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Bleeding Always Stops

vWD and Bleeding Disorders in the Doberman

"A little learning is a dangerous thing", (Alexander Pope, An Essay on Criticism, 1711). The wisdom of this premise is particularly relevant to the current confusion regarding von Willebrand's Disease (vWD) in the Doberman. There are legitimate reasons for this lack of understanding. Most bleeding disorders, vWD included, are well understood. The problem is they are so complex that their explanations are not readily grasped by those without benefit of an in-depth background in molecular biology (gene structure and function, enzymatic reactions, hormones, etc.). A full comprehension of these diseases requires years of scientific training and specialization. Pope's words are at least as relevant today as they were 290 years ago.

Differences in terminology tend to compound the problem. For example, when dog show enthusiasts call attention to the "pasterns", they are referring to the wrist area of the front legs. To a veterinarian, that same location is designated as "metacarpals", reserving the term "pastern" for horses. Similarly, in the case of vWD , understanding is disadvantaged because of the incongruous designations assigned by geneticists and those of us trained to diagnose and treat clinical disease. To the geneticist, a Doberman will be classified as vWD "clear", "carrier", or "affected". It is with the label "affected" that the jargon becomes misleading as it relates to clinical disease. But if we were to substitute the genetic designation "affected" with the phrase "at risk for" we would have a more understandable basis for the practical implications of this potentially life-threatening condition.

There are some breeders who choose to believe that vWD is not a real threat to Dobermans. There are some veterinarians who think that almost all bleeding disorders in Dobermans are due to vWD. BOTH ARE WRONG! It is important to understand that a Doberman "at risk for" vWD will be further compromised by any hemorrhagic episode, whether traumatic, surgical, or a co-existing bleeding disease. Just as a person can suffer from a nasal allergy and the common cold at the same time, a Doberman can have vWD and other clotting related disease simultaneously. One can make the other far more severe, possibly deadly. But experience tells us that the concept of two medical conditions existing at the same time in one animal and causing very similar symptoms is a difficult one for the average person to comprehend. So for ease of understanding, as you read further, keep in mind the case of the person with allergies and a common cold - two conditions, similar symptoms, but the treatment for one may not help the other. At the risk of causing Alexander Pope to turn over in his grave, let's try to explain vWD and other bleeding disorders in such a way that the average person will be able to have a workable understanding of these conditions.

Any basic understanding of bleeding disorders, of which vWD is only one, necessarily involves familiarity with platelet function. Platelets are small disks or plate-like structures, the smallest of the formed elements in blood. At any given time, about 2/3 of total platelets can be found in circulating blood; the remaining 1/3 are stored in the spleen. Their function relates directly to blood clotting because of adhesive and clumping capabilities that cause them to occlude small breaks in blood vessels, thereby preventing the escape of blood. The biochemical pathways, though complex, are well known and not germane to the limited scope of this article. Platelets, also called thrombocytes (from the Greek, thrombo = clot and cyte = cell), can be present in below-normal numbers, above-normal numbers, normal numbers that are diseased, and normal numbers that are functional. Any of the first three can lead to a bleeding disorder.

Laboratory platelet assessment is the first step in an accurate diagnosis of a Doberman with a bleeding problem. It is not necessarily a simple analysis, nor is it always a straightforward diagnosis. NO ONE CAN CORRECTLY ASSUME THAT ANY ONE PARTICULAR BLEEDING EPISODE IN A DOBERMAN IS DUE TO vWD. Every Doberman with a bleeding disorder demands a complete laboratory work-up EVERY time hemorrhagic disease occurs, assuming of course, there is time to do so. Charles H. Sodikoff, DVM, MS in the 2nd Edition of Laboratory Profiles of Small Animal Diseases lists no less than 12 "simple" coagulation tests. To the uninitiated, "simple" is a relative term that belies the diagnostic dilemma presented. The number of tests available renders the point obvious that, even in a vWD "affected" or "at risk" Doberman, bleeding may be due solely to vWD, or to a different bleeding condition, or a combination of the two. Where one or the other alone might be manageable, the presence of both together can be lethal. And this is why it is so important to understand the necessity of getting the proper diagnosis and treatment for a Doberman with a bleeding episode because, as Heather Jans, DVM, ACVIM, of Dundee Animal Hospital once stated as succinctly as is possible, "one way or another, bleeding always stops!"

Bleeding conditions associated with diseased platelets in normal numbers include genetically caused vWD and acquired diseases brought about by aspirin use or kidney disease severe enough to cause uremic poisoning, among others. Disorders elicited by low platelet counts (Thrombocytopenia) as enumerated in the Textbook of Veterinary Internal Medicine, 5th Edition, vol. 2, Ettinger and Feldman, are classified as follows: Idiopathic (cause unknown); Infectious (either viral, bacterial, protozoal, fungal, or metazoal, i.e., heartworm); Immune-mediated. Immune-mediated thrombocytopenia (IMT) is the most common cause of severe platelet disease in dogs with Dobermans well represented. While the primary cause of IMT is unclear, the presence of IMT auto-immune antibodies associated with cancer, infection, drugs, and other auto-immune diseases is well documented. Drugs that can induce hemorrhagic disease include at least 10 antibiotics, 8 antimicrobials, 5 anticonvulsants, 7 anti-inflammatory agents, 12 anti-cancer drugs, 7 cardiovascular medicants, 1 diuretic, 1 hormone (estrogen), and 12 in the miscellaneous category. There are doubtless more and who knows about drugs used in combination with the seemingly endless array of alternative medical therapies? One combination we do know can be lethal and should NEVER be used together is aspirin-related products such as Rimadyl, Ascriptin, etc. and steroids such as Prednisone, Dexamethasone, etc. In fact, many such drug combinations can be life-threatening. No over-the-counter drugs should EVER be used in combination with prescription drugs without the knowledge and approval of your primary care veterinarian. Low platelet counts can result from diseases of the spleen and liver or from any of several types of cancer as well as be secondary to protein-losing processes, inflammation of blood vessels (allergic and auto-immune), and the frequently fatal disseminated intravascular coagulation (DIC). DIC is a widespread formation of clots in the microcirculation, mainly in capillaries. It is a secondary complication of a wide variety of disorders all of which in some way activate the clotting sequence in small blood vessels. Platelet numbers are reduced in the rest of the general circulation resulting in life-threatening hemorrhage elsewhere, frequently, if not usually, ending in an unsuccessful conclusion. Pathologic causes of DIC include infections, obstetric complications, gastric dilation-volvulus (bloat), diabetes, cancer, trauma, post-surgical shock, heat stroke, liver disease, snake and insect venoms, and inflammation of the pancreas.

Diseases of the bone marrow may result in decreased production of platelets. The point to be made is that Dobermans are susceptible to many bleeding diseases, all of which are serious and all of which are made worse by the presence of vWD, a condition for which there is a one-time, life-time genetic DNA test.

von Willebrand's Disease, initially known as pseudohemophilia, was first described in 1926. von Willebrand's factor (vWF), which is deficient in "affected" or "at risk" dogs, was first identified in 1971 when it was designated Factor VIII - related antigen (FVIIIR:Ag). There are three types of vWD in the 54 breeds known to have the condition. While Type I vWD as seen in Dobermans is the least severe of the three types, it must be pointed out that Dobermans are among the over-represented breeds in terms of percentage afflicted. This is a genetic disease. There are no confirmed reports of acquired vWD in dogs. Three tests are available to confirm vWD. Von Willebrand's factor can be measured by electroimmunoassay (EIA), or more accurately, by enzyme-linked immunoabsorbant assay (ELISA). A third, and by far the easiest and most accurate because it is a one-time, life-time genetic evaluation which can be done on puppies still in the whelping box, is by a DNA based genetic test.

Developing a DNA-based test was dependent upon finding the genetic mutation in the vWD gene in Dobermans causing the disease. This mutation was discovered by a team at the University of Michigan and Michigan State University (Brewer and Venta, unpublished). The mutation in the Doberman is not "gene knockout," meaning that it doesn't completely destroy the normal function of the gene. The mutated gene still produces 5-10% of normal vWF, which accounts for why the bleeding phenotype is milder (Type I vWD) in the Doberman than in some other breeds. For example, a different mutation is present in the Scottie, and still another different one in the Sheltie. Both of these mutations are gene knockouts, so affected dogs in these two breeds have a very severe bleeding problem (Type III).

The DNA test can be carried out by obtaining cheek swab brushes from VetGen LLC in Ann Arbor, MI (Phone: 1-800-4VETGEN) and swabbing the inside of the dog's mouth. Mucosal cells that line the inside of the mouth come off on the brush, and provide the DNA for analysis. The brushes are mailed to VetGen for the Doberman vWD DNA analysis. (VetGen is the exclusive licensee of the University of Michigan and Michigan State University for this patented mutation detection in the Doberman). Results are generally available in two weeks. vWD in the Doberman is inherited as an autosomal recessive disease, so dogs with two copies of the mutation are affected, and those with one copy are carriers. Carriers will have no medical problems. Dogs with two copies of the normal gene are called clear.

The frequency of the vWD mutation in Dobermans is quite high, such that about 30% of dogs are affected, a little over half are carriers, and only 20-25% are clear. It is too much of a bottleneck in the gene pool to only breed clear animals. Breeders can use both clear to clear and clear to carrier matings with no risk of producing affected animals. In the next generation or two, carriers can be eliminated (or at least the frequency can be reduced) by increasingly breeding clear to clear animals.

Clinical signs of vWD in Dobermans, either when presented alone or when present in combination with other maladies, can be severe enough to warrant transfusion therapy. Symptoms vary widely from prolonged estrual hemorrhage to spontaneous urogenital tract bleeding. The latter was accorded the most common (but certainly not the only) sign in Dobermans as reported by M. Brooks, et al: "Epidemiological Features of von Willebrand's Disease in Doberman Pinschers, Scottish Terriers, and Shetland Sheepdogs: 260 Cases (1984-1988), JAVMA, 200:1123,1992. Additional sites even include hemorrhage into an area around the spinal cord (subarachnoid space) documented by T. Stokol, et al: "von Willebrand's Disease in Doberman Dogs in Australia", Aust. Vet. J, 72:257, 1995. MAKE NO MISTAKE ABOUT IT, vWD CAN AND DOES KILL DOBERMANS! It is suspected as a cause of reduced litter size, i.e., abortions, stillbirths, and resorbed fetuses. Even in apparently healthy dogs it lurks as a potentially fatal complication when present in combination with other medical afflictions. Think, for example, if we have a dog known to be vWD "affected" or "at risk" via the DNA genetic test. This dog is also known to be a "bleeder" from a previous episode during surgery. Now comes the "Catch 22" when this dog is presented with a potentially life-threatening situation requiring surgery. The dog may die without treatment for the one problem, but that treatment may trigger another life-threatening situation because of the vWD condition. The large number of conditions that are unknowingly compromised by vWD contributes to the lack of awareness associated with the virulence with which Dobermans are impacted.

Where does all this lead us? If we have a bleeding dog we most likely want it treated. If we want it treated we must have an accurate diagnosis. To obtain an accurate diagnosis with hemorrhagic disease we must have laboratory assessment for confirmation. Confirmation is essential for treatment because while one course of therapy may be life-saving in a particular hemorrhagic disease, it may be exactly the wrong therapy (contraindication) in another. At the risk of oversimplification (remember how many hemorrhagic conditions and tests there are to consider), an example of the necessity for laboratory confirmation can be illustrated by differentiating between arguably the two most likely (but far from only) diagnosis in a bleeding Doberman, namely vWD and IMT (immune mediated thrombocytopenia). A platelet count will rule out one or the other. With vWD, platelets are available but ineffective. With IMT, platelet counts are low because they are being destroyed. While the platelet count does not make the final, definitive diagnosis, it rules out one of the two most likely conditions along with the others that fall into the same category of either normal or below normal numbers. Based on this information other tests can be appropriately selected and serial eliminations made until the final diagnosis is confirmed. All of this is essential in order to select therapeutic options. For vWD, the treatment of choice is cryoprecipitate (a frozen blood component replacement) because a low volume (i.e., concentrated) is needed to infuse a large quantity of vWF (Factor VIII). If that is not available, fresh frozen plasma is indicated. In addition, a drug designated as DDAVP increases vWF activity in some Dobermans within 10 minutes of administration with anticipated action for 2 hours, making it useful prophylactically in elective surgery for "at risk" patients. On the other hand, transfusion therapy is not usually indicated for IMT because the transfused platelets are so quickly destroyed by the antiplatelet antibodies (although sometimes an exception is made prior to surgery in the IMT platelet deficient dog). Instead, immune suppressive therapy in the form of corticosteroids (prednisone) is indicated. In fact, it is life-saving.

Although no two case histories are ever alike, they can be used as illustrative paradigms:
Case #1. A four year old Doberman bitch, known to be vWD "affected" via the ELISA test, presented with an uncontrollable nose bleed. The possibility that medication not intended to be given intranasally may have been mistakenly administered complicated the list of diagnoses to rule out. After finding an abnormally long clotting time, an in-office thrombocyte count revealed only 1000 platelets/ul. Normals in dogs range from 150,000 to 500,000/ul. Anything below 100,000/ul is significant. Any number of less than 50,000/ul is at risk for spontaneous bleeding. And vWD alone is NOT associated with low numbers of platelets. A diagnosis of autoimmune thrombocytopenia was made and the bitch transferred to a veterinary college teaching hospital for a platelet transfusion. Although IMT rapidly destroys platelets, their presence for even a few hours was necessary to slow hemorrhage until life-saving cortisone (prednisone) could begin to allow the thrombocyte numbers to increase. Thanks to a quick and accurate diagnosis and the rapid initiation of the proper treatment, a favorable outcome resulted.
Case #2. The owner of a six year old apparently normal Doberman bitch, and whose DNA vWD test indicated she was not "at risk", insisted her veterinarian run a clotting time prior to surgery. The clotting time was longer than normal and a subsequent platelet count revealed below normal numbers approaching cause for concern. Surgery was canceled but follow-up counts on succeeding days revealed steadily decreasing numbers. IMT was suspected and referral to a veterinary teaching hospital was requested by the owner. All tests at the university proved inconclusive and although platelet counts were low on admission, they began to rise inexplicably. The bitch was spayed uneventfully when her counts returned to the normal range. Though no diagnosis was ever made, had the spay been done during the period of prolonged clotting time and low platelet counts, surgical complications would have been likely and a favorable outcome placed in jeopardy.
Of course, where possible, in the myriad of bleeding disorders, the underlying cause of hemorrhage must be eliminated as in the examples of infections and drug reactions. There is no substitute for the most thorough laboratory work-up and subsequent precise interpretation. Thomas Fuller, MD stated in Gnomologia (1732), "A disease known is half cured."
Assuming Alexander Pope has stopped spinning in his grave and hopefully has come to rest in his original position, it is imperative to remember his admonition in the opening sentence of this article. We have attempted to explain, by oversimplification, an exceedingly complex but well understood group of diseases with special emphasis on vWD in the Doberman. And the practical application of all this?

ALWAYS have bleeding time tests run on Dobermans prior to every elective surgical procedure.

NEVER assume every bleeding episode in a Doberman is vWD, even in "affected" or "at risk" dogs. Each episode of bleeding must be evaluated.

NEVER assume vWD is not a problem in Dobermans. It is a documented killer either directly or indirectly if disguised in combination with other conditions.

LEARN the vWD status of your Doberman prior to a bleeding crisis or breeding. DNA genetic testing can be accomplished by analysis of a cheek swab. It is accurate, once in a lifetime, assuming a mutation (an exceedingly rare event) does not occur after the test. The ELISA test, and to a lesser extent, the EIA test, are clinically significant but vWF concentrations provide less accurate methods by which to separate "carriers" from "clear" individuals.

PLAN ahead if you have an "affected" or "at risk" Doberman. Ask your veterinarian if appropriate drugs and transfusion therapy are available before elective surgeries or if they are available on short notice should an emergency arise. These are expensive, short-dated products that realistically may only be inventoried by large central hospitals, specialty clinics or made available through canine blood replacement centers.

NEVER give a health guarantee. It simply is not possible to guarantee health. If a puppy purchaser wants a guarantee, tell them to buy an ice box! Tomorrow is promised to none of us, so why on earth would a breeder guarantee the health of a puppy? To do so is just plain foolish.

Even with the advent of DNA analysis, overall genetic health cannot be verified because so many conditions are now known to be hereditary, and more genetic tests are likely in the near future. If a breeder DNA tests all the puppies in a litter for vWD, then they can be sold with their vWD status "guaranteed", but that is only one genetic test confirming the presence or absence of one disease. The most any breeder can guarantee is that this dog is healthy the day it goes out the door and it will live until the day it dies. Period. Now, a breeder can have a replacement policy with whatever conditions and restrictions they deem appropriate, but that is not the same as guaranteeing the health of the first puppy.

Another caveat: Be careful how you represent the genetic background of the dogs you sell. The advances in genetic research are widely publicized and the puppy-buying public will take advantage of that information. Lawyers know this. The great benefits derived from the human-animal bond are well documented in human medical literature. Misrepresentation of genetic health will result in ever-increasing settlements for human pain and suffering, making that $1000 puppy worth millions when a genetically defective vWD Doberman succumbs to von Willebrand's Disease.

In summary then, this is a very complex group of diseases which are well understood by those with scientific training and technical expertise. The responsible Doberman owner will seek out such expert help to evaluate every individual bleeding episode, and to ensure an accurate diagnosis, informed prognosis, and correct treatment. This is the only way to provide the best possible resolution of the problem. Remember, bleeding always stops, but with proper evaluation and treatment, one way is infinitely better than the other!

Submitted by C. David McLaughlin, DVM and George J. Brewer, MD
Dr. McLaughlin is the retired director of Dundee Animal Hospital, which has 19 veterinarians on staff, providing specialty services and in-house 24-hour emergency and critical care. He currently serves as President of the Doberman Pinscher Foundation of America.
Dr. Brewer is a professor in both the Department of Human Genetics and the Department of Internal Medicine at the University of Michigan, and an adjunct professor of Veterinary Medicine at Michigan State University. Dr. Brewer was instrumental in isolating the gene and in the development of the DNA test for Doberman vWD.
Reprinted with permission from the original article printed in Doberman Digest