Early-phase drug development increasingly demands innovative design and rational choice of biomarkers. This is particularly true for drugs affecting the coagulation cascade.

Effect markers

The effects of novel coagulation compounds, such as selective and reversible inhibitors of coagulation factors, are not evaluated well with commonly used effect markers. The most commonly used effect markers, such as activated partial thrombin time (aPTT) and prothrombin (PT), were developed for the heparins and coumarins, and these tests are uninformative for compounds with a different pharmacology. Such compounds therefore require the 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 ‘on-line’ assessment of the level of anticoagulation. This helps ensure subject safety, as excess anticoagulation increases bleeding risk. It is also important to have easy access to patients in which the results of the first-in-human trial tests can be applied. Dose selection in the first studies facilitates a rapid transition from proof-of-pharmacology to proof-of-concept. This can be achieved by studying a relevant dose in ambulant or hospitalised 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 of inducers)
  • Activated Protein-C in complex with Protein-C inhibitor (APC-PCI) levels
  • Thromboelastometry
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