02988: Plasminogen-activator Inhibitor-1 (PAI-1) and Impaired Fibrinolysis in Immune-Mediated Hemolytic Anemia

Grant Status: Open

Grant Amount: $116,865
Tracy Stokol, BVSc, PhD and Steven Friedenberg, DVM, PhD; Cornell University and University of Minnesota
January 1, 2022 - December 31, 2023

Sponsor(s): American Spaniel Club Foundation, Tibetan Terrier Club of America

Breed(s): -All Dogs
Research Program Area: Blood Disorders
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Abstract

Immune-mediated hemolytic anemia (IMHA) is a common, and often life-threatening, blood disorder in dogs where the dog’s immune system attacks its own red blood cells, leading to a severe anemia that is treated with immunosuppressive drugs. However, affected dogs suffer from more than just anemia. They also have over-active clotting systems that lead to abnormal blood clot formation. These blood clots can be fatal if they block off the blood supply and delivery of nutrients and oxygen to vital tissues, causing serious organ damage and failure. Veterinarians now treat dogs with blood thinners to try and prevent these clots from forming, but dogs with IMHA continue to suffer from lethal blood clots, indicating that a more effective therapy is needed.

When clots form in the body, they are gradually broken down by enzymes – this normal process is called fibrinolysis. If clots are not broken down properly, they will persist in the blood vessels, causing tissue damage. Researchers suspect that clot breakdown is defective in dogs with IMHA, leading to persistence of blood clots. They believe the decreased fibrinolysis is caused by too much of a blood protein, called PAI-1. PAI-1 protein is the main inhibitor of clot breakdown and if it is too high, clots remain in blood vessels and prevent normal blood flow. Preliminary studies have also shown decreased clot breakdown in blood samples from dogs with IMHA.

In this study, investigators will determine whether dogs with IMHA have high levels of active PAI-1 protein as a major cause of reduced clot breakdown. They will collect blood samples from 40 dogs with IMHA and 40 healthy control dogs and measure PAI-1 protein activity levels and mRNA levels, and perform laboratory tests of clot breakdown. They will also test whether a drug that blocks PAI-1 activity can improve fibrinolysis in these test samples since blood-thinning drugs currently given to dogs with IMHA to prevent clot formation do not affect clot breakdown at all. If investigators find that high PAI-1 levels result in reduced clot breakdown in dogs with IMHA, then PAI-1 inhibitor drugs will open up new possibilities for more effective treatment and improve current IMHA treatment so that abnormal blood clot formation no longer limits dogs’ survival.

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