Results of clot waveform analysis and thrombin generation test for a plasma‐derived factor VIIa and X mixture (MC710) in haemophilia patients with inhibitors—phase I trial: 2nd report

We reported the results of a clinical pharmacological study of MC710 (a mixture of plasma‐derived FVIIa and FX) in haemophilia patients with inhibitors during a non‐haemorrhagic state. This report provides the results of a clot waveform analysis (CWA) and thrombin generation test (TGT) using blood samples obtained in this study. CWA and TGT were conducted using blood samples obtained from a pharmacokinetic and pharmacodynamic study in which MC710 (five dose rates: 20, 40, 80, 100 and 120 μg kg−1) was compared with NovoSeven (120 μg kg−1) and FEIBA (two dose rates: 50 and 75 U kg−1) as control drugs in 11 haemophilia patients with inhibitors without haemorrhagic symptoms. CWA showed that MC710 provided significantly greater improvement than the control drugs in activated partial thromboplastin time (APTT) at 80 μg kg−1; maximum clot velocity and maximum clot acceleration were more enhanced by MC710 than by control drugs. TGT revealed that MC710 significantly shortened the initiation time of thrombin generation in comparison to FEIBA and induced greater thrombin generation potency than NovoSeven. It was not clear whether or not MC710 caused significant dose‐dependent changes in the two measurements; however, differences between MC710 and the control drugs were clarified. MC710 was confirmed to have superior coagulation activity and thrombin productivity and is expected to have superior bypassing activity.

[1]  Y. Ohashi,et al.  Clinical pharmacological study of a plasma‐derived factor VIIa and factor X mixture (MC710) in haemophilia patients with inhibitors – Phase I trial , 2012, Haemophilia : the official journal of the World Federation of Hemophilia.

[2]  K. Fischer,et al.  Sequential combined bypassing therapy is safe and effective in the treatment of unresponsive bleeding in adults and children with haemophilia and inhibitors , 2011, Haemophilia : the official journal of the World Federation of Hemophilia.

[3]  J. Rosing,et al.  Thrombin generation tests. , 2011, Thrombosis research.

[4]  Y. Nakatomi,et al.  Combining FVIIa and FX into a mixture which imparts a unique thrombin generation potential to hemophilic plasma: an in vitro assessment of FVIIa/FX mixture as an alternative bypassing agent. , 2010, Thrombosis research.

[5]  Y. Abe,et al.  Frequency of Abnormal Biphasic aPTT Clot Waveforms in Patients with Underlying Disorders Associated with Disseminated Intravascular Coagulation , 2006, Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis.

[6]  K. Mann,et al.  Thrombin generation profiles in deep venous thrombosis , 2005, Journal of thrombosis and haemostasis : JTH.

[7]  S. Bajaj,et al.  The first epidermal growth factor‐like domains of factor Xa and factor IXa are important for the activation of the factor VII–tissue factor complex , 2005, Journal of Thrombosis and Haemostasis.

[8]  M. Shima.  Understanding the hemostatic effects of recombinant factor VIIa by clot wave form analysis. , 2004, Seminars in hematology.

[9]  Y. Nakatomi,et al.  A novel therapeutic approach combining human plasma‐derived Factors VIIa and X for haemophiliacs with inhibitors: evidence of a higher thrombin generation rate in vitro and more sustained haemostatic activity in vivo than obtained with Factor VIIa alone , 2003, Vox sanguinis.

[10]  Jean-Luc Pellequer,et al.  Model of a Ternary Complex between Activated Factor VII, Tissue Factor and Factor IX , 2002, Thrombosis and Haemostasis.

[11]  A. Giles,et al.  The Utility of activated Partial Thromboplastin Time (aPTT) Clot Waveform Analysis in the Investigation of Hemophilia A Patients with very Low Levels of Factor VIII Activity (FVIII:C) , 2002, Thrombosis and Haemostasis.

[12]  M. Hoffman,et al.  The action of high-dose factor VIIa (FVIIa) in a cell-based model of hemostasis. , 2001, Seminars in hematology.

[13]  S. Béguin,et al.  The Thrombogram: Monitoring Thrombin Generation in Platelet Rich Plasma , 2000, Thrombosis and Haemostasis.

[14]  C. Toh,et al.  Early Identification and Prognostic Implications in Disseminated Intravascular Coagulation through Transmittance Waveform Analysis , 1998, Thrombosis and Haemostasis.

[15]  J. Oliver,et al.  A possible mechanism of action of activated factor VII independent of tissue factor. , 1998, Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.

[16]  J. Oliver,et al.  Platelet activity of high‐dose factor VIIa is independent of tissue factor , 1997, British journal of haematology.