2014B08 Outline the important pharmacological considerations when stopping warfarin and commencing
prophylactic (low dose) low molecular weight heparin in the peri-op period.

List:

· Intro: aim, problems, risks

· Bridging plans

· PK

· PD

Intro:

Aim

· Minimize time with inadequate anticoagulation if at high risk (e.g mechanical mitral valve)

Problems

· Warfarin: slow onset; long and variable duration of action

· LMWH: short duration, parenteral only, only partially reversible

Risks

· Of bleeding: Warfarin and LMWH have additive effects -> avoid overlap pre-op

· Of clotting: Warfarin initially procoagulant -> ensure overlap post-op

Bridging plans:

Pre-op

· Stop warfarin 5 x 24h pre-op

· Start LMWH 1.5mg/kg daily 3/24 pre-op; 1mg/kg 24h pre-op then no more.

· Check INR on AM of surgery; usually aim <1.5 (surgery dependent)

· Warfarin reversal if required

o Vitamin K e.g. 2mg IV (6-12 hours), 5-10mg PO (12-24 hours)

o FF 2-4mL/kg + Prothrombinex 25-50 units/kg (immediate effect)

o FFP only 10-15mL/kg (immediate effect)

Post-op

· Start LMWH 1.5mg/kg daily or 1mg/kg bd when safe

· Start warfarin at same time

· Cease LMWH when INR at target (e.g. 2-3)

Pharmacokinetics:

	Warfarin	Low molecular weight heparins (LMWH)
Admin	· PO daily	· S/C therapeutic 1.5mg/kg daily or 1mg/kg bd · S/C prophylactic 40mg daily
Time course (normal)	· Onset 8-12 hours · Peak anticoag 72 hours · Offset 3-5 days	· Peak 4 hours · Offset 24 hours therapeutic dose 1.5mg/kg daily, 12 hours prophylactic (40mg in adult)
Absorption	· Oral bioav 90%	· Oral bioav minimal
Distribution	· V_D 0.1L/kg · Plasma protein binding >95% (albumin, own site) · Crosses placenta	· V_D 0.1L/kg · PPB >95% (AT3)
Metabolism	· Phase 1 (multiple CYP) then Phase 2 · t_1/2_β 40 hours	· Minimal metabolism by heparinase (desulfation, depolymerization)
Excretion	· Inactive metabolites -> urine and faeces	· Mostly renal elimination · ↓GFR -> ↑duration hence ↓dose
Factors ↑duration	· CYP inhibitor: e.g. cimetidine · Liver dysfunction: e.g. cirrhosis · Vit K deficiency: e.g. malnutrition	· ↓GFR

Pharmacodynamics:

Warfarin

LMWH

Mechanism

· Inhibit Vit K epoxide reductase

->↓ γ-glutamyl carboxylation

->↓ synthesis of zymogen

· Pentasaccharide sequence binds and potentiates AT3 by conformational change

· LMWH-bound AT3 inhibits coag factors

Anticoagulation

(and t_1/2_β)

Reduced synthesis of:

· II (60), VII (6), IX (24), X (36)
(note long t_1/2 II, X)

Inhibition of:

· Xa:IIa (ratio 2-3:1)

· Also VIIa-TF complex, IX, XI

Procoagulation

(and t_1/2_β)

Reduced synthesis of:

· Protein C (8), protein S (30)
(note short t_1/2 protein C)

· Nil