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•  Discuss pathophysiology of vitamin K antagonists with regards to coagulation.

•  Review pharmacology of vitamin K.

•  Review several guidelines for warfarin reversal.

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•  There are no conflicts of interest to disclose.

•  79 year old female presents with headache, confusion for 2 hours.

•  PMH: A-Fib, HTN, CAD.

•  Meds: Metoprolol, warfarin, HCTZ.

•  INR: 2.2.

•  Head CT with intraparenchymal hemorrhage.

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•  Which of the following represents the best treatment strategy? a) 4 units FFP b) 10 mg SQ vitamin K c) 10 mg IV vitamin K d) 4 units FFP and 2 mg SQ vitamin K e) 4 units FFP and 10 mg IV vitamin K

•  50 year old female with history of DVT, on warfarin, presents to the ED for high INR.

•  Routine check by PCP revealed INR of 8. She was referred to the ED.

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•  Which of the following represents the best treatment strategy? a) 2.5 mg PO vitamin K b) 10 mg PO vitamin K c) 5 mg SQ vitamin K d) 4 units FFP and 2 mg SQ vitamin K e) 4 units FFP and 10 mg IV vitamin K

•  A 2 year old male presents to the emergency department after ingestion of 5 pellets of D-con.

•  The patient is asymptomatic, and not normally on any medication.

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•  Which represents the best treatment option for this patient? a) No therapy required; if there is concern the

patient ate many pellets, the patient can be referred for labs in 24-36 hours

b) 10 mg oral vitamin K c) 10 mg IV vitamin K d) 2 Units FFP, 5 mg IV vitamin K e) 4 Units FFP, 10 mg IV vitamin K

•  1920’s: Chicken fed a poor diet bleed.

•  1935: Administration of a fat-soluble substance in the diet reduces bleeding “Koagulation factor.”

•  1948: warfarin used as rodenticide.

•  2004: 31 million Americans on warfarin.

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•  Current uses of vitamin K antagonists include: – Medicinal (warfarin) – Rodenticides (bordifacoum)

CLOTTING FACTOR HALF-LIFE (H)

II 50

VII 6

IX 24

X 36

Protein C 8

Protein S 30

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•  2-3 half-lives needed before significant change in INR noted.

•  Full effect may not be apparent for several days.

•  Term “vitamin K” actually encompasses: – Vitamin K1 (phytonadione, phylloquinone)

– Vitamin K2 (menaquinones)

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•  Vitamin K1 (phytonadione, phylloquinone) – Synthesized from plants and algae – Primary form in diet

•  Vitamin K2 (menaquinones) – Synthesized by bacteria; destruction of bacteria

partly explains interaction between warfarin and many antibiotics

•  Relatively little required in diet.

•  Adult RDA 1 mcg/kg/d.

•  10 mcg/kg/d needed in infants to maintain normal homeostasis.

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•  Bile salts and fatty acids are required for vitamin K absorption.

•  After absorption, vitamin K moved to liver via lymphatic system.

•  Travels bound to chylomicrons.

•  Once in liver, it helps with production of clotting factors.

•  Several different forms of vitamin K are available: – K1 (phylloquinone, phytonadione) – K3 (menadione) – K4 (menadiol sodium diphosphate)

•  K3, K4 associated with several adverse effects: – Neonates: Hemolysis, hyperbilirubinemia, and

kernicterus – G6PD deficient: Hemolysis

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De Zee KJ, Shimeall WT, Douglas KM. Treatmetn of excessive anticoagulation with phytonadione (vitamin K): A meta-analysis. Arch Intern Med. 2006; 166:391-7.

Percentage of patients having an INR in the therapeutic range (1.8-4.0) 24 hours after vitamin K vs. placebo.

Percentage of patients having an INR remain > 4.0 24 hours after vitamin K vs. placebo.

•  Vitamin K cycles between inactive and active forms.

•  Only the reduced (quinol) form has biologic activity.

•  The active quinol form can be formed via vitamin K dependent pathway or via NADPH-dependent pathway.

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OH O

CO2 + O2

Vitamin K epoxide reductase

Vitamin K quinone reductase

Inactive factors II, VII, IX, X, Protein C and S

Active factors II, VII, IX, X, Protein C and S

Vitamin K Quinol

Vitamin K Quinone

Vitamin K 2, 3 epoxide

NADPH dependent quinone reductase

(Active)

•  The NADPH-dependent pathway is insensitive to warfarin.

•  The epoxide reducatase and the quinone reductase are dithiol-dependent vitamin K reductases.

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•  Deficiency can result from inadequate intake, malabsorption, or interference with vitamin K cycle.

•  Deficiency can also be acquired from xenobiotics.

•  Warfarin interferes with vitamin K cycle, resulting in accumulation of the inactive 2,3 epoxide.

•  Super-warfarins even more potent vitamin K reductase inhibitors.

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•  PO: no significant adverse effects.

•  IM/SQ: hematoma. No role in routine management.

•  IV: Potential for anaphylactoid reaction.

•  In general, IV route very safe if administered slowly.

•  IV vitamin K available as colloidal suspension of polyoxythylated castor oil, dextrose, and benzyl alcohol.

•  Previously with higher rates of anaphylactoid reaction because of different components of suspension.

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•  Doses of up to 250 mg daily for several weeks to months may be required for massive bordifacoum ingestions.

•  Published guidelines are for reversal of warfarin and do not apply to bordifacoum ingestions.

INR CHEST Guidelines

Australasian Society of Thrombosis and Haemostasis

2-5; no bleeding

Lower or omit dose Lower or omit dose

5-9; no bleeding

Hold 1-2 doses. OR 1-2.5 mg PO vitamin K*

Hold warfarin. If bleeding risk high, 1-2 mg PO or 0.5-1 mg IV vitamin K

> 9; no bleeding

Hold warfarin; give 5 mg PO vitamin K

Hold warfarin. If bleeding risk low, give 2.5-5 mg PO vitamin K or 1 mg IV vitamin K. If high risk, give 1 mg IV vitamin K, consider PCC, FFP

Serious bleeding

Hold warfarin. Give 10 mg IV vitamin K, supplemented by FFP, PCC, or rVIIa

Hold warfarin. Give 5-10 mg IV vitamin K, PCC and FFP

Life threatening bleeding

Hold warfarin. Give FFP, PCC, or rVIIa, supplemented by 10 mg IV vitamin K

* 5 mg can be given if more rapid reduction in INR needed (e.g. patient going to surgery)

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•  Correct coagulopathy in liver failure patients; can give dose to correct any nutritional component of the coagulopathy.

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•  79 year old female presents with headache, confusion for 2 hours.

•  PMH: A-Fib, HTN, CAD.

•  Meds: Metoprolol, warfarin, HCTZ.

•  INR: 2.2.

•  Head CT with intraparenchymal hemorrhage.

•  Which of the following represents the best treatment strategy? a) 4 units FFP b) 10 mg SQ vitamin K c) 10 mg IV vitamin K d) 4 units FFP and 2 mg SQ vitamin K e) 4 units FFP and 10 mg IV vitamin K

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•  Which of the following represents the best treatment strategy? a) 4 units FFP b) 10 mg SQ vitamin K c) 10 mg IV vitamin K d) 4 units FFP and 2 mg SQ vitamin K e) 4 units FFP and 10 mg IV vitamin K

•  50 year old female with history of DVT, on warfarin, presents to the ED for high INR.

•  Routine check by PCP revealed INR of 8. She was referred to the ED.

3/10/11

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•  Which of the following represents the best treatment strategy? a) 2.5 mg PO vitamin K b) 10 mg PO vitamin K c) 5 mg SQ vitamin K b) 4 units FFP and 2 mg SQ vitamin K c) 4 units FFP and 10 mg IV vitamin K

•  Which of the following represents the best treatment strategy? a) 2.5 mg PO vitamin K b) 10 mg PO vitamin K c) 5 mg SQ vitamin K d) 4 units FFP and 2 mg SQ vitamin K e) 4 units FFP and 10 mg IV vitamin K

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•  A 2 year old male presents to the emergency department after ingestion of 5 pellets of D-con.

•  The patient is asymptomatic, and not normally on any medication.

•  Which represents the best treatment option for this patient? a) No therapy required; if there is concern the

patient ate many pellets, the patient can be referred for labs in 24-36 hours

b) 10 mg oral vitamin K c) 10 mg IV vitamin K d) 2 Units FFP, 5 mg IV vitamin K e) 4 Units FFP, 10 mg IV vitamin K

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•  Which represents the best treatment option for this patient? a) No therapy required; if there is concern the

patient ate many pellets, the patient can be referred for labs in 24-36 hours

b) 10 mg oral vitamin K c) 10 mg IV vitamin K d) 2 Units FFP, 5 mg IV vitamin K e) 4 Units FFP, 10 mg IV vitamin K

•  Vitamin K antagonists block vitamin K cycle resulting in accumulation of inactive precursors.

•  IV route rarely associated with anaphylactoid reactions.

•  IM/SQ routes should not be used.

•  Guidelines available for reversal of warfarin-induced supratherapeutic INRs.

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THANK YOU