Vitamin K and Coumadin
Andres Ferber MD
September 15 2009
Coumadin is an anticoagulant because….
1)
2)
3)
4)
It inhibits blood coagulation
It prevents the (protein) synthesis of factors 2,7,9,10
Its action results in hypo functioning factors 2,7,9,10
All of the above
Vitamin K
Gamma Carboxylation
•
Introduction of an additional carboxylic group in the position
gamma of glutamic acid
•
The vitamin K dependent factors; II,VII, IX,X,Protein C,Protein
S,Protein Z and the Bone proteins; Bone Gla protein and Matrix
Gla protein have a Gla domain where several glutamic acids are
clustered and get gamma carboxylated.
•
Other proteins including GAS-6 (growth arrest protein), two thyroid
and spinal cord proteins and certain peptide toxin from mollusks
contain Gla domains.
•
In the coagulation factors gamma carboxylation increases Calcium
binding. Upon Ca++ binding a conformational change of the
molecule occurs exposing an three hydrophobic residues that are
responsible for phospholipid membrane binding. This in turn
produces a marked increased in the activity of the factor.
Procoagulant factors
Anticoagulant factors
Gamma Carboxylation
gCarboxylase
Endoplasmic Reticulum
mRNA
gCarboxylation in Progress
Gamma Carboxylation
gCarboxylation in Progress
Last gCarboxylation Event
Cleavage of the propetide peptide
Golgi
Ca++
Enzyme/Cofactor/membrane complex
activation vs “activation”
Vitamin K dependent factor
Ca++
gCarboxylation
VIIa+TF
FX
Ca++
F Xa
Ca++
Va F Xa
Ca++
The carboxylation reaction
•
The vitamin K dependent carboxylase requires Oxigen and Uses CO2 as a
source of carbon.
•
The reduced vitamin K is converted to the epoxide during the reaction.
•
The vitamin K dependent step is the removal of the H from the gamma
carbon,the reduced vitamin K is the oxygen acceptor in the step and gets
oxydized.
•
The carboxylase has a glutamate and a propeptide binding sites.
•
Both carboxylation and epoxidase activity are in the same protein.
The Gammacarboxylation reaction
Vitamin K
Hydroquinone
Vitamine K
Epoxide
gCarboxyglutamate
Glutamate
O2
CO2
Recycling of vitamin K
•
After forming part of the polypeptide and after proteolyis free gamma
carboxyglutamic acid enters the circulation and it is not re-used.It is excreted
in the urine.Therefore there is a 1:1 ratio of the number of Gla residues and the
conversion of KH2 into KO.
•
On the basis of nutritional intake of vitamin K and urinary Gla excretion it can
be calculated that the number of carboxylation events exceeds the number of
vitamin K molecules by several thousand folds.
•
Vitamin K is recycled
•
The enzyme KO reductase accomplishes that function.
Recycling of Vitamin K
VKOR
Vitamin K
Hydroquinone
Vitamine K
Epoxide
gCarboxyglutamate
Glutamate
O2
CO2
Coumadin
Coumadin
•
Coumadin interferes with KO reductase
•
Recycling of KO is blocked and results in exhaustion of KH2 stores resulting in
apparent vitamin K deficiency
Mechanism of action of warfarin
Warfarin
Vitamin K
Hydroquinone
Vitamine K
Epoxide
X
Glutamate
O2
VKOR
CO2
gCarboxyglutamate
Coumadin
•
Because conversion of vitamin K to KH2 is not affected the coumadin effect
can be bypassed by administration of exogenous vitamin K
Exogenous vitamin K can revert coumadin effect
Warfarin
VKOR
Exogenous Vitamin K
Vitamin K
Hydroquinone
Vitamine K
Epoxide
gCarboxyglutamate
Glutamate
O2
CO2
Vitamin K1 is reduced to vitamin KH2
Ansell J et al. Chest 2008;133:160S-198S
©2008 by American College of Chest Physicians
VKOR genetic polymorphisms
Warfarin Sensitive Warfarin Resistant
Coumarins
•
Most clinically used coumarins have relatively short half life
acenocoumarol
10hs
warfarin
40hs
phenprocoumon
100hs
•
Rodents have developped resistance to this first generation coumarins by
mutating their KO reductase to a form that has less affinity for coumarins
•
Second generation coumarins or super warfarins are used now as
rodenticides.Their half life is 6 months or more.
•
Treatment of intoxication with these products may require high doses of
vitamin K (up to 200mg/day) for several years.
My patient INR is too high
What to do?
My patient INR is too high
What to do?
Condition
Intervention
INR more than therapeutic range but < 5.0; no significant
bleeding
Lower dose or omit dose; monitor more frequently and resume
at lower dose when INR therapeutic; if only minimally above
therapeutic range, no dose reduction may be required (Grade
1C).
INR ≥ 5.0, but < 9.0; no significant bleeding
Omit next one or two doses, monitor more frequently, and
resume at an appropriately adjusted dose when INR in
therapeutic range. Alternatively, omit dose and give vitamin K
(1–2.5 mg po), particularly if at increased risk of bleeding
(Grade 1C). If more rapid reversal is required because the
patient requires urgent surgery, vitamin K (≤ 5 mg po) can be
given with the expectation that a reduction of the INR will occur
in 24 h. If the INR is still high, additional vitamin K (1–2 mg po)
can be given (Grade 2C).
INR ≥ 9.0; no significant bleeding
Hold warfarin therapy and give higher dose of vitamin K (2.5–5
mg po) with the expectation that the INR will be reduced
substantially in 24–48 h (Grade 1B). Monitor more frequently
and use additional vitamin K if necessary. Resume therapy at
an appropriately adjusted dose when INR is therapeutic.
Serious bleeding at any elevation of INR
Hold warfarin therapy and give vitamin K (10 mg by slow IV
infusion), supplemented with FFP, PCC, or rVIIa, depending on
the urgency of the situation; vitamin K can be repeated q12h
(Grade 1C).
Life-threatening bleeding
Hold warfarin therapy and give FFP, PCC, or rVIIa
supplemented with vitamin K (10 mg by slow IV infusion).
Repeat, if necessary, depending on INR (Grade 1C).
Administration of vitamin K
In patients with mild to moderately elevated INRs without major
bleeding, give vitamin K orally rather than subcutaneously
(Grade 1A).
PCCs (Replace factors)
• Prothrombin Complex Concentrates
– Variable amount of vit K factors including IX
– Variable amounts of factor VII
– No activated factors
– Heparin
– Natural anticoagulants
Recombinant factor VIIa (Activates
Blood Coagulation X to Xa)
TISSUE FACTOR
Tissue Factor Bearing cell
BEARING STRUCTURE
Mode of Action