Critical Role of Factors II and X During Coumarin Anticoagulation and Their Combined Measurement with a New Prothrombin Time Variant (Fiix-PT),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3354-3354
Author(s):  
Pall T. Onundarson ◽  
Brynja R. Gudmundsdottir ◽  
Charles W. Francis
Keyword(s):  
Prothrombin Time ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Critical Role ◽  
Patent Application ◽  
Maximum Velocity ◽  
Coagulation Factors ◽  
Clot Formation ◽  
Normal Platelet ◽  
Anticoagulated Patients

Abstract Abstract 3354 Introduction: Vitamin K antagonists (VKA) are monitored with prothrombin time (PT) based assays that are equally sensitive to reductions in factors II, VII or X. However, previous studies suggest that the anticoagulant effect of VKA depends primarily on reductions in factors II and X and not VII. Aim and methods: We compared the effect of vitamin K dependent (VKD) coagulation factors on PT (Quick and Owren methods) and also on rotational thromboelastometric (ROTEM) parameters. The experiments used normal platelet poor plasma (PPP) and PPP selectively immunodepleted of individual VKD factors, with and without added platelet phospholipid or washed platelets. Results: The PT was equally sensitive to reductions in factors II, VII or X. However, ROTEM parameters correlated poorly with the PT in anticoagulated patients` plasmas. ROTEM experiments showed that the clotting time, maximum velocity of clot formation and the maximum clot firmness were more affected by reductions in FII or FX than by FVII or FIX concentrations which had little influence except at very low concentrations. We developed a modified PT that was sensitive only to reductions in factors II and X by using factor II and X (Fiix) depleted plasma in the PT system. The Fiix-PT (Fiix-INR) correlated well with PT (INR) but the Fiix-INR fluctuated less than the INR in anticoagulated patients reflecting its insensitivity to FVII. Conclusion: The ROTEM results suggest that mild to moderate reductions in factors II or X are more important in clot formation than factors VII or IX at therapeutically relevant factor concentrations. Reductions in FII and X may therefore better reflect anticoagulation with VKA than FVII or IX. FVII may be a confounding source of unwanted variation in PT-INR. The new Fiix-PT that is sensitive only to FII and FX may more accurately reflect the degree of therapeutic anticoagulation in patients treated with VKA than do the current PT assays which may overestimate the fluctuation in anticoagulation. Disclosures: Onundarson: See i. other: Patent application for Fiix method in process. Gudmundsdottir:Other, see i: patent applicaiton filed for Fiix method.

scholarly journals Effectivity of a joint didactic intervention by School for Patients on inappropriate control prothrombin time anticoagulated patients. Protocol for developing a randomized and controlled clinical trial.

2020 ◽  
Author(s):  
Leovigildo Ginel-Mendoza ◽  
Alfonso Hidalgo Hidalgo-Natera ◽  
Rocio Reina-Gonzalez ◽  
Rafael Poyato-Ramos ◽  
Inmaculada Lupianez-Perez ◽  
...  
Keyword(s):  
Social Support ◽  
Clinical Trial ◽  
Prothrombin Time ◽  
Vitamin K ◽  
Oral Anticoagulant ◽  
Vitamin K Antagonists ◽  
International Normalized Ratio ◽  
Control Group ◽  
Therapeutic Level ◽  
Anticoagulated Patients

Abstract Background Oral anticoagulant drugs represent an essential tool in thrombo-embolic events prevention. Most used are vitamin K antagonists, whose plasma level is monitored by measuring prothrombin time using the International Normalized Ratio. If it takes values out of the recommended range, the patient will have a higher risk of suffering from thromboembolic or hemorrhagic complications. Previous research has shown that about 33% of total patients keep values on inappropriate level. The purpose of the study is to improve International Normalized Ratio control figures by a joint didactic intervention based on the Junta de Andalucía School for Patients method that will be implemented by anticoagulated patients themselves. Methods A randomized clinical trial was carried out at primary care centers from one healthcare area in Málaga (Andalusia, Spain). Study population: patients included in an oral anticoagulant therapy program consisting in using vitamin K antagonists. First step detection of patients on oral anticoagulation program with International Normalized Ratio control on therapeutic level during 65% or less over total time. Second step: patients with inappropriate International Normalized Ratio control were included in two groups: Group 1 or Joint Intervention Group: patients were instructed a joint didactic intervention “from peer to peer”, by a previously trained and expert anticoagulated patient. Group 2 or Control Group: Control group performed usual clinical practice: people were schedule by nurses about one time per month, except cases in which controls were inappropriate; in those circumstances patients were schedule before that period expired. In order to built the study group and the control group, 312 individuals were required (156 in each group) to detect differences in INR figures equal or higher than 15% between both groups. Study variables time on therapeutic levels before and after intervention, sociodemographic variables, vital signs, existence of cardiovascular risk factors or accompanying diseases in the clinical records, laboratory test including complete blood count, bleeding time, and prothrombin time or partial thromboplastin time and blood chemistry, other prescribed drugs, and social support. Almost-experimental analytic study with before-after statistical analysis of the intervention were made. Lineal regression models were applied on main variables results (International Normalized Ratio value, time on therapeutic level) inputting sociodemographic variables, accompanying diseases and social support.

Coagulation Induced by Dilute Tissue Factor Depends More Critically on Factor II and X Concentration Than on FVII or FIX

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4084-4084
Author(s):  
Brynja R. Gudmundsdottir ◽  
Alexia M Bjornsdottir ◽  
Pall T. Onundarson
Keyword(s):  
Prothrombin Time ◽  
Vitamin K ◽  
Platelet Rich Plasma ◽  
Coagulation Factor ◽  
Maximum Velocity ◽  
Coagulation Factors ◽  
Factor X ◽  
Platelet Poor Plasma ◽  
Stabilization Phase ◽  
Maximum Clot Firmness

Abstract Prothrombin time based tests used to monitor coumarin anticoagulation measure the initiation phase of fibrin formation (clotting time, CT) in platelet poor plasma. Additional information can be obtained using computerized rotational thromboelastometry (ROTEM) which also measures the consequent propagation phase (measured as maximum velocity, Vmax), and the stabilization phase (maximum clot firmness, MCF). We used ROTEM to study the effect of individual vitamin K dependent (VK) coagulation factor (F) concentration on clotting induced by dilute thromboplastin in platelet poor and platelet rich plasma (PPP and PRP). As expected, FII, FVII and FX in PPP equally affected the prothrombin time whereas FIX did not. In PPP the ROTEM CT, however, was affected more by the concentration of FII and FX than by FVII (data not shown). To imitate physiological clotting better, factor deficient platelet poor plasma was repleted by adding frozen platelets in an optimal concentration corresponding to 100 × 109/L.. In the PRP the ROTEM CT was more dependent on the concentration of FII than of FVII, more dependent on FX than on FII and not dependent on FIX at all (left figure). The Vmax (reflecting the propagation phase) was also more dependent on FII and factor X than on the concentration of FVII or FIX which both may demonstrate a threshold effect (right figure). The stabilization phase or maximum clot firmness (MCF, not shown) was influenced similarly by FII and FX but was not influenced by FVII or FIX. Figure Figure Conclusion: During deficiency of vitamin K dependent coagulation factors the concentration of FII and FX may be more critical for hemostasis than FVII or FIX concentration. This may have practical implications for the appropriate choice of monitoring assays during coumarin administration.

scholarly journals Replacement of traditional prothrombin time monitoring with the new Fiix prothrombin time increases the efficacy of warfarin without increasing bleeding. A review article

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Pall T. Onundarson ◽  
Ragnar Palsson ◽  
Daniel M. Witt ◽  
Brynja R. Gudmundsdottir
Keyword(s):  
Relative Risk ◽  
Prothrombin Time ◽  
Vitamin K ◽  
Major Bleeding ◽  
Clinical Studies ◽  
Vitamin K Antagonists ◽  
Coagulation Factors ◽  
Review Article ◽  
Antithrombotic Effect ◽  
Monitoring Test

AbstractThe antithrombotic effect of vitamin K antagonists (VKA) depends on controlled lowering of the activity of factors (F) II and X whereas reductions in FVII and FIX play little role. PT-INR based monitoring, however, is highly influenced by FVII, which has the shortest half-life of vitamin K-dependent coagulation factors. Hence, variability in the anticoagulant effect of VKA may be partly secondary to an inherent flaw of the traditional monitoring test itself. The Fiix prothrombin time (Fiix-PT) is a novel test that is only sensitive to reductions in FII and FX and is intended to stabilize the VKA effect. Two clinical studies have now demonstrated that when warfarin is monitored with the Fiix-PT based normalized ratio (Fiix-NR) instead of PT-INR, anticoagulation is stabilized and less testing and fewer dose adjustments are needed. Furthermore, the relative risk of thromboembolism was reduced by 50–56% in these studies without an increase in major bleeding.

Spectrophotometric Assays of Prothrombin in Plasma of Patients Using Oral Anticoagulants

1979 ◽  
Vol 42 (04) ◽  
pp. 1296-1305 ◽  
Author(s):  
R M Bertina ◽  
W van der Marel-van Nieuwkoop ◽  
E A Loeliger
Keyword(s):  
Prothrombin Time ◽  
Vitamin K ◽  
Oral Anticoagulation ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Factor V ◽  
Anticoagulant Treatment ◽  
Factor Ii ◽  
K Deficiency

SummaryTwo spectrophotometric assays for prothrombin have been developed and compared with a one stage coagulant and an immunological assay. One of these assays (called the XAPC assay) uses a combination of factor Xa, phospholipid, Ca2+ and factor V as activator of prothrombin, and measures only normal prothrombin. The second (the ECAR assay) uses Echis carinatus venom as activator. This assay measures both normal prothrombin and PIVKA II (protein induced by vitamin K antagonists/absence). Combination of the results obtained by the XAPC and ECAR assays provides rapid and reliable information on the degree of “subcarboxylation” of prothrombin (oral anticoagulation, vitamin K deficiency).For patients on long term anticoagulant treatment the prothrombin time (Thrombotest) shows better correlation with the ratio prothrombin/prothrombin plus PIVKA II (XAPC/ ECAR) than with the factor II concentration. For patients starting the anticoagulant treatment there is no correlation between the Thrombotest time and the XAPC/ECAR ratio.It seems doubtful that (a) spectrophotometric factor II assay(s) will be as useful as the prothrombin time in the control of oral anticoagulation.

scholarly journals Falls in ED patients: do elderly patients on direct oral anticoagulants bleed less than those on vitamin K antagonists?

2021 ◽  
Vol 29 (1) ◽  
Author(s):  
Martin Müller ◽  
Ioannis Chanias ◽  
Michael Nagler ◽  
Aristomenis K. Exadaktylos ◽  
Thomas C. Sauter
Keyword(s):  
Elderly Patients ◽  
Vitamin K ◽  
Intracranial Haemorrhage ◽  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Bleeding Complications ◽  
Lower Odds ◽  
Anticoagulated Patients ◽  
Proportional Incidence

Abstract Background Falls from standing are common in the elderly and are associated with a significant risk of bleeding. We have compared the proportional incidence of bleeding complications in patients on either direct oral anticoagulants (DOAC) or vitamin K antagonists (VKA). Methods Our retrospective cohort study compared elderly patients (≥65 years) on DOAC or VKA oral anticoagulation who presented at the study site – a Swiss university emergency department (ED) – between 01.06.2012 and 01.07.2017 after a fall. The outcomes were the proportional incidence of any bleeding complication and its components (e.g. intracranial haemorrhage), as well as procedural and clinical parameters (length of hospital stay, admission to intensive care unit, in-hospital-mortality). Uni- and multivariable analyses were used to compare the studied outcomes. Results In total, 1447 anticoagulated patients were included – on either VKA (n = 1021) or DOAC (n = 426). There were relatively more bleeding complications in the VKA group (n = 237, 23.2%) than in the DOAC group (n = 69, 16.2%, p = 0.003). The difference persisted in multivariable analysis with 0.7-fold (95% CI: 0.5–0.9, p = 0.014) lower odds for patients under DOAC than under VKA for presenting with any bleeding complications, and 0.6-fold (95% 0.4–0.9, p = 0.013) lower odds for presenting with intracranial haemorrhage. There were no significant differences in the other studied outcomes. Conclusions Among elderly, anticoagulated patients who had fallen from standing, those under DOACs had a lower proportional incidence of bleeding complications in general and an even lower incidence of intracranial haemorrhage than in patients under VKAs.

scholarly journals Fetal Effects of Coumadin Administered During Pregnancy

Blood ◽  
1970 ◽  
Vol 36 (5) ◽  
pp. 623-627 ◽  
Author(s):  
J. HIRSH ◽  
J. F. CADE ◽  
A. S. GALLUS
Keyword(s):  
Cesarean Section ◽  
Vitamin K ◽  
Early Pregnancy ◽  
Vitamin K Antagonists ◽  
Practical Method ◽  
Coagulation Factors ◽  
Coagulation Defect ◽  
In Pregnancy

Abstract The safest and most practical method of administering long-term anticoagulants in pregnancy is uncertain because treatment of the mother with vitamin K antagonists may be complicated by hemorrhage in the fetus. The effects on the fetus of giving coumadin in pregnancy was evaluated in rabbits. When coumadin was given from early pregnancy until term, all of the fetuses were stillborn with widespread hemorrhages. However, the fetuses were born alive and without hemorrhage when (1) coumadin was stopped 4-5 days before delivery, at which time the level of coagulation factors had almost returned to normal and (2) when delivery was performed by cesarean section at a time when the fetal coagulation defect was severe. It is suggested that the risk of fetal hemorrhage is high only when fetuses with a severe coagulation defect are exposed to the trauma of delivery.

scholarly journals New artificial intelligence prediction model using serial prothrombin time international normalized ratio measurements in atrial fibrillation patients on vitamin K antagonists: GARFIELD-AF

2019 ◽  
Vol 6 (5) ◽  
pp. 301-309 ◽  
Author(s):  
Shinichi Goto ◽  
Shinya Goto ◽  
Karen S Pieper ◽  
Jean-Pierre Bassand ◽  
Alan John Camm ◽  
...  
Keyword(s):  
Neural Network ◽  
Artificial Intelligence ◽  
Atrial Fibrillation ◽  
Prothrombin Time ◽  
Clinical Outcomes ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
International Normalized Ratio ◽  
One Dimensional ◽  
Major Bleed

Abstract Aims Most clinical risk stratification models are based on measurement at a single time-point rather than serial measurements. Artificial intelligence (AI) is able to predict one-dimensional outcomes from multi-dimensional datasets. Using data from Global Anticoagulant Registry in the Field (GARFIELD)-AF registry, a new AI model was developed for predicting clinical outcomes in atrial fibrillation (AF) patients up to 1 year based on sequential measures of prothrombin time international normalized ratio (PT-INR) within 30 days of enrolment. Methods and results Patients with newly diagnosed AF who were treated with vitamin K antagonists (VKAs) and had at least three measurements of PT-INR taken over the first 30 days after prescription were analysed. The AI model was constructed with multilayer neural network including long short-term memory and one-dimensional convolution layers. The neural network was trained using PT-INR measurements within days 0–30 after starting treatment and clinical outcomes over days 31–365 in a derivation cohort (cohorts 1–3; n = 3185). Accuracy of the AI model at predicting major bleed, stroke/systemic embolism (SE), and death was assessed in a validation cohort (cohorts 4–5; n = 1523). The model’s c-statistic for predicting major bleed, stroke/SE, and all-cause death was 0.75, 0.70, and 0.61, respectively. Conclusions Using serial PT-INR values collected within 1 month after starting VKA, the new AI model performed better than time in therapeutic range at predicting clinical outcomes occurring up to 12 months thereafter. Serial PT-INR values contain important information that can be analysed by computer to help predict adverse clinical outcomes.

Role of vitamin K-dependent proteins in the arterial vessel wall

2011 ◽  
Vol 31 (04) ◽  
pp. 251-257 ◽  
Author(s):  
M. L. L. Chatrou ◽  
C. P. Reutelingsperger ◽  
L. J. Schurgers
Keyword(s):  
Vascular Calcification ◽  
Vitamin K ◽  
Independent Predictor ◽  
Vitamin K Antagonists ◽  
Venous Blood ◽  
Coagulation Factors ◽  
Coagulation Cascade ◽  
High Intake ◽  
Smooth Muscle Cell Migration

SummaryVitamin K was discovered early last century at the same time as the vitamin K-antagonists. For many years the role of vitamin K was solely ascribed to coagulation and coagulation was thought to be involved only at the venous blood side. This view has dramatically changed with the discovery of vitamin K-dependent proteins outside the coagulation cascade and the role of coagulation factors at the arterial side. Vitamin K-dependent proteins are involved in the regulation of vascular smooth muscle cell migration, apoptosis, and calcification. Vascular calcification has become an important independent predictor of cardiovascular disease. Vitamin K-antagonists induce inactivity of inhibitors of vascular calcification, leading to accelerated calcification. The involvement of vitamin K-dependent proteins such as MGP in vascular calcification make that calcification is amendable for intervention with high intake of vitamin K. This review focuses on the effect of vitamin K-dependent proteins in vascular disease.

Antikoagulation bei Vorhofflimmern

2012 ◽  
Vol 32 (01) ◽  
pp. 37-39 ◽  
Author(s):  
C. Bode ◽  
M. Moser
Keyword(s):  
Atrial Fibrillation ◽  
Vitamin K ◽  
Vitamin K Antagonists ◽  
Bleeding Risk ◽  
Coagulation Factors ◽  
Additional Risk ◽  
New Anticoagulants ◽  
Therapeutic Anticoagulation ◽  
Impaired Quality

SummaryAtrial fibrillation is one of the most frequent reasons for therapeutic anticoagulation in everyday practice. Oral vitamin K antagonists such as Marcumar have been state of the art anticoagulants to prevent thrombembolic events in patients with atrial fibrillation and additional risk factors. But these drugs are accompanied by disadvantages such as increased bleeding risk and impaired quality of life caused by interactions with food or other medications as well as frequent controls of INRs.The new anticoagulants apixaban, rivaroxaban and dabigatran are direct antagonists of coagulation factors (FXa or FIIa) and demonstrate a promising risk/benefit profile in large clinical trials compared with vitamin K antagonists.Their approval for clinical use will open up new therapeutic perspectives for patients with atrial fibrillation and indication for anticoagulation.

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