Artikel av Marion Klok angående Thrombopathia

Background
In the Landseer a hereditary bleeding tendency exists which consists of an interruption in the blood staunching process (haemostasis). The haemostatic mechanism exists of interference between the damaged wall of the vein, blood platelets and coagulation factors (coagulating proteins in the blood plasma).The interaction occurs through a complicated transfer mechanism whereby signals are generated through certain chemicals (such as enzymes) which influence each other in a stepwise process. This results in the coagulation of blood platelets and their attachment to the damaged wall of the vein, the forming of a clot (protein lump) mixed with blood platelets and subsequently reinforcement of the clot, so that no more blood leaks through the wall whereby the clot keeps in place. A defect in, or the lack of one of the molecules that transmit or receive (receptors) these signals can lead to interruption of the haemostasis and subsequently to an increased tendency to bleed.
At first it was suspected in Utrecht that the cause of the bleeding disorder in the Landseer lay in the absence or dysfunction of a certain receptor on the blood platelet (integrin αIIb-β3). This disorder is known as “Glanzmann’s disease”. In 2003 some blood samples were sent to the USA for DNA-research; it has become clear that in Landseers the platelet disorder is not Glanzmann’s Disease.
It has now become clear that Landseers are missing a protein necessary for proper signalling to the receptor to bind fibrinogen at the appropriate time. Because the platelets cannot signal properly there is an absence of platelet aggregation in response to most platelet activating agents.

Symptoms of the disorder
Symptoms of the disorder in the Landseer are not always very clear. Often the problem is first recognized during teething, apart from that nose bleeds sometimes occur. Especially changing the larger premolars causes significantly prolonged bleeding, sometimes up to 12 hours. Of course there can be wounds of numerous causes at any age that bleed extremely long. Beside external wounds, bruises or internal bleeding (also in the joints) may occur. Large wounds or an operation are life-threatening. In bitches that have the disease the heat is a large risk. We found that the severity in which the disorder appears varies. There are Landseers that reach a normal age without significant problems in spite of the disease. Severe cases are obvious but in milder cases it is often assumed the bleeding is directly due to the trauma and the raised tendency to bleed is not recognised.

State of affairs now
The blood samples sent in 2003 resulted in an extensive cooperation with Prof.Dr. Mary K. Boudreaux (Auburn University, Alabama, USA), who finally discovered the cause of the disorder in Landseers during the summer of 2006. It is interesting to know that she was doing research on a similar mutation in Basset hounds and Eskimo Spitz dogs and therefore compared the Landseers’ DNA with these breeds and much to her and my surprise there turned out to be present a mutation in the same gene. That was a piece of luck! A mutation was found in a gene that encodes for a protein vitally important in transmitting signals that result in normal platelet aggregation and forming of a blood clot. The results of this study will probably be published in a scientific magazine in August 2007. Fortunately we still have Winston Thorn Asgard, a dog with the disorder born in 2003, who leads a perfectly normal dog’s life with a befriended family, together with another Landseer from our kennel. Thanks to Winston the mutation could be proven and with his blood there will soon be a follow up research on the exact cause of the disorder in collaboration with Utrecht University and Cornell University, New York, (USA). This will then result in a second scientific publication. In the mean time more DNA samples have been sent to the States, from the period that Utrecht collected blood for DNA-storage, starting at the end of the 1990’s and later. Also thanks to the cooperation with Taina Nygård and Tapio Helin many samples have been sent from Finland to Utrecht too. The results are now known. These tests were done by Mary Boudreaux completely “blind”: she didn’t know who she was testing, although we (Utrecht and undersigned) did know from some dogs whether they were carriers or affected, or sometimes we were fairly sure they had to be clear, and the answers were accurate.  hat only confirms the accuracy of the test. It is possible for all Landseers to be tested for Thrombopathia at Auburn University, USA; however, the goal should be to test the parental generation instead of the pups to prevent the birth of thrombopathic puppies. That is an important step ahead, because heterozygous symptom-less carriers of the disorder can now be identified. It is certain the disorder inherits as an autosomal recessive trait, i.e. the disorder is caused by one single gene that is not sex-linked. In an affected dog this recessive gene is twice present. A carrier has one recessive gene beside a normal dominant gene, which causes him not to have problems himself, but he can pass on the disorder.

How to continue?
The use of carriers in breeding means spreading of the disease, but exclusion of carriers is something that we cannot permit ourselves, given the small population. Good breeding material has already been lost because DNA research was not possible yet. It speaks for itself that given the developments the obligation to test puppies in the Landseer Club’s breeding rules really is superseded, however under the circumstances it was a very good measure. It is highly recommended that from now on all breeding stock be DNA-tested (that will of course only be necessary once in a lifetime). From clear partners, only clear puppies will be born, so in that case there will be no more need to test the puppies (no more DNA-test either). Carriers could possibly be used for breeding, provided they are mated to a clear partner. Of course there will be offspring that are clear as well as symptom-less carriers, but thanks to the DNA-test they will be identifiable.
From such a combination affected puppies can never be born, so such puppies don’t need to be tested in Utrecht either.

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