Differential regulation of thrombin activatable fibrinolytic inhibitor by low molecular weight heparins. Pharmacologic implications.
OBJECTIVE
Thrombin activatable fibrinolytic inhibitor (TAFI) is activated via cleavage by thrombin thrombomodulin in complex, and can be regulated by anticoagulant drugs such as the heparins. Low molecular weight heparins (LMWHs) have different antithrombin/anti-Xa profiles and therefore vary in the degree to which they inhibit TAFI. The purpose of this study was to determine the differential regulation of TAFI by LMWHs.


METHODS
Dalteparin, enoxaparin, tinzaparin, parnaparin and heparin were supplemented to normal human pooled plasma at different concentrations (0-2.5 U). A chromogenic based assay (Pentapharm Inc., Basil, Switzerland) was used to measure activatable TAFI in each set of samples.


RESULTS
Heparin clearly had the highest degree of TAFI inhibition with an IC50 of 0.10 U, which correlates with its coagulation profile. Dalteparin, Tinzaparin, Parnaparin had similar IC50s, 0.6-0.8 U/ml respectively, while enoxaparin had a higher IC50 (>1.0 U/ml). These results strongly correlate with the anti-IIa inhibition of each agent but not with the anti-Xa. However, it is interesting to note that these drugs are administered according to anti-Xa units not anti-IIa.


CONCLUSIONS
These results suggest that each LMWH may inhibit TAFI to a different extent that is not dependent on the anti-Xa potency. Indiscriminate inhibition of TAFI may cause bleeding, while suboptimal inhibition may result in thrombosis. Because of the compositional difference, heparin and LMWHs may produce differential inhibition of TAFI and therefore result in product dependent modulation of hemostatic process which may or may not be related to their antithrombin effects.
Florian-Kujawski
M
M
Loyola University Medical Center, Maywood, IL, USA. mfloria@lumc.edu
Hoppensteadt
D
D
Maddineni
J
J
Ziegler
H
H
Fareed
J
J
D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors / Q000097:blood*; D017985:Dalteparin / Q000494:pharmacology; D017984:Enoxaparin / Q000494:pharmacology; D005260:Female; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010949:Plasma / Q000187:drug effects / Q000378:metabolism; D012016:Reference Values; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy; D000078222:Tinzaparin
D017984:Enoxaparin; D005343:Fibrinolytic Agents; D006495:Heparin, Low-Molecular-Weight; D000078222:Tinzaparin; D025901:Carboxypeptidase B2; C080945:parnaparin; D017985:Dalteparin