1. Anticoagulant Therapy

2. Definition of Anticoagulation
Therapeutic interference ("blood-thinning") with the clotting mechanism of the blood to prevent or treat thrombosis and embolism.

3. Overview Indications A basic case study
Heparin/heparin like drugs and their complications
Warfarin
New anticoagulant drugs

4. 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.

5. 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

6. 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.

7. 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.

8. 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?

9. 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 hrs - monitor APTT
Adverse effect - haemorrhage - antidote - protamine sulphate

10. Enhances Antithrombin Activity

11. Heparin mechanism of action
Antithrombin III
Thrombin

12. Monitoring Heparin Activated Partial Thromboplastin Time (APTT)
Normal range: seconds
Therapeutic Range: seconds
Timing
4-6 hours after commencing infusion
4-6 hours after changing dosing regimen

13. 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

14. 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

19. Complications of Heparin
Haemorrhage
Heparin-induced thrombocytopaenia (HIT)
Osteoporosis (long-term only)

20. 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.

21. 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 > /ul
Returns to normal within 5 days despite continued heparin use (or within 2 days if heparin is stopped).

22. 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

27. Trreatment of HIT Discontinue all heparin
If need to continue anti-coagulation, use danaparoid (orgaran).
Avoid platelet transfusions
Thrombosis: use danaparoid or thrombin inhibitor

28. Vitamin K-Dependent Clotting Factors
VII
Synthesis of Functional Coagulation Factors IX X
The four Vitamin K dependent clotting factors are synthesized in the liver. II

29. Warfarin Mechanism of Action
Vitamin K
Antagonism of
Vitamin K
VII
Synthesis of Non Functional Coagulation Factors IX X
Warfarin acts as an anticoagulant by blocking the ability of Vitamin K to carboxylate the Vitamin K dependent clotting factors, thereby reducing their coagulant activity. II
Warfarin

31. Warfarin
Enhances Antithrombin Activity

32. 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
The major side effect of warfarin is hemorrhage. The factors that can influence the bleeding risk are shown on this slide; three of these potential risk factors, namely: the intensity of anticoagulation, concomitant use of other medications, and quality of management are controllable.
The intensity of anticoagulation is an extremely important risk factor for adverse events. This is because warfarin, a narrow therapeutic index drug, has a small window of therapeutic effectiveness and dosing must be carefully managed. Such management is best achieved in the setting of an anticoagulation management service (anticoagulation clinic).

33. Warfarin-induced Skin Necrosis

34. 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)
The prothrombin time (PT) is the test most commonly used to monitor warfarin dosing. The reliability of the result of the PT is influenced adversely by the variability in the sensitivity of thromboplastin reagents used by different laboratories. This problem has been markedly reduced by reporting the PT ratio as an International Normalized Ratio (INR).

35. 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
The INR is a mathematical correction that normalizes the PT ratio by adjusting for the variability in the sensitivity of the different thromboplastins.

36. Patient’s PT in Seconds Mean Normal PT in Seconds
INR Equation ( )
Patient’s PT in Seconds
Mean Normal PT in Seconds
ISI
INR =
INR = International Normalised Ratio
ISI = International Sensitivity Index
The INR is calculated by the formula shown on this slide. The ISI is the International Sensitivity Index. Each thromboplastin is assigned an ISI which reflects the sensitivity of the thromboplastin to Warfarin-mediated reduction of the Vitamin K dependent clotting factors. By convention, the ISI of the reference thromboplastin is 1.0. The higher the ISI, the less sensitive the thromboplastin is to Warfarin-mediated reduction of the Vitamin K dependent clotting factors.
The next two slides provide an example of how the ISI (sensitivity) of the thromboplastin influences the PT ratio (PTR) and how the resulting variability is corrected by expressing the results as an INR.
Target INR
DVT, PE, Atrial Fibrillation: 2-3
Artificial Cardiac Valve: 3-3.5

37. 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)
When short-term heparin followed by long-term warfarin are used, both anticoagulants can be started simultaneously. Heparin should be continued for a minimum of four days because the peak antithrombotic effect of warfarin is delayed for about 96 hours, independently of the INR, until Factor II (prothrombin is reduced). Heparin can be discontinued after a minimum of four days when the INR reaches the therapeutic range.

38. 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
This slide provides guidelines for safe and effective warfarin use. The dose of warfarin should be monitored daily until the INR is in the therapeutic range and then less frequently when a stable dose-response relationship is achieved. Regardless of the degree of stability in warfarin dosing and INR value in the hospital, it is important to monitor the INR frequently post hospital discharge (i.e., at least 1–3 days after discharge) and to spread out the interval of monitoring thereafter depending on INR response. Monitoring is necessary in all patients, but can be reduced to four weekly intervals in the low risk (for bleeding) patient who shows a stable dose-response.

39. 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
The relative contraindications for warfarin are listed on this slide. Warfarin crosses the placenta and is teratogenic in the first trimester, producing warfarin embryopathy in about 5% of exposed neonates. It is also fetopathic when used after the first trimester in an unknown (but much smaller) percentage of fetuses. Warfarin is contraindicated (relative or absolute) in patients with an increased risk of serious bleeding. The indication for warfarin should be reviewed carefully in patients with relative contraindications.

40. 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
The signs of warfarin overdosage are listed on this slide.
Hemorrhagic complications from warfarin therapy are more likely to occur with excessive degrees of anticoagulation, but even with an INR in the therapeutic range, bleeding can occur. Because of the likelihood of finding an underlying lesion in an individual who has gastrointestinal bleeding or significant genito-urinary bleeding in the face of therapeutic levels of anticoagulation, one is advised to consider and evaluate for underlying abnormalities predisposing to the bleeding. The return on such evaluations in the face of an excessive degree of anticoagulation diminishes, and one must use judgement whether or not to pursue an evaluation.

41. 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.

42. New Anticoagulation Drugs
Direct Thrombin Inhibitors
Ximelagatran, hirudin, bivalirudin, and argatroban
Synthetic pentasaccharide
Acivated Protein C
Tissue Factor Pathway Inhibitor (TFPI)

43. 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

44. 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

45. 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.

46. Ximelagatran
Enhances Antithrombin Activity

47. 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