Anticoagulant Therapy

Stephen Larsen
Institute of Haematology
RPAH
Definition of Anticoagulation
Therapeutic interference ("blood-thinning")
with the clotting mechanism of the blood
to prevent or treat thrombosis and
embolism.

Overview
Indications
A basic case study
Heparin/heparin like drugs and their
complications
Warfarin
New anticoagulant drugs
Indications of Anticoagulant
Therapy
Treatment and Prevention of Deep Venous
Thrombosis
Pulmonary Emboli
Prevention of stroke in patients with atrial
fibrillation, artificial heart valves, cardiac
thrombus.
Ischaemic heart disease
During procedures such as cardiac
catheterisation and apheresis.

A basic case study
51 year old man
Has severe osteoarthritis
Required surgery on his right knee
Underwent a total knee replacement
4 days after surgery complained of an
increase in pain and swelling in the calf
of the right leg
A doppler ultrasound demonstrated a
thrombosis in the deep veins of the calf
extending up to the popliteal vein.
Was started on 12 hourly injections of the low
molecular weight heparin clexane given as
subcutaneous injection
Simultaneously started on an oral tablet,
warfarin, 5mg once per day.
Had daily blood tests to monitor the INR.
After 5 days, the INR had gone up to 2.2. The
clexane was stopped and he was discharged
from hospital to continue on warfarin 5mg
daily.
He underwent INR testing every two weeks.
The warfarin was stopped after 3 months. He
had no recurrence.
Pertinent Questions from this
case
How do heparin drugs work?
How does warfarin work?
Why start both clexane and warfarin?
What is an INR and how is heparin
monitored?
What are the risks of both of these
types of drugs?

Standard Heparin
Heterogenous mixture of polysaccharide
chains
MW 3k to 30k
Active in vitro and in vivo
Administration - parenteral- Do not inject IM -
only IV or deep s.c.
Half-life 1 - 2 hrs - monitor APTT
Adverse effect - haemorrhage - antidote -
protamine sulphate
Enhances
Antithrombin Activity
Heparin mechanism of action
Heparin
Antithrombin III
Thrombin
Monitoring Heparin
Activated Partial Thromboplastin Time
(APTT)
Normal range: 25-40 seconds
Therapeutic Range: 55-70 seconds
Timing
4-6 hours after commencing infusion
4-6 hours after changing dosing regimen

Low Molecular Weight Heparin
Changed management of venous
thromboembolism
Standard (Unfractionated) heparin 3k to
30k
LMWH contains polysaccharide chains
MW 5k
Enriched with short chains with higher
anti-Xa:IIa ratio
Differences in Mechanism of
Action
Any size of heparin chain can inhibit the
action of factor Xa by binding to antithrombin
(AT)
In contrast, in order to inactivate thrombin
(IIa), the heparin molecule must be long
enough to bind both antithrombin and
thrombin
Less than half of the chains of LMWH are
long enough

Complications of Heparin
Haemorrhage
Heparin-induced thrombocytopaenia
(HIT)
Osteoporosis (long-term only)
Heparin-Induced
Thrombocytopaenia
Most significant adverse effect of
heparin after haemorrhage
Most common drug-induced
thrombocytopenia
A large number of patients receive
heparin in the hospital environment.
Non-immune heparin-associated
thrombocytopaenia (HIT Type I)
Benign
Up to 10% patients on heparin
Rapid decline in platelet count within
first 2 days of heparin administration
Platelet count >100 000/ul
Returns to normal within 5 days despite
continued heparin use (or within 2 days
if heparin is stopped).
Heparin-induced
thrombocytopaenia: HIT type 2
Potentially catastrophic thrombosis (Heparin-
induced thrombocytopenia and thrombosis)
8% of patients on heparin develop antibody
without becoming thrombocytopenic
1-5% patients on heparin develop
thrombocytopaenia
Of those with thrombocytopaenia, 30%
develop venous and/or arterial thrombosis
Bleeding uncommon
Trreatment of HIT
Discontinue all heparin
If need to continue anti-coagulation, use
danaparoid (orgaran).
Avoid platelet transfusions
Thrombosis: use danaparoid or
thrombin inhibitor

Vitamin K
Synthesis of
Functional
Coagulation
Factors
VII
IX
X
II
Vitamin K-Dependent Clotting
Factors
Warfarin
Synthesis of
Non
Functional
Coagulation
Factors
Antagonism
of
Vitamin K
Warfarin Mechanism of Action
Vitamin K
VII
IX
X
II
Enhances
Antithrombin Activity
Warfarin
Warfarin: Major Adverse Effect
Haemorrhage
Factors that may influence bleeding
risk:
Intensity of anticoagulation
Concomitant clinical disorders
Concomitant use of other medications
Quality of management
Warfarin-induced Skin Necrosis
Prothrombin Time (PT)
Historically, a most reliable and relied upon
clinical test
However:
Proliferation of thromboplastin reagents
with widely varying sensitivities to reduced
levels of vitamin K-dependent clotting
factors has occurred
Problem addressed by use of INR
(International Normalised Ratio)
INR: International Normalised
Ratio
A mathematical correction (of the PT ratio)
for differences in the sensitivity of
thromboplastin reagents
INR is the PT ratio one would have obtained if
the reference thromboplastin had been used
Allows for comparison of results between labs
and standardises reporting of the prothrombin
time
( )
Patients PT in Seconds
Mean Normal PT in Seconds
INR =
ISI
INR = International Normalised Ratio


ISI = International Sensitivity Index
INR Equation
Target INR
DVT, PE, Atrial Fibrillation: 2-3
Artificial Cardiac Valve: 3-3.5
Changing over from Heparin to
Warfarin
May begin concomitantly with heparin therapy
Heparin should be continued for a minimum
of four days
Time to peak antithrombotic effect of
warfarin is delayed 96 hours (despite INR)
When INR reaches desired therapeutic
range, discontinue heparin (after a minimum
of four days)
Warfarin: Dosing & Monitoring
Start low
Initiate 5 mg daily
Educate patient
Stabilise
Titrate to appropriate INR
Monitor INR frequently (daily then weekly)
Adjust as necessary
Monitor INR regularly (every 14 weeks) and adjust
Relative Contraindications to
Warfarin Therapy
Pregnancy
Situations where the risk of hemorrhage
is greater than the potential clinical
benefits of therapy
Uncontrolled alcohol/drug abuse
Unsupervised dementia/psychosis
Signs of Warfarin Overdosage
Any unusual bleeding:
Blood in stools or urine
Excessive menstrual bleeding
Bruising
Excessive nose bleeds/bleeding gums
Persistent oozing from superficial injuries
Bleeding from tumor, ulcer, or other lesion
Reversing action of warfarin
Plasma
Rapid but short-lasting
Vitamin K
Not rapid, but lasts 1-2 weeks. Do not use
if wishing to restart warfarin within next
week.
New Anticoagulation Drugs
Direct Thrombin Inhibitors
Ximelagatran, hirudin, bivalirudin, and
argatroban
Synthetic pentasaccharide
Acivated Protein C
Tissue Factor Pathway Inhibitor (TFPI)

Why do we need new
anticoagulation drugs?
Heparin-induced thrombocytopenia
Heparin prophylaxis is imperfect
Heparin-associated osteoporosis
Warfarin takes several days for its effect
Warfarin is not as effective in some situations
e.g antiphospholipid syndrome
Warfarin interacts with many other drugs
Warfarin is dangerous if not monitored

Synthetic Pentasaccharide
E.g Fonaparinux
Synthetic, single molecular entity
Targets Factor Xa
Does not cause thrombocytopenia
Shown promise in DVT prevention
during orthopedic procedures.
Also being examined in ischaemic heart
disease
Ximelagatran
Promising oral direct thrombin inhibitor
Converted to the active form melagatran
in vivo
No dosing problems
No monitoring needed.
Recent atrial fibrillation study showed it
to possibly be superior to warfarin.

Enhances
Antithrombin Activity
Ximelagatran
Conclusion
Anticoagulant therapy is use extensively.
Current mainstays of treatment are heparin or
heparin-like drugs and oral warfarin.
Both have problems but when monitored
closely are generally safe.
New anticoagulation drugs are arriving and in
particular ximelagatran may revolutionise oral
anticoagulation therapy