Mouse models of spontaneous thrombosis
Thrombosis comes in two flavours:
- VT: Venous thrombosis (with pulmonary embolism as possible results)
- AT: Arterial thrombosis (with myocardial infarction or stroke as possible result)
Venous and arterial thrombosis are a major source of morbidity and mortality worldwide and both are complex vascular diseases for which pathogenesis is incompletely understood. Animal models are fundamental in our effort to understand the disease and develop better therapy (“Holy Grail” an antithrombotic without bleeding risk as side-effect).
Currently there are limited (venous thrombosis) or no (arterial thrombosis) technically reproducible or clinically relevant mouse models for these diseases.
Researchers at the LUMC have developed a mouse model for VT via “humanizing” mouse coagulation via RNAi of the hepatic antithrombin (Serpinc1) and protein C (Proc) genes.
In addition, they have developed a mouse model for AT via RNAi of Proc in Apoe-/- mice. In initial studies organized and large thrombi superimposed on an aortic root atherosclerotic plaque were observed, a unique and novel finding. This model needs further optimization.
Figure 1: MRI of spontaneous venous thrombosis in a large vessel in the head (mandibular area)
The VTE model:
- Generates highly reproducible acute venous thrombosis
- Is technically simple and fast
- Reproduces morphologically venous thrombosis in humans
- Is responsive to (pharmacological) thrombin and platelet inhibition
- Is used by LUMC researchers and others to study VT pathogenesis
The AT model:
- Is technically simple and fast (i.e. the thrombosis part)
- Is reproducible, but has a low incidence (0.16)
- Responsiveness to drugs currently used to prevent AT unknown
- The occurrence of spontaneous atherothrombosis in the siProc apoE-/- mice is a truly unique event so far lacking in other preclinical models.
[Figure 2: Arterial (athero)thrombosis in apoliporotein E deficient mouse following RNAi]
VTE model: Heestermans et al., Blood. 2016 May 26;127(21):2630-7
AT model: Ouweneel et al., Arterioscler Thromb Vasc Biol. 2017 May;37(5):782-785
Potential applications would be in preclinical research of venous thrombosis and pulmonary embolism, and arterial thrombosis and myocardial infarction and stroke.
Venous Thrombosis and Pulmonary Embolism (source: World Thrombosis Day 2016)
- Every year, there are approximately 10 million cases of VTE worldwide
- In the U.S., there are 100,000 - 300,000 VTE-related deaths every year
- In Europe, there are 544,000 VTE-related deaths every year
- Up to 60 percent of VTE cases occur during or after hospitalization, making it a leading preventable cause of hospital death.
Arterial Thrombosis and Myocardial Infarction and Stroke (source Netherlands Heart Foundation)
- Every day over 100 related deaths in The Netherlands
- Every day over 1000 cases hospitalized in The NetherlandsOver 1 million cases in The Netherlands
Know-how on the VTE model is available for partnering and/or licensing.
LUMC are seeking co-development partners to further optimize the AT model and/or study its response to drugs that are currently used in MI/stroke (lipid-lowering/antiplatelet drugs) and to those in current pipelines (PAR inhibitors, FXI inhibitors, others).
Luris reference numberINV-0700.0875
- VTE model: published
- AT model: initial findings published, optimized model might be patented