Novel Mouse Model Could Shed Light on Blood-Disease Interactions

Published Aug. 4, 2016

Scientists at Cincinnati Children’s have engineered a new line of mice that will not form blood clots as rapidly as normal mice, an advance that could help investigators accelerate studies of heart disease, lung cancer and other conditions that can be affected by how blood reacts to injury or disease.

The new mouse model was developed by a research team led by first author Maureen Shaw, MS, and senior author Eric Mullins, MD, research director, Hemophilia Treatment Center.

In normal conditions, the blood clotting cascade moves from the activation of prothrombin (fII) to the formation of thrombin (fIIa), which converts fibrinogen to fibrin, which in turn leads to fibrin deposition and the activation of platelets to form blood clots. In the new line of mice, the cascade stops when prothrombin forms meizothrombin, a proteinase precursor of thrombin.

A number of previous efforts to produce mice with modified levels or activity of prothrombin have failed because the engineered mice rarely survive long enough to breed or to be studied in meaningful ways. However, the study authors report that mice expressing meizothrombin (fIIMZ) are viable, survive well into adulthood, and have reproductive success.

The fIIMZ mice demonstrated two advantages compared to mice expressing normal prothrombin. They fail to form artery-blocking blood clots when subjected to arterial injury. They also have many fewer tumor metastases in a model of metastatic cancer.

“These animals provide a unique tool to further assess the role of both prothrombin and meizothrombin in physiologic and pathologic processes,” the authors state. “Tools such as fIIMZ animals will be crucial to determining how the activation and activity of fII can modify disease severity.”

These images show diminished experimental tumor metastasis in fIIMZ animals. Cohorts of fIIWT and fIIMZ animals were challenged with lung cancer cells expressing green fluorescent protein. Two weeks later, metastatic foci in the lung were determined. A substantial, statistically significant diminution in the number of lung metastases was noted in the fIIMZ animals compared with fIIWT mice (A). FIIWT animals had prominent metastatic foci (B), whereas many fIIMZ animals demonstrated few, if any, metastases (C).

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Cohorts of fIIWT and fIIMZ animals were challenged with IV bolus of B16 melanoma. Eighteen days later, metastatic foci in the lung were determined. As was seen with LLC, fIIMZ animals had significantly fewer metastatic foci when compared with fIIWT mice (D). The same pattern was found when comparing fIIWT mice with mice with 50% prothrombin (fII+/-) (E). Numerous metastatic foci were seen in fIIWT animals (F), whereas metastases were rare in fIIMZ mice (G).

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Shaw MA, Kombrinck KW, McElhinney KE, Sweet DR, Flick MJ, Palumbo JS, Cheng M, Esmon NL, Esmon CT, Brill A, Wagner DD, Degen JL, Mullins ES. Limiting prothrombin activation to meizothrombin is compatible with survival but significantly alters hemostasis in mice. Blood. 2016  Aug 4;128(5):721-731.