Increased Activity of Vitamin K-Dependent Clotting Factors in Human Hyperlipoproteinaemia – Association with Cholesterol and Triglyceride Levels

1977 ◽  
Vol 38 (02) ◽  
pp. 0465-0474 ◽  
Author(s):  
M Constantino ◽  
C Merskey ◽  
D. J Kudzma ◽  
M. B Zucker
Keyword(s):  
Vitamin K ◽  
Plasma Lipids ◽  
Coagulation Factors ◽  
Clotting Factor ◽  
Factor X ◽  
Clotting Factors ◽  
Blood Coagulation Factors ◽  
Cholesterol Levels ◽  
Type V ◽  
Increased Activity

SummaryLevels of blood coagulation factors, cholesterol and triglyceride were measured in human plasma. Prothrombin was significantly elevated in type Ha hyperlipidaemia; prothrombin and factors VII, IX and X in type lib; and prothrombin and factors VII and IX in type V. Multiple regression analysis showed significant correlation between the levels of these plasma lipids and the vitamin K-dependent clotting factors (prothrombin, factors VII, IX and X). Higher cholesterol levels were associated with higher levels of prothrombin and factor X while higher triglyceride levels were associated with higher levels of these as well as factors VII and IX. Prothrombin showed a significant cholesterol-triglyceride interaction in that higher cholesterol levels were associated with higher prothrombin levels at all levels of triglyceride, with the most marked effects in subjects with higher triglyceride levels. Higher prothrombin levels were noted in subjects with high or moderately elevated (but not low) cholesterol levels. Ultracentrifugation of plasma in a density of 1.21 showed activity for prothrombin and factors VII and X only in the lipoprotein-free subnatant fraction. Thus, a true increase in clotting factor protein was probably present. The significance of the correlation between levels of vitamin K-dependent clotting factors and plasma lipids remains to be determined.

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.

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.

Reversible Factor VIII-Abnormalities in Reye’s Syndrome

1979 ◽  
Author(s):  
J. H. Joist ◽  
J. Vargo ◽  
M. W. Haymond ◽  
J. P. Keating ◽  
D. C. DeVivo
Keyword(s):  
Factor Viii ◽  
Coagulation Factors ◽  
Clotting Factor ◽  
Metabolic Disturbances ◽  
Clotting Factors ◽  
Reye's Syndrome ◽  
Blood Coagulation Factors ◽  
Qualitative And Quantitative ◽  
Quantitative Studies ◽  
Slow Moving

Reye’s syndrome, an acute and frequently fatal viral infection with severe metabolic disturbances is frequently associated with marked hemostatic alterations. Hypopro-thrombinemia and deficiencies of other clotting factor activities as well as findings suggestive of disseminated intravascular coagulation have been reported. This report deals with detailed sequential qualitative and quantitative studies of blood coagulation factors in four children with this disorder. Depression of factors IX, X, VII, V and II and marked disproportionate elevation of VIIIAHF, VIIIAGN and VIIIvWF associated with a loss of the slow moving component of VIIIAGU on crossed immunoelectro phoresis were consistently observed during the initial phase of the illness. in three of the four children who survived, the changes were fully reversible. Since laboratory evidence for DIC was lacking (normal fibrinogen, consistently negative protamine sulfate precipitation test) the findings seem to indicate that Reye’s syndrome is associated with an acute, transient stimulation of synthesis of normal and abnormal factor VIII as well as decreased synthesis or synthesis of functionally abnormal clotting factors by the liver.

Properties of Recombinant Human Thromboplastin that Determine Sensitivity to Vitamin K-Dependent Coagulation Factors.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 533-533
Author(s):  
Stephanie A. Smith ◽  
James H. Morrissey
Keyword(s):  
Ionic Strength ◽  
Vitamin K ◽  
Phospholipid Composition ◽  
Coagulation Factors ◽  
Factor Vii ◽  
Clotting Factor ◽  
Sensitivity Index ◽  
Clotting Factors ◽  
Individual Factor ◽  
Factor Deficiency

Abstract Patients undergoing oral anticoagulant therapy (OAT) with coumarins have reduced plasma levels of vitamin K-dependent clotting factors. The primary laboratory test for monitoring OAT is the prothrombin time (PT), in which clotting is initiated by tissue factor (TF). Clotting factors that contribute to the PT, and whose levels respond to OAT, are factor VII (FVII), factor X (FX), and prothrombin, although they are not suppressed to the same extent. Thromboplastin reagents (the source of TF activity in PT tests) can vary dramatically in their sensitivities to the effects of OAT. A calibration system, the International Sensitivity Index (ISI), is widely used to correct the PT for variable thromboplastin sensitivity, but discrepant responses by reagents of similar ISI have been reported. We have undertaken studies aimed at understanding which factors control the sensitivity of thromboplastin reagents, with a goal of creating “designer thromboplastins” whose sensitivities to specific clotting factors can be individually tailored. Thromboplastin reagents were prepared by reconstituting recombinant human TF into phospholipid vesicles containing varying amounts of phosphatidylcholine, phosphatidylserine (PS), and phosphatidylethanolamine (PE). Thromboplastins containing low levels of PS and high ionic strength had the highest sensitivity to OAT (i.e., lowest ISI). PE shifted the dose-response such that lower levels of PS were required to obtain the same ISI value. These studies demonstrate that multiple combinations of phospholipid composition and ionic strength can be used to produce reagents of identical ISI. We hypothesized that reagents of identical ISI values but different composition could have very different responses to changes in the levels of individual coagulation factors. Accordingly, thromboplastin reagents of varying composition were evaluated for their responses to deficiencies of FVII, FX and prothrombin. PT tests were performed using pooled normal plasma mixed with individual factor-depleted plasmas to yield 10%, 3%, 1% or 0.3% of the normal level of the specific clotting factor. Responses of thromboplastin reagents to individual factors were compared by plotting the clotting times obtained with these plasmas on log-log scales versus the percent factor level and fitting lines to the data by linear regression. Interestingly, altering the composition of the thromboplastin reagents dramatically and independently altered their sensitivities to individual clotting factors. For example, increasing ionic strength had no impact on the response to FVII, but markedly enhanced the response to prothrombin deficiency. Furthermore, the effect of changes in ionic strength on specific factors levels differed depending upon the phospholipid composition. These studies demonstrate that thromboplastin reagents of dissimilar composition but nearly identical ISI values can have very different sensitivities to deficiencies in FVII, FX, or prothrombin, so reagents of identical ISI do not necessarily respond to the factor deficiencies induced by OAT in an identical fashion. These studies evaluated samples with isolated individual factor deficiency, whereas patients on OAT have combined factor deficiency and therefore have more potential for discrepancy in PT responses between reagents. Controlling the responsiveness of thromboplastin reagents to deficiencies in individual clotting factors may therefore be desirable for monitoring OAT and for the other clinical diagnostic uses to which PT tests are commonly applied.

VKCFD2 – from clinical phenotype to molecular mechanism

2016 ◽  
Vol 36 (S 02) ◽  
pp. S13-S20 ◽  
Author(s):  
K. J. Czogalla ◽  
M. Watzka ◽  
J. Oldenburg
Keyword(s):  
Vitamin K ◽  
Physiological Activity ◽  
Coagulation Factors ◽  
Clotting Factor ◽  
Clotting Factors ◽  
Vitamin K Cycle ◽  
Factor Deficiency ◽  
Er Retention ◽  
Deficiency Type ◽  
Diagnosis Therapy

SummaryVitamin K 2,3-epoxide reductase complex, subunit 1 (VKORC1) is an enzyme essential for the vitamin K cycle. VKORC1 catalyses the reduction of vitamin K 2,3-epoxide to the quinone form of vitamin K and further to vitamin K hydroquinone. The generated vitamin K hydroquinone serves as substrate for the enzyme γ-glutamyl-carboxylase which modifies all vitamin K-dependent proteins, allowing them to bind calcium ions necessary for physiological activity. Vitamin K-dependent proteins include the coagulation factors FII, FVII, FIX, FX, and proteins C, S und Z. Insufficient VKORC1 enzyme activity results in deficiency of the vitamin K-dependent clotting factors leading to haemorrhagic disorders. This phenotype is known as vitamin K clotting factor deficiency type 2 (VKCFD2). Worldwide, only four families of independent origin have been reported with this rare bleeding disorder. Affected family members carry the mutation VKORC1:p.Arg98Trp in homozygous form, the only mutation found so far to be associated with VKCFD2. Now, ten years after the identification of the VKORC1 gene, the molecular pathomechanism of VKCFD2 has been clarified. The Arg98Trp mutation disrupts an ER retention motif of VKORC1 leading to mislocalisation of the protein to outside the endoplasmatic reticulum. In this review, we summarize the clinical data, diagnosis, therapy and molecular patho -mechanism of VKCFD2.

scholarly journals Intracellular maturation of the γ-carboxyglutamic acid (Gla) region in prothrombin coincides with release of the propeptide

1993 ◽  
Vol 291 (3) ◽  
pp. 723-727 ◽  
Author(s):  
R Wallin ◽  
C Stanton ◽  
S M Hutson
Keyword(s):  
Conformational Change ◽  
Vitamin K ◽  
Secretory Pathway ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Coagulation System ◽  
Clotting Factor ◽  
Clotting Factors ◽  
Post Translational Modifications ◽  
Carboxyglutamic Acid

Vitamin K-dependent coagulation factors undergo several post-translational modifications before the proteins are secreted into the blood as functional zymogens of the coagulation system. The modifications include Asn-linked glycosylation, Asn/Asp hydroxylation, removal of a signal peptide for translocation of the polypeptide into the endoplasmic reticulum and removal of a propeptide which, when attached to the intracellular coagulation factor precursor, directs the protein for vitamin K-dependent gamma-carboxylation. gamma-Carboxylation of targeted Glu residues results in formation of Ca(2+)-binding gamma-carboxyglutamic acid (Gla) residues. Ca2+ binding by these residues induces a conformational change in the protein which is a necessary event for optimal activation or activity of the clotting factor in blood. In the present study we have monitored the intracellular prothrombin precursor in the secretory pathway of liver cells to determine the effect that the propeptide has on Ca(2+)-dependent folding of the protein. The data provide evidence that the Ca(2+)-induced conformational change required for activation of prothrombin coincides with release of the propeptide in the trans-Golgi apparatus of the liver cell and elucidates an important function for the endoproteinase furin in biosynthesis of vitamin K-dependent clotting factors.

Reversible Factor VIII-Abnormalities in Reye’s Syndrome.

1979 ◽  
Author(s):  
J. H. Joist ◽  
J. Vargo ◽  
M. W. Haymond ◽  
J. P. Keating ◽  
D. C. DeVivo
Keyword(s):  
Factor Viii ◽  
Coagulation Factors ◽  
Clotting Factor ◽  
Metabolic Disturbances ◽  
Clotting Factors ◽  
Reye's Syndrome ◽  
Blood Coagulation Factors ◽  
Quantitative Studies ◽  
Crossed Immunoelectrophoresis ◽  
Slow Moving

Reye’s syndrome, an acute and frequently fatal viral infection with severe metabolic disturbances is frequently associated with marked hemostatic alterations. Hypoprothrombinemia and deficiencies of other clotting factor activities as well as findings suggestive of disseminated intravascular coagulation have been reported. This report deals with detailed sequential qualitative and quantitative studies of blood coagulation factors in four children with this disorder. Depression of factors IX, X, VII, V and II and marked disproportionate elevation of VIIIAHF, VIIIAGN VIIIVWF associated with a loss of the slow moving component of VIIIAGN on crossed Immunoelectrophoresis were consistently observed during the initial phase of the illness. In three of the four children who survived, the changes were fully reversible. Since laboratory evidence for DIC was lacking (normal fibrinogen, consistently negative protamine sulfate precipitation test) the findings seem to indicate that Reye's syndrome is associated with an acute, transient stimulation of synthesis of normal and abnormal factor VIII as well as decreased synthesis or synthesis of functionally abnormal clotting factors by the liver.

scholarly journals Hyperlipidemia, hypercoagulability, and accelerated thrombosis: studies in congenitally hyperlipidemic rats and in rats and monkeys with induced hyperlipidemia

Blood ◽  
1976 ◽  
Vol 47 (2) ◽  
pp. 275-286 ◽  
Author(s):  
WM Kim ◽  
C Merskey ◽  
QB Deming ◽  
HN Adel ◽  
H Wolinsky ◽  
...  
Keyword(s):  
Serum Cholesterol ◽  
Plasma Lipids ◽  
Blood Platelets ◽  
Elevated Serum ◽  
Coagulation Factors ◽  
Normal Diet ◽  
Factor Vii ◽  
Factor X ◽  
Cholesterol Levels ◽  
Elevated Serum Cholesterol

Abstract Inbred Carworth Farms Nelson (CFN) congenitally hyperlipidemic rats had significantly shorter coagulation and prothrombin times and higher levels of coagulation factors, II, V, VII, VIII, and X than did controls. Conversely, congenitally hypolipidemic rats of the same strain had significantly longer coagulation and prothrombin times and lower levels of factors II, V, VII, X and XII and of blood platelets than did controls. A loop-shaped polyethylene cannula was inserted into the aorta to assess the potential for thrombosis. The hyperlipidemic group obstructed this significantly faster and the hypolipidemic group slower than did the controls. Normal CFN rats made hypertensive by unilateral renal artery clip developed hypertension together with significantly elevated serum cholesterol and factor VII and X levels. Rhesus monkeys with diet-induced hyperlipidemia showed shorter prothrombin times and higher factor X levels than did controls on normal diet. By selective breeding, two groups of squirrel monkeys were obtained. Both groups had similar serum cholesterol levels on a normal diet but one group (hyperresponders) showed higher serum cholesterol levels on a cholesterol-containing diet than did the other (hyporesponder) group. Both groups showed significantly elevated levels of factors II, V, VII, IX and X on a cholesterol-containing diet. There was good correlation between the levels of many coagulation factors and serum cholesterol in both rats and monkeys. If thrombosis is important in the genesis of atherosclerosis, these findings could indicate that elevation of plasma lipids may play a role, via the coagulation pathway, in the production of human vascular disease.

scholarly journals Hyperlipidemia, hypercoagulability, and accelerated thrombosis: studies in congenitally hyperlipidemic rats and in rats and monkeys with induced hyperlipidemia

Blood ◽  
1976 ◽  
Vol 47 (2) ◽  
pp. 275-286
Author(s):  
WM Kim ◽  
C Merskey ◽  
QB Deming ◽  
HN Adel ◽  
H Wolinsky ◽  
...  
Keyword(s):  
Serum Cholesterol ◽  
Plasma Lipids ◽  
Blood Platelets ◽  
Elevated Serum ◽  
Coagulation Factors ◽  
Normal Diet ◽  
Factor Vii ◽  
Factor X ◽  
Cholesterol Levels ◽  
Elevated Serum Cholesterol

Inbred Carworth Farms Nelson (CFN) congenitally hyperlipidemic rats had significantly shorter coagulation and prothrombin times and higher levels of coagulation factors, II, V, VII, VIII, and X than did controls. Conversely, congenitally hypolipidemic rats of the same strain had significantly longer coagulation and prothrombin times and lower levels of factors II, V, VII, X and XII and of blood platelets than did controls. A loop-shaped polyethylene cannula was inserted into the aorta to assess the potential for thrombosis. The hyperlipidemic group obstructed this significantly faster and the hypolipidemic group slower than did the controls. Normal CFN rats made hypertensive by unilateral renal artery clip developed hypertension together with significantly elevated serum cholesterol and factor VII and X levels. Rhesus monkeys with diet-induced hyperlipidemia showed shorter prothrombin times and higher factor X levels than did controls on normal diet. By selective breeding, two groups of squirrel monkeys were obtained. Both groups had similar serum cholesterol levels on a normal diet but one group (hyperresponders) showed higher serum cholesterol levels on a cholesterol-containing diet than did the other (hyporesponder) group. Both groups showed significantly elevated levels of factors II, V, VII, IX and X on a cholesterol-containing diet. There was good correlation between the levels of many coagulation factors and serum cholesterol in both rats and monkeys. If thrombosis is important in the genesis of atherosclerosis, these findings could indicate that elevation of plasma lipids may play a role, via the coagulation pathway, in the production of human vascular disease.

Oral anticoagulation reduces activated protein C less than protein C and other vitamin K–dependent clotting factors

Blood ◽  
2002 ◽  
Vol 100 (12) ◽  
pp. 4232-4233 ◽  
Author(s):  
Marleen J. A. Simmelink ◽  
Philip G. de Groot ◽  
Ronald H. W. M. Derksen ◽  
José A. Fernández ◽  
John H. Griffin
Keyword(s):  
Anticoagulant Therapy ◽  
Vitamin K ◽  
Oral Anticoagulant ◽  
Protein C ◽  
Anticoagulant Activity ◽  
Oral Anticoagulant Therapy ◽  
Activated Protein C ◽  
Clotting Factor ◽  
Factor X ◽  
Clotting Factors

Oral anticoagulant therapy, which is used for prophylaxis and management of thrombotic disorders, causes similar reductions in plasma levels of vitamin K–dependent procoagulant and anticoagulant clotting factor zymogens. When we measured levels of circulating activated protein C, a physiologically important anticoagulant and anti-inflammatory agent, in patients on oral anticoagulant therapy, the results unexpectedly showed that such therapy decreases levels of activated protein C substantially less than levels of protein C, prothrombin, and factor X, especially at lower levels of prothrombin and factor X. Thus, we suggest that oral anticoagulant therapy results in a relatively increased expression of the protein C pathway compared with procoagulant pathways not only because there is less prothrombin to inhibit activated protein C anticoagulant activity, but also because there is a disproportionately higher level of circulating activated protein C.

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