DOCSLIB.ORG

Calreticulin Mutations and Long-Term Survival in Essential Thrombocythemia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Calreticulin Mutations and Long-Term Survival in Essential Thrombocythemia Leukemia (2014) 28, 2300–2303 & 2014 Macmillan Publishers Limited All rights reserved 0887-6924/14 www.nature.com/leu ORIGINAL ARTICLE Calreticulin mutations and long-term survival in essential thrombocythemia A Tefferi1, EA Wassie1, TL Lasho1, C Finke1, AA Belachew1, RP Ketterling2, CA Hanson3, A Pardanani1, N Gangat1 and AP Wolanskyj1 The impact of calreticulin (CALR) mutations on long-term survival in essential thrombocythemia (ET) was examined in 299 patients whose diagnosis predated 2006. Mutational frequencies were 53% for Janus kinase 2 (JAK2), 32% for CALR and 3% for MPL; the remaining 12% were ‘triple-negative’. We confirmed the association of mutant CALR (vs JAK2V617F) with younger age (P ¼ 0.002), male sex (P ¼ 0.01), higher platelet count (0.0004), lower hemoglobin (Po0.0001), lower leukocyte count (0.02) and lower incidence of recurrent thrombosis (0.04). Triple-negative patients were also younger than their JAK2-mutated counterparts (P ¼ 0.003) and displayed lower hemoglobin (P ¼ 0.003), lower leukocyte count (o0.0001) and lower thrombotic events (P ¼ 0.02). Median follow- up time was 12.7 years and 47% of the patients were followed until death. Survival was the longest for triple-negative and shortest for MPL-mutated patients. Median survival was 19 years for JAK2 and 20 years for CALR-mutated cases (P ¼ 0.32); the corresponding figures for patients of age p65 years were 26 and 32 years (P ¼ 0.56). The two mutational categories were also similar for leukemic (P ¼ 0.28) and fibrotic (P ¼ 0.28) progression rates. The current study is uniquely characterized by its very long follow-up period and provides accurate estimates of long-term survival in ET and complements current information on mutation-specific phenotype and prognosis. Leukemia (2014) 28, 2300–2303; doi:10.1038/leu.2014.148 INTRODUCTION MATERIALS AND METHODS Janus kinase 2 (JAK2), calreticulin (CALR) and myeloproliferative The current study was approved by the Mayo Clinic institutional review leukemia virus oncogene (MPL) mutations are recurrent and board. to obtain mature survival data, we queried an institutional database of patients with ET, whose diagnosis predated 2006 (diagnosis period was mutually exclusive in myeloproliferative neoplasms; their reported 10 frequencies were 95–100%, 0 and 0% for polycythemia vera (PV), between 1956 and 2005). From this database, we identified consecutive 59–64%, 15–24% and 4% for essential thrombocythemia (ET) and patients (the current study population) in who archived bone marrow or peripheral blood DNA was available. All bone marrow specimens as well as 53–58%, 25–35% and 6–8% for primary myelofibrosis (PMF), 1–5 cytogenetic studies were either performed or reviewed at our institution to respectively. In ET, mutant CALR (vs JAK2V617F) was associated ensure accuracy of diagnosis. Patients who received a diagnosis of ET before with younger age, male sex, higher platelet count, lower the formal publications of the World Health Organization (WHO) criteria 1–4 hemoglobin level and lower leukocyte count. In PMF, CALR- were re-evaluated retrospectively and included in the current study only if mutated patients were also younger and presented with higher they also fulfilled the 2001 or 2008 WHO criteria for ET.11,12 Special care was platelet count, lower risk scores as per the dynamic international undertaken to avoid inadvertent inclusion of patients with either ‘prefibrotic’ prognostic scoring system (DIPSS)-plus6 and lower frequencies of PMF or PV.13 The occurrence of leukemic or fibrotic disease progression was anemia, leukocytosis and spliceosome mutations.5 annotated by the treating physician and reviewed by the authors, 11,14 CALR mutations have been associated with superior thrombosis- wherever possible, for compliance to formal criteria. Treatment free survival in ET1–4 and overall survival in PMF;5 the latter was approaches reflected the individual physician’s best clinical judgment and independent of both ASXL1 mutational status7 and DIPSS-plus.6,8 included anti-platelet and cytoreductive agents, such as hydroxyurea, anagrelide, interferon alpha, busulfan, chlorambucil and radiophosphorus Mutational status according to both CALR and ASXL1 and the (P-32). Follow-up information was updated in February 2014. number of prognostically-detrimental mutations have recently 8,9 Previously published methods were used for CALR, JAK2 and MPL been shown to enable robust molecular prognostication in PMF. mutation analysis.5 All statistical analyses considered clinical and laboratory In contrast, the observations regarding CALR mutation impact on parameters obtained at the time of diagnosis. Differences in the distribution overall survival in ET were inconclusive owing to inadequate of continuous variables between categories were analyzed by either follow-up time (median 5.2–6 years)3,4 and low number of events Mann–Whitney (for comparison of two groups) or Kruskal–Wallis (12.1%).3 The particular scenario also creates overly optimistic (for comparison of three or more groups) test. Patient groups with nominal 2 survival estimates because of excess early censoring. In the current variables were compared by w -test. Overall survival analysis was considered study, we sought to address these issues by querying an from the date of diagnosis to the date of death (uncensored) or last contact institutional database of patients with ET, whose diagnosis (censored). Leukemia-free survival calculation considered leukemic transfor- mation as the uncensored variable. Survival curves were prepared by the predated 2006, thus ensuring a minimum follow-up time of 8 Kaplan–Meier method and compared by the log-rank test. Cox proportional years; the main objectives were to provide accurate estimates of hazard regression model was used for multivariable analysis. P-values less long-term survival in ET and clarify the survival impact of CALR than 0.05 were considered significant. The Stat View (SAS Institute, Cary, NC, mutations in such a setting. USA) statistical package was used for all calculations. 1Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA; 2Division of Cytogenetics, Laboratory Medicine, Mayo Clinic, Rochester, MN, USA and 3Division of Hematopathology, Laboratory Medicine, Mayo Clinic, Rochester, MN, USA. Correspondence: Professor A Tefferi, Division of Hematology, Department of Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. E-mail: [email protected] Received 10 March 2014; revised 9 April 2014; accepted 11 April 2014; accepted article preview online 5 May 2014; advance online publication, 30 May 2014 CALR mutations and survival in ET A Tefferi et al 2301 RESULTS thrombosis was documented in 70 patients and was less frequent A total of 299 patients fulfilled the above-stipulated criteria for in CALR-mutated (P ¼ 0.04) and triple-negative (P ¼ 0.02) patients, inclusion in the current study. Clinical and laboratory features at compared to JAK2-mutated cases. Overall, survival was the longest presentation are outlined in Table 1. Median age at diagnosis in triple-negative patients (median not reached) and shortest in was 56 years (range 15–91) and women constituted 60% of the MPL-mutated cases (median 9 years) (P ¼ 0.007; Figure 2). patients. Median hemoglobin, leukocyte and platelet counts However, the differences were no longer significant when adjusted were 13.9 g/dl, 9.6 Â 10(9)/l and 1000 Â 10(9)/l, respectively. for age (P ¼ 0.42). Median survival was 19 years for JAK2 and 20 Palpable splenomegaly, mostly described as ‘tip palpable’ was years for CALR-mutated cases (P ¼ 0.32); the corresponding figures recorded in 68 (23%) patients. Thrombosis history before or at for patients of age p65 years were 26 and 32 years (P ¼ 0.56; the time of diagnosis was obtained in 54 (18%) patients. Twenty Figure 3). The two mutational categories were also similar for (6.7%) patients presented with major bleeding. Microcirculatory leukemic (P ¼ 0.28) and fibrotic (P ¼ 0.28) progression rates. symptoms were mentioned by 53 (18%) patients. Risk stratifica- Multivariable analysis that included age confirmed the lack of tion per the international prognostic scoring system for ET mutation effect on survival and instead confirmed the prognostic 15 (IPSET)15 were low in 109 (36%) patients, intermediate in 119 relevance of IPSET (Figure 4). (40%) and high in 71 (24%). Cytogenetic information was available in 218 patients and showed abnormal results in 19 (8.7%). DISCUSSION Mutational frequencies were 53% for JAK2, 32% for CALR and Considering the fact that JAK2, CALR and MPL mutations can be 3% for MPL. Approximately 13% of the patients were triple- present or absent in otherwise morphologically-defined ET, it is negative. Figure 1 lists all the CALR mutation variants seen; type 1 important to clarify their impact on disease characteristics and and type 2 mutations constituted 48 and 35% of all CALR-mutated patient outcome. The current study confirms previous observa- cases. As outlined in Table 1, we confirmed mutation-specific tions regarding the phenotypic differences between JAK2- differences in several clinical and laboratory characteristics at mutated, CALR-mutated and triple-negative patients with ET.3,4 presentation. Compared to JAK2V617F, CALR mutations were We show that CALR-mutated and triple-negative ET patients were associated with younger age (P ¼ 0.002), male sex (P ¼ 0.01), significantly younger than their JAK2-mutated counterparts, which higher platelet count (0.0004), lower hemoglobin level underscores the need to adjust for age when comparing overall (Po0.0001), lower leukocyte count (0.02) and lower incidence of and thrombosis-free survival. These two mutational categories microcirculatory symptoms (0.005). Triple-negative patients were were also similar in terms of displaying lower hemoglobin levels also younger than their JAK2-mutated counterparts (P ¼ 0.003) and leukocyte counts, compared with JAK2-mutated cases, but and displayed lower hemoglobin (P ¼ 0.003), lower leukocyte differed in their platelet counts and sex distribution. These count (o0.0001) and lower thrombotic events (P ¼ 0.02).
Load more

Recommended publications
  • The Impact of Thrombophilia in the Management Of
    S6 MPN III – Abstracts of the 8th International Hematology Expert Meeting / Leukemia Research 44 S1 (2016) S1–S12 Figure 1. Possible new treatment algorithm in polycythemia vera and essential thrombocythemia (CVR = cardiovascular risk factors). Adapted from: Tefferi A, Barbui T. Am J Hematol 2015;90(8):683–5 MPN III the Czech part of the international registry (“Registry”) of anagrelide (Thromboreductin®)-treated patients. The impact of thrombophilia in the management of MPN The recent analysis of the “Registry” [6] included altogether 1179 patients having MPD-T – either ET, PV or PMF according to PVSG criteria. In 812 J. Schwarz patients, the WHO/CZEMP diagnosis could be established: ET – 445 CZEMP (Czech Group for Ph– Myeloproliferative Disorders), Prague, Czech (54.8%), PMF – 206 (25.4%), PV – 107 (13.2%), and other (mostly MPN- Republic unclassifiable) – 54 (6.7%) cases. The M/F ratio was 2:3, the median age of The overall thrombotic risk in a normal healthy population is always based patients was 52 years (6–91 years) at diagnosis. The incidence of vascular on a combination of multiple risk factors present in one individual. The events was compared in the history (before entering the Registry) and risk parameters for arterial and venous events differ. MPD-T represents during follow-up (on anagrelide treatment). History and follow-up a situation in which the specific MPD-related risks (such as the JAK2 represented 4149 and 4742 patient-years, respectively. For arterial events, mutation) are combined with other risk factors present in the general there was a decrease in the incidence of events from 5.04 to 2.74 per 100 population.
    [Show full text]
  • Immune Thrombocytopenia and JAK2V617F Positive Essential Thrombocythemia: Literature Review and Case Report
    Hindawi Case Reports in Hematology Volume 2017, Article ID 3725089, 4 pages https://doi.org/10.1155/2017/3725089 Case Report Immune Thrombocytopenia and JAK2V617F Positive Essential Thrombocythemia: Literature Review and Case Report M. A. Sobas,1 T. Wróbel,1 K. Zduniak,2 M. Podolak-Dawidziak,1 J. Rybka,1 M. BiedroN,1 M. Sawicki,1 J. Dybko,1 and K. Kuliczkowski1 1 Department of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Medical University of Wrocław, Wrocław, Poland 2Department of Pathology, Medical University of Wrocław, Wrocław, Poland Correspondence should be addressed to M. A. Sobas; [email protected] Received 27 March 2017; Revised 28 May 2017; Accepted 27 June 2017; Published 20 July 2017 Academic Editor: Eduardo Arellano-Rodrigo Copyright © 2017 M. A. Sobas et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We present the case where immune thrombocytopenia (ITP) and essential thrombocythemia (ET) sequentially appeared in the space of twenty-one years of follow-up. Impaired platelet production is present in both diseases, but clinical presentation and treatment are different. On the basis of this case history a possible role of autoimmunity as a predisposing factorto myeloproliferation has been discussed. 1. Introduction but proved one with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) [6]. Primaryimmunethrombocytopeniapreviouslycalledidio- pathic thrombocytopenic purpura or immune thrombocy- Here we present a case report of a patient with ITP who topenic purpura (ITP) is characterized by autoimmune- was diagnosed with ET, after 21 years of follow-up.
    [Show full text]
  • Essential Thrombocythemia Effective Date: July, 2021
    Guideline Resource Unit [email protected] Essential Thrombocythemia Effective Date: July, 2021 Clinical Practice Guideline LYHE-012 – Version 1 www.ahs.ca/guru Background Thrombocytosis, defined as a platelet count of ≥ 450 x 109/L, is common in clinical practice and can be related to primary or secondary causes. Essential thrombocythemia (ET), a primary cause, is a Philadelphia-negative classical myeloproliferative neoplasm (MPN) defined by clonal thrombocytosis1. Similar to other classical MPNs, mutually exclusive driver mutations including JAK2, CALR and MPL are responsible for the pathogenesis of ET with the most frequent mutation JAK2V617F found in 55% of ET, 15-30% having CALR and 4-8% having MPL, while 10-20% lack a driver mutation and are referred to as “triple negative”2. ET is complicated by thrombosis and bleeding risk with potential of transformation to myelofibrosis or alternative aggressive myeloid neoplasm. This guideline is to provide information regarding the diagnosis and management of ET based on our current standards. Guideline Questions 1. What diagnostic and baseline investigations are recommended for adult patients with suspected or confirmed ET? 2. What are the recommended treatment options for ET? 3. How do you manage extreme thrombocytosis? 4. How do you treat thrombosis in the setting of ET and other MPNs? 5. What is the current peri-operative and peripartum management strategies for ET/MPN patients? Search Strategy This guideline was generated using systematic literature searches of PubMed and MEDLINE databases, ASCO, EHA abstracts and proceedings, and ASH abstracts and proceedings. The search included practice guidelines, systematic reviews, meta-analyses, randomized controlled trials and clinical trials.
    [Show full text]
  • Essential Thrombocythemia Facts No
    Essential Thrombocythemia Facts No. 12 in a series providing the latest information for patients, caregivers and healthcare professionals www.LLS.org • Information Specialist: 800.955.4572 Introduction Highlights Essential thrombocythemia (ET) is one of several l Essential thrombocythemia (ET) is one of a related “myeloproliferative neoplasms” (MPNs), a group of closely group of blood cancers known as “myeloproliferative related blood cancers that share several features, notably the neoplasms” (MPNs) in which cells in the bone “clonal” overproduction of one or more blood cell lines. marrow that produce the blood cells develop and All clonal disorders begin with one or more changes function abnormally. (mutations) to the DNA in a single cell; the altered cells in l ET begins with one or more acquired changes the marrow and the blood are the offspring of that one (mutations) to the DNA of a single blood-forming mutant cell. Other MPNs include polycythemia vera and cell. This results in the overproduction of blood cells, myelofibrosis. especially platelets, in the bone marrow. The effects of ET result from uncontrolled blood cell l About half of individuals with ET have a mutation production, notably of platelets. Because the disease arises of the JAK2 (Janus kinase 2) gene. The role that this from a change to an early blood-forming cell that has the mutation plays in the development of the disease, capacity to form red cells, white cells and platelets, any and the potential implications for new treatments, combination of these three cell lines may be affected – and are being investigated. usually each cell line is affected to some degree.
    [Show full text]
  • Immune Thrombocytopenic Purpura with Subsequent Development of JAK2 V617F-Positive Essential Thrombocythemia: Case Report
    ISSN: 2640-7914 DOI: https://dx.doi.org/10.17352/ahcrr CLINICAL GROUP Received: 13 July, 2021 Case Report Accepted: 03 August, 2021 Published: 04 August, 2021 *Corresponding author: Marisabel Hurtado-Castillo, Immune thrombocytopenic PGY-3, Internal Medicine, Department of Medicine at NYU, 536 Ovington Avenue Apartment 3, Brooklyn NYC 11209, USA, Tel: 718-312-9641; purpura with subsequent Email: Keywords: Immune thrombocytopenic purpura; development of JAK2 Essential thrombocythemia; JAK-STAT signaling path- way; JAK2(V617F) mutation V617F-positive essential https://www.peertechzpublications.com thrombocythemia: Case Report Marisabel Hurtado-Castillo1*, Brian Flaherty2 and Morris Jrada2 1PGY-3, Internal Medicine, Department of Medicine at NYU, Brooklyn, NY, USA 2Clinical Assistant Professor, Department of Medicine at NYU Grossman School of Medicine, Brooklyn, NY, USA Abstract The sequential occurrence of Immune Thrombocytopenic Purpura (ITP) and Essential Thrombocythemia (ET) has been reported in the literature on a few occasions, as these are two hematologic disorders with distinct etiologies and patients usually have contrasting clinical presentations. Our case highlights the sequential occurrence of ITP, followed by Janus kinase 2 (JAK2) (V617F)-positive ET in a 64-year-old white woman, after four years of follow-up. The pathophysiology relating to these two conditions is incompletely understood, however, JAK2(V617F) mutation has been found in all the cases reported. Early identifi cation of JAK2(V617F) mutation in a patient with a
    [Show full text]
  • Erythromelalgic Microvascular Disturbances, Major Thrombosis
    & Throm gy b o o l e o t m Journal of Hematology & a b o m l e i c H D f o i s l e a Thromboembolic Diseases ISSN: 2329-8790 a Michiels, J Hematol Thromb Dis 2014, 2:5 n s r e u s o J DOI: 10.4172/2329-8790.1000149 Review Article Open Access Erythromelalgic Microvascular Disturbances, Major Thrombosis and Hemorrhagic Manifestations of Thrombocythemia in Patients with Essential Thrombocythemia and Polycythemia Vera: Therapeutic Implications Jan Jacques Michiels* Academic Hospital Dijkzigt, Erasmus University Rotterdam (EUR 1974-1998), Department of Hematology, Antwerp University Hospital, Belgium, and Goodheart Institute, Bloodcoagulation and Vascular Medicine Center, Rotterdam, (1998-2014) The Netherlands Abstract Aspirin responsive erythromelalgia is the presenting symptom of thrombocythemia in patients with essential thrombocythemia (ET) and polycythemia vera (PV). Skin punch biopsies taken from the affected areas of erythromelalgia and acrocyanotic compications show typical arteriolar inflammation, fibromuscular intimal proliferation and thrombotic occlusions. If left untreated both microvascular and major thrombosis frequently do occur in thrombocythemia in ET and PV patients, but can easily be cured and prevented by low dose aspirin. The stratification as low, intermediate and high thrombotic risk in the retrospective Bergamo studies has been performed in ET patients not treated with aspirin. The risk of thrombosis in aspirin treated ET and PV is not age dependent when on low dose aspirin, and does recur when not on low dose aspirin during follow-up. The persistence of the Bergamo definition of low, intermediate and high thrombotic risk in the 2012 International Prognostic Score of Thrombosis in ET (IPSET) is applicable for JAK2 mutated ET and PV patients not on aspirin and has led to significant overtreatment with hydroxyurea.
    [Show full text]
  • First-Line Idiopathic Thrombocytopenic Purpura Therapies – Benefits and Limitations
    Rodeghiero.qxp 6/3/08 12:11 Page 25 Coagulation Disorders Platelet Disorders First-line Idiopathic Thrombocytopenic Purpura Therapies – Benefits and Limitations a report by Francesco Rodeghiero and Marco Ruggeri Department of Haematology, San Bortolo Hospital, Vicenza DOI: 10.17925/EOH.2007.0.0.25 Idiopathic thrombocytopenic purpura (ITP) is a primary acquired time. The use of anti-DIg in order to delay or avoid splenectomy proved disease of adults and children characterised by transient or persistent ineffective in at least two prospective studies.16,17 The efficacy of decrease of the platelet count.1,2 Bleeding may be severe and is usually high-dose dexamethasone in inducing a higher rate of durable related to the platelet count. When platelet count is lower than remissions remains unsettled. 20–30x109/l, bleeding is manifested by variably extensive purpura and mucosal haemorrhages; occasionally, in the case of a much lower In a recent paper, Cheng and colleagues18 reported their experience platelet count, this can be severe enough to cause a cerebral of treating 125 new cases of severe ITP with one course of high-dose haemorrhage. Haemorrhagic deaths are reported in fewer than 1% of dexamethasone. A good response was reached in 85% of patients cases. When a safe platelet count (more than 20–30X109/l) cannot be and it was durable in up to 45%. In 50% of those relapsing, a maintained, the mortality rate is greatly increased and proportional to second durable response was achieved with a second course. These the time at risk and age of the patient, reaching an age-adjusted death promising results were confirmed in a subsequent multicentre rate of 13/100 patient-years.3–6 prospective Italian study19 in which high-dose dexamethasone was given every 14 days for up to four cycles, with an initial response rate The diagnosis is one of exclusion, based on the absence of additional of 85.6%.
    [Show full text]
  • Essential Thrombocythemia Characterization: Mutational, Cytokine, and Thrombotic Profiling
    Research Article Published: 21 May, 2019 Journal of Hematology and Oncology Forecast Essential Thrombocythemia Characterization: Mutational, Cytokine, and Thrombotic Profiling Hernandez-Matias L1, Maysonet-Cruz J2, Calzada-Jorge N1, Pérez-Donato L1, Torres Rivera W3, Ramírez-Rodríguez J1, Laureano-Torres F1, Méndez LB3, Ríos O1, Menéndez-Pérez J1, Washington AV1* and Hunter-Mellado R2 1Department of Biology, University of Puerto Rico, Rio Piedras Campus, San Juan, Puerto Rico 2Retrovirus Research Center, Universidad Central del Caribe, School of Medicine, Bayamón, Puerto Rico 3Department of Pathology and Laboratory Medicine, School of Science and Technology, Universidad del Este, Carolina, Puerto Rico Abstract Essential Thrombocythemia (ET) is characterized by a persistent thrombocytosis associated with mutations in Janus Kinase 2 (JAK2V617F), Myeloproliferative Leukemia protein (MPL), and/ or Calreticulin (CALR). Although ET mutational background has been defined for some sub populations, the proportion and diversification of ET mutations have not been defined for the Puerto Rican population. Furthermore, its cytokine profiling and clinical characteristics have also yet to be defined. In order to understand and further provide better treatment for the ET Puerto Rican cohort, this study defines the proportion of common ET mutations, cytokine profiles, plasma levels of Lysyl Oxidase (LOX), soluble Trem-Like Transcript-1 (sTLT-1) and, correlates these levels to the patients’ clinical background. Results show that JAK2V617F, CALR, and MPL mutations were present in the ET Puerto Rican cohort in the proportions of 52%, 18%, and 4% respectively. It was also found that TWEAK/TNSF12 was significantly lower and, that MMP-1, IL-35, IL-8, IFN-α2, IL- 19, IL-22, IL-28A/IFNλ2, and IL-29/IFNλ1 were significantly higher in ET patients when compared to controls.
    [Show full text]
  • Pathophysiological Aspects of Platelet-Mediated Thrombosis and Bleeding in Essential Thrombocythemia Isbn 90-9011490-4
    PATHOPHYSIOLOGICAL ASPECTS OF PLATELET-MEDIATED THROMBOSIS AND BLEEDING IN ESSENTIAL THROMBOCYTHEMIA ISBN 90-9011490-4 Lay-out by Karola van Rooyen Printed by: Offsetdrukkerij Haveka BV te Alblasserdam PATHOPHYSIOLOGICAL ASPECTS OF PLATELET-MEDIATED THROMBOSIS AND BLEEDING IN ESSENTIAL THROMBOCYTHEMIA Pathofysiologischc aspecten van trombocyt-gemedieerde trombose en bloeding bij essentiele thrombocythemie PROEFSCHRIFT Ter verkrijging van de graad van doctor aan de Erasmus Universiteit te Rotterdam op gezag van de rector magnificus Prof. Dr P.W.c. Akkermans M.A. en volgens besluit van het college voor promoties De open bare verdediging zal plaatsvinden op woensdag 13 mei 1998 om 15:45 mu door Picter Jan Johan van Genderen geboren te Spijkenisse Promotiecommissie Promotor Prof. Dr. B. Lowenberg Co-promotor Dr. J.J. Michiels Overige leden Prof. ].H.P. Wilson Prof. D,: J.W. ten Cate Prof. Dr. P.]. Koudstaal The work described in this thesis was performed at the Department of Hematology, University Hospital Dijkzigt, Rotterdam, The Netherlands The financial support of ASTA Medica, bioMerieux, Bristol-Myers Squibb, Byk, Centeon, Ferring, Kordia, Leo Pharmaceutical Products, Merck, Sharp & Dohllle, Nodia/Chromogenix, Nourypharma, Parke-Davis, Rh6ne-Poulenc Rorel; Sanofi Winthrop and Schering-Plough is gratefully acknowledged. CONTENTS CHAPTER 1 9 Introduction to essential thrombocythemia and its hemostatic complications CHAPTER 2 29 Platelet consumption m thrombocythemia complicated by erythromelalgia: reversal by aspirin CHAPTER 3 41 Erythromelalgia
    [Show full text]
  • Essential Thrombocythemia ET
    ABOUT BLOOD CANCERS Essential Thrombocythemia ET WHAT YOU NEED TO KNOW You or your loved one has been diagnosed with essential thrombo- cythemia (ET). What does it mean and how will it affect you? This fact sheet will help you: Learn about ET Get an overview Understand what and how it is of treatment happens next diagnosed options bloodcancers.ca | 1 833 222-4884 Essential Thrombocythemia (ET) | 1 What is essential thrombocythemia (ET)? ET is a type of myeloproliferative neoplasm (MPN). This group of blood cancers features too many blood cells of a particular type made in the ET is a rare blood bone marrow. MPNs begin with one or more changes to the DNA of a disease. If treated single stem cell in the bone marrow. These changes cause the stem cell to and monitored create more and more abnormal stem cells. carefully, many people living with ET People with ET have too many platelets, a type of blood cell. Too many have a normal life platelets can result in a blood clot (thrombosis) forming in a blood vessel. expectancy. This can cause serious health problems such as a stroke, heart attack, or pulmonary embolism (blockage of a major blood vessel in the lung). About ET • Most cases of ET feature genetic mutations to a bone marrow stem cell. • May mean that your body makes too many platelets (blood clotting cells). • Occurs most often in adults and is more common in women. • The median age at diagnosis is 65 years. Signs and ET is often detected during a routine blood test before you notice any symptoms symptoms.
    [Show full text]
  • Myelofibrosis, Polycythemia Vera, Essential Thrombocythemia
    MYELOFIBROSIS, POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA ADVOCACY & EDUCATION mpnadvocacy.com INTERNATIONAL mpnadvocacy.com MPN Advocacy & Education International MPN Advocacy and Education International provides educational programs, materials, Ann Brazeau, CEO and resources for patients, caregivers, physicians, and entire healthcare teams to improve their understanding of myelofibrosis, polycythemia vera, and essential thrombocythemia. They are dedicated to making a difference in the lives of those affected by MPNs and strive to grow awareness and advocate on behalf of the MPN community. Kathleen Michael Vice President Advocacy Our advocacy efforts extend beyond responding to the unmet needs of the MPN Community. We identify concerns in a meaningful and productive way and create initiatives that impact quality care, treatment access, new drug development and represent MPN patients and organizations who are unable to address the issues surrounding a blood cancer diagnosis. Women and MPN and Pediatric and Young Adult initiatives have expanded Dr. Ruben Mesa, MD, Scientific Advisor the interest and exploration into the unmet needs of these UT Health San Antonio patient groups. Cancer Center Education MPN Education programs are held across the country and internationally each year. Our speakers are MPN specialists who share updated information on research, clinical trials, treatment options, and comprehensive quality of life direction. Dr. Ruben Mesa, MD, is our scientific advisor and frequent speaker at our educational programs. Please visit our website at www.mpnadvocacy.com for more information on events, advocacy initiatives, patient support groups in your area and numerous resources. PAGE ONE What are Myeloproliferative Neoplasms (MPN)? Myelo – prefix referring to bone marrow Proliferative – increasing the numbers of cells Neoplasm – any new and abnormal growth, where cell multiplication is uncontrolled and progressive.
    [Show full text]
  • Hemorrhage in Essential Thrombocythemia Or Polycythemia Vera: Epidemiology, Location, Risk Factors, and Lessons Learned from the Literature
    Published online: 2020-11-13 Review Article 553 Hemorrhage in Essential Thrombocythemia or Polycythemia Vera: Epidemiology, Location, Risk Factors, and Lessons Learned from the Literature Christophe Nicol1 Karine Lacut2,3 Brigitte Pan-Petesch1,3 Eric Lippert4,5 Jean-Christophe Ianotto1,3,5 1 Service d’Hématologie Clinique, Institut de Cancéro-Hématologie, Address for correspondence Christophe Nicol, MD, Service CHRU de Brest, Bretagne, France d’Hématologie Clinique, Institut de Cancéro-Hématologie, CHRU de 2 Département de Médecine Interne et Pneumologie, CHRU de Brest, Brest, 29200 Bretagne, France Bretagne, France (e-mail: [email protected]). 3 GETBO, Groupe d’Etude de la Thrombose de Bretagne Occidentale, CHRU de Brest, Brest, Bretagne, France 4 Laboratoire d’Hématologie, CHRU de Brest, Bretagne, France 5 FIM, France Intergroupe des Néoplasies Myéloprolifératives, France Thromb Haemost 2021;121:553–564. Abstract Hemorrhage is a well-known complication of essential thrombocythemia (ET) and polycy- themia vera (PV), but evidence-based data on its management and prevention are lacking to help inform clinicians. In this review, appropriate published data from the past 15 years regarding bleeding epidemiology, classification, location, and risk factors are presented and discussed. Research was conducted using the Medline database. The bleeding classifications were heterogeneous among the collected studies. The median incidences of bleeding and major bleeding were 4.6 and 0.79% patients/year, in ET patients and 6.5 and 1.05% patients/year in PV patients, respectively. The most frequent location was the gastrointestinal tract. Bleeding accounted for up to 13.7% of deaths, and cerebral bleeding was the main cause of lethal hemorrhage.
    [Show full text]