Recommendation grades (A-C) and levels of evidence (Ia-IV) are defined at the end of the "Major Recommendations" field.
General and Gynaecological Surgery
Patients undergoing major non-orthopaedic surgery should be considered for low molecular weight heparin (LMWH) or unfractionated heparin (UFH) at recommended prophylactic dose (grade A).
Major Elective Orthopaedic Surgery
Patients undergoing major elective orthopaedic surgery should be considered for LMWH (or fondaparinux) at recommended prophylactic dose for at least 7–10 days (grade A).
Hip Fracture
Thromboprophylaxis with LMWH (or fondaparinux) at recommended prophylactic dose should be considered for hip fracture patients (grade A).
Major Trauma
Thromboprophylaxis with LMWH at recommended prophylactic dose should be considered for major trauma when not contraindicated by bleeding risk (grade B).
Lower Limb Plaster Casts
Patients considered to be at high risk of venous thromboembolism (VTE) associated with lower limb plaster cast immobilisation may be considered for thromboprophylaxis with LMWH at recommended prophylactic dose (grade B).
Medical Patients
Medical patients determined to be at high risk of VTE should be considered for thromboprophylaxis with LMWH at recommended prophylactic dose (grade A).
Heparin and Cancer
Heparins are not recommended for use as antineoplastic agents outside clinical trials.
Heparin and Sickle Syndromes
Patients in sickle cell crisis should be considered for LMWH at recommended prophylactic dose until recovery from crisis (grade C).
Pregnancy and the Puerperium
Heparins, including LMWHs do not cross the placenta and are the anticoagulant of choice for prevention and treatment of pregnancy-associated VTE.
The principal considerations are:
- Due to the altered pharmacokinetics a twice daily dosing regimen for LMWHs is recommended.
- Frequent anti-Xa monitoring is not recommended but, if possible, anti-Xa activity should be measured to confirm appropriate dosing, at least until more information is available on the therapeutic use of LMWH in pregnancy (but see below regarding the limitations of monitoring).
- The platelet count should be monitored in the early stages of administration to avoid delayed diagnosis of heparin-induced thrombocytopenia. However, this complication is exceedingly uncommon when LMWH is used prophylactically in asymptomatic pregnant women and in this situation monitoring is not required.
- The duration of therapeutic anticoagulation in the non-pregnant subject with VTE is usually 6 months. As pregnancy is associated with prothrombotic changes in the coagulation system and venous flow, and as the increased coagulation activation persists for some weeks after delivery, a similar duration of anticoagulation is prudent in pregnancy VTE. Thus, therapeutic anticoagulation should usually be continued for at least 6 months. If the VTE occurs early in the pregnancy, provided that there are no additional risk factors, reduction of the dose of LMWH or UFH to prophylactic levels could be considered after 6 months of treatment.
- The woman should be advised that once she is established in labour or thinks that she is in labour, she should not inject any further heparin. She should be reassessed on admission to hospital and further doses should be prescribed by medical staff.
Decisions regarding the use of spinal anaesthesia in relation to heparin administration should be guided by the perceived benefits in the individual case balanced against the potentially catastrophic effects of local bleeding and should be made by an experienced anaesthetist.
Heparin-associated skin reactions appear to be more common in pregnant women. This may relate to the unusual duration of heparin exposure. Cross-reactivity between heparin preparations, including LMWHs is common and several different heparins may have to be tried.
Ovarian hyperstimulation syndrome during assisted reproduction may be complicated by arterial or VTE. There are insufficient data to reach conclusions on the efficacy of heparin thromboprophylaxis in this situation.
Treatment of VTE
Limb Deep Vein Thrombosis and Pulmonary Embolus
LMWH at recommended therapeutic dose should be used in patients with VTE who are candidates for anticoagulant treatment (grade A).
If UFH is used for treatment of VTE a bolus dose of 5000 units (U) (75 units per kilograms [U/kg]) should be followed by an intravenous infusion of 18 U/kg per hour with adjustment of the dose according to at least once daily activated partial thromboplastin time (APTT) measurement, with repeat measurement at around 4 hours after any dose adjustment. Alternatively an equivalent daily dose can be given by two subcutaneous injections (grade A).
Cerebral Venous Sinus Thrombosis
Patients with cerebral venous thrombosis should be treated with heparin. If UFH is used it should be at a standard therapeutic dose sufficient to prolong the APTT ratio to twice that of normal (grade B). If a LMWH is used it should be given at a conventional therapeutic dose (grade C).
Intra-Abdominal Venous Thrombosis
Patients with intra-abdominal venous thrombosis should be considered for treatment with heparin. If UFH is used it may be at low dose or at a therapeutic dose sufficient to prolong the APTT ratio to twice that of normal (grade C). If a LMWH is used it should be given at either conventional prophylactic or therapeutic doses (grade C).
Superficial Vein Thrombosis
If heparin treatment is given it can be either LMWH or UFH at either prophylactic or therapeutic dose (grade C).
Arterial Thromboembolism
Myocardial Infarction (MI)
LMWH thromboprophylaxis should be considered for all patients with acute MI (grade A). Patients at high risk of systemic or pulmonary embolism (PE) should be considered for initial treatment with intravenous UFH at therapeutic dose (grade A). Patients treated with thrombolytic therapy may be considered for initial treatment with intravenous UFH at therapeutic dose for the first 48 hours.
Acute Coronary Syndromes
LMWH (dose regimens from trials and in the British National Formulary) or intravenous UFH at therapeutic dose should be considered in patients with acute coronary syndromes in addition to the administration of aspirin (grade A).
Stroke
Stroke patients should be assessed for VTE risk and considered for thromboprophylaxis. If heparin is used then standard prophylactic doses of either UFH or LMWH should not be exceeded.
Peripheral Vascular Reconstructive Surgery
If heparin is given to prevent thromboembolic complications it should be given at therapeutic dose (grade C).
Acute Critical Limb Ischaemia
When heparin is given it should be at therapeutic dose.
Special Situations
Central Venous Catheters
Low-dose oral anticoagulation reduces the risk of thrombosis but the role of and need for heparin at the time of catheter insertion is unclear. It is common practice to give a prophylactic dose of UFH or a LMWH at the end of the insertion procedure and a small dose of heparin may also be used to flush the catheter. Established thrombosis is treated with standard doses of heparin and oral anticoagulation with or without removal of the catheter (grade C).
Arterial Catheters
Prevention and management of thrombosis associated with arterial catheters is similar to that with central venous catheters (grade C).
Haemodialysis
Heparin is used extensively during haemodialysis and haemofiltration to prevent extracorporeal coagulation. For haemodialysis the standard procedure is to administer a bolus dose of UFH followed by a continuous infusion at 250–1000 U/hour until the procedure is completed. Treatment is not usually monitored. For haemofiltration heparin is typically monitored by the APTT in much the same way as during treatment of VTE, with a bolus dose followed by an infusion aiming to keep the APTT ratio at two to three times normal. Haemofiltration can also be performed without heparin use, for example, with prostacyclin or in some patients without anticoagulant therapy. There is no randomised trial from which to recommend a preferred heparin regimen, and, consequently, no evidence-based guidelines have been published.
Disseminated Intravascular Coagulation
Given the heterogeneity of the causes of disseminated intravascular coagulation (DIC) and its severity, it is often difficult to decide on the optimum management of individual patients. Heparin is not used generally, but situations in which it may be considered are:
- Retained dead fetus syndrome
- Giant haemangioma
- Solid tumour
- Acute promyelocytic leukaemia
Heparin is not typically administered to patients with sepsis, placental abruption or liver disease.
In principle, UFH is preferable to LMWHs as there is a high risk of bleeding, and rapid reversal, usually by simply stopping a heparin infusion, is often required. The optimal dose of UFH has not been determined, but a lower dose than that used to treat localised thrombosis is often used. For example, an infusion of 500 U/hour, which equates to 5–10 U/kg/hour (a typical standard dose is 15–20 U/kg/hour), may be appropriate. In some patients, the heparin dose may be titrated to the clinical response; for example, a rise in fibrinogen may be used to determine heparin dose in patients with chronic DIC with hypofibrinogenaemia as in giant haemangioma or aortic aneurysm.
For many years, UFH was used in patients presenting with acute promyelocytic leukaemia. The beneficial effect of all trans-retinoic acid (ATRA) on the associated coagulopathy has obviated the need for heparin in most patients. The benefit of heparin in ATRA-resistant patients is unknown.
Monitoring of Heparin Dosage
Please refer to the original guideline document for recommendations on monitoring of heparin dosage by the Control of Anticoagulation Subcommittee of the Scientific and Standardisation Committee of the International Society for Thrombosis and Haemostasis.
Definitions:
Evidence Levels
Ia Evidence obtained from meta-analysis of randomised controlled trials.
Ib Evidence obtained from at least one randomised controlled trial.
IIa Evidence obtained from at least one well-designed controlled study without randomisation.
IIb Evidence obtained from at least one other type of well-designed quasi-experimental study (a situation in which implementation of an intervention is without the control of the investigators, but an opportunity exists to evaluate its effect).*
III Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies and case studies.
IV Evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities.
*Refers to a situation in which implementation of an intervention is out with the control of the investigators, but an opportunity exists to evaluate its effect.
Grades of Recommendations
Grade A - Requires at least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing specific recommendation. (Evidence levels Ia, Ib).
Grade B - Requires the availability of well conducted clinical studies but no randomised clinical trials on the topic of recommendation. (Evidence levels IIa, IIb, III).
Grade C - Requires evidence obtained from expert committee reports or opinions and/or clinical experiences of respected authorities. Indicates an absence of directly applicable clinical studies of good quality. (Evidence level IV).
