Download Anticoagulant Therapy

Anticoagulant Therapy
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
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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
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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 (Heparininduced 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-Dependent Clotting
Factors
Vitamin K
VII
IX
X
II
Synthesis of
Functional
Coagulation
Factors
Warfarin Mechanism of Action
Vitamin K
Antagonism
of
Vitamin K
VII
IX
X
II
Warfarin
Synthesis of
Non
Functional
Coagulation
Factors
Warfarin
Enhances
Antithrombin Activity
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
INR Equation
(
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Patient’s PT in Seconds ISI
INR =
Mean Normal PT in Seconds
INR = International Normalised Ratio
ISI = International Sensitivity Index
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 1–4 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?
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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
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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
Ximelagatran
Antithrombin Activity
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