FAQ's about VWD in Doberman Pinschers

Email correspondence between Dr. Patrick Venta and James Anable Jr.
Posted on [DOBERWORLD-L] listserv
Date: Tue, 19 Nov 1996 12:17:14 -0800
From: "James W. Anable, Jr."
Subject: READ THIS--Dr. Venta's response to vWD questions List members,

Hi Jim,

My colleagues finally had a chance to comment and make changes to this letter to you, and so it is now a joint effort. So here it is.

As you know, VetGen is now offering DNA tests for von Willebrand's disease (vWD) in Scotties, Shelties, and Dobes, and Kristi, of VetGen, is beginning to post information about these tests. The responses indicate some confusion, particularly about the Doberman. You have asked me, as one of the investigators who discovered the mutation, to clarify the genetics and usefulness of the new DNA tests. This is a fairly long letter, and I will apologize for its length now, but I felt that much of what is presented is information that you and other interested parties will want. I have not followed the posts for the lists, so I hope that you will forgive me if I might repeat something that has already been said a million times.

A key part of this message that you must understand is that we now know the precise DNA mutations and why and how they cause vWD in these three breeds. So all past hypotheses and speculations in the Merck Vet Manual and elsewhere, which were based upon the old protein-based factor assay, are out the window. Ignore them--they are past history. Now that we have the mutations in Scotties, Shelties, and Dobes, we can speak from fact not speculation regarding these three breeds. We are working on other breeds as well, but we cannot promise the date at which we will find any of the other mutations (although, of course, we hope it will be sooner rather than later).

The bottom line of what is given below is as follows: (1) vWD in Doberman pinschers is a true clinical disease in which affected animals are predisposed to have abnormally (and sometimes fatally) prolonged bleeding times. (2) The Dobe disease is recessively inherited, contrary to what some previous research had suggested in the past. (3) Carriers are unlikely to have bleeding problems but affected (that is, homozygous mutant) animals are at a significant risk of serious bleeding problems, if they undergo surgery or sustain moderate trauma. Penetrance is *far* less important than was inferred from the dominant, incompletely penetrant model. (4) If this one mutant gene was eliminated from the breed, vWD would become a very rare disease, indeed, in Dobes.

I will begin by describing the disease in two other breeds, because I believe that this will lead into the Dobe situation very well. Both the Scottie and Sheltie have the severe Type 3 form of the disease. The Sheltie may be a rare exception to the rule, that better than 99% of any simply inherited disease in a breed is caused by one mutation. In other words, while the major and most severe form of vWD in Shelties is Type 3, there is a possibility that a minor portion of the vWD problem is due to Type 1 vWD. This is according to data developed by Dr. Jean Dodds and her colleagues (Brooks et al., 1992--see below for complete references). We are working to see if this is true (it seems likely). Type 2 vWD, by the way, has only been seen in only two breeds of dogs, German shorthaired pointers and German wirehair pointers, so we will ignore it, in this letter. Both the Scottie and Sheltie Type 3 vWDs are caused by mutations that prevent *any* von Willebrand factor (vWF) from being produced. The technical term for these mutations are "single base deletions." These diseases are recessive, so that both copies of the gene that a dog possesses must be mutant before the animal has a bleeding problem. Carriers almost never have bleeding problems (Johnson et al., 1988).

The Doberman pinscher mutation, on the other hand, is Type 1 but it is *recessively* inherited! Most human Type 1 vWD is inherited in a dominant, incompletely penetrant mode. There are two things that made the Dobe vWD appear to be inherited in a fashion like the human disease. (1) The Dobe mutation is what geneticists refer to as "leaky." That is, the mutant gene makes a small amount of normal vWF protein. The amount made by each mutant gene is about 5% of the total normal amount. A normal gene would make 50% (so that two genes produce 100%). (2) The frequency of the mutant gene in the Doberman pinscher breed is greater than 60%! The parent of an affected animal can be also be affected, due to the high gene frequency (thus, the apparent dominant inheritance), but this is not always the case (thus, the apparent incomplete penetrance). This result was easily (and understandably) misinterpreted as the dominant, incompletely penetrant mode of inheritance as seen in humans. In human genetics, it is assumed that each genetic disease is rare, and one would not expect the parents of "affecteds" to also be affected if the disease was recessive. With animals, rarity of a disease gene cannot always be assumed, as illustrated by Dobe vWD. Other researchers have also presented data and arguments that Dobe vWD is actually a recessive disease (Moser et al., 1996; Johnson et al., 1988). The identification of the mutation fully explains it. Homozygotes for the disease in Dobermans do *not* die in utero. The mode of inheritance with other breeds, such as the German shepherd dog, could still be dominant, incompletely penetrant. We simply are not certain of the inheritiance pattern for other breeds at this time.

Dobe carriers should produce 55% of normal vWF, on average (5% from the mutant gene and 50% from the normal gene). However, other biological variables can affect the amount of factor found in the blood. These variables include thyroid hormone level, estrous, liver status (diseased or not), etc. Variation can also be produced by inappropriate handling of the blood sample or some variability in the protein-based tests themselves. These variations for concentration of the protein in the blood can make an animal appear to be a carrier on one day and homozygous normal (clear) on the next (which value does a breeder believe?). This is why the protein-based tests are not as useful as they might otherwise be. The DNA-based tests are completely different, because they detect the genetic change at the gene level, which does not vary. There are only three possible results from the DNA-based test. An animal is either clear, a carrier, or affected. Re-testing is pointless, because the result will always be the same for a given animal. So one test is good for the life of the animal. Incidentally, we have also set up the test so that it is noninvasive (you swab the inside of the dog's mouth with a small, soft brush), convenient (you can send the brush by regular mail--no need to refrigerate), and you can test at any age, even young puppies.

Dobe *carriers* with abnormally long bleeding times are not common. Dodds, Johnson and Stokol et al. have all reported that animals do not usually bleed excessively when they have factor levels greater than 36% of normal (Dodds, 1982; Johnson et al., 1988; Stokol et al., 1995). Carriers will occasionally go below this level, but usually not by very much. Surveys of fairly large numbers of animals have been conducted, and the data appear to show the expected trimodel distributions for number of animals vs. factor concentrations (Dodds and Covey, 1981; Moser et al., 1996; Johnson et al., 1988; Stokol et al., 1995). By extrapolating the overlapping curves it can be seen that carriers do not dip into the danger range more than occasionally. Therefore, the fear that an animal who tests as a carrier might someday suddenly become a severe bleeder because of the dominant, incompletely penetrant scenario is completely negated. Occasional carriers might have bleeding times that are prolonged, but these are the exceptions. Clear animals will never bleed abnormally, due to hereditary vWD (the removal of the disease gene should be, after all, the eventual goal).

Fortunately, even affected Dobes usually do not bleed spontaneously (unlike the case for Scotties, and perhaps Shelties). If they did, there probably would have been a stronger natural selective pressure to remove the disease gene. However, with surgery or moderate trauma, these dogs are at risk for serious bleeding problems (there are numerous reports in the scientific literature addressing this fact, and I am sure that there have been numerous anecdotal reports in this forum as well). So the disease and its causative gene are something that breeders should most certainly want to remove from their breeding programs. This will have to be done with care, however, because we do not believe that it is in the best interest of the breed to limit the gene pool by breeding only clear to clear. By following the guidelines that Kristi at VetGen posted previously (also available at http://www.vetgen.com/), it should be possible to allow the desirable genes to separate from the disease gene over a few generations, while at the same time preventing the occurrence of affected animals.

The mutation that we have found accounts for essentially all of the vWD seen in Dobermans. It is always possible that a rare mutation in combination with the common mutation would cause a bleeder. However, this should be very rare, because the rate of occurrence of *new* mutations for most genes is between one in one hundred thousand to one in a million per generation (Crow, 1993 and references contained therein). If the mutation we have found is eliminated from the breed, von Willebrand's disease will also be eliminated from the breed (ignoring those one in a million new mutations that can never be prevented). The same is true for specific lines, as well. Breed out the disease gene (which can now be detected) and the disease will be gone from the line.

If some portion of this letter needs clarification, please let me know and I will do my best to do so. The other primary investigators for this research are Vilma Yuzbasiyan-Gurkan, Ph.D. and William Schall, DVM at Michigan State University , and George Brewer, MD and Jianping Li in the Department of Human Genetics at the University of Michigan . I hope that you find this letter useful and, once again, Jim, I apologize for its length.

Sincerely,

Pat
Patrick Venta, Ph.D.
College of Veterinary Medicine
Michigan State University

References:

For Barrett - In memory of my beloved Dobermann

In memory of my beloved Dobermann
by Gini Free - CHIMERA Dobermanns. April 1997

I wanted to get one more litter out of her...She came back ELISE tested vWD factor of 2% ! ... OK, couldn't believe that, since she was seven years old, not exactly a delicate flower type she had lots and lots of opportunities to display bleeding problems in her life! ... re-tested, and it came back a 4% vWf ... whoopee!

So, she was spayed. I administered various immune-system boosting supplements; pumped up her blood as best I could from the outside .... administered three units of plasma pre-surgery and she did fine!

At the same time, we found that Barrett had adenocarcinoma [very aggressive, nasty type of malignant cancer] in her mammary glands...[had
the lumps biopsied at the time of spay]--I caught them when they were smaller than peas, but after removing the first three small lumps, others returned within two months.

When the lumps re-appeared, I was forced to make a very serious decision -- I opted for a radical mastectomy, as the lumps were spread out on both sides, top, and bottom...since you can only do one side at a time ... we prepared her for the first side.

Same safety measures ... blood building, supplements, plasma and opted for the safer [but more expensive] anesthesia NO PRECAUTION NOT TAKEN...except for one ...

I was there through the whole procedure -- an incision was made from breast to crotch, and the skin peeled back to her ribs...she then had a four inch wide strip the whole length of her abdomen --the entire mammary system on that side --removed.

I was watching the clotting...she was doing fine. Closed the site, and wrapped her--waiting for her to come out of the anesthesia. I never left her side for ONE MINUTE.
Because I TOO did not feel that she was in any danger [after all, I'd taken all the precautions, right?] what followed was to be the worst thirteen
hours of my life.

Since I completely discounted the possibility of ANY problems relating to vWD, I failed to force the attending vet to do what SHOULD have been done, what she needed, was ....
A WHOLE BLOOD TRANSFUSION .... I later found out that because of the very large surgical work done, she was bleeding through capillaries. No one vein, etc. but, through a myriad of tiny, tiny seepages .... and the plasma was not sufficient to stop them. For those of you who don't know this, only a whole blood transfusion will handle this sort of problem in a vWD affected dog...again, not my personal opinion, but that of Dr.Jean Dodds, ... ok?

He sent her home later that afternoon, telling me she was fine .. not to worry, that the pressure wraps he'd put on top of the original surgical bindings would handle that 'little seepage' she'd leaked through the first wraps with.

Because of those additional wraps, I was not to know till it was too late that she never stopped bleeding.... later that night, I called my vet back, saying I was alarmed by her continuing cries and moans of pain and that I thought she was showing shock symptoms [cool extremities, eyes looking glazed, obvious distress]. He advised upping the pain meds she was on and loosening the bandages ... well, it DID alleviate her.

Just think about it folks, the loosening of the bandages allowed what little blood there was to circulate for a while longer, the pain meds, dropped her right out of it, but within the next three hours, I REALLY became alarmed ... but remember, I was NOT thinking about the vWD, dismissed it, like I hear so many of you doing in these posts --- I left the room, to get dressed to take her into emergency....I was out of the room less than FIVE minutes ... and when I came back in, she had stopped breathing.

For those who wanted this 'documentation' I want you to know how very hard this is for me to write about--I'm absolutely sobbing as I write this. My heart was broken, smashed, destroyed, that night...I loved her more than anything I've ever been blessed with--she was the light of my life, and we shared an almost magical connection with one another ... she was EVERYTHING I had ever wanted in a dog, and so much more.

We attempted CPR ... in the process, the pressure bandages came open .... there was so much blood everywhere and she had a massive hematoma the entire length of her abdomen, wider than the span of my opened hand, where the lessening blood pressure had pooled the bleeding under the skin...not enough pressure left to make it leak thro.

We cremated her 36 hours later... and when we lifted her body, she was STILL seeping blood --
it NEVER clotted, even in death.

She died from vWD .... WITH precautions ... WITH fore-knowledge of this problem...in SPITE of every thing being done I could think of. But I am NOT A VET -- I didn't know at the time about the nature of vWD and what should have been done for her ... she should have stayed at the hospital, on IV, and given whole blood ... she'd be alive today. Had I taken this issue more seriously, been more informed, maybe I could have saved her.

My original point in ALL of this is that vWD is a potential killer. At the very least, it is expensive to have to take precautions, "just in case'...and I don't know about any of you, but these dogs of mine are very important, and I will do what I can to protect them ... so when someone buys a vWD AFFECTED dog, they are opening themselves up to having to make decisions, spend money, etc., that could possibly mean life or death -- it's one hell of a cloud to have looming over one's loved canine companion, and your pocket book.

So, based on this very personal experience, I will INCLUDE in my breeding decisions, the vWD results of the dogs involved ... I will test before selling, if I have a possibility of producing a vWD affected pup -- I will adjust the price for what I now charge, to as close to the actual basic costs of the pup [ears, shots, food and care.

I will inform the prospective owner of what they MAY possibly face, give them all the relevant literature and information about how to safely live with one .. tell them all about clotting tests, VetGen DNA tests, and just basically EDUCATE them to what they are dealing with. I have found Vets can be appallingly uninformed about new procedures, research results, etc., and that in this day and age of so much information, that I must take responsibility for being as informed as I possibly can before turning over my animals' lives to their care]--and give them carte blanc to come to me at any time for help, assistance, or advise.

My pups are a life-time commitment to me ... I go by the old rule ..'do unto others, as you would have them do unto you' ... and again, I wouldn't wish on someone else, what I went through. That's it folks, that's the reasons for my opinion.#Reprinted by VetGen with permission
of the Writer. (March, 2003)

http://www.vetgen.com/canine-ref-barret.html