Novel, high incidence exercise-induced muscle bleeding model in hemophilia B mice: rationale, development and prophylactic intervention

TY - JOUR

T1 - Novel, high incidence exercise-induced muscle bleeding model in hemophilia B mice

T2 - rationale, development and prophylactic intervention

AU - Tranholm, M.

AU - Kristensen, Annemarie Thuri

AU - Broberg, M. L.

AU - Groth, Mette Perch

N1 - © The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Summary: Introduction: Muscle hematomas are the second most common complication of hemophilia and insufficient treatment may result in serious and even life-threatening complications. Hemophilic dogs and rats do experience spontaneous muscle bleeding, but currently, no experimental animal model is available specifically investigating spontaneous muscle bleeds in a hemophilic setting. Aim: The objective of this study was to develop a model of spontaneous muscle bleeds in hemophilia B mice. We hypothesized that treadmill exercise would induce muscle bleeds in hemophilia B mice but not in normal non-hemophilic mice and that treatment with recombinant factor IX (rFIX) before treadmill exercise could prevent the occurrence of pathology. Methods: A total of 203 mice (123 F9-KO and 80 C57BL/6NTac) were included in three separate studies: (i) the model implementation study investigating the bleeding pattern in hemophilia B mice after treadmill exercise; (ii) a study evaluating the pharmacokinetics of recombinant FIX (rFIX) in hemophilia B mice and based on these data; (iii) the treatment study, which tested therapeutic intervention with rFIX. At termination of the treadmill studies the presence of bleeds was evaluated. Results: Treadmill exercise resulted in a high incidence of muscle bleeds in F9-KO mice but not in C57BL/6NTac mice. Treating hemophilia B mice with rFIX before treadmill exercise prevented muscle bleeds. Conclusion: A novel model of muscle bleeds in hemophilia B mice, responsive to rFIX, has been developed.

AB - Summary: Introduction: Muscle hematomas are the second most common complication of hemophilia and insufficient treatment may result in serious and even life-threatening complications. Hemophilic dogs and rats do experience spontaneous muscle bleeding, but currently, no experimental animal model is available specifically investigating spontaneous muscle bleeds in a hemophilic setting. Aim: The objective of this study was to develop a model of spontaneous muscle bleeds in hemophilia B mice. We hypothesized that treadmill exercise would induce muscle bleeds in hemophilia B mice but not in normal non-hemophilic mice and that treatment with recombinant factor IX (rFIX) before treadmill exercise could prevent the occurrence of pathology. Methods: A total of 203 mice (123 F9-KO and 80 C57BL/6NTac) were included in three separate studies: (i) the model implementation study investigating the bleeding pattern in hemophilia B mice after treadmill exercise; (ii) a study evaluating the pharmacokinetics of recombinant FIX (rFIX) in hemophilia B mice and based on these data; (iii) the treatment study, which tested therapeutic intervention with rFIX. At termination of the treadmill studies the presence of bleeds was evaluated. Results: Treadmill exercise resulted in a high incidence of muscle bleeds in F9-KO mice but not in C57BL/6NTac mice. Treating hemophilia B mice with rFIX before treadmill exercise prevented muscle bleeds. Conclusion: A novel model of muscle bleeds in hemophilia B mice, responsive to rFIX, has been developed.

U2 - 10.1111/jth.12775

DO - 10.1111/jth.12775

M3 - Journal article

C2 - 25370152

SN - 1538-7933

VL - 13

SP - 82

EP - 91

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

IS - 1

ER -