Gilbert, James C

Gorczyca, Monika E

Jilma, Bernd

Male, Christoph

Pabinger, Ingrid

Reitter, Sylvia

BMC Pharmacology

English

PubMed

Monika E Gorczyca

Bernd Jilma

Christoph Male

Sylvia Reitter

James C Gilbert

Ingrid Pabinger

Springer - Publisher Connector

Inhibition of tissue factor pathway inhibitor (TFPI) by ARC19499 improves clotting of hemophiliac blood

MEETING ABSTRACT Open Access
Inhibition of tissue factor pathway inhibitor
(TFPI) by ARC19499 improves clotting of
hemophiliac blood
Monika E Gorczyca1, Bernd Jilma1*, Christoph Male2, Sylvia Reitter3, James C Gilbert4, Ingrid Pabinger3
From 16th Scientific Symposium of the Austrian Pharmacological Society (APHAR)
Vienna, Austria. 25-27 November 2010
Background
Hemophilia A and B are disorders resulting from a defi-
ciency in factor VIII (FVIII), and factor IX (FIX), respec-
tively. Tissue Factor (TF) is a key component of the
extrinsic pathway and plays a role in the coagulation
defect of hemophilic blood. Neutralizing the activity of
TFPI represents a promising treatment concept in
patients with hereditary or acquired hemophilia.
ARC19499 is a polyethylene glycol (PEG)-conjugated
aptamer that binds to TFPI and inhibits its function as a
negative regulator of coagulation.
Methods
We evaluated the effect of the anti-TFPI aptamer
ARC19499 on thrombin generation and clot formation
in 40 hemophilia patients (congenital hemophilia:
29 adults, 10 children, one acquired hemophilia patient)
and 27 healthy male controls. Concentration-effect
curves of ARC19499 were assessed by the calibrated
automated thrombogram (CAT) and rotational throm-
belastometry (ROTEM) with and without corn trypsin
inhibitor (CTI) in whole blood and platelet-poor plasma.
Results
Clotting patterns were significantly compromised in
patients vs. controls. Measured FVIII:C levels in hemo-
philiacs correlated with parameters of the CAT assay
(except lag time) and also with the clotting time
assessed by ROTEM. ARC19499 had a concentration-
dependent pro-hemostatic effect in CAT and ROTEM.
ROTEM results with and without CTI were consistent.
ARC19499 normalized ROTEM clotting parameters and
rendered CAT patterns of hemophilia patients practi-
cally indistinguishable from those of controls. In
patients, ARC19499 normalized the endogenous throm-
bin potential, time-to-peak and the start tail, and
increased peak thrombin more than 2-fold. ARC19499
raised peak thrombin in patients with FVIII:C under 1%
to levels within the range of healthy controls and higher
than baseline in patients with FVIII:C above 5%. Effec-
tive concentrations of ARC19499 started at 2 nM. In an
acquired hemophilia patient ARC19499 worked
synergistically with activated prothrombin-complex con-
centrate/factor VIII inhibitor bypass activity (FEIBA)
pre-treatment. Similarly, in blood spiked with a FVIII
antibody, simulating a state of acquired hemophilia,
ARC19499 restored normal coagulation.
Conclusions
The anti-TFPI aptamer ARC19499 effectively enhanced
coagulation in blood of patients with congenital
or acquired hemophilia and therefore deserves further
evaluation in clinical trials.
Author details
1Department of Clinical Pharmacology, Medical University of Vienna, 1090
Vienna, Austria. 2Department of Pediatrics and Adolescent Medicine, Medical
University of Vienna, 1090 Vienna, Austria. 3Department of Medicine I,
Division of Hematology and Hemostasis, Medical University of Vienna, 1090
Vienna, Austria. 4Archemix Corp., Cambridge, MA 02142, USA.
Published: 16 November 2010
doi:10.1186/1471-2210-10-S1-A44
Cite this article as: Gorczyca et al.: Inhibition of tissue factor pathway
inhibitor (TFPI) by ARC19499 improves clotting of hemophiliac blood.
BMC Pharmacology 2010 10(Suppl 1):A44.
* Correspondence: bernd.jilma@meduniwien.ac.at
1Department of Clinical Pharmacology, Medical University of Vienna, 1090
Vienna, Austria
Full list of author information is available at the end of the article
Gorczyca et al. BMC Pharmacology 2010, 10(Suppl 1):A44
http://www.biomedcentral.com/1471-2210/10/S1/A44
© 2010 Jilma et al; licensee BioMed Central Ltd.


Crossref

file:///data/remote/core/dit/data/Springer-OA/pdf/851/aHR0cDovL2xpbmsuc3ByaW5nZXIuY29tLzEwLjExODYvMTQ3MS0yMjEwLTEwLVMxLUE0NC5wZGY=.pdf

Inhibition of tissue factor pathway inhibitor (TFPI) by ARC19499 improves clotting of hemophiliac blood

Abstract

Similar works

Full text

Available Versions

Springer - Publisher Connector

Springer - Publisher Connector

Crossref