Page 389 - Essential Haematology

Chapter 27 Thrombosis and antithrombotic therapy / 375

International n ormalized r atio cells, warfarin is degraded in microsomes to an inac-
tive water - soluble metabolite which is conjugated

Th e effect of oral anticoagulants is monitored by the
and excreted in the bile and partially reabsorbed to

PT. The INR is caculated from it and is based on
be also excreted in urine. Drugs that aff ect the
the ratio of the patient s PT to a mean normal PT
’
albumin binding or excretion of warfarin (or of
‘
with correction for the sensitivity ’ of the thrombo-
other oral anticoagulants) or those that decrease the
plastin used. This is calibrated against a primary

absorption of vitamin K will interfere with the
World Health Organization (WHO) standard
control of therapy (Table 27.7 ).
thromboplastin. The indications and recommended

ranges for INR with warfarin treatment are sum-
marized in Table 27.6 . Management of w arfarin o verdose
Warfarin crosses the placenta and is teratogenic.
If the INR is in excess of 4.5 without bleeding,
Heparin is preferred for pregnant patients because
warfarin should be stopped for 1 or 2 days and the
it does not cross the placenta and its action is
dosage adjusted according to the INR. Th e long
short - lived.
half - life of warfarin (40 hours) delays the full impact
It is usual to continue warfarin for 3 – 6 months
of dose changes for 4 – 5 days. If the INR is very
for established DVT, PE and following xenograft
high (e.g. > 8) without bleeding, an oral dose of
heart valves. Long - term therapy is given for recur-
0.5 – 2.5 mg vitamin K may be given. Mild bleeding
rent venous thrombosis, for embolic complications
usually only needs an INR assessment, drug with-
of rheumatic heart disease or atrial fi brillation, and
drawal and subsequent dosage adjustment (Table
with prosthetic valves and arterial grafts and in
27.8 ). More serious bleeding may need cessation
selected patients with the APS.
of therapy, vitamin K therapy or the infusion of
fresh frozen plasma or prothrombin concentrates.

Drug i nteractions Vitamin K is the specific antidote; an oral or intra-
venous dose of 2.5 mg is usually eff ective. Higher
Approximately 97% of warfarin in the circulation
doses result in resistance to further warfarin therapy
is bound to albumin and only a small fraction of
for 2 – 3 weeks.
warfarin is free and can enter the liver parenchymal
cells; it is this free fraction that is active. In the liver
Management of s urgery

Table 27.6 Oral anticoagulant control tests.
For minor surgery (e.g. dental extraction) antico-
Target levels recommended by the British
agulation can be maintained and mouth rinses with
Society for Haematology.
tranexamic acid given. For major surgery, warfarin
is stopped to get an INR < 1.5 and LMWH given
Target INR Clinical state
when the INR falls to < 2.0 (except on the day of
2.5 Treatment of DVT, pulmonary surgery) and continued until the INR is > 2.0 after
(2.0 – 3.0) embolism, atrial fi brillation, restarting warfarin.
recurrent DVT off warfarin;
symptomatic inherited
thrombophilia, cardiomyopathy, New a nticoagulants
mural thrombus, cardioversion
Traditional anticoagulant therapy has disadvan-
3.0 Recurrent DVT while on tages. LMWH has to be given subcutaneously and
(2.5 – 3.5) warfarin, mechanical prosthetic
warfarin requires frequent monitoring and dose
heart valves, antiphospholipid
adjustment and there is interaction with drugs and
syndrome (some cases)
food.
Factor Xa inhibitors: fondaparinux , a syn-
DVT, deep venous thrombosis; INR, international
normalized ratio. thetic analogue of the antithrombin - binding pen-
tasaccharide of heparin, is an indirect irreversible