Extreme Thrombocytosis Research Articles

Antiplatelet therapy versus observation in low-risk essential thrombocythemia with a CALR mutation.

The role of antiplatelet therapy as primary prophylaxis of thrombosis in low-risk essential thrombocythemia has not been studied in randomized clinical trials. We assessed the benefit/risk of low-dose aspirin in 433 patients with low-risk essential thrombocythemia (271 with a CALR mutation, 162 with a JAK2(V617F) mutation) who were on antiplatelet therapy or observation only. After a follow up of 2215 person-years free from cytoreduction, 25 thrombotic and 17 bleeding episodes were recorded. In CALR-mutated patients, antiplatelet therapy did not affect the risk of thrombosis but was associated with a higher incidence of bleeding (12.9 versus 1.8 episodes per 1000 patient-years, P=0.03). In JAK2(V617F)-mutated patients, low-dose aspirin was associated with a reduced incidence of venous thrombosis with no effect on the risk of bleeding. Coexistence of JAK2(V617F)-mutation and cardiovascular risk factors increased the risk of thrombosis, even after adjusting for treatment with low-dose aspirin (incidence rate ratio: 9.8; 95% confidence interval: 2.3-42.3; P=0.02). Time free from cytoreduction was significantly shorter in CALR-mutated patients with essential thrombocythemia than in JAK2(V617F)-mutated ones (median time 5 years and 9.8 years, respectively; P=0.0002) and cytoreduction was usually necessary to control extreme thrombocytosis. In conclusion, in patients with low-risk, CALR-mutated essential thrombocythemia, low-dose aspirin does not reduce the risk of thrombosis and may increase the risk of bleeding.

English

S60 morbidity and mortality. It is characterized by sustained megakaryocyte proliferation that increases the number of circulating platelets. To diagnose ET, it requires the combination of excluding causes of reactive thrombocytosis and ruling out other myeloproliferative disorders. Further genetic workup may require evaluating Jak2 mutation, which is present in 55% of cases in ET. We present an unusual presentation of essential thrombocytosis which initially presented as iron deficiency anemia (IDA) and thrombocytopenia. Case presentation: This is a 72 year old female who presented with chest pain. Initial lab evaluation revealed severe anemia with hemoglobin of 3.4 and mean corpuscular volume (MCV) of 55, with the rest of complete blood count and basic metabolic profile unremarkable. In light of severe anemia, patient had a work up that showed severe IDA with ferritin at 6. She was thereafter started on intravenous (IV) iron treatment. Initially at presentation, she was thrombocytopenic with platelets count of 95,000, but after 4 days of IV iron replacement, her platelets count increased to 700,000. In spite of discontinuing the IV iron, her platelets continued to rise to more than 1 million 14 days after admission. Her prior labs eight years ago showed platelet count of more than a million. Patient admitted to being noncompliant on iron supplements for the last several years. She underwent bone marrow biopsy which showed hypercellular bone marrow with increased megakaryocytes. Additional work up with fluorescence in situ hybridization-flow cytometry and further genetic testing were negative. Discussion: IDA normally presents with reactive thrombocytosis, but usually it responds to iron replacement therapy by normalization. There have been few case reports of IDA presenting as thrombocytopenia and the pathogenesis remain unknown. Additionally, iron replacement therapy demonstrated platelet level normalization. In light of persistent and extreme thrombocytosis is response to iron replacement therapy, this case demonstrates unusual presentation of iron deficiency anemia masking ET. Conclusion: Our patient represents a unique case presentation of ET which was masked by severe iron deficiency anemia and unmasked through iron replacement therapy.

Systemic lupus erythematosus and extreme thrombocytosis without autosplenectomy

Systemic Lupus Erythematosus (SLE) is an autoimmune disorder characterized by multiorgan system involvement. Hematologic manifestations are common in SLE and include thrombocytopenia in as many as 50% of patients. Thrombocytosis is much less common in SLE, occurring in less than 5% of patients, and is typically reported in association with autosplenectomy. The following case report describes a 35-year-old female patient who presented for evaluation with extreme thrombocytosis of unclear etiology. The patient was diagnosed with reactive thrombocytosis due to active SLE for which treatment with corticosteroids and plaquenil was provided with subsequent decline in platelet counts. This report highlights the importance of considering SLE in the differential for thrombocytosis despite its classic association with thrombocytopenia.

A Study of the Role of Antiplatelet Therapy in the Prevention of Thrombosis in Patients with Calr-Mutated Low Risk Essential Thrombocythemia

▪Young patients (age < 60 years) with essential thrombocythemia (ET) and no history of thrombosis are considered at low risk of thrombosis and therefore managed on a conservative approach with antiplatelet therapy or even without any treatment. JAK2 V617F and CALR exon 9 mutations are the most frequent molecular alterations observed in ET, with CALR-positive ET being considered a distinct clinical entity due to its higher platelet counts and lower incidence of thrombosis as compared with JAK2 V617F-positive ET. There is some evidence supporting a role for antiplatelet therapy in JAK2 V7617F-positive neoplasms. However, the role of antiplatelet therapy in CALR-positive ET has not been studied.The aim of the present study was to assess the effect of antiplatelet therapy in the primary prevention of thrombosis in patients with CALR-positive ET without indication of cytoreductive therapy. For such purpose, 240 patients (107 males, 133 females) diagnosed with ET at a median age of 42 years (range 13-59) were included in a multicenter retrospective study. Initial treatment consisted of antiplatelet therapy (n=109) or careful observation (n=108), whereas 23 patients received cytoreduction since diagnosis and were excluded. During a median follow up of 8 years, 137 patients were started on cytoreductive therapy because of the following indications: age > 60 years (n=10), thrombosis (n=10), bleeding (n=2), microvascular symptoms (n=18), extreme thrombocytosis (n=89), and others (n=8). Median time free of cytoreductive therapy was 3.2 years. Thrombosis-free survival restricted to the time of cytoreductive therapy abstention was calculated using the Kaplan-Meier method. Variables attaining a significant level at the univariate analysis were included in a Cox proportional hazard model.During the period of abstention of cytoreductive therapy, a total of 10 thrombotic events and 8 major bleeding episodes were registered. The probability of thrombosis at 3 years was 5% in patients managed with careful observation and 1% in those receiving antiplatelet therapy (p = 0.2). At multivariate analysis, antiplatelet therapy did not result in a lower risk of thrombosis after correction for age, sex and presence of cardiovascular risk factors. Interaction studies did not identify any subgroup of patients that benefited from antiplatelet therapy in thrombosis prevention. Regarding major bleeding, patients receiving antiplatelet therapy experienced a higher rate than those managed on observation (3-year probability of major bleeding, 5.5% and 0%, respectively, p=0.05). At multivariate analysis, antiplatelet therapy was associated with a tendency towards and increased risk of major bleeding (HR: 7.7, 95%CI: 0.9-66.2, p=0.06) independently of platelet count at diagnosis, age and gender.In conclusion, CALR-mutated low-risk ET patients under cytoreductive therapy abstention may not obtain a clear benefit from antiplatelet therapy since the increase in the rate of bleeding may offset the reduction in the rate of thrombosis DisclosuresGarcía-Gutierrez:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria; Sanofi: Honoraria, Speakers Bureau; Shire: Speakers Bureau. Cervantes:Sanofi-Aventis: Consultancy; Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau. Vannucchi:Shire: Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Blast transformation and fibrotic progression in polycythemia vera and essential thrombocythemia: a literature review of incidence and risk factors.

Polycythemia vera (PV) and essential thrombocythemia (ET) constitute two of the three BCR-ABL1-negative myeloproliferative neoplasms and are characterized by relatively long median survivals (approximately 14 and 20 years, respectively). Potentially fatal disease complications in PV and ET include disease transformation into myelofibrosis (MF) or acute myeloid leukemia (AML). The range of reported frequencies for post-PV MF were 4.9–6% at 10 years and 6–14% at 15 years and for post-ET MF were 0.8–4.9% at 10 years and 4–11% at 15 years. The corresponding figures for post-PV AML were 2.3–14.4% at 10 years and 5.5–18.7% at 15 years and for post-ET AML were 0.7–3% at 10 years and 2.1–5.3% at 15 years. Risk factors cited for post-PV MF include advanced age, leukocytosis, reticulin fibrosis, splenomegaly and JAK2V617F allele burden and for post-ET MF include advanced age, leukocytosis, anemia, reticulin fibrosis, absence of JAK2V617F, use of anagrelide and presence of ASXL1 mutation. Risk factors for post-PV AML include advanced age, leukocytosis, reticulin fibrosis, splenomegaly, abnormal karyotype, TP53 or RUNX1 mutations as well as use of pipobroman, radiophosphorus (P32) and busulfan and for post-ET AML include advanced age, leukocytosis, anemia, extreme thrombocytosis, thrombosis, reticulin fibrosis, TP53 or RUNX1 mutations. It is important to note that some of the aforementioned incidence figures and risk factor determinations are probably inaccurate and at times conflicting because of the retrospective nature of studies and the inadvertent labeling, in some studies, of patients with prefibrotic primary MF or ‘masked' PV, as ET. Ultimately, transformation of MPN leads to poor outcomes and management remains challenging. Further understanding of the molecular events leading to disease transformation is being investigated.

The prognostic importance of immunohistochemical biomarkers in Diffuse Large B Cell Lymphoma

S60 morbidity and mortality. It is characterized by sustained megakaryocyte proliferation that increases the number of circulating platelets. To diagnose ET, it requires the combination of excluding causes of reactive thrombocytosis and ruling out other myeloproliferative disorders. Further genetic workup may require evaluating Jak2 mutation, which is present in 55% of cases in ET. We present an unusual presentation of essential thrombocytosis which initially presented as iron deficiency anemia (IDA) and thrombocytopenia. Case presentation: This is a 72 year old female who presented with chest pain. Initial lab evaluation revealed severe anemia with hemoglobin of 3.4 and mean corpuscular volume (MCV) of 55, with the rest of complete blood count and basic metabolic profile unremarkable. In light of severe anemia, patient had a work up that showed severe IDA with ferritin at 6. She was thereafter started on intravenous (IV) iron treatment. Initially at presentation, she was thrombocytopenic with platelets count of 95,000, but after 4 days of IV iron replacement, her platelets count increased to 700,000. In spite of discontinuing the IV iron, her platelets continued to rise to more than 1 million 14 days after admission. Her prior labs eight years ago showed platelet count of more than a million. Patient admitted to being noncompliant on iron supplements for the last several years. She underwent bone marrow biopsy which showed hypercellular bone marrow with increased megakaryocytes. Additional work up with fluorescence in situ hybridization-flow cytometry and further genetic testing were negative. Discussion: IDA normally presents with reactive thrombocytosis, but usually it responds to iron replacement therapy by normalization. There have been few case reports of IDA presenting as thrombocytopenia and the pathogenesis remain unknown. Additionally, iron replacement therapy demonstrated platelet level normalization. In light of persistent and extreme thrombocytosis is response to iron replacement therapy, this case demonstrates unusual presentation of iron deficiency anemia masking ET. Conclusion: Our patient represents a unique case presentation of ET which was masked by severe iron deficiency anemia and unmasked through iron replacement therapy.

Qualitative and quantitative modifications of von Willebrand factor in patients with essential thrombocythemia and controlled platelet count

Essential thrombocythemia (ET) is characterized by increased platelets and prevalent thrombosis. An acquired von Willebrand factor (VWF) disease has been hypothesized and inconsistently associated with extreme thrombocytosis or rare bleeding in ET.Whether VWF is modified in ET patients with controlled platelet count remains unclear. We studied different VWF- and platelet-associated parameters in ET patients treated according to current recommendations. Sixty-nine ET patients (M=29; median age, 62 [48-70]years; platelets, 432 [337-620]×10(3) μL(-1) ), 69 matched controls and 10 subjects with reactive thrombocytosis (RT) were studied. VWF:antigen (Ag), activity (act), electrophoretic patterns, VWF:propeptide, plasma glycocalycin (GC), glycoproteinV (GpV), ADAMTS-13, elastase, C-reactive protein and serum thromboxane (TX)B2 were measured. In ET patients, VWF:Ag was increased by 31±13% vs. controls (P<0.01), without dependence of blood groups, while VWF:act was reduced by 21±12% vs. controls and by 50±24% vs. RT (P<0.01). The VWF:act/VWF:Ag ratios in ET were reduced by 35±17% vs. controls and RT patients (P<0.001) and significantly associated with: immature or total platelet counts, GC, GpV and TXB2 . In multivariable analysis, only GC inversely predicted ET patients' VWF:act/VWF:Ag ratios (β=-0.42, P=0.01). By electrophoresis analyses, high-molecular-weight VWF multimers were variably reduced with atypical cleavage bands in ET only. VWF:propeptide, ADAMTS-13 and elastase levels were normal in ET patients. Platelet-associated ADAM-10 and ADAM-17 hydrolyzed VWFm invitro, showing patterns similar to those in ET samples. In ET patients with controlled platelet counts, the VWF:act/VWF:Ag ratio is decreased and predicted by GC, a product of platelet activation. ADAM-10 and/or ADAM-17 might be involved. In vivo platelet activation, which characterizes ET, might contribute to disease-specific VWF alterations.

Extreme Thrombocytosis: A Unique Constellation of Reactive Thrombocytosis, Iron Deficiency Anemia and Atypical Celiac Disease

Reactive thrombocytosis refers to elevated platelet count in the absence of a myeloproliferative or myelodysplastic syndrome and is secondary to a medical or surgical condition. Extreme thrombocytosis (>1000) is unlikely to be autonomous in origin and an underlying reactive process should be strongly suspected. A 22 year old apparently healthy male presented with fatigue of five months duration. Labs showed marked hypochromic microcytic anemia with hemoglobin of 5 g/dL, extremely high platelet count of 1600 x 10<SUP>9</SUP> and undetectable ferritin. Upper and lower GI scopes failed to reveal any source of bleeding. Ultrasound abdomen revealed mildly enlarged spleen. Besides markedly increased megakaryopoesis, erythropoesis and low iron stores; bone marrow biopsy did not reveal any myelodysplasia. Patient was transfused 4 units of Packed RBC with rapid improvement of hemoglobin and platelet count within one week. Villous atrophy on duodenal biopsy and elevated tissue transglutaminase antibody levels confirmed diagnosis of celiac disease. Patient was started on iron supplements and gluten free diet. Follow up in 3 months revealed completely normal hemoglobin, ferritin level and platelet count. Extreme thrombocytosis should raise suspicion for a secondary cause rather than a primary myeloproliferative disorder. Iron deficiency anemia, a relatively rare but benign cause should be strongly considered in work up of reactive thrombocytosis. Atypical forms of celiac disease can be relatively asymptomatic. If clinical suspicion is high serum antibody assay and intestinal biopsy should be considered. The case illustrates rare constellation of extreme thrombocytosis from iron deficiency anemia in an otherwise asymptomatic celiac disease patient.

Nadpłytkowości pierwotne i wtórne u dzieci

BackgroundThrombocytosis is defined as increased number of peripheral blood platelets. With respect to this value, it is graded as: mild thrombocytosis with platelet number 500–700 G/L; moderate thrombocytosis with platelet number 700–900 G/L; severe thrombocytosis with platelet number >900 G/L and extreme thrombocytosis if the platelet count is >1000 G/L. ObjectiveAnalysis of epidemiology, etiology and clinical course of essential and reactive thrombocytoses in children. MethodsAll consecutive children hospitalized in pediatric, hematology and oncology ward during 48 months were potential subjects of this retrospective analysis. All children with at least one platelet count above 500 G/L were included into the study. ResultsThrombocytosis was observed in 628/12910 (4.86%) hospitalizations. It was diagnosed as mild in 83.9% of cases; moderate and severe in 14.0%, and extreme in 2.1% cases. The most frequent cause of thrombocytosis was infections and iron deficiency anemia, as well as bone marrow regeneration after chemotherapy administered due to malignancy and patients after splenectomy. It was found that essential thrombocythemia is a very rare disease in children and constitutes only 0.47% off all cases of thrombocytosis, and 0.02% of all hospitalizations in pediatric, hematology and oncology ward. Clinical course of reactive thrombocytosis is usually symptomless with fast normalization of platelet count after underlying condition has been cured. ConclusionsSecondary thrombocytosis occurs in nearly 5% of hospitalized children, while essential thrombocythemia is a very rare disease of childhood. There are no recommendations for routine prophylaxis with thrombolytic agents or inhibitors of platelet aggregation in secondary thrombocytosis.

Polycythemia vera and essential thrombocythemia: 2015 update on diagnosis, risk-stratification and management.

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms, respectively characterized by erythrocytosis and thrombocytosis. Other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus, and risk of leukemic or fibrotic transformation. PV is defined by a JAK2 mutation, whose absence, combined with normal or increased serum erythropoietin level, makes the diagnosis unlikely. Differential diagnosis in ET includes reactive thrombocytosis, chronic myeloid leukemia, and prefibrotic myelofibrosis. Janus kinase 2 (JAK2), calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations occur in approximately 55%, 25%, and 3% of ET patients, respectively. The same molecular markers are also present in prefibrotic myelofibrosis, which needs to be morphologically distinguished from ET. Survival and leukemic/fibrotic transformation: Median survivals are ∼14 years for PV and 20 years for ET; the corresponding values for younger patients are 24 and 33 years. Life-expectancy in ET is inferior to the control population. JAK2/CALR mutational status does not affect survival in ET. Risk factors for survival in ET and PV include advanced age, leukocytosis, and thrombosis. Leukemic transformation rates at 20 years are estimated at <10% for PV and 5% for ET; fibrotic transformation rates are slightly higher. Thrombosis risk stratification: Current risk stratification in PV and ET is designed to estimate the likelihood of recurrent thrombosis: high-risk is defined by the presence of age >60 years or presence of thrombosis history; low-risk is defined by the absence of both of these two risk factors. Recent data consider JAK2V617F and cardiovascular risk factors as additional risk factors. Presence of extreme thrombocytosis might be associated with acquired von Willebrand syndrome (AvWS) and, therefore, risk of bleeding. The main goal of therapy in PV and ET is to prevent thrombohemorrhagic complications. In low risk patients, this is accomplished by the use of low-dose aspirin and phlebotomy (hematocrit target <45%) in PV. In high risk (for thrombosis) patients, treatment with hydroxyurea is additionally recommended. Treatment with busulfan or interferon-α is usually effective in hydroxyurea failures and the additional value of JAK inhibitor therapy in such cases is limited. Screening for AvWS is recommended before administrating aspirin, in the presence of extreme thrombocytosis.

A Case of Essential Thrombocythemia in a Patient with Ankylosing Spondylitis Concomitantly Treated with Adalimumab

Extreme thrombocytosis in patients with ankylosing spondylitis (AS) is rarely reported. Because the relationship between high disease activity and increased platelet counts is somewhat contradictory, severe thrombocytosis in AS patients can be secondary to infection, iron deficiency anemia, drug administration, and hematologic malignancies. Essential thrombocythemia (ET) is a rare acquired stem cell neoplasm characterized by overproduction of platelets by megakaryocytes in the bone marrow in the absence of other causes of thrombocytosis. There is no report in the literature regarding the association between AS and ET. We report on a case of a 34-year-old Korean man with active AS diagnosed as JAK2V617F mutation negative ET during adalimumab treatment. (J Rheum Dis 2015;22:51-55)

Study of significance of thrombocytosis in lower respiratory tract infections in children

Background: Lower Respiratory Tract Infections (LRTI) continues to threaten the health of children worldwide. Up to 13% of inpatient deaths in pediatric wards are due to LRTI. Platelets play a major role in antimicrobial host defence, the induction of inflammation and tissue repair. Inflammatory thrombocytosis is related to increased levels of several cytokines such as thrombopoietin, interleukin-6, interleukin-1alpha, interleukin-8 and tumour necrosis factor alpha. Methods: A prospective study was done on thrombocytosis in children aged from 2 months to 5 years admitted with lower respiratory tract infections meeting the criteria of ARI control programme. Results: Among 220 cases, 63.2% of the cases were males and 36.8% of the cases were females, with male to female ratio being 1.7: 1. Among total 220 admitted cases of LRTI, 50% of the cases were severe pneumonia, 26.4% were very severe pneumonia and 23.6% were pneumonia. Among 220 cases, thrombocytosis was found in 77 children. Among 4 children with severe thrombocytosis (9.01-10.00 L/mm 3 ), 3 had very severe pneumonia and 1 had severe pneumonia. It indicates that platelet count increases as the severity of pneumonia increases. All 4 cases of severe thrombocytosis (9.01-10.00 Lakhs/mm 3 ) and 1 case of extreme thrombocytosis (>10.00 Lakhs/mm 3 ) had TLC >15000/mm 3 . Conclusions: Children admitted with LRTI having thrombocytosis had longer duration of hospital stay, which indirectly indicate more severity of pneumonia. Children with thrombocytosis have more severe clinical condition and longer hospitalization. Platelet count may be used as a useful marker associated with severity of lower respiratory tract infection and its complications.

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.

Extreme reactive thrombocytosis in a healthy 6 year-old child.

Thrombocytosis is usually found by chance in children. Reactive or secondary thrombocytosis is the more common form, with infectious diseases being the most prevalent cause of it. Regarding the number of platelets there are four degrees of thrombocytosis; in its extreme degree the number of platelets exceeds 1,000,000/mm3. We describe a case of extreme reactive thrombocytosis in a healthy 6-year-old child. He required critical care admission for diagnosis and treatment (maximum number of platelets 7,283,000/mm3). We review the different causes of thrombocytosis in childhood, the differential diagnosis, and the available treatments in case of extreme thrombocytosis.

Target hematologic values in the management of essential thrombocythemia and polycythemia vera.

Treatment of essential thrombocythemia (ET) and polycythemia vera (PV) is aimed at preventing vascular complications, which are the main cause of morbidity and mortality in these diseases. Over the years, clinical trials have demonstrated that the incidence of thrombosis and bleeding can be reduced by controlling the blood cell counts, but the target hematological levels have varied across the studies. In this article, we review the evidence supporting the use of predefined target hematologic values for the management of ET and PV in routine clinical practice. At present, the recommended target hematocrit in PV is below 45%, regardless of the patients' risk profile. Concerning platelet counts, no direct correlation has been demonstrated with thrombotic risk in either ET or PV. Thus, although cytoreductive treatment reduces the rate of vascular complications in high-risk patients, no particular threshold of the platelet counts has been shown to be more protective against thrombosis. Extreme thrombocytosis is a risk factor for bleeding, particularly when aspirin or anagrelide are given. Leukocytosis at baseline or during follow-up appears to be a risk factor for thrombosis, mostly in high-risk patients. However, the clinical benefit of strictly controlling this parameter is not yet established. Finally, standardized definitions of response to cytoreductive treatment in ET and PV have recently been published. Nevertheless, they have been produced to compare the efficacy of new therapies in clinical trials, whereas its relevance in clinical practice has been questioned in retrospective studies showing that such response definitions do not correlate with the patients' clinical outcome.

Elevated telomerase activity in essential thrombocythemia with extreme thrombocytosis

IntroductionWe performed a comparative analysis of telomerase activity (TA) in patients with myeloproliferative neoplasm (MPN) and myelodysplastic syndrome (MDS). The relationships between TA and known prognostic factors were also analyzed. Materials and methodsA telomeric repeat amplification protocol was performed with bone marrow hematopoietic cells from 96 normal controls, 44 MPNs, and 40 MDSs. ResultTA (measured as molecules/reaction) showed no correlation with age in the control group (R2=0.0057, p=0.464). MPN showed elevated TA compared with controls (15,537.57 vs. 7775.44, p=0.020). Patients with essential thrombocythemia showed markedly elevated TA (22,688.56, p=0.030), particularly in cases with extreme thrombocytosis versus those without extreme thrombocytosis (34,522.19 vs. 9375.71, p=0.041). MDS patients showed a TA value of 7578.50. ConclusionThere was no association between age and TA in bone marrow hematopoietic cells. TA was elevated in MPN but borderline in MDS, probably because of differences in the nature of the diseases. Elevated TA in patients with essential thrombocythemia, especially those with extreme thrombocytosis, suggests that an anti-telomerase strategy could be beneficial in the prevention of thrombotic complications.

Trombocitosis extrema reactiva en un niño sano de 6 años

Thrombocytosis is usually a casual finding in children. Reactive or secondary thrombocytosis is the more common form, being the infections diseases the most prevalent cause of it. Regarding the number of platelets there are four degrees of thrombocytosis; in its extreme degree the number of platelets exceeds 1,000,000/mm3. We describe a case of extreme reactive thrombocytosis in a healthy 6-year-old child. He required critical care admission for diagnosis and treatment (maximum number of platelets 7,283,000/mm3). We review the different causes of thrombocytosis in childhood, the differential diagnosis, and the available treatments in case of extreme thrombocytosis.

Clinical Factors Associated With Bleeding In Ph-Negaitve MPN

BackgroundPatients with Ph-negative myeloproliferative neoplasms (MPN) that include polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF), share an increased risk of thrombotic and hemorrhagic complications. Risk factors for hemorrhagic complications are less defined compared to thrombosis, but acquired von Willebrand disease (aVWD) and extreme thrombocytosis have been implicated. AimTo define whether aVWD, extreme thrombocytosis or treatment history associates with bleeding in Ph-negative MPN patients. MethodsThe Northwestern University Electronic Data Warehouse identified MPN patients ≥18 years, seen between 2005-2013, with available testing for aVWD and/or extreme thrombocytosis, defined by a platelet count of > 800 x 109/L. Eligibility criteria also included availability of JAK2 status, complete blood count (CBC) results, clinical history and treatment history. aVWD was defined by vW antigen and/or ristocetin cofactor activity below the laboratory reference range for blood type (usually<40% for blood group O or <53% for non blood group O). We defined aVWD type by the ratio of vW antigen to activity. Associations were tested using Fisher exact test; p<0.05 was considered statistically significant. Results I: Baseline characteristics64 MPN patients were identified: 14 with PV (22%), 35 with ET (54%), 5 with MF (8%) and 10 with MPN NOS (16%). Median age at diagnosis was 70 years (range 18-87) and 64% were women. Most patients were Caucasian (64%) with Asians, African Americans and Hispanics representing 6% each in the study population. JAK2 V617Fwas positive in 30 patients (47%). To date, 7 (11%) patients had died and one had leukemic transformation. Results II: Bleeding and thrombotic complications.Bleeding complications were reported in 13 cases (20%) while thrombotic events were reported in 11 cases (17%): ACS (2), TIA (2), CVA (1), PVT (3) and DVT/PE (3). 62% of cases had neither bleeding nor thrombosis, and only 2 of 13 cases with bleeding (unrelated to warfarin) had prior history of thrombosis. Bleeding episodes included mucocutaneous sites with 4 cases of epistaxis and 3 cases of menorrhagia. There were 5 cases of minor GI bleeding not requiring transfusion (3 with lower GI and 2 with upper GI bleeding). There was 1 case of bleeding after a bone marrow biopsy. Bleeding events were more common in ET and PV than MF or MPN NOS (6, 4, 1 and 2 cases respectively). Aspirin (ASA) was discontinued in 9 of 13 cases (70%) and hydroxyurea was added or adjusted in 5 of 13 (38%) cases. The mean platelet count at the time of bleeding was 998 x 109/L (range 41-1816), mean white blood count (WBC) 15.8 x 109/L (range 6.4-38.6) and mean hemoglobin (Hgb) 11.5 x 109/L (range 7.6-17.1). 36 patients had testing for aVWD; the median ristocetin activity was 81% (range 12-190%), vW Antigen 112% and factor VIII activity 93%. Multimer analysis was done in 2 cases. In 1 case, an absence of large multimers was reported, suggestive of type II avWD, and was normal in the other. Of 36 patients, there were 6 (17%) cases of aVWD (ristocetin activity 12%, 22%, 37%, 38%, 38% and 53% respectively); 5 with vWD type 2 and 1 with vWD type 1. Only 2 of 6 patients with aVWD had bleeding, both while on ASA (bleeding after bone marrow biopsy and menorrhagia). Using Fisher exact test, bleeding was associated with ASA therapy only (p<0.0001). Cytoreductive therapies, age, MPN subtype, JAK2 status, aVWD and CBC did not correlate with bleeding. ConclusionsWe identified a similar prevalence of bleeding and thrombotic events, reflecting the selective criteria of our search, since thrombocytosis better associates with bleeding and aVWD is typically evaluated in patients with bleeding or thrombocytosis. In our study, bleeding was associated with ASA intake, was often mucocutaneous in origin and typically resulted in ASA discontinuation and/or change in cytoreductives. An evidence-base supports ASA use in PV, but is lacking in other MPN. Therefore, treatment with ASA should be initiated on an individual rather than empirical basis given a potential for bleeding in some MPN patients. The mean platelet count at the time of bleeding was extremely increased, but aVWD was rare. Moreover, bleeding was infrequent in those with aVWD. Prospective studies are needed to identify the incidence and clinical relevance of aVWD in MPN, but acquired platelet dysfunction by another mechanism may be a more relevant cause of MPN-associated bleeding. Disclosures:No relevant conflicts of interest to declare.

The JAK Inhibitor Ruxolitinib Elicits Hematologic and Symptomatic Improvement In Patients With Chuvash Polycythemia

Chuvash polycythemia (CP) is a rare congenital polycythemia caused by mutations in the VHL gene. Patients with CP present with erythrocytosis and are at high risk for thrombosis. Accordingly, CP patients have a significantly reduced lifespan. Currently, there are no proven therapies for CP. Studies demonstrating a potential benefit from phlebotomy or myelosuppressive agents have been lacking.CP exhibits features of both secondary and primary polycythemia. The former has been attributed to dysfunction of the mutant VHL protein leading to upregulation of HIFa under normoxic conditions, thereby resulting in increased erythropoietin (Epo) production. The latter is manifested by hypersensitivity of CP erythryoid progenitors to Epo in vitro, but the mechanism for this finding has not been fully explained.Recently, the VHL protein was shown to target phosphorylated JAK2 (pJAK2) for ubiquitin-mediated degradation. CP-associated VHL mutants were unable to degrade pJAK2, thereby leading to hyperactivation of downstream STAT signaling. In a CP mouse model, treatment with a JAK2 inhibitor led to normalization of hematocrit and reduction in splenomegaly. These findings provide a strong rationale for JAK2 inhibition as a therapeutic modality for CP. We now report preliminary data from two CP patients treated with the JAK inhibitor ruxolitinib.Baseline and on-treatment characteristics for the two patients are summarized in Table 1. Both patients were confirmed to be homozygous for the VHL R200W mutation. CP-01 first presented with erythrocytosis at 18 months. He was treated with intermittent phlebotomies and underwent a splenectomy at age 10. The patient had multiple thrombotic complications, including a deep vein thrombosis, pulmonary embolism, and portal vein thrombosis. He suffered from recurrent episodes of severe abdominal pain presumed to be related to his history of intra-abdominal thrombosis. The patient had a hemoglobin as high as 22.0 g/dL, and required four phlebotomies in a span of four weeks to achieve a hematocrit of 45.2% prior to initiating ruxolitinib. [Display omitted] CP-01 was initiated on ruxolitinib at a starting dose of 10 mg orally twice daily and titrated up to the current dose of 20 mg twice daily. As of the most recent follow-up at 12 weeks, the patient has not required any phlebotomies since starting ruxolitinib and has not had any new episodes of abdominal pain.CP-02 was initially found to have erythrocytosis at the age of three. He was treated with intermittent phlebotomies but developed multiple thrombotic complications, including mesenteric vein thrombosis as well as a myocardial infarction at the age of 27. He also suffered from severe back pain presumed to be related to bone marrow expansion. The patient exhibited oscillations in his platelet count that were exacerbated after he underwent a splenectomy (platelet counts ranging between 7 x 109/L and 1900 x 109/L on a ∼30 day cycle). Periods of extreme thrombocytosis were associated with severe headaches requiring plateletpheresis.CP-02 was initiated on treatment with ruxolitinib, initially at a dose of 5 mg twice daily due to his periodic thrombocytopenia, and gradually titrated up to 20 mg twice daily. As of the most recent evaluation at 23 weeks, the patient reported significant improvement in his back pain, though he continued to require regular phlebotomies. His platelet count oscillations have improved dramatically, particularly at the current ruxolitinib dose of 20 mg twice daily (Figure 1). Strikingly, his lowest platelet count since starting ruxolitinib has been 187 x 109/L. This stabilization in his platelet count has been associated with an improvement in his headaches. [Display omitted] To our knowledge, these two cases represent the first CP patients treated with a targeted inhibitor of JAK2. Both patients have experienced hematologic and symptomatic improvement, with no significant safety issues to date. These preliminary observations validate pre-clinical studies suggesting a role for JAK2 inhibition in CP. Correlative studies examining endogenous erythroid colony formation, JAK-STAT signaling, and inflammatory cytokine levels are ongoing. Disclosures:Oh:Incyte: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Ruxolitinib for Chuvash polycythemia.

Managing uncontrolled postsplenectomy reactive thrombocytosis in idiopathic thrombocytopenic purpura: Role of thrombocytapheresis

Reactive thrombocytosis occurs in response to infection, trauma, or surgery. Splenectomy alone accounts for 19% of all possible causes of extreme thrombocytosis. We performed thrombocytapheresis in a young lady with chronic idiopathic thrombocytopenic purpura (ITP) who developed postsplenectomy reactive thrombocytosis. Her post splenectomy platelet count was 227×106/ml which elevated to 1623×106/ml on the 7th postoperative day. A single thrombocytapheresis procedure reduced her platelet to 403×106/ml. She was discharged on the 10th postoperative day and then maintained a count of 204–238×106/ml with aspirin. Thrombocytapheresis reduces the platelet count rapidly in thrombocytosis and prevents patients from having thrombotic events. However, such procedures should be performed very meticulously to ensure patient safety.