Antithrombin III
Independent
Anticoagulants
Benedict R. Lucchesi, M.D., Ph.D.
Department of Pharmacology
University of Michigan Medical School
Antithrombin III Independent Anticoagulants
• Hirudin
– From the medicinal leech
– Synthesized by recombinant DNA techniques
– Direct inhibitor of thrombin
• Lepirudin (Refludin™)
– desulfohirudin - a recombinant hirudin* derived from yeast cells.
• Hirugen (bivalirudin, Angiomax™)
– Synthetic dodecapeptide derived from hirudin.
• Argatroban
– Arginine based compound
– Weak competitive inhibitor of thrombin.
• These compounds are used in those patients who have
developed thrombocytopenia during treatment with heparin.
Lepirudin
(Refludin™)
Lepirudin [rDNA] (Refludan™)
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highly specific direct inhibitor of thrombin - [Leu1-Thr2]-63desulfohirudin - a recombinant hirudin* derived from yeast cells.
polypeptide - 65 amino acids MW=6979.5
identical to natural hirudin except for the substitution of leucine for
isoleucine at the N-terminal end of the molecule and the absence of a
sulfate group on tyrosine 63.
action independent of ATIII and not inhibited by platelet factor 4
one molecule of lepirudin binds one molecule of thrombin - all
thrombin-dependent coagulation pathways are affected
approved for clinical use in the treatment of heparin-induced
thrombocytopenia type II.
* Hirudin derived from the leech Hirudo medicinalis
Bivalirudin
(Hirulog,
™
Angiomax )
Bivalirudin (Hirulog, Angiomax™)
• Synthetic 20-amino acid peptide analog of naturally
occurring hirudin
• Bivalirudin is a specific and reversible direct thrombin
inhibitor that binds to the catalytic site and the anionbinding exosite of circulating and clot-bound thrombin.
• Inhibition of thrombin prevents activation of factors V,
VIII, and XIII; conversion of fibrinogen to fibrin;
platelet activation and aggregation).
Bivalirudin (Hirulog, Angiomax™)
• The effects of bivalirudin are reversed as thrombin slowly
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cleaves the bilvalirudin-Arg3-Pro4 bond, resulting in
recovery of thrombin active site function.
The onset of anticoagulant effect is immediate after direct IV
injection of bivalirudin.
Bivalirudin therapy prolongs several coagulation assays:
– activated clotting time (ACT),
– activated partial thromboplastin time (aPTT),
– thrombin time (TT),
– prothrombin time (PT)
– Coagulation times return to the normal range approximately 1—2
hours after discontinuance of the drug.
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(A) Structure of bivalirudin and (B)
bivalirudin / hirudin complexes
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Bivalirudin consists of an active
site-directed moiety linked by a
poly-glycine spacer to a dodecapeptide analogue of the carboxy
terminal of hirudin.
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Once bivalirudin complexes
thrombin, it is converted from a
noncompetitive inhibitor that
interacts with both the active site
and exosite 1 on thrombin to a
competitive inhibitor that only
binds to exosite 1.
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Potential for enhanced protein C
activation by bivalirudin. Fluidphase thrombin is complexed and
inhibited by bivalirudin.
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Upon arrival to the microcirculation
where thrombomodulin is concentrated, the amino-terminal domain
of bivalirudin is released, leaving
only the carboxy-terminal domain
bound to exosite 1 on thrombin.
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The affinity of thrombomodulin for
thrombin is higher than that of the
carboxy-terminal dodecapeptide of
bivalirudin, thus thrombin binds to
thrombomodulin, where it activates
protein C.
Argatroban
Argatroban
• Argatroban, a synthetic piperidine carboxylic acid derivative of
l-arginine, is an anticoagulant.
• Commercially available argatroban is a racemic mixture of the
R- and S-diastereoisomers in a ratio of approximately 65 to 35,
with the S-isomer having about twice the thrombin-inhibitory
potency of the R-isomer.
• Argatroban, a highly selective, reversible, small-molecule direct
thrombin inhibitor that binds rapidly to the catalytic site/a polar
region of both circulating (free) and clot-bound thrombin.
Argatroban
• Inhibition of thrombin prevents various steps in the
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coagulation process (e.g., activation of factors V, VIII, and XIII
and of protein C; conversion of fibrinogen to fibrin; platelet
activation and aggregation).
At infusion rates up to 40 mcg/kg per minute, argatroban
produces dose-dependent increases inactivated partial
thromboplastin time (aPTT) and several other coagulation
assays (activated clotting time [ACT], prothrombin time [PT],
and thrombin time [TT]).
Metabolized principally by the liver via hydroxylation and
aromatization.
Does not induce antibody formation to itself nor does it interact
with heparin-induced antibodies.
Argatroban
• Administered by
continuous IV infusion.
• Before administering
argatroban, all parenteral
anticoagulants must be
discontinued and a baseline
activated partial
thromboplastin time
(aPTT) obtained.
Supplied, as a concentrated
drug (100 mg/ml), which must
be diluted 100-fold prior to
infusion.
Should not be mixed with
other drugs prior to dilution in
a suitable intravenous fluid.