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Comparative Coagulation


Comparative Coagulation Heparin Site

 

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Overview
Heparin and Low Molecular Weight Heparin: Mechanism and Metabolism
Heparin Anticoagulant Therapy
Heparin Monitoring
References and links
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Overview

Heparins act by greatly enhancing antithrombin’s inhibition of coagulation factors. Heparins are used at high dose to treat systemic thrombosis and at lower doses for thromboprophylaxis. New low molecular weight heparins (LMWH) have more predictable pharmacokinetic profiles and longer duration of action than unfractionated heparin (UFH), but are much more expensive.

Heparin and Low Molecular Weight Heparin: Mechanism and Metabolism

  • Unfractionated heparin
    Unfractionated heparin (UFH) is a heterogeneous mixture of glycosaminoglycans consisting of polysaccharide chains of highly variable length (slide 1). Heparin interacts with antithrombin (AT) to increase its affinity for its target serine protease coagulation factors, particularly thrombin (Factor IIa) and Factor Xa (slides 2-3). The A domain of heparin, a  specific pentasaccharide sequence, binds to AT (slides 4-7). Once bound, the AT-Factor complex is cleared from circulation (slide 8).  The long chains also mediate UFH’s interactions with numerous plasma proteins, platelets, endothelial cells and macrophages. This extensive protein and cell binding, dependent on saccharide chain length, produces a complex pharmacokinetic profile and a wide variation in UFH anticoagulant effect between individuals and during the course of disease.
  • Low molecular weight heparin

    The newer heparins are produced by depolymerization of UFH. The resultant molecules average about 15 monosaccharide units per chain with average molecular weight 1/3  that of UFH (slide 9). These shorter chains reduce binding affinity for plasma proteins and cells, resulting in a longer half-life and more predictable dose-response. The shorter chains also reduce the formation of a ternary complex among heparin chains, AT, and thrombin, so that LMWH primarily inactivate Factor Xa (slide 10).

Heparin Anticoagulant Therapy

Heparin has defined indications in human medicine. UFH is often used for short term, high intensity anticoagulant effect for cardiac bypass and other cardiac interventions, whereas lower doses of UFH and LMWH are used for  prophylaxis after surgery or chronic thrombotic syndromes. In contrast, there are few controlled studies of heparin therapy in animals to develop evidence-based guidelines for specific disorders. The most common uses of heparin in clinical practice include the following:

Veterinary use of heparin therapy

    • Cardiac, aortic, arterial thrombosis
    • Pulmonary thrombosis and thromboembolism
    • Disseminated intravascular coagulation
    • Systemic thrombotic or “hypercoagulable” syndromes
      • Immune hemolytic anemia
      • Pancreatitis
      • Neoplasia
      • Protein losing disorders

Empiric treatment regimens
Human dosage guidelines:

    • UFH: High dose = 400 to 800 U/kg/24 hr; Low dose = 200 to 300 U/kg/24 hr
    • LMWH: High dose = 100 U/kg/12 hr; Low dose = 2,000 to 5,000 U/adult/ 24 hr

Veterinary dosage guidelines have not yet been defined. Recent studies indicate that adjusted dose UFH may be more effective than fixed dose therapy for canine IMHA (slide 11) and that LMWH has shorter half-life in dogs, cats, and foals than in people (each linked torefs below).

Heparin Monitoring (see Heparin anti-Xa Assay FAQs)

  • Clinical status
    All patients receiving heparin should be closely examined to detect disease progression, or signs of bleeding and bruising, the major complication of heparin therapy.
  • Clotting time tests
    Clotting time tests (ACT and aPTT link to aPTT test) assess UFH anticoagulant effect, and can be used to detect excess anticoagulation before clinical signs develop. Target prolongation for high dose UFH therapy is 1.5X to 2X clotting time of the patient's baseline value. Clotting time tests are not useful for monitoring LMWH.
  • Heparin anti-Xa assays (slides 12 & 13)
    Heparin anti-Xa assays gauge anticoagulant intensity of UFH and LMWH. High anti-Xa activity indicates high heparin anticoagulant effect. Target peak anti-Xa ranges for animals are adapted from human guidelines pending species-specific clinical studies
      • Target ranges for UFH
        Therapeutic range (high intensity anticoagulation) = 0.3 to 0.7 Units/mL
        Prophylactic range (low intensity anticoagulation) = 0.1 to 0.4 Units/mL
        * Ranges are based on human treatment trials
      • Target ranges for LMWH
        Therapeutic range (high intensity anticoagulation) = 0.5 to 1.2 Units/mL
        Prophylactic range (low intensity anticoagulation) = 0.2 to 0.5 Units/mL
        * Ranges are based on human treatment trials
      • Sampling for peak anticoagulant effect
        • Steady state: sample after 24 to 48 hours of starting heparin
        • Canine peak: sample 3 hours after SQ dose
        • Feline peak: sample 2 hours after SQ dose
        • Equine peak: sample 3 to 4 hours after SQ dose


References and Links

  • Veterinary References:
    • Canine
      Kidd L, Mackman N. Prothrombotic mechanisms and anticoagulant therapy in dogs with immune-mediated hemolytic anemia. J Vet Emerg Crit Care 2013;23(1):3-13. PubMed PMID: 23356703.  

      Helmond SE, Polzin DJ, Armstrong PJ, Finke M, Smith SA. Treatment of immune-mediated hemolytic anemia with individually adjusted heparin dosing in dogs. J Vet Intern Med. 2010;24(3):597-605. PubMed PMID: 20384956.

      Swann JW, Skelly BJ. Systematic review of evidence relating to the treatment of immune-mediated hemolytic anemia in dogs. J Vet Intern Med. 2013;27(1):1-9. PubMed PMID: 23279007.  

      Smith SA. Antithrombotic therapy. Top Companion Anim Med. 2012;27(2):88-94. PubMed PMID: 23031461

      Scott KC, Hansen BD, DeFrancesco TC. Coagulation effects of low molecular weight heparin compared with heparin in dogs considered to be at risk for clinically significant venous thrombosis. J Vet Emerg Crit Care (San Antonio). 2009 Feb;19(1):74-80.  PMID: 19691587. http://www.ncbi.nlm.nih.gov/pubmed/19691587

      Lunsford KV, Mackin AJ, Langston VC, Brooks M. Pharmacokinetics of subcutaneous low molecular weight heparin (enoxaparin) in dogs. J Am Anim Hosp Assoc. 2009;45(6):261-7. PubMed PMID: 19887383.  

      Breuhl EL, Moore G, Brooks MB, Scott-Moncrieff JC. A prospective study of unfractionated heparin therapy in dogs with primary immune-mediated hemolytic anemia. J Am Anim Hosp Assoc. 2009;45(3):125-33. PubMed PMID: 19411648.  

      Brooks MB. Evaluation of a chromogenic assay to measure the factor Xa inhibitory activity of unfractionated heparin in canine plasma. Vet Clin Pathol.  2004;33(4):208-14. PubMed PMID: 15570557..

    • Feline
      Mischke R, Schmitt J, Wolken S, Böhm C, Wolf P, Kietzmann M. Pharmacokinetics  of the low molecular weight heparin dalteparin in cats. Vet J. 2012;192(3):299-303. PubMed PMID: 21978598


      Fiakpui NN, Hogan DF, Whittem T, Green HW 3rd, Shipley EA, Sederquist KA. Dose determination of fondaparinux in healthy cats. Am J Vet Res. 2012;73(4):556-61. PubMed PMID: 22452504.

      Alwood AJ, Downend AB, Brooks MB, Slensky KA, Fox JA, Simpson SA, Waddell LS,  Baumgardner JE, Otto CM. Anticoagulant effects of low-molecular-weight heparins in healthy cats. J Vet Intern Med. 2007;21(3):378-87. PubMed PMID: 17552440.

    • Equine
      Tennet-Brown BS, Epstein KL, Whelchel DD, Giguère S. Use of viscoelastic coagulation testing to monitor low molecular weight heparin administration to healthy horses. J Vet Emerg Crit Care 2013;23(3):291-9. PubMed PMID: 23656212.


      Armengou L, Monreal L, Delgado MÁ, Ríos J, Cesarini C, Jose-Cunilleras E. Low-molecular-weight heparin dosage in newborn foals. J Vet Intern Med. 2010;24(5):1190-5. PubMed PMID: 20695987

      de la Rebière de Pouyade G, Grulke S, Detilleux J, Salciccia A, Verwilghen DR, Caudron I, Gangl M, Serteyn DD. Evaluation of low-molecular-weight heparin for the prevention of equine laminitis after colic surgery. J Vet Emerg Crit Care 2009;19(1):113-9. PubMed PMID: 19691592.

    • Medical References:
      Guervil DJ, Rosenberg AF, Winterstein AG, Harris NS, Johns TE, Zumberg MS. Activated partial thromboplastin time versus antifactor Xa heparin assay in monitoring unfractionated heparin by continuous intravenous infusion. Ann Pharmacother. 2011 45(7-8):861-8. PubMed PMID: 21712506.


      Price EA, Jin J, Nguyen HM, Krishnan G, Bowen R, Zehnder JL. Discordant aPTT and anti-Xa values and outcomes in hospitalized patients treated with intravenous unfractionated heparin. Ann Pharmacother. 2013;47(2):151-8. PubMed PMID: 23386070.

      Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI; American College of Chest Physicians. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):141S-159S. PubMed PMID: 18574264.

    • Links:
      http://mghlabtest.partners.org/coagbook/CO005000.htm
      http://emedicine.medscape.com/article/2085000-overview#aw2aab6b2