Inhibition of tissue factor pathway inhibitor by the aptamer BAX499 improves clotting of hemophilic blood and plasma.
BACKGROUND
Tissue factor pathway inhibitor (TFPI) is the major inhibitor of tissue factor-initiated coagulation, making it an interesting and novel therapeutic target in hemophilia treatment. The aptamer BAX499 (formerly ARC19499) is designed to improve hemostasis by specifically inhibiting TFPI.


OBJECTIVE
The aim of the study was to examine the concentration-dependent augmentation of clotting by BAX499.


METHODS
Whole blood clot formation was quantified by rotational thromboelastometry and thromboelastography, and thrombin generation in platelet-poor plasma was assessed with the calibrated automated thrombogram, in samples from patients with congenital hemophilia A (N=55) and B (N=11), patients with acquired hemophilia A (N=1), and healthy controls (N=37).


RESULTS
BAX499 significantly improved clotting of samples from hemophilic patients in a concentration-dependent manner, resulting in clotting profiles in samples from patients with severe hemophilia that were similar to those of healthy controls.


CONCLUSIONS
BAX499 improved ex vivo clotting parameters in blood and plasma from patients with hemophilia A and B with different severity of disease, and also in a patient with acquired hemophilia. These results further support the contention that anti TFPI strategies may be an effective treatment for hemophilic patients.
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
M E
ME
Gorczyca
S C
SC
Nair
B
B
Jilma
S
S
Priya
C
C
Male
S
S
Reitter
P
P
Knoebl
J C
JC
Gilbert
R G
RG
Schaub
M
M
Dockal
K E
KE
McGinness
I
I
Pabinger
A
A
Srivastava
D000293:Adolescent; D000328:Adult; D000368:Aged; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D001317:Austria; D001777:Blood Coagulation / Q000187:drug effects* / Q000235:genetics; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D006467:Hemophilia A / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D002836:Hemophilia B / Q000097:blood* / Q000175:diagnosis / Q000235:genetics; D006490:Hemostatics / Q000494:pharmacology*; D006801:Humans; D007194:India; D008074:Lipoproteins / Q000037:antagonists & inhibitors* / Q000097:blood / Q000235:genetics; D008875:Middle Aged; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects*; D013916:Thrombelastography; D013917:Thrombin / Q000378:metabolism; D014914:Whole Blood Coagulation Time; D055815:Young Adult
C577143:ARC19499; D052157:Aptamers, Nucleotide; D006490:Hemostatics; D008074:Lipoproteins; C051928:lipoprotein-associated coagulation inhibitor; D013917:Thrombin