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The characterization of mice with a targeted combined deficiency of protein c and factor XI
J C Chan1, J G Ganopolsky, I Cornelissen
1Department of Chemistry and Biochemistry, W. M. Keck Center for Transgene Research, and the Freimann Life Science Center, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Abstract:
Activated protein C functions directly as an anticoagulant and indirectly as a profibrinolytic enzyme. To determine whether the fibrin deposition previously observed in PC(-/-) murine embryos and neonates was mediated through the FXI pathway, PC(+/-)/FXI(-/-) mice were generated and crossbred to produce double-deficient progeny (PC(-/-)/FXI(-/-)). PC(-/-)/FXI(-/-) mice survived the early lethality observed in the PC(-/-)/FXI(+/+) neonates, with the oldest PC(-/-)/FXI(-/-) animal living to 3 months of age. However, the majority of these animals was sedentary and significantly growth-retarded. On sacrifice or natural death, all of these PC(-/-)/FXI(-/-) mice demonstrated massive systemic fibrin deposition with concomitant hemorrhage and fibrosis, as confirmed through histological analyses. Several of these animals also presented with enlarged lymph nodes and extensive lymphatic fluid in the thoracic cavity. Thus, although a number of the PC(-/-)/FXI(-/-) mice survived the lethal perinatal coagulopathy seen in the PC(-/-) neonates, they nonetheless succumbed to overwhelming thrombotic disease in later life. This combined deficiency state provided the first clear indication that the course of a severe thrombotic disorder could be manipulated by blocking the intrinsic pathway and provided the first opportunity to study a total protein C deficiency in an adult animal.
Insights
Mice lacking protein C (PC) and factor XI (FXI) survived early death but developed severe thrombosis and hemorrhage. Blocking the intrinsic pathway delayed, but did not prevent, lethal thrombotic disease in protein C deficiency.
Area of Science:
- Biochemistry
- Hematology
- Genetics
Background:
- Activated protein C (APC) is crucial for anticoagulation and fibrinolysis.
- Protein C deficiency (PC-/-) leads to perinatal lethality due to coagulopathy.
- The role of the Factor XI (FXI) pathway in PC-/- thrombotic complications is unclear.
Purpose of the Study:
- To investigate the contribution of the FXI pathway to fibrin deposition in protein C deficient mice.
- To generate and characterize double-deficient PC-/-/FXI-/- mice to study prolonged protein C deficiency.
Main Methods:
- Generation of PC-/-/FXI-/- mice through crossbreeding.
- Histological analysis of tissues from double-deficient mice.
- Observation of survival, growth, and clinical signs in PC-/-/FXI-/- mice.
Main Results:
- PC-/-/FXI-/- mice survived perinatal lethality but exhibited growth retardation and reduced lifespan.
- All double-deficient mice displayed massive systemic fibrin deposition, hemorrhage, and fibrosis.
- Enlarged lymph nodes and thoracic lymphatic effusion were observed in some mice.
Conclusions:
- While FXI deficiency mitigates early lethality in PC deficiency, it does not prevent severe thrombotic disease.
- Blocking the intrinsic pathway can modulate the course of severe thrombotic disorders.
- This study provides the first model for investigating total protein C deficiency in adult animals.
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