Heparin and LMWH Pharmacology
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Direct answer
Heparin and low molecular weight heparin (LMWH) are parenteral anticoagulants that work by enhancing antithrombin's inhibition of thrombin and factor Xa. Unfractionated heparin is monitored by aPTT and fully reversed by protamine, whereas LMWH is monitored by anti-Xa activity and only partly reversed by protamine.
What you must remember
- Mechanism of unfractionated heparin: It binds antithrombin and inhibits both thrombin (factor IIa) and factor Xa, so its effect is broad.
- Mechanism of LMWH: Agents such as enoxaparin and dalteparin have a higher ratio of anti-Xa to anti-IIa activity than unfractionated heparin.
- Monitoring: The aPTT tracks unfractionated heparin, while anti-Xa levels are the preferred measure for LMWH and are not needed for every patient.
- Reversal: Protamine neutralises unfractionated heparin well, but it only partly neutralises the anti-Xa effect of LMWH.
- Fondaparinux: A synthetic pentasaccharide that acts through antithrombin to inhibit factor Xa selectively, with no routinely available specific antidote.
- Renal clearance: LMWH and fondaparinux are cleared mainly by the kidneys, so they accumulate in renal impairment.
- Heparin-induced thrombocytopenia: An antibody against platelet factor 4 bound to heparin causes platelet activation and thrombosis, and it requires stopping all heparin.
Choosing the right monitoring and reversal approach
A 58-year-old man on unfractionated heparin for pulmonary embolism develops a bleed from a gastric ulcer. The steps depend on which heparin he received and how strong the anticoagulant effect is at the time.
- Confirm the agent: Check whether the patient received unfractionated heparin or an LMWH, because the reversal options differ.
- Measure the effect: Use the aPTT for unfractionated heparin, and use anti-Xa activity calibrated to the specific LMWH when monitoring LMWH.
- Stop and hold: Stop further doses immediately and hold the next dose until the bleeding is controlled.
- Reverse unfractionated heparin: Give intravenous protamine, which neutralises unfractionated heparin effectively, with the dose guided by the amount given and the time since the last dose.
- Limit LMWH reversal: Protamine neutralises only part of the anti-Xa effect of LMWH, so local haemostasis and supportive care carry more weight.
- Manage fondaparinux bleeding: No specific antidote is routinely available, so supportive care and clinical judgement guide management.
- Reassess the thrombotic risk: Once bleeding is controlled, weigh the original indication against the bleeding risk before restarting any anticoagulant.
Where the exam tries to catch you
Most traps involve the choice of test, the reversal agent and the response to thrombocytopenia.
- Trap: Using the aPTT to monitor LMWH. Correct: Anti-Xa activity is the preferred test, because the aPTT is an insensitive guide to the factor Xa-predominant effect of LMWH.
- Trap: Expecting protamine to fully reverse enoxaparin. Correct: Protamine reverses unfractionated heparin well but only partly reverses LMWH.
- Trap: Continuing heparin when a platelet fall appears on therapy. Correct: Stop all heparin sources and switch to a non-heparin anticoagulant such as argatroban, since continued exposure worsens thrombosis.
- Trap: Giving standard LMWH doses in severe renal failure. Correct: LMWH accumulates when renally cleared, so dose adjustment or unfractionated heparin is preferred in severe impairment.
Frequently asked questions
Which test monitors unfractionated heparin therapy?
The activated partial thromboplastin time, or aPTT, is the standard test for monitoring unfractionated heparin, because heparin prolongs it in a dose-related way. Anti-Xa activity can also be used, but the aPTT remains the classic answer for monitoring an unfractionated heparin infusion.
Which drug reverses unfractionated heparin?
Protamine sulphate is the antidote for unfractionated heparin, because it is a positively charged protein that binds the negatively charged heparin. It is given intravenously with care, since it can cause hypotension and allergic reactions.
Why does fondaparinux have no specific reversal agent?
Fondaparinux is a synthetic pentasaccharide that acts through antithrombin, and protamine does not neutralise it effectively. Bleeding on fondaparinux is therefore managed with supportive measures and local haemostasis.
Which anticoagulant is preferred in heparin-induced thrombocytopenia?
In heparin-induced thrombocytopenia, all heparin must be stopped and a non-heparin anticoagulant such as argatroban is used. The choice of alternative depends on renal function, liver function and local protocols.
Do heparin and LMWH cross the placenta?
Unfractionated heparin and LMWH do not cross the placenta in meaningful amounts, which is why they are preferred over warfarin in pregnancy. Warfarin is teratogenic, so heparin-based therapy is the usual choice for pregnant women who need anticoagulation.