heparin
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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
Expression
Indications
- treatment of venous thromboembolism*
- arterial thromboembolism
- DVT prophylaxis*
- unstable angina
- acute myocardial infarction
- disseminated intravascular coagulation (DIC)
- cystitis
- patency of indwelling lines/devices
* LMW heparin is better than unfractionated heparin except if emergent surgery or thrombolysis is planned
Contraindications
Caution:
- avoid IM injections in patients receiving therapeutic doses of heparin
- avoid use of heparin with benzyl alcohol
- use with caution/avoid use in premature neonates
- antithrombin-3 deficiency
* variations in the bioavailability of unfractionated heparin result in a delays in attaining therapeutic levels vs LMW heparin[9]
Dosage
- deep vein thrombosis (DVT) prophylaxis
- 5000 U SQ every 12 hours
- anticoagulation
| 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 |
- stop heparin
- after 5-7 days of coumadin therapy when INR is 2-3
- thrombocytopenia or bleeding
- otherwise deemed unnecessary
- stop heparin
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
- SC bioavailability is 20-40% & is dose-dependent
- heparin is extensively bound to LDL, globulin & fibrinogen
- metabolized by liver & reticuloendothelial system
- consumed by anti-thrombin 3 & clotting factors
- 1/2life is 85 minutes
- steady state with infusion occurs in 4-6 hours
- variations in bioavailability of unfractionated heparin may lead to a delay in achieving therapeutic dose vs LMW heparin[4]
- PTT many not prolong in patients with antithrombin-3 deficiency[4]
Monitor
- aPTT
- platelet count every 1-3 days
- anti-factor Xa heparin assays*
- patients with lupus anticoagulant
- patients also taking warfarin
- patients refractory to heparin (> 40,000 units/day)
- baseline elevated aPTT[10]
*anti-factor Xa heparin assay instead of aPTT
Adverse effects
- common (> 10%)
- hemorrhage, hematuria, constipation, hematemesis, bleeding from gums, easy bruising
- less common (1-10%)
- 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]
- other
- thrombocytopenia (major risk, monitor platelet count) may be delayed response[5]
- osteoporosis with more prolonged heparin therapy
- hyperkalemia via inhibition of aldosterone secretion
- overdose: see heparin toxicity
Drug interactions
- warfarin, NSAIDs, ticlopidine, dipyridamole & other anti-platelet agents or anticoagulants increase risk of bleeding
- dihydroergotamine (DHE) increases the risk of bleeding
- nitroglycerin may antagonize the effects of heparin
- protamine sulfate antagonizes the effects of heparin (used to reverse anticoagulant effects of heparin)
- drug interaction(s) of oral anticoagulants with selective serotonin reuptake inhibitor (SSRI)
- drug interaction(s) of aspirin, P2Y12 inhibitors & anticoagulants
Laboratory
interactions
- prolonged aPTT
- heparin may not prolong aPTT in patients with antithrombin III deficiency[4]
- anti-factor Xa heparin assays (baseline elevated aPTT, see Monitor)
- PT is generally normal, but may be slightly prolonged
- prolonged thrombin time
- bleeding time is normal
- other labs with Loincs
- 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
- heparin binds to anti-thrombin 3
- heparin-bound anti-thrombin 3 neutralizes thrombin & factor Xa (also VII, IX, XI, XII)
- neutralization of factor Xa prevents conversion of prothrombin to thrombin
- inhibits fibrin stabilizing factor, thus preventing clot stabilization
- heparin has no fibrinolytic activity, thus does not lyse established thrombi
- specific to intrinsic coagulation pathway, prolongs aPTT & activated clotting time with little effect on PT
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]
More general terms
- glycosaminoglycan
- secreted protein
- pharmaceutical anticoagulant
- fibrinolytic agent (thrombolytic agent)
More specific terms
Additional terms
- 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)
References
- ↑ 1.0 1.1 Salmivirta M, Lidholt K, Lindahl U. Heparan sulfate: a piece of information. FASEB J. 1996 Sep;10(11):1270-9. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/8836040
- ↑ 2.0 2.1 Drug Information & Medication Formulary, Veterans Affairs, Central California Health Care System, 1st ed., Ravnan et al eds, 1998
- ↑ Kaiser Permanente Northern California Regional Drug Formulary, 1998
- ↑ 4.0 4.1 4.2 4.3 4.4 Medical Knowledge Self Assessment Program (MKSAP) 11, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2012, 2015, 2018, 2022.
- ↑ 5.0 5.1 FDA Medwatch http://www.fda.gov/medwatch/safety/2006/safety06.htm#Heparin
Prescriber's Letter 15(5): 2008 Heparin Contamination and Shortage Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=240512&pb=PRL (subscription needed) http://www.prescribersletter.com - ↑ 6.0 6.1 FDA MedWatch Heparin: Change in Reference Standard http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm184687.htm
- ↑ 7.0 7.1 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
- ↑ 8.0 8.1 8.2 8.3 Deprecated Reference
- ↑ 9.0 9.1 9.2 Medical Knowledge Self Assessment Program (MKSAP) 18, 19. American College of Physicians, Philadelphia 2018, 2022.
- ↑ 10.0 10.1 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: https://www.ncbi.nlm.nih.gov/pubmed/21712506
Database
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=32756
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=444410
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=163556
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=5289052
- PubChem: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=163742