Quantifying the Dose-Response of Unfractionated Heparin Using a System Pharmacology Model of Coagulation

Introduction: Unfractionated heparin (UFH) is commonly used in the treatment and prevention of a variety of thromboembolic disorders. Its short duration of action and reversibility of its effect with the use of protamine sulphate make it the agent of choice in acute settings such as cardiac surgery. However, optimal dosing of UFH remains challenging partly due to the lack of quantification of its pharmacokinetic (PK) properties and the lack of a universal and direct pharmacodynamic (PD) biomarker. In addition, interpretation of the PD response is distorted by the inherent variability of the haemostatic system upon which UFH acts.

Aim: To explore the use of a systems pharmacology model of coagulation to simulate the dose-response relationship of UFH.

Methods: The coagulation model by Wajima [1] was modified to allow for dose titration used to simulate the time course of anti-Xa and activated partial thromboplastin time (aPTT) activity of UFH following IV infusion. Anti-Xa response was calculated through polynomial regression of the Xa clotting time (XaCT) predicted by the coagulation model [2]. Data were available on 31 paediatric patients who received UFH for thromboprophylaxis during extracorporeal membrane oxygenation procedure. UFH infusion rate was titrated to maintain a target anti-Xa level of 0.4-0.6 IU/mL. The simulated anti-Xa and aPTT responses were overlaid with observed data. No modelling was performed.

Results: Observations-overlaid prediction plots showed reasonable model agreement for model predictions and the individual data for anti-Xa activity. In general there was reasonable agreement between the model predictions and aPTT observations in some patients.  In contrast, in other patients the model predictions were significantly different from the observations (generally underpredicting the observations by 2-3 fold at usual clinical infusion rates).  It is possible that this might be due to the supersensivity of some children to UFH.

Conclusion: Simulations from the model showed that it can adequately describe the time course of anti-Xa activity during UFH infusion. Further refinement of the model is required to be able to describe the aPTT response, particularly in some children. The model can then be used as a basis for quantifying the dose-response relationship of UFH and will be extended further to account for its time varying pharmacokinetics.


  1. Wajima T, Isbister GK, Duffull SB. A comprehensive model for the humoral coagulation network in humans. Clin Pharmacol Ther. 2009;86(3):290-8.
  2. Gulati A, Faed JM, Isbister GK, Duffull SB. Development and evaluation of a prototype of a novel clotting time test to monitor enoxaparin. Pharm Res. 2012;29(1):225-35.