There has been much recent discussion on the question of whether vWF levels vary with time in individual dogs. I recently posed this question to John Duffendack of VetGen, who forwarded it to vWD researcher Dr. Pat Venta of the MSU College of Veterinary Medicine. Below, is Dr. Venta's response that I received via E-mail. Dr. Venta confirms that vWF does vary significantly in individual dogs. His comments are supported by professional papers and studies. This has been posted with Dr. Venta's permission, do not republish without permission. Subject: Re: vWD questions Date: Mon, 16 Jun 1997 15:38:00 EST From: "Pat Venta" [E-mail address deleted] Organization: MSU College of Veterinary Medicine To: anable@halcyon.com CC: [E-mail address for John Duffendack, VetGen] Hi Jim, John Duffendack forwarded your message to me. I have made replies to your questions in the appropriate places below. Pat Venta > Date: Thu, 12 Jun 1997 14:06:23 -0700 > From: "James W. Anable, Jr." > Reply-to: anable@halcyon.com > Organization: James W. Anable, Jr., Attorney at Law > To: [E-mail address for John Duffendack] > Subject: vWD questions > John, > > I recently received a copy of a draft of an article written for a local > Doberman club newsletter by an internet friend. She requested that I > review the article for obvious mistakes. I told her that I was not an > expert, but that I would do my best. I have a few questions regarding > some of her assertions and would appreciate any help that you, or > others, could offer. > > She relates the information on your website which discusses the fact > that vWD affected Dobermans may produce 10 to 20% of the normal amount > of vWF. Then she says: > > "So whether or not an affected dog is at risk of bleeding to death > depends on whether the two genes are producing the full 20% that day, or > maybe only 10%. The risk also depends on how much bleeding occurs, as > this will affect how much vWF is 'used up' during the injury or > surgery. Of course, other coagulation and tissue factors are also > involved, and can either increase or decrease the risk of bleeding." > > Are that above statements accurate to the best of your knowledge? It is > unclear to me whether the first sentence is accurate--does the > production of vWF vary in an individual dog over time, or does it just > vary between different affected dogs? The fact that breeders get wide variations in values when retesting the same animals certainly indicate that something varies. Basically, it can either be variations in the test (inaccuracies in the test), variations in the vWF in the dog over time (true biological variation), or a combination of the two. It appears from the scientific literature that it is a combination of the two, with the biological variation being the more important. So the short answer is that vWF does vary over time within the same animal. Perhaps more surprisingly is the amount of variation that can occur on a daily and weekly basis. Janet Moser, Ken Myers, Jim Meinkoth, and Jaqueline Brassard published a very interesting paper addressing exactly these points a very short time ago (Moser et al., Temporal variation and factors affecting measurement of canine von Willebrand factor (1996) American Journal of Veterinary Research, Vol 57, pp. 1288-1293). I will quote some of their paper: (from the abstract) ..."Plasma vWF concentration varied over time. In dogs with mean vWf concentration [greater than or equal to] 79 U/dl [units of vWF per tenth of a liter], the largest intraindividual range in vWf spanned 64 U/dl with daily and 53 U/dl with weekly sample collection... Conclusion--There was a substantial temporal variation in vWf concentration within individual dogs. Clinical relevance--Multiple tests may be necessary to obtain a reliable estimate of vWF concentration in dogs." The test seems to produce about 10% of the total variation, but these data makes it clear that the vWF circulating in a dog's bloodstream has *wide* daily variation. The same was true with affected animals. If you like, I will send you a copy of the paper. > > Is the last part of the paragraph accurate in saying that bleeding times > may vary in individual dogs due to other factors? Can factors such as > stress cause a variance in bleeding times? Do bleeding times stay > static, or do they vary due to environmental or other biological > factors? vWF may vary in individual dogs due to other factors (there are many--I am not certain about stress, but it is entirely possible). It appears that there are a number of environmental and genetic factors that can cause this variation. What I think is most important to keep in mind is that, in clear animals, these factors are not enough by themselves to ever cause abnormally long bleeding due to von Willebrand's disease. In other words, if the defective gene is removed from a line, that line is safe from abnormal bleeding, irrespective of the other factors. However, I realize that this question is not only related to the importance of eventually eliminating the disease gene from the breed, but also "What about the animals I have now?" von Willebrand's disease is a *tendency* to bleed abnormally, not a guarantee that in any given situation this will actually happen. The are anecdotal reports of animals having a diagnosis of being affected, and not bleeding abnormally on one or more given occasions where you might expect a lot of bleeding (example, some spays have been done apparently without any problems). However, there are many reports in which affected animals bleed profusely. These are both scientific reports and anecdotal reports, many of which have been put on the list-serves. This information tends to indicate that we cannot, with certainty, predict when a given animal will have a problem and when it will not. Some vets will test bleed times shortly before a surgery. Gary Johnson and his colleagues Mark Turrentine, and Karl Kraus wrote an excellent review of canine vWF a few years ago (Hemostasis, Vol. 18, pp 195-229.) Here are a few quotes from that review: "...a double-blind study has shown that Doberman puppies with vWF: Ag [von Willebrand factor: antigen, the protein measured in the blood test] concentrations below 22 percent bled more during and after cosmetic otoplasty than Doberman puppies with vWF: Ag concentrations above 38 per cent. Finally, Doberman Pinschers with vWF;Ag concentrations below 20 per cent have consistently had prolonged buccal mucosa [inside of the cheek] bleeding times (4.6 to 18 minutes), whereas normal dogs, including Doberman Pinschers with vWF:Ag concentrations above 50 per cent, have had buccal mucosa bleeding times between 1.7 and 4.2 minutes." I would probably take precautions for any animal that is affected. For example, with a scheduled surgery, I would have my veterinarian be prepared to handle a case of excessive bleeding. > > This issue has also came up in some of my recent posts. I recently > asserted that the owner of a vWD affected dog would want to do a buccal > mucosal bleeding time test immediately prior to any elective surgery to > check clotting ability. Another list member said that bleeding times should NOT > vary in individuals over time. Buccal mucosal bleeding times may be a good way to pre-screen an animal. Given the daily variation in the protein-based test, it would seem to be a reasonable precaution. I would have it done if I had an affected animal (please do not take this as medical advice; I am a geneticist, not a veterinarian. This is simply my own view). But this will be up to the veterinarian in consultation with their client. Factor values vary over time in both humans (the variation is also quite wide) and dogs (I have given a reference for dogs; one for humans is Blomback et al., On laboratory problems in diagnosing mild von Willebrand's disease, American Journal of Hematology, Vol. 40, pp 117-120). It would be nice if this were not true because it would probably make it easier to predict susceptibility to bleeding. I hope I have answered all of your questions satisfactorily. If any points need clarification, please let me know. Sorry to be so wordy again. Pat > > Thank you in advance for any help. > > -- > Jim Anable > Seattle, WA > anable@halcyon.com (Please put the word "PRIVATE" in the subject line) > Member, DPCA/COPE Committee (Please inquire about rescue dogs) > Storm's home page: http://www.halcyon.com/anable/storm/ > Rescue page: http://www.halcyon.com/anable/storm/rescue.html > > > >