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Parenteral anticoagulation

Last updated: December 21, 2020

Summary

Parenteral anticoagulants are routinely indicated for the prevention and treatment of venous thromboembolism. Heparin is typically the preferred agent for inpatient parenteral anticoagulation. Serious side effects include bleeding complications and type 2 heparin-induced thrombocytopenia (HIT), which causes arterial and venous thromboembolism due to an antibody-mediated aggregation of platelets. A drop in platelet count (< 100,000 platelets /μL or decrease of > 50% compared to baseline) may indicate HIT; therefore, the platelet count must be closely monitored in patients on parenteral anticoagulants, especially heparin. If HIT is suspected, treatment involves discontinuing all heparins and beginning nonheparin anticoagulation (usually argatroban).

Overview

Unfractionated heparin (UFH)

  • Drug: heparin
  • Administration
    • Prophylaxis: subcutaneous
    • Therapeutic: continuous intravenous infusion
  • Monitoring during therapy: activated partial thromboplastin time (aPTT); , platelet count (including baseline before treatment is started)
  • Clearance: hepatic (preferred agent for patients with renal insufficiency)
  • Antidote: protamine sulfate (a positively-charged protein that can neutralize negatively-charged heparin by forming inactive complexes)

In order to detect heparin-induced thrombocytopenia, platelets must be continuously monitored during heparin therapy and a baseline should be established before commencing treatment.

Low molecular weight heparin (LMWH)

  • Drugs: enoxaparin, dalteparin, tinzaparin, nadroparin,
  • Administration: subcutaneous
  • Monitoring during therapy: anti-factor Xa activity; can be assessed in specific cases; not generally recommended
  • Clearance: renal (therefore, contraindicated for patients with renal insufficiency)
  • Antidote: protamine sulfate (partial reversal)

Synthetic heparin

  • Drugs: fondaparinux
  • Administration: subcutaneous
  • Monitoring during therapy:
  • Antidote: : possibly activated prothrombin complex concentrates (aPCC)

Direct thrombin inhibitors


References:[2][3][4]

Pharmacodynamics

Unfractionated heparin (UFH)

Low molecular weight heparin (LMWH) and synthetic heparin (fondaparinux)

Direct thrombin inhibitors

  • Directly inhibit thrombin (freely circulating and in association with clots)

The effect of most parenteral anticoagulants (except for direct thrombin inhibitors) depends on native antithrombin. In patients with antithrombin III deficiency (e.g., due to nephrotic syndrome), this effect is reduced!

References:[7][8][9]

Adverse effects

General side effects

  • Bleeding
  • Drug-drug interactions

Specific side effects

Heparin-induced thrombocytopenia (HIT)

  • Treatment with heparin, especially UFH, can cause thrombocytopenia.
  • HIT can be differentiated into type 1 (asymptomatic), and type 2, which is antibody-related and prognostically worse.
Characteristics Type 1 HIT Type 2 HIT
Frequency
  • ∼ 10–20%
  • More commonly occurs with UFH
    • ∼ 1–5% for UFH
    • ∼ 0.1–1% for LMWH
Onset
  • Within the first 5 days after beginning treatment
  • Day 5–14
Severity of thrombocytopenia
  • Massive reduction: < 100,000 platelets/μL (or decrease of > 50% compared to baseline)
Pathophysiology
Clinical features
  • Clinically insignificant
Complications
  • Usually none
Management

The significantly increased risk of bleeding is the main side effect of all anticoagulants.

Heparin treatment requires regular monitoring of the platelet count, especially for UFH, even before starting treatment.
References:[11][12]

We list the most important adverse effects. The selection is not exhaustive.

Indications

Heparin

Low-dose therapy

  • DVT prophylaxis for prolonged bedrest, peri- and postoperative state, immobility

High-dose therapy

Low molecular weight heparin [13]

Direct thrombin inhibitors

Use direct thrombin inhibitors (Bivalirudin, Argatroban, Dabigatran) to treat the BAD HIT (type 2 HIT has a worse prognosis than type 1 HIT).

References:[8][14][15]

Contraindications

References:[8]

We list the most important contraindications. The selection is not exhaustive.

Additional considerations

Overview of advantages and disadvantages
Unfractionated heparin (UFH) Low-molecular-weight heparin (LMWH)
Application
  • Subcutaneous or intravenous administration
  • Therapeutic administration requires infusion pump
  • Always administer subcutaneously
Dosing
  • Low dose: subcutaneous administration every 8–12 hrs
  • High dose: intravenous administration with bolus and continuous application via infusion pump
  • Dosage depends on specific drug used, indication, body weight, and kidney function; adjust to body weight and decreased kidney function
Advantages
  • Adequate anticoagulation is achieved sooner due to direct effect on thrombin
  • Protamine (the antidote) antagonizes effect of UFH
  • Effect of LMWH lasts for about 12 hours
  • Monitoring of anti-factor Xa is only necessary in patients with decreased kidney function (and significant over- or underweight); anti-factor Xa activity is measured 4 hrs after administration
Limitations
  • Short half-life means anticoagulant effect quickly ceases once stopped
  • If used therapeutically, PTT levels have to be monitored frequently (target range: 1.5–2.5-fold prolongation)
  • In comparison with LMWH
    • Type 2 HIT is about 10-fold more common
    • Severe bleeding is more common
Preferred use
  • Emergencies (more easily titrated, available as IV infusion)
  • For patients with advanced renal failure (e.g., in patients with severe renal insufficiency (CrCl < 30mL/min) or the elderly)
  • DVT prophylaxis, outpatient care (longer half-life → fewer injections)
  • Generally preferred to UFH (fewer side effects, easier handling) as long as there are no contraindications

References:[8][16][17]

Special patient groups

Pregnancy

Patients with decreased renal function

  • In severe renal failure: accumulation of LMWH → increased bleeding risk → adjust dose or switch to UFH

References

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  2. Le T, Bhushan V,‎ Sochat M, Chavda Y, Abrams J, Kalani M, Kallianos K, Vaidyanathan V. First Aid for the USMLE Step 1 2019. McGraw-Hill Medical
  3. Harter K, Levine M, Henderson SO. Anticoagulation drug therapy: a review. West J Emerg Med. 2015; 16 (1): p.11-17. doi: 10.5811/westjem.2014.12.22933 . | Open in Read by QxMD
  4. Bauer KA. Fondaparinux: Dosing and adverse effects. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/fondaparinux-dosing-and-adverse-effects.Last updated: May 31, 2016. Accessed: February 21, 2017.
  5. Le T, Bhushan V,‎ Sochat M, Chavda Y, Zureick A. First Aid for the USMLE Step 1 2018. McGraw-Hill Medical ; 2017
  6. Katzung B,Trevor A. Basic and Clinical Pharmacology. McGraw-Hill Education ; 2014
  7. Mulloy B, Barrowcliffe T, Gray E. Heparin and low-molecular-weight heparin. Thromb Haemost. 2008; 99 (11): p.807-818. doi: 10.1160/th08-01-0032 . | Open in Read by QxMD
  8. Le T, Bhushan V. First Aid for the USMLE Step 1 2015. McGraw-Hill Education ; 2014
  9. UpToDate. Heparin (unfractionated): Drug information. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/heparin-unfractionated-drug-information.Last updated: January 1, 2017. Accessed: March 14, 2017.
  10. Hook KM, Abrams CS. Treatment options in heparin-induced thrombocytopenia. Curr Opin Hematol. 2010; 17 (5): p.424-431. doi: 10.1097/moh.0b013e32833c07a7 . | Open in Read by QxMD
  11. Coutre S. Clinical presentation and diagnosis of heparin-induced thrombocytopenia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/clinical-presentation-and-diagnosis-of-heparin-induced-thrombocytopenia.Last updated: November 2, 2016. Accessed: February 21, 2017.
  12. 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected Heparin-Induced Thrombocytopenia (HIT) . http://www.hematology.org/Clinicians/Guidelines-Quality/Quick-Ref/529.aspx. Updated: January 1, 2013. Accessed: February 21, 2017.
  13. Merli GJ, Groce JB. Pharmacological and clinical differences between low-molecular-weight heparins: implications for prescribing practice and therapeutic interchange.. P & T : a peer-reviewed journal for formulary management. 2010; 35 (2): p.95-105.
  14. Pai M, Douketis JD. Prevention of venous thromboembolic disease in surgical patients. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/prevention-of-venous-thromboembolic-disease-in-surgical-patients.Last updated: January 18, 2017. Accessed: February 21, 2017.
  15. Pai M, Douketis JD. Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/prevention-of-venous-thromboembolic-disease-in-acutely-ill-hospitalized-medical-adults.Last updated: September 1, 2016. Accessed: February 22, 2017.
  16. Medscape. enoxaparin (Rx). enoxaparin (Rx). New York, NY: WebMD. http://reference.medscape.com/drug/lovenox-enoxaparin-342174. Updated: February 22, 2017. Accessed: February 22, 2017.
  17. Merli GJ, Groce JB. Pharmacological and clinical differences between low-molecular-weight heparins: implications for prescribing practice and therapeutic interchange. P T. 2010; 35 (2): p.95-105.
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