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CALR exon 9 mutations in idiopathic splanchnic vein thrombosis in an Australian cohort
Thrombosis Research 150 (2017) 51–52
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Correspondence CALR exon 9 mutations in idiopathic splanchnic vein thrombosis in an Australian cohort Keywords: CALR exon 9 JAK2 V617F Splanchnic vein thrombosis Myeloproliferative neoplasms
Budd-Chiari syndrome (BCS) and thrombosis of the extra-hepatic portal vein and other splanchnic veins can be associated with much long-term morbidity. Recent studies have shown a strong association between Philadelphia-negative myeloproliferative neoplasms (MPNs) and splanchnic vein thrombosis (SVT) [1]. Recognising underlying MPNs is important as it changes management of SVT and has implications for prognosis. The Philadelphia-negative MPNs include polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF). These disorders have overlapping clinical findings and at the molecular level, may share the same underlying somatic mutations. In cases of PV, the JAK2 V617F mutation is present in approximately 96% and mutations in JAK2 exon 12 account for almost all the remaining cases [2]. On the other hand, in ET and PMF, JAK2 V617F is found in about 60%, whereas mutations in CALR exon 9 are present in 25% and MPL exon 10 in 5%; in the remaining 10% of cases, none of these three mutations is present [3]. Of note is that JAK2 V617F and CALR mutations almost invariably occur exclusively of each other. The two most common mutations in CALR exon 9 are characterised by a 52 base pair deletion (Type 1 mutation) and a 5 base pair insertion (Type 2 mutation). Among CALR-mutated cases of MPNs, Type 1 and Type 2 mutations occur at a frequency of approximately 2:1. It is now apparent that JAK2 V617F and CALR exon 9 mutations confer slightly different clinical and prognostic features: among ET patients with the former mutation, platelet counts are not as high yet thrombotic risk is significantly greater than those with CALR mutations [4]. Within the cohort of ET patients defined by the CALR mutation, Type 1 mutation appears to confer a higher risk of thrombosis than Type 2 [3]. In SVT, a meta-analysis of predominantly European studies found that MPNs were present in 41% of patients with primary BCS; a similar proportion of patients had the JAK2 V617F mutation [1]. In contrast, among Chinese patients with BCS, 4.1% had a diagnosis of MPN and only 2.4% harboured the JAK2 V617F mutation [5], reflecting differences in the importance of MPNs and this mutation in the aetiology of SVT. Since the description of the CALR mutation, some authors have noted its low prevalence (b2%) among patients with SVT [6–14]. To date, however, all studies have been based in centres in Europe. Given inter-ethnic and geographical differences in the aetiology of SVT, we evaluated the
http://dx.doi.org/10.1016/j.thromres.2016.12.010 0049-3848/© 2016 Elsevier Ltd. All rights reserved.
frequency of the CALR mutation among our cohort of patients in a tertiary referral centre in Melbourne, Australia. Our cohort comprised patients with BCS and thrombosis (in the absence of local pathology) in the portal vein and/or other intra-abdominal veins that constitute the portal venous system. For the purpose of this study, local pathology refers to hepatic cirrhosis and abdominal risk factors such as malignancy, surgery/trauma, sepsis/abscess or inflammation (e.g., pancreatitis, appendicitis or cholecystitis). These patients were referred to, or had been followed up at, our institution from January 2010 until December 2015. Among patients who met the above inclusion criteria, we tested for the JAK2 V617F mutation first in line with recent recommendation [6,10]; if it was undetected, we then tested for the CALR exon 9 mutations. Patients who did not complete this diagnostic algorithm were excluded from analysis. We also documented the types of CALR exon 9 mutations that were present in our cohort. Of the 41 patients that constituted our cohort, median age was 45 years (range: 18–75 years). There were 19 males (46.3%). Twenty had BCS, and the remaining 21 had thrombosis in the portal and/or other splanchnic veins. The JAK2 V617F mutation was detected in 26 patients (63.4%), being present in all 11 patients with PV, in 7 of 8 patients with ET, in 1 of 2 with PMF, in both patients with pre-fibrotic myelofibrosis and in all 3 patients with MPN unclassifiable. It was also harboured by 2 of 15 patients without a histological diagnosis of MPN. There were two patients (both males and both had BCS) with CALR exon 9 mutations, giving a prevalence of 4.9%; 13 patients had neither somatic mutation. One patient was 53 years of age when he developed BCS. JAK2 V617F was not detected. He was eventually diagnosed ten years later with primary myelofibrosis on bone marrow biopsy with del(13q) on cytogenetic karyotyping and at the molecular level, was found to have CALR exon 9 mutation with a 52-base pair deletion (Type 1 mutation). The other patient was 24 years of age when he presented with thrombosis in the hepatic segment of the inferior vena cava, and in the right and middle hepatic veins consistent with BCS. About 2 ½ years earlier, he had idiopathic right cerebral transverse sinus thrombosis for which he was anticoagulated with warfarin. The JAK2 V617F mutation was undetected. BCS developed despite him being on warfarin anticoagulation. Bone marrow biopsy when he presented with BCS was non-diagnostic, but repeat biopsy six months later demonstrated features of ET. CALR exon 9 mutation testing showed a 9-base pair insertion. Pooling all the published reports on SVT [6–14] and including our study shows that JAK2 V617F is much more common than CALR exon 9 mutations (258:10) (Table 1). Among patients with CALR mutations, Type 1 appears to be the most frequent, but it is not possible to make definitive conclusions given the small number of patients described thus far. Only when further studies are reported and results pooled that a sufficiently large cohort of patients will be available for more definitive conclusions to be made. In conclusion, our study, the first outside of Europe, confirms that CALR mutations are rare in patients with SVT. Despite this, it remains
52
Correspondence
Table 1 Prevalence of JAK2 V617F and CALR mutations in reported studies. PVT, portal vein thrombosis, MPN, myeloproliferative neoplasm.
Centre
Cohort characteristics
Number
Turon et al. [6]
Spain
Non-cirrhotic
209
Haslam & Langabeer [7] Roques et al. [8] Castro et al. [9] Colaizzo et al. [10]
Ireland France Spain Italy
Iurlo et al. [11] & Gianelli et al. [12] Sekhar et al. [13]
Italy
Unselected Unselected Unselected Non-cirrhotic and non-malignant extra-hepatic PVT MPN only
UK
Plompen et al. [14] Present study
Median age (years)
Male:Female
JAK2 V617F
CALR exon 9
CALR mutation (number)
104:105
61 (29.2%)
4 (1.9%)
144 66 40 132
BCS: 36 PVT: 45 52 53.5 48 53
77:67 44:22 21:19 68:64
27 (18.8%) 12 (18.0%) 9 (22.5%) 39 (29.5%)
0 1 (1.5%) 0 0
Type 1 (3) Del 34 bp (1) – Del 5 bp (1) – –
29
42
9:20
27 (93.1%)
0
–
No local pathology
83
Not stated
Not stated
24 (28.9%)
2 (2.4%)
European multicentre
Non-cirrhotic and non-malignant
141
61:80
33 (23.4%)
1 (0.7%)
Australia
No local pathology
41
BCS: 36 PVT: 50 45
Complex (1) Type 1 (1) Type 1 (1)
19:22
26 (63.4%)
2 (4.9%)
Total
885
285 (32.2%)
10 (1.1%)
important to screen for somatic mutations associated with MPN, as a diagnosis of MPN will influence clinical management and inform prognosis. Acknowledgments Nil. References [1] J.H. Smalberg, L.R. Arends, D.C. Valla, J.J. Kiladjian, H.L. Janssen, F.W. Leebeek, Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis, Blood 120 (2012) 4921–4928. [2] B.L. Stein, S.T. Oh, D. Berenzon, G.S. Hobbs, M. Kremyanskaya, R.K. Rampal, C.N. Abboud, K. Adler, M.L. Heaney, E.J. Jabbour, R.S. Komrokji, A.R. Moliterno, E.K. Ritchie, L. Rice, J. Mascarenhas, R. Hoffman, Polycythemia vera: an appraisal of the biology and management 10 years after the discovery of JAK2 V617F, J. Clin. Oncol. 33 (2015) 3953–3960. [3] D. Pietra, E. Rumi, W. Ferretti, C.A. Di Buduo, C. Milanesi, C. Cavalloni, E. Sant'Antonio, V. Abbonante, F. Moccia, I.C. Casetti, M. Bellini, M.C. Renna, E. Roncoroni, E. Fugazza, C. Astori, E. Boveri, V. Rosti, G. Barosi, A. Balduini, M. Cazzola, Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms, Leukemia 30 (2016) 431–438. [4] E. Rumi, D. Pietra, V. Ferretti, T. Klampfl, A.S. Harutyunyan, J.D. Milosevic, N.C. Them, T. Berg, C. Elena, I.C. Casetti, C. Milanesi, E. Sant'antonio, M. Bellini, E. Fugazza, M.C. Renna, E. Boveri, C. Astori, C. Pascutto, R. Kralovics, M. Cazzola, Associazione Italiana per La Ricerca Sul Cancro Gruppo Italiano Malattie Mieloproliferative investigators. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes, Blood 123 (2014) 1544–1551. [5] X. Qi, F. Wu, W. Ren, C. He, Z. Yin, J. Niu, M. Bai, Z. Yang, K. Wu, D. Fan, G. Han, Thrombotic risk factors in Chinese Budd-Chiari syndrome patients. An observational study with a systematic review of the literature, Thromb. Haemost. 109 (2013) 878–884. [6] F. Turon, F. Cervantes, D. Colomer, A. Baiges, V. Hernández-Gea, J.C. Garcia-Pagán, Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis, J. Hepatol. 62 (2015) 72–74. [7] K. Haslam, S.E. Langabeer, Incidence of CALR mutations in patients with splanchnic vein thrombosis, Br. J. Haematol. 168 (2015) 459–460.
Type 1 (1) Ins 9 bp (1)
[8] M. Roques, J.H. Park, A. Minello, J.N. Bastie, F. Girodon, Detection of the CALR mutation in the diagnosis of splanchnic vein thrombosis, Br. J. Haematol. 169 (2015) 601–603. [9] N. Castro, I. Rapado, R. Ayala, J. Martinez-Lopez, CALR mutations screening should not be studied in splanchnic vein thrombosis, Br. J. Haematol. 170 (2015) 588–589. [10] D. Colaizzo, L. Amitrano, M.A. Guardascione, G. Favuzzi, G.L. Tiscia, G. D'Andrea, R. Santacroce, E. Grandone, M. Margaglione, Clinical utility of screening for CALR gene exon 9 mutations in patients with splanchnic venous thrombosis, Thromb. Haemost. 113 (2015) 1381–1382. [11] A. Iurlo, D. Cattaneo, U. Gianelli, E. Fermo, C. Augello, A. Cortelezzi, Molecular analyses in the diagnosis of myeloproliferative neoplasm-related splanchnic vein thrombosis, Ann. Hematol. 94 (2015) 881–882. [12] U. Gianelli, A. Iurlo, D. Cattaneo, A. Bossi, I. Cortinovis, C. Augello, A. Moro, F. Savi, R. Castelli, C. Brambilla, P. Bianchi, M. Primignani, A. Cortelezzi, S. Bosari, Discrepancies between bone marrow histopathology and clinical phenotype in BCR-ABL1–negative myeloproliferative neoplasms associated with splanchnic vein thrombosis, Leuk. Res. 39 (2015) 525–529. [13] M. Sekhar, D. Patch, B. Austen, J. Howard, S. Hart, Calreticulin mutations and their importance in splanchnic vein thrombosis, Br. J. Haematol. 174 (2015) 158–160. [14] E.P.C. Plompen, P.J.M. Valk, I. Chu, S. Darwish Murad, A. Plessier, F. Turon, J. Trebicka, M. Primignani, J.C. Garcia-Pagán, D.C. Valla, H.L.A. Janssen, F.W.G. Leebeek, Somatic calreticulin mutations in patients with Budd-Chiari syndrome and portal vein thrombosis, Haematologica 100 (2015) e226–e228.
Wai Khoon Ho* Frank S. Hong Thrombosis & Haemostasis Clinic and Austin Pathology Coagulation Laboratory, Austin Hospital, Melbourne, Australia *Corresponding author at: Department of Laboratory Haematology, Level 6 – HSB, Austin Hospital, 145 Studley Road, Heidelberg VIC 3084, Australia. E-mail address: [email protected]. 29 September 2016 Available online 15 December 2016
Contents lists available at ScienceDirect
Thrombosis Research journal homepage: www.elsevier.com/locate/thromres
Correspondence CALR exon 9 mutations in idiopathic splanchnic vein thrombosis in an Australian cohort Keywords: CALR exon 9 JAK2 V617F Splanchnic vein thrombosis Myeloproliferative neoplasms
Budd-Chiari syndrome (BCS) and thrombosis of the extra-hepatic portal vein and other splanchnic veins can be associated with much long-term morbidity. Recent studies have shown a strong association between Philadelphia-negative myeloproliferative neoplasms (MPNs) and splanchnic vein thrombosis (SVT) [1]. Recognising underlying MPNs is important as it changes management of SVT and has implications for prognosis. The Philadelphia-negative MPNs include polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF). These disorders have overlapping clinical findings and at the molecular level, may share the same underlying somatic mutations. In cases of PV, the JAK2 V617F mutation is present in approximately 96% and mutations in JAK2 exon 12 account for almost all the remaining cases [2]. On the other hand, in ET and PMF, JAK2 V617F is found in about 60%, whereas mutations in CALR exon 9 are present in 25% and MPL exon 10 in 5%; in the remaining 10% of cases, none of these three mutations is present [3]. Of note is that JAK2 V617F and CALR mutations almost invariably occur exclusively of each other. The two most common mutations in CALR exon 9 are characterised by a 52 base pair deletion (Type 1 mutation) and a 5 base pair insertion (Type 2 mutation). Among CALR-mutated cases of MPNs, Type 1 and Type 2 mutations occur at a frequency of approximately 2:1. It is now apparent that JAK2 V617F and CALR exon 9 mutations confer slightly different clinical and prognostic features: among ET patients with the former mutation, platelet counts are not as high yet thrombotic risk is significantly greater than those with CALR mutations [4]. Within the cohort of ET patients defined by the CALR mutation, Type 1 mutation appears to confer a higher risk of thrombosis than Type 2 [3]. In SVT, a meta-analysis of predominantly European studies found that MPNs were present in 41% of patients with primary BCS; a similar proportion of patients had the JAK2 V617F mutation [1]. In contrast, among Chinese patients with BCS, 4.1% had a diagnosis of MPN and only 2.4% harboured the JAK2 V617F mutation [5], reflecting differences in the importance of MPNs and this mutation in the aetiology of SVT. Since the description of the CALR mutation, some authors have noted its low prevalence (b2%) among patients with SVT [6–14]. To date, however, all studies have been based in centres in Europe. Given inter-ethnic and geographical differences in the aetiology of SVT, we evaluated the
http://dx.doi.org/10.1016/j.thromres.2016.12.010 0049-3848/© 2016 Elsevier Ltd. All rights reserved.
frequency of the CALR mutation among our cohort of patients in a tertiary referral centre in Melbourne, Australia. Our cohort comprised patients with BCS and thrombosis (in the absence of local pathology) in the portal vein and/or other intra-abdominal veins that constitute the portal venous system. For the purpose of this study, local pathology refers to hepatic cirrhosis and abdominal risk factors such as malignancy, surgery/trauma, sepsis/abscess or inflammation (e.g., pancreatitis, appendicitis or cholecystitis). These patients were referred to, or had been followed up at, our institution from January 2010 until December 2015. Among patients who met the above inclusion criteria, we tested for the JAK2 V617F mutation first in line with recent recommendation [6,10]; if it was undetected, we then tested for the CALR exon 9 mutations. Patients who did not complete this diagnostic algorithm were excluded from analysis. We also documented the types of CALR exon 9 mutations that were present in our cohort. Of the 41 patients that constituted our cohort, median age was 45 years (range: 18–75 years). There were 19 males (46.3%). Twenty had BCS, and the remaining 21 had thrombosis in the portal and/or other splanchnic veins. The JAK2 V617F mutation was detected in 26 patients (63.4%), being present in all 11 patients with PV, in 7 of 8 patients with ET, in 1 of 2 with PMF, in both patients with pre-fibrotic myelofibrosis and in all 3 patients with MPN unclassifiable. It was also harboured by 2 of 15 patients without a histological diagnosis of MPN. There were two patients (both males and both had BCS) with CALR exon 9 mutations, giving a prevalence of 4.9%; 13 patients had neither somatic mutation. One patient was 53 years of age when he developed BCS. JAK2 V617F was not detected. He was eventually diagnosed ten years later with primary myelofibrosis on bone marrow biopsy with del(13q) on cytogenetic karyotyping and at the molecular level, was found to have CALR exon 9 mutation with a 52-base pair deletion (Type 1 mutation). The other patient was 24 years of age when he presented with thrombosis in the hepatic segment of the inferior vena cava, and in the right and middle hepatic veins consistent with BCS. About 2 ½ years earlier, he had idiopathic right cerebral transverse sinus thrombosis for which he was anticoagulated with warfarin. The JAK2 V617F mutation was undetected. BCS developed despite him being on warfarin anticoagulation. Bone marrow biopsy when he presented with BCS was non-diagnostic, but repeat biopsy six months later demonstrated features of ET. CALR exon 9 mutation testing showed a 9-base pair insertion. Pooling all the published reports on SVT [6–14] and including our study shows that JAK2 V617F is much more common than CALR exon 9 mutations (258:10) (Table 1). Among patients with CALR mutations, Type 1 appears to be the most frequent, but it is not possible to make definitive conclusions given the small number of patients described thus far. Only when further studies are reported and results pooled that a sufficiently large cohort of patients will be available for more definitive conclusions to be made. In conclusion, our study, the first outside of Europe, confirms that CALR mutations are rare in patients with SVT. Despite this, it remains
52
Correspondence
Table 1 Prevalence of JAK2 V617F and CALR mutations in reported studies. PVT, portal vein thrombosis, MPN, myeloproliferative neoplasm.
Centre
Cohort characteristics
Number
Turon et al. [6]
Spain
Non-cirrhotic
209
Haslam & Langabeer [7] Roques et al. [8] Castro et al. [9] Colaizzo et al. [10]
Ireland France Spain Italy
Iurlo et al. [11] & Gianelli et al. [12] Sekhar et al. [13]
Italy
Unselected Unselected Unselected Non-cirrhotic and non-malignant extra-hepatic PVT MPN only
UK
Plompen et al. [14] Present study
Median age (years)
Male:Female
JAK2 V617F
CALR exon 9
CALR mutation (number)
104:105
61 (29.2%)
4 (1.9%)
144 66 40 132
BCS: 36 PVT: 45 52 53.5 48 53
77:67 44:22 21:19 68:64
27 (18.8%) 12 (18.0%) 9 (22.5%) 39 (29.5%)
0 1 (1.5%) 0 0
Type 1 (3) Del 34 bp (1) – Del 5 bp (1) – –
29
42
9:20
27 (93.1%)
0
–
No local pathology
83
Not stated
Not stated
24 (28.9%)
2 (2.4%)
European multicentre
Non-cirrhotic and non-malignant
141
61:80
33 (23.4%)
1 (0.7%)
Australia
No local pathology
41
BCS: 36 PVT: 50 45
Complex (1) Type 1 (1) Type 1 (1)
19:22
26 (63.4%)
2 (4.9%)
Total
885
285 (32.2%)
10 (1.1%)
important to screen for somatic mutations associated with MPN, as a diagnosis of MPN will influence clinical management and inform prognosis. Acknowledgments Nil. References [1] J.H. Smalberg, L.R. Arends, D.C. Valla, J.J. Kiladjian, H.L. Janssen, F.W. Leebeek, Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis, Blood 120 (2012) 4921–4928. [2] B.L. Stein, S.T. Oh, D. Berenzon, G.S. Hobbs, M. Kremyanskaya, R.K. Rampal, C.N. Abboud, K. Adler, M.L. Heaney, E.J. Jabbour, R.S. Komrokji, A.R. Moliterno, E.K. Ritchie, L. Rice, J. Mascarenhas, R. Hoffman, Polycythemia vera: an appraisal of the biology and management 10 years after the discovery of JAK2 V617F, J. Clin. Oncol. 33 (2015) 3953–3960. [3] D. Pietra, E. Rumi, W. Ferretti, C.A. Di Buduo, C. Milanesi, C. Cavalloni, E. Sant'Antonio, V. Abbonante, F. Moccia, I.C. Casetti, M. Bellini, M.C. Renna, E. Roncoroni, E. Fugazza, C. Astori, E. Boveri, V. Rosti, G. Barosi, A. Balduini, M. Cazzola, Differential clinical effects of different mutation subtypes in CALR-mutant myeloproliferative neoplasms, Leukemia 30 (2016) 431–438. [4] E. Rumi, D. Pietra, V. Ferretti, T. Klampfl, A.S. Harutyunyan, J.D. Milosevic, N.C. Them, T. Berg, C. Elena, I.C. Casetti, C. Milanesi, E. Sant'antonio, M. Bellini, E. Fugazza, M.C. Renna, E. Boveri, C. Astori, C. Pascutto, R. Kralovics, M. Cazzola, Associazione Italiana per La Ricerca Sul Cancro Gruppo Italiano Malattie Mieloproliferative investigators. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes, Blood 123 (2014) 1544–1551. [5] X. Qi, F. Wu, W. Ren, C. He, Z. Yin, J. Niu, M. Bai, Z. Yang, K. Wu, D. Fan, G. Han, Thrombotic risk factors in Chinese Budd-Chiari syndrome patients. An observational study with a systematic review of the literature, Thromb. Haemost. 109 (2013) 878–884. [6] F. Turon, F. Cervantes, D. Colomer, A. Baiges, V. Hernández-Gea, J.C. Garcia-Pagán, Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis, J. Hepatol. 62 (2015) 72–74. [7] K. Haslam, S.E. Langabeer, Incidence of CALR mutations in patients with splanchnic vein thrombosis, Br. J. Haematol. 168 (2015) 459–460.
Type 1 (1) Ins 9 bp (1)
[8] M. Roques, J.H. Park, A. Minello, J.N. Bastie, F. Girodon, Detection of the CALR mutation in the diagnosis of splanchnic vein thrombosis, Br. J. Haematol. 169 (2015) 601–603. [9] N. Castro, I. Rapado, R. Ayala, J. Martinez-Lopez, CALR mutations screening should not be studied in splanchnic vein thrombosis, Br. J. Haematol. 170 (2015) 588–589. [10] D. Colaizzo, L. Amitrano, M.A. Guardascione, G. Favuzzi, G.L. Tiscia, G. D'Andrea, R. Santacroce, E. Grandone, M. Margaglione, Clinical utility of screening for CALR gene exon 9 mutations in patients with splanchnic venous thrombosis, Thromb. Haemost. 113 (2015) 1381–1382. [11] A. Iurlo, D. Cattaneo, U. Gianelli, E. Fermo, C. Augello, A. Cortelezzi, Molecular analyses in the diagnosis of myeloproliferative neoplasm-related splanchnic vein thrombosis, Ann. Hematol. 94 (2015) 881–882. [12] U. Gianelli, A. Iurlo, D. Cattaneo, A. Bossi, I. Cortinovis, C. Augello, A. Moro, F. Savi, R. Castelli, C. Brambilla, P. Bianchi, M. Primignani, A. Cortelezzi, S. Bosari, Discrepancies between bone marrow histopathology and clinical phenotype in BCR-ABL1–negative myeloproliferative neoplasms associated with splanchnic vein thrombosis, Leuk. Res. 39 (2015) 525–529. [13] M. Sekhar, D. Patch, B. Austen, J. Howard, S. Hart, Calreticulin mutations and their importance in splanchnic vein thrombosis, Br. J. Haematol. 174 (2015) 158–160. [14] E.P.C. Plompen, P.J.M. Valk, I. Chu, S. Darwish Murad, A. Plessier, F. Turon, J. Trebicka, M. Primignani, J.C. Garcia-Pagán, D.C. Valla, H.L.A. Janssen, F.W.G. Leebeek, Somatic calreticulin mutations in patients with Budd-Chiari syndrome and portal vein thrombosis, Haematologica 100 (2015) e226–e228.
Wai Khoon Ho* Frank S. Hong Thrombosis & Haemostasis Clinic and Austin Pathology Coagulation Laboratory, Austin Hospital, Melbourne, Australia *Corresponding author at: Department of Laboratory Haematology, Level 6 – HSB, Austin Hospital, 145 Studley Road, Heidelberg VIC 3084, Australia. E-mail address: [email protected]. 29 September 2016 Available online 15 December 2016