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

• 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 KVitamin K

Synthesis of Synthesis of Functional Functional

Coagulation Coagulation FactorsFactors

VIIVII

IXIX

XX

IIII

Vitamin K-Dependent Clotting Factors

WarfarinWarfarin

Synthesis of Synthesis of Non Non

Functional Functional Coagulation Coagulation

FactorsFactors

Antagonismof

Vitamin K

Warfarin Mechanism of Action

Vitamin KVitamin K

VIIVII

IXIX

XX

IIII

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 testHowever:– 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

(( ))Patient’s PT in SecondsPatient’s PT in SecondsMean Normal PT in SecondsMean Normal PT in SecondsINR =INR =

ISIISI

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 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?

• 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