12.1 Unfractionated Heparin

Unfractionated heparin is a naturally-occurring glycosaminoglycan (porcine or bovine) with a molecular weight range of 5,000-35,000 daltons (mean 12-14,000). It inactivates activated clotting factors (thrombin, factor Xa) by potentiating the effect of the endogenous coagulation inhibitor, antithrombin; and thereby prolongs the activated partial thromboplastin time (APTT) when given in therapeutic doses. Heparin is given parenterally, either by intravenous (IV) injection which has an immediate effect and short plasma half-life (30 minutes-2 hours); or by subcutaneous (SC) injection which has a delayed (2 hours) but more prolonged (10 hours) effect. There is a 10-fold intersubject variability in response to a given dose of heparin; hence with full-dose heparin therapy its coagulation effect (APTT ratio) must be monitored at least daily and the dose adjusted to achieve the target therapeutic range, within which the risks of bleeding and thrombosis are each minimised.¹⁵²

12.1.1 INITIATION, DOSAGE AND MONITORING

Indications for heparin are summarised in Table 2. Heparin is usually given in hospital and replaced by warfarin for outpatient anticoagulation; however subcutaneous heparin therapy is increasingly used in some outpatients (e.g. pregnancy).

After clinical assessment has demonstrated an indication for heparin treatment (see Table 2), the patient's medical and drug history should be assessed for cautions and contraindications (see Table 7).

A baseline blood count including platelet count, coagulation screen, urea, electrolytes and liver function tests should be obtained prior to starting full-dose heparin therapy. This may show contraindications or risk factors for bleeding, such as anaemia, thrombocytopenia, renal failure, or coagulopathy (e.g. due to severe liver disease). A baseline platelet count is useful for the subsequent diagnosis of heparin-induced thrombocytopenia. In venous thromboembolism, a baseline sample may help in diagnosis of antithrombin deficiency prior to reduction in antithrombin by heparin therapy.

Low dose unfractionated heparin (5,000 IU 8-12 hourly or 7,500 IU 12-hourly subcutaneously), given as routine prophylaxis of venous thromboembolism, does not require monitoring of the APTT ratio; nor does low dose infusion for prevention of clotting in peripheral arterial catheters.

In patients given full-dose unfractionated heparin therapy, routine monitoring of the APTT ratio (at least daily) and adjustment of heparin doses according to a local protocol, to achieve the target therapeutic range of anticoagulant effect (APTT ratio) is strongly recommended.

Table 7

Contraindications to and cautions with full-dose Anticoagulant drugs

Note: These depend on individual circumstances and are seldom absolute.

• Uncontrolled severe hypertension

  e.g. systolic >200 mm Hg or diastolic >120 mm Hg

• Potential bleeding lesions

  e.g. active peptic ulcer, oesophageal varices
  aneurysm, proliferative retinopathy
  recent organ biopsy
  recent trauma or surgery to head, orbit, spine
  recent stroke
  confirmed intracranial or intraspinal bleed

• Heparin

  history of heparin-induced thrombocytopenia or thrombosis

• Warfarin

  pregnancy (usually)
  homozygous protein C deficiency (risk of skin necrosis)
  history of warfarin-related skin necrosis
  uncooperative/unreliable patients (long-term therapy)

This recommendation is based on five trials in acute deep vein thrombosis or acute myocardial infarction which showed that that failure to reach the lower limit of the target range of the APTT ratio (usually 1.5-2.5) was associated with substantial increases in relative risks of recurrent thrombotic events;^{32, 152} on evidence from randomised controlled trials that use of protocols for heparin dose adjustment according to APTT ratio results improves the achievement of therapeutic target ranges, ^{32, 53, 56} and on a large reported clinical experience that the risk of bleeding increases with APTT ratios above the upper limit of the target therapeutic range.^{152, 153} Evidence level Ib

Each laboratory should standardise its own target range for APTT ratio.32, 54

Clinically-important heparin-induced thrombocytopenia is immune-mediated and usually occurs between six and 10 days (up to 20 days) after initiation of heparin therapy; it may be complicated by thrombosis.

The platelet count should be monitored in all patients receiving heparin for 5 days or more, to detect heparin-induced thrombocytopenia, as recommended by the Committee on Safety of Medicines.154

If thrombocytopenia is detected, heparin should be stopped immediately, and alternative anticoagulation considered, e.g. with recombinant hirudin; the heparinoid, danaparoid (unlicensed indication in UK); or the defibrinating agent, ancrod (unlicensed indication in UK). Warfarin may be considered once the platelet count has recovered.152

Osteoporosis and fractures have followed prolonged heparin use, e.g. in pregnancy.¹⁵² Evidence level III

Monitoring of bone density may be considered patients at high risk of osteoporosis.

Full-dose unfractionated heparin is usually initiated with an initial intravenous loading dose over five minutes (5000 IU in an average-sized adult; or 75 IU/kg body weight in children, small adults and large adults). For most indications for full-dose heparin, an intravenous infusion is then given (1400 IU/hour in an average-sized adult; 15-25 IU/kg body weight/hour in children, small adults and large adults). A lower initial infusion rate (1000 IU/hour) is usually given if heparin is given following thrombolytic therapy, which produces an anticoagulant effect (see section 5.1). The APTT ratio should be measured about six hours after the initial bolus injection, and the infusion rate adjusted using a local schedule. After each change of heparin dose, the APTT ratio should be measured after 6-10 hours, when a steady state will have been reached. When the target therapeutic range has been achieved, the APTT ratio should be measured at least daily.¹⁵²

As noted in section 2.3, 12-hourly subcutaneous injection of unfractionated heparin is as effective and as safe as intravenous heparin in treatment of deep vein thrombosis.^{55, 56} Treatment should be initiated with a conventional intravenous bolus, and monitoring of the APTT ratio (4-6 hours after injection, preferably at the same time each day) and dose adjustment performed. It should be noted that there have been no reported trials of subcutaneous unfractionated heparin in patients with pulmonary embolism.

12.1.2 REVERSAL OF UNFRACTIONATED HEPARIN

As the half-life of unfractionated heparin is short, it is usually sufficient to stop heparin if there is mild bleeding. If severe bleeding occurs, protamine sulphate should be given.154

12.2 Low molecular weight Heparins

Several low molecular weight (LMW) heparins have recently been licensed in the UK as alternatives to unfractionated heparin for the prophylaxis of DVT and PE (see section 2.1) and treatment of DVT and PE (see section 2.3) or unstable angina (see section 5.3).⁴⁹ Their lower molecular weight gives the advantage of greater bioavailability after subcutaneous injection compared to standard, unfractionated heparin: hence they are effective antithrombotic agents when given once or twice daily (as compared to twice or thrice daily) and do not require routine daily monitoring of coagulation tests. LMW heparins have little effect on the APTT, hence if monitoring of their anticoagulant effect is required, plasma anti-Xa levels should be used.^{49, 152}

12.2.1 MONITORING OF LMW HEPARINS

Monitoring of plasma anti-Xa levels should be performed if there are complications such as haemorrhage, extension of thrombosis, or accidental overdose; and in patients with renal failure.¹⁵⁵ Monitoring of the platelet count is recommended to detect heparin-induced thrombocytopenia.²⁰

Long term LMW heparin therapy may carry a lower risk of bone fractures than unfractionated heparin in older patients,²² but monitoring of bone density may be considered in high risk patients.

12.2.2 REVERSAL OF LMW HEPARINS

The manufacturer's data sheet should be consulted.