• Clinical science

Parenteral anticoagulation

Abstract

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 thromboembolisms 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 non-heparin anticoagulation (usually argatroban).

Overview

Unfractionated heparin (UFH)

Low molecular weight heparin (LMWH)

Synthetic heparin

  • Drugs: fondaparinux
  • Administration: subcutaneous
  • Monitoring during therapy: anti-factor Xa activity
  • Antidote: : possibly activated prothrombin complex concentrates (aPCC)

Heparinoid (glycosaminoglycan)

  • Drugs: danaparoid
  • Administration
    • Prophylaxis: subcutaneous
    • Therapeutic: continuous intravenous infusion
  • Monitoring during therapy: anti-factor Xa activity
  • Antidote: protamine sulfate (partial reversal)

Direct thrombin inhibitors

Platelets should always be monitored during heparin therapy and a baseline should be established before commencing treatment!
References:[1][2][8114;423]

Effects

Unfractionated heparin (UFH)

Fractionated heparin or Low molecular weight heparin (LMWH)

Synthetic heparin

Direct thrombin inhibitors

  • Directly inhibit thrombin
  • Act independently from antithrombin

The effect of most parenteral anticoagulants depends on native antithrombin. In patients with antithrombin III deficiency (e.g., due to nephrotic syndrome), this effect is reduced!
References:[3][4][5]

Side effects

Specific side effects
UFH and fractionated heparin or LMWH

Synthetic heparin

Heparinoid (glycosaminoglycan)
  • Asthma exacerbation (rarely)
Direct thrombin inhibitors

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.

Heparin treatment requires regular monitoring of the platelet count, especially for UFH, even before starting treatment.

Type 1 HIT Type 2 HIT
Frequency
  • Appr. 10–20%
  • 1–5% for UFH; 0.1–1% for LMWH
Onset
  • Within the first 5 days after beginning treatment Often day 1–2
  • Day 5–14
Severity of thrombocytopenia
  • Massive reduction: < 100,000 platelets/μL (or decrease of > 50% compared to baseline)
Pathophysiology
  • Direct interaction between heparin and platelets (e.g., heparin directly induces platelet aggregation), no antibodies involved
Clinical features
  • Clinically insignificant
Complications
  • Usually none
Management
  • Continue heparin (platelets usually return to normal with continued heparin administration)
  • Monitor platelets

The significantly increased risk of bleeding is the main side effect of all anticoagulants!
References:[6][7]

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

Indications

Low-dose therapy

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

High-dose therapy

References:[8][4][9]

Contraindications

References:[4]

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

Guidelines & therapy recommendations

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 5,000 U IV bolus, then 32,000 U per 24 hours IV
  • 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
  • Use cautiously in renal failure because of its renal elimination
  • Contraindicated if poor renal function (CrCl < 30mL/min)
  • No full antagonist available
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:[4][10][11]

Special patient groups

Pregnancy

  • Physiological hypercoagulability (e.g., due to increased levels of clotting factors) leads to increased risk of thrombosis.
  • UFH and LMWH can be used during pregnancy: neither cross the placenta, nor are they transferred through breast milk.
  • LMWH has fewer side effects.

Patients with decreased renal function

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