Initiation of the tissue factor pathway of coagulation in the presence of heparin: control by antithrombin III and tissue factor pathway inhibitor.
Activation of factor X by both the unactivated tissue factor:factor VII complex (TF:VII) and the activated tissue factor:factor VIIa complex (TF:VIIa) has been studied in the presence of tissue factor pathway inhibitor (TFPI), antithrombin III (ATIII), and heparin. At near-plasma concentrations of TFPI, ATIII, and factor X, factor X activation that occurs in response to TF:VII is essentially abolished in the presence of heparin (0.5 micromol/L). This effect requires both inhibitors, acting on different targets: (1) ATIII, which in the presence of heparin blocks the activation of TF:VII, and (2) TFPI, which inhibits the TF:VIIa that is generated. In the absence of ATIII, TFPI alone with heparin reduces but does not abolish factor X activation. Conversely, in the absence of TFPI, ATIII + heparin reduces but does not abolish TF:VIIa generation and allows continuing activation of factor X. These results indicated that when the unactivated TF:VII complex is the initiating stimulus, heparin-dependent reduction in the rate and extent of factor X activation requires both ATIII and TFPI. In contrast, if TF:VIIa is used to initiate activation, only TFPI is involved in its regulation.
Jesty
J
J
Department of Medicine, State University of New York, Stony Brook, NY.
Lorenz
A
A
Rodriguez
J
J
Wun
T C
TC
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000595:Amino Acid Sequence; D000990:Antithrombin III / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D002863:Chromogenic Compounds / Q000378:metabolism; D003619:Dansyl Compounds / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D015942:Factor VIIa / Q000378:metabolism; D005170:Factor X / Q000378:metabolism; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D008074:Lipoproteins / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000378:metabolism; D013925:Thromboplastin / Q000502:physiology*
D000590:Amino Acid Chloromethyl Ketones; D002863:Chromogenic Compounds; D003619:Dansyl Compounds; D008074:Lipoproteins; D011994:Recombinant Proteins; C051928:lipoprotein-associated coagulation inhibitor; C030824:dansylglutamyl-glycyl-arginine chloromethyl ketone; C027587:phenylalanyl-phenylalanyl-arginine chloromethyl ketone; D000990:Antithrombin III; D005170:Factor X; D006493:Heparin; D013925:Thromboplastin; D015942:Factor VIIa