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Monitoring the Traditional & the
New Anticoagulants
Michael J. Sanfelippo, M.S.
Technical Director, Coagulation Services Marshfield Labs Anticoagulants to be Discussed Heparin Warfarin Low Molecular Weight heparin Fonaparienux Direct Thrombin Inhibitor Unfractionated Heparin Chemical Composition Sulfated glycosaminoglycan Polysaccharide chains with moleculr weights of 30,000 – 100,000 Chains alternating N-acetylglucosamine and glucuronic acid Purified heparin polysaccharide chains of 3,000 – 35,000 with average molecular weight of 12,000 Pharmacokinetics of Heparin Intravenous administration – immediate anticoagulation half life of one hour anticoagulant effect for 2 – 6 hours Subcutaneous administration – peak anticoagulation at 4 hours with effect up to 12 hours In high doses, most is excreted in the urine unaltered Use of Heparin Immediate anticoagulant Activity is variable requires monitoring Used for initial treatment of DVT and PE Used in open heart surgery Used to cap intravenous lines Factors Affecting Anticoagulant Effect Level of Antithrombin Heparin binding to acute phase proteins Release of platelet factor 4 Monitoring Heparin Therapeutic range 0.3 – 0.7 units/ml Specific heparin assay, inhibition of Xa measured with chromogenic substrate APTT Establishment of Therapeutic Range for APTT Brill-Edwards Method Measure heparin level in at least 30 patients on heparin only. Do APTTs on all specimens Calculate dose response curve by regression analysis Therapeutic range is APTT range that corresponds to 0.3 – 0.7 units/ml Determined from dose response curve using regression analysis Problems for small hospital Getting enough patients Doing heparin assay Example of Brill-Edwards Method Specimen APTT Heparin 1 25 0.15 2 45 0.38 3 55 0.45 4 88 0.85 5 75 0.70 6 65 0.55 7 35 0.25 8 47 0.35 9 68 0.72 10 98 0.92 Brill-Edwards cont . . . APTT at 0.30 units 47 sec
APTT at 0.7 unit 75 sec
Thus therapeutic range is 47 – 75 sec
approximate Specific Heparin Assay Based on inhibition of Xa Heparin forms complex with antithrombin (heparin-AT) Heparin-At +Xa AT-Xa + Xa Free Xa + chromogenic substrate peptide +Paranitroanaline Heparin Assay Protamine Sulfate Low molecular weight protein from salmon sperm Inhibits heparin effect by displacing heparin from antithrombin 1 mg protamine will neutralize 80-100 units of unfractionated heparin Heparin rebound due to protamine being cleared faster than heparin Adverse Effects of Protamine Sulfate Hemorrhage Allergic reaction Heparin Induced Thrombocytopenia Type I Platelet count drops slightly but returns to normal while heparin is continued-not antibody mediated Type II Severe antibody mediated thrombocytopenia with life threatening arterial and venous thrombosis if heparin is continued Heparin Induced Thrombocytopenia Type II Potentially fatal complication of heparin therapy due to the development of a heparin dependent antibody against platelet factor 4 Thrombocytopenia results from activation of platelets by complex of IgG, heparin, and platelet factor 4 Platelet activation causes release of ADP which causes platelet aggregate formation Diagnostic Features of HIT Type II Platelet count of less than 100,000/mm 3 or count of less that 50% of the platelet count before heparin was started Occurs 5 – 12 days after heparin is started Abnormal results in tests for antibody to platelet factor 4 or heparin mediated platelet activation Occurrence of arterial or venous thrombus formation while on heparin Tests for HIT Type II Elisa assay for antibody to platelet factor 4 Release of radio-labeled serotonin from normal donor platelets Daily platelet counts recommended for all patients on heparin Treatment of HIT – Type II Stop heparin Use direct thrombin inhibitors Argatroban Lepiruden (Refluden®)
Warfarin is contraindicated Low Molecular Weight Heparin Low Molecular Weight Heparin Made by enzymatic or chemical depolymerization Lower molecular weight 4,000 – 5,000 Loss of most anti IIa activity but retain anti Xa Predicable anticoagulant activity Administration and Monitoring Low Molecular Weight Heparins Given subcutaneously Peak level at 4 hours post injection Half life of 4.5 hours with significant activity at 12 hours Laboratory Monitoring Low Molecular Weight Heparin Usually not required Assayed by inhibition of Xa using a chromogenic substrate Same assay as unfractionated heparin but different calibrator APTT not reliable but may be slightly prolonged Conditions Requiring Monitoring of Low Molecular Weight Heparin Patients with renal insufficiency Exceptionally large or small patients Newborn and children Low Molecular Weight Heparins in Common Use Enoxaparin (Lovenox®) Daltaparin (Fragmin®) Both calibrated against the same standard Warfarin Action of Warfarin Inhibits vitamin K epoxide reductase Prevents attachment of glutamic acid residues to factors II, VII, IX, X, protein C, and protein S Glutamic acid residues necessary for factor to bind to catalytic phospholipid surfaces Methods of Monitoring Accepted method is one stage prothrombin time Assay of factor X with chromogenic substrate for special conditions Traditional clotting assay of factor X Half-Lives of Vitamin K Dependent Factors II 60 Hours VII 4 – 6 Hours
IX 20 – 24 Hours
X 48 – 72 Hours
Protein C 8 Hours Protein S 30 Hours Monitoring Warfarin with Prothrombin Time Reported as International Normalized Ration (INR) Reporting as clotting time in seconds only is not acceptable INR Calculated by the formala
INR = Patient Time (sec)/Normal Mean Time(sec) ISC
Where ISC = International Sensitivity Index
ISI Test Plasma Time (sec) INR Mean Normal Plasma Time Therapeutic Range INR 2.0 – 3.0 for most conditions INR 2.5 – 3.5 for patients with mechanical heart valves Use of the Chromogenic Factor X Assay Patients with the lupus anticoagulant Patients with abnormal fibrinogen and problem in detection of fibrin endpoint Therapeutic range 43% to 17% correspondes to INR 2.0 – 3.5 The Assay of Factor X with a Chromogenic Substrate Factor X is activated by Russell’s Viper Venom and Ca++ Factor Xa hydrolyses substrate (S2765) liberating paranitroanaline Optical density read at 405 nm-directly related to factor X concentration Effect of Lupus Anticoagulant on Prothrombin Time May bind phospholipid in test reagent May also bind prothrombin Case History of Patient with Abnormal Fibrinogen 65 year old female with atrial fibrillation on warfarin for several years with good control Had INR performed at a different lab with a value of > 11.0 Warfarin stopped Warfarin restarted with INRs at original lab acceptable INR performed at different lab with > 11.0 again Case History cont . . . Duplicate specimens drawn Original lab INR 1.3 Other lab INR > 11.0 Chromogenic X 79% (Normal 65 – 165%) Thrombin time 21.6 sec (16.4 – 20.7 sec) Fibrinogen 642 mg/dl (174-442 mg/dl) Fibrinogen antigen 750 mg/dl (180 – 310 mg/dl) Reptilase time 16.1 sec (15.5 – 19.0 sec) Similar to Fibrinogen Longmont Adverse Affects of Warfarin Bleeding, anticoagulation reversal by vitamin K Tissue necrosis Occurs in patients with underlying protein C or S deficiency prevented by giving small loading dose of 2 – 5 mg/day starting warfarin while patient is on heparin Effect of Unfractionated Heparin on INR Heparin can prolong the prothrombin time (increase INR) Most reagents now contain a heparin antagonist protamine sulfate or polybrene Most reagents will neutralize up to 1.0 units/ml Fondaparinux Chemistry and Action of Fondaparinux A pentasaccharide with a molecular weight of 1,728 daltons Anticoagulates by accelerating the binding of antithrombin to Xa Has no effect on thrombin binding Therapeutic Levels for Fondaparinux Administered by subcutaneous injections Peak level at 3 hour post injection Half life 14 – 20 hours, once per day dosing Fondaparinux Used for Prophylaxis
2.5 mg daily Peak level 0.39 – 0.50 mg/L Fondaparinux Used for Treatment of Deep Venous Thrombosis or Pulmonary Embolism
50 kg body weight 5.0 mg once/day
50 – 100 kg body weight 7.5 mg/day Over 100 kg body weight 10.0 mg/day Anticipated peak plasma levels 1.20 – 1.26 mg/L Methods of Monitoring Common laboratory tests, prothrombin time and activated partial thromboplastin time are insensitive to fondaparinux Specific assay based on inhibition of Xa with calibration curve using fondaparinux Monitoring generally not required due to the predictability of the drugs anticoagulant action Should be monitored in patients with renal impairment and elderly patients (over 75 years) Should be monitored in patients less than 50 kg body weight Advantages of Fondaparinux Long half life Low incidence of HIT, may be used to treat patient who have suffered HIT Generally doesn’t require monitoring Argatroban ®
A small molecule molecular weight of 526
Derived from arginine Inhibits by reversibly binding to thrombin independent of antithrombin Half life of 39 – 51 minutes Therapeutic Levels and Monitoring Given by continuous infusion Monitor with activated partial thromboplastin time (APTT) At 2 hour of infusion target APTT range is 1.5 – 3.0 times baseline Argatroban® will prolong prothrombin time (PT) Use chromogenic assay factor X to monitor warfarin during transition from argatroban to warfarin Drug Use and Adverse Affects Primary use to treat patients with HIT Hemorrhage is the only major adverse affect No known antidote Lepiruden (Refluden ) ® Therapeutic Levels and Monitoring Monitored by APTT General target range 1.5 – 2.5 baseline APTT Adverse Affects of Lepiruden Hemorrhage No known antidote
