Posted April 17, 2013
Yelena Kier, DO
Discovered in 1916, heparin is one of the oldest and most widely used anticoagulants available.1,2 It is primarily used for systemic anticoagulation with venous embolisms, acute coronary syndromes, as well as for catheter patency maintenance.
Heparin is an indirect anticoagulant that acts on antithrombin (AT). Activated antithrombin inactivates factors IIa, Xa, IXa, Xia, and XIIa, thereby promoting anticoagulation.1 At high concentrations heparin binds to platelets and heparin cofactor II. Heparin is safe for use in pregnancy because it does not cross the placenta.3 The administration and use of heparin is limited by several factors, including a narrow therapeutic window, development of heparin-induced thrombocytopenia, variability of dose response, and reduced ability of heparin to inactivate bound thrombin (which can result in continued thrombus propagation while on heparin therapy).4
Unfractionated heparin (UFH) administration has two preferred routes: 1) intravenous infusion (IV) or 2) subcutaneous injection (SC). Of note, SC injection results in lower bioavailability.1 The dose for IV administration is lower than SC and depends upon the indication, such as thrombus prophylaxis or treatment for deep venous thrombus (DVT), coronary artery disease, or acute myocardial infarction (MI).8
The current standard UFH dosing for most institutions is to follow a weight-based dosing nomogram. Initial dosing for DVT therapy is weight based at 80 U/kg or bolus administration of 5000 U followed by infusion of 18 units/kg/hour.4 UFH therapy for coronary artery disease depends on the further cardiac treatment algorithm (ST elevation MI versus non-ST elevation MI) and whether additional fibrinolytic therapy is planned to be administered. The routine initial dosing for non-ST elevation MI and unstable angina is a bolus of 60–70 U/kg followed by infusion of 12 units/kg/hr.6
UFH therapy and anticoagulation are monitored using either activated partial thromboplastin time (aPTT) or the anti-factor Xa assay for unfractionated heparin. The UFH activity must be checked prior to administration, four to six hours after initiation and four to six hours after any dosage changes.8 The activity of UFH may be followed by laboratory measurements of aPTT.
The aPTT measures the function of the intrinsic coagulation pathway in the coagulation cascade that is affected by heparin administration. Normal values for aPTT range between 24 to 39 seconds and vary by laboratory depending on the testing reagent and instrumentation used. When a laboratory changes its laboratory reagents and/or instruments for the aPTT, the aPTT therapeutic range for UFH may change. Typically laboratories change reagents every 12 to 24 months, and thus the therapeutic range may also change that frequently. The laboratory should determine the therapeutic range for UFH when it changes its reagents and/or instruments. The presence of lipemia or hyperbilirubinemia in the testing sample can interfere with detection of clot formation by photo-optical methods. Under filled samples may falsely prolong the aPTT.9
The anti-factor Xa assay or heparin assay measures heparin activity, and it is often confused with the factor Xa assay. The anti-factor Xa assay may be used to monitor both UFH and low molecular weight heparin administration and action. The therapeutic range for UFH is 0.3–0.7 anti-Xa units per mL of plasma. As with aPTT, lipemia and hyperbilirubinemia can interfere with results.7,9 A disadvantage is the increased cost of the heparin assay compared to the aPTT.
The risk of bleeding on heparin increases with dose increase along with concurrent administration of thrombolytic or antiplatelet medications. When reversal of heparin is necessary due to overdose, IV protamine sulfate is the drug of choice.1 Protamine sulfate is derived from salmon and other fish and when given alone is an anticoagulant; however, in the presence of heparin, the administration of protamine sulfate forms a salt and neutralizes of the anticoagulant properties of heparin. Dosage of protamine is 1 mg of IV protamine sulfate for every 100 IU of active heparin administered. Protamine sulfate, however, is contraindicated in patients with fish allergies due to its origin.
- Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th Edition. Chest. 2008;133(6 Suppl):141S.
- Rosenberg RD, Lam L. Correlation between structure and function of heparin. Proc Natl Acad Sci USA. 1979; 76(3):1218–1222.
- Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J.. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest. 1990;86(2):385.
- Hirsh J, van Aken WG, Gallus AS, Dollery CT, Cade JF, Yung WL. Heparin kinetics in venous thrombosis and pulmonary embolism. Circulation. 1976;53(4):691.
- McLean J. The thromboplastic action of cephalin. Am J Physiol. 1916;41:250–257.
- Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):e574–651.
- Pharmaceutical Partners of Canada Inc. Protamine sulfate injection, USP. April 2009 Medication insert. ppcdrugs.com/en/products/.../EN_WebInsert_ProtaminSulf.pdf. Accessed September 17, 2012.
- Hirsh J, Warkentin TE, Raschke R, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1998;114(5 Suppl):489S–510S.
- Lehman CM, Frank EL. Laboratory monitoring of heparin therapy: partial thromboplastin time or anti-Xa assay? Lab Medicine. 2009;40:47–51. doi:10.1309/LM9NJGW2ZIOLPHY6.
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