (ET) is one such condition. This particular myeloproliferative disorder is most commonly associated with thrombotic complications of the microvasculature and bleeding complications involving mucosal surfaces (e.g., gastrointestinal tract bleeding). This case identifies an uncommon manifestation of ET-aortic mural thrombus leading to visceral embolism. Vascular surgeons should be aware of the diagnosis, treatment, and complications of ET, as patients with this condition may first present with an arterial occlusion.