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

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

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 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).

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) 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).

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.

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

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.

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.

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.

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.

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.

Ximelagatran Enhances 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