© 1991 S. Karger AG, Basel 0001-5792/91/0852-0088 S 2.75/0
Acta Haematol 1991;85:88-92
Generation of Arachidonic Acid Metabolites from Stimulated Whole Blood in Patients with Chronic Myeloproliferative Disorders P. Parisea, E. Huybrechtsh, S. Grasselli*, F. FalcinellP, G.G. Nenci'\ P. Gresele\ J. Vermylenb Institute of Semeiotica Medicaand Hematology Department, University of Perugia, Italy; b Center for Thrombosis and Vascular Research, University of Leuven, Belgium
“
Key Words. Arachidonic Acid • Myeloproliferative disorders • Platelets • Prostaglandins • Thromboxane B, Abstract. We have evaluated the arachidonic acid (AA) metabolism in patients with myeloproliferative dis orders (MPD). In essential thrombocythemia (ET), the generation of thromboxane B; was found significantly reduced and inversely correlated with platelet count. Polycythemia vera (PV) patients showed an increased for mation of this metabolite of AA. Prostaglandin E2 and 6-keto-PGFlrt generation were markedly reduced in pa tients with chronic myelogenous leukemia. Our study confirms that the arachidonate metabolism is frequently deranged in patients with MPD. The opposite changes in thromboxane formation in ET and PV could be one of the factors responsible for the different incidences of thrombotic and hemorrhagic complications in these diseases.
Myeloproliferative disorders (MPD), a group of related diseases of the bone marrow stem cell, include polycythemia vera (PV), chronic myelogenous leu kemia (CML), myeloid metaplasia with myelofibrosis (MF), and essential thrombocythemia (ET), all of which are characterized by a high incidence of bleed ing and thromboembolic complications [1, 2]. Abnor malities in platelet function are frequently observed in these disorders. Both reduced platelet adhesive ness, aggregability, and coagulant activities, which could contribute to hemorrhagic diathesis, and in creased platelet reactivity, which could play a role in thrombotic complications, have been reported [3-8], Modifications of arachidonic acid (AA) metabolism by either the cyclooxygenase or lipoxygenase path ways have been observed frequently in MPD [7,9-11]. In order to better characterize the abnormality in the AA metabolism in MPD, we have evaluated pros taglandin synthesis from whole blood of patients with different kinds of M PD.
Patients and Methods We examined 35 patients with MPD with a mean age of 46.9, range 19-78 years. Eleven males (M) and 6 females (F) had CML, 4 M and 2 F had PV, 2 M and 4 F had MF, and 3 M and 3 F had ET. The patients were followed up at the Hematology Division of the Internal Medicine Department of the Perugia University. Informed consent was obtained from each patient. The diagnostic criteria for PV were established according to the recommendations of the Poly cythemia Vera Study Group [12], and those for the other MPD were defined according to standard criteria [13], All CML patients had the Philadelphia chromosome. Twenty-two patients were studied just after diagnosis and before specific treatment was undertaken. The other 13 patients were studied at least 2 months after the last phlebotomy or chemotherapy. For control purposes, 14 healthy adult volunteers, 8 M and 6 F, mean age 39.4, range 25-67 years, were selected from the laboratory and medical personnel. Patients and volunteers denied having taken drugs interfering with platelet functions or prostaglandin metabolism in the 10 days preceding the assay. The detailed clinical history, with special attention to previous hemorrhagic or thromboembolic episodes, was recorded for all pa tients and controls. A complete hematological evaluation, includ ing hematocrit, hemoglobin, erythrocyte, leukocyte and platelet counts, and a differential leukocyte count, was also performed. The bleeding time was measured in duplicate by using a commercial
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Introduction
89
Arachidonic Acid Metabolites in MPD
Table 1. White blood cell and platelet counts, bleeding time, and previous hemorrhagic or thrombotic complications in controls and patient groups White blood cells x I06/I
Controls (n = 14) Mean SD CML ( = 17) Mean SD
Platelets x lO’/ l
Bleeding time s
Complications, n hemorrhagic
thrombotic
311 78
-
-
67,862“ 71,354
200 159
728b 397
1
2
9,466 5,965
173 39
490c 195
1
2
8,833 8,587
191 146
650‘ 338
2
1
6,633 3,818
791“ 210
492“ 149
3
2
>
203 44
CL
6,208 1,380
Mean SD M F(n = 6) Mean SD ET (n = 6) Mean SD
“ p < 0.01 ; b < 0.025; an d c < 0.05 versus controls.
parison was adopted for statistical analysis; when the result of this test showed statistical significance at a level of 0.05 or less, we per formed selected comparisons between groups by means of Wilcoxon’s sum of ranks test [16]. Spearman’s test was used to evaluate correlations between two different parameters.
Results The mean leukocyte and platelet counts, bleeding times, as well as previous hemorrhagic and throm botic events in the different patient groups are re ported in table 1. The bleeding times were signifi cantly prolonged in all groups of MPD patients; the highest values were found in CML patients, in which the prolongation of the bleeding time was signifi cantly correlated with the WBC count (p
Acta Haematol 1991;85:88-92
Generation of Arachidonic Acid Metabolites from Stimulated Whole Blood in Patients with Chronic Myeloproliferative Disorders P. Parisea, E. Huybrechtsh, S. Grasselli*, F. FalcinellP, G.G. Nenci'\ P. Gresele\ J. Vermylenb Institute of Semeiotica Medicaand Hematology Department, University of Perugia, Italy; b Center for Thrombosis and Vascular Research, University of Leuven, Belgium
“
Key Words. Arachidonic Acid • Myeloproliferative disorders • Platelets • Prostaglandins • Thromboxane B, Abstract. We have evaluated the arachidonic acid (AA) metabolism in patients with myeloproliferative dis orders (MPD). In essential thrombocythemia (ET), the generation of thromboxane B; was found significantly reduced and inversely correlated with platelet count. Polycythemia vera (PV) patients showed an increased for mation of this metabolite of AA. Prostaglandin E2 and 6-keto-PGFlrt generation were markedly reduced in pa tients with chronic myelogenous leukemia. Our study confirms that the arachidonate metabolism is frequently deranged in patients with MPD. The opposite changes in thromboxane formation in ET and PV could be one of the factors responsible for the different incidences of thrombotic and hemorrhagic complications in these diseases.
Myeloproliferative disorders (MPD), a group of related diseases of the bone marrow stem cell, include polycythemia vera (PV), chronic myelogenous leu kemia (CML), myeloid metaplasia with myelofibrosis (MF), and essential thrombocythemia (ET), all of which are characterized by a high incidence of bleed ing and thromboembolic complications [1, 2]. Abnor malities in platelet function are frequently observed in these disorders. Both reduced platelet adhesive ness, aggregability, and coagulant activities, which could contribute to hemorrhagic diathesis, and in creased platelet reactivity, which could play a role in thrombotic complications, have been reported [3-8], Modifications of arachidonic acid (AA) metabolism by either the cyclooxygenase or lipoxygenase path ways have been observed frequently in MPD [7,9-11]. In order to better characterize the abnormality in the AA metabolism in MPD, we have evaluated pros taglandin synthesis from whole blood of patients with different kinds of M PD.
Patients and Methods We examined 35 patients with MPD with a mean age of 46.9, range 19-78 years. Eleven males (M) and 6 females (F) had CML, 4 M and 2 F had PV, 2 M and 4 F had MF, and 3 M and 3 F had ET. The patients were followed up at the Hematology Division of the Internal Medicine Department of the Perugia University. Informed consent was obtained from each patient. The diagnostic criteria for PV were established according to the recommendations of the Poly cythemia Vera Study Group [12], and those for the other MPD were defined according to standard criteria [13], All CML patients had the Philadelphia chromosome. Twenty-two patients were studied just after diagnosis and before specific treatment was undertaken. The other 13 patients were studied at least 2 months after the last phlebotomy or chemotherapy. For control purposes, 14 healthy adult volunteers, 8 M and 6 F, mean age 39.4, range 25-67 years, were selected from the laboratory and medical personnel. Patients and volunteers denied having taken drugs interfering with platelet functions or prostaglandin metabolism in the 10 days preceding the assay. The detailed clinical history, with special attention to previous hemorrhagic or thromboembolic episodes, was recorded for all pa tients and controls. A complete hematological evaluation, includ ing hematocrit, hemoglobin, erythrocyte, leukocyte and platelet counts, and a differential leukocyte count, was also performed. The bleeding time was measured in duplicate by using a commercial
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/24/2019 11:26:56 PM
Introduction
89
Arachidonic Acid Metabolites in MPD
Table 1. White blood cell and platelet counts, bleeding time, and previous hemorrhagic or thrombotic complications in controls and patient groups White blood cells x I06/I
Controls (n = 14) Mean SD CML ( = 17) Mean SD
Platelets x lO’/ l
Bleeding time s
Complications, n hemorrhagic
thrombotic
311 78
-
-
67,862“ 71,354
200 159
728b 397
1
2
9,466 5,965
173 39
490c 195
1
2
8,833 8,587
191 146
650‘ 338
2
1
6,633 3,818
791“ 210
492“ 149
3
2
>
203 44
CL
6,208 1,380
Mean SD M F(n = 6) Mean SD ET (n = 6) Mean SD
“ p < 0.01 ; b < 0.025; an d c < 0.05 versus controls.
parison was adopted for statistical analysis; when the result of this test showed statistical significance at a level of 0.05 or less, we per formed selected comparisons between groups by means of Wilcoxon’s sum of ranks test [16]. Spearman’s test was used to evaluate correlations between two different parameters.
Results The mean leukocyte and platelet counts, bleeding times, as well as previous hemorrhagic and throm botic events in the different patient groups are re ported in table 1. The bleeding times were signifi cantly prolonged in all groups of MPD patients; the highest values were found in CML patients, in which the prolongation of the bleeding time was signifi cantly correlated with the WBC count (p
