A 10 Year Retrospective Analysis of Carotid Stenosis in Patients with Polycythemia Vera or Essential Thrombocythemia

Abstract Patients with polycythemia vera (PV) or essential thrombocythemia (ET) are at an increased risk for thrombotic events. The pathophysiology of hyperviscosity, leukocyte-induced endothelial damage, and the over-expression of JAK2 and STAT5 genes contributing to the development of atherothrombosis is poorly understood. As such, the goal of our study was to retrospectively examine carotid stenosis severity in patients with PV or ET and to determine if carotid stenosis is associated with thrombotic events in this patient group. We examined patients in a ten year period (2004 to 2014) who were under the care of a hematologist at our tertiary care-teaching hospital for either PV or ET, and, having one or more carotid duplex. Patients having diagnoses of secondary polycythemia or secondary thrombocytosis were excluded. Data obtained from patient charts included demographics, cardiovascular risk factors, thrombotic events, platelet and hematocrit levels, medications, and carotid stenosis severity. Clinically significant carotid stenosis was defined as >50 % stenosis. We compared patients with carotid stenosis to those without stenosis using Fisher exact tests. Of the 31 patients meeting study inclusion, only 9 (29%) presented with clinically significant carotid stenosis with 1 (3%) patient having increasing carotid stenosis severity during the study period. Elevated cell counts did not correlate with carotid stenosis. Elevated hematocrit levels of >45% or elevated platelet counts >400x 109/L, had no stasticial difference in the incidence of carotid stenosis versus no stenosis (50% vs. 18%, P = 0.16) and (63% vs. 64%, P = 1.00) respectively. There was no difference between the two groups with the use of either anti-platelet therapy (P = 0.68) or cytoreduction medications (P = 1.00) at the time of duplex. A total of 21 patients had 1 or more thrombotic event during the 10 year period. A total 35 thrombotic events occurred, with the distribution of events being 29% deep venous thrombosis, 28% stroke, 23% transient ischemia attack (TIA), 11% myocardial infarction, 3% peripheral arterial thrombosis, 3% pulmonary embolism and 3% retinal artery or vein occlusion. Rates of thrombotic events were comparable between ET and PV patients, with 10 of 15 patients with PV, 10 of 15 patients with ET and 1 patient with ET + PV experiencing a thrombotic event (P = 0.75). Carotid stenosis did not associate with increased rates of stroke or other thrombotic events. Stroke/TIA after duplex occurred in 22% of patients with carotid stenosis versus 9% of patients with no carotid stenosis (P = 0.56). Likewise, the rate of all thrombotic events after duplex was similar in patients with and without carotid stenosis (33% and 41%, respectively, P = 1.00). Two patients received carotid revascularization during the study period. Carotid endarterectomy appeared to be successful in one asymptomatic patient who presented with severe bilateral internal carotid artery stenosis. The other patient who received angioplasty for fibromuscular dysplasia and found to have carotid stenosis of <30% stenosis, later required neurological consults months post procedure due to TIA like symptoms. Thus, in this patient’s case, the underlying cause of the recurring symptoms may have been related to ET. This preliminarily study suggests that carotid stenosis may not predict thrombotic events in patients with ET or PV. Furthermore, patients with suspected carotid stenosis and/or presenting with stroke and having sustained elevated platelet/hematocrit levels may need to be evaluated for an underlying hematological disorder. Disclosures No relevant conflicts of interest to declare.

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Observational study of thrombosis and bleeding in COVID-19 VV ECMO patients

The International Journal of Artificial Organs ◽

10.1177/0391398821989065 ◽

2021 ◽

pp. 039139882198906

Author(s):

Brianda Ripoll ◽

Antonio Rubino ◽

Martin Besser ◽

Chinmay Patvardhan ◽

William Thomas ◽

...

Keyword(s):

Intensive Care ◽

Ct Scan ◽

Thrombotic Event ◽

Area Under The Curve ◽

Whole Body ◽

Bleeding Events ◽

Heparin Resistance ◽

Increased Risk ◽

Thrombotic Complications ◽

Clinically Significant

Introduction: COVID-19 has been associated with increased risk of thrombosis, heparin resistance and coagulopathy in critically ill patients admitted to intensive care. We report the incidence of thrombotic and bleeding events in a single center cohort of 30 consecutive patients with COVID-19 supported by veno-venous extracorporeal oxygenation (ECMO) and who had a whole body Computed Tomography Scanner (CT) on admission. Methodology: All patients were initially admitted to other hospitals and later assessed and retrieved by our ECMO team. ECMO was initiated in the referral center and all patients admitted through our CT scan before settling in our intensive care unit. Clinical management was guided by our institutional ECMO guidelines, established since 2011 and applied to at least 40 patients every year. Results: We diagnosed a thrombotic event in 13 patients on the initial CT scan. Two of these 13 patients subsequently developed further thrombotic complications. Five of those 13 patients had a subsequent clinically significant major bleeding. In addition, two patients presented with isolated intracranial bleeds. Of the 11 patients who did not have baseline thrombotic events, one had a subsequent oropharyngeal hemorrhage. When analyzed by ROC analysis, the area under the curve for % time in intended anticoagulation range did not predict thrombosis or bleeding during the ECMO run (0.36 (95% CI 0.10–0.62); and 0.51 (95% CI 0.25–0.78); respectively). Conclusion: We observed a high prevalence of VTE and a significant number of hemorrhages in these severely ill patients with COVID-19 requiring veno-venous ECMO support.

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Clonal Dynamics of JAK2V617F and Non-Driver Mutations in Polycythemia Vera and Essential Thrombocythemia Patients Receiving Hydroxyurea Therapy

Blood ◽

10.1182/blood-2021-150491 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3623-3623

Author(s):

Lierni Fernández-Ibarrondo ◽

Joan Gibert ◽

Concepción Fernández-Rodríguez ◽

Laura Camacho ◽

Anna Angona ◽

...

Keyword(s):

Dna Repair ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Research Funding ◽

Evolutionary Dynamics ◽

Driver Mutations ◽

Molecular Response ◽

Increased Risk ◽

Cytoreductive Treatment ◽

Allelic Burden

Abstract Introduction : Hydroxyurea (HU) is the most widely used cytoreductive treatment for patients with essential thrombocythemia (ET) and polycythemia vera (PV) at high risk of thrombosis. It remains unknown whether long-term HU therapy modulates or promotes the acquisition of mutations in non-driver (ND) genes, especially, when assessing hematological (HR) and molecular (MR) response. The objective of the study was to analyze the clonal dynamics of ND genes in HR and MR with HU in a cohort of JAK2V617F-mutated PV and ET patients. Method s: The study included 144 JAK2V617F positive patients (PV n = 73, TE n = 71) receiving HU as first-line cytoreductive treatment. The baseline sample (before HU treatment) and at the timepoint of best molecular response to JAK2V617F were analyzed. The allelic burden of J AK2V617F was assessed by allele-specific PCR and the mutational profile of ND genes was analyzed by next generation sequencing with a custom panel including 27 myeloid-associated genes. HR was defined according to the criteria of the European LeukemiaNet 2009 and MR of JAK2V617F was defined as complete, major, partial and no response (Table I). Results : Median molecular follow-up was 54.1 months for PV and 55.5 months for ET. Patients with PV were more likely to be males (p<0.001), and displayed higher leukocyte count (p<0.001) compared to those with ET. The respective numbers of deaths, leukemic transformations and fibrotic progressions were: 22 (30%), 4 (5%), 6 (8%) for PV cases, and 19 (27%), 1 (1%), 0 (0%) for ET patients. At baseline, a total of 62 somatic mutations in ND genes were detected in 42/73 (57%) PV patients while 58 were detected in 36/71 (51%) ET patients. Complete HR was observed in 102 patients: 44 (60%) PV and 58 (81%) ET. Partial MR in 67 cases: 35 (48%) PV and 32 (45%) ET and major or complete MR in 21 cases: 8 (11%) PV and 13 (18%) ET. The median duration of HU treatment was 45.8 months (range: 17.5-189.5) for PV and 45.6 months (range: 14.6-168.6) for ET. The most frequently mutated genes detected at pre-therapy samples were TET2 (34%), ASXL1 (12%), SF3B1 (7%) and EZH2 (5%) in PV patients, and TET2 (34%), ASXL1 (13%), DNMT3A (13 %) and SRSF2 (5%) in ET patients. No significant differences were observed in the MR (p=0.358) or HR (p=0.917) according to the presence or absence of mutations in ND genes at baseline. Clonal dynamics of DNMT3A, ASXL1, and TET2 (DAT) genes were not modulated by HU therapy to the same extent as JAK2V617F. Disappearance and emergence of additional mutations in DAT genes were observed independently of the molecular response achieved by the JAK2V617F clone. These findings suggest the existence of clones with mutations in ND genes independent from the pathogenic driver clone, and the lack of modulation by HU treatment. Finally, an increase of allelic burden or the appearance of mutations in TP53, a gene related to progression, and in other DNA repair genes (PPM1D and CHEK2) was observed in 14 (19.1%) PV patients and 9 (12.6%) ET cases during HU treatment. However, no increased risk of myelofibrotic transformation or progression to acute myeloid leukemia was observed in these patients. Conclusion s: Pre-treatment ND mutations are not associated with HR and MR to HU in JAK2V617F-mutated patients. 2. The clonal dynamics of ND mutations (decrease, increase, appearance, disappearance) are not related to the evolutionary dynamics of JAK2V617F. 3. An increase or appearance of progression-related mutations in TP53 and/or other genes of the DNA repair pathway such as CHEK2 and PPM1D is observed during HU treatment. Acknowledgments : Instituto de Salud Carlos III-FEDER, PI16/0153, PI19/0005, 2017SGR205, PT20/00023 and XBTC. Figure 1 Figure 1. Disclosures Salar: Janssen: Consultancy, Speakers Bureau; Roche: Consultancy, Speakers Bureau; Gilead: Research Funding; Celgene: Consultancy, Speakers Bureau. Besses: Gilead: Research Funding. Bellosillo: Thermofisher Scientific: Consultancy, Speakers Bureau; Qiagen: Consultancy, Speakers Bureau; Roche: Research Funding, Speakers Bureau.

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Leukocytosis and thrombosis in essential thrombocythemia and polycythemia vera: a systematic review and meta-analysis

Blood Advances ◽

10.1182/bloodadvances.2019000211 ◽

2019 ◽

Vol 3 (11) ◽

pp. 1729-1737 ◽

Cited By ~ 20

Author(s):

Alessandra Carobbio ◽

Alberto Ferrari ◽

Arianna Masciulli ◽

Arianna Ghirardi ◽

Giovanni Barosi ◽

...

Keyword(s):

Systematic Review ◽

Blood Cell ◽

Polycythemia Vera ◽

White Blood Cell ◽

Essential Thrombocythemia ◽

Recurrent Events ◽

Myeloproliferative Neoplasms ◽

Meta Analysis ◽

Sensitivity Analyses ◽

Cell Counts

Abstract In the last years, a growing amount of evidence has been produced regarding the role of leukocytosis as a risk factor for thrombosis in patients with myeloproliferative neoplasms, predominantly in polycythemia vera (PV) and essential thrombocythemia (ET). Results from epidemiologic studies on this issue, however, are inconclusive. We conducted a systematic review and meta-analysis of articles published in the last 12 years addressing the issue, according to a predefined protocol. Forty-one articles analyzing >30 000 patients met our inclusion criteria and were deemed of acceptable methodologic quality. In addition to data on thrombosis, data were collected on bleeding, hematologic evolution, secondary cancer, and death. The relative risk (RR) of thrombosis in the presence of leukocytosis was 1.59 (95% CI, 1.40-1.80), mainly accounted for by ET (RR, 1.65; 95% CI, 1.43-1.91) and arterial thrombosis (RR, 1.45; 95% CI, 1.13-1.86) subgroups; the effect was not significant in venous thrombosis alone. Sensitivity analyses considering recurrent events as well as white blood cell estimates adjusted or unadjusted for confounding factors confirmed the primary results. In addition, the pooled RR of studies that tested white blood cell counts in time-dependent models suggested a causative effect of leukocytes in the mechanism that triggers thrombosis. The effect of leukocytosis on bleeding (RR, 1.87; 95% CI, 1.26-2.77) and death (RR, 1.89; 95% CI, 1.59-2.23) was confirmed, whereas conclusions on hematologic evolutions and solid tumors were uncertain. To confirm the accuracy of these results, an investigation on individual patient data in a large collective archive of homogeneous patients is warranted.

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Thrombocytosis: Diagnostic Evaluation, Thrombotic Risk Stratification, and Risk-Based Management Strategies

Thrombosis ◽

10.1155/2011/536062 ◽

2011 ◽

Vol 2011 ◽

pp. 1-16 ◽

Cited By ~ 43

Author(s):

Jonathan S. Bleeker ◽

William J. Hogan

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasms ◽

Treatment Options ◽

Treatment Strategies ◽

Diagnostic Evaluation ◽

Diagnostic Process ◽

Special Focus ◽

Thrombotic Risk ◽

Increased Risk

Thrombocytosis is a commonly encountered clinical scenario, with a large proportion of cases discovered incidentally. The differential diagnosis for thrombocytosis is broad and the diagnostic process can be challenging. Thrombocytosis can be spurious, attributed to a reactive process or due to clonal disorder. This distinction is important as it carries implications for evaluation, prognosis, and treatment. Clonal thrombocytosis associated with the myeloproliferative neoplasms, especially essential thrombocythemia and polycythemia vera, carries a unique prognostic profile, with a markedly increased risk of thrombosis. This risk is the driving factor behind treatment strategies in these disorders. Clinical trials utilizing targeted therapies in thrombocytosis are ongoing with new therapeutic targets waiting to be explored. This paper will outline the mechanisms underlying thrombocytosis, the diagnostic evaluation of thrombocytosis, complications of thrombocytosis with a special focus on thrombotic risk as well as treatment options for clonal processes leading to thrombocytosis, including essential thrombocythemia and polycythemia vera.

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miRNAs Expression Pattern in Essential Thrombocythemia and Polycythemia Vera Patients.

Blood ◽

10.1182/blood.v114.22.1912.1912 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1912-1912

Author(s):

Aina Pons ◽

Carlos Besses ◽

Luz Martínez-Avilés ◽

Alberto Alvarez-Larran ◽

Raquel Longaron ◽

...

Keyword(s):

Polycythemia Vera ◽

Expression Pattern ◽

Essential Thrombocythemia ◽

Mirna Expression ◽

Fold Change ◽

Differentially Expressed ◽

Hematopoietic Stem ◽

Mutational Status ◽

Increased Risk ◽

Normal Controls

Abstract Abstract 1912 Poster Board I-935 Background: Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are myeloproliferative neoplasms (MPN) arising from a multipotent hematopoietic stem cell characterized by an unregulated production of platelets, red cells and white cells alone or in combination, a tendency to clonal evolution and an increased risk of thrombohemorrhagic complications. MicroRNAs (miRNA) are negative regulators of genes involved in cellular proliferation, apoptosis and/or carcinogenesis. Aim: To analyze the expression pattern of miRNA between PV and ET patients and to find distinctive signatures in ET patients according to JAK2V617F and c-MPL mutational status. Material and Methods: Total RNA was extracted from peripheral blood granulocytes of 50 ET patients, 10 PV patients and 10 controls. Median age of patients was 57 years (range, 20-88); males 36%. The JAK2V617F mutation was present in 23 (46%) of 50 ET patients and in all PV patients. MPL mutations were present in 5 (18%) of 27 JAK2V617F negative cases (3 cases MPLW515L, 1 case MPLW515K and 1 case MPLS505N). miRNA expression was profiled in 384 miRNA via Taqman Low Density Array in ABI PRISM 7900. Expression data was normalized with RNU48 and relative quantification was calculated with the 2–σσCt method. The data were presented as log10 of relative quantity of target miRNA. Median of normal controls was used as calibrator for all samples. Data were analyzed by means of Significant Analysis of MicroArrays (SAM), Prediction Analysis of MicroArrays (PAM) and Class Comparison methods using BRB array tools version 3.7.0 and TIGR multiexperiment viewer version 4.3. Results: We found a general downregulation of miRNA in ET and PV patients respect to normal controls. A set of 29 miRNA allowed us to discriminate between ET and PV versus normal controls; three of these miRNA were up-regulated and 16 down-regulated in PV and ET vs. normal controls with a >2 fold change and p value <0.01. A distinctive signature of 79 miRNAs differentiated ET, PV and controls and a hierarchical clustering analysis defined miRNA expression profiles of the three particular groups. When we compared miRNA differentially expressed between PV and ET patients, we found nine miRNA, 4 up-regulated and 5 down-regulated in ET with respect to PV patients (p<0.01). Statistical comparisons between ET JAK2V617F-positive and ET JAK2V617F-negative cases showed a distinctive signature of 13 miRNA that allowed us to discriminate between the two groups. In addition, we also found in JAK2V617F cases 19 miRNA differentially expressed between MPL positive and MPL negative patients, with a >2 fold change and p<0.01. Finally, an increased expression of miR-142-5p correlated with JAK2V617F allele burden in ET patients Conclusions: Our study demonstrates that ET and PV can be defined by specific signatures of miRNA. In ET, some miRNA allow us to discriminate cases according to JAK2V617F mutational status and also between MPL-positive and MPL-negative JAK2V617F-negative patients. Research Funding: FIS EC07/90791 Disclosures: No relevant conflicts of interest to declare.

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Analysis of JAK2 V617F Mutation and Its Clinical Significance in Patients with Thrombocythemia and Other Myeloproliferative Neoplasms in Chinese

Blood ◽

10.1182/blood.v118.21.4687.4687 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4687-4687

Author(s):

Yue Xu ◽

Changxin Yin ◽

Han He ◽

Lingling Shu ◽

Fuqun Wu ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Conflicts Of Interest ◽

Myeloproliferative Neoplasms ◽

Jak2 V617f ◽

Jak2 V617f Mutation ◽

Jak2 Mutation ◽

Western Countries ◽

Arms Pcr ◽

V617f Mutation

Abstract Abstract 4687 JAK2 mutation is commonly found in Philadelphia-negative myeloproliferative neoplasms (MPNs). In Western countries, this mutation is found in approximately 96 percent of people with polycythemia vera, half of individuals with essential thrombocythemia or primary myelofibrosis. We used the method of amplification refractory mutation PCR (ARMS-PCR) to investigate MPN patients in China. We focused our study on patients with essential thrombocythemia (ET). ARMS-PCR was used to detect JAK2 V617F mutation in the bone barrow (BM) or peripheral blood of 37 MPN patients, which consisting of 7 ET, 5 polycythemia vera (PV), 5 chronic myeloid leukemia (CML), 5 chronic idiopathic myelofibrosis (CIMF), as well as 15 suspected MPNs. 17 cases of JAK2 V617F mutation (45.9%) were found in 37 patients, including 4 ET (57.1%), 4 PV (80.0%), 3 CIMF (60.0%), 6 suspected MPNs (40.0%). We did not find JAK2 V617F in the patients with CML. Our results indicated that the frequency of JAK2 V617F mutation in bcr/abl-negative MPNs in Chinese is similar to that in MPN patients in Western countries. At the same time, ARMS-PCR can distinguish the mutation is heterozygous or homozygous. Most patients were heterozygous for JAK2 but only a few were homozygous. In conclusion, our study showed that JAK2 V617F mutation frequency in Chinese MPN patients is similar to that in patients with this disorder in the West. It is the major molecular genetic abnormality in bcr-abl negative MPN and it can be used for diagnosis of MPN in China. Disclosures: No relevant conflicts of interest to declare.

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Essential Thrombocythemia Patients with CALR Mutations Have Increased Platelet Activation Markers Compared to JAK2V617F Mutated Patients

Blood ◽

10.1182/blood.v124.21.3223.3223 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3223-3223

Author(s):

Maya Koren-Michowitz ◽

Hagit Hauschner ◽

Yulia Shuly ◽

Meital Nagar ◽

Elena Ribakovsky ◽

...

Keyword(s):

Essential Thrombocythemia ◽

Conflicts Of Interest ◽

Thrombus Formation ◽

Absolute Number ◽

Median Number ◽

Healthy Controls ◽

Activation Markers ◽

Increased Risk ◽

Platelet Aggregates ◽

Calr Mutations

Abstract Essential thrombocythemia (ET) is associated with an increased risk for thrombo-hemorrhagic complications. The presence of the JAK2V617F mutation, found in approximately 50% of ET patients, has been associated with increased indices of platelet (PLT) activation suggesting its casual role in thrombus formation. Mutations in CALR were recently described in the majority of JAK2V617F negative ET patients, and are associated with a decreased rate of thrombotic events. This has led us to hypothesize that CALR mutations have a different influence on PLT activation compared to JAK2V617F. To evaluate the PLT activation state, surface expression of two PLT activation markers - p-selectin (CD62P) and PAC1 was studied using specific antibodies. MFI was analyzed by flow cytometry at baseline, as well as following ADP addition to PLT rich plasma. Monocyte-platelet aggregates were studied in whole blood samples by gating CD45+/CD14+ cells and calculating the percentage of CD41+ cells in the monocytes population. The immature PLT fraction (IPF) was analyzed with the XE-5000 hematology analyzer (Sysmex UK Ltd., Milton Keynes, UK), and the absolute number of immature PLT (nIP) was calculated from the total PLT count. Low risk ET patients (N-13, M/F-5/8) and healthy controls (N-10, M/F-4/6) are included in this analysis. JAK2V617F and CALR mutations were present in 8 and 5 patients, respectively; low dose aspirin (range 75-100mg) was taken by 85% of patients and 90% of controls. Median PLT count in CALR mutated, JAK2V617F mutated and healthy subjects was 913, 579 and 247 K/uL, respectively (p=0.0002), and it was higher in CALR compared to JAK2V617F positive patients (p=0.09). Both patient subgroups had a lower baseline MFI of p-selectin and PAC1 compared to healthy controls (p-selectin: 2.8, 3 and 4.5 for JAK2V617F [p=0.01], CALR [p=0.05] and controls; PAC1: 3, 3.3 and 5.2 for JAK2V617F [p=0.01], CALR [p=0.02] and controls, respectively) with no difference between CALR and JAK2V617F mutated patients. CALR compared to JAK2V617F mutated patients had higher median number of immature PLT (30 and 10.6 K/uL, p=0.04), and a higher fraction of monocyte- platelet aggregates (90 and 58%, p=0.05). nIP and monocyte- platelet aggregates were also significantly higher in CALR mutated but not in JAK2V617F mutated patients compared to healthy controls. Interestingly, there was no difference in post ADP PLT activation (post/baseline ratio) between ET patients and healthy controls. Finally, there were correlations between the PLT counts and nIP (R=0.8, p<0.0001), monocyte- platelet aggregates (R=0.5, p=0.02), baseline p-selectin MFI (R=-0.5, p=0.02) and PAC1 MFI (R=-0.5, p=0.01). Our preliminary results suggest a correlation between PLT activation markers and the PLT numbers, which can explain why CALR mutated patients in our cohort had higher nIP and monocyte- platelet aggregates fractions. The absence of an increased ADP induced PLT activation between patients and controls in this cohort compared with previous reports could be explained by the use of aspirin in the majority of patients and the high ADP concentration used for PLT activation. These results will be further studied in a lager cohort of patients. Disclosures No relevant conflicts of interest to declare.

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Leukocytosis Can Predict Thrombotic Events in Myelofibrosis

Blood ◽

10.1182/blood.v126.23.5191.5191 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5191-5191

Author(s):

Laura Coutinho Vassalli ◽

Emilia Carolina Malafaia ◽

Maria L. Chauffaille ◽

Daniella Kerbauy

Keyword(s):

Polycythemia Vera ◽

Blood Cells ◽

Myeloproliferative Neoplasms ◽

Thrombotic Event ◽

White Blood Cells ◽

Jak2 V617f ◽

The Other ◽

Jak2 V617f Mutation ◽

Increased Risk ◽

V617f Mutation

Abstract Thrombotic events are the main complication of Philadelphia-negative chronic myeloproliferative neoplasms (MPN). In polycythemia vera (PV) and essential thrombocythemia (ET), risk factors for thrombosis are well established, such as age greater than 60 years and previous thrombosis. However, the role of JAK2 V617F mutation and leukocytosis at diagnosis as risk factor for thrombosis is still controversial. Our aim was to identify factors related to the risk for thrombotic events in the studied population.This study is a retrospective non-interventional cohort. All of the analyses were performed using the database of 142 patients with MPN regularly followed at the Hematology Division (at UNIFESP-SP) from 1992 to 2014. Diagnosis was established according to WHO criteria. We analyzed the JAK2 V617F mutation, hemoglobin (g/dL), hematocrit (%), white blood cells (x109/L) and platelets (x109/L) at the diagnosis and DIPSS-Plus risk score (International Working Group for Myelofibrosis Research and Treatment, 2009). These variables were associated with thrombotic event at any time.Of the 142 patients, 54 had diagnosis of PMF, 28 of PV, 33 of ET and 27 of post-essential thrombocythaemic myelofibrosis (post ET MF) or post-polycythaemic myelofibrosis (post-PV MF). This last group was included in myelofibrosis group for statistical purposes. Thrombotic events were more frequent in PV patients (39.2%), followed by ET (33.3%), and PMF (20.9%). From those which JAK2 mutation was obtained, it was positive in 92.4% of PV patients, 62% of PMF and 50% of ET. In none of the three groups, the presence of JAK2 V617F mutation was related to increased risk of thrombosis. In myelofibrosis, leukocytosis was higher among thrombotic patients (median of 13.7 in thrombotic group versus 9.7x 109/L; p 0.0379). None of the other parameters, hemoglobin, hematocrit, platelets and DIPSS-Plus were statistically significant. In ET, the hemoglobin level at diagnosis was significantly higher in the presence of thrombosis (mean of 14.57 in thrombotic group against 13.03 g/dL in the non-thrombotic one, p 0.0428). The other parameters, hematocrit, white blood cells and platelets were not relevant. The median WBC in the thrombotic group was 9.4 and in the non-thrombotic one 9.3 x109/L. Finally, in polycythemia vera, none of the variables were related to thrombosis. Among the studied population, leukocytosis was increased in patients with thrombotic event in MF. Thus, monitoring leukocyte count in MF is essential to predict thrombosis risk and should be further studied in order to define therapeutic goals in these patients. Disclosures No relevant conflicts of interest to declare.

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Transgenic expression of JAK2V617F causes myeloproliferative disorders in mice

Blood ◽

10.1182/blood-2007-05-091579 ◽

2008 ◽

Vol 111 (10) ◽

pp. 5109-5117 ◽

Cited By ~ 155

Author(s):

Shu Xing ◽

Tina Ho Wanting ◽

Wanming Zhao ◽

Junfeng Ma ◽

Shaofeng Wang ◽

...

Keyword(s):

Bone Marrow ◽

Transgenic Mice ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Gene Promoter ◽

Primary Myelofibrosis ◽

Myeloproliferative Disorders ◽

Transgenic Expression ◽

Cell Counts

Abstract The JAK2V617F mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2V617F, showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2V617F expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hematopoietic progenitor cells in peripheral blood, spleen, and bone marrow, and these cells formed autonomous colonies in the absence of growth factors and cytokines. The data show that JAK2V617F can cause MPDs in mice. Our study thus provides a mouse model to study the pathologic role of JAK2V617F and to develop treatment for MPDs.

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An Inpatient COVID-19 Prophylaxis Protocol and Its Outcomes: Adherence and Efficacy

Blood ◽

10.1182/blood-2021-154453 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4267-4267

Author(s):

Adrienne Kaufman ◽

Yael Kusne ◽

Molly Klanderman ◽

Heidi E. Kosiorek ◽

Thomas Oliver ◽

...

Keyword(s):

Native American ◽

Critically Ill ◽

Critically Ill Patients ◽

Conflicts Of Interest ◽

Demographic Data ◽

Thrombotic Event ◽

Thrombosis Risk ◽

Therapeutic Anticoagulation ◽

Increased Risk ◽

Venous Thromboembolic Events

Abstract Introduction: Patients with coronavirus disease 2019 (COVID-19) have an increased risk for venous thromboembolic events. Thrombotic events contribute to the morbidity and mortality associated with COVID-19 infection, and have prompted investigation into strategies for mitigating thrombosis risk in patients hospitalized with COVID-19 infection. Our team reviewed the charts of patients hospitalized with COVID-19 pneumonia at a tertiary hospital in metropolitan Phoenix Arizona between 2020-2021, to assess frequency and efficacy of utilizing a VTE prophylaxis algorithm designed to prevent thrombosis in patients infected with COVID-19. Methods: A total of 846 patients were retrospectively evaluated to determine if they were treated with guideline-appropriate anticoagulation while hospitalized with COVID-19, as well as if they developed venous or arterial thrombotic events, or major or minor bleeds. 317 patients were excluded for taking therapeutic anticoagulation prior to admission, or for having a COVID-19 diagnosis >7 days after admission. Appropriate anticoagulation was determined by an institutionally designed COVID-19 thromboprophylaxis algorithm, based on platelet count, d-dimer, bleeding risk, and level of medical care required. Regimen options included: no anticoagulation, prophylactic enoxaparin (40 mg SQ daily) or heparin in the setting of kidney dysfunction, weight-based dosing of enoxaparin (40 mg SQ BID if BMI>40), intermediate intensity enoxaparin without thrombus (30 mg BID if BMI<40, or 40 mg BID if BMI>40), and therapeutic anticoagulation (for example enoxaparin 1 mg/kg BID) with thrombus. Demographics: Demographic data and clinical characteristics were collected for 529 patients. Average age was 59 years old, and the majority were men (58.4%). Most patients were White (58.3%), followed by Hispanic (17.8%), or Native American (15.7%). Fewer patients had a normal BMI (21.3%; BMI 18.5 - 24.9) compared to those who were overweight (31.2%; BMI 25-29.9) or obese (43.1% BMI > 30). Other comorbidities included Type 1 or Type 2 diabetes mellitus (N= 172, 32.5%), hypertension (N = 271, 51.2%), and hyperlipidemia (N = 176, 33.3%). Results: A total of 42 patients (8%), were diagnosed with a venous thrombosis during hospitalization. Patients admitted to the ICU were significantly more likely to have a thrombotic event of any type compared to non-ICU patients (21.6% to 5.7%; p < 0.001). Specifically, critically ill patients had higher incidences of deep vein thrombosis (9.5% to 0.7%), pulmonary emboli (8.1% to 4.8%), and superficial thrombi (2.7% to 0.2%). Only 1.1% of patients (6/529) experienced any bleeding, of which 3 were classified as a major bleed. Discussion: Among patients hospitalized at our institution with COVID-19, the majority were anticoagulated appropriately according to the COVID-19 thromboprophylaxis algorithm. Overall incidence of thrombosis in the study population was 8%. A significantly higher percent of critically ill patients had thrombi, supporting reports of correlation between severity of illness and thrombosis risk. The two regimens of anticoagulation least adhered to were weight-based and intermediate-based dosing, likely reflecting a departure from the hospital's thromboprophylaxis regimens prior to COVID-19 pandemic. Further studies are needed to characterize whether identifiable risk factors correlate with the incidence of thrombosis, and whether treatment with lower than recommended doses of anticoagulation, based on the COVID-19 thromboprophylaxis algorithm, were associated with thrombosis. Disclosures No relevant conflicts of interest to declare.

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