General aspects of anticoagulant therapy

This is achieved by anti-coagulation initially by heparin and subsequently by warfarin for 3 to 6 months. Anti-coagulants are commonly used in cardiological practice and in the prevention and the treatment of deep venous thrombosis (DVT) and pulmonary thrombosis (PE). The objective of anti-coagulant treatment is to achieve a level of anti-coagulant at which there is complete anti-thrombotic effect, but no increased risk of bleeding. This ideal is not achieved with current drugs, the main ones in the UK being heparin and warfarin. Careful and regular laboratory control is required to achieve a compromise between efficacy and risk.


Unfractionated heparin (UFH) is a naturally occurring strongly anionic mucopolysaccharide, MW 5000-35,000 d. Its main action is to augment the effect of the physiological anti-coagulant, anti-thrombin (AT). Arginine residues on the AT molecule interact with serine residues on certain activated coagulation factors — thrombin, Xa, IXa, XIa, XIIa-forming irreversible complexes, which are removed by reticulo-endothelial cells. Heparin increases the inhibitory action of AT by 1000-fold. Low molecular weight heparin (LMWH) MW 2000-8000 d are prepared from UFH by chemical or enzymatic depolymerisation. Acceleration of inhibition of factor Xa requires only the pentasaccharide sequence, but acceleration of thrombin inhibition requires a minimum total chain length of 18 saccharides (MW5000 d). Therefore, in all LMWHs the anti-Xa activity is greater than the anti-IIa activity.146--149

The usual routes of administration are by continuous IVI for UFH (half-life about 1 hour); twice daily SC injections have also been used. LMWH is usually given by once or twice daliy SC injection.

Laboratory monitoring

The APTT should be measured 4 to 6 hours after starting the IV UFH and, thereafter, once daily aiming to keep the APTT ratio between 1.5-2.5. The platelet count should also be monitored because of the risk (1-2%), of heparin-induced thrombocytopenia (HIT), which may be associated with arterial thrombosis.

No laboratory monitoring is required for LMWH therapy in routine circumstances. For certain patient groups this will be required and is carried out by measuring anti-Xa levels (see diagnosis and treatment of DVT).

Side effects

Bleeding is the most common side effect.157 The infusion should be stopped, a clotting screen checked, and blood transfusion may be necessary. Due to its short half-life, heparin may be recommenced after few hours at a lower dose. If bleeding is severe, heparin can be neutralised by IV administration of protamine sulphate. Other side effects include HIT,180 osteopenia (on prolonged administration), skin necrosis, alopecia, and hypersensitivity reactions.180


It antagonises vitamin K, required for gamma carboxylation ofcertain glutamic acid residues that facilitate calcium binding of coagulation factors II, VII, IX, and X and the naturally occurring anti-coagulants proteins C and S. Warfarin takes 3 to 5 days to achieve an anticoagulant effect which is dependent on achieving a sufficiently low level of factor II (half-life 60 hours). Therefore, heparin and warfarin should be overlapped for at least 72 hours, and heparin should not be stopped until the International Normalised Ratio (INR) is > 2.0 (usually after 5 days of overlap). A number of drugs may interact with warfarin (potentiate or antagonise) and change warfarin requirements, sometimes dramatically.153,181,182

Laboratory monitoring

The INR is a standardised PT. The usual recommended therapeutic range is 2 to 3 or 3 to 4.5 depending upon the indication. The dose of heparin may need to be reduced as the INR rises. The patient should be counselled about warfarin treatment and seen in the anticoagulant clinic within a week of discharge.

Side effects

Bleeding, usually related to overdosage, is the most common side effect. If the INR is > 4.5 and there is no bleeding, stop the warfarin, check the INR at 24 to 48 hours, and restart warfarin at a lower dosage. Serious bleeding necessitates treatment with fresh frozen plasma or clotting factor II, IX, X, and VII concentrates. Vitamin K1 given IV slowly acts within a few hours, but may cause problems with reanti-coagulation for unpredictable lengths of time (up to 3 weeks). Small doses are advised (1 to 2 mg) unless further warfarinisation is not required (10 mg). Other side effects include skin necrosis (protein C or S deficiencies), skin rashes, or alopecia.156,157,182


Warfarin crosses the placenta and is teratogenic, particularly between weeks 6 to 12. Later in pregnancy it may precipitate intracerebral haemorrhage in the fetus. Heparin does not cross the placenta and is the anti-coagulant of choice during pregnancy. Neither heparin nor warfarin is excreted in breast milk.

Advantages of LMWH (Table 8)

1. LMWH have a greater bioavailability at low doses, longer half-life, and more predictable response when administered at fixed doses than UFH.

2. No need for routine laboratory monitoring.

Table 8. Comparison of the Properties of LMWH and UFH




Mean MW (range)

15 (4-30)

4.5 (2.4-15)

Saccaride units (mean)



Anti-Xa: Anti-IIa



Inhibited by PF4



Anti-thrombotic effect via anti-IIa



Inhibits platelet function



Bioavailability (at low dose)




Hepatic and renal


Half-life of anti-Xa: IV

1 hour

2 hour


2 hour

4 hour

Monitoring required



Frequency of HIT


Very low

3. LMWH provide an anti-thrombotic efficacy in the prevention of postoperative DVT and PE, at least as good as UFH in general surgery. This effect may be obtained by once daily SC dose.

4. In orthopaedic surgery, LMWH is superior to UFH as prophylaxis for postoperative DVT, in terms of efficacy without increasing the bleeding risk.

5. SC LMWH is as effective and safe as UFH (IV or SC) for the initial treatment of DVT.

6. LMWH is effective as anti-coagulant in chronic haemodialysis, given as a single bolus injection.

7. LMWH treatment may be associated with a lower incidence of thrombocytopenia and fewer cases of heparin-induced thrombo-cytopenia and thrombosis.

8. LMWH can be used to treat some patients with DVT and PE as outpatients and at home.

9. LMWH is associated with less osteopenia and heparin-induced osteoporosis related clinical fractures.

Disadvantages of LMWH; cost Heparin-induced thrombocytopenia

The incidence of heparin-induced thrombocytopenia (HIT) with full dose unfractionated heparin appears to be around 1 to 3%, higher with heparin of bovine than porcine origin, and the incidence is somewhat less with heparin used at prophylactic doses and new LMWHs. HIT has been divided into two groups. Type I is a mild immediate transient thrombocytopenia that occurs soon after heparin exposure. It is seldom associated with a platelet count below 100 x 109/l and resolves spontaneously even if treatment is continued. This very seldom, if ever, results in clinical problems. Type II has its onset after greater than 5 days' exposure to heparin. It is associated with a platelet count often below 100 x 109/l and is the immune mediated form that is associated with arterial and venous occlusion.180

Diagnosis remains primarily clinical being based on a fall in the platelet count to less than half the baseline value and usually lower than 100 x 109/l with, onset 5 or more days after exposure to heparin.180 Other causes of thrombocytopenia, such as, sepsis and ITP should be excluded and the thrombocytopenia will resolve following heparin withdrawal, usually after 5 to 7 days, but this can take up to a month. Clinical diagnosis can be supplemented by positive laboratory tests for the presence of a heparin-dependent antibody.

HIT may be preventable by minimising the duration of hep-arin exposure and performing regular platelet counts on patients with heparin and ensuring prompt withdrawal of therapy should the platelet count fall.

The treatment of HIT involves the immediate cessation of exposure to heparin. In the majority of cases, particularly where thrombosis has occurred, it will be necessary to commence warfarin. There is often a need for a short acting anti-coagulant to substitute for hep-arin until warfarin has reached therapeutic levels. Therapy is between the heparanoid Danaparoid, which has only 10% cross-reactivity with unfractionated heparin or hirudin which does not cross-react in HIT. LMWH suffers 40 to 90% incidence of cross-reactivity with unfrac-tionated heparin. Other treatments, such as, ancrod is not used routinely.180 Fondaparinux is another potential alternative in HIT.112

As the platelet count seldom falls into single figures, the placement of IVC filters and the use of fibrinolytics and surgery have all been safely performed to alleviate thrombotic complications despite the thrombocytopenia.

The mechanism of HIT is due to the formation of antibodies against the complex of heparin with platelet factor-4, a highly positively charged heparin binding protein released from platelet «-granules. The immune complex with heparin and PF-4 binds to platelet surface FC receptors, and this binding results in in vivo platelet activation and subsequent aggregation. The mechanisms of thrombosis are probably multifactorial as in addition to in vivo platelet aggregation, there is also evidence of activation of the coagulation cascade with increased levels of markers of thrombin generation and depletion of the proteins of the natural anti-coagulant pathway. Furthermore, endothelial cell immune mediated damage results in the exposure of endothelial cell tissue factor and the formation of a procoagulant endothelial surface to favour thrombosis.180

Pathophysiological Aspects of Coagulation ■ 57 Table 9. INR Targets for Anti-coagulation

INR (International Randomised Ratio)

Clinical State

Prophylaxis of DVT, including high risk surgery

Hip surgery, repair of fractures of femur Treatment of DVT and pulmonary embolism Prevention of VTE after myocardial infarction Mitral stenosis with embolism Atrial fibrillation Transient ischaemic attacks

Recurrent DVT

Recurrent pulmonary embolism

Arterial disease including myocardial infarction

and grafts Prosthetic valves and grafts

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