Drugs and Coagulation at Point-of-Care Stacie Krick Evans, Pharm.D. Orlando Regional Medical Center

Objectives Review the mechanisms of action between oral and parenteral antiplatelet drugs. Explain the differences in mechanisms of action between vitamin K antagonists, factor Xa inhibitors, indirect thrombin inhibitors, and direct thrombin inhibitors (DTIs). Discuss the impact of multiple antiplatelet and anticoagulant drugs on point of care testing. Discuss the limitations associated with unfractionated heparin. Identify opportunities for collaboration among pharmacists and laboratory personnel in the healthcare setting.

Antiplatelet Drugs

Oral antiplatelet drugs Aspirin Clopidogrel (Plavix®) Ticlopidine (Ticlid®) Aspirin/Dipyridamole (Aggrenox®)

Oral antiplatelet drugs Aspirin Irreversible inhibitor of cyclooxygenase (COX) which prevents formation of the platelet-aggregating substance thromboxane A2. Monitoring Clopidogrel Blocks platelet aggregation by inhibition of ADP receptor on the platelet membrane.

Parenteral antiplatelet drugs Glycoprotein IIb/IIIa Inhibitors Abciximab (Reopro®), eptifibatide (Integrilin®), tirofiban (Aggrastat®) Prevent fibrinogen binding to Gly IIb/IIIa receptor and block platelet aggregation producing profound platelet inhibition. Used in conjunction with percutaneous coronary interventions (PCI).

Parenteral antiplatelet drugs Often administered with ASA, heparin/LMWH, clopidogrel. Monitoring ACT Platelet count

Antithrombin Drugs Vitamin K Antagonists - Warfarin (Coumadin®) Recent clinical uses and applications: Development of clinical guidelines for management of oral anticoagulants; the 7th ACCP Consensus Conference on Antithrombotic Therapy to be released Summer 2004. Standardization of laboratory monitoring New indications and treatment protocols Point-of-care testing.

Antithrombin Drugs Warfarin interferes with vitamin-K dependent carboxylation of several coagulation factors including II, VII, IX, and X, as well as anticoagulant proteins C and S. Full anticoagulant effect is delayed Average daily dose 4-5mg.

Warfarin - monitoring International Normalized Ratio (INR) The need for frequent testing and dose adjustments detracts from warfarin’s ease of use in clinical practice. Anticoagulation Clinics Coagucheck S ®

Unfractionated Heparin Complex glycosaminoglycan isolated and purified from animal tissues (porcine intestinal mucosa). Bovine lung heparin no longer available. Binds to endothelial cells and macrophages, as well as plasma proteins (platelet factor 4 and von Willebrand factor).

Unfractionated Heparin (UFH) Exerts its anticoagulant effect via antithrombin Heparin binds to and produces a conformational change in antithrombin. Anticoagulant effect reversed with protamine.

UFH - monitoring Activated partial thromboplastin time (aPTT) - most commonly used test to monitor heparin therapy. Activated clotting time (ACT) – bedside test most often used when high doses of heparin are required. The laboratory-based aPTT has a stronger correlation to heparin concentration than the bedside-based aPTT and ACT. (Ann Pharmacother 2002;36:7-11)

Heparin Resistance (Lab Hematol. 2003;9:125-131) Definition: An inadequate response to heparin at a standard dose for achieving a therapeutic goal. Need for heparin doses > 500 units/kg to prolong an ACT > 400 seconds. An ACT < 480 seconds after > 400 units/kg of heparin.

Heparin Resistance (Lab Hematol. 2003;9:125-131) Proposed mechanisms of heparin resistance: Heparin-induced thrombocytopenia Up to 38% of patients with HIT may develop subsequent heparin resistance. Decreased antithrombin (AT) level Acquired or hereditary Heparin therapy is thought to induce deficiency of AT in the first 12 hours of therapy. Elevated factor VIII level

Low Molecular Weight Heparin Low molecular weight heparins (LMWH) are prepared from UFH by enzymatic or chemical hydrolysis. Available products Fragmin® (dalteparin) Lovenox® (enoxaparin) Innohep® (tinzaparin)

LMWH Binds to antithrombin and inactivates thrombin to a lesser extent than UFH because the smaller molecule fragments cannot bind thrombin and antithrombin simultaneously.

LMWH Advantages Disadvantages Better bioavailability Longer half-life Administered subcutaneously either once or twice daily More predictable dose response HIT Type II occurs less often with LMWH Disadvantages Protamine only partially reverses anticoagulant response.

LMWH – Monitoring (Thromb Haemost 2002;87:163-164) Debate over need to monitor LMWH in certain subgroups (i.e., children, pregnant women, morbidly obese, patients with renal failure). Anti-Xa assay is generally used.

LMWH – Monitoring (Thromb Haemost 2002;87:163-164) Limitations to Anti-Xa Assay: Anti-Xa level has not been demonstrated to be a good predictor of bleeding during treatment with LMWH. The clinical status of the patient and dose administered are more informative. Ani-Xa level has not been demonstrated to be a good predictor of bleeding risk and antithrombotic efficacy in thrombophylaxis with LMWH. Relative anti-Xa and anti-IIa activities vary between preparations, and the antithrombin activity appears to be the more important in kinetic studies. The comparability between commercially available anti-Xa chromogenic assays is poor. Assays should preferably be LMWH, method and equipment specific.

Factor Xa Inhibition Arixtra ® (fondaparinux) Synthetic version of the pentasaccharide sequence of UFH and LMWH that binds to antithrombin and modifies its confirmation, inhibiting factor Xa.

Arixtra® (fondaparinux) FDA approved for prophylaxis of venous thromboembolism in patients undergoing hip fracture, hip replacement, or knee replacement surgery.

Arixtra® (fondaparinux) Does not affect platelet function In vitro studies suggest that fondaparinux does not react with platelet factor 4 antibodies, potentially eliminating the risk of HIT. No monitoring indicated; only fondaparinux can be used to calibrate the anti-Xa assay; the international standards of heparin or LMWH are not appropriate for this use.

Direct Thrombin Inhibitors (DTI) Available Agents Refludan® (lepirudin) Argatroban Angiomax® (bivalirudin) Exanta® (ximelagatran)* *Awaiting FDA approval

Direct Thrombin Inhibitors Thrombin is the central effector of coagulation and amplifies its own production, it is a natural target for pharmacologic intervention. Target sites on the thrombin molecule responsible for substrate recognition and/or cleavage. By blocking either the active site alone or both the active site and exosite I, DTIs specifically inhibit thrombin activity.

Refludan® (lepirudin) First DTI to become available. Potent and specific thrombin inhibitor. Due to the almost irreversible nature of the bond between lepirudin and thrombin, bleeding problems have occurred. No antidote is available to reverse the effect.

Refludan® (lepirudin) Therapeutic Use Patients with HIT or HIT with thrombosis. Monitoring aPTT aPTT ratio of 1.5-2.5 is used because the bleeding risk increases above this range with no increase in efficacy.

Refludan® (lepirudin) Ecarin Clotting Test (ECT) Pharmanetics has received an Humanitarian Device Exemption (HDE) for its Ecarin Clotting Time (ECT) test card from FDA www.fda.gov/cdrh/ode/h990012sum.html . ECT has been studied in patients with HIT receiving lepirudin and bivalirudin undergoing coronary artery bypass grafting (CABG). Anesth Anal 2003;96:283-286 Am J Cardiol 2003;91:1110-1113 J Cardiothorac Vasc Anesth 2000 Jun;14(3):249-252

Argatroban Small molecule that binds reversibly to the active site of the thrombin molecule. Approved for patients with HIT or HIT with thrombosis and patients undergoing percutaneous transluminal coronary angioplasty (PTCA) in conjunction with aspirin. No reversal agent available.

Argatroban - Monitoring aPTT with a ratio of 1.5 to 3.0 times the mean normal value is used. Argatroban synergistically interferes with the INR; the PT or INR cannot always be reliably used to monitor warfarin therapy in patients receiving argatroban. Effect dependent on argatroban dose and ISI of thromboplastin used. Argatroban alone also interferes with the INR and is dependent upon the ISI of the thromboplastin used.

Angiomax® (bivalirudin) Synthetic molecule designed on the basis of structural studies of hirudin; formerly known as hirulog. Undergoes reversible binding may lead to less bleeding. No antidote available for reversal.

Angiomax® (bivalirudin) Therapeutic use FDA- approved Anticoagulation in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) in conjunction with aspirin. Other Treatment of patients with HIT and unstable angina. Anticoagulation for patients with HIT undergoing CABG (on pump or off-pump).

Angiomax® (bivalirudin) Monitoring ACT for patients undergoing PTCA. ACT for patients undergoing CABG. aPTT for patients with HIT or unstable angina.

Ximelagatran Prodrug administered orally and transformed after absorption into active drug melagatran. Selective, competitive reversible active-site inhibitor of both free and clot-bound thrombin. The stable and reproducible pharmacokinetic profile of ximelagatran suggests that coagulation monitoring should not be required. Will be marketed as Exanta®

Ximelagatran vs. Warfarin

Ximelagatran Potential uses Prophylaxis for VTE in orthopedic patients Treatment of Acute DVT Prevention of stroke in AFIB patients Prevention of recurrent coronary events

Pharmacists and Point of Care Point of care testing provides immediate availability of lab results that are beneficial in clinical decision making. Point-of-care testing allows pharmacists to increase their participation in the provision of health care.

Pharmacists and the Lab Areas for opportunity Education regarding new drugs. Collaboration in research. Participation in performance improvement teams.

Summary New anticoagulant therapeutic agents continue to be studied; including antiplatelet agents, direct Xa inhibitors, and direct thrombin inhibitors. Heparin resistance should be considered in certain populations. Opportunities for pharmacists and laboratory personnel include both inpatient and outpatient settings.

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