Differential regulation of thrombin activatable fibrinolytic inhibitor by low molecular weight heparins. Pharmacologic implications.

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Florian-Kujawski M, Hoppensteadt D, Maddineni J, Ziegler H, Fareed J

Differential regulation of thrombin activatable fibrinolytic inhibitor by low molecular weight heparins. Pharmacologic implications.

Int Angiol. 2004 Dec;23(4):346-54.

PubMed ID

15767980 [ View in PubMed

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Abstract

AIM: 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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Tinzaparin	Antithrombin-III	Protein	Humans	Yes	Potentiator	Details