Familial Warfarin Resistance

1983 ◽  
Vol 17 (4) ◽  
pp. 281-283 ◽  
Author(s):  
Robert J. Holt ◽  
César O. Freytes
Keyword(s):  
Venous Thrombosis ◽  
Vitamin K ◽  
Genetic Basis ◽  
Clotting Factors ◽  
First Report ◽  
Documented Case ◽  
Coumarin Anticoagulant ◽  
Familial Type ◽  
Warfarin Resistance ◽  
Hepatic Synthesis

Warfarin, a coumarin anticoagulant, acts by interfering with the hepatic synthesis of the vitamin-K-dependent clotting factors. It is used clinically in the treatment or prophylaxis of venous thrombosis and embolisms. Resistance to the effects of the coumarin and indanedione anticoagulants has been reported in rats and man, but its incidence has been defined as extremely rare. Resistance has been described as relative, acquired, or hereditary. The first well-documented case was also the first report to identify a genetic basis for this resistance. Since that time, there has been only one other study that strengthened the evidence for a hereditary transmission, and only a few other reports have suggested hereditary influence as a reason for coumarin resistance. In this report, a patient who presented with a familial-type warfarin resistance is described. A discussion of previous reports and possible mechanisms for nonfamilial warfarin resistance is also included.

scholarly journals Vitamin K-Dependent Coagulation Factors That May be Responsible for Both Bleeding and Thrombosis (FII, FVII, and FIX)

2018 ◽  
Vol 24 (9_suppl) ◽  
pp. 42S-47S ◽  
Author(s):  
Antonio Girolami ◽  
Silvia Ferrari ◽  
Elisabetta Cosi ◽  
Claudia Santarossa ◽  
Maria Luigia Randi
Keyword(s):  
Venous Thrombosis ◽  
Vitamin K ◽  
Protein C ◽  
Protein S ◽  
Coagulation Factors ◽  
Bleeding Tendency ◽  
Clotting Factors ◽  
Protein Z ◽  
Clinical Observations

Vitamin K-dependent clotting factors are commonly divided into prohemorrhagic (FII, FVII, FIX, and FX) and antithrombotic (protein C and protein S). Furthermore, another protein (protein Z) does not seem strictly correlated with blood clotting. As a consequence of this assumption, vitamin K-dependent defects were considered as hemorrhagic or thrombotic disorders. Recent clinical observations, and especially, recent advances in molecular biology investigations, have demonstrated that this was incorrect. In 2009, it was demonstrated that the mutation Arg338Leu in exon 8 of FIX was associated with the appearance of a thrombophilic state and venous thrombosis. The defect was characterized by a 10-fold increased activity in FIX activity, while FIX antigen was only slightly increased (FIX Padua). On the other hand, it was noted on clinical grounds that the thrombosis, mainly venous, was present in about 2% to 3% of patients with FVII deficiency. It was subsequently demonstrated that 2 mutations in FVII, namely, Arg304Gln and Ala294Val, were particularly affected. Both these mutations are type 2 defects, namely, they show low activity but normal or near-normal FVII antigen. More recently, in 2011-2012, it was noted that prothrombin defects due to mutations of Arg596 to Leu, Gln, or Trp in exon 15 cause the appearance of a dysprothrombinemia that shows no bleeding tendency but instead a prothrombotic state with venous thrombosis. On the contrary, no abnormality of protein C or protein S has been shown to be associated with bleeding rather than with thrombosis. These studies have considerably widened the spectrum and significance of blood coagulation studies.

The Effect of 6-Substituted Imidazo(4,5-b)Pyridines on Vitamin K-Dependent Procoagulants in Dogs, Warfarin-Sensitive and Resistant Rats

1975 ◽  
Author(s):  
N. U. Bang ◽  
G. O. P. O’Doherty ◽  
R. D. Barton
Keyword(s):  
Vitamin K ◽  
Mechanism Of Action ◽  
General Structure ◽  
Vitamin K Antagonists ◽  
Female Rats ◽  
Clotting Factor ◽  
Clotting Factors ◽  
Sodium Bisulphite ◽  
Selective Suppression ◽  
Warfarin Resistance

Dogs and warfarin-sensitive rats chronically fed a series of 6-substituted imidazo (4,5-b)-pyridines (6-I[4,5-b]P)General structure:died with a picture of generalized hemorrhage. The mechanism of action of these compounds was a selective suppression of the activities of vitamin K-dependent clotting factors II, VII, IX and X. Like warfarin, 6-I(4,5-b)P were significantly more effective in suppressing vitamin K -dependent clotting factor activities in male than in female rats. Rats proven resistant to warfarin also exhibited resistance to 6-I(4,5-b)P. Menadione sodium bisulphite did not antagonize the suppression of vitamin K-dependent clotting factor activities by 6-I(4,5-b)P. 6-I(4,5 -b)P structurally far removed from either vitamin K or the conventional vitamin K antagonists, the coumarins and indandiones may represent important tools to further elucidate the chain of events leading to vitamin K-dependent procoagulant synthesis and in pinpointing the biochemical defect responsible for warfarin resistance.

Presence of a T383G Mutation in the Vitamin K Epoxide Reductase Gene (VKORC1) in a Patient Resistant to Four Different Vitamin K Antagonists.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4068-4068
Author(s):  
Michel-Meyer M.M. Samama ◽  
Laurent L. Bodin ◽  
Marie Helene M.H. Horellou ◽  
Florence F. Parent ◽  
Anne A. Kereveur ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Vitamin K ◽  
Low Molecular Weight Heparin ◽  
Vitamin K Antagonists ◽  
Low Molecular Weight ◽  
Clotting Factors ◽  
Vitamin K Epoxide Reductase ◽  
Vitamin K Cycle ◽  
Epoxide Reductase ◽  
Warfarin Resistance

Abstract Resistance to vitamin K antagonists is a rare disorder which until recently has not been associated to a genetic factor. The existence of inherited warfarin resistant rat strains has been related to mutations of the genes involved in the vitamin K cycle. Vitamin K dependent carboxylase was cloned in 19911, while human vitamin K epoxide reductase complex 1 (VKORC1), another enzyme implicated in vitamin K cycle, has been cloned more recently2,3. Mutations in this gene are responsible for both human and rat warfarin resistance 3. In 1997, we reported 4 a 63-year old patient with recurrent pulmonary embolism and deep vein thrombosis without known hereditary or acquired thrombophilia who was found resistant to warfarin (up to 45mg/day), fluindione (up to 80mg/day), acenocoumarol (up to 12 mg/day) and phenprocoumon (up to 30 mg/day). With phenprocoumon, long-acting vitamin K antagonist, drug concentration reached 85 mg/L (usual range 1–5 mg/L) but the INR remained around 1. Daily low molecular weight heparin (LMWH) was continued 3 months. Treatment was discontinued on 2 occasions and a recurrent thrombotic episode was observed. The patient is now receiving a single daily dose of low molecular weight heparin (80 mg Enoxaparin, body weight 120 kg, 67 IU/kg once a day) for the past 10 years without thrombotic or bleeding episodes. Osteodensitometry remains normal after 9 years of treatment. Careful biochemichal investigation had demonstrated a deficiency in vitamin K dependent carboxylation and absence of blockade of vitamin K epoxide reductase by phenprocoumon. This year, we sequenced the three exons of VKORC1 in this patient and detected a heterozygous T383G transversion resulting in a leucine to arginine substitution (L128R). This mutation has been recently identified by Rost3 et al. in an individual with warfarin resistance. It was not found in 259 control subjects that we had tested. Interestingly, another gene mutation of the VKORC1 can be responsible for a combined deficiency of vitamin K dependent clotting factors 3. In conclusion, a resistance to all vitamin K antagonists, including warfarin up to 45 mg/day is extremely rare and the mutation T383G of the VKORC gene has been reported in only one patient before the case reported here. Testing for mutation in VKORC1 will help in explaining some cases of anti vitamin K resistance.

Copy Number Variation of PROS1 and Protein S Deficiency Are Rare in a Population-Based Case-Control Study On Venous Thrombosis (MEGA study).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3166-3166
Author(s):  
Maria Carolina Pintao ◽  
Irene D Bezemer ◽  
Andrea Aparecida Garcia ◽  
Marieke C.H. de Visser ◽  
Carine J.M. Doggen ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thrombosis ◽  
Vitamin K ◽  
Copy Number ◽  
Genetic Basis ◽  
Conflicts Of Interest ◽  
Protein S ◽  
Population Based ◽  
Copy Number Variations ◽  
Control Group

Abstract Abstract 3166 Poster Board III-106 Protein S (PS) deficiency increases the risk of venous thrombosis (VT) in family studies, but it has been difficult to estimate the risk in population-based studies. Moreover, the genetic basis of PS deficiency is only poorly understood as in about 50% of PS deficient families no mutations are found by exon-targeted sequencing of the PS gene PROS1. Further, the laboratory diagnosis of PS deficiency is complicated by physiological variation due to age and sex, as well as interference by pregnancy, use of hormones and medication and vitamin K deficiency. We recently showed with the multiplex ligation-dependent probe amplification (MLPA) methodology, that whole or partial deletion of PROS1 explained PS deficiency in around 40% of point mutation-negative French PS deficient families. Here, we analyzed PS deficiency in the MEGA (Multiple Environmental and Genetic Assessment) study to verify whether gross gene deletions or duplications are also common in unselected individuals with venous thrombosis. The MEGA study included 5000 patients with a first episode of deep VT or pulmonary embolism and 5000 controls. Questionnaires and DNA samples were taken for every participant and blood was collected in around half of patients and controls. Total PS (tPS) was measured in plasma by ELISA. For analysis, vitamin K users were excluded yielding 2198 patients and 2904 controls. The mean tPS (±SD) was 102.6 U/dL (±19.1) in patients and 100.8 U/dL (±19.7) in controls. OR and 95% confidence interval were computed to estimate the relative risk of thrombosis. PS was not a risk factor for thrombosis in the MEGA study when deciles were used to calculate OR neither when lowest 2.5% or 1% PS levels was examined (data not shown). We then randomly analyzed DNA samples from 2270 participants out of 10000 individuals (1395 patients and 875 controls) by MLPA to look for copy number variations (CNVs). In only one individual an abnormal MLPA pattern was found and the test was repeated confirming results. This individual, a female patient of 66 years who was not using estrogens, was heterozygous for a deletion of the complete PROS1 gene. Her tPS was 64.3 U/dL, which was below the 2.5th percentile (tPS = 65.3 U/dL) of the total MEGA control group. To check if the frequency of CNVs in PROS1 was indeed low in the MEGA, we zoomed in on PS deficiency by selecting DNA from individuals with low tPS (cuttof: mean tPS -2SD of the total MEGA control group), not excluding vitamin K users. This selection yielded 404 individuals, out of which 198 had been previously analyzed in the first round. MLPA was performed for the remaining 206 individuals and no new CNV was found in PROS1. In conclusion, PS deficiency was not a risk factor for VT in this population-based study and deletions or duplications in PROS1 were not common. This is in contrast with previous data from family-based studies but in accordance with the fact that the genetic basis of PS deficiency and its risk for VT outside of a family setting was also not evident in other studies. Disclosures No relevant conflicts of interest to declare.

Idiopathic venous thrombosis

2006 ◽  
Vol 26 (01) ◽  
pp. 52-54 ◽  
Author(s):  
P. A. Kyrle
Keyword(s):  
Chronic Disease ◽  
Venous Thrombosis ◽  
Vitamin K ◽  
Clinical Benefit ◽  
Plasma Levels ◽  
Vitamin K Antagonists ◽  
Antithrombin Deficiency ◽  
Optimal Duration ◽  
Risk Of Treatment

SummaryVenous thrombosis is a chronic disease with a recurrence rate of approximately 30% within 5-8 years. The optimal duration of secondary thromboprophylaxis in these patients entails balancing the risk of recurrence against the risk of treatment-associated bleeding. There is agreement that patients with a first idiopathic venous thrombosis should receive vitamin K antagonists for at least 3-6 months. Convincing trials showing a clinical benefit in terms of morbidity or mortality with respect to expansion of anticoagulation beyond 6 months are lacking. Nevertheless, some subgroups of patients with venous thrombosis may benefit from indefinite anticoagulation. Thus, patients with antithrombin deficiency, combined or homozygous defects, more than one unprovoked episode of thrombosis, the lupus anticoagulant or high factor VIII plasma levels are good candidates for long-term prevention.

Hypercoagulable State in the Watanabe Heritable Hyperlipidemic Rabbit, an Animal Model for the Progression of Atherosclerosis

1989 ◽  
Vol 61 (01) ◽  
pp. 140-143 ◽  
Author(s):  
Yoshitaka Mori ◽  
Hideo Wada ◽  
Yutaka Nagano ◽  
Katsumi Deguch ◽  
Toru Kita ◽  
...  
Keyword(s):  
Vitamin K ◽  
Fibrinogen Level ◽  
Plasma Cholesterol ◽  
Age Groups ◽  
Clotting Factor ◽  
Clotting Factors ◽  
Group A ◽  
Hyperlipidemic Rabbit ◽  
Group B ◽  
Progression Of Atherosclerosis

SummaryBlood coagulation in a strain of rabbits designated as Watanabe heritable hyperlipidemic (WHHL) rabbits was examined. The activities of vitamin K-dependent clotting factors, contact factors and clotting factor VIII (F VIII) and the fibrinogen level were significantly higher in WHHL rabbits than in normolipidemic rabbits (all age groups). Values for vitamin Independent clotting factor were already higher at 2 months of age. Contact factors and fibrinogen levels increased age after 5 to 8 months. F VIII increased between 5 and 8 months and then decreased. At 2 months of age, WHHL rabbits were divided into two groups. Group A was fed standard rabbit chow and group B standard rabbit chow containing 1% probucol. Probucol prevented the progression of atherosclerosis in group B in the absence of a significant reduction in plasma cholesterol level. F VIII and fibrinogen levels were statistically decreased in all rabbits at all ages in group B (P<0.05). These differences in clotting factors between the two groups were most obvious at 8 months (P<0.02).We conclude that vitamin K-dependent clotting factors may increase with hyperlipemia and that increases in F VIII and fibrinogen may be closely related to the progression of throm- boatherosclerosis.

Mutations which Introduce Free Cysteine Residues in the Gla-Domain of Vitamin K Dependent Proteins Result in the Formation of Complexes with α1-Microglobulin

1996 ◽  
Vol 75 (01) ◽  
pp. 070-075 ◽  
Author(s):  
E G C Wojcik ◽  
P Simioni ◽  
M v d Berg ◽  
A Girolami ◽  
R M Bertina
Keyword(s):  
Vitamin K ◽  
Protein C ◽  
Cysteine Residue ◽  
Factor Ix ◽  
Disulphide Bond ◽  
Clotting Factors ◽  
High Molecular Weight Complex ◽  
Low Concentrations ◽  
Gla Domain ◽  
Formation Of Complexes

SummaryWe have previously described a genetic factor IX variant (Cys18→Arg) for which we demonstrated that it had formed a heterodimer with armicroglobulin through formation of a disulphide bond with the remaining free cysteine residue of the disrupted disulphide bond in the Gla-domain of factor IX. Recently, we observed a similar high molecular weight complex for a genetic protein C variant (Arg-1→Cys). Both the factor IX and the protein C variants have a defect in the calcium induced conformation. In this study we show that the aminoterminus of this protein C variant is prolonged with one amino acid, cysteine. This protein C variant, as well as protein C variants with Arg9→Cys and Ser12→Cys mutations which also carry a free cysteine residue, are shown to be present in plasma as a complex with α1-microglobulin. A prothrombin variant with a Tyr44→Cys mutation, had not formed such a complex. Furthermore, complexes between normal vitamin K-dependent clotting factors and α1-microglobulin were shown to be present in plasma at low concentrations. The data suggest that the presence of an unpaired cysteine residue in the propeptide or the N-terminal half of the Gla-domain has strongly promoted the formation of a complex with α1-microglobulin in the variants.

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.

The Reaction of Thiol Compounds with the Vitamin-K Dependent Clotting Factors

1969 ◽  
Vol 21 (03) ◽  
pp. 573-579 ◽  
Author(s):  
P Fantl
Keyword(s):  
Prothrombin Time ◽  
Vitamin K ◽  
Anaerobic Conditions ◽  
Clotting Factors ◽  
Thiol Compounds ◽  
Aerobic Conditions ◽  
One Stage ◽  
Factor Ii ◽  
Ph Dependent ◽  
The One

SummaryTreatment of human and dog oxalated plasma with 0.2 to 1.0 × 10−1 M 2.3-dithiopropanol (BAL) or dithiothreitol (DTT) at 2–4° C for 30 min results in the reduction of the vitamin-K dependent clotting factors II, VII, IX and X to the respective-SH derivatives. The reaction is pH dependent. Under aerobic conditions the delayed one stage prothrombin time can be partly reversed. Under anaerobic conditions a gradual prolongation of the one stage prothrombin time occurs without reversal.In very diluted plasma treated with the dithiols, prothrombin can be converted into thrombin if serum as source of active factors VII and X is added. In contrast SH factors VII, IX and X are inactive in the specific tests. Reoxidation to active factors II, VII, IX and X takes place during adsorption and elution of the SH derivatives. The experiments have indicated that not only factor II but also factors VII, IX and X have active-S-S-centres.

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.

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