The Combined Use of Hydroxyurea and Anagrelide Allows Better Hematologic Control in Patients with Chronic Myeloproliferative Disorders and Thrombocytosis. A Report on 13 Patients with Poor Tolerance to Hydroxyurea Monotherapy.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4892-4892 ◽  
Author(s):  
Moira Micheletti ◽  
Mariella D’Adda ◽  
Monica Drera ◽  
Samantha Ferrari ◽  
Giuseppe Rossi
Keyword(s):  
Platelet Count ◽  
Side Effects ◽  
Gastrointestinal Bleeding ◽  
Imatinib Mesylate ◽  
Myeloproliferative Disorders ◽  
Vascular Events ◽  
Thrombotic Risk ◽  
Chronic Myeloproliferative Disorders ◽  
Combined Use ◽  
Daily Dose

Abstract Background: Anagrelide has proven effective in selectively lowering platelet count in patients with chronic myeloproliferative disorders (CMPD). It has been approved for the control of thrombocytosis in patients with CMPD and in patients with essential thrombocytemia (ET) refractory or intolerant to hydroxyurea (HU). In spite of their different mechanisms of action, its use in combination with other active agents, particularly HU, has not been explored. Aim of the study: We have reviewed the records of patients with CMPD treated at our Institution and report herein on the combined use of anagrelide and HU in a series of 13 patients, mean age 66,7 years, followed for 1–21 years. Their diagnoses were: essential thrombocythemia (7), polycythemia vera (3), chronic myeloid leukaemia (CML) (1), and idiopathic myelofibrosis (1). Previous treatments included HU (13), phlebotomy (2), busulphan (4), r-interferon (1), imatinib mesylate (1). All had thrombocytosis (mean platelet count: 948.9 × 109/L), with coexistent risk factors for vascular events in 11 of 13. Results: Anagrelide was started because of poor platelet control by a HU daily dose of 0,5– 3 g (median: 1,5 g), which caused anemia (Hb < 10,5 g/dL) (3 transfusion-dependent) and/or leukopenia (WBC < 4.0 × 109/L) in 12/13 cases and because of HU-related cutaneous ulcers in 1. Initial anagrelide daily dose was 0,5 – 2 mg. It was associated with HU at the significantly reduced daily dose of 0,25 – 2 g (median 1g) (Wilcoxon: P<0.001). After a median of 1 month on combined therapy (range 0,5 – 4) the mean peripheral blood cell (PBC) count changes compared to treatment with HU alone were as follows: platelets: 507.5 vs 948.9 × 109/L (P=0.013); WBC: 8.392 vs 5047 × 109/L (P=0.039); hemoglobin: 11,28 vs 10,15 g/dL (P:=0.026) (1 vs 3 pts transfused). In 6 patients HU was stopped after a median of 1,5 months and anagrelide was continued as monotherapy. In 1 CML patient in accelerated phase anagrelide was associated with imatinib mesylate to control thrombocytosis, without side effects. In 6 patients anagrelide and HU combined treatment has been carried on for 19 – 40+ months (median 28 months) by modulating doses according to PBC counts. Anagrelide’s dosage had to be reduced in 1 patient because of fatigue. Further mild side effects included peripheral edema (1) dyspepsia and abdominal meteorism (1), dyarrhoea (2). Three patients had gastrointestinal bleeding from duodenal ulcer (1), intestinal polyps (1), stomach angiodysplasia while on oral anticoagulation (1). One patient had cerebral TIA during a transient thrombocytosis rebound after haemorrhage. Their CMPD did not show evidence of progressive disease. In one pt a marrow trephine biopsy after 18 months showed a slight increase of fibrosis from grade 1–2 focal to grade 1–2 diffuse. Two patients died, both of comorbid conditions. Conclusion: This preliminary clinical experience shows that the association of anagrelide and hydroxyurea allows a significant reduction of the dose of HU needed to control thrombocytosis and causes significant less toxicity on the erythroid series. Compared to anagrelide monotherapy it should allow costs saving as well as a better control of WBC count, whose correlation with thrombotic risk is currently debated. The combination was well tolerated, although the frequency of gastrointestinal bleeding needs careful monitoring. This innovative therapeutic approach merits further investigation.

Megakaryocytes and Platelets as the Main Cause for Vascular Events in Chronic Myeloproliferative Disorders

1996 ◽  
Vol 16 (02) ◽  
pp. 151-163 ◽  
Author(s):  
W. Schneider ◽  
A. Wehmeier
Keyword(s):  
Mononuclear Cells ◽  
Buoyant Density ◽  
Myeloproliferative Disorders ◽  
Term Therapy ◽  
Volume Distribution ◽  
Bleeding Tendency ◽  
Vascular Events ◽  
Chronic Myeloproliferative Disorders ◽  
Clonal Hematopoiesis ◽  
Induced Aggregation

SummaryMegakaryocytes are part of clonal hematopoiesis in chronic myeloproliferative disorders and are responsible for most of the clinical complications in this disease. About 30-40% of patients with polycythemia vera (PV) and essential thrombocythemia (ET) suffer from thrombotic complications, and microcirculatory disorders are common. Spontaneous bleeding mainly from the gastrointestinal tract is another complication that is especially prevalent in myelofibrosis and advanced stages of chronic myeloid leukemia.In vivo, the bone marrow is hypercellular and the concentration of megakaryocytes increased with characteristic morphological abnormalities. Megakaryocytes are enlarged and ploidy is increased in PV and ET but small mononuclear cells with decreased ploidy are a feature of CML. Despite spontaneous growth in cul-ture, megakaryocytes in chronic MPD are hypersensitive to added interleukin-3, interleukin-6 and GM-CSF.Platelets released from these megakaryocytes show abnormal morphology and ultrastructure, reflected in loss of storage granules and organelles, increased volume distribution and low buoyant density. Uptake, storage and secretion of platelet dense granule constituents is abnormal, and the plasma levels of platelet specific proteins which may also include growth factors for fibroblasts are elevated. At high platelet counts, spontaneous aggregation is observed, whereas agonist-induced aggregation in vitro with adrenaline, ADP and collagen is often defective. Platelet thromboxane generation may be stimulated, and production along the lipoxygenase pathway is decreased. Abnormalities of glycoprotein receptors and decreased fibrinogen binding have been reported but their clinical significance is uncertain. Several observations suggest that not only receptor defects but ineffective intracellular signalling may be responsible for platelet function abnormalities.No single underlying defect has been discovered that could explain this variety of pathological findings. Moreover, a combination of intrinsic megakaryocyte abnormalities and increased susceptibility of platelets to activation makes it difficult to differentiate secondary phenomena from effects of clonal hematopoiesis. How-ever, there are some clinical guidelines for therapy.Most elderly patients will be treated with cytoreductive therapy. Alkylating drugs and 32P have been shown to be leukemogenic, but even hydroxyurea may have a 10% incidence of leukemia induction after long-term therapy. Therapy with platelet-inhibitory drugs is often not sufficient to control thrombosis, and may aggravate a bleeding tendency, so that younger patients with PV and ET are increasingly treated with anagrelide or interferon alpha (A-IFN). Anagrelide is a quinazolin derivative that specifically inhibits megakaryocytopoiesis, while A-IFN may suppress clonal hematopoiesis by an unknown mechanism.

The JAK2V617F Mutation but NOT Platelet Parameters Predict Thrombotic RISK IN Patients with Philadelphia-Negative MYELOPROLIFERATIVE Disorders (MPDs).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4984-4984
Author(s):  
Deepti Wijayasinghe ◽  
Stephen Hart ◽  
Saida Solkar ◽  
Christopher j McNamara
Keyword(s):  
Platelet Count ◽  
Disease Risk ◽  
Conflicts Of Interest ◽  
Thrombotic Event ◽  
Myeloproliferative Disorders ◽  
Jak2v617f Mutation ◽  
Polycythaemia Vera ◽  
Platelet Volume ◽  
Thrombotic Risk ◽  
The Absolute

Abstract Abstract 4984 Venous and arterial thromboses are important disease complications of both essential thrombocytopenia (ET) and polycythaemia vera (PV), the commonest MPDs. Predicting and managing this risk is not straightforward as the absolute platelet count does not necessarily correlate with thrombotic risk. We retrospectively studied the platelet parameters, median platelet volume and platelet crit, in addition to the absolute platelet count using a Sysmex XE-2100 in patients with MPDs to determine if there was any relationship between these and subsequent thrombotic risk, as well as the JAK2V617F gene status. This has not been done previously. There were 82 patients (25 PV, 33 ET, 13 chronic idiopathic myelofibrosis, 11 MPD unclassifiable) with a median age of 63 (range 37-94). Thromboses occurred in 32/82 patients (26 venous, 6 arterial) after follow up of 12-108 months. The JAK2V617F mutation was found in 77% of all patients. The median platelet count at diagnosis, prior to any therapy, of those patients who subsequently went on to experience a thrombotic event was not significantly different from those who did not: median platelet count 529 v 563 (p=0.06), median platelet volume 8.6 v 8.3 (p=0.36), platelet crit 0.49 v 0.5 (p=0.079). Thrombosis was more likely to occur in those patients with a JAK2V617F mutation; thrombosis occurred in 43 % of JAK2V617F cases compared with 26% of cases without the mutation. The median platelet count in the JAK2V617F unmutated group was higher than in the group with the mutation (620 v 530 p=0.04); other platelet parameters in the two groups did not show any difference based on the presence of the mutation (median platelet volume 8.2 v 8.6 (p= 0.29), median platelet crit 0.52 v 0.5 (p=0.06)). We conclude that platelet parameters, as assessed by a modern automated haematology analyser, do not predict for thrombotic risk in patients with newly diagnoses MPDs. Other factors such as platelet dysfunction, inherited thrombophilia and underlying vascular disease risk factors may be important. Our findings support the notion proposed by others that the presence of the JAK2V617F is a thrombotic risk factor. Disclosures No relevant conflicts of interest to declare.

Inherited and Acquired Thrombophilia in Children and Young Adults with Bcr-Abl Negative Chronic Myeloproliferative Disorders.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4949-4949
Author(s):  
Fiorina Giona ◽  
Giovanna Palumbo ◽  
Patrizia Pignoloni ◽  
Angela Amendola ◽  
Antonio Chistolini ◽  
...  
Keyword(s):  
Young Adults ◽  
Platelet Count ◽  
Mthfr C677t ◽  
Myeloproliferative Disorders ◽  
C677t Polymorphism ◽  
Hematocrit Level ◽  
Mthfr C677t Polymorphism ◽  
Chronic Myeloproliferative Disorders ◽  
G20210a Mutation ◽  
Children And Young Adults

Abstract Several associated thrombophilic abnormalities have been reported in adults with Bcr-Abl negative chronic myeloproliferative disorders (MPD), mostly essential thrombocythemia (ET) and polycythemia vera (PV), but sporadic data are available in younger patients (pts). In order to define coagulation abnormalities in very young pts, we evaluated thrombophilic parameters in MPD pts aged &lt;20 years (yrs) at diagnosis. Prothrombin time (PT), activated partial thromboplastin time (aPTT), lupus anticoagulant (KCT and dRVVT), functional protein C (PC), free protein S (PS) antigen, functional antithrombin (AT), homocysteine (HCY), factor V Leiden (FVL) mutation, factor II (FII) G20210A mutation and methylentethrahydrofolate reductase (MTHFR) C677T polymorphism were investigated. Thirty-two MPD pts (16 males and 16 females) with a median age of 166/12 yrs (range: 3mo-1911/12 yrs) diagnosed at the study Institution between March 1980 and February 2005 were tested after informed consent of pts or parents. Twenty-five had a diagnosis of ET (7 familial forms) and 5 had PV, according to the criteria of the PV Study Group; in 2, a diagnosis of MPD with thrombocytosis and erythrocytosis was made. Cytogenetic and molecular studies were normal in all cases. At diagnosis, median platelet count for ET and MPD pts was 1,184 x 109/L (range 611–2,640); median hematocrit level for PV and MPD pts was 54% (range 52–72%). Among the ET cohort, 6 asymptomatic pts received no treatment, 4 were treated with aspirin alone and 15 received cytoreductive therapy. PV and MPD pts were phlebotomized to maintain a hematocrit level &lt;50%. Median interval between diagnosis and the time of the study was 8.8 yrs (range: 1 mo – 24 yrs ). No thrombotic events occurred. Four female ET became pregnant and had 4 children, 1 of them being affected by familial thrombocythemia. At the time of the coagulation study, median platelet count for ET and MPD pts was 695 x 109/L (range 325–1,120); the median hematocrit level for those with PV and MPD was 53% (range 52–60.5%). Increased PT and aPTT ratios (n.v. &lt;1.14 and &lt;1.16) were observed in 8/32 (20%) and 16/32 (50%) pts, combined in 7. KCT ratio (n.v. &lt;1.31) was increased in 4/31 (13%) pts, while the dRVVT ratio was normal in 31/31 tested pts. Functional PC and free PS levels were decreased in 3/30 (10%) and 3/31 (10%) tested pts, respectively. AT levels were normal in all pts (32/32). An increased HCY level was found in 1 PV pt. Of the 27 pts investigated for FVL, FII G20210A mutations and MTHFR C677T polymorphism, 1 ET pt was heterozygous for both the FVL and FII G20210A mutations, 1 ET pt was heterozygous for both MTHFR C677T polymorphism and FII G20210A mutation. One ET pt showed an isolated FII G20210A mutation. Screening for the C677T polymorphism in the MTHFR gene revealed that 18 pts (66.5%) were heterozygous, 15 of them affected by ET (7 with the familial form). In our MPD population of children and young adults, the frequencies of heterozygosis of FII G20210A mutation (3/27 pts = 11%) and MTHFR C677T polymorphism (66.5%) were higher than those reported in the normal population (about 2.5% and 45%, respectively). Larger multicenter studies are required to further extend these observations.

Elevated Circulating Platelet-Derived Microparticles in Ph1 Negative Chronic Myeloproliferative Disorders.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1906-1906
Author(s):  
Véronique Tintillier-Colin ◽  
Nathalie Cambier ◽  
Emmanuelle Bourgeois-Petit ◽  
Christian Rose ◽  
Gérard Forzy ◽  
...  
Keyword(s):  
Platelet Count ◽  
Flow Cytometric Analysis ◽  
Myeloproliferative Disorders ◽  
Control Group ◽  
Plasma Membrane Vesicles ◽  
Chronic Myeloproliferative Disorders ◽  
Testing Procedures ◽  
Increased Risk ◽  
Significant Difference ◽  
Thrombotic Complications

Abstract Abstract 1906 Poster Board I-929 Microparticles (MP) are plasma membrane vesicles bearing potent procoagulant proteins and released into the circulation by various blood and endothelial cells during cellular activation and apoptosis. Their concentration has been shown markedly increased in vascular and thromboembolic diseases and in several types of cancer. Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Primary Myelofibrosis (PM) are Bcr-Abl-negative chronic myeloproliferative disorders (MPD) with common biological and clinical features, especially thrombocytosis and more or less effective megakaryocytic proliferation. ET, PV and PMF are also characterized by an increased risk of thrombotic complications. Given the involvement of megacaryocytopoiesis in this group of diseases, we chose to focus on circulating platelet-derived microparticles (PMP) whose count can be established by flow cytometry. Our goals were to look for an increased release of PMP in MPD and if so, try to establish a correlation between thrombotic events recorded retrospectively and PMP level. Patients and methods: Plasma samples were collected from 85 patients with MPD (40 ET, 28 PV, 17 PMF) at any time of the disease course except blastic phase and 31 healthy age-paired controls ; the quantity of PMP (positive for the platelet marker CD41 and the microparticle marker AnnexinV) was measured by flow cytometric analysis using the FC500 cytometer from Beckmann-Coulter™. Pre-analytic and testing procedures complied with the recommendations of the ISTH Standardization Subcommittee and besides, our laboratory participates in a multicenter program to standardize the enumeration of cellular microparticles. Results: The number of PMP is significantly higher in ET, PV and MFP patients (median: 4862 MPP/mL, 3289 MPP/mL and 6114 MPP/mL respectively) than in controls (median 1310 MPP/mL) [p=0.000018, p=0.0013, p=0.0009]. Neither in MPD patients nor in control group PMP correlates with platelet count and appears thus as an independent parameter. ROC method allows to fix a cut-off at 3121 MPP/mL to discriminate MPD from controls. This value has a sensibility of 75 % and a specificity of 94%. Interestingly, the total number of PMP is not different between untreated patients (mean=7246 MPP/mL) and those who received myelosuppressive therapy (mean=6320 MPP/mL). Regarding thrombotic events, we failed to demonstrate any significant difference between patients with previous thrombosis and those without; however, the small size of the series and the retrospective assessment are possible bias. Conclusion: Patients with Phi negative MPDs have a high number of circulating PMP, irrelevant to platelet count or treatment by Hydroxy-urea or aspirin. A role for microparticles in the development of these diseases and in the occurrence of thrombotic complications can be hypothesized but requires further studies -;preferably prospective- on larger cohorts of patients. Disclosures: Charpentier: Schering-Plough: Research Funding.

scholarly journals Correlation of Thrombosis With Increased Platelet Turnover in Thrombocytosis

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1288-1294 ◽  
Author(s):  
Henry M. Rinder ◽  
Judith E. Schuster ◽  
Christine S. Rinder ◽  
Chao Wang ◽  
Helen J. Schweidler ◽  
...  
Keyword(s):  
Platelet Count ◽  
Treatment Response ◽  
Myeloproliferative Disorders ◽  
Healthy Controls ◽  
Thrombotic Risk ◽  
Platelet Counts ◽  
Normal Platelet ◽  
Reticulated Platelets ◽  
Thrombotic Complications ◽  
Deep Vein

Abstract There are no readily applicable methods to routinely assess thrombosis risk and treatment response in thrombocytosis. Reticulated platelets (RP) define the most recently released platelets in the circulation, and the RP% has been shown to estimate platelet turnover in thrombocytopenic states. We examined whether increased RP values were associated with thrombotic complications in thrombocytosis. Platelet count, RP%, and absolute RP count were measured at presentation in 83 patients with chronic or transient thrombocytosis, 46 patients with deep vein (DVT) or arterial (ART) thrombosis and normal platelet counts, and 83 healthy controls with normal platelet counts. Chronic thrombocytosis patients presenting with thrombosis (n = 14) had significantly higher RP% (14.7% ± 10.1%, mean ± SD) than asymptomatic chronic thrombocytosis patients (n = 23, RP% = 3.4% ± 1.8%), healthy controls (3.4% ± 1.3%), DVT patients (n = 21, 3.8% ± 2.1%), or ART patients (n = 25, 4.5% ± 4.1%, P < .05 for all comparisons). Chronic thrombocytosis patients with thrombosis also had significantly higher absolute RP counts than asymptomatic chronic thrombocytosis patients (98 ± 64 × 109/L [range, 54 to 249 × 109/L] v 30 ± 13 × 109/L [range, 11 to 51 × 109/L]; P = .0004), whereas healthy controls, DVT, and ART patients had similarly low absolute RP counts (6 ± 6 × 109/L, 9 ± 7 × 109/L, and 11 ± 7 × 109/L, respectively; P > .49). The RP% and absolute RP counts remained significantly higher in chronic thrombocytosis patients with thrombosis when patients were further subdivided into primary myeloproliferative disorders versus secondary thrombocytosis. Similarly elevated RP percentages and absolute counts were also noted in transient thrombocytosis patients with thrombosis (n = 6, 11.5% ± 4.4% and 90 ± 46 × 109/L, respectively) when compared with asymptomatic transient thrombocytosis patients (n = 40, 4.5% ± 2.7% and 35 ± 16 × 109/L, respectively) and to all control groups (P < .05 for all comparisons). In addition, 7 of 8 thrombocytosis patients who were studied before developing symptoms of thrombosis had elevated absolute RP counts compared with only 1 of 63 thrombocytosis patients who remained asymptomatic. Follow-up studies in seven chronic thrombocytosis patients showed that successful aspirin treatment of symptomatic recurrent thrombosis significantly reduced the RP% from 17.1% ± 10.9% before therapy to 4.8% ± 2.0% after therapy; absolute RP counts decreased from 102 ± 67 × 109/L to 26 ± 10 × 109/L (P < .01 for both). We conclude that thrombosis in the setting of an elevated platelet count is associated with increased platelet turnover, which is reversed by aspirin therapy. Measurement of reticulated platelets to assess platelet turnover may be useful in evaluating both treatment response and thrombotic risk in thrombocytosis.

Anagrelide and imatinib mesylate combination therapy in patients with chronic myeloproliferative disorders

2003 ◽  
Vol 52 (3) ◽  
pp. 229-234 ◽  
Author(s):  
Apostolia M. Tsimberidou ◽  
Dawn E. Colburn ◽  
Mary Alma Welch ◽  
Jorge E. Cortes ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Combination Therapy ◽  
Imatinib Mesylate ◽  
Myeloproliferative Disorders ◽  
Chronic Myeloproliferative Disorders

scholarly journals Morning Vs Bedtime Aspirin Intake in Patients with Essential Thrombocythemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4295-4295
Author(s):  
Emma Cacciola ◽  
Elio Gentini Cacciola ◽  
Veronica Vecchio ◽  
Rossella Rosari Cacciola
Keyword(s):  
Platelet Count ◽  
Essential Thrombocythemia ◽  
Conflicts Of Interest ◽  
Clot Formation ◽  
Optimal Timing ◽  
Platelet Factor ◽  
Thrombotic Risk ◽  
Once Daily ◽  
Daily Dose ◽  
The Mean

Abstract The essential thrombocythemia (ET) is a myeloid neoplasm characterized by platelet hyperreactivity and thrombotic risk. The treatment with aspirin (ASA) is recommended in ET patients at risk of first-time or recurrent thrombotic events. An unexplored topic is the optimal timing of once daily ASA intake. On the basis of the presumptions that 1) platelet aggregation is higher in the morning and that 2) the platelet inhibitory effect of ASA is not sustained during the usual 24-hour (h) dosing interval and that 3) a higher gastric mucosal resistance in the evening, we evaluated platelet count, β-thromboglobulin (β-TG) and platelet factor 4 (PF4), as markers of platelet activation, the clotting time (CT), clot formation time (CFT) and maximum clot formation/firmness (MCF), as indicators of aspirinated platelet contribution to clot formation/firmness. We studied 60 patients (20 men, 40 women; mean age 51 years, range 32-70) with ET according to WHO criteria. The mean duration of disease was 11 years. All patients were on ASA 100 mg once daily. Of these, 30 took ASA on awakening and 30 took ASA at bedtime. Of the 60 patients, 45 were on anagrelide hydrochloride (daily dose 1.5 mg) (10 men, 35 women), 15 were on hydroxyurea (daily dose 2 mg) (10 men 5 women). None had inherited or acquired thrombotic risk factors. Sixty subjects served as controls. Platelets were measured by automated analyzer. β-TG and PF4 were determined by ELISA. CT, CFT and MCF were measured by ROTEM delta. The mean platelet count was 455±200x109/L. The awakening ASA patients had normal β-TG and PF4 (12±5 IU/ml and 4±1 IU/ml), normal CT (CT, unit: s. n.v. 100-240 s) ( 110±20 s), normal CFT (CFT, unit: s, n.v. 30-110 s) (45±5 s) and normal MCF (MCF, unit: mm, n.v. 50-72 mm) (61±2 mm), whereas the bedtime ASA patients had high β-TG and PF4 (200±15 IU/ml vs 20±11 IU/ml and 170±50 IU/ml vs 6±2 IU/ml, respectively) (p<.0001 and p<.0001, respectively), shortened CT (CT, unit: s. n.v. 100-240 s) ( 80±10 s), CFT (CFT, unit: s, n.v. 30-110 s) (15±5 s) and MCF (MCF, unit: mm, n.v. 50-72 mm) (40±2 mm). These findings suggest that in ET patients the optimal timing of once daily ASA intake is in the morning. Disclosures No relevant conflicts of interest to declare.

scholarly journals Increased Thromboxane in Patients with Polycythemia Vera and Thrombosis: Evidence for Aspirin-Unsuppressible Platelet Activation In Vivo

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5372-5372
Author(s):  
Rossella Rosari Cacciola ◽  
Elio Gentilini Cacciola ◽  
Veronica Vecchio ◽  
Emma Cacciola
Keyword(s):  
Platelet Count ◽  
Platelet Activation ◽  
Platelet Function ◽  
Conflicts Of Interest ◽  
Myeloproliferative Neoplasm ◽  
Vascular Events ◽  
Platelet Factor ◽  
Thrombotic Risk ◽  
Closure Time ◽  
The Mean

Polycyhemia vera (PV) is a myeloproliferative neoplasm characterized by increased thromboxane (TX) production and thrombotic risk. It is reported that serum TXB2 concentrations in PV patients are twofold higher than healthy controls and that low-dose aspirin (ASA) therapy reduces the risk of major vascular events by 50 to 60%. To evaluate this unusual size of the effect of ASA we have studied platelet count, hematocrit (HCT), β-thromboglobulin (β-TG) and platelet factor 4 (PF4), as markers of platelet activation, TXB2, as primary indicator of platelet activation, the platelet function activity (PFA), as indicator of ASA platelet sensitivity, and the clotting time (CT), as parameter of thrombin formation. We studied 60 patients (38 men, 22 women; mean age 51 years, range 32-70) with PV according to WHO criteria. The mean duration of disease was 12 years. All patients were on ASA 100 mg once daily. All patients were on phlebotomy. None had inherited or acquired thrombotic risk factors. Of 60 patients, 30 had thrombosis (20 men, 10 women) and 30 had no thrombosis. Of 30 with thrombosis, 15 developed nonfatal myocardial infarction (10 men, 5 women) defined by chest pain of typical intensity and duration and ST-segment elevation in any limb lead on electrocardiography, 10 had nonfatal stroke (8 men, 2 women) confirmed with the use of magnetic resonance imaging, and 5 (2 men , 3 women) had deep venous thrombosis confirmed by ultrasonography. Platelet count and HCT were measured by automated analyzer. β-TG and PF4 were determined by ELISA. TXB2 was measured by radioimmunoassay technique. ASA platelet sensitivity was measured by Platelet Function Analyzer (PFA-100). CT was measured by thromboelastometry. The mean platelet count was 430±170x109/L. The mean HCT value was 42±3%. The patients with thrombosis had high β-TG, PF4 and TXB2 (110±45 IU/ml, 45±21 IU/ml, and 1.700±1.990 nmol/L, respectively), shortened C/EPI closure time (T, unit: s, n.v. 84-160 s) (55±10 s) and shortened CT (CT, unit: s. n.v. 100-240 s) (45±20 s) whereas the patients without thrombosis had normal β-TG, PF4 and TXB2 (20±11 IU/ml, 6±2 IU/ml, and 800±280 nmpl/L, respectively), prolonged C/EPI closure time (249±40 s) and normal CT (110±20 s). These findings might suggest that in PV patients and thrombotic complications might need a platelet-selective dosage of ASA. Disclosures No relevant conflicts of interest to declare.

Microparticles (platelet, Endothelial, and Leucocyte) Are Elevated in Patients with Myeloproliferative Disorders.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1552-1552
Author(s):  
Susan Lynch ◽  
David Stirling ◽  
Christopher A. Ludlam
Keyword(s):  
Platelet Count ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Active Role ◽  
Current Treatment ◽  
Polycythaemia Vera ◽  
Healthy Controls ◽  
Thrombotic Risk ◽  
Significant Difference ◽  
Thrombotic Complications

Abstract Patients with myeloproliferative disorders (MPD) have an excess of thrombotic complications which is not fully corrected by normalisation of their elevated haematocrit or thrombocytosis. The mechanisms responsible for this are not completely understood but platelets, leucocytes and endothelial cells have all been implicated. Plasma microparticles are observed to be elevated in other diseases associated with thrombotic complications. We measured platelet (PMP), endothelial (EMP), red cell (RMP) and leucocyte (LMP) microparticles in patients with MPD compared to healthy controls. Microparticles, of less than 1μm were measured by flow cytometry on platelet poor plasma obtained from citrated peripheral blood samples. Subtypes were identified using fluorescent conjugated monoclonal antibodies; EMP CD31+CD42-, PMP CD31+42+, RMP Glycophorin A + and LMP CD45+ events. Absolute concentrations of microparticles per μl plasma were calculated using Trucount beads. Results are currently available for 27 MPD patients, 9 polycythaemia vera (PV), and 18 primary thrombocythaemia and 14 healthy controls. All patients except 1 PV were on current treatment with hydroxycarbamide and all but 3 were receiving aspirin. PMP and LMP were elevated in MPD patients compared to healthy controls, PMP 12432 (1653) v 2371 (278) per μl, mean (SEM) p&lt;0.001, LMP 98.7 (14) v 62.6 (7.7) per μl, p=0.03. EMP were elevated in MPD patients at 202 (34) v 34 (14) per μl, p&lt;0.001. There was no significant difference in RMP levels 646 (131) v 589 (241) per μl, p=0.84. There were no significant differences in MP numbers between the PT and PV patients or by Jak2 V617F mutation status. Platelet count (x109/l) was higher in the MPD patients, PT 503 (39) v PV 372 (43) v control 236 (12), all comparisons p&lt;0.04. PMP/platelet count was calculated to adjust for this and the ratio remained elevated in the MPD patients, PV 28.5 (4.5) and PT 26.1 (3.7) v controls 9.9 (1.2), both p=&lt;0.03. In conclusion, these results demonstrate that PMP, EMP and LMP are elevated in MPD despite standard treatment, with the PMP elevated disproportionately to the platelet count. This is further evidence for platelet activation, endothelial dysfunction and a role for leucocytes in the thrombotic risk of MPD and that the microparticles also play an active role in promoting the prothrombotic state.

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