Novel anticoagulant activity of polyamino acid offsets bacterial endotoxin-induced extrinsic hypercoagulation: Downregulation of monocytic tissue factor-dependent FVII activation

Arthur J. Chu, Mihai Rauci, Obioma I. Nwobi, Suresh T. Mathews, Salwa Beydoun

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

The extrinsic hypercoagulation often resulting from sepsis could contribute to disseminated intravascular coagulation and cardiovascular complications. The effective prevention and intervention remained largely complex and unclear. In a cell model of human leukemia THP-1 monocytes following bacterial endotoxin (LPS) exposure, we show the novel anticoagulant ability of polyamino acid (polyAA) to suppress the extrinsic hypercoagulation. LPS-induced monocytic tissue factor (mTF) procoagulation was readily offset by poly-L-lysine (PLK), poly-L-arginine (PLR), or poly-L-ornithine (POR) included in single-stage clotting assays. IC50 was estimated at 0.35, 0.30, or 0.58 μM for PLR, POR, or PLK, respectively, whereas, poly-L-asparatic acid (PLD) remained ineffective. In a separate approach, inclusion of cationic polyAA in human plasma significantly prolonged prothrombin time, confirming the depressed extrinsic coagulation. In chromogenic assays dissecting the extrinsic pathway, we further determined the inhibitory site(s). PLK, PLR, or POR significantly inhibited LPS-induced FVII activation, which was consistent with the diminished FVIIa formation shown on Western blotting analysis. In contrast, polyAA did not show any additional effect on either FVIIa/FXa amidolytic activities or mTF/FVIIa-catalyzed FX activation. Nor did polyAA show any effect on FVII activation directly catalyzed by FXa. Taken together, PLK, PLR, or POR preferentially inhibited mTF-dependent FVII activation, accounting for their novel anticoagulant activities. PolyAA might present the specific antagonists to arrest the extrinsic hypercoagulation following inflammation.

Original languageEnglish (US)
Pages (from-to)477-483
Number of pages7
JournalJournal of Cardiovascular Pharmacology
Volume42
Issue number4
DOIs
StatePublished - Oct 1 2003

Fingerprint

Thromboplastin
Endotoxins
Anticoagulants
Down-Regulation
Acids
Disseminated Intravascular Coagulation
Prothrombin Time
Inhibitory Concentration 50
Lysine
Monocytes
Sepsis
Leukemia
Western Blotting
Inflammation
polyarginine
polyornithine

Keywords

  • Endotoxin
  • Extrinsic coagulation
  • FVII activation
  • Polyamino acids
  • Sepsis
  • Tissue factor

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Novel anticoagulant activity of polyamino acid offsets bacterial endotoxin-induced extrinsic hypercoagulation : Downregulation of monocytic tissue factor-dependent FVII activation. / Chu, Arthur J.; Rauci, Mihai; Nwobi, Obioma I.; Mathews, Suresh T.; Beydoun, Salwa.

In: Journal of Cardiovascular Pharmacology, Vol. 42, No. 4, 01.10.2003, p. 477-483.

Research output: Contribution to journalArticle

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AB - The extrinsic hypercoagulation often resulting from sepsis could contribute to disseminated intravascular coagulation and cardiovascular complications. The effective prevention and intervention remained largely complex and unclear. In a cell model of human leukemia THP-1 monocytes following bacterial endotoxin (LPS) exposure, we show the novel anticoagulant ability of polyamino acid (polyAA) to suppress the extrinsic hypercoagulation. LPS-induced monocytic tissue factor (mTF) procoagulation was readily offset by poly-L-lysine (PLK), poly-L-arginine (PLR), or poly-L-ornithine (POR) included in single-stage clotting assays. IC50 was estimated at 0.35, 0.30, or 0.58 μM for PLR, POR, or PLK, respectively, whereas, poly-L-asparatic acid (PLD) remained ineffective. In a separate approach, inclusion of cationic polyAA in human plasma significantly prolonged prothrombin time, confirming the depressed extrinsic coagulation. In chromogenic assays dissecting the extrinsic pathway, we further determined the inhibitory site(s). PLK, PLR, or POR significantly inhibited LPS-induced FVII activation, which was consistent with the diminished FVIIa formation shown on Western blotting analysis. In contrast, polyAA did not show any additional effect on either FVIIa/FXa amidolytic activities or mTF/FVIIa-catalyzed FX activation. Nor did polyAA show any effect on FVII activation directly catalyzed by FXa. Taken together, PLK, PLR, or POR preferentially inhibited mTF-dependent FVII activation, accounting for their novel anticoagulant activities. PolyAA might present the specific antagonists to arrest the extrinsic hypercoagulation following inflammation.

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