The origin of the thrombocytopenia and leucopenia induced by protamine-heparin complexes is unknown. We studied the biochemical and cellular effects of protamine (6 mg X kg(-1), i.v.) injected after heparin (5 mg X kg(-1), i.v.) in New Zealand rabbits. After protamine injection (0.5 min) increases in blood platelet-activating factor (PAF-acether, PAF) (27.6 +/- 27.6 to 148.2 +/- 48.9 pg X ml(-1) P < 0.05), thrombocytopenia (403 +/- 64 to 166 +/- 13 cells X 10(-3) X mm(-3), P < 0.05) and leucopenia (7650 +/- 930 to 4300 +/- 668 cells X mm(-3) P < 0.05) were noted. Plasma thromboxane B-2 increased at 1 min (125.6 +/- 24.4 to 879.7 +/- 141.0 pg X ml(-1), P < 0.01). Protamine alone induced no change. Indomethacin (3 mg X kg(-1), i.v.) did not counteract the effects of heparin-protamine. Pretreatment with the PAF receptor antagonist BN 52021 [9H1,7a-(epoxymethano)-1H,6aH-cyclopenta[c]furo[2,3-b]furo-[3',2',3,4]cyclopenta[1,2-d]furan-5,9,12-(4H)trione,3-tert-butylhexahydro-4,7b,11 hydroxy-8 methyl] alone (3 mg X kg(-1) i.v.) delayed thrombocytopenia and reduced plasma thromboxane B-2 concentration but did not modify leucopenia. Thus thrombocytopenia and thromboxane B-2 release triggered by heparin-protamine may be potentiated by the release of PAF.

OBJECTIVE--To evaluate the role of platelet activating factor (PAF) in the early stage of arthritis. METHODS--Arthritis was induced in rabbits by weekly intra-articular injections of carrageenan. A PAF receptor antagonist, BN 50730, was used as a preventive or curative agent. RESULTS--BN 50730 was able partially to prevent the development of arthritis, and was also active on established arthritis. The joint arthritis scores of BN treated animals were significantly lower than those of the non-treated animals. The blood concentrations of PAF, PAF bound to lipoproteins (lipo-PAF), and its precursor, lyso-PAF, were not correlated with clinical variations. CONCLUSIONS--The present data demonstrate a therapeutic action of a PAF antagonist in experimental arthritis and suggest a critical role for PAF during the early stage of arthritis.

Objectives: To assess after cardiopulmonary bypass (CPB) the role of paf-acether (paf), a phospholipid mediator whose injection in animal mimics the hemodynamics observed after CPB.Design: Prospective double-blind randomized study.Setting: Single institutional university hospital.Participants: 18 patients scheduled to undergo coronary artery bypass graft.Interventions: 18 patients randomly received a placebo (n = 8) or 120 mg BN52021 (n = 10), a paf-receptor antagonist injected twice just before vascular cannulation and before cross-clamp release.Measurements and Main Results: Hemodynamic measurements were performed with a pulmonary artery and a radial artery catheter before and after the first injection of BN52021 or placebo, at the end of CPB, 1, 15, and 30 minutes after protamine infusion, then 6 hours and 24 hours postoperatively. BN52021 infusion, did not affect hemodynamic parameters. After CPB, the pulmonary artery pressures, the cardiac index, and the pulmonary artery occlusion pressures were statistically the same between groups. By contrast, the pulmonary vascular resistances (1.5 +/- 0.5 IU v 4.5 +/- 0.6 IU, p < 0.05), the right ventricular systolic work index (5.33 +/- 0.91 g m m(-2) v 9.37 +/- 1.02 g m m(-2), p < 0.05) and the transpulmonary gradient (4.7 +/- 1.1 mmHg v 12.0 +/- 1.2 mmHg, p < 0.05) were lower in the BN52021 group as compared with the placebo group. After protamine infusion, these differences between groups disappeared.Conclusion: Because the inotropic and vasodilator therapy and the volume loading were the same between groups, this study suggests that pretreatment with a paf-receptor antagonist improves post-CPB pulmonary resistance. Nevertheless, this beneficial effect is transient without consequences on left ventricular function indices. (C) 1995 by W.B. Saunders Company

Cardiopulmonary bypass (CPB)-induced thrombocytopenia and leukopenia is augmented after heparin reversal of protamine. Platelet-activating factor (PAF) might be implicated in these disorders. To evaluate the effects of PAF on the hematologic disorders and blood loss during and after CPB, patients were pretreated with BN 52021, a PAF receptor antagonist, or a placebo. BN 52021 (120 mg) (n = 13) or placebo (n = 15) were infused intravenously before vascular cannulation and before cross-clamp release. Platelet and leukocyte counts were assessed in venous blood before and after the first dose of BN 52021 or placebo, 2 min after the beginning of CPB (at the entry of the oxygenator), at the end of CPB, 1, 15, and 30 min after protamine infusion, and 6 and 24 h after CPB. The decrease in platelet and leukocyte counts were the same between groups during and after CPB and after protamine infusion. Bleeding times were not modified by the pretreatment of patients with BN 52021. During surgery, blood loss reached 1660 +/- 297 mL in the BN 52021 group and 1599 +/- 283 mL in the placebo group (P > 0.05). Forty-eight hours postoperatively, the chest tube outputs were not different between groups (1460 +/- 418 mL vs 1640 +/- 362 mL in the BN 52021 and placebo groups, respectively). This study shows that BN 52021 infusion did not change the hematologic variables studied. Moreover, a PAF antagonist pretreatment did not protect the patients against CPB- or protamine-induced hematologic changes.

The effects of protamine (6 mg kg-1) injected after heparin (5 mg kg-1) have been studied in five groups of five New Zealand white rabbits. Group I was treated with the sequence heparin-protamine and group II with protamine alone. The animals of groups III and IV received respectively intravenous indomethacin (3 mg kg-1) and BN 52021 (3 mg kg-1), a paf receptor antagonist before the sequence heparin-protamine. Group V was pre-treated with indomethacin and BN 52021 before heparin reversal with protamine. In group I, immediate thrombocytopenia (44.1 +/- 4.6% of baseline level, P less than 0.05) and leucopenia (55.5 +/- 2.3% of baseline level, P less than 0.05) were observed 30 s after protamine reversal of heparin, paralleled with an increase in blood paf levels (27.6 +/- 27.6 vs. 148.2 +/- 48.9 pg ml-1, P less than 0.05). In group II, protamine alone induced no change in platelet count nor in blood paf levels (55 +/- 10 vs. 52.5 +/- 20 pg ml-1, P greater than 0.05). Pre-treatment with indomethacin alone (group III) did not protect the animals against the haematological changes induced by the heparin-protamine complexes. Pre-treatment with the paf receptor antagonist, alone or in association with indomethacin, delayed the occurrence of thrombocytopenia 3 min after protamine administration but the leucopenia was the same as in group I. This study demonstrated that paf is implicated in the immediate thrombocytopenia occurring after protamine reversal of heparin in rabbit.

Infusion of paf-acether (paf, first described as platelet-activating factor) into animals stimulates glycogenolysis and lipolysis and decreases insulin levels. This study reports a 50-fold increase in blood levels of paf in patients with Type 1 insulin-dependent diabetes mellitus without micro or macrovascular complications (1.07 +/- 0.42 ng/ml, n = 10) as compared with healthy volunteers (0.04 +/- 0.02 ng/ml, n = 9). By contrast, paf is not statistically elevated (p greater than 0.05) in patients with Type 2 non-insulin-dependent, diabetes mellitus with lipid abnormalities and micro or macrovascular complications (0.32 +/- 0.18 ng/ml, n = 9). In the three groups same levels of paf precursors and acetylhydrolase activity (the enzyme which inactivates paf) were noted suggesting an increase in paf biosynthesis by Type 1 diabetic patients. Elevated paf levels could perpetuate hyperglycaemia and tend to promote or accentuate micro or macrovascular complications. This study adds another biological difference between Type 1 and Type 2 diabetes.

Extracorporeal circulation (ECC) is associated with thrombocytopenia and transient leukopenia. After ECC and coronary artery bypass graft (CABG) surgery, some patients can develop pulmonary and cardiac dysfunction, which might be related to the release of various mediators such as thromboxane A2, C5a, and C3a anaphylatoxins. The involvement of PAF-acether (PAF), a potent vasoactive thrombocytopenic and leukoneutropenic agent, has not been determined. Therefore, 10 patients were studied during and after CABG. The release of PAF, lipo PAF (PAF bound to blood lipoproteins), and lypo PAF (PAF precursor and metabolite) was measured in blood from the left atrium, radial artery, and pulmonary artery before and after CABG. PAF, lipo PAF, and lyso PAF were also determined during ECC at the entry and exit points of the oxygenator. Hemodynamic parameters, platelet, and leukocyte counts in the pulmonary artery were measured simultaneously. PAF did not increase significantly during ECC; it showed a transitory six-fold increase immediately after CABG in the radial artery (0.18 ± 0.13 v 1.09 ±0.36 ng/ mL, P < 0.05), but not in the pulmonary artery (0.10 ± 0.03 v 0.56 ± 0.21 ng/mL, P > 0.05). Blood PAF amounts in the radial artery were significantly higher than in the left atrium following ECC (1.09 ± 0.36 v 0.06 ± 0.04, P < 0.05), probably indicating PAF production in the heart. No variation of blood lipo PAF and lyso PAF was observed. No correlation was seen between PAF amounts and blood cell count. The positive correlation observed between PAF levels in the left atrium and the pulmonary arterial pressure (r = 0.80, P < 0.001) strengthens the putative physiologic role of this agent in pulmonary artery hypertension. The clinical use of PAF antagonists may help to determine PAF involvement in human physiology and pathology.

Paf-acether (platelet-activating factor) is a phospholipid described as a potent mediator of inflammatory response. We have recently shown that the level of paf bound to lipoproteins was significantly higher in the serum from patients with rheumatic diseases, compared to that of control subjects. In serum, paf is inactivated in part by a paf acetylhydrolase that catalyses the hydrolysis of the acetate residue. Acetylhydrolase activity was measured in the serum and synovial fluid of patients with rheumatoid arthritis and other arthritides, i.e. osteoarthritis and chondrocalcinosis. In serum, the activity of acetylhydrolase was significantly increased in patients with rheumatic diseases when compared with that in the control group. However, it was enhanced to a lesser degree in rheumatoid arthritis than in non inflammatory rheumatic diseases. These results suggest a role for acetylhydrolase in controlling paf levels in rheumatic diseases.

The potent inflammatory mediator PAF-acether (PAF = platelet-activating factor) can produce the same hemodynamic and hematological effects as protamine infusion. In 10 patients, blood PAF and precursor levels were measured in the left atrium, the pulmonary and the radial artery before and after protamine reversal of heparin during coronary artery bypass graft. Blood PAF level in the left atrium increased 6-fold (17 +/- 12 pg.ml-1 vs 98 +/- 46 pg.ml-1, P = 0.03) after protamine infusion. By contrast, a 4-fold decrease was observed in the pulmonary artery blood (130 +/- 48 pg.ml-1 vs 31 +/- 23 pg.ml-1, P = 0.03) and a 9-fold decrease was noted in the radial artery blood (285 +/- 104 pg.ml-1 vs 31 +/- 15 pg.ml-1, P = 0.01). No cardiovascular impairment was observed but all patients exhibited thrombocytopenia. After protamine, PAF in the left atrium reached lower levels than those observed in the pulmonary and radial artery before protamine infusion. Moreover, no significant correlation was observed between platelet counts and PAF levels. Thus PAF seems not to mediate the platelet drop induced by heparin-protamine complexes. A positive correlation was obtained between leukocyte counts in the pulmonary artery and PAF levels in the left atrium (r = 0.78, P = 0.02). Protamine infusion may stimulate PAF biosynthesis by leukocytes in the lung, on the one hand, and accelerate the disappearance of PAF in the arterial bed, on the other hand.

Paf-acether (paf) is a naturally occurring phospholipid involved in inflammatory processes. The presence of paf, its precursor lyso paf, and lipo-paf has been determined in blood and synovial fluid from 13 patients with rheumatoid arthritis (RA), 11 with spondylarthropathies, eight with other inflammatory rheumatisms, 13 with chondrocalcinosis, 15 with osteoarthritis, and also in blood from nine healthy subjects. Paf and lipo-paf were measured by rabbit platelet aggregation after isolation by high performance liquid chromatography, whereas lyso paf was first chemically acetylated to give paf. Lipo-paf in blood was higher in patients than in controls; lipo-paf concentrations in blood and in synovial fluid were significantly higher in rheumatoid arthritis than in osteoarthritis and chondrocalcinosis. By contrast, paf and lyso paf reached their lower values in rheumatoid arthritis. The amounts of lipid mediators were not correlated with biological parameters of inflammation. Lipo-paf, which is considered as a storage form of paf, may be the important form of paf in active inflammatory rheumatism.

Infusion of paf-acether (paf, first described as platelet-activating factor) into animals stimulates glycogenolysis and lipolysis and decreases insulin levels. This study reports a 50-fold increase in blood levels of paf in patients with Type 1 insulin-dependent diabetes mellitus without micro or macrovascular complications (1.07 +/- 0.42 ng/ml, n = 10) as compared with healthy volunteers (0.04 +/- 0.02 ng/ml, n = 9). By contrast, paf is not statistically elevated (p greater than 0.05) in patients with Type 2 non-insulin-dependent, diabetes mellitus with lipid abnormalities and micro or macrovascular complications (0.32 +/- 0.18 ng/ml, n = 9). In the three groups same levels of paf precursors and acetylhydrolase activity (the enzyme which inactivates paf) were noted suggesting an increase in paf biosynthesis by Type 1 diabetic patients. Elevated paf levels could perpetuate hyperglycaemia and tend to promote or accentuate micro or macrovascular complications. This study adds another biological difference between Type 1 and Type 2 diabetes.