Photo by Heather Hart.
Dr. Michael’s Court 2021 National Specialty health seminar presentation as well as a written summary.
Dr. Michael Court, Professor at Washington State University College of Veterinary Medicine, has been working closely with the SDCA since 2014. We were honored to have him as the health seminar speaker at the 2021 National Specialty in Richland, Washington. Here is a video of his presentation on the three health issues on which he has partnered with the SDCA: slow drug metabolism, hyperthermia, and delayed-bleeding syndrome, followed by a summary of his presentation he wrote for The Claymore.
Dr. Court’s research is ongoing, and samples are still needed. If you have a dog that had an adverse event from a drug used for anesthesia, sedation, or pain relief; experienced a hyperthermic reaction; or experienced delayed post-operative bleeding, please participate in this study by emailing Dr. Court for a cheek swab kit.
Presentation Summary
Reprinted from the September/October 2021 issue of The Claymore.
Dr. Michael H. Court is a researcher at the Pharmacogenomics Laboratory in the College of Veterinary Medicine at Washington State University. He and the SDCA have collaborated for years to investigate the genetic basis of several Deerhound health issues. At this year’s National Specialty, Dr. Court updated the club on his progress and future areas of research. For this month’s column, Dr. Court has kindly written a summary of his presentation for those who were not able to attend the National Specialty.
John Dillberger, DVM, PhD, The Claymore Health & Genetics columnist
Genetics of Anesthesia Sensitivity and Postoperative Bleeding in Scottish Deerhounds
by Dr. Michael H. Court
As a boarded veterinary anesthesiologist, who actively practiced for over 20 years, I am well aware of the idiosyncrasies of sighthound dog breeds that can make them a challenge to anesthetize and surgically treat. Although we now have a good idea as to how veterinarians should treat sighthounds differently from other breeds, we do not yet have good explanations as to why sighthounds are different from other breeds. Furthermore, it is unclear whether all sighthound breeds should be treated similarly, or whether individual dogs within a breed are equally affected. This presentation focused on research being conducted in our laboratory to understand the genetics of three conditions that afflict Scottish Deerhounds—slow anesthesia recovery, perianesthetic stress hyperthermia, and delayed post-operative bleeding.
Slow anesthesia recovery
Delayed recovery after injectable anesthetics, especially barbiturates like thiopental and propofol (to a lesser extent), has been well documented in greyhounds and is thought to occur in other sighthound breeds. This has been attributed in part to the low body fat content of sighthounds. That’s because recovery from these anesthetics normally occurs as the anesthetic agent rapidly diffuses out of the blood and into body fat, where it prefers to be. But lean dogs like sighthounds may have too little body fat to soak up all the anesthetic. In that situation, recovery occurs only when the anesthetic left in the blood is broken down (metabolized) by the liver, a process that can take many hours.
Our laboratory has evidence that another factor contributing to slow anesthetic recovery in sighthound breeds may be that their livers metabolize anesthetics more slowly. We have found that the metabolism of propofol is slower in greyhounds than in other (non-sighthound) breeds. We have identified two different mutations in two different genes that code for enzymes that are critical to propofol metabolism (CYP2B11-H3 and POR-H3). These mutations are most commonly found in greyhounds and deerhounds.
So far, we have conducted lab-based studies and shown that these mutations dramatically decrease propofol metabolism in vitro. The next step is to determine whether these mutations also decrease drug metabolism in dogs. We have recently completed a study to compare drug metabolism between greyhounds that have these mutations and greyhounds that lack these mutations. The results of this study are currently pending.
Perianesthetic stress hyperthermia
Another condition that we have been investigating in Scottish deerhounds that also occurs in greyhounds is stress hyperthermia. Frequently this is observed in association with an anesthetic episode for a surgical procedure (i.e. perianesthetic). Signs include an unexpected rapid increase in body temperature to more than 105°F, panting, and deep red mucous membranes. Treatment includes rapid cooling and administration of fluids and sedatives. According to a greyhound medicine expert (Dr. Guillermo Couto, DVM), stress hyperthermia often can be prevented by judicious use of sedatives before a triggering event (veterinary visit), as well as taking other steps to minimize stress.
While stress hyperthermia is serious and potentially life-threatening, no Scottish deerhound cases have been reported to me that were fatal. This differs from malignant hyperthermia, a more severe condition in dogs, which is invariably fatal.
Since not all greyhounds or deerhounds are susceptible to stress hyperthermia, a genetic predisposition has been suspected. With support from SDCA, we have identified a mutation in the RYR1 gene of dogs with a history of stress hyperthermia. This mutation appears to be a milder form of the mutation that causes malignant hyperthermia in dogs.
Since we have studied only a limited number of dogs so far (8 deerhounds and one greyhound), the usefulness of clinical testing for this mutation is unclear. Consequently, we are continuing to recruit cases to see if the RYR1 mutation can explain all cases. Please contact the lab if you have a dog that has experienced hyperthermia to donate DNA.
Delayed postoperative bleeding
Finally, we have been working on another problem that was first described in greyhounds, delayed post-operative bleeding. The clinical presentation of this condition typically involves a dog that has undergone a major orthopedic or abdominal surgery (including spays and neutering). Although no bleeding issues are experienced during surgery, within the next 24 to 48 hours, signs of bleeding are detected. These symptoms may range from moderate to severe bruising around the surgical site, up to frank bleeding from the wound. For abdominal procedures, internal hemorrhage may go unnoticed until the dog is severely ill. Treatment includes blood transfusions and intravenous administration of antifibrinolytic drugs (aminocaproic acid or tranexamic acid). Delayed bleeding can also be prevented by administration of these drugs orally before surgery and for up to 5 days after surgery.
We have conducted several studies (funded in part by SCDA) that implicate a mutation in the SERPINF2 gene as the cause of delayed bleeding. SERPINF2 codes for alpha-2 antiplasmin, which is essential for preventing blood clots from breaking down prematurely (a condition called hyperfibrinolysis).
We performed a case-control study using information collected from the SCDA health survey and DNA samples from surviving and deceased dogs (CHIC repository). We were able to find 7 affected dogs (i.e. cases) and 55 dogs that had surgery without postoperative bleeding (i.e. controls). All dogs were genotyped for the SERPINF2 mutation. The results indicated that the risk for delayed bleeding was 40 times higher in dogs that had at least one copy of the mutation, and over 500 times higher in dogs with two copies of the mutation, compared with dogs without the mutation. Importantly, all affected dogs had this mutation, while none of the dogs that lacked the mutation had delayed bleeding.
In a separate study in healthy greyhounds, we also showed that dogs with 2 copies of the SERPINF2 mutation had significantly lower levels of antiplasmin in their blood compared to dogs with one or no copies of the mutation.
Taken together, our results suggest that testing for the SERPINF2 mutation could be used to identify dogs that would benefit from prophylactic administration of aminocaproic acid or tranexamic acid. Just as importantly, the delayed postoperative bleeding test could identify dogs that would not benefit from these drugs.
The SERPINF2 test is currently available without charge by contacting the lab to request a DNA sample kit.
Like all genetic tests, we realize that the delayed postoperative bleeding test can and will be used by Deerhound breeders to inform breeding decisions. The SDCA Health & Genetics Committee is preparing guidelines for breeders about how this test should and should not be used. In this regard, it is important to stress that breeders need not try to eliminate the SERPINF2 mutation from the breed or a particular breeding line, since the disease the mutation causes can be effectively prevented in dogs at risk.