Blockade by ruthenium red of tissue factor-initiated coagulation

Arthur J. Chu, Zhen Guo Wang, Obioma Ikechukwu Nwobi, Salwa Beydoun

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

1. The ability of ruthenium red (RuR) to inhibit tissue factor (TF)-initiated blood coagulation was demonstrated at the protein and cellular levels as well as in human plasma. 2. In a single-stage clotting assay, RuR concentration-dependently inhibited rabbit brain thromboplastin (rbTF)-induced coagulation and offset bacterial endotoxin (LPS)-induced monocytic TF (mTF) hypercoagulation; the IC50s were estimated at 7,5 and 12.3 μM, respectively. 3. A 15-min preincubation of RuR with rbTF or monocyte suspension resulted in the pronounced inhibition with a significantly lowered IC50 at 1.8 or 7.7 μM for rbTF or mTF procoagulation, respectively. The differences in IC50s between rbTF and mTF without or with the preincubation indicated that TF was a primary target for RuR action. 4. The effect of RuR on the physiological function of TF in FVII activation was demonstrated by the proteolytic cleavage of FVII zymogen to its active forms of serine protease on Western blotting analyses. RuR readily blocked TF-catalyzed FVII activation (diminished FVIIa formation), thus down regulating the initiation of blood coagulation. 5. Inclusion of RuR into human plasma samples in vitro significantly prolonged prothrombin time, indicating the depressed coagulation. FVII activity was inhibited by 30-60% depending on the dose; as a result, FX activity also decreased. However, RuR showed no effect on thrombin time. Thus, RuR inhibited FVII activation to block the initiation of coagulation.

Original languageEnglish (US)
Pages (from-to)659-664
Number of pages6
JournalBritish Journal of Pharmacology
Volume133
Issue number5
DOIs
StatePublished - Jan 1 2001

Fingerprint

Ruthenium Red
Thromboplastin
Blood Coagulation
Thrombin Time
Enzyme Precursors
Prothrombin Time
Serine Proteases
Endotoxins
Inhibitory Concentration 50
Monocytes
Suspensions
Western Blotting
Rabbits

Keywords

  • Antithrombosis
  • Coagulation
  • Endotoxin
  • Factor VIIa
  • Monocytes
  • Ruthenium red
  • Tissue factor

ASJC Scopus subject areas

  • Pharmacology

Cite this

Blockade by ruthenium red of tissue factor-initiated coagulation. / Chu, Arthur J.; Wang, Zhen Guo; Nwobi, Obioma Ikechukwu; Beydoun, Salwa.

In: British Journal of Pharmacology, Vol. 133, No. 5, 01.01.2001, p. 659-664.

Research output: Contribution to journalArticle

Chu, Arthur J. ; Wang, Zhen Guo ; Nwobi, Obioma Ikechukwu ; Beydoun, Salwa. / Blockade by ruthenium red of tissue factor-initiated coagulation. In: British Journal of Pharmacology. 2001 ; Vol. 133, No. 5. pp. 659-664.
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AB - 1. The ability of ruthenium red (RuR) to inhibit tissue factor (TF)-initiated blood coagulation was demonstrated at the protein and cellular levels as well as in human plasma. 2. In a single-stage clotting assay, RuR concentration-dependently inhibited rabbit brain thromboplastin (rbTF)-induced coagulation and offset bacterial endotoxin (LPS)-induced monocytic TF (mTF) hypercoagulation; the IC50s were estimated at 7,5 and 12.3 μM, respectively. 3. A 15-min preincubation of RuR with rbTF or monocyte suspension resulted in the pronounced inhibition with a significantly lowered IC50 at 1.8 or 7.7 μM for rbTF or mTF procoagulation, respectively. The differences in IC50s between rbTF and mTF without or with the preincubation indicated that TF was a primary target for RuR action. 4. The effect of RuR on the physiological function of TF in FVII activation was demonstrated by the proteolytic cleavage of FVII zymogen to its active forms of serine protease on Western blotting analyses. RuR readily blocked TF-catalyzed FVII activation (diminished FVIIa formation), thus down regulating the initiation of blood coagulation. 5. Inclusion of RuR into human plasma samples in vitro significantly prolonged prothrombin time, indicating the depressed coagulation. FVII activity was inhibited by 30-60% depending on the dose; as a result, FX activity also decreased. However, RuR showed no effect on thrombin time. Thus, RuR inhibited FVII activation to block the initiation of coagulation.

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