title: Deficient lipoxin synthesis: a novel platelet dysfunction in myeloproliferative disorders with special reference to blastic crisis of chronic myelogenous leukemia.
abstract: The capacity to convert exogenous leukotriene A4 to lipoxins (LXs) was investigated in platelet suspensions from patients with myeloproliferative disorders (MPD) (n = 22) and healthy control subjects (n = 14). Platelets isolated from the controls produced mainly LXA4, but also 6(S)-LXA4 and the all-trans isomers of lipoxins A4 and B4, as determined by high-performance liquid chromatography and computerized UV spectroscopy. In comparison to control levels, the mean LX synthesis was significantly lower in platelets from the MPD patients (438.7 +/- 62.8 and 157.4 +/- 31.2 pmol LXA4 per 10(9) platelets, respectively; mean +/- SEM; P = .0001). Platelets from six of the patients showed a particularly low capacity to produce LXs, resulting in LX levels below the detection limit or less than 7% of mean control levels. Notably, all these patients were in blastic crisis of chronic myelogenous leukemia (CML). This severely deficient LX production was paralleled by a dramatically attenuated conversion of arachidonic acid to 12-HETE (12-hydroxyheptadecatrienoic acid), a product formed via the prostaglandin endoperoxide synthase pathway, was normal. In addition, longitudinal studies of CML patients showed that blastic metamorphosis was associated with a markedly reduced capability to synthesize LXs, while this capacity improved after retransformation into a second chronic phase. The results reveal deficient LX synthesis as a novel platelet dysfunction in MPD, particularly in blastic crisis of CML in which an essentially abolished 12-lipoxygenase activity may be a general phenomenon.
authors.affiliation: Department of Physiological Chemistry, Danderyd Hospital, Stockholm, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Stenke
authors.forename: C
authors.initials: C
authors.lastname: Edenius
authors.forename: J
authors.initials: J
authors.lastname: Samuelsson
authors.forename: J A
authors.initials: JA
authors.lastname: Lindgren
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D001752:Blast Crisis; D001792:Blood Platelets / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis* / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism*; D017572:Leukotriene A4; D015289:Leukotrienes / Q000378:metabolism; D044045:Lipoxins; D009196:Myeloproliferative Disorders / Q000378:metabolism*; D013189:SRS-A / Q000378:metabolism
chemical_list: D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D017572:Leukotriene A4; D015289:Leukotrienes; D044045:Lipoxins; D013189:SRS-A; C040527:lipoxin A4; C008033:12-hydroxy-5,8,10-heptadecatrienoic acid; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; C042651:lipoxin B4