Challenges in the laboratory analyses of bleeding disorders

Standard coagulation assays such as the activated partial thromboplastin time and prothrombin time are sufficient to detect deficiencies in coagulation factors contributing to the intrinsic and extrinsic pathways, respectively. Deficiencies in factors VIII and IX can also be detected by one-stage and two-stage clotting assays. While these assays are instrumental in assessing the initiation of clot formation, sufficient formation of a clot is a continuous process that may be better studied by the use of a global hemostasis assay. Several global assays are currently being studied, including the thrombin generation assay, thromboelastography, clot waveform analysis, clot formation and lysis (CloFAL) assay, euglobulin clot lysis assay, thromboplastin generation assays and simultaneous thrombin and plasmin generation assays. This review will concentrate on the thrombin generation test, thromboelastography, the activated partial thromboplastin time waveform analysis and the CloFAL which measure the production of thrombin, as well as the kinetics of clot formation. As such, these global assays can provide greater insight into deficiencies in the mechanisms mediating hemostasis and fibrinolysis in patients with hemophilia, other bleeding disorders or even thrombophilia. These assays have been shown to be clinically relevant for assessing the response to treatment with bypassing agents (recombinant activated FVII and plasma-derived prothrombin complex concentrate) used for the hemostatic control of acute bleeding in patients with congenital hemophilia A/B. The limitations of standard coagulation assays and the use of global hemostasis assays to assess bleeding disorders and the clinical efficacy of bypassing agents will be discussed in detail.