DICOUMAROL STUDIES: I. ORAL ADMINISTRATION OF SYNTHETIC DICOUMAROL TO VARIOUS CLASSES OF SHEEP AND CATTLE

1963 ◽  
Vol 43 (2) ◽  
pp. 344-352 ◽  
Author(s):  
J. H. Linton ◽  
B. P. Goplen ◽  
J. M. Bell ◽  
L. B. Jaques
Keyword(s):  
Vitamin K ◽  
Blood Clotting ◽  
Post Partum ◽  
Late Pregnancy ◽  
Cumulative Effects ◽  
Factor Vii ◽  
Factor X ◽  
Clotting Time ◽  
Sodium Bisulphite ◽  
Bull Calves

In one experiment 3 steers, 4 bull calves and 4 wether lambs were orally administered 2 milligrams dicoumarol per kilogram body weight and blood-clotting time measurements were made over a 4-day period. All animals responded to the dicoumarol but differences were evident between sheep and cattle; sheep were apparently more tolerant of the drug.The ’one-stage prothrombin’ test was more reliable and sensitive than the clotting tests employed for factor VII, factor X and prothrombin concentration.In a second experiment, 16 ewes in late pregnancy were fed rations containing 0 to 30 p.p.m. of synthetic dicoumarol and vitamin K3 as a cross treatment. Evidence of abnormal clotting power of ewe blood was observed in ewes fed diets containing 10 p.p.m. of dicoumarol. There was some indication of cumulative effects at this level after 32 days on test. At intake levels of 20 and 30 p.p.m. clotting times were affected more markedly and some ewes exhibited extended bleeding times after 2 to 4 weeks on test. No unusual hemorrhaging occurred at parturition. In general, the lambs’ blood did not reflect the pre- or post-partum dicoumarol intake of their mothers but a few lambs, as in the case of the ewes, exhibited low tolerance for dicoumarol without showing much disturbance in terms of clotting time. A large single oral dose of menadione sodium bisulphite demonstrated the effectiveness of vitamin K3 as an antidote. However, vitamin K3 as a ration supplement at 12 milligrams per pound feed failed to protect ewes against the effects of dicoumarol.

Kinetic Aspects of the Interaction of Blood-Clotting Enzymes

1968 ◽  
Vol 20 (01/02) ◽  
pp. 078-087 ◽  
Author(s):  
H. C Hemker ◽  
A. D Muller
Keyword(s):  
Vitamin K ◽  
Blood Clotting ◽  
Experimental Results ◽  
Factor X ◽  
Clotting Factors ◽  
Vitamin K Deficiency ◽  
K Deficiency

SummaryPIVKA, the circulating anticoagulant protein found in vitamin K deficiency can, on kinetical grounds, be recognized as an analogue of factor X. The existence of analogues of other vitamin K-dependent clotting factors cannot be ruled out, but need not be assumed to explain the experimental results.

scholarly journals Reduction of salivary tissue factor (thromboplastin) activity by warfarin therapy

Blood ◽  
1979 ◽  
Vol 53 (3) ◽  
pp. 366-374 ◽  
Author(s):  
LR Zacharski ◽  
R Rosenstein
Keyword(s):  
Tissue Factor ◽  
Vitamin K ◽  
Coagulation Factors ◽  
Human Saliva ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Total Protein Content ◽  
Factor X ◽  
Clotting Factors

Abstract The coagulant of normal human saliva has been identified as tissue factor (thromboplastin, TF) by virtue of its ability to cause rapid coagulation in plasmas deficient in first-stage coagulation factors and to activate factor x in the presence of factor VII and by virtue of the fact that its activity is expressed only in the presence of factor VII and is inhibited by an antibody to TF. The TF is related to cells and cell fragments in saliva. Salivary TF activity has been found to be significantly reduced in patients taking warfarin. The decline in TF activity during induction of warfarin anticoagulation occurs during the warfarin-induced decline in vitamin-K-dependent clotting factor activity, as judged by the prothrombin time. The decrease in TF activity is not related to a reduction in salivary cell count or total protein content or to a direct effect of warfarin on the assay. It is hypothesized that the mechanism by which warfarin inhibits TF activity may be related to the mechanism by which it inhibits expression of the activity of the vitamin-K-dependent clotting factors. Inhibition of the TF activity may be involved in the antithrombotic effect of warfarin.

Clinical Implications of Crosstalk Between Coagulation and Inflammation: The Role of Anticoagulation in Treating Sepsis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2874-2874
Author(s):  
Zhi Xu ◽  
Elizabeth Phillips ◽  
Prasanta Basak ◽  
Stephen Jesmajian
Keyword(s):  
Vitamin K ◽  
Inflammatory Responses ◽  
Conflicts Of Interest ◽  
Vitamin K Antagonist ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Clinical Implications ◽  
Factor X ◽  
All Cause Mortality

Abstract BACKGROUND: Despite decades of active investigation, sepsis remains one of the leading causes of mortality worldwide. Multiple lines of evidence have illustrated that up-regulation of the activated Factor VII (FVIIa)/Tissue Factor (TF) complex, and its downstream extrinsic coagulation cascade, are major contributors to coagulopathies and inflammatory response during sepsis. For example, decreased mortality and inflammatory responses during sepsis were observed in mice with significantly reduced FVII expression. Another recent study demonstrated the association of increased mortality with higher levels of FVIIa in septic patients. Similar results have been demonstrated for Factor X (FX) and thrombin. In addition, several studies have been conducted to investigate the role of heparin in treating sepsis and have yielded promising results, however, the exact mechanisms remain elusive, and the clinical implications of crosstalk between coagulation pathways and sepsis are yet to be determined. Furthermore, the role of vitamin-K antagonist in sepsis has not been investigated. OBJECTIVE: To assess the effects of pre-existing anticoagulation with warfarin on the clinical course of septic patient. METHODS: This was a retrospective observational study undertaken in a community-based teaching hospital. Patients who were admitted with a primary diagnosis of sepsis from January 01 to June 30, 2012 were included in the study. The clinical characteristics between patient groups without and with prior anticoagulation were compared and analyzed. The primary outcomes include the severity of sepsis, length of hospitalization, and mortality rate during hospitalization. RESULTS: A total of 134 septic patients were included in the study. Among them, 105 patients were not anticoagulated, while 29 patients were anticoagulated, prior to admission (mean age: 76.0 + 1.2 vs. 77.5 + 2.6, p = 0.603). All of the patients with anticoagulation had been taking warfarin due to either pre-existing atrial fibrillation (79.3%) or deep vein thrombosis/pulmonary embolism (20.7%). There were significant differences in International Normalized Ratio (INR) of prothrombin time between groups without and with anticoagulation at the time of admission (1.28 + 0.04 vs. 4.59 + 0.83, p < 0.001). Septic patients who did not take warfarin prior to admission presented with higher Sepsis Indices (0.93 + 0.03 vs. 0.82 + 0.05, p < 0.05), resulting in longer hospitalizations (11.60 + 1.02 vs. 8.40 + 0.70, p < 0.001). The overall all-cause mortality rates during the hospitalization between patients without anticoagulation and those with anticoagulation were 23% vs. 14%, respectively. CONCLUSION: To our knowledge, this is the first study to demonstrate that septic patients with prior anticoagulation by a vitamin-K antagonist presented with less severity of sepsis, reduced length of hospital stay, and decreased all-cause mortality during hospitalization as compared with those without anticoagulation. In our study, prior administration of anticoagulation with warfarin may have had significant clinical implications in septic patients. This warrants further prospective studies. Disclosures No relevant conflicts of interest to declare.

The Inhibitor of Prothrombin Conversion in Plasma of Patients on Oral Anticoagulant Treatment

1981 ◽  
Vol 45 (03) ◽  
pp. 237-241 ◽  
Author(s):  
R M Bertina ◽  
M E J Westhoek-Kuipers ◽  
G H J Alderkamp
Keyword(s):  
Vitamin K ◽  
Spectrophotometric Assay ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
Dilution Curve ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Coagulation Assays ◽  
Factor Ii

SummaryPooled plasma of patients under stable oral anticoagulation has been analysed with respect to the presence of the vitamin-K dependent factors (factors II, VII, IX and X). Of all factors 1.5-2 times more antigen than procoagulant activity was present. The concentration of factors II, X (measured spectrophotometrically) and VII is about 0.25 U/ml while factor IX is slightly higher. Coagulation assays of factor X always gave lower values than the spectrophotometric assay. This discrepancy was not influenced by the removal of either factor II-factor VII- or factor IX antigen. However, when the factor X antigen was replaced by normal factor X, all factor X assays gave identical results, indicating that PIVKA X is responsible for these discrepancies. Using the technic of the Thrombotest-dilution curve it was shown that PIVKA X is the factor that causes the abnormal prolongation of ox-brain prothrombin time in these plasmas.

ACUTE INTERRUPTION OF ORAL ANTICOAGULANT THERAPY: A THROMBOTIC RISK?

1987 ◽  
Author(s):  
J Rouvier ◽  
H Vidal ◽  
J Gallino ◽  
M Boccia ◽  
A Scazziota ◽  
...  
Keyword(s):  
Anticoagulant Therapy ◽  
Vitamin K ◽  
Oral Anticoagulant ◽  
Protein C ◽  
Oral Anticoagulant Therapy ◽  
Factor Vii ◽  
Factor X ◽  
Functional Protein ◽  
Thrombotic Risk ◽  
Factor Ii

It is still on discussion how oral anticoagulant therapy must be interrupted. A progressive diminution of drug intake have been proposed in order to avoid a MreboundM of vitamin K-dependent procoagulant factors. At the present, it is well known that coumarin drugs affect not only the biologic activity of factors II, VII, IX and X but also Protein C (PC), an inhibitor of coagulation kinetics, and their cofactor Protein S. With the aim to determine the recovery level of PC in relation with the others vitamin K-dependent factors, the effect of suppression of anticoagulant therapy in patients under chronic treatment with acenocoumarin was studied.Quick time, functional factors II, VII, X (one stage methods), functional PC (Francis method) and immunological Factor II and Protein C (Laurell) were determined before and 36 hours after suspension of acenocoumarin administration.Results showed that: 1) Recovery levels of functional Protein C (increased from 28.55% ±2.57 to 72.64% ±5.9) were significantly higer than functional Factor II (22.09% ±2.34 to 30.73% ±8.64), Factor VII (22.55% ±2.01 to 40.73% ±4.85) and Factor X (23.27% ±2.66 to 39.18% ±3.19). Statistical analysis (Newmann-Keuls test) showed at least a p<0.01 between PC increase and factors II, VII or X increment.2) No significant differences were seen between immunological levels of Factor II before and after suspension of acenocoumarin.3) Levels of immunological PC in patients under anticoagulant therapy were higer than functional PC. After acenocoumarin suppression, not correlation was seen between immunological and functional Protein C recovery.It is concluded that acute suppression of acenocoumarin does not induce a thrombotic tendency because the recuperation of functional Protein C is more important than factors II, VII and X recovery.

scholarly journals Surface-dependent reactions of the vitamin K-dependent enzyme complexes

Blood ◽  
1990 ◽  
Vol 76 (1) ◽  
pp. 1-16 ◽  
Author(s):  
KG Mann ◽  
ME Nesheim ◽  
WR Church ◽  
P Haley ◽  
S Krishnaswamy
Keyword(s):  
Tissue Factor ◽  
Vitamin K ◽  
Blood Clotting ◽  
Catalytic Efficiency ◽  
Coagulation Cascade ◽  
Factor Xii ◽  
Factor X ◽  
Membrane Bound ◽  
Factor X Activation ◽  
Enzyme Complexes

Abstract During the past 20 years contributions from many laboratories have led to the development of isolation procedures, delineation of primary structures, and more recently, to the expression of recombinant proteins associated with the coagulation cascade. In general, studies of coagulation proteins under defined conditions have demonstrated the prescience of Davie and Ratnoff and MacFarlane in their proposals of the coagulation cascade. The more recent discovery of thrombomodulin by Esmon et al has led to the identification and characterization of components of the vitamin K-dependent anticoagulant pathway. In this review we have attempted to analyze and compare the functional properties of each of the vitamin K-dependent enzyme complexes associated with the procoagulant and anticoagulant phases of blood clotting. Although dissimilarities exist, the vitamin K-dependent complexes have analogous requirements and appear to function with a common general mode of organization. Membrane-bound cofactors serve as anchoring sites for the appropriate membrane-binding enzymes. This process localizes the complex on the membrane surface and increases the catalytic efficiency for substrate utilization. Complex formation provides extraordinary improvements in the catalytic efficiency for the complexes as compared with their soluble enzyme components. Membrane- bound complexes provide a mechanism that can be regulated at a site by membrane presentation, zymogen activation, and cofactor activation or presentation. The kinetic constants obtained for the various coagulation reactions determined in vitro provide some insights into how these pathways may function in vivo. The catalytic efficiency (kcat/Km) for factor X activation by factor VIIIa/factor IXa is far in excess of the catalytic efficiency of activation of factor X by tissue factor/factor VIIa (Table 3). This may provide a rational interpretation for the observation that patients with hemophilia A and B bleed even though they appear to have an alternative pathway to factor X activation. In addition, tissue factor is not ordinarily presented by the vascular tissue that has direct access to blood. However, it appears that extravascular constitutive tissue factor is available once the blood vessel becomes disrupted. The efforts to identify the initiating reactions of the blood coagulation process have not been unambiguously successful. We conclude that factor VII is most likely a zymogen, just as are the other proenzymes of the blood clotting process. In addition, it is difficult to rationalize the importance of the intrinsic pathway of coagulation involving factor XII, prekallikrein, and high molecular weight kininogen since the congenital absence of any one of these factors does not result in abnormal bleeding.

scholarly journals Reduction of salivary tissue factor (thromboplastin) activity by warfarin therapy

Blood ◽  
1979 ◽  
Vol 53 (3) ◽  
pp. 366-374 ◽  
Author(s):  
LR Zacharski ◽  
R Rosenstein
Keyword(s):  
Tissue Factor ◽  
Vitamin K ◽  
Coagulation Factors ◽  
Human Saliva ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Total Protein Content ◽  
Factor X ◽  
Clotting Factors

The coagulant of normal human saliva has been identified as tissue factor (thromboplastin, TF) by virtue of its ability to cause rapid coagulation in plasmas deficient in first-stage coagulation factors and to activate factor x in the presence of factor VII and by virtue of the fact that its activity is expressed only in the presence of factor VII and is inhibited by an antibody to TF. The TF is related to cells and cell fragments in saliva. Salivary TF activity has been found to be significantly reduced in patients taking warfarin. The decline in TF activity during induction of warfarin anticoagulation occurs during the warfarin-induced decline in vitamin-K-dependent clotting factor activity, as judged by the prothrombin time. The decrease in TF activity is not related to a reduction in salivary cell count or total protein content or to a direct effect of warfarin on the assay. It is hypothesized that the mechanism by which warfarin inhibits TF activity may be related to the mechanism by which it inhibits expression of the activity of the vitamin-K-dependent clotting factors. Inhibition of the TF activity may be involved in the antithrombotic effect of warfarin.

Effect of physical exercise on blood clotting and fibrinolysis

1963 ◽  
Vol 18 (2) ◽  
pp. 337-344 ◽  
Author(s):  
Sotirios G. Iatridis ◽  
John H. Ferguson
Keyword(s):  
Blood Clotting ◽  
Normal Subjects ◽  
Factor Vii ◽  
Strenuous Exercise ◽  
Factor Xii ◽  
Factor V ◽  
Factor X ◽  
Plasma Factor ◽  
Deficient Subject ◽  
Direct Activator

The effect of strenuous exercise on the clotting and fibrinolytic systems was studied on 1 Hageman-deficient and 59 normal subjects (males aged 18–37 years). In the normal subjects there was a significant shortening of the whole-blood clotting time and of the partial thromboplastin time both in glass and in siliconized tubes. Plasma factor VIII (AHF or AHG) assays rose to 188% (average), but the specificity of the test is questioned. Factor XII (HF) increased to 318% (average) unequivocally. A postexercise increased heparin tolerance was also noted. There was no significant increase in the levels of fibrinogen, prothrombin, factor V (AcG), or factor VII (proconvertin) and factor X (Stuart). Fibrinolytic activity as measured by the euglobulin lysis and plasma plate methods increased significantly in most of the normal subjects. The data suggest that the fibrinolytic factor which increases after exercise is not active plasmin, but is related to the “activator” mechanisms. A plasma lysokinase (indirect activator) seems to preponderate in over half the cases. In 20% of cases a plasminoplastin (direct activator) may be involved. In the Hageman-deficient subject there was no improvement in clotting, and the slight changes in some of the fibrinolysis tests were nonsignificant. Submitted on October 16, 1962 Submitted on October 16, 1962

Protein Z, a protein seeking a pathology

2008 ◽  
Vol 100 (10) ◽  
pp. 548-556 ◽  
Author(s):  
Marc Vasse
Keyword(s):  
Risk Factor ◽  
Vitamin K ◽  
Factor V Leiden ◽  
Factor Vii ◽  
Factor V ◽  
Factor X ◽  
Protein Z ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
G20210a Mutation

SummaryProtein Z (PZ) is a vitamin K-dependent factor identified in human plasma in 1984 characterized by an homology with other vitamin K-dependent factors (factor VII, IX, X, protein C). In contrast to these factors, PZ does not possess any enzymatic activity but is involved as a cofactor in the down-regulation of coagulation by forming a complex with the protein Z-dependent protease inhibitor (ZPI). ZPI inhibits the activated factor X (FXa) on phospholipid surface. In mice, the disruption of PZ gene is asymptomatic, but the association with the factor V Leiden mutation leads to a quasi complete mortality during the neonatal period with microvascular thrombosis. In humans, PZ is characterized by an unusual wide distribution in plasma, and a major decrease induced by warfarin. Isolated PZ deficiency does not seem to constitute a risk for venous thrombosis, but a severe PZ deficiency could increase the risk of well recognized venous thrombotic risk factors such as factor V Leiden, G20210A mutation or hyperhomocysteinemia. Unexpectedly, a relationship between PZ deficiency and ischemic arterial diseases such as stroke, acute coronary syndromes or peripheral arterial disease was described but not confirmed by all studies. PZ deficiency could be also a risk factor for early fetal losses, and increases the arterial risk in antiphospholipid syndrome. This review analyzes the different studies so far published and discusses the various results obtained in order to understand whether or not protein Z deficiency could be considered as an arterial ischemic risk factor.

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