Parenteral anticoagulation

Parenteral anticoagulants are routinely indicated for the prevention and treatment of venous thromboembolism (VTE). Heparin is typically the preferred agent for inpatient parenteral anticoagulation. Serious side effects include bleeding complications and 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/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).

See also “Anticoagulation reversal.”

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

Synthetic heparin

• Drugs: fondaparinux
• Administration: subcutaneous
• Monitoring during therapy
  • Not generally recommended
  • Anti-factor Xa activity can be assessed in specific cases
• 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

• Drugs: argatroban, bivalirudin, desirudin; , dabigatran
• Administration
  • Intravenous: argatroban, bivalirudin, desirudin
  • Oral: dabigatran (see direct oral thrombin inhibitors)
• Monitoring during therapy: not generally recommended
• Antidote
  • Possibly aPCC and/or antifibrinolytics (e.g., tranexamic acid)
  • Dabigatran: idarucizumab (monoclonal antibody)

Unfractionated heparin (UFH)

• Enhances the activity of antithrombin
• Indirect inhibitor of
  • Factor Xa: antithrombin III potentiation → inhibition of factor Xa → decreased activation of prothrombin → ↓ thrombin→ ↓ fibrinogen activation → ↓ fibrin
  • Thrombin (factor IIa); : UFH binds antithrombin III and thrombin simultaneously at two distinct binding sites → antithrombin III and thrombin held by heparin in close proximity (complex formation) → ↑ thrombin inhibition → ↓ fibrinogen activation → ↓ fibrin
• Short half-life: anticoagulant effect quickly ceases once administration is stopped

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

• Mechanism of action ^[1][2]
  • LMWH: binds to antithrombin III ; → inhibition of factor Xa → decreased conversion of prothrombin → ↓ thrombin
  • Synthetic heparin: only binds to antithrombin III → selective inhibition of factor Xa
• Higher bioavailability than unfractionated heparin
• Long half-life: 2–4 times longer than unfractionated heparin

Direct thrombin inhibitors

• Directly inhibit thrombin (freely circulating and in association with clots)
• Act independently from antithrombin

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.

General side effects

• Bleeding
• Drug-drug interactions

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

Specific side effects

Thrombocytopenia

• Treatment with heparin, especially UFH, can cause thrombocytopenia.
• Thrombocytopenia may be immune-mediated heparin-induced thrombocytopenia (formerly known as type 2 HIT) or non-immune heparin associated thrombocytopenia (formerly known as type 1 HIT): See “Alternative diagnoses of HIT” for distinguishing features.

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

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

Unfractionated heparin

Low-dose therapy

• VTE prophylaxis

High-dose therapy

• Treatment of:
  • Acute DVT
  • Acute pulmonary embolism
  • Acute coronary syndrome
  • Acute arterial thrombosis
• Prophylaxis of VTE for patients during hemodialysis, ECMO, mechanical heart valve replacement
• Atrial fibrillation

Low molecular weight heparin ^[3]

• Treatment of:
  • Acute DVT
  • Acute pulmonary embolism
  • Unstable angina
  • Non-ST-elevation acute coronary syndrome
  • STEMI in patients undergoing fibrinolysis
• Prophylaxis of:
  • VTE
  • Stent thrombosis in patients undergoing percutaneous coronary intervention
  • Stroke in patients with Afib undergoing cardioversion

Direct thrombin inhibitors

• Treatment of heparin-induced thrombocytopenia
• Prophylaxis of:
  • VTE
  • Stroke and systemic embolism in patients with nonvalvular Afib

Use direct thrombin inhibitors (Bivalirudin, Argatroban, Dabigatran) to treat the BAD HIT (Heparin-Induced Thrombocytopenia), which has a worse prognosis than non-immune heparin-associated thrombocytopenia.

• Recent stroke
• Uncontrolled hypertension
• Active bleeding
• HIT (except for direct thrombin inhibitors which can be used for anticoagulation in HIT)

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

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