Leukocytosis is a risk factor for recurrent arterial thrombosis in young patients with polycythemia vera and essential thrombocythemia

Abstract Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are chronic myeloproliferative diseases characterized by frequent episodes of deep venous thrombosis (DVT), arterial thromboembolism (AT) and by hemorrhagic complications. Surgical procedures could represent a risk factor for thrombosis and bleeding, but no data on the real frequency of these complications are available. To estimate the frequency of thrombosis and haemorrhages after surgical procedures and their outcomes, a multicenters retrospective analysis was performed. Data from 105 PV and 150 ET patients (128 males, 127 females, median age at diagnosis 60, were analyzed, for a total of 311 surgical interventions. At least one risk factor for arterial thrombosis (diabetes mellitus, hypercholesterolemia, arterial hypertension, previous AT, smoke) was present in 128/255 (50.1%), more frequently in PV than in ET patients (58.5 vs. 46.8%, p=0.02). An excess of male and older patients in PV than in ET explained this finding (multivariate analysis). Previous DVT was present in 9/255 patients (3.5%). After diagnosis, antiplatelet drugs were given to 211/255 patients (82.7%); cytoreductive treatments to 188/255 (74%), warfarin to 16/255 (6.2%); all PV patients were phlebotomized. In 25/311 surgeries (8.0%), an emergency procedure was performed; 195 surgeries were done under general anaesthesia; 21/91 abdominal interventions (23%) were performed under laparoscopy. Major surgeries were 160/311 (51.4%). Data about antithrombotic prophylaxis were available for 292/311 surgeries: in 126 (43.2%) low molecular heparin, in 38 (13%) unfractioned heparin, in 5 (1.7%) warfarin and in 123 no anticoagulant therapy was administered. In 45/123 (36.6%) patients without antithrombotic prophylaxis, antiplatelet therapy was administered before surgery. 189/255 (74%) were on cytoreductive therapy before surgery; for 9 surgical procedures, a short cycle of chemotherapy was administered before surgery. Clinical outcomes after surgery were recorded with a 3 months follow-up. No event was observed in 259/311 procedures (83.2%); there were 12 arterial and 12 venous thrombotic events, 23 major and 7 minor hemorrhages and 5 deaths. AT were more frequent in ET patients (5.3 vs. 1.5%, p=0.08) while venous events were more frequent in PV patients (7.7 vs. 1.1%, p=0.002). There was a strong risk gradient for AT associated with the presence of one or more arterial risk factors (OR for 4 or more risk factors: 40.9, p=0.003). Platelet count and hematocrit at surgery (median 477 x 109 /l and 42.6%, respectively) were not associated with either venous or arterial thrombosis. There was no correlation between bleeding episodes and type of diagnosis, use of antithrombotic prophylaxis and type of surgery. In conclusion, despite an active approach (cytoreduction and antithrombotic prophylaxis in the majority of the cases) a high proportion of PV and ET surgeries was complicated by DVT and AT (7.7%) but also by major hemorrhages (7.3%), requiring more investigation on the optimal prophylaxis in these patients.

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Mutations and Thrombosis in Essential Thrombocythemia and Polycythemia Vera: Mayo-Careggi Alliance Study

Blood ◽

10.1182/blood-2018-99-110045 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3040-3040 ◽

Cited By ~ 1

Author(s):

Paola Guglielmelli ◽

Naseema Gangat ◽

Giacomo Coltro ◽

Terra L. Lasho ◽

Giuseppe Gaetano Loscocco ◽

...

Keyword(s):

Risk Factors ◽

Venous Thrombosis ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Arterial Thrombosis ◽

Older Patients ◽

Leukocyte Count ◽

Young Patients ◽

World Health ◽

Younger Age

Abstract Background : Thrombosis is a characteristic feature in essential thrombocythemia (ET) and polycythemia vera (PV). Previous studies had focused on thrombotic events occurring after diagnosis and did not always distinguish between arterial and venous thrombosis. Arterial thrombosis in ET has been associated with age >60 years, JAK2 mutations, leukocyte count >11 x 109/l, history of thrombosis and cardiovascular risk factors, and venous thrombosis with male sex (Blood 2011;117:5857). In the current two-enter study, we looked for associations between both driver and other mutations, with first incidences of arterial and venous thrombosis in ET and PV, analyzed together and separately. Methods : Study patients were recruited from the Mayo Clinic, Rochester, MN, USA and the University of Florence, Florence, Italy, based on availability of next-generation sequencing-derived mutation information. Diagnoses were according to the 2016 World Health Organization criteria (Blood. 2016;127:2391). Conventional statistics was employed to examine significance of associations, with separate analysis of arterial vs venous thrombosis, occurring at any time before or after formal diagnosis of ET or PV. For the purposes of the current study, only first events were considered. Results: 906 molecularly-annotated patients (416 from Mayo and 490 from Florence), including 502 ET and 404 PV cases, were included in the current study. The Mayo/Florence cohorts included 270/232 ET (median age 57/54 years, 60%/59% females) and 146/258 PV (median age 63/58 years, 52%/44% females) patients; median follow-up was 9.9/12.9 years for ET and 10.7/12.4 years for PV. Driver mutation distribution in ET was 55% JAK2, 27% CALR, 5% MPL and 13% triple-negative. Most frequent mutations, other than JAK2/CALR/MPL, were TET2 (14%; 11% in ET and 18% in PV) and ASXL1 (13%; 13% in ET and 13% in PV). 301 (33%) patients experienced first time thrombosis, before or after diagnosis, including 152 (30%) in ET and 149 (37%) in PV (p=0.03); arterial events occurred in 174 (19%) patients, including 96 (19%) in ET and 78 (19%) in PV (p=0.9); venous events occurred in 177 (20%) patients, including 82 (16%) in ET and 95 (24%) in PV (p=0.007). The number of vascular events after diagnosis was 174 (19%) for arterial and 154 (17%) for venous thrombosis, with no significant difference between ET and PV. Associations with arterial thrombosis: In multivariable logistic regression analysis that included both ET and PV (n=906), age >60 years (23% vs 16%; OR, 1.6, 95% CI 1.1-2.2) and absence of ASXL1 and RUNX1 mutations (21% vs 9%; OR 2.6, 95% CI 1.4-4.8) were associated with arterial thrombosis; these associations remained significant (or near significant) when ET and PV were analyzed separately; in addition, JAK2 mutations in ET displayed borderline significance (p=0.05). Overall incidence of arterial events in ET was estimated at 27% in the presence of all three risk factors (i.e. older age, presence of JAK2 mutations and absence of ASXL1/RUNX1 mutations), 21% with two risk factors, 13% with one risk factor and 9% in the absence of all three risk factors (p=0.01). Associations with venous thrombosis: In multivariable analysis, including both ET and PV (n=906), JAK2 mutations (p<0.001), higher leukocyte count (p=0.03) and younger age (p=0.04) were identified as being significant. Analysis of ET patients only (n=502) identified JAK2 mutations (p<0.001; OR 2.4, 95% CI 1.4-4.1), absence of SRSF2 mutations (p=0.03) and younger age (p=0.04) as independent risk factors and in PV patients (n=404), higher leukocyte count (p=0.06). Prognostic interaction between JAK2 mutations and age: In ET, the overall frequency of venous events was 27% for young patients with JAK2 mutations vs 13% for older JAK2 mutated cases vs 10% for JAK2 unmutated young patients vs 13% for JAK2 unmutated older patients (p<0.001). The corresponding percentages for arterial events were 20%, 24%, 14% and 19%, respectively (p=0.1). Conclusions: JAK2 mutations contribute to the risk of both venous (younger patients) and arterial (young and older patients) thrombosis, in an age-dependent manner; the association with venous thrombosis might explain the higher incidence of venous thrombosis in PV, compared to ET. Additional studies are required to confirm the observed lower risk of thrombosis in patients with ASXL1, RUNX1 and SRSF2 mutations and provide insight into the underlying biological explanation. Disclosures No relevant conflicts of interest to declare.

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Use of pegylated interferon in young patients with polycythemia vera and essential thrombocythemia

Pediatric Blood & Cancer ◽

10.1002/pbc.28888 ◽

2020 ◽

Author(s):

Nicole Kucine ◽

Shayla Bergmann ◽

Spencer Krichevsky ◽

Devin Jones ◽

Michael Rytting ◽

...

Keyword(s):

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Young Patients ◽

Pegylated Interferon

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Chronic kidney disease could be a risk factor for thrombosis in essential thrombocythemia and polycythemia vera

International Journal of Hematology ◽

10.1007/s12185-020-02898-7 ◽

2020 ◽

Vol 112 (3) ◽

pp. 377-384 ◽

Cited By ~ 1

Author(s):

Ivan Krečak ◽

Hrvoje Holik ◽

Morić Perić Martina ◽

Ivan Zekanović ◽

Božena Coha ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Risk Factor ◽

Kidney Disease ◽

Polycythemia Vera ◽

Essential Thrombocythemia

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Neutrophil-to-Lymphocyte Ratio (NLR) Is a Risk Factor for Venous Thrombosis in Polycythemia Vera

Blood ◽

10.1182/blood-2021-146793 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1499-1499

Author(s):

Alessandra Carobbio ◽

Alessandro Vannucchi ◽

Paola Guglielmelli ◽

Giuseppe Gaetano Loscocco ◽

Ayalew Tefferi ◽

...

Keyword(s):

Risk Factor ◽

Venous Thrombosis ◽

Polycythemia Vera ◽

Board Of Directors ◽

Arterial Thrombosis ◽

Research Funding ◽

Multivariate Model ◽

Advisory Committees ◽

Thrombotic Risk ◽

Lymphocyte Ratio

Abstract Background. The tendency towards thrombosis in myeloproliferative neoplasms (MPNs) is linked to the JAK2-mutant clone which leads to hypercellularity and functional interplay between abnormal erythrocytes, platelets, leukocytes and dysfunctional endothelium. The resulting cell activation that also involves stromal cells in their microenvironment, has been shown associated with chronic, systemic, subclinical pro-inflammatory state, and has been implicated in the pathogenesis of thrombosis in MPN. Neutrophil to lymphocyte ratio (NLR) is a novel inflammatory marker found to be associated with the severity and prognosis of cardiovascular diseases but there is little evidence for its prognostic significance in MPN. We investigated whether NLR could predict the onset of arterial and venous thrombosis in polycythemia vera (PV). Methods. Subjects of this study were 1508 patients included in the ECLAP trail with NLR evaluation available. In addition to standard statistical methods, we used proportional hazards additive models (GAM) as they can provide an excellent fit in the presence of nonlinear relationships, for the prediction of total, arterial and venous thrombosis as smooth functions with cubic splines of different blood parameters. Results. After a median follow-up of 2.76 years, 169 thrombotic events (10.3%) were objectively diagnosed and analyzed: 87 arterial (MI, Stroke, TIA, PAT) and 88 venous thrombosis (DVT±PE, superficial thrombophlebitis). In univariate analysis, arterial thrombosis was associated with age (p=0.003) and previous thrombosis, especially if arterial (p<0.001), and with the presence of at least one cardiovascular risk factor (p=0.009). No association between baseline platelet and leukocyte counts and NLR with arterial events was found. Conversely, in venous thrombosis, beside age (p=0.039) and history of venous thrombosis (p<0.001), additional risk factors were low hemoglobin (p=0.039) and increasing values of NLR (p=0.002) resulting from a simultaneous increase of neutrophils (p=0.002) and to a decrease of absolute number lymphocytes (p=0.002).To predict outcomes, we tested total leukocytes, neutrophils, lymphocytes, platelets and NLR by GAM to evaluate their trend in continuous scale of thrombotic risk. A significant association between the risk of venous thrombosis and the progressive lower counts of lymphocytes (p=0.002) emerged, leading to increase the NLR values (p=0.005). However, given the greater precision of the NLR estimates and the markedly wide confidence interval of lymphocyte counts estimates, NLR was used in multivariate model. Conversely, neither absolute values of neutrophils and lymphocytes nor NLR were found associated with arterial events.In multivariate model, adjusted for age, gender and treatments at baseline, the risk of venous thrombosis was independently associated with previous venous events (HR=5.48, p ≤0.001) and NLR values ≥5 -the best cut-off resulted applying the Liu's method (HR=2.13, p=0.001). NLR effect for total venous thrombosis was not modified by excluding superficial venous thrombosis (HR=2.90, p=0.001) in a sensitivity analysis. Older age (i.e., ≥65 years, HR=1.88, p=0.005) and previous arterial thrombosis (HR=1.92, p=0.003) retained the prognostic statistical significance for arterial thrombosis.Our learning cohort findings, indicating a correlation between NLR values and venous thrombosis, have been validated in two Italian independent external cohorts (Florence, n=282 and Rome, n=173) of contemporary PV patients (Figure 1). Conclusions. The NLR is an inexpensive and easily accessible test compared to other inflammatory markers. We found that NLR-alone is an independent predictor of venous thrombosis and could be included in a new scoring system. In addition to guiding the stratification of thrombotic risk, these data confirm that inflammation is a relevant target of antithrombotic therapy in PV. Figure 1 Figure 1. Disclosures Vannucchi: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Barbui: AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Inherited Thrombophilias in Essential Thrombocythemia and Polycythemia Vera Are Not an Additional Risk Factor for Thrombosis.

Blood ◽

10.1182/blood.v106.11.4934.4934 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4934-4934

Author(s):

Emma Cacciola ◽

Antonio Cipolla ◽

Ernesto Di Francesco ◽

Rosario Giustolisi ◽

Rossella R. Cacciola

Keyword(s):

Risk Factor ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Thrombotic Complication ◽

Additional Risk Factor ◽

Clotting Factors ◽

Platelet Factor ◽

Thrombotic Risk ◽

Additional Risk ◽

Mthfr Mutation

Abstract Patients with essential thrombocythemia (ET) and polycythemia vera (PV) have a high risk of thrombosis. Inherited thrombophilias are established risk factors for thrombosis. To determine if inherited thrombophilic abnormalities might contribute to the thrombotic risk in ET and PV, we investigated antitrombin III (ATIII), protein C (PC) and protein S (PS), polymorphisms of clotting factors V (FVQ506) and II (G20210A) and methylenetetrahydrofolate reductase (MTHFR) mutation in patients with ET and PV and we tried to correlate these results with prothrombotic markers such as bthromboglobulin (bTG), platelet factor 4 (PF4), prothrombin fragment 1+2 (F1+2) and d-dimer (DD). In addition, we analysed a possible association between inherited coagulopathy and thrombosis. ATIII, PC and PS antigen levels were assayed by ELISA as well as bTG, PF4 and F1+2. PCR-based assays were used for FVQ506, prothrombin and MTHFR. DD was measured by immunoturbimetric latex agglutination. The study involved 101 patients diagnosed with ET (71 patients, 30 men, 41 women, mean age 62.3 years) or PV (30 patients, 21 men, 9 women, mean age 65.4 years) according to conventional criteria. The duration of disease ranged between 1 to 12 years. Of 101 patients, 53 (52,47%) were non-carriers of mutations and among these 24 (45.28%) experienced thrombosis, 48 (47.52%) were carriers and 27 (56.25%) had thrombosis. With reference to carriers, 9/48 (14.58%) had combined mutations such as PC and PS (2/9), PS and G20210A (1/9), PC and MTHFR (4/9), G20210A and MTHFR (2/9). The prevalence of studied defects was 31.25% (15/48) and 18.75% (9/48) for deficiency of PC and PS, respectively, 8.33% (4/48) and 14.58% (7/48) for heterozygosity of FVQ502 and G20210A, respectively, and 45.83% (22/48) for MTHFR mutation. Deficiency of ATIII was not present. All patients had higher bTG, PF4 and F1+2 (365±654 IU/ml, 133±64 IU/ml and 2.6±2.5 nmol/L, respectively) than to controls (23.8±9.1 IU/ml, 5.5±2.8 IU/ml and 0.60.2 nmol/L, respectively) (p<0.0001) and normal DD (144±92 ng/L). No correlation between studied polymorphisms genetic and bTG, PF4, F1+2 and DD was found as well as with thrombotic complication. The frequency of thrombosis was not statistically different between non-carriers and carriers. Based on these data, it appears that inherited thrombophilias are not an additional risk factor for thrombosis in ET and PV and that the thrombotic phenomena are due to the abnormal platelet function that is part of the myeloproliferative disorders.

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Efficacy and Safety of Primary Antithrombotic Prophylaxis with Ticlopidine and with Aspirin In Patients with Essential Thrombocythemia and Polycythemia Vera. Results from a Cohort Study.

Blood ◽

10.1182/blood.v112.11.1743.1743 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1743-1743

Author(s):

Marco Ruggeri ◽

Alberto Tosetto ◽

Irene Bolgan ◽

Francesco Rodeghiero

Keyword(s):

Cohort Study ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Arterial Thrombosis ◽

Primary Prophylaxis ◽

Secondary Prophylaxis ◽

Antiplatelet Drug ◽

Efficacy And Safety ◽

Cytoreductive Treatment

Abstract Background. Essential Thrombocythemia (ET) and Polycythemia Vera (PV) are two chronic myeloproliferative diseases with prolonged survival, but with a high rate of vascular complications, mainly arterial thrombosis (AT). For this reason, clinical guidelines recommend the use of aspirin for primary and secondary prophylaxis. There are no data on the efficacy and safety of tienopyridine antiplatelet drugs (ticlopidine, clopidogrel), which could be useful alternatives in patients with contraindication or when aspirin is unable to prevent thrombotic event. Aims. To estimate the frequency of thrombotic and hemorrhagic complications, in ET and PV patients treated with ticlopidine in comparison with patients taking aspirin, in single institution, prospective cohort study. Patients and method. Data from 246 PV (143 males, 58%), median age at diagnosis 63 years (range 20–89) and 339 ET (114 males, 33.6%) patients, median age 62 (range 20–95) consecutively diagnosed from 1985 to 2005 were analyzed. Risk factors for arterial thrombosis (diabetes mellitus, arterial hypertension, hypercholesterolemia, smoking, cardiovascular disease, previous AT) were present in around 30% of patients. At diagnosis, median values of hemoglobin, leukocyte and platelet level in ET and PV were 137 and 180 g/L, 9.3 and 11 x 109/L, 888 and 582 x 109/L, respectively. After diagnosis, aspirin (100–300 mg daily) was given to 270 patients (155 ET, 57%), in 70 of them (25%) for secondary prophylaxis; ticlopidine (250 mg twice day) was administered to 84 patients with a previous history of gastric ulcer, gastritis or allergy to ASA (48 ET, 57%), in 19 of them (22%) for secondary prophylaxis. In 216 (137 ET, 63%) patients no antiplatelet drug was given. The two treated group had similar cardiovascular risk profile, higher than in those untreated. Cytoreductive treatment was given to 87 (32%) patients in ASA, 14 (17%) in ticlopidine and 61 (28%) in those not on antiplatelet treatment (p=0.02). An higher percentage of patients received hydroxyurea in ASA group compared with ticlopidine (19.6% vs 8.6%). Warfarin was administered to 10 patients for atrial fibrillation or venous thrombosis (not analyzed). 2 cases were lost from follow-up. All PV patients were phlebotomized to reduce hematocrit level. Results. After a median follow-up of 7.8 years (very similar in the 3 groups of patients), 29 (14.5%) thrombotic events (5 fatal) among 200 ASA patients and 18 (27.7%, 1 fatal) among 65 ticlopidine patients treated for primary prophylaxis were recorded (p=0.016). In 216 not-treated patients, 40 (18.5%) thromboses were recorded. Major hemorrhages (need of transfusions, surgical intervention or hospital admission) were 17 (8.5%) in ASA, 8 (12.3%) in ticlopidine (p= 0.299) and 25 (11.6%)) in not-treated patients (p= 0.392 between antiplatelet treated and not treated patients). Thrombotic rates for patients in primary prophylaxis were 0.4%, 0.8% and 2.5% in patients on ASA, ticlopidine and not-treated, respectively. Conclusion. In a cohort of ET and PV patients, ASA therapy appears more effective than ticlopidine in the primary prevention of thrombosis, without a significative increase of hemorrhagic risk in comparison with ticlopidine or untreated patients. This increased efficacy should be further investigated by stratifying patients accordingly to cytoreductive treatment.

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Hemorrhage in Essential Thrombocythemia or Polycythemia Vera: Epidemiology, Location, Risk Factors, and Lessons Learned from the Literature

Thrombosis and Haemostasis ◽

10.1055/s-0040-1720979 ◽

2020 ◽

Author(s):

Christophe Nicol ◽

Karine Lacut ◽

Brigitte Pan-Petesch ◽

Eric Lippert ◽

Jean-Christophe Ianotto

Keyword(s):

Risk Factors ◽

Polycythemia Vera ◽

Essential Thrombocythemia ◽

Myeloproliferative Neoplasm ◽

Young Patients ◽

Lessons Learned ◽

Published Data ◽

Bleeding Events ◽

Future Studies ◽

Increased Risk

AbstractHemorrhage is a well-known complication of essential thrombocythemia (ET) and polycythemia 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. Thirty-nine potential risk factors were analyzed at least once, but the results were discrepant. Among them, age >60 years, bleeding history, splenomegaly, myeloproliferative neoplasm subtype, and platelet count should deserve more attention in future studies. Among the treatments, aspirin seemed to be problematic for young patients with ET (especially CALR-mutated ET patients) and anagrelide was also identified as a bleeding inducer, especially when associated with aspirin. Future studies should analyze bleeding risk factors in more homogeneous populations and with common bleeding classifications. More tools are needed to help clinicians manage the increased risk of potentially lethal bleeding events in these diseases.

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