Deficient lipoxin synthesis: a novel platelet dysfunction in myeloproliferative disorders with special reference to blastic crisis of chronic myelogenous leukemia.
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.
Stenke
L
L
Department of Physiological Chemistry, Danderyd Hospital, Stockholm, Sweden.
Edenius
C
C
Samuelsson
J
J
Lindgren
J A
JA
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
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