Monitoring the Anti-Xa Anticoagulants, from Heparin to Eliquis

Abstract

1. George A. Fritsma, MS MT (ASCP)[⇑][1] 1. The Fritsma Factor, Your Interactive Hemostasis ResourceSM, Fritsma & Fritsma LLC, Birmingham, AL <!-- --> 1. Address for Correspondence: George A. Fritsma MS MT (ASCP), The Fritsma Factor, Your Interactive Hemostasis ResourceSM, Fritsma & Fritsma LLC, 153 Redwood Drive, Birmingham, AL 357173, 205-655-0687, George{at}fritsmafactor.com. 1. Describe the physiologic action of heparin, low molecular weight heparin, and pentasaccharide on antithrombin and activated coagulation factor X. 2. Prepare an ex vivo “Brill-Edwards curve” and employs the partial thromboplastin time to monitor unfractionated heparin. 3. Employ the prothrombinase-induced clotting time and the chromogenic anti-Xa assay to monitor unfractionated heparin, low molecular weight heparin, pentasaccharide, or direct anti-Xa therapy. Standard Unfractionated Heparin Therapy Unfractionated heparin (UFH) is a crude mixture of sulfated linear glycosaminoglycans extracted from porcine mucosa composed of an average of 60 saccharide units.1 UFH is one of nature's most negatively charged molecules with a molecular weight of 3000–30,000 Daltons and a median of 15,000 Daltons.2 A pentasaccharide sequence that binds a specific site on plasma antithrombin (AT, antithrombin III, AT III) appears on one-third of UFH molecules. This sequence provides the catalytic anticoagulant action of UFH as it binds its AT receptor site. UFH-bound AT undergoes a conformational change, exposing a second site that covalently inactivates the coagulation pathway serine proteases IIa (thrombin), IXa, Xa, XIa, and XIIa. We take clinical interest only in AT binding of thrombin and Xa, despite its additional properties. Activated AT is a serine protease inhibitor (SERPIN), and the protease binding reaction yields an inactive plasma complex thrombin-antithrombin (TAT). Heparin supports the TAT “approximation” reaction. When the UFH molecule exceeds 17 linear saccharide units, thrombin assembles on the molecule in approximation to (near) the activated AT. Approximation drives the TAT reaction at four times the rate of the AT-factor Xa reaction because Xa is inactivated only by antithrombin's protease binding site, independent of approximation. UFH lots are unrefined and vary in MW, molecule length, and anticoagulant efficacy. Individual patient UFH metabolism rates diverge markedly because human plasma and cellular proteins bind heparin at varying rates and concentrations. Consequently, laboratory monitoring is essential to UFH therapy. Physicians administer UFH intravenously to treat… ABBREVIATIONS: AMI - acute myocardial infraction; APTT or PTT - activated partial thromboplastin time; AT - antithrombin; CAD - coronary artery disease; DTI - direct thrombin inhibitor; DVT - deep venous thrombosis; FDA - US Food and Drug Administration; GFR - glomerular filtration rate; HIT - heparin-induced thrombocytopenia with thrombosis; LMWH - low molecular weight heparin; PE - pulmonary embolism; PiCT - prothrombinase-induced clotting time; PT - prothrombin time; RI - reference interval; RUO - research use only; SERPIN - serine protease inhibitor; TAT - thrombin-antithrombin; UFH - unfractionated heparin; VTE - venous thromboembolism. 1. Describe the physiologic action of heparin, low molecular weight heparin, and pentasaccharide on antithrombin and activated coagulation factor X. 2. Prepare an ex vivo “Brill-Edwards curve” and employs the partial thromboplastin time to monitor unfractionated heparin. 3. Employ the prothrombinase-induced clotting time and the chromogenic anti-Xa assay to monitor unfractionated heparin, low molecular weight heparin, pentasaccharide, or direct anti-Xa therapy. [1]: #corresp-1