The In Vivo Effects of Oral Anticoagulants in Man: Comparison Between Liver and Non-Hepatic Tissues

SummaryThe in vivo effects of oral anticoagulant therapy with 4–hydroxycoumarins on various vitamin K–dependent enzyme systems in man were compared. In hepatic microsomes obtained from donors who has been treated with 4–hydroxycoumarins for more than 6 months, the vitamin K 2,3 epoxide reductase activity and the DTT–dependent vitamin K quinone reductase activity were diminished to 35% and 20% of the corresponding normal values. In the non–hepatic tissues, only a small decrease in vitamin K 2,3 epoxide reductase activity could be demonstrated, while no differences were found in the vitamin K quinone reductase activities. In none of the tissues a significant increase of non–carboxylated precursor proteins was observed, whereas also vitamin K hydroquinone–dependent carboxylase activities seemed to be unaffected by the anticoagulant treatment.

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The in vivo effects of acenocoumarol, phenprocoumon and warfarin on vitamin K epoxide reductase and vitamin K-dependent carboxylase in various tissues of the rat

Biochimica et Biophysica Acta (BBA) - General Subjects ◽

10.1016/0304-4165(86)90238-2 ◽

1986 ◽

Vol 884 (1) ◽

pp. 150-157 ◽

Cited By ~ 18

Author(s):

Marian A.G. de Boer-van den Berg ◽

Henk H.W. Thijssen ◽

Cees Vermeer

Keyword(s):

Vitamin K ◽

Vitamin K Epoxide Reductase ◽

Epoxide Reductase ◽

In Vivo Effects

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HISTOCHEMICAL INVESTIGATIONS ON THE IN VIVO EFFECTS OF FLUORIDE ON TRICARBOXYLIC ACID CYCLE DEHYDROGENASES FROM PELARGONIUM ZONALE: PART II

Journal of Histochemistry & Cytochemistry ◽

10.1177/15.4.202 ◽

1967 ◽

Vol 15 (4) ◽

pp. 202-206

Author(s):

C. JAMES LOVELACE ◽

GENE W. MILLER

Keyword(s):

Sodium Fluoride ◽

Reductase Activity ◽

Tricarboxylic Acid Cycle ◽

Leaf Tissue ◽

Tca Cycle ◽

Tricarboxylic Acid ◽

Pelargonium Zonale ◽

Acid Cycle ◽

In Vivo Effects

In vivo effects of fluoride on tricarboxylic acid (TCA) cycle dehydrogenase enzymes of Pelargonium zonale were studied using p-nitro blue tetrazoleum chloride. Plants were exposed to 17 ppb HF, and enzyme activities in treated plants were compared to those in controls. Leaves of control plants were incubated in 5 x 10–3 M sodium fluoride. Injuries observed in fumigation and solution experiments were similar. Leaf tissue subjected to HF or sodium fluoride evidenced less succinic p-nitro blue tetrazoleum reductase activity than did control tissue. Other TCA cycle dehydrogenase enzymes were not observably affected by the fluoride concentrations used in these experiments. Excised leaves cultured in 5 x 10–3 M sodium fluoride exhibited less succinic p-nitro blue tetrazoleum reductase activity after 24 hr than did leaves cultured in 5 x 10–3 M sodium chloride.

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VKORC1 deficiency in mice causes early postnatal lethality due to severe bleeding

Thrombosis and Haemostasis ◽

10.1160/th09-03-0204 ◽

2009 ◽

Vol 101 (06) ◽

pp. 1044-1050 ◽

Cited By ~ 43

Author(s):

Gabriele Spohn ◽

Andre Kleinridders ◽

F. Thomas Wunderlich ◽

Matthias Watzka ◽

Frank Zaucke ◽

...

Keyword(s):

Vitamin K ◽

Knockout Mice ◽

Severe Bleeding ◽

Clotting Factors ◽

Vitamin K Cycle ◽

Severe Deficiency ◽

Epoxide Reductase ◽

Bone Calcification

SummaryVitamin K hydroquinone is oxidised to the epoxide form (K>O) during vitamin K-dependent posttranslational γ-glutamyl carboxylation resulting in biological active so called vitamin K-dependent proteins. In turn, K>O is reduced by the enzyme VKORC1 (vitamin K epoxide reductase complex component 1) to complete the vitamin K cycle. To investigate the biological role of VKORC1 in vivo, we generated VKORC1 knockout mice. Homozygous VKORC1-deficient mice developed normally until birth. Within 2–20 days after birth, the knockout mice died due to extensive, predominantly intracerebral haemorrhage. Bleeding resulted from a severe deficiency of γ-carboxylated clotting factors. This lethal phenotype could be rescued by oral administration of vitamin K. Additionally, morphometric analysis of the limbs in VKORC1-deficient animals revealed reduced length of bone calcification relative to wild-type control mice. The observed phenotype of VKORC1 knockout mice excludes the existence of other enzymes with VKOR activity that can substitute to supply vitamin K hydroquinone required for maturation of blood clotting factors. Thus, our study underscores the essential role of VKORC1 in vitamin K-dependent γ-glutamyl carboxylation.

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Rebound Phenomenon After Discontinuation Of Oral Anticoagulant Therapy?

10.1055/s-0038-1653092 ◽

1981 ◽

Cited By ~ 1

Author(s):

J Harenberg ◽

R Haas ◽

R Zimmermann

Keyword(s):

Anticoagulant Therapy ◽

Oral Anticoagulant ◽

Oral Anticoagulant Therapy ◽

Oral Anticoagulants ◽

Anticoagulation Therapy ◽

In Vitro Release ◽

Oral Anticoagulant Treatment ◽

Thrombin Activity ◽

Rebound Phenomenon

Duration and discontinuation of oral anticoagulant therapy in the prophylaxis of recurrent thrombembolic diseases is often discussed. After stopping of the therapy an elevated incidence of rethromboses are observed. Therefore we determined fibrinopeptide A (FPA) as the most sensitive parameter of thrombin activity in vivo in patients treated with phenprocoumon in order to get information on the effectivity of the oral anticoagulant therapy and on the rebound phenomenon after discontinuation of the treatment.In 136 outpatients a significant relation between FPA and the effectivity of the anticoagulant therapy was observed: 2.7 ng/ml plasma (mean, thrombotest values < 5%), 3.5 ng/ml (5%-15%) and 4.1 ng/ml (>15%, p < 0.01). Normal FPA were 1.4ng/ml. In 11 patients with low FPA the oral anticoagulants were discontinued. FPA was determined in weekly intervalls. Within four weeks a continous increase of FPA from 1.6 ng/ml (median) to 3.8 ng/ml was observed. After eight weeks FPA was 8.2 ng/ ml (p < 0.05). The in vitro release of FPA after 10 min incubation of blood increased from 3.4ng/ml to 72 ng/ml after eight weeks (p < 0.05, normal release up to 5 ng/ml).The data indicate the clinical relevance and the different therapeutic implications of the determination of FPA in patients treated with phenprocoumon. They further give the first criterion, which outlines the effectivity of an oral anticoagulation therapy by reducing the thrombin activity in vivo. They give some evidence for a rebound like phenomenon after discontinuation of the oral anticoagulant treatment.

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Effects of oral anticoagulant therapy and haplotype 1 of the endothelial protein C receptor gene on activated protein C levels

Thrombosis and Haemostasis ◽

10.1160/th11-07-0510 ◽

2012 ◽

Vol 107 (03) ◽

pp. 448-457 ◽

Cited By ~ 2

Author(s):

Pilar Medina ◽

Elena Bonet ◽

Silvia Navarro ◽

Laura Martos ◽

Amparo Estellés ◽

...

Keyword(s):

Anticoagulant Therapy ◽

Lupus Erythematosus ◽

Protein C ◽

Oral Anticoagulant Therapy ◽

Receptor Gene ◽

Oral Anticoagulants ◽

Activated Protein C ◽

Endothelial Protein C Receptor ◽

Haplotype 1

SummaryOral anticoagulants (OACs) reduce activated protein C (APC) plasma levels less than those of protein C (PC) in lupus erythematosus and cardiac patients. Carriers of the H1 haplotype of the endothelial PC receptor gene (PROCR) have higher APC levels than non-carriers. We aimed to confirm these results in a large group of patients treated with OACs because of venous thromboembolism (VTE) and to assess whether the effect is influenced by the PROCR H1 haplotype. We evaluated APC, PC, and factor (F)II levels in 502 VTE patients (158 with and 344 without OACs) and in 322 healthy individuals. Mean APC, PC and FII levels were significantly lower in OAC patients than in patients not taking OACs. During anticoagulant therapy, the FII/PC ratios were independent of the PC values, whereas APC/FII and APC/PC ratios significantly increased when FII and PC levels decreased. Of the 22 OAC patients carrying the H1H1genotype, 11 (50%) showed APC/PCag ≥2.0 and 10 (45%) APC/ FIIag ratios ≥2.0, whereas for the 49 OAC patients non-carrying the H1 haplotype these figures were 6 (12%) and 4 (8%), respectively (p<0.001). Barium citrate adsorption of plasma from OAC patients showed that most of the circulating free and complexed APC, but only part of PCag, is fully carboxylated. In conclusion, during anticoagulant therapy VT patients have APC levels disproportionately higher than the corresponding PC levels, mainly due to the presence of the PROCR H1 haplotype. Furthermore, a sufficiently carboxylated PC Gla-domain seems to be essential for PC activation in vivo.

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Effect of warfarin on plasma and liver vitamin K levels and vitamin K epoxide reductase activity in relation to plasma clotting factor levels in rats

Thrombosis Research ◽

10.1016/0049-3848(90)90320-c ◽

1990 ◽

Vol 57 (2) ◽

pp. 205-214 ◽

Cited By ~ 9

Author(s):

Yoshitaka Yamanaka ◽

Masahiro Yamano ◽

Kojiro Yasunaga ◽

Tsutomu Shike ◽

Kiyohisa Uchida

Keyword(s):

Vitamin K ◽

Reductase Activity ◽

Clotting Factor ◽

Vitamin K Epoxide Reductase ◽

Epoxide Reductase ◽

Liver Vitamin

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A gyógyszer indukálta vérzékeny betegek fogorvosi, szájsebészeti ellátása: a 2015-ös hazai szakmai ajánlás alkalmazása és értékelése

Orvosi Hetilap ◽

10.1556/650.2016.30568 ◽

2016 ◽

Vol 157 (43) ◽

pp. 1722-1728

Author(s):

Dénes Lukács ◽

Nóra Stáczer ◽

László Vajta ◽

Lajos Olasz ◽

Árpád Joób-Fancsaly ◽

...

Keyword(s):

Antiplatelet Therapy ◽

Vitamin K ◽

Dental Treatment ◽

Oral Anticoagulant Therapy ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Postoperative Bleeding ◽

Bleeding Risk ◽

Night Duty ◽

Anticoagulated Patients

Introduction: In 2015 a new Hungarian guideline was published regarding dental treatment and management of anticoagulated patients in agreement of the Hungarian Association of Oral and Maxillofacial Surgeons and the Dental Implantology Association of Hungarian Dentists. Aim: The aim of the authors was to evaluate the efficiency and safety of local hemostatic measures recommended by the guideline in anticoagulated patients. Method: In these patients, postoperative bleeding episodes were examined after dental and oral surgical treatments, retrospectively. Results: Overall 263 bleeding risk cases were treated; 138 patients with vitamin K antagonists, 97 patients with antiplatelet therapy and 6 patients with novel oral anticoagulants. Six patients (2.3%) had minor postoperative bleeding after the “one hour control”, while one patient needed a night duty support (0.5%). In contrast, 86 patients who were treated in rural practices neglecting the guideline attended the night duty with postoperative bleeding (3 patients treated with vitamin K antagonists, 24 patients taking low molecular weight heparin, 30 patients receiving antiplatelet therapy and one patient on novel oral anticoagulant therapy. Conclusions: The Hungarian guideline can be applied safely, without increasing the risk of postoperative bleeding, however, rural dental practices are frequently unprepared for these treatments. Orv. hetil., 2016, 157(43), 1722–1728.

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