PROTAC, A COMMERCIALLY AVAILABLE PROTEIN C ACTIVATOR FROM THE VENOM OF AGKISTRODON CONTORTRIX CONTORTRIX, CAN ACTIVATE FACTOR V AND FACTOR VIII

1997 ◽  
Vol 86 (1) ◽  
pp. 79-84 ◽  
Author(s):  
Preston S Gable ◽  
Dzung T Le ◽  
Samuel I Rapaport
Keyword(s):  
Factor Viii ◽  
Protein C ◽  
Activate Factor ◽  
Factor V ◽  
Agkistrodon Contortrix ◽  
Agkistrodon Contortrix Contortrix

scholarly journals Unfractionated heparin inhibits thrombin-catalysed amplification reactions of coagulation more efficiently than those catalysed by factor Xa

1989 ◽  
Vol 257 (1) ◽  
pp. 143-150 ◽  
Author(s):  
F A Ofosu ◽  
J Hirsh ◽  
C T Esmon ◽  
G J Modi ◽  
L M Smith ◽  
...  
Keyword(s):  
Factor Viii ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Activate Factor ◽  
Factor V ◽  
Inhibitory Effects ◽  
Exogenous Factor ◽  
Additional Support ◽  
Prothrombin Activation ◽  
Inhibit Factor

We have proposed previously that the steps in coagulation most sensitive to inhibition by heparin are the thrombin-dependent amplification reactions, and that prothrombinase is formed in heparinized plasma only after Factor Xa activates Factor VIII and Factor V. These propositions were based on the demonstration that both heparin and Phe-Pro-Arg-CH2Cl completely inhibited 125I-prothrombin activation for up to 60 s when contact-activated plasma (CAP) was replenished with Ca2+. Furthermore, the addition of thrombin to CAP before heparin or Phe-Pro-Arg-CH2Cl completely reversed their inhibitory effects. Additional support for the above hypotheses is provided in this study by demonstrating that, when the activity of thrombin is suppressed by heparin (indirectly) or by Phe-Pro-Arg-CH2Cl (directly), exogenous Factor Xa reverses the ability of these two agents to inhibit prothrombin activation. Prothrombin activation was initiated by adding Factor Xa (1 nM) or thrombin (1 or 10 nM) simultaneously with CaCl2 to CAP. In the absence of heparin or Phe-Pro-Arg-CH2Cl, prothrombin activation was seen 15 s later in either case. Heparin failed to delay, and Phe-Pro-Arg-CH2Cl delayed for 15 s, prothrombin activation in CAP supplemented with Factor Xa. In contrast, heparin and Phe-Pro-Arg-CH2Cl completely inhibited prothrombin activation for at least 45 s in CAP supplemented with 1 nM-thrombin. Heparin failed to delay prothrombin activation in CAP supplemented with 10 nM-thrombin, whereas Phe-Pro-Arg-CH2Cl completely inhibited prothrombin activation in this plasma for 45 s. These results suggest that in CAP: (1) Factor Xa can effectively activate Factor VIII and Factor V when the proteolytic activity of thrombin is suppressed; (2) heparin-antithrombin III is less able to inhibit Factor Xa than thrombin; (3) suppression of the thrombin-dependent amplification reactions is the primary anticoagulant effect of heparin.

scholarly journals Proteolytic inactivation of human factor VIII procoagulant protein by activated human protein C and its analogy with factor V

Blood ◽  
1984 ◽  
Vol 63 (2) ◽  
pp. 486-489 ◽  
Author(s):  
CA Fulcher ◽  
JE Gardiner ◽  
JH Griffin ◽  
TS Zimmerman
Keyword(s):  
Factor Viii ◽  
Protein C ◽  
Human Factor ◽  
Activated Protein C ◽  
Light Chains ◽  
Factor V ◽  
Human Factor Viii ◽  
Thrombin Activation ◽  
A Site ◽  
Polypeptide Chains

Abstract Purified human factor VIII procoagulant protein (VIII:C) was treated with purified human activated protein C (APC) and the loss of VIII:C activity correlated with proteolysis of the VIII:C polypeptides. APC proteolyzed all VIII:C polypeptides with mol wt = 92,000 or greater, but not the doublet at mol wt = 79–80,000. These results and our previous thrombin activation studies of purified VIII:C, are analogous with similar studies of factor V and form the basis for the following hypothesis: activated VIII:C consists of heavy and light chain polypeptides [mol wt = 92,000 and mol wt = 79–80,000 (or 71–72,000), respectively] which are similar in Mr to the heavy and light chains of activated factor V. Thrombin activates VIII:C and V by generating these polypeptide chains from larger precursors and APC inactivates both molecules by cleavage at a site located in the heavy chain region of activated VIII:C and V.

Primary structure of a protein C activator from Agkistrodon contortrix contortrix venom

Biochemistry ◽  
1989 ◽  
Vol 28 (2) ◽  
pp. 674-679 ◽  
Author(s):  
Brad A. McMullen ◽  
Kazuo Fujikawa ◽  
Walter Kisiel
Keyword(s):  
Primary Structure ◽  
Protein C ◽  
Agkistrodon Contortrix ◽  
Agkistrodon Contortrix Contortrix

Anticoagulant Response to Agkistrodon Contortrix Venom (ACV test): a New Global Test to Screen for Defects in the Anticoagulant Protein C Pathway

1996 ◽  
Vol 75 (04) ◽  
pp. 562-566 ◽  
Author(s):  
A Robert ◽  
V Eschwège ◽  
H Hameg ◽  
L Drouet ◽  
M-F Aillaud
Keyword(s):  
Protein C ◽  
Control Group ◽  
Factor V ◽  
Antithrombin Deficiency ◽  
Global Test ◽  
Vein Thrombosis ◽  
Agkistrodon Contortrix ◽  
Factor V Gene ◽  
Deep Vein ◽  
Anticoagulant Response

SummaryAs specific assays used to identify defects in the protein C (PC) anticoagulant pathway are laborious and expensive, we describe here a global test to screen for these defects. This assay is expressed as the ratio of two activated partial thomboplastin times, one in the absence and one in the presence of 0,125 U/ml of the PC activator of Agkistrodon contortrix venom (ACV). Eight of the 168 healthy volunteers of the control group exhibited an ACV ratio below the lower normal limit of 3.37 [6 subjects with the mutation Arg 506 to Gin in their factor V gene (FV R506Q) and one with PS deficiency]. 128 patients who have had at least one episode of deep-vein thrombosis were retrospectively studied. All patients carrying FV Q506R (n = 48), PC deficiency (n = 14) or combined defects, i. e. FV Q506R and PC deficiency (n = 4) or FV Q506R and PS deficiency (n = 3), had ACV ratios < 3.37. PS deficient plasmas (n = 20) exhibited ACV ratios which overlapped normal range. ACV ratios of one out of seven patients with antithrombin deficiency, and 10% of patients without identified defect in the PC anticoagulant pathway (n = 30) were < 3.37. An ACV ratio raised to 3.70 could lead to a test identifying all patients with a defect in the PC anticoagulant pathway.

Haemophilia and thrombophilia

2003 ◽  
Vol 23 (01) ◽  
pp. 36-40 ◽  
Author(s):  
C. Escuriola ◽  
K. Kurnik ◽  
R. Schobess ◽  
S. Horneff ◽  
A. Kosch ◽  
...  
Keyword(s):  
Risk Factors ◽  
Factor Viii ◽  
Protein C ◽  
Methylenetetrahydrofolate Reductase ◽  
Haemorrhagic Stroke ◽  
Type I ◽  
Haemophilia A ◽  
Factor V ◽  
Severe Haemophilia ◽  
Prothrombotic Risk Factors

SummaryFor the study presented here 135 pediatric PUP patients with haemophilia consecutively admitted to German pediatric haemophilia treatment centers were investigated. In addition to factor VIII activity, the factor V (FV) G1691A mutation, the factor II (FII) G20210A variant, methylenetetrahydrofolate reductase (MTHFR) T677T genotype, elevated lipoprotein a (Lp a), antithrombin, protein C, and protein S were investigated. 103 out of 122 HA patients (FVIII activity <1%) were suffering from severe HA. The prevalence of prothrombotic risk factors in children with severe haemophilia A (HA) did not differ from previously reported data: FV GA 5.8%, FII GA 3.9%, MTHFR TT 10%, elevated Lp a 7%, protein C type I deficiency 1.1%. The first symptomatic bleeding leading to diagnosis of severe haemophilia occurred with a median age of 1.6 years (range: 0.5-7.1 years) in children carrying prothrombotic risk factors compared to non-carriers (0.9 years (0.1-4.0; p = 0.01). Two patients presenting with neonatal stroke due to elevated Lp a and the FII GA variant showed haemorrhagic stroke transformation triggered by severe haemophilia. In addition, when haemophilia A was corrected by administration of factor VIII concentrates eight out of 25 children with central lines in place developed catheter-related thrombosis. Conclusion: The data of this multicentre cohort study demonstrate that the clinical phenotype of severe haemophilia A in childhood is clearly influenced by the coinheritance of prothrombotic risk factors.

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