Parenteral Anticoagulants

Heparin remains the most widely used parenteral anti-thrombotic.¹ Low Molecular Weight Heparins (LMWHs) represent a significant advance over standard unfractionated heparin (UFH) because of their ease of use. However, standard heparin remains first choice if there is a risk of bleeding because it is more quickly reversed.

Standard heparin works by binding to a circulating anti-coagulant (thromboplastin-III) and enhancing its ability to block both factor Xa and thrombin. LMWHs mainly block factor Xa, and have only slight effect on thrombin. The new LMWH fondaparinux is a pure factor Xa blocker but seems just as effective.

Both UFH and LMWHs are given parenterally by intravenous or subcutaneous injection.

The antithrombic superiority of LMWHs has not been proven in all clinical situations but they do have a lower risk of heparin-induced thrombocytopenia with thrombosis which means that their use over UFH is generally favoured.²

This family of closely related drugs (tinzaparin, enoxaparin, dalteparin and bemiparin) are all factor Xa inhibitors with similar properties, although produced by different chemical methods. They are all of porcine origin.

So far, differences in effectiveness and safety seem extremely small but further studies are needed.¹

Fondaparinux (a new synthetic factor Xa inhibitor with a long half-life of 17 hours) is licensed for the prophylaxis of venous thromboembolism (VTE) in patients with hip fracture or having total knee or hip replacements.

Monitoring of LMWHs (by anti-Xa assay) is only necessary in certain situations, e.g. renal failure (excretion is mainly via the kidneys for LMWHs so there is increased risk of bleeding in renal failure). They are only partially reversed by protamine.

They have several advantages over standard heparin including:

• They are safe and effective
• They have a long half-life/duration of action which means a once-daily subcutaneous dosage
• Routine laboratory monitoring is not needed
• There is less risk of heparin-induced thrombocytopenia
• They are more effective as VTE prophylaxis for orthopaedic surgery

They are available in a range of once daily single-dose syringes. There are different doses for prophylaxis (sometimes different doses dependent on risk) and for therapeutic treatment.

Indications for LMWHs¹³

• Prophylaxis of venous thromboembolism:
  • During general, urological, cardiac, thoracic, neurosurgical, vascular and gynaecological surgery if patients have 1 or more risk factors for VTE.
  • During major orthopaedic surgery and after hip fracture. Treatment should be for at least 7-10 days and for 4 weeks after hip fracture surgery. Fondaparinux may be superior when given > 6 hours post-operatively ⁴ and after hip fracture.^5,6
  • After major trauma when not contraindicated by bleeding risk
  • In patients at high risk of venous thromboembolism associated with plaster cast immobilisation
  • In medical inpatients determined to be at high risk of venous thromboembolism
  (Please refer to article on Prevention of Deep Vein Thrombosis for details about risk factors for VTE and other prophylactic measures to be taken during hospital admission.)
• Treatment of venous thromboembolism
  • Treatment of deep vein thrombosis (DVT)
  • Treatment of pulmonary embolus (PE)
  There is no evidence that LMWHs are less effective in the treatment of massive DVT or PE but some clinicians prefer to use UFH because of its rapid effect and their clinical experience. ¹
• Other indications¹
  • Cerebral venous thrombosis (no data on its use)
  • Intra-abdominal venous thrombosis
  • Treatment of acute coronary syndromes in addition to treatment with aspirin
  • Treatment of acute myocardial infarction. (Patients at high risk of systemic emboli or VTE should be considered for initial treatment with UFH. Patients treated with thrombolytic therapy should be considered for initial treatment with UFH for the first 48 hours.)
  • LMWH should be considered in patients in sickle cell crisis until recovery from the crisis.

Standard heparin has a rapid onset and shorter duration of action. It remains more suitable than LMWHs when there is a high risk of bleeding (e.g. renal failure, disseminated intravascular coagulation, trauma) or if a rapid onset is needed, e.g. massive pulmonary embolus.

Other indications are:¹

• Cerebral venous thrombosis and intra-abdominal venous thrombosis
• Some instances of myocardial infarction
• To remove thrombosis in venous or arterial catheters and for coronary angiography
• During cardiopulmonary bypass operations
• During haemodialysis and haemofiltration

It can be terminated rapidly by stopping the infusion, or even more rapidly reversed with IV protamine sulphate.

Standard heparin should be given by a bolus loading dose of 5,000U (75 U/kg) and then an infusion of 18U/kg/hr with daily measurement of APTT and dose adjustment. There should be a repeat measurement at 4 hours after any dose adjustment. Alternatively, an equivalent daily dose can be given by two subcutaneous injections.¹

(Refer to individual Specific Product Characteristics for full list.)

• Untreated haemophilia
• Haemorrhagic disorders
• Thrombocytopenia with platelets <80 x 10⁹/l
• History of heparin-induced thrombocytopenia
• Peptic ulcer
• Oesophageal varices
• Recent cerebral haemorrhage
• Severe hypertension
• Severe liver disease
• Major trauma
• Recent neurosurgery or eye surgery
• In conjunction with spinal or epidural anaesthesia
• Hypersensitivity to heparin

(Refer to individual Specific Product Characteristics for full list.)

• Hyperkalaemia
• Thrombocytopenia
• Heparin-induced thrombocytopenia (an immune-mediated process that can lead to life-threatening thrombosis)
• Bleeding - it is usually sufficient to stop heparin but consider protamine
• Allergy (urticaria, angioedema, anaphylaxis)
• Osteoporosis (after prolonged use - exact risk unknown).^7,8 Risk with LMWH may be less.
• Alopecia (rarely after prolonged heparin)

• There is no evidence that UFH or LMWHs cross the placenta.¹ They are safe for both prevention and treatment of thrombosis in pregnancy.
• Anti-Xa activity should be measured to ensure appropriate dosing. Platelet count should be monitored initially.
• Therapeutic anticoagulation is usually given for 6 months. The woman should be advised to stop the heparin once labour starts and medical staff should reassess the need for continuation.
• LMWHs need to be given twice daily in pregnancy due to altered pharmaco-kinetics.
• There is no contraindication to breastfeeding when the mother is being treated with heparins.⁹

The other alternative parenteral anticoagulants are mainly indicated if thrombocytopenia has occurred with heparin. They include:

• Danaparoid (a heparinoid)
• Lepirudin (a thrombin inhibitor based on the anticoagulant secreted by the leech, made by recombinant technology, given intravenously and adjusted according to APTT)
• Bivalirudin (a thrombin inhibitor which is similar to lepirudin and is licensed for percutaneous coronary intervention)¹⁰