The risk of thrombosis in essential thrombocythemia is associated with the type of CALR mutation: A multicentre collaborative study

2020 ◽  
Author(s):  
Manuel M. Pérez Encinas ◽  
Marta Sobas ◽  
María Teresa Gómez‐Casares ◽  
Aitor Abuin Blanco ◽  
María Soledad Noya Pereira ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Collaborative Study ◽  
Calr Mutation

scholarly journals ANAGRELIDE AND THE CALR MUTATION ALLELE BURDEN IN ESSENTIAL THROMBOCYTHEMIA

2018 ◽  
Vol 40 (2) ◽  
pp. 152-152
Author(s):  
E Atkinson ◽  
M Bakri ◽  
A Hayat ◽  
S E Langabeer
Keyword(s):  
Essential Thrombocythemia ◽  
Allele Burden ◽  
Calr Mutation ◽  
Mutation Allele

LETTER TO EDITOR

scholarly journals Thrombocytapheresis in Patient with Essential Thrombocythemia: A Case Report

2020 ◽  
Vol 13 (2) ◽  
pp. 675-679
Author(s):  
Afra M. Elhassan ◽  
Arwa Alsaud ◽  
Mohamed A. Yassin ◽  
Mahmood Aldapt ◽  
Lubna Riaz ◽  
...  
Keyword(s):  
Platelet Count ◽  
Case Report ◽  
Essential Thrombocythemia ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Favorable Outcome ◽  
Who Criteria ◽  
Icu Admission ◽  
Calr Mutation ◽  
Clonal Abnormalities

Essential thrombocythemia (ET) is one of the myeloproliferative neoplasms, characterized by persistent thrombocytosis, platelets >450,000/μL, and evident clonal abnormalities like JAK2 V617F, MPL, CALR mutation and not fulfilling WHO criteria for MDS, CML, PV, and IDA. Here we report a 24-year-old female who presented with headache and was found to have thrombocytosis with a platelet count of 2,141 × 103/μL, diagnosed as ET as per WHO criteria 2008; she required ICU admission and thrombocytapheresis with a favorable outcome.

Function of Integrin αIIbβ3 in Essential Thrombocythemia with Calreticulin Mutation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4079-4079
Author(s):  
Jun Yamanouchi ◽  
Takaaki Hato ◽  
Etsuko Matsubara ◽  
Taichi Azuma ◽  
Hiroshi Fujiwara ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Lower Risk ◽  
Healthy Subjects ◽  
Thrombotic Event ◽  
Jak2 V617f ◽  
Β1 Integrin ◽  
Wild Type ◽  
Integrin Αiibβ3 ◽  
Calr Mutations ◽  
Calr Mutation

Abstract Mutations in the calreticulin (CALR) gene were recently discovered in patients with essential thrombocythemia and it has been turned out that CALR mutated patients have a lower risk of thrombosis than JAK2 V617F patients. However, the molecular mechanism for this differential risk remains obscure. It has been reported that CALR is a potential regulatory protein of integrin activation based on the interaction between CALR and a conserved sequence of GFFKR in the integrin α cytoplasmic tails. Recent studies suggest that calreticulin activates β1 integrin and modulates integrin-associated signaling. In this study, we examined if the mutant CALR proteins observed in patients with ET affect integrin αIIbβ3 activation which plays a crucial role on thrombus formation. We first identified mutations of JAK2, MPL, and CALR genes in 37 patients with WHO defined ET and explored clinical characteristics of patients with CALR mutation. The patients with JAK2 V617F were 22 (59%), MPL W515L was 1 (3%), and CALR mutations were 10 (27%). The two types of CALR mutations were found; deletion (52-bp deletion; c.1092_1143del) and insertion (5-bp insertion; c.1154_1155insTTGTC) mutations. The patients with CALR mutations had lower hemoglobin and leukocyte count compared with JAK2 V617F patients, but platelet count did not have a difference between the CALR and JAK2 mutation groups. Nine (41%) of 22 patients with JAK2V617F had a thrombotic event while 1 (10%) of 10 patients with CALR mutation did (p<0.05), suggesting that patients with CALR mutation had a lower risk of thrombosis than JAK2 V617F patients. Two patients with CALR mutations developed myelofibrosis while no patient with JAK2V617F did. One patient with CALR mutation developed acute myeloid leukemia, with persistence of the CALR mutation in his leukemic cells. To see if the CALR mutation affects functional status of αIIbβ3, we examined the binding of PAC1, a monoclonal antibody recognizing the active conformation of αIIbβ3, to platelets from 5 patients with CALR mutation and 12 patients with JAK2V617F in the presence or absence of ADP. Platelets from all the 5 patients with CALR mutation showed the same level of PAC1 binding as platelets from healthy subjects. Overexpression of recombinant CALR proteins in Chinese Hamster Ovary (CHO) cells expressing αIIbβ3 by transfection of a protein-expression vector containing wild-type, deletion, or insertion mutant CALR had no effect on PAC1 binding. We further examined adhesive function of CHO cells stably expressing αIIbβ3 and mutant or wild-type CALR to various concentrations of immobilized fibrinogen. Expression of wild-type or mutant CALR had no effect on αIIbβ3-mediated cell adhesion to fibrinogen. Moreover, each cell adherent to fibrinogen showed apparently the similar extent of spreading. On the other hand, platelets from 4 of 12 patients with JAK2V617F had an increase in PAC1 binding in the presence and absence of ADP compared with platelets from healthy subjects. All 4 (100%) of 4 patients with increased PAC1 binding had a thrombotic event while 4 (30%) of 13 patients with normal PAC1 binding did. Our study suggests no functional activation of integrin αIIbβ3 by CALR mutation, which is contrary to a recent finding that CALR activates β1 integrin. Nonetheless, our finding is rather in line with a clinical finding of a low risk for thrombosis in patients with CALR mutation and may provide the molecular basis for the differential thrombotic risk between the patient with CALR and JAK2 mutations. Disclosures Fujiwara: Celgene: Honoraria, Other: Travel, Acomodations, Expenses.

Activation Status of Integrin αIIbβ3 in Essential Thrombocythemia with Calreticulin Mutation

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4571-4571
Author(s):  
Jun Yamanouchi ◽  
Takaaki Hato ◽  
Etsuko Matsubara ◽  
Taichi Azuma ◽  
Hideyuki Nakanishi ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Healthy Subjects ◽  
Conflicts Of Interest ◽  
Thrombotic Event ◽  
Jak2 V617f ◽  
Insertion Mutant ◽  
Integrin Αiibβ3 ◽  
Calr Mutations ◽  
Calr Mutation ◽  
Activation Status

Abstract Mutations in the calreticulin (CALR) gene were recently discovered in patients with essential thrombocythemia (ET) lacking the JAK2V617F and MPLW515 mutations. It has been reported that CALR is a potential regulatory protein of integrin activation based on the interaction between CALR and a conserved sequence of GFFKR in the integrin α cytoplasmic tails. Recent studies suggest that calreticulin activates β1 integrin and modulates integrin-associated signaling. In this study, we examined the effect of CALR mutations on integrin αIIbβ3 activation. We first identified mutations of JAK2, MPL, and CALR genes in 37 patients with WHO defined ET and explored clinical characteristics of patients with CALR mutation. The patients with JAK2 V617F were 22 (59%), MPL W515L was 1 (3%), and CALR mutations were 10 (27%). The two types of CALR mutations were found; deletion (52-bp deletion; c.1092_1143del) and insertion (5-bp insertion; c.1154_1155insTTGTC) mutations. The patients with CALR mutations had lower hemoglobin and leukocyte count compared with JAK2 V617F patients, but platelet count did not have a difference between the CALR and JAK2 mutation groups. Nine (41%) of 22 patients with JAK2V617F had a thrombotic event while 1 (10%) of 10 patients with CALR mutation did (p<0.05), suggesting that patients with CALR mutation had a lower risk of thrombosis than JAK2 V617F patients. Two patients with CALR mutations developed myelofibrosis while no patient with JAK2V617F did. One patient with CALR mutation developed acute myeloid leukemia, with persistence of the CALR mutation in his leukemic cells.To see if the CALR mutation affects activation status of αIIbβ3, we examined the binding of PAC1, a monoclonal antibody recognizing the active conformation of αIIbβ3, to platelets from 5 patients with CALR mutation and 12 patients with JAK2V617F in the presence or absence of ADP. Platelets from all the 5 patients with CALR mutation showed the same level of PAC1 binding as platelets from healthy subjects. Overexpression of recombinant CALR proteins in CHO cells expressing αIIbβ3 by transfection of a protein-expression vector containing wild-type, deletion, or insertion mutant CALR had no effect on PAC1 binding. On the other hand, platelets from 4 of 12 patients with JAK2V617F had an increase in PAC1 binding in the presence and absence of ADP compared with platelets from healthy subjects. All 4 (100%) of 4 patients with increased PAC1 binding had a thrombotic event while 4 (30%) of 13 patients with normal PAC1 binding did. Our study suggests no activation of integrin αIIbβ3 by CALR mutation, which may explain a clinical finding of a low risk for thrombosis in patients with CALR mutation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Selected Parameters of Angiogenesis and the JAK2, CALR, and MPL Mutations in Patients With Essential Thrombocythemia

2018 ◽  
Vol 24 (7) ◽  
pp. 1056-1060 ◽  
Author(s):  
Grażyna Gadomska ◽  
Alicja Bartoszewska-Kubiak ◽  
Joanna Boinska ◽  
Karolina Matiakowska ◽  
Katarzyna Ziołkowska ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Essential Thrombocythemia ◽  
Leukemia Virus ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Vascular Endothelial ◽  
High Concentration ◽  
Endothelial Growth Factor ◽  
Calr Mutation

The aim of the study was to evaluate selected angiogenic factors in patients with essential thrombocythemia (ET) depending on JAK2V617F, calreticulin gene (CALR) and myeloproliferative leukemia virus oncogene (MPL) mutations. Sixty ET patients and 20 healthy volunteers were enrolled in the study. The following tests were performed: vascular endothelial growth factor- A (VEGF-A), soluble vascular endothelial growth factor receptor-1 (sVEGFR-1),soluble vascular endothelial growth factor receptor-2 (sVEGFR-2), platelet-derived growth factor( PDGF-BB), and stromal-derived factor-1α (SDF-1α). We observed an increased PDGF-BB level in patients with ET compared to the controls. Patients with CALR mutation had significantly higher concentration of PDGF-BB and lower concentration of SDF-1α than patients with JAK2V617F mutation. High concentration of PDGF-BB and low concentration of SDF-1α in patients with CALR(+) ET may indicate a contribution of these chemokines in disturbed Ca2+ metabolism in platelets.

scholarly journals Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: A collaborative study of 1027 patients

2014 ◽  
Vol 89 (8) ◽  
pp. E121-E124 ◽  
Author(s):  
Ayalew Tefferi ◽  
Emnet A. Wassie ◽  
Paola Guglielmelli ◽  
Naseema Gangat ◽  
Alem A. Belachew ◽  
...  
Keyword(s):  
Essential Thrombocythemia ◽  
Collaborative Study
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