Inherited platelet disorders

Boudreaux, Mary K.

doi:10.1111/j.1476-4431.2011.00702.x

Cited by 19 publications

(41 citation statements)

References 102 publications

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“…Hemostatic function, however, is not altered presumably due to the presence of a normal circulating platelet mass indicated by the measurement of a normal plateletcrit in affected dogs . The prevalence of asymptomatic macrothrombocytopenia in CKCS is very high with more than 90% of dogs being either carriers or affected . Several other breeds as well as mixed‐breed dogs have also been identified with this mutation since it was first reported in CKCS.…”

Section: Platelet Counts Dna Sequences With and Without Polymorphismmentioning

confidence: 94%

“…Similar to that observed in people, inherited thrombopathias and thrombocytopenia have been reported in animals. The severity of bleeding observed with inherited thrombopathias varies as a reflection of their molecular basis and ensuing phenotype . However, not all the inherited intrinsic platelet disorders cause hemorrhage.…”

Section: Platelet Counts Dna Sequences With and Without Polymorphismmentioning

confidence: 99%

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A novel point mutation in the β1‐tubulin gene in asymptomatic macrothrombocytopenic Norfolk and Cairn Terriers

Gelain

Bertazzolo

Tutino

et al. 2014

Veterinary Clinical Pathol

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Section: Platelet Counts Dna Sequences With and Without Polymorphismmentioning

confidence: 94%

Section: Platelet Counts Dna Sequences With and Without Polymorphismmentioning

confidence: 99%

A novel point mutation in the β1‐tubulin gene in asymptomatic macrothrombocytopenic Norfolk and Cairn Terriers

Gelain

Bertazzolo

Tutino

et al. 2014

Veterinary Clinical Pathol

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“…VWF has been implicated in bleeding disorders in breed dogs (27), suggesting the increased level of amino acid changes in this gene may be of relevance to health.…”

Section: Significancementioning

confidence: 99%

Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs

Marsden

Vecchyo

O’Brien

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

293

348

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Population bottlenecks, inbreeding, and artificial selection can all, in principle, influence levels of deleterious genetic variation. However, the relative importance of each of these effects on genome-wide patterns of deleterious variation remains controversial. Domestic and wild canids offer a powerful system to address the role of these factors in influencing deleterious variation because their history is dominated by known bottlenecks and intense artificial selection. Here, we assess genome-wide patterns of deleterious variation in 90 whole-genome sequences from breed dogs, village dogs, and gray wolves. We find that the ratio of amino acid changing heterozygosity to silent heterozygosity is higher in dogs than in wolves and, on average, dogs have 2-3% higher genetic load than gray wolves. Multiple lines of evidence indicate this pattern is driven by less efficient natural selection due to bottlenecks associated with domestication and breed formation, rather than recent inbreeding. Further, we find regions of the genome implicated in selective sweeps are enriched for amino acid changing variants and Mendelian disease genes. To our knowledge, these results provide the first quantitative estimates of the increased burden of deleterious variants directly associated with domestication and have important implications for selective breeding programs and the conservation of rare and endangered species. Specifically, they highlight the costs associated with selective breeding and question the practice favoring the breeding of individuals that best fit breed standards. Our results also suggest that maintaining a large population size, rather than just avoiding inbreeding, is a critical factor for preventing the accumulation of deleterious variants.M any of the mutations that arise in genomes are weakly deleterious and reduce fitness but are not always eliminated from the population by purifying natural selection. Consequently, understanding the reasons why deleterious mutations persist in populations and the role of demographic history in this process is of considerable interest (1-9). The radiation of domestic dogs offers a unique opportunity to address these questions. Dogs were originally domesticated from ancestral gray wolf populations >15,000 y ago in a process involving one or more severe population bottlenecks (10-12). The more recent isolation of modern dog breeds, which occurred over the last 300 y, involved additional population bottlenecks, intense artificial selection, and inbreeding Fig. 1A). Although this history is predicted to have resulted in the accumulation of deleterious variants, its specific effect on genomewide patterns of deleterious variation remains unclear.Here, we use complete genome sequencing data from 46 dogs representing 34 breeds, 25 village dogs, and 19 wolves to directly examine patterns of deleterious genetic variation across the dog genome (Dataset S1). Because more than half of these data derive from our own sequencing efforts, this project represents the largest survey of dog...

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“…Transfusion of platelets is indicated to control active hemorrhage and prevent bleeding prior to surgery in dogs severely affected with platelet function disorders. 25 Interestingly, following administration of DDAVP immediately prior to the second exploratory laparotomy, excessive bleeding was not evident during or after surgery, so additional platelet transfusions were not deemed necessary.…”

Section: Discussionmentioning

confidence: 99%

Heterozygosity for P2Y12 receptor gene mutation associated with postoperative hemorrhage in a Greater Swiss Mountain dog

Flores

Boudreaux

Vasquez

et al. 2017

Veterinary Clinical Pathol

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A 3-year-old, female Greater Swiss Mountain dog developed a hemoperitoneum following an exploratory laparotomy and ovariohysterectomy. Platelet count, PT, APTT, and plasma von Willebrand factor antigen concentration were within RIs. A buccal mucosal bleeding time (BMBT) was prolonged. Given the probability of a hereditary thrombopathia, the dog was administered desmopressin, fresh platelet transfusions, and aminocaproic acid to control hemorrhage. Subsequently, DNA testing for the P2Y12 receptor gene mutation identified the dog as being a heterozygote (carrier). Further platelet function testing was performed following complete recovery. Results of a repeat BMBT and a point-of-care screening test using the Platelet Function Analyzer-100 (collagen/adenosine-diphosphate [ADP] test cartridge) were within RIs. Flow cytometric studies demonstrated a marked reduction in fibrinogen binding to the dog's platelets in response to ADP -adenosine diphosphate activation. Likewise, turbidimetric aggregometry revealed a complete absence of platelet aggregation in response to ADP. However, there were a normal aggregation response to the platelet agonist convulxin and a mild reduction in amplitude in response to c-thrombin. This is the first report of a dog heterozygous for the P2Y12 receptor gene mutation exhibiting a bleeding tendency and having evidence of impaired platelet function in vitro in response to ADP activation. Given that the mutant allele for the P2Y12 thrombopathia appears to be widespread in the Greater Swiss Mountain dog breed, veterinarians need to be aware that both homozygotes and heterozygotes for this platelet receptor mutation are at risk of developing life-threatening bleeding following trauma or surgery. Case PresentationA 3-year-old, intact female, Greater Swiss Mountain dog was presented to the Matthew J. Ryan Veterinary Hospital of the University of Pennsylvania for gastrointestinal biopsies and a routine ovariohysterectomy (OVH). The dog had a 9-month history of vomiting, large bowel diarrhea, and weight loss that were minimally responsive to metronidazole, tylosin, and a diet change. Initial diagnostic evaluation included a CBC, serum chemistry profile, adrenocorticotropic hormone (ACTH) stimulation test, and serum cobalamin and folate concentrations, with all results within RIs. A zinc sulfate fecal flotation was negative for parasites. An abdominal ultrasonographic examination revealed small intestinal submucosal thickening and mesenteric and iliac lymphadenopathy.Preoperative PCV and total protein (TP) were 45% (RI 40-60%) and 6.0 g/dL (RI 5.5-7.5 g/dL), respectively. The dog was placed under general anesthesia, and a colonoscopy with colonic biopsies was performed, followed by an exploratory laparotomy with full thickness biopsies of the duodenum, jejunum, and ileum, and an OVH. The procedures were uncomplicated; however, mild oozing of blood was noted from the skin incision, body wall, and multiple surfaces within the abdomen. One day postoperatively, tachycardia, pallor, and a moder...

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Inherited platelet disorders

Cited by 19 publications

References 102 publications

A novel point mutation in the β1‐tubulin gene in asymptomatic macrothrombocytopenic Norfolk and Cairn Terriers

A novel point mutation in the β1‐tubulin gene in asymptomatic macrothrombocytopenic Norfolk and Cairn Terriers

Bottlenecks and selective sweeps during domestication have increased deleterious genetic variation in dogs

Heterozygosity for P2Y12 receptor gene mutation associated with postoperative hemorrhage in a Greater Swiss Mountain dog

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