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heparin

Indications: - treatment of venous thromboembolism* - deep vein thrombosis - pulmonary embolism [8] - arterial thromboembolism - DVT prophylaxis* - total knee arthroplasty - abdominal surgery - malignant neoplasm [8] - unstable angina - acute myocardial infarction - ST segment-elevated myocardial infarction - non-Q-wave myocardial infarction - disseminated intravascular coagulation (DIC) - cystitis - patency of indwelling lines/devices - percutaneous coronary intervention [8] * LMW heparin is better than unfractionated heparin except if emergent surgery or thrombolysis is planned Contraindications: Caution: 1) avoid IM injections in patients receiving therapeutic doses of heparin 2) avoid use of heparin with benzyl alcohol 3) use with caution/avoid use in premature neonates 4) antithrombin-3 deficiency * variations in the bioavailability of unfractionated heparin result in a delays in attaining therapeutic levels vs LMW heparin [9] Dosage: 1) deep vein thrombosis (DVT) prophylaxis - 5000 U SQ every 12 hours 2) anticoagulation a) bolus 5000-10,000 U IV or 80 units/kg b) begin 1300 U/hr IV (heparin 20,000 U in 500 mL D5W infused at 33 mL/hr) or 18 units/kg/hour c) check aPTT every 6 hours to keep aPTT 1.5-2.5 x control (55-85 sec) d) dose adjustment aPTT rate change additional action <45 sec + 6 mL/hr rebolus with 5000 U 45-54 sec + 3 mL/hr none 55-85 sec none none 86-110 sec - 3 mL/hr stop infusion 1 hr > 110 sec - 6 mL/hr stop infusion 1 hr e) stop heparin 1] after 5-7 days of coumadin therapy when INR is 2-3 2] thrombocytopenia or bleeding 3] otherwise deemed unnecessary Injection: 1000 units/mL (1 mL, 10 mL, 30 mL) 5000 units/mL (1 mL) 10,000 units/mL (1 mL, 4 mL) 20,000 units/mL (1 mL) Solution: (lock flush) 10 units/mL (1 mL Tubex) 100 units/mL (1 mL Tubex, 10 mL vial) * in patients for whom heparin is initiated for anticoagulation, & titration to therapeutic effect is difficult, consider antithrombin-3 deficiency Pharmacokinetics: 1) SC bioavailability is 20-40% & is dose-dependent 2) heparin is extensively bound to LDL, globulin & fibrinogen 3) metabolized by liver & reticuloendothelial system 4) consumed by anti-thrombin 3 & clotting factors 5) 1/2life is 85 minutes 6) steady state with infusion occurs in 4-6 hours 7) variations in bioavailability of unfractionated heparin may lead to a delay in achieving therapeutic dose vs LMW heparin [4] 8) PTT many not prolong in patients with antithrombin-3 deficiency [4] Monitor: 1) aPTT 2) platelet count every 1-3 days 3) anti-factor Xa heparin assays* a) patients with lupus anticoagulant b) patients also taking warfarin c) patients refractory to heparin (> 40,000 units/day) d) baseline elevated aPTT [10] *anti-factor Xa heparin assay instead of aPTT Adverse effects: 1) common (> 10%) - hemorrhage, hematuria, constipation, hematemesis, bleeding from gums, easy bruising 2) less common (1-10%) - allergic reactions, chest pain, priapism, peripheral neuropathy 3) uncommon (< 1%) - fever/chills, headache, urticaria, nausea, thrombocytopenia, elevation of liver function tests (benign), irritation, ulceration - cutaneous necrosis with deep SC injection - onset in 1st 5-10 days of therapy - may be associated with thrombocytopenia [4] 4) other a) thrombocytopenia (major risk, monitor platelet count) may be delayed response [5] b) osteoporosis with more prolonged heparin therapy c) hyperkalemia via inhibition of aldosterone secretion 5) overdose: see heparin toxicity Drug interactions: 1) warfarin, NSAIDs, ticlopidine, dipyridamole & other anti-platelet agents or anticoagulants increase risk of bleeding 2) dihydroergotamine (DHE) increases the risk of bleeding 3) nitroglycerin may antagonize the effects of heparin 4) protamine sulfate antagonizes the effects of heparin (used to reverse anticoagulant effects of heparin) Laboratory: interactions 1) prolonged aPTT - heparin may not prolong aPTT in patients with antithrombin III deficiency [4] - anti-factor Xa heparin assays (baseline elevated aPTT, see Monitor) 2) PT is generally normal, but may be slightly prolonged 3) prolonged thrombin time 4) bleeding time is normal 5) other labs with Loincs - heparin unfractionated in blood - heparin in plasma - heparin unfractionated in plasma - heparin unfractionated in 24 hour urine 6) heparin displaced thyroxine from thyroxine-binding proteins, increasing free T4, but no effect of serum TSH, serum thyroxine or serum T3 [9] Mechanism of action: 1) heparin binds to anti-thrombin 3 2) heparin-bound anti-thrombin 3 neutralizes thrombin & factor Xa (also VII, IX, XI, XII) 3) neutralization of factor Xa prevents conversion of prothrombin to thrombin 4) inhibits fibrin stabilizing factor, thus preventing clot stabilization 5) heparin has no fibrinolytic activity, thus does not lyse established thrombi 6) specific to intrinsic coagulation pathway, prolongs aPTT & activated clotting time with little effect on PT Biochemistry: Function: In intact tissue, heparin is confined to mast cells where it is stored in cytoplasmic granules [1]. It serves to neutralize positive charge of histamine within the granules. Structure: Heparin has the highest density of negative charge of any biological macromolecule [2]. It is composed of alternating sulfated (2,6)-glucosamine & glucuronate-2-sulfate residues (1,4 alpha linkage). Iduronate & its 2-sulfate are present in variable amounts. Heparan sulfate is like heparin, but contains fewer N- & O-linked sulfates (1,4 alpha linkage). The core protein of heparin is exclusively serglycin in contrast to heparan sulfate which contains a variety of core proteins (see heparan sulfate). Compartment: cytoplasmic granule Expression: mast cell Notes: - isolated on a commercial basis from pig intestinal mucosa & bovine lung. - effective October 1, 2009, a change, which will also harmonize the USP unit dose with the WHO International Standard unit dose, will result in approximately a 10% reduction in the potency of the heparin marketed in the United States. [6] - total drug strength of entire container on label required by FDA [7]

Related

antithrombin-III (ATIII, heparin cofactor, SERPINC1, AT3, PRO0309) coagulation cascade heparin-induced thrombocytopenia; heparin-associated antibody syndrome (HIT) hyperheparinemia (heparin overdose, heparin toxicity) partial thromboplastin time (PTT) protamine sulfate serglycin; secretory granule proteoglycan core protein; platelet proteoglycan core protein; P.PG; hematopoietic proteoglycan core protein (SRGN, PRG, PRG1)

Specific

heparan proteoglycan Heparin Parenteral low molecular weight (LMW) heparin

General

fibrinolytic agent (thrombolytic agent) glycosaminoglycan pharmaceutical anticoagulant secreted protein

Properties

SIZE: MW = 15 kD COMPARTMENT: extracellular compartment SECRETED-BY: mast cell

Database Correlations

PUBCHEM correlations

References

  1. Salmivirta M, Lidholt K, Lindahl U. Heparan sulfate: a piece of information. FASEB J. 1996 Sep;10(11):1270-9. Review. PMID: 8836040
  2. Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
  3. Kaiser Permanente Northern California Regional Drug Formulary, 1998
  4. Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018, 2022.
  5. FDA Medwatch http://www.fda.gov/medwatch/safety/2006/safety06.htm#Heparin - Prescriber's Letter 15(5): 2008 Heparin Contamination and Shortage Detail-Document#: 240512 (subscription needed) http://www.prescribersletter.com
  6. FDA MedWatch Heparin: Change in Reference Standard http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm184687.htm
  7. FDA MedWatch: 12/06/2012 Heparin: Drug Safety Communication - Important change to heparin container labels to clearly state the total drug strength http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm331168.htm
  8. Deprecated Reference
  9. Medical Knowledge Self Assessment Program (MKSAP) 18, 19. American College of Physicians, Philadelphia 2018, 2022.
  10. NEJM Knowledge+ Hematology - Guervil DJ, Rosenberg AF, Winterstein AG et al Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. Ann Pharmacother. 2011 Jul;45(7-8):861-8 PMID: 21712506