von Willebrand's disease in Scottish Terriers in Australia

SUMMARY Over a 5-year period (1988–92), von Willebrand factor antigen (vWf:Ag) assays were performed on plasma samples from 207 Scottish Terriers. Based on these tests, 47 dogs (23%) had vWf:Ag concentrations < 50 canine units (CU)/dL and were classified as heterozygous carriers of the von Willebrand's disease (vWD) gene, while 9 (4%) had concentrations below the sensitivity of the assays and were classified as homozygous. There was thus an overall prevalence of 27% for the vWD gene in the Scottish Terriers tested. The homozygous dogs (median age 0.6 years at diagnosis) consisted of 7 males and 2 females. Eight of these had haemorrhage attributable to the disease, mostly spontaneous and from the oral mucosa. Other signs included haemorrhage induced by trauma or surgery, easy bruising and epistaxis. Many haemorrhagic episodes were severe enough to warrant therapeutic intervention and there was a single fatality. Pedigree analysis, possible in 7 of the dogs, revealed that each was the progeny of a mating between dogs with vWf:Ag concentrations < 50 CU/dL, which supported an autosomal recessive mode of inheritance. A single heterozygous carrier suffered haemorrhage after surgery that, in contrast to the homozygotes, was mild and did not require therapy. The data indicate that vWD is a significant problem in Scottish Terriers in Australia. Accordingly, we recommend that steps be taken to reduce the prevalence of the disease and thereby the number of clinically affected dogs, such as the establishment of a national testing scheme to determine the vWD status of all breeding dogs.     

Type III von Willebrand's disease in Dutch kooiker dogs

Summary

Type III von Willebrand's disease (vWD) was diagnosed in 38 Dutch kooiker dogs. Ten male and 9 female probands had been referred independently of each other to the Utrecht University Clinic for Companion Animals because of a moderate to severe bleeding tendency. Screening of 717 Dutch kooiker dogs, including 356 puppies, detected vWD in another 19 dogs. Diagnosis was based on non‐detectable amounts (< 1.6%) of von Willebrand factor antigen (vWF:Ag) in plasma by ELISA. Capillary bleeding time (CBT) was prolonged (> 10 min) and polybrene cofactor activity (vWF:PbCo) was not detectable in 11 dogs tested. No distinguishable protein bands were detected by multimer analysis. As in Scottish terriers with type III vWD, factor VIII clotting activity (F_VIII:C) in affected Dutch kooiker dogs was decreased but considerably less than in humans with type III vWD. A recessive mode of inheritance was indicated by the normal or subnormal but measurable amounts of vWF:Ag in the plasma of eight pairs of parents of affected dogs. The F₁ offspring resulting from the experimental mating of two affected dogs consisted of three affected males and four affected females. In 39 obligatory carriers vWF:Ag ranged from 30% to 114% with median and mean vWF values of 64% and 64.2%, respectively, and was subnormal (< 50%) in only 9 animals.     

Von Willebrand's disease in dogs

Von Willebrand's disease, the most common, mild, inherited bleeding disorder of animals, is an autosomal trait generally causing high morbidity and low mortality and affecting many breeds of dogs. Clinical signs include hematuria, epistaxis, gingival or genital mucosal bleeding, lameness, and prolonged bleeding from cut nails or wounds. Concurrent hypothyroidism exacerbates the disease. Affected dogs and carriers should not be bred or should be tested for von Willebrand's factor before breeding. Treatment involves IV infusion of fresh whole blood or plasma, at 3-5 ml/lb, with topical use of hemostatic compounds, and avoidance of drugs that interfere with hemostasis.     

Plasma von Willebrand factor-collagen binding activity in normal dogs and in dogs with von Willebrand's disease.

A sensitive enzyme-linked immunosorbent assay was used for the simultaneous assessment of the amount of von Willebrand factor (vWF) in canine plasma and its ability to bind to canine collagen in vitro. In 60 normal dogs, there was close correlation between the concentration of vWF and its activity as determined by vWF-collagen binding. In 14 dogs with type I expressions of von Willebrand's disease, the ratio of vWF antigen to collagen binding activity was normal or only slightly increased. In 7 dogs with type II expressions of the disease, this ratio was consistently elevated suggesting a significant functional deficiency of the protein. Plasma from 3 dogs with type III von Willebrand's disease had little collagen binding activity because of the severe quantitative deficiency of the protein. The described assay permits the rapid assessment of both the quantity and quality of vWF in a dog. This information is necessary for the detection and characterization of canine von Willebrand's disease, particularly the type II expressions, which cannot be diagnosed by quantitative vWF assays alone.     

Factor XII deficiency and von Willebrand's disease in a family of miniature poodle dogs

The simultaneous occurrence of factor XII deficiency and von Willebrand's disease (VWD) is described in a family of Miniature Poodles affected concurrently with a familial non-spherocytic hemolytic anemia. Although there was a dominant distribution of factor XII deficiency in this family of dogs, only the dogs suffering from non-spherocytic hemolytic anemia had concurrent VWD gene expression. Neither the factor XII deficient dogs nor the VWD carrier dogs displayed bleeding tendencies.     

Von Willebrand's disease in dogs in the United Kingdom

An assay for the measurement of von Willebrand factor antigen has been established. In a period of 18 months, 13 dogs have been identified as suffering from von Willebrand's disease. The affected animals had levels of von Willebrand factor antigen which ranged from undetectable to 43 per cent of normal. Factor VIII levels were also reduced. Haemorrhagic episodes were usually associated with trauma or surgery, and often required transfusion with fresh blood or plasma to arrest haemorrhage.     

Mutation causing von Willebrand's disease in Scottish Terriers

Von Willebrand's Disease (vWD) in the Scottish Terrier breed is a serious, often fatal, hereditary bleeding disorder. Elimination of the mutated gene by selective breeding is an important goal for the health of this breed. Although the standard protein-based tests are accurate for identification of affected Scottish Terriers, they are not reliable for the identification of carriers of the mutant gene unless multiple replicate assays are performed. A simple, highly accurate test for carriers of the disease is needed so that veterinarians can counsel clients on which animals to use in their breeding programs. The complete coding region of von Willebrand factor (vWF) complementary DNA (cDNA) was sequenced from an affected animal, and a single base deletion in the codon for amino acid 85 of the prepro-vWF cDNA that leads to Scottish Terrier vWD was identified. A highly accurate polymerase chain reaction assay was developed that can distinguish homozygous normal animals from those that are homozygous affected or heterozygous. In a voluntary survey of 87 animals provided by Scottish Terrier owners, 15 were carriers and 4 were affected with vWD, 2 of which had previously been shown to have undetectable vWF. The determination of the complete canine vWF cDNA sequence should facilitate the identification of additional vWD alleles in other breeds and other species.     

Desmopressin enhances the binding of plasma von Willebrand factor to collagen in plasmas from normal dogs and dogs with type I von Willebrand's disease.

A new in vitro von Willebrand factor-collagen binding activity (vWF:CBA) assay was used to assess qualitative changes in vWF in normal dogs and dogs with Type I von Willebrand's disease (vWD) following treatment with desmopressin acetate (DDAVP). Although DDAVP induced increases in vWF antigen concentrations at 1 hour postinfusion in both normal and vWD dogs (57% and 60% increases, respectively), there were disproportionately greater increases in vWF:CBA (96% and 103% increases). These results support the hypothesis that the enhanced hemostatic activity induced by DDAVP is, at least in part, due to the selective release of more functionally active vWF multimers. The assay, as described, provides a convenient means of simultaneously assessing vWF quantity and function before and after DDAVP administration.     

Type 3 von Willebrand's disease in a Shetland sheepdog

A 3.75-year-old, spayed female, Shetland sheepdog was presented with excessive bleeding from a gingival surface. The dog's condition deteriorated over 24 h and whole fresh blood was transfused. Type 3 von Willebrand's disease was diagnosed. Coagulation was achieved and the dog was released with recommendations for a sedentary lifestyle and careful monitoring.     

A von Willebrand's factor genomic nucleotide variant and polymerase chain reaction diagnostic test associated with inheritable type-2 von Willebrand's disease in a line of german shorthaired pointer dogs

Heritable, type-2 von Willebrand's disease (vWD) was studied in a line of German Shorthaired Pointers (GSPs) in which some members had a nucleotide variant in exon 28 of the von Willebrand factor (VWF) gene. A polymerase chain reaction (PCR) diagnostic test for the nucleotide variant was developed to establish the disorder's mode of inheritance and to eliminate it from the line. Thirty-six of the 49 GSPs in the line, 14 unrelated GSP controls, and 71 unrelated dogs of various breeds were tested for the presence of the variant nucleotide. All the dogs with a vWF antigen deficiency (<70% of normal) were either homozygous or heterozygous for the nucleotide variant. The variant was not located in any tested dog in the line or outside of the line with a vWF antigen value greater than 68%. Of the GSPs in the line tested, two were homozygous for the variant, 15 were heterozygous, and 19 were variant free. The collective evidence of this and other studies is consistent with the variant nucleotide being the cause of the type-2 vWD in this line of GSPs and German Wirehaired Pointers. The PCR diagnostic test for the variant nucleotide was successfully used to select and produce progeny that were variant free and vWD free. This test should be effective in the subsequent elimination of this same variant from other lines of dogs.     

Buccal mucosa bleeding times of healthy dogs and of dogs in various pathologic states, including thrombocytopenia, uremia, and von Willebrand's disease

The buccal mucosa bleeding time (BMBT; duration of hemorrhage from standardized cuts made with a spring-loaded disposable device in the mucosal surface of the upper lip) was used to evaluate the hemostatic competence of dogs. The mean (+/- SD) BMBT for 34 healthy dogs was 2.62 +/- 0.49 minutes. The BMBT of healthy dogs anesthetized with halothane or tranquilized with xylazine were not significantly different from the BMBT of healthy dogs evaluated without chemical restraint. The BMBT was significantly (P less than 0.01) prolonged 21 hours after aspirin (10 mg/kg of body weight) was administered orally to 10 healthy dogs; however, the mean aspirin-induced increase in BMBT was only 0.40 minutes. The BMBT of 28 of 30 dogs with various diseases not traditionally associated with hemostatic deficiencies were near or within the range of BMBT for healthy dogs; however, 2 dogs had BMBT of greater than 8 minutes. In contrast, BMBT were prolonged in most dogs with diseases known to induce deficient primary hemostasis; the 3 dogs with thrombocytopenia (less than or equal to 20,000 platelets/microliter), the 7 Doberman Pinschers with von Willebrand's disease (von Willebrand factor antigen; less than or equal to 18 U/dl), and 5 of the 6 dogs with severe azotemia (serum urea nitrogen; greater than or equal to 124 mg/dl) had prolonged BMBT. The BMBT of 16 dogs were determined immediately before they were subjected to various surgical procedures, and the severity of the hemorrhage encountered during these procedures was subjectively evaluated; the amount of hemorrhage from 12 of the 16 dogs was considered to be appropriate for the corresponding surgical procedures, but the remaining 4 dogs bled excessively during surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inheritance of von Willebrand's disease in a colony of Doberman Pinschers

OBJECTIVE: To determine the mode of inheritance of von Willebrand's disease (vWD) and perform linkage analysis between vWD and coat color or narcolepsy in a colony of Doberman Pinschers. ANIMALS: 159 Doberman Pinschers. PROCEDURE: von Willebrand factor antigen (vWF:Ag) concentration was measured by use of ELISA, and results were used to classify dogs as having low (< 20%), intermediate (20 to 65%), or high (> 65%) vWF:Ag concentration, compared with results of analysis of standard pooled plasma. Buccal bleeding time was measured, and mode of inheritance of vWD was assessed by pedigree analysis. RESULTS: von Willebrand's disease was transmitted as a single autosomal gene defect. Results suggested that 27.04% of dogs were homozygous for vWD, 62.26% were heterozygous, and 10.69% did not have the defect. Most homozygous and some heterozygous dogs had prolonged bleeding times. Dogs with diluted coat colors (blue and fawn) were significantly overrepresented in the homozygous group, compared with black and red dogs, but a significant link between vWD and coat color was not detected. CONCLUSIONS AND CLINICAL RELEVANCE: von Willebrand's disease is transmitted as an autosomal dominant trait with variable penetrance; most dogs in this colony (89.3%) were carriers of vWD. Homozygosity for vWD is not likely to be lethal. Some heterozygous dogs have prolonged bleeding times. An association between diluted coat colors and vWD may exist.     

Potential central nervous system complications of von Willebrand's disease.

Three Doberman pinschers were presented on emergency referral for progressive neurological deficits. All three dogs had a similar onset of clinical signs associated with an apparently minor traumatic event. Each dog progressed to significant neurological dysfunction including paraplegia, tetraplegia, and/or loss of deep pain sensation. None of the animals was apparently affected by cervical vertebral instability ("Wobbler's Syndrome"). All were confirmed to have von Willebrand's disease. In all cases, significant epidural hemorrhage was identified. The etiology of each hemorrhage, however, was different for each animal. The cases presented here demonstrate a potential relationship between neurological deficits and the patient's ability to effectively coagulate blood. Hemostatic abnormalities, such as von Willebrand's disease, should be included as possible differential diagnoses or contributing factors in animals demonstrating neurological deficits. These abnormalities should especially be considered following trauma, intervertebral disk extrusion, or spinal surgery.     

Canine von Willebrand's disease. A heterogeneous group of bleeding disorders

The term "von Willebrand's disease," refers to a group of inherited bleeding disorders, all of which are caused by a deficiency of the multimeric plasma glycoprotein, von Willebrand factor. The various forms of canine von Willebrand's disease can be categorized into one of three major types: in type I canine von Willebrand's disease, all sizes of von Willebrand factor multimers can be detected in the plasma; in type II canine von Willebrand's disease, only the smaller von Willebrand factor multimers are found in the plasma (larger multimers are absent); and in type III canine von Willebrand's disease, von Willebrand factor is completely absent from the plasma or present in only trace amounts. Von Willebrand's disease is common in dogs, but some forms of the disease are so mild that they are of questionable clinical significance.     

Hemorrhage from the cosmetic otoplasty of Doberman Pinschers with von Willebrand's disease

The hemorrhagic tendencies of 23 Doberman Pinscher pups were observed during cosmetic otoplasty and were ranked by a +1 to +4 grading system (+1 = least hemorrhage, and +4 = most hemorrhage). A second estimate of the hemostatic competencies of these dogs was made by counting the gauze sponges used in the otoplasties. Factor VIII-related antigen concentrations and coagglutinin cofactor concentrations were measured in plasma samples from blood drawn not more than 30 hours before the surgical procedures were done. The factor VIII-related antigen concentrations were between 9% and 147% of the concentration in a normal plasma pool, and the coagglutinin cofactor concentrations were between 1% and 165%, indicating that some of these dogs had von Willebrand's disease. The hemorrhagic tendencies of 12 pups were graded +1. This group had a mean antigen concentration of 75% (min-max, 38% to 147%) and a mean coagglutinin cofactor concentration of 89% (min-max, 42% to 165%). These were significantly greater than the antigen and cofactor concentrations of the grades +2 (n = 5), +3 (n = 3), or +4 (n = 3) dogs. Significant differences were not found when antigen concentrations of the grade +2 dogs (mean, 16%; min-max, 11% to 22%), grade +3 dogs (mean, 13%; 12% to 16%), and grade +4 dogs (mean, 11%; 9% to 12%) were compared with each other, nor were significant differences seen among the coagglutinin cofactor concentrations of the grade +2 dogs (mean, 7%; min-max, 1% to 11%), grade +3 dogs (mean, 6%, 4% to 8%), and grade +4 dogs (mean, 5%; 2% to 9%).(ABSTRACT TRUNCATED AT 250 WORDS)