Platelet and Coagulation Activation in Myeloproliferative Diseases (MPD), and Relationship to JAK2(V617F) Mutation Status and Clonality.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4082-4082
Author(s):  
Beverley J. Robertson ◽  
Colin Urquhart ◽  
Isobel Ford ◽  
Henry G. Watson ◽  
Mark Vickers ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Significant Proportion ◽  
Jak2 V617f ◽  
Coagulation Activation ◽  
Jak2 Mutation ◽  
Activation Markers ◽  
Thrombotic Risk ◽  
Mutation Status ◽  
Increased Risk ◽  
Significant Difference

Abstract Patients with MPD have an increased risk of thrombosis. Previous reports suggest an association between clonality and thrombosis in ET. The contribution of the JAK2 mutation to thrombotic risk is unclear. In our cohort of patients with MPD (n=122) (PRV n = 54, ET n = 64, IMF n= 4), we compared coagulation and platelet activation markers (D-Dimers, thrombin antithrombin complexes (TAT), prothrombin fragments 1+2 (F1+2), soluble E-selectin(sE-selectin) and soluble P-selectin(sP-selectin)) between MPD patients and hypertensive controls. sP-selectin was significantly increased in patients with MPD (p=<0.001). The JAK2 mutation status was determined in our cohort by ARMS PCR. Of the total MPD cohort, 59% were JAK2 positive, (76% of PRV, 45% of ET, and 50% of IMF). Coagulation activation markers were compared in JAK2 positive and JAK2 negative patients. sP-selectin levels were highly significantly elevated in JAK2 positive patients compared to JAK2 negative (p= 0.002), or controls (p<0.001). There was no significant difference in platelet count between JAK2 positive and negative patients (p=0.19). The clonality of the MPD was determined in 54 female patients using an x-chromosome inactivation pattern (XCIP) assay (HUMARA). A significant proportion of “polyclonal” patients, as defined by XCIPs were positive for the JAK2 mutation. We therefore calculated the proportion clonality of samples and found no correlation between proportion clonality and any coagulation or platelet activation marker. Our results show an increase in platelet activation, as determined by sP-selectin levels, in patients with MPD compared to controls. Furthermore, platelet activation was a feature of patients positive for the JAK2 mutation when compared with wild type patients and controls. The role of the JAK2 mutation as a risk factor for thrombosis in MPD is still unclear but our study indicates that the presence of the mutation may be linked to platelet activation in MPD. Whether this translates into a higher clinical thrombosis risk requires further evaluation in a large prospective study.

Tissue Factor and Soluble Markers of Platelet and Endothelial Activation in Essential Thrombocythemia: Relationship with Thrombosis and JAK2 V617F Mutation Status.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2707-2707
Author(s):  
Francisco Cervantes ◽  
Eduardo Arellano-Rodrigo ◽  
Alberto Alvarez-Larran ◽  
Juan-Carlos Reverter ◽  
Neus Villamor ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Essential Thrombocythemia ◽  
Plasma Concentrations ◽  
Jak2 V617f ◽  
Endothelial Activation ◽  
Jak2 V617f Mutation ◽  
Jak2 Mutation ◽  
Mutation Status ◽  
Significant Difference ◽  
V617f Mutation

Abstract There is increasing evidence that platelet and leukocyte activation plays an important role in the thrombotic complications of patients with essential thrombocythemia (ET), but the relationship of both thrombosis occurrence and JAK2 V617F mutation status with the levels of circulating tissue factor (TF) and of soluble markers of platelet and endothelial activation is not known. In 53 ET patients (26 of whom had a previous history of thrombosis), platelet TF expression and plasma levels of TF, soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), von Willebrand factor antigen (VWF:Ag), soluble thrombomodulin (sTM), D-dimer, and prothrombin fragment 1+2 (F1+2), measured by ELISA, were compared with those in matched healthy individuals and correlated with thrombosis occurrence and JAK2 V617F mutation status. ET patients with thrombosis had significantly higher levels of sP-selectin than patients without thrombosis and the controls, whereas ET patients without thrombosis had significantly higher levels than the controls (99.8 ± 47.1 ng/mL versus 70.6 ± 37.8 ng/mL versus 32.4 ± 11.9 ng/mL; p= 0.0001 for all comparisons). The same applied to sCD40L levels (226.7 ± 104.7 pg/mL in patients with thrombosis, 186.4 ± 92.1 pg/mL in patients without thrombosis, and 81.3 ± 22.0 pg/mL in controls; p= 0.0001 for all comparisons). Circulating VWF:Ag and F1+2 levels were higher in ET patients than in controls, but no significant difference was observed between patients with and without thrombosis. No differences in TF platelet expression, TF and sTM plasma concentrations were found between patients and controls. A positive correlation was observed between sP-selectin and F1+2, a marker of thrombin generation (r= 0.378, p= 0.01). Patients with the JAK2 mutation (22 out of 52 assessable patients), as compared with those with the wild-type allele, had significantly higher levels of sP-selectin (p= 0.002), sCD40L (p= 0.03), TF (p= 0.016), VWF:Ag (p= 0.0001), and sTM (p= 0.032). These results support a role for soluble markers of platelet activation in the thrombosis of ET as well as their potential to identify ET patients at greater risk of thrombosis. The association between JAK2 mutation and increased levels of TF and soluble markers of platelet and endothelial activation would suggest that the mutation could promote an enhanced prethrombotic state in ET.

JAK2 (V617F) Mutation Status and Neutrophil Apoptotic Resistance in Myelofibrosis with Myeloid Metaplasia (MMM): Correlation and Potential Identification through Phosphorylation Status of STAT3.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3503-3503
Author(s):  
Ruben A. Mesa ◽  
Ayalew Tefferi ◽  
Heather Powell ◽  
Terra Lasho ◽  
David Loegering ◽  
...  
Keyword(s):  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Neutrophil Apoptosis ◽  
Wild Type ◽  
Jak2 Mutation ◽  
Myeloid Metaplasia ◽  
Mutation Status ◽  
Stat3 Phosphorylation ◽  
V617f Mutation ◽  
Myelofibrosis With Myeloid Metaplasia

Abstract Background: We have previously described a resistance to the normal process of apoptosis in neutrophils of patients with myelofibrosis with myeloid metaplasia (MMM) (Blood2003;102:11). Most recently, an activating mutation of JAK2 (V617F) has been described in approximately half of the patients with MMM as well as in variable proportion of patients with other myeloproliferative disorders (MPD). In the current study, we investigated the correlation between JAK2 V617F mutation status and neutrophil apoptosis in MMM. Methods: Neutrophils were isolated by density centrifugation from patients with MMM, other MPDs, and normal controls and assessed for apoptosis at baseline and after 24 hours in culture (IMDM with 20% sterilized fetal calf serum to simulate spontaneous apoptosis). Apoptosis was quantified using three-color flow cytometry using CD45 (to confirm leukocyte presence), annexin V (AN) (marker of apoptosis; detects aberrant externalization of phosphatidylserine during apoptosis), and propidium iodide (PI) (marker of dead cells). Mutation analysis for JAK2 V617F was performed in DNA derived from the isolated neutrophils using genomic DNA amplified by PCR, or extracted from cytogenetic pellets in archived specimens. Apoptotic rates after 24 hours in culture were correlated between patients and controls for both JAK2 mutation status and clinical parameters. Immunoblotting was performed on a subset of patients for correlation of JAK2 mutation status and downstream phosphorylation of the JAK2 target, STAT3, which transcriptionally activates several antiapoptotic genes. Results: Spontaneous neutrophil apoptosis was significantly decreased in MMM patients (n=50; median % apoptotic cells at 41%) compared to both healthy volunteers (n=9; 66%) and patients with other MPD (n=11; 53%) (p=0.002). Resistance to apoptosis in MMM correlated with both anemia (p=0.01) and the presence of the JAK2 V617F mutation (p=0.01). Furthermore, the specific abnormality was more pronounced in patients with homozygous JAK2 V617F; median % apoptotic cells of 47% for patients with wild-type allele (n=22) vs. 39% for heterozygotes (n=23) vs. 22% for homozygotes (n=5; p=0.008). The JAK2 mutation status did not appear dependent on other peripheral blood or clinical features. Neutrophils from 14 MMM patients were assessed simultaneously for both JAK2 mutation and STAT3 phosphorylation status by immunoblotting. Strong expression of phosphorylation of STAT3 was seen in all 3 homozygotes and 4 of 5 heterozygotes, but only 1 of 6 with wild-type allele (p=0.026). Conclusions: Impaired neutrophil apoptosis in patients with MMM correlates with the functional presence of JAK2 V617F in an allele-dose dependent manner and STAT3 phosphorylation. The current observation supports a pathogenetic role for the specific mutation in sustaining clonal myeloproliferation.

Hypercoagulability in Ovarian Cancer Revisited: A Prospective Analysis of Coagulation and Platelet Activation Markers.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1762-1762
Author(s):  
Ali Amirkhosravi ◽  
Glenn Bigsby ◽  
Hina Desai ◽  
Mildred Amaya ◽  
Enriqueta Coll ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Platelet Activation ◽  
Malignant Disease ◽  
Benign Tumors ◽  
Surgical Trauma ◽  
Ovarian Mass ◽  
Coagulation Activation ◽  
Soluble Cd40 Ligand ◽  
Activation Markers ◽  
D Dimer

Abstract Coagulation and platelet activation occurs in patients with ovarian cancer, and several factors underlying such hypercoagulability have been implicated in tumor growth and metastasis. The incidence of venous thromboembolism throughout the course of ovarian cancer is high, and identification of hypercoagulable patients may be important not only for effective thromboprophylaxis, but also for future anti-hemostatic treatment strategies targeting disease progression. The purpose of this prospective study was therefore, first, to characterize in more detail, the hypercoagulable state in patients with ovarian tumors and, second, to define markers of coagulation or platelet activation that specifically identify patients with malignant disease. Thirty nine patients presenting to our institution with an ovarian mass of unknown type (41–69 yrs) and 32 age-matched controls were included in the study. Pre- and postoperative (7–14 days) blood samples were collected, and all whole blood (WB) analyses were performed and plasmas prepared and frozen within 2 hours thereafter. WB thrombelastography (TEG) served for global coagulation assessment. D-Dimer and prothrombin fragment F1+2 were used as markers of coagulation activation. Soluble CD40 ligand (sCD40L), soluble P-selectin, platelet-monocyte conjugates, and platelet-derived microparticles (PMP) were measured to assess in vivo platelet activation. Tissue factor (TF) antigen and TF+ microparticles were quantified in plasma by ELISA and flow cytometry, respectively. Compared to controls, mean values for TEG-R, a measure of clotting time, and TEG-MA, a measure of clot strength, were significantly decreased (10.1 vs. 7.3 min, P<0.05) and increased (63 vs. 68 mm, P<0.001), respectively, in preoperative samples. Median levels of TF antigen (88 vs. 28 pg/ml, P<0.01), D-Dimer (255 vs. 133 ng/ml, P<0.01), and sCD40L (223 vs. 162 pg/ml, P<0.01) as well as platelet-monocyte conjugates (66 vs. 45%, P<0.001) and plasma PMP (10.2 vs. 5.7x106/ml, P=0.01) were significantly higher in preoperative samples than in controls. Interestingly, no correlation was found between plasma TF antigen levels and absolute numbers of TF+ microparticles. Moreover, while we found significant correlations between the various markers of platelet activation, there was no obvious association between the two TF indices and any of the hemostatic parameters analyzed. D-Dimer values (1310 vs. 255 ng/ml, P<0.001) and TEG-MA (73 vs. 68 mm, P<0.05) were significantly elevated in postoperative as compared to preoperative samples, indicating further and prolonged coagulation activation by the surgical trauma. Furthermore, when compared to patients with benign tumors (n=31), values for D-Dimer (215 vs. 2329 ng/ml, P=0.009) and TEG-MA (66.9 vs. 72.6 mm, P=0.007) were significantly elevated in those with histologically proven ovarian cancer (n=8). Importantly, two of three patients with metastatic disease had the highest D-Dimer and TEG-MA values of the entire patient cohort. In summary, our results demonstrate significant coagulation and platelet activation in women presenting with an ovarian mass. In addition, plasma D-Dimer and WB TEG may be helpful in identifying individuals at high risk for perioperative thromboembolic complications and metastatic malignant disease.

The Effect of BIBT 986, a Novel Small Molecule Dual Inhibitor of Thrombin and Factor Xa, on Coagulation in a Model of Endotoxin Induced, Tissue Factor Triggered Coagulation Activation in Humans.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 912-912 ◽  
Author(s):  
Bernd Jilma ◽  
Judith M. Leitner ◽  
Francesco Cardona ◽  
Florian B. Mayr ◽  
Christa Firbas ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Platelet Activation ◽  
Thrombin Generation ◽  
Anticoagulant Activity ◽  
Thrombin Time ◽  
Coagulation Activation ◽  
Dual Inhibitor ◽  
Activation Markers ◽  
Markers Of Inflammation ◽  
Prolonged Aptt

Abstract Background: BIBT 986 is a novel potent anticoagulant that dually inhibits Factors Xa and IIa. We hypothesized that BIBT 986 would dose-dependently decrease endotoxin-induced, tissue factor triggered coagulation activation. Hence it was the aim of the study to compare with placebo the anticoagulant activity of three dosages of BIBT 986 on parameters of coagulation, platelet activation and inflammation and to examine the safety of BIBT 986 in this setting. Methods: This study was a prospective, randomized, double-blind, placebo-controlled, parallel-group dose escalation trial in 48 healthy male volunteers. Participants were randomised to receive bolus primed continuous infusions of one of the three doses of BIBT 986 or placebo. All of them received a bolus infusion of 2ng/kg body weight lipopolysaccharide (LPS). Results: BIBT dose-dependently increased anti-Xa activity, activated partial thromboplastin time (APTT), ecarin clotting time (ECT), thrombin time (TT) and the international normalisation ratio (INR). Importantly, BIBT 986 dose-dependently blocked the LPS-induced coagulation as assessed by the in vivo markers of thrombin generation and action: BIBT 986 doses that prolonged APTT by 25% were already effective. The BIBT dose that prolonged APTT by 100%, completely suppressed the increase in prothrombin fragment (F1+2), thrombin-antithrombin complexes (TAT) and D-dimer. BIBT 986 had no influence on activation markers of inflammation, fibrinolysis, endothelial or platelet activation. Conclusion: Infusion of BIBT 986 was safe and well tolerated. BIBT 986 specifically and dose-dependently blocked LPS-induced, tissue factor trigger coagulation. When compared to different anticoagulants tested previously in this standardized model, BIBT 986 was more effective in suppressing thrombin generation (F1+2 levels) than standard doses of danaparoid, dalteparin or lepirudin. BIBT 986 represents the first drug of a new class of dual FXa and FIIa inhibitors, and displays high potency.

Correlation of JAK2 V617F Mutation Status and Cytogenetic Findings in Myeloproliferative Disorders.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3633-3633
Author(s):  
Guoxian Sun ◽  
Frank Buccini ◽  
Elizabeth Fuentes ◽  
James Weisberger
Keyword(s):  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Chromosome Abnormalities ◽  
Jak2 V617f Mutation ◽  
Homozygous Mutation ◽  
Jak2 Mutation ◽  
Mutation Status ◽  
Trisomy 9 ◽  
V617f Mutation ◽  
Trisomy 9P

Abstract Detection of JAK2 V617F mutation is quickly becoming a front-line screening test for suspected myeloproliferative disorders (MPDs), as the mutation shows high frequency and specificity in non-CML MPDs, PV, ET or CIMF. Routine cytogenetics can detect chromosome abnormalities in approximately 20% of MPDs and is very helpful in establishing or confirming the presence of aberrant clonality, although chromosome changes are often numerical gains and losses, deemed non-specific. To see if there is correlation between JAK2 mutation and karyotypes, we studied 57 consecutive patients with clinically and morphologically confirmed diagnosis of non-CML MPDs. JAK2 V617F mutation performed using allele-specific PCR (sensitive to 10% using pyrosequencing) was found in 72% of patients (41/57), whereas clonal chromosome abnormalities were observed in 15.8% (9/57). There was no correlation between JAK2 mutational status and karyotypes. In 41 patients positive for the JAK2 mutation, 6 were cytogenetically abnormal and 35 normal. In 16 patients negative for the mutation, 3 showed abnormal karyotypes and 13 had normal karyotypes (X2 test, p>0.5). Among 6 patients with both JAK2 mutation and an abnormal karyotype, JAK2 mutation was seen in >50% of each sample in 4 patients, consistent with a homozygous mutation. Interestingly, in two cases, one with PV and trisomy 9 and another with MPD unclassifiable and trisomy 9p resulting from an unbalanced translocation between chromosomes 9p and 13, JAK2 mutation was present in >65% of each sample. Trisomy 9 and trisomy 9p are common abnormalities in MPDs, particularly in PV, seen in over 20% of cytogenetically abnormal cases. JAK2 gene is located on 9p24. Mitotic recombination is considered the most likely cause of loss of heterozygosity (LOH) and thus mutant homozygosity which is undetectable at the cytogenetic level. However, in cases with trisomy 9 or 9p, the JAK2 allele genotypes may be G/T/T and/or T/T/T as well as the usual G/T and/or T/T. Our observations suggest that trisomy 9 or 9p should be taken into consideration when interpreting JAK2 mutation status and that further molecular studies are needed to delineate the implication of trisomy 9 or 9p in potential mutant allele selective advantage and clonal evolution in JAK2 mutation positive MPDs.

Cytoreductive Therapeutic Approach in the Essential Thrombocythemia (ET) Patients of the Registro Italiano Trombocitemia (RIT): Preliminary Data

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5248-5248
Author(s):  
Luigi Gugliotta ◽  
Alessia Tieghi ◽  
Anna Candoni ◽  
Monia Lunghi ◽  
Gianluca Gaidano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Essential Thrombocythemia ◽  
Therapeutic Approach ◽  
Jak2 V617f ◽  
Bone Marrow Biopsies ◽  
Thrombotic Risk ◽  
Significant Difference ◽  
Cytoreductive Treatment ◽  
Wbc Count

Abstract Background: the Registro Italiano Trombocitemia, that is a GIMEMA project, has been activated to registry Italian Essential Thrombocythemia (ET) patients, to improve the diagnosis appropriateness (WHO criteria), to verify the prognostic value of the clinical and biological parameters, to evaluate the compliance to the therapeutical Italian guidelines (1), and to create a network for activation of new studies. Objective: this analysis is mainly devoted to describe the ET patients registered in the RIT and to evaluate the therapeutic approach adopted in the 102 participating hematological centers. Material and methods: two thousand and fifteen ET patients have been registered after the written informed consent was obtained, and data validation by various expert panels is in progress. This preliminary report considers 1785 patients, diagnosed mainly (1078, 60.4%) since the publication in the year 2004 of the ET therapy Italian guidelines (1). Results: the patients, 678 (38%) males and 1107 (62%) females, showed at diagnosis: age 60.3 ± 16.8 years with higher values in males than in females (61.7 ± 15.3 vs. 59.4 ± 17.7, p&lt;0.05), being the patients below 40 years 14% and those over 70 years 33% of cases; PLT count (109/L) 846 ± 309 with lower values in males than in females (813 ± 261 vs. 866 ± 334, p&lt;0.002), and with values 1001–1500 and over 1500 in 16% and 4% of cases, respectively; WBC count (109/L) 9.1 ± 2.9, without difference by sex, and with values 12–15 in 10% and over 15 in 3% of cases; Hgb (g/dL) 14.2 ± 1.6 with higher values in males than in females (14.8 ± 1.5 vs. 13.8 ± 1.5, p&lt;0.001), and with values over 16.5 in 8.5% of males and 2.7% of females, respectively; splenomegaly in 488 (27%), echo-documented in 324 cases (18%); history of hemorrhage and thrombosis in 90 (5%) and 325 (19%) of cases, respectively; disease-related symptoms in 41% and general thrombotic risk factors in 93% of cases, respectively. The WHO 2001 diagnostic criteria were reported for 33% of cases observed before the year 2004 and for 53 % of cases observed since the year 2004. Detailed data at diagnosis were reported as follows: bone marrow biopsy in 1087 cases (61%) with a frequency of 51% and 68% before and since the year 2004, respectively; bcr-abl study in 1045 cases (59%); cytogenetics in 828 cases (46%) with karyotype abnormalities in 27 patients (3%). The JAK2 V617F mutation, searched in 574 cases (32%), was observed in 320 of them (56%). The patient follow-up was 4.5 ± 4.5 years with a total of 5245 pt-yrs. During the follow-up the hemorrhagic events were 5.7% (1.3/100 pt-yrs), being the major events 1.9% (0.4/100 pt-yrs); the thrombotic complications were 14.9 % (3.3/100 pt-yrs), resulting the major arterial 9.4% (2.1/100 pt-yrs), the major venous 3.5% (0.8/100 pt-yrs) and the minor thrombosis 2% (0.4/100 pt-yrs). An antiplatelet treatment, almost always with low dose aspirin, was performed in 75% of the patients, without significant difference in the cases diagnosed before and since the 2004. A cytoreductive treatment was done with use of Hydroxyurea (HU, 64%), Interferon alpha (IFN, 16%), Anagrelide (ANA, 15%), Busulfan (BUS, 4%), and Pipobroman (PIPO, 2 %). In the ET patients diagnosed since the year 2004 respect those diagnosed before, it was observed a decrease in the use of all the cytoreductive drugs, particularly BUS (−62%), IFN ((−62%), and ANA ((−68%). The use of the cytoreductive drugs was related to the patient mean age (years): BUS (76), PIPO (72), HU (67), ANA (53), IFN (48). In the patients diagnosed since the 2004 as compared with those before 2004, the mean age of the treated patients increased for BUS (from 69 to 81 yrs, p&lt;0.001) and for HU (from 64 to 69 yrs, p&lt;0.001) while it decreased for IFN (from 49 to 46 yrs, p&lt;0.05). Conclusion: in the analyzed patients of the ET Italian registry the diagnosis appropriateness resulted improved in the cases observed since the year 2004 respect those observed before, with an increase of bone marrow biopsies from 51% to 68% of patients. Moreover, in accord with the ET therapy Italian guidelines, the use of the cytoreductive drugs was less frequent in the patients diagnosed since the year 2004 than before (particularly for BUS, IFN, and ANA) and the more safe molecules IFN and ANA were preferentially deserved to the younger patients.

Predictive Value of Coagulation Markers Concerning Clinical Outcome 90 Days after Anterior Myocardial Infarction

1999 ◽  
Vol 81 (05) ◽  
pp. 701-704 ◽  
Author(s):  
Frederic Kontny ◽  
Ulrich Abildgaard ◽  
Carl-Erik Dempfle
Keyword(s):  
Myocardial Infarction ◽  
Clinical Outcome ◽  
Predictive Value ◽  
Thrombus Formation ◽  
Left Ventricular ◽  
Adverse Clinical Outcome ◽  
Coagulation Activation ◽  
Activation Markers ◽  
Increased Risk ◽  
D Dimer

SummaryTo study the predictive value of coagulation markers concerning clinical outcome, prothrombin fragment F1.2 (F1.2), fibrin monomer antigen (FM), D-Dimer (DD), and fibrinogen were measured in plasma samples drawn 2 and 7 days after acute myocardial infarction (AMI) in 314 consecutive patients randomized in a clinical trial of low molecular weight heparin (Dalteparin) (the FRAMI trial). Placebo-treated patients suffering death or new AMI within 90 days had significantly higher levels at day 2 of FM (Enzymun-Test FM), and DD (TINAquant D-dimer) (p = 0.001 and 0.02, respectively), but not F1.2 (Enzygnost F1.2 micro), relative to those without serious clinical events. At day 7 all three coagulation activation markers were significantly higher in patients with subsequent adverse clinical outcome. The Dalteparin group had significantly lower levels of these markers as compared to the placebo group. Left ventricular (LV) thrombus formation was not associated with changes in coagulation activation. However, patients with thrombus had significantly higher fibrinogen levels than those without thrombus (p = 0.004 day 2), independent of treatment group. Thus, markers of coagulation activation may be useful in stratification of patients when estimating risk for adverse clinical outcome after AMI. Furthermore, elevated fibrinogen levels are associated with increased risk of LV thrombus formation.

scholarly journals Interferon Alpha Therapy Increases Pro-Thrombotic Biomarkers in Patients with Myeloproliferative Neoplasms

Cancers ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 992
Author(s):  
Dorothée Faille ◽  
Lamia Lamrani ◽  
Stéphane Loyau ◽  
Marie-Geneviève Huisse ◽  
Marie-Charlotte Bourrienne ◽  
...  
Keyword(s):  
Interferon Alpha ◽  
Myeloproliferative Neoplasms ◽  
Anticoagulant Activity ◽  
Protein S ◽  
Pegylated Interferon ◽  
Coagulation Activation ◽  
Thrombotic Risk ◽  
Interferon Alpha Therapy ◽  
Increased Risk ◽  
Ifn Therapy

Myeloproliferative neoplasms (MPN) are associated with an increased risk of arterial and venous thrombosis. Pegylated-interferon alpha (IFN) and hydroxyurea (HU) are commonly used to treat MPN, but their effect on hemostasis has not yet been studied. The aim of our study was to determine whether IFN and HU impact the biological hemostatic profile of MPN patients by studying markers of endothelial, platelet, and coagulation activation. A total of 85 patients (50 polycythemia vera and 35 essential thrombocythemia) were included: 28 treated with IFN, 35 with HU, and 22 with no cytoreductive drug (non-treated, NT). Von Willebrand factor, shear-induced platelet aggregation, factor VIII coagulant activity (FVIII:C), fibrinogen, and thrombin generation with and without exogenous thrombomodulin were significantly higher in IFN-treated patients compared to NT patients, while protein S anticoagulant activity was lower. In 10 patients in whom IFN therapy was discontinued, these hemostatic biomarkers returned to the values observed in NT patients, strongly suggesting an impact of IFN therapy on endothelial and coagulation activation. Overall, our study shows that treatment with IFN is associated with significant and reversible effects on the biological hemostatic profile of MPN patients. Whether they could be associated with an increased thrombotic risk remains to be determined in further randomized clinical studies.

Platelet vWF, ADAMTS-13, and Neutrophil Activation in Patients with Essential Thrombocythemia (ET)

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1548-1548
Author(s):  
Anna Falanga ◽  
Marina Marchetti ◽  
Laura Russo ◽  
Tiziano Barbui
Keyword(s):  
Jak2 V617f ◽  
Neutrophil Activation ◽  
Adamts13 Activity ◽  
Wild Type ◽  
Jak2 Mutation ◽  
Activation Markers ◽  
Mutation Carriers ◽  
Leukocyte Alkaline Phosphatase ◽  
Chronic Myeloproliferative Disorder

Abstract ET is a chronic myeloproliferative disorder, the benign clinical course of which can be complicated by both thromboses and hemorrhages. The levels of the largest multimers of plasma vWF, are relevant for the hemostatic balance in this disease. vWF is stored in the cellular granules of both endothelial cells and platelets, from which is released upon activation. Neutrophils and platelets circulate in an activation status in ET patients, leading to an increased formation of platelet/neutrophil aggregates. In this study we evaluated in ET patients, the platelet vWF content and its relation to neutrophil activation. In addition, the activity of ADAMTS13, the enzyme responsible for maintaining the normal size distribution of vWF multimers, was studied. A group of 61 consecutive ET patients (50% carrying the JAK2 V617F mutation) and 30 healthy controls were included into the study. Total vWF antigen (vWF:Ag) and activity (vWF:Act) levels were determined in both plasma and in isolated washed platelets by ELISA and collagen binding assay (CBA), respectively. ADAMTS13 activity was measured in plasma according to Gerritsen’s method. CD11b and leukocyte alkaline phosphatase (LAP) were measured on neutrophil membrane as activation markers. Plasma vWF:Ag levels resulted significantly increased in ET patients compared to controls (p&lt;0.05), the subgroup of patients with the JAK2 mutation showing the highest levels; whereas vWF:Act was not statistically different. The vWF Act/Ag ratio was significantly lower in ET compared to controls (0.85±0.15 vs 0.95±0.23; p&lt;0.01). A significant inverse relation between platelet count and plasma vWF:Act existed. On the other hand, platelets from these patients had a decreased content of both vWF:Ag and vWF:Act than platelets form controls (p&lt;0.01), suggesting an increased platelet release of vWF. In addition, platelets from ET JAK2 mutation carriers had significantly lower vWF:Act compared to wild-type subjects. Accordingly, the platelet vWF Act/Ag ratio of JAK2 mutation carriers was significantly (p&lt;0.01) lower vs wild-type patients and controls. Neutrophil confirmed to be activated in these patients, as previously described. Indeed, surface activation markers were increased in ET patients compared to controls, and, in particular, CD11b levels were inversely related to platelet vWF:Act (p&lt;0.01). The measurement of plasma ADAMTS13 showed a reduction in the activity of this protease in ET patients (68±16%) compared to normal control mean (p&lt;0.01). In conclusion, in ET patients and particularly in JAK2 mutation carriers, a decrease in platelet vWF:Ag and Act is found and correlates with neutrophil activation, suggesting a role of neutrophil in platelet degranulation. Increased vWF release and reduced ADAMTS13 activity can represent a mechanism of hypercoagulation in these patients.

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