Heparin

From Anvita Health Wiki

Contents 1 More Specific Terms 2 Function 3 Structure 4 Compartment 5 Expression 6 Indications 7 Contraindications 8 Dosage 9 Pharmacokinetics 10 Monitor 11 Adverse-effects 12 Drug-interactions 13 Laboratory 14 Mechanism-of-action 15 Notes 16 More General Terms 17 Additional Terms 18 Internet Database 19 References

More Specific Terms

• heparan proteoglycan
• low molecular weight (LMW) heparin

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

Indications

• treatment of venous thrombosis
• pulmonary embolism
• DVT prophylaxis
• unstable angina
• acute myocardial infarction
• disseminated intravascular coagulation ( DIC)
• cystitis
• patency of indwelling lines/devices

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

Dosage

• deep vein thrombosis (DVT) prophylaxis

• 5000 U SQ every 12 hours

• anticoagulation

• bolus 5000-10,000 U IV or 80 units/kg
• begin 1300 U/hr IV (heparin 20,000 U in 500 mL D5W infused at 33 mL/hr) or 18 units/kg/hour
• check aPTT every 6 hours to keep aPTT 1.5-2.5 x control (55-85 sec)
• 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
• stop heparin

• after 5-7 days of coumadin therapy when INR is 2-3
• thrombocytopenia or bleeding
• 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)

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

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)

Adverse-effects

• common (> 10%)

• hemorrhage, hematuria, constipation, hematemesis, bleeding from gums, easy bruising

• less common (1-10%)

• allergic reactions, chest pain, priapism, peripheral neuropathy

• uncommon (< 1%)

• fever/ chills, headache, urticaria, nausea, thrombocytopenia, elevation of liver function tests (benign), irritation, ulceration, cutaneous necrosis with deep SC injection,

• other

• thrombocytopenia (major risk, monitor platelet count) may be delayed response [5]
• osteoporosis with more prolonged heparin therapy
• hyperkalemia via inhibition of aldosterone secretion

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)

Laboratory

• interactions
• prolonged aPTT
• PT is generally normal, but may be slightly prolonged
• prolonged thrombin time
• bleeding time is normal

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

• It is isolated on a commercial basis from pig intestinal mucosa & bovine lung.
  
• Effective October 1, 2009, a change, which will also harmonize the unit dose with the International Standard unit dose, will result in approximately a 10% reduction in the potency of the heparin marketed in the United States. [6]

More General Terms

• glycosaminoglycan
• secreted protein
• anticoagulant
• fibrinolytic agent (thrombolytic agent)

Additional Terms

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

Internet Database

PubChem: 32756
PubChem: 444410
PubChem: 163556
PubChem: 5289052
PubChem: 163742

References

1. Salmivirta M, Lidholt K, Lindahl U. Heparan sulfate: a piece of information. FASEB J. 1996 Sep;10(11):1270-9. Review. PMID: [1]
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, American College of Physicians, Philadelphia 1998
5. FDA Medwatch [2]
   - Prescriber's Letter 15(5): 2008 Heparin Contamination and Shortage Detail-Document#: [3] (subscription needed) [4]
6. FDA MedWatch Heparin: Change in Reference Standard [5]
7. National Guideline Clearinghouse Heparin and low molecular weight heparin. In: Sixth ACCP Consensus Conference on Antithrombotic Therapy ngc-guideline: [6]

heparin