scholarly journals Differential Impact of Dietary Vitamin K (phylloquinone) on Coagulation Factor Activities and Clotting Times in Warfarin-Treated Rats

2021 ◽  
Vol 5 (Supplement_2) ◽  
pp. 1310-1310
Author(s):  
Guylaine Ferland ◽  
Cylia Djennadi ◽  
Bouchra Ouliass
Keyword(s):  
Vitamin K ◽  
Clinical Laboratory ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Diet Group ◽  
Dietary Vitamin ◽  
Plain Water ◽  
Coagulation Activity ◽  
Warfarin Treatment ◽  
The Impact

Abstract Objectives Investigate the impact of variable vitamin K (VK) intakes on the coagulation activities of four VK-dependent factors and clotting times, in warfarin-treated rats. Methods Male Wistar rats were randomly allocated to a AIN-93 based diet containing low (L: 80 mcg/kg/d), adequate (A: 750 mcg/kg/d) or enriched (E: 2000 mcg/kg/d) phylloquinone (K1) containing diet (n = 24/diet group). After one week, half the animals from each diet group were randomly allocated to receive 0.2 mg warfarin/kg/d through drinking water (W gp) or plain water (C gp), for 10 weeks. Coagulation activity (%) was assessed for factors II, VII, IX and X, and clotting times were based on prothrombin [PT (sec)] and activated thromboplastin times [APTT (sec)]. Measures were obtained at the end of the study and were conducted in the hospital clinical laboratory using standard procedures. Diet effects within C and W groups were investigated using one-way ANOVA and uncorrected Fisher post-hoc tests. Results Warfarin treatment resulted in significantly higher clotting times (PT and APTT) in all diet groups when compared to corresponding C groups (p < 0.05), the highest increase being observed in the L, followed by A and E groups, each diet being statistically different from each other (p < 0.01). Warfarin treatment also resulted in statistically significant decreases in activities of all coagulation factors although the impact of the diets varied according to factors: FVII and FX, between L and E groups only; FIX, between L and A, and L and E groups; FII, between all diet groups; (p < 0.05 in all cases). Conclusions Results from this study confirm the impact of dietary VK on coagulation factor activities and resulting clotting times, and suggest that for a given dose of W, this impact will depend on VK intake levels. Currently, individuals undergoing warfarin treatment are advised to aim for stable daily VK intakes. Results from this study provide data supporting this recommendation. Funding Sources This study was funded by CIHR and MHI Foundation.

International Normalized Ratio Versus Plasma Levels of Coagulation Factors in Patients on Vitamin K Antagonist Therapy

2011 ◽  
Vol 135 (4) ◽  
pp. 490-494 ◽  
Author(s):  
Gene Gulati ◽  
Megan Hevelow ◽  
Melissa George ◽  
Eric Behling ◽  
Jamie Siegel
Keyword(s):  
Vitamin K ◽  
Warfarin Therapy ◽  
Clinical Laboratory ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
International Normalized Ratio ◽  
Activity Levels ◽  
Factor X ◽  
Life Threatening ◽  
Average Factor

Abstract Context.—The key question when managing patients on warfarin therapy who present with life-threatening bleeding is how to use the international normalized ratio (INR) to best direct corrective therapy. The corollary question for the clinical laboratory is at what level will the INR reflect a critical value that requires notifying the clinician. Objective.—To determine the levels of vitamin K–dependent factors over a range of INR values. Design.—Evaluation of the vitamin K–dependent coagulation factor levels on plasma remnants from patients in whom a prothrombin time and INR was ordered to monitor warfarin therapy. There were a total of 83 specimens evaluated with an INR range from 1.0 to 8.26. Results.—The mean activity levels of all 4 factors remained near or above 50% when the INR was less than 1.5. The average factor X level was 23% when the INR range was 1.6 to 2.5, but levels of factors II, VII, and IX did not drop below the hemostatic range until the INR was greater than 2.5. At an INR of 3.6 or more, the activity levels of all 4 factors were less than 30% in more than 90% of the specimens. Conclusion.—Levels of factors II, VII, IX, and X declined with increasing INR but not at the same rate and not to the same level at a given INR. However, most of the values were below the hemostatic value once the INR was 3.6 or more, the level that was also considered critical for physician notification.

scholarly journals INR and Vitamin K Dependent Coagulation Factor Fluctuation during Warfarin Initiation and Stable Therapy in Patients Dosed with the Fiix-Prothrombin Time or the Quick Prothrombin Time. the Fiix Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4278-4278 ◽  
Author(s):  
Brynja R. Gudmundsdottir ◽  
Petur I. Jonsson ◽  
Pall T. Onundarson
Keyword(s):  
Prothrombin Time ◽  
Vitamin K ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Target Range ◽  
Startup Company ◽  
Warfarin Treatment ◽  
Monitoring Group ◽  
Equity Ownership ◽  
Patent Applications

Abstract Introduction: The Quick prothrombin time (PT) is equally sensitive to the influence of factors (F) II, VII and X but experiments suggest that it is mainly the influence of warfarin on factors (F) II and X that cause its anticoagulant effect. The new Fiix prothrombin time (Fiix-PT) differs from the PT in it being sensitive only to factors (F) II and X and not being sensitive at all to FVII activity in the test plasma. The Fiix-trial has demonstrated increased stability of warfarin anticoagulation and possibly improved efficacy when monitored with Fiix-PT compared to PT monitoring (unpublished data). However, as very low levels of vitamin K dependent (VKD) factors not measured with the Fiix-PT could possibly have deleterious effect on anticoagulation (AC) outcome, we measured the VKD coagulation factors in plasma obtained from patients on stable warfarin anticoagulation and during the first 30 days of warfarin treatment monitored either with the Fiix-PT or the PT. Methods: In order to define stable anticoagulation in terms of coagulation factor activity, samples from patients enrolled in the Fiix trial and monitored either with Fiix-PT or PT were used. Frozen samples from 20 patients were obtained from each monitoring group. All the samples had been drawn from patients during very stable warfarin treatment (INR within range 2-3 for over 10 months by serial monitoring). Serial samples were also obtained from 10 patients in each group during days 1-30 of warfarin initiation. PT, Fiix-PT and VKD coagulation factors were measured. An INR was calculated for both PT and Fiix-PT. Results: During stable AC, the median INR (range) was 2.5 (2.1-3.0) in the Fiix-group vs 2.4 (2.0-3.0) in the PT group (p=ns). The median (95% range) VKD factor percent coagulant activity was as follows in the stable Fiix-group vs the stable PT-group: FII 28 (19-40) vs 25 (18-40), FVII 48 (30-88) vs 42 (23-85), FIX 66 (41-85) vs 61 (36-79), and FX 15 (11-17) vs 15 (10-22). Although the medians tended to be higher in the Fiix group except for FX, p was n.s. for all. In patients starting on warfarin a stable Fiix-INR (defined as two INRs within target range) was reached on day 14 (median) in the Fiix group vs a stable PT-INR on day 11 in the PT controls. Following this, however, the PT-INR fluctuates more out of the INR target range than the Fiix-INR does. As shown in the figures, the earlier rise in INR in the PT group is mainly a reflection of a rapid fall in FVII activity. The FVII level decreases to a nadir of 20% in the Fiix group compared to a nadir of 30% in the PT monitoring group. Subsequently FII, FVII and FX fluctuate less in the Fiix-PT group than in the PT group. During the first 30 days 46% of Fiix-INRs in the Fiix-group were within target range vs 29% of INRs in the controls (p=0.06). Also during the initiation period FII was 47% vs. 30% within the 95% stable range established for the PT method (p=0.06), FVII 60% vs. 73% (p=0.13), FIX 41% vs 36% (p=0.69), and FX 51% vs 38% (p=0.20), respectively. The more fluctuating INR in the PT group is also reflected by a rollercoaster like pattern of warfarin dosing as opposed to the more cascade like pattern that is observed in the Fiix group. Figure 1 Figure 1. Figure 2 Figure 2. Conclusion: During stable warfarin AC VKD factors are similarly reduced with Fiix-PT or PT monitoring.During initiation of warfarin monitored with the Fiix-PT, FVII decreases initially more than with PT monitoring but subsequently stabilizes and fluctuates less. Fiix-PT leads to smoother reduction in FII and X which stabilize faster than during PT monitoring. The smoother anticoagulant effect is also reflected by the warfarin dose pattern during initiation. The results may suggest that the Quick-PT confounds warfarin management during initiation and dose changes. Disclosures Gudmundsdottir: Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties. Onundarson:Fiix Diagnostics Ltd: Equity Ownership, I am a co-inventor of the Fiix prothrombin time and have stocks in Fiix Diagnostics, a startup company with the two inventors of the test as majority shareholders. The company is responsible for patent applications in process. Patents & Royalties.

A Plasma Factor Enhances Activity of Vitamin K-Dependent Coagulation Proteins

1983 ◽  
Vol 50 (03) ◽  
pp. 749-752 ◽  
Author(s):  
Michael R Owens ◽  
Catherine D Cimino
Keyword(s):  
Rat Liver ◽  
Vitamin K ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Rat Plasma ◽  
Factor Vii ◽  
Coagulation Activity ◽  
Factor Ii ◽  
Plasma Factor ◽  
Coagulation Proteins

SummaryA plasma factor, “coagulopoietin”, present in animals with depleted vitamin K-dependent coagulation factors, appears to enhance activity of these factors in normal animals. We have investigated the effects of “coagulopoietin” on synthesis of certain coagulation proteins by the isolated rat liver perfused for eight hours. Liver donor rats received plasma injections from vitamin K-deficient rats or from normal rats 24 hr before sacrifice. Coagulation activity of Factor VII and Factor II in liver perfusate samples was measured with a coagulation assay; Factor II synthesis was also measured by rocket immunoelectrophoresis and by activation with E. carinatus venom. Cumulative hepatic synthesis of. Factor VII coagulation activity was increased by 43% when rat liver donors received vitamin K-deficient rat plasma compared to normal rat plasma. Cumulative synthesis of Factor II coagulation activity was increased by 51%, but synthesis of the protein measured immunologically or by activation with venom was not affected. The “coagulopoietin” factor in these studies appears to increase measurable coagulation factor activity without increasing total protein synthesis.

Immunological Studies on the Blood Coagulation Factor X and Its Warfarin-induced Precursor

1974 ◽  
Vol 31 (01) ◽  
pp. 040-051 ◽  
Author(s):  
Gustav Gaudernack ◽  
Åse Gladhaug Berre ◽  
Bjarne Østerud ◽  
Hans Prydz
Keyword(s):  
Coagulation Factor ◽  
Factor X ◽  
Intrinsic Pathway ◽  
Coagulation Activity ◽  
Factor X Deficiency ◽  
Warfarin Treatment ◽  
The Cross ◽  
Monospecific Antisera ◽  
Purified Antigen ◽  
Congenital Factor

SummaryMonospecific antisera against the human coagulation factor X have been raised in rabbits by injections of purified antigen. Such antiserum was used to study the cross-reacting material without factor X activity which is present in the blood of warfarin-treated patients and animals as well as to study the changes in factor X during coagulation. One patient with congenital factor X deficiency was also studied.A complete identity was found between factor X in Macaca mulatta and human blood. During warfarin treatment antigenically cross-reacting material appeared in plasma. This was not adsorbed on BaSO4, and inhibited the coagulation activity of normal factor X.Both this material, normal factor X and the cross-reacting material in plasma from a patient congenitally deficient in factor X gave rise to split products during coagulation by the intrinsic pathway, i. e. all of them served as substrates for the intrinsic activator of factor X.

Dietary Vitamin and Stability of Oral Anticoagulation: Proposal of a Diet with Constant Vitamin K1 Content

1997 ◽  
Vol 77 (03) ◽  
pp. 504-509 ◽  
Author(s):  
Sarah L Booth ◽  
Jacqueline M Charnley ◽  
James A Sadowski ◽  
Edward Saltzman ◽  
Edwin G Bovill ◽  
...  
Keyword(s):  
Dietary Intake ◽  
Vitamin K ◽  
High Performance ◽  
Case Reports ◽  
Food Composition ◽  
Dietary Guidelines ◽  
Dietary Vitamin ◽  
Vitamin K1 ◽  
The Stability ◽  
The Impact

SummaryCase reports cited in Medline or Biological Abstracts (1966-1996) were reviewed to evaluate the impact of vitamin K1 dietary intake on the stability of anticoagulant control in patients using coumarin derivatives. Reported nutrient-drug interactions cannot always be explained by the vitamin K1 content of the food items. However, metabolic data indicate that a consistent dietary intake of vitamin K is important to attain a daily equilibrium in vitamin K status. We report a diet that provides a stable intake of vitamin K1, equivalent to the current U.S. Recommended Dietary Allowance, using food composition data derived from high-performance liquid chromatography. Inconsistencies in the published literature indicate that prospective clinical studies should be undertaken to clarify the putative dietary vitamin K1-coumarin interaction. The dietary guidelines reported here may be used in such studies.

Immunoaffinity purification of factor IX from commercial concentrates and infusion studies in animals

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1269-1277
Author(s):  
KJ Smith
Keyword(s):  
Replacement Therapy ◽  
Vitamin K ◽  
Disease Transmission ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Heat Treated ◽  
Coagulation Factor Concentrates ◽  
Risk Of Disease ◽  
Factor Ix Deficiency

Thrombosis and transmission of viral diseases are the principal adverse effects of current replacement therapy for factor IX deficiency when using heat-treated concentrates of vitamin K-dependent coagulation factors. More highly purified factor IX preparations could decrease the risk of disease transmission, reduce patient exposure to allogeneic proteins, and reduce the risk of thrombosis. In this study, two immunoaffinity-purified factor IX preparations from commercial vitamin K-dependent coagulation factor concentrates had specific activities of 134 and 155 U/mg. Crude concentrates and purified factor IX preparations were tested for thrombogenicity in rabbits. One of two crude concentrates tested in the stasis-thrombosis assay caused large thrombi at doses of 50 U/kg. Purified factor IX from this concentrate was not thrombogenic at 106 to 234 U/kg. A heparin-treated concentrate that was not active in the stasis model at 100 U/kg caused significant (P less than .05) delayed consumption of rabbit fibrinogen, platelets, antithrombin III antigen, and factor VIII activity at the same dose. Factor IX prepared from this concentrate caused no consumption of coagulation factors at 214 to 243 U/kg despite the presence of trace amounts of activated factor IX. These results indicate that more highly purified preparations could reduce the risk of thrombosis in replacement therapy for hemophilia B. Also, at least for the preparations tested, factor IX and factor IXa were not the thrombogenic components of the crude concentrates.

Use of Low Dose Oral Vitamin K in the Treatment of Patients with INR Values of More Than 10.0.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 547-547
Author(s):  
Mark A. Crowther ◽  
David Garcia ◽  
Walter Ageno ◽  
Daniel M. Witt ◽  
Sam Schulman ◽  
...  
Keyword(s):  
Vitamin K ◽  
Low Dose ◽  
Coagulation Factor ◽  
Study Drug ◽  
Additional Patient ◽  
Oral Vitamin ◽  
Risk Of Bleeding ◽  
Dose Oral ◽  
The Mean ◽  
The Impact

Abstract The optimal therapy for patients who present with markedly prolonged INR values during warfarin therapy is undefined. Evidence suggests that the risk of bleeding increases directly with the degree of prolongation of the INR. Traditional therapy for patients with excessive warfarin associated anticoagulation has included warfarin withdrawal with or without vitamin K, transfusion therapy and admission to the hospital. As part of an ongoing international study, we prospectively enrolled 32 consecutive warfarin-treated patients presenting with an INR of more than 10.0. Eligible patients had no evidence of active bleeding or need for immediate correction of their INR. All patients received 2.5 mg of oral vitamin K, were not treated with coagulation factor replacement, and were followed over 90 days for clinical events and their INR response. Seventeen of the 32 patients were women, with an average age of 65.8 (range 31 to 89). Treatment of venous thrombosis and atrial fibrillation (12 patients each) were the most common indications for warfarin. Twenty-five patients had a target INR of 2.0 to 3.0; the remainder had a target of 2.5 to 3.5. The mean INR at presentation was 12.9 (range 10.0 to 21.2). Of the 25 patients with a recorded INR value on the day following vitamin K, 19 (76%) had an INR of 6.0 or less (range 1.6 to 17.5, mean 5.0, 2 less than 2.0). On day 7 after study drug, the mean INR was 3.5 (range 1.6 to 17.5). Six (19%) patients reported bleeding over the 90 days after study drug: 1 (3%) bleed was major (retroperitoneal hemorrhage diagnosed the day after study drug) and 3 patients reported epistaxis or bruising within three days of study drug. Two patients reported late bleeding; one had a fall on day 8 at which time the INR was 10.5, and the other had bleeding associated with a surgical procedure 25 days after study drug. No patients had suspected or confirmed thrombosis, and no patients died during follow-up. This the first prospective study of vitamin K monotherapy for patients with INR values above 10, and confirms prior retrospective analyses which suggest that low dose oral vitamin K effectively lowers the INR in such patients. Our preliminary results also suggest that coagulation factor replacement may be unneeded in such patients. The true risk of bleeding, and the impact of degree of prolongation of the INR on the vitamin K response, will require additional patient recruitment.

scholarly journals Immunoaffinity purification of factor IX from commercial concentrates and infusion studies in animals

Blood ◽  
1988 ◽  
Vol 72 (4) ◽  
pp. 1269-1277 ◽  
Author(s):  
KJ Smith
Keyword(s):  
Replacement Therapy ◽  
Vitamin K ◽  
Disease Transmission ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Factor Ix ◽  
Heat Treated ◽  
Coagulation Factor Concentrates ◽  
Risk Of Disease ◽  
Factor Ix Deficiency

Abstract Thrombosis and transmission of viral diseases are the principal adverse effects of current replacement therapy for factor IX deficiency when using heat-treated concentrates of vitamin K-dependent coagulation factors. More highly purified factor IX preparations could decrease the risk of disease transmission, reduce patient exposure to allogeneic proteins, and reduce the risk of thrombosis. In this study, two immunoaffinity-purified factor IX preparations from commercial vitamin K-dependent coagulation factor concentrates had specific activities of 134 and 155 U/mg. Crude concentrates and purified factor IX preparations were tested for thrombogenicity in rabbits. One of two crude concentrates tested in the stasis-thrombosis assay caused large thrombi at doses of 50 U/kg. Purified factor IX from this concentrate was not thrombogenic at 106 to 234 U/kg. A heparin-treated concentrate that was not active in the stasis model at 100 U/kg caused significant (P less than .05) delayed consumption of rabbit fibrinogen, platelets, antithrombin III antigen, and factor VIII activity at the same dose. Factor IX prepared from this concentrate caused no consumption of coagulation factors at 214 to 243 U/kg despite the presence of trace amounts of activated factor IX. These results indicate that more highly purified preparations could reduce the risk of thrombosis in replacement therapy for hemophilia B. Also, at least for the preparations tested, factor IX and factor IXa were not the thrombogenic components of the crude concentrates.

scholarly journals Thrombin Inhibition Reduces the Expression of Brain Inflammation Markers upon Systemic LPS Treatment

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Efrat Shavit Stein ◽  
Marina Ben Shimon ◽  
Avital Artan Furman ◽  
Valery Golderman ◽  
Joab Chapman ◽  
...  
Keyword(s):  
Systemic Inflammation ◽  
Specific Inhibitor ◽  
Coagulation Factor ◽  
Coagulation Factors ◽  
Brain Inflammation ◽  
Coagulation Activity ◽  
Microglia Cell ◽  
The Brain

Systemic inflammation and brain pathologies are known to be linked. In the periphery, the inflammation and coagulation systems are simultaneously activated upon diseases and infections. Whether this well-established interrelation also counts for neuroinflammation and coagulation factor expression in the brain is still an open question. Our aim was to study whether the interrelationship between coagulation and inflammation factors may occur in the brain in the setting of systemic inflammation. The results indicate that systemic injections of lipopolysaccharide (LPS) upregulate the expression of both inflammatory and coagulation factors in the brain. The activity of the central coagulation factor thrombin was tested by a fluorescent method and found to be significantly elevated in the hippocampus following systemic LPS injection (0.5 ± 0.15 mU/mg versus 0.2 ± 0.03 mU/mg in the control). A panel of coagulation factors and effectors (such as thrombin, FX, PAR1, EPCR, and PC) was tested in the hippocampus, isolated microglia, and N9 microglia cell by Western blot and real-time PCR and found to be modulated by LPS. One central finding is a significant increase in FX expression level following LPS induction both in vivo in the hippocampus and in vitro in N9 microglia cell line (5.5 ± 0.6- and 2.3 ± 0.1-fold of increase, resp.). Surprisingly, inhibition of thrombin activity (by a specific inhibitor NAPAP) immediately after LPS injection results in a reduction of both the inflammatory (TNFα, CXL9, and CCL1; p<0.006) and coagulation responses (FX and PAR1; p<0.004) in the brain. We believe that these results may have a profound clinical impact as they might indicate that reducing coagulation activity in the setting of neurological diseases involving neuroinflammation may improve disease outcome and survival.

Compound Heterozygosity in the Novel Mutations W157R and T591K in the γ-Glutamyl Carboxylase Gene Causes Hereditary Combined Vitamin K-Dependent Coagulation Factor Deficiency in a Tunisian Family.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2147-2147
Author(s):  
Dhouha Darghouth ◽  
Kevin W. Hallgren ◽  
Rebecca L. Hain ◽  
Amel Mrad ◽  
Youssef Gharbi ◽  
...  
Keyword(s):  
Vitamin K ◽  
Protein Function ◽  
Mutational Analysis ◽  
Coagulation Factor ◽  
Normal Subjects ◽  
Coagulation Factors ◽  
Compound Heterozygosity ◽  
Wild Type ◽  
Family Analysis ◽  
Coagulation Factor Deficiency

Abstract Combined deficiency in vitamin K-dependent (VKD) coagulation factors is an autosomal recessive bleeding disorder associated with defects in either the VKD carboxylase which converts Glus to Glas in VKD proteins to render them active or the vitamin K epoxide reductase (VKORC1) which supplies the reduced vitamin K cofactor required for carboxylation. Such defects are rare, and we now report the fourth case of deficiency caused by mutations in the carboxylase gene. The mutations were identified in a two year old Tunisian girl who exhibited impaired function in several VKD procoagulant and anticoagulant factors that was not restored by vitamin K administration. Sequence analysis of the propositus did not identify any mutations in the VKORC1 gene but, remarkably, revealed three heterozygous mutations in the carboxylase gene, D31N, W157R and T591K within exons 2, 4 and 13, respectively. None of these mutations have previously been reported. Family analysis showed that D31N and T591K were coallelic and transmitted by the mother while W157R was transmitted by the father. The mutations were not found in the genomes of 200 normal subjects, ruling out frequent polymorphisms. Mutational analysis indicated wild type activity for the D31N carboxylase. In contrast, the W157R and T591K enzymes had activities that were, respectively, 7% and 0% that of wild type carboxylase, and their compound heterozygosity can therefore account for defective carboxylation. Residues 157 and 591 are both highly evolutionarily conserved, and residue 157 lies within a region previously suggested to be important for carboxylase binding to VKD Glus or propeptide. However, the hydrophobic nature of this region and inability of vitamin K administration to restore VKD protein function alternatively suggests that residue 157 may be important for vitamin K binding.

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