Activated protein C inhibitor for correction of thrombin generation in hemophilia A blood and plasma1.

Abstract

BACKGROUND:

Replacement therapy for hemophilic patient treatment is costly, because of the high price of pharmacologic products, and is not affordable for the majority of patients in developing countries.

OBJECTIVE:

To generate and evaluate low molecular weight agents that could be useful for hemophilia treatment.

METHODS:

Potential agents were generated by synthesizing specific inhibitors [6-(Lys-Lys-Thr-[homo]Arg)amino-2-(Lys[carbobenzoxy]-Lys[carbobenzoxy]-O-benzyl)naphthalenesulfonamide] (PNASN-1)] for activated protein C (APC) and tested in plasma and fresh blood from hemophilia A patients.

RESULTS:

In the activated partial thromboplastin time-based APC resistance assay, PNASN-1 partially neutralized the effect of APC. In calibrated automated thrombography, PNASN-1 neutralized the effect of APC on thrombin generation in normal and congenital factor VIII-deficient plasma (FVIII:C < 1%). The addition of PNASN-1 to tissue factor-triggered (5 pm) contact pathway-inhibited fresh blood from 15 hemophilia A patients with various degrees of FVIII deficiency (FVIII:C < 1-51%) increased the maximum level of thrombin generated from 78 to 162 nm, which approached that observed in blood from a healthy individual (201 nm). PNASN-1 also caused a 47% increase in clot weight in hemophilia A blood.

CONCLUSIONS:

Specific APC inhibitors compensate to a significant extent for FVIII deficiency, and could be used for hemophilia treatment.

• Authors: K E Brummel-Ziedins, M F Whelihan, G E Rivard, S Butenas
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 9 Issue 11 Pg. 2262-7 (Nov 2011) ISSN: 1538-7836 [Electronic] England
• PMID: 21920012 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2011 International Society on Thrombosis and Haemostasis.

Chemical References

• Protein C Inhibitor
• Thrombin

Topics

• Blood (drug effects)
• Blood Coagulation (drug effects)
• Blood Coagulation Tests
• Case-Control Studies
• Drug Evaluation
• Hemophilia A (drug therapy)
• Humans
• Partial Thromboplastin Time
• Protein C Inhibitor (chemical synthesis, pharmacology)
• Thrombin (biosynthesis, drug effects)