Neutralization of heparin activity by neutrophil lactoferrin.
Lactoferrin is a prominent component of neutrophil secondary granules, and its blood concentration is increased in certain inflammatory diseases. In contrast to the well-described biochemical characterization of lactoferrin as an iron-binding protein, its physiologic role in the regulation of inflammation and other host defense mechanisms is unclear. In this report, we provide evidence that lactoferrin has a potent heparin-neutralizing activity during thrombin inhibition by the serine proteinase inhibitors (serpins) antithrombin and heparin co-factor II. Activated neutrophil supernatant, which contains lactoferrin and other heparin-binding proteins, could neutralize the heparin-dependent antithrombin-thrombin inhibition reaction. The addition of lactoferrin to plasma corrected the heparin-induced prolongation of blood plasma coagulation as measured by the activated partial thromboplastin time (aPTT). Treatment of whole blood with specific inflammatory mediators, fMLP, lipopolysaccharide (LPS), and tumor necrosis factor-alpha (TNF-alpha) increased the concentration of both plasma lactoferrin and platelet factor 4 while inhibiting the blood anticoagulant activity of heparin as measured by the aPTT. These results suggest that the prothrombotic sequelae of some inflammatory processes may be partly due to various agonists that release neutrophil lactoferrin, which can then neutralize glycosaminoglycan-dependent serpin-thrombin inhibition reactions.
Wu
H F
HF
Department of Pathology, University of North Carolina at Chapel Hill School of Medicine 27599-7035.
Lundblad
R L
RL
Church
F C
FC
D000595:Amino Acid Sequence; D000991:Antithrombins / Q000378:metabolism; D001777:Blood Coagulation / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004211:Disseminated Intravascular Coagulation / Q000503:physiopathology; D006494:Heparin Antagonists / Q000494:pharmacology*; D006801:Humans; D007781:Lactoferrin / Q000737:chemistry / Q000494:pharmacology* / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008895:Milk, Human / Q000737:chemistry; D008969:Molecular Sequence Data; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009504:Neutrophils / Q000737:chemistry*; D010314:Partial Thromboplastin Time; D010978:Platelet Factor 4 / Q000032:analysis; D015843:Serpins / Q000378:metabolism*; D013917:Thrombin / Q000037:antagonists & inhibitors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000991:Antithrombins; D017077:Culture Media, Conditioned; D006494:Heparin Antagonists; D008070:Lipopolysaccharides; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D010978:Platelet Factor 4; D009240:N-Formylmethionine Leucyl-Phenylalanine; D007781:Lactoferrin; D013917:Thrombin