The early phase development of drugs has entered into a new era and requires novel designs and rational choice of biomarkers. This is particularly true for drugs affecting the coagulation cascade. The most commonly used effect markers such as the activated partial thrombin time (aPTT) and the prothrombin (PT) were developed for the heparins and coumarins and these tests are hardly informative for compounds with a different pharmacology.

Effect markers

The effects of novel coagulation compounds, such as selective and reversible inhibitors of coagulation factors, are indeed not evaluated well with commonly used effect markers. These compounds require adaptation of existing tests or the use of novel tests. When selecting a test, it is important to make sure that it allows frequent measurements and that it can assess the level of anticoagulation ‘on-line’. This helps ensure subject safety, because excess anticoagulation increases bleeding risk. Easy access to patients in which the results of the first-in-human trial tests can be applied is important as well. Dose selection in the first studies facilitates a rapid transition from proof-of-pharmacology to proof-of-concept. This can for instance be done by studying a relevant dose in ambulant or hospitalized patients.

Available tests

  • aPTT, PT, Ecarin Clotting Time (ECT), Prothrombinase Induced Clotting Time (PiCT), fibrinogen levels
  • Concentration of coagulation or fibrinolysis factors in quiescent or active form
  • TAT, D-dimer, prothrombin fragment 1+2, fibrinogen degradation products, PAP, plasminogen, etc.
  • Thrombin generation test – several variants
  • Whole blood platelet aggregometry using different inducers or combinations thereof
  • Activated Protein-C in complex with Protein-C inhibitor (APC-PCI) levels
  • Thromboelastometry
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