Heparin

CLASS

• anticoagulant
• unfractionated heparin (UFH) is a sulfated polysaccharide with a molecular weight range of 3 to 30 kDa

MECHANISM OF ACTION

• inhibits Factors IIa and Xa
• binds reversibly to antithrombin III
  -> has a high affinity pentasaccharide binding site which is present in ~ 1/3 of heparin molecules
  -> conformational change
  -> 1000 times more potent inhibition of  these proteases in the coagulation cascade:

• IIa (thrombin) and Xa primarily
• also IX and IX
• others: XII, XIII, plasmin

• Maximal anti-IIa activity is dependent upon the binding of heparin to both thrombin and antithrombin III — molecules <18 saccharide units lack the necessary chain length to form a bridge between the two molecules and so short chain heparin molecules have primarily anti-Xa inhibitory activity
• also binds directly to several coagulation proteases and thereby facilitates their reaction with antithrombin III
• UFH binds to a number of plasma proteins and which accounts for the variable intra-individual anticoagulant response

PHARMACEUTICS

• mixture of acid mucopolysaccharides extracted from bovine lung or porcine intestinal mucosa
• clear colourless solution of Na-heparin (1000 to 25,000IU/mL)
• heparin calcium (25,000IU/mL)
• MW 3,000 to 30,000

DOSE

• IV: titrated to APTT (usually: 80 U/kg bolus then 18 U kg/h and check APTT at 6h – aiming for 60-80 seconds)
• SC: 5000 12hrly or q8h in the obese for VTE prophylaxis

INDICATIONS

1. prevention of venous thromboembolism
2. priming of cardiopulmonary bypass or haemodialysis
3. maintenance of patency of indwelling lines
4. DIC
5. fat embolism

ADVERSE EFFECTS

• bleeding
• thrombocytopaenia (HITS type 1 and 2)
• osteoporosis

PHARMACOKINETICS

• Absorption – SC or IV
• Distribution -1/3 bound to antithrombin III, 2/3 bound to albumin, fibrinogen & proteases, Vd = 40-100 mL/kg
• Metabolism – liver, renal and reticuloendothelial system
  Elimination – urine, t ½ = 2 hrs

OTHER INFORMATION

Activity can be tested by:

1. APTT
2. Anti-Xa assay
3. Activated Clotting Time [ACT]

Reasons for failure of heparin anticoagulation:

• insufficient dose (e.g. dose error, increased protein binding, increased clearance)
• failure can occur with infections, fever, cancer, post-operative state or other thrombophilia
• antithrombin III deficiency
• high Factor VIII
• DIC
• high clot burden

How to correct failure to anticoagulate with heparin:

• confirm correct dose/ rate
• consider changing to LMWH
• consider antithrombin III concentrate (or FFP or cryoprecipitate)

References and Links