Inhibition by heparin of the human blood coagulation intrinsic pathway factor X activator.
The effect of heparin and other glycosaminoglycans on the activation of factor X by the phospholipid membrane-bound human factor IXa-factor VIIIa complex (intrinsic fXase) was studied. Standard heparin inhibited purified intrinsic fXase by 50% at approximately 0.08 unit/ml (0.4 microgram/ml), which is below the normal range of heparin concentrations achieved during antithrombotic therapy (0.2-0.7 unit/ml). Kinetic and binding experiments revealed that heparin behaves as a partial noncompetitive inhibitor. The inhibition constant of heparin with low affinity for antithrombin was indistinguishable from heparin with high affinity for antithrombin (Ki = 20 nM). Additionally, "low molecular weight" heparin, which also is used as an antithrombotic drug, was a potent inhibitor of intrinsic fXase (Ki = 60 nM). Dermatan sulfate inhibited intrinsic fXase much more weakly than standard heparin (IC50 = 80 micrograms/ml). The IC50 of the other mammalian glycosaminoglycans, chondroitin sulfate, keratan sulfate, and hyaluronic acid, were greater than 100 micrograms/ml. Purified prothrombinase and extrinsic fXase were not inhibited by heparin. We propose that part of the antithrombotic action of heparin and low molecular weight heparin is due to anti-thrombin-independent inhibition of intrinsic fXase and that heparin with low affinity for antithrombin may be useful as an antithrombotic agent.
Barrow
R T
RT
Department of Medicine, Emory University, Atlanta, Georgia 30322.
Parker
E T
ET
Krishnaswamy
S
S
Lollar
P
P
D001777:Blood Coagulation / Q000502:physiology*; D001779:Blood Coagulation Factors / Q000187:drug effects*; D003546:Cysteine Endopeptidases / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D015949:Factor IXa / Q000378:metabolism; D015944:Factor VIIIa / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D008956:Models, Chemical; D009363:Neoplasm Proteins; D013925:Thromboplastin / Q000187:drug effects
D001779:Blood Coagulation Factors; D009363:Neoplasm Proteins; D015944:Factor VIIIa; D006493:Heparin; D013925:Thromboplastin; D015949:Factor IXa; D003546:Cysteine Endopeptidases; C030910:cancer procoagulant