A hereditary bleeding disorder of dogs caused by a lack of platelet procoagulant activity

Abstract

We have discovered a novel canine hereditary bleeding disorder with the characteristic features of Scott syndrome, a rare defect of platelet procoagulant activity. Affected dogs were from a single, inbred colony and experienced clinical signs of epistaxis, hyphema, intramuscular hematoma, and prolonged bleeding with cutaneous bruising after surgery. The hemostatic abnormalities identified were restricted to tests of platelet procoagulant activity, whereas platelet count, platelet morphology under light microscopy, bleeding time, clot retraction, and platelet aggregation and secretion in response to thrombin, collagen, and adenosine diphosphate stimulation were all within normal limits. Washed platelets from the affected dogs demonstrated approximately twice normal clotting times in a platelet factor 3 availability assay and, in a prothrombinase assay, generated only background levels of thrombin in response to calcium ionophore, thrombin, or combined thrombin plus collagen stimulation. While platelet phospholipid content was normal, flow cytometric analyses revealed diminished phosphatidylserine exposure and a failure of microvesiculation in response to calcium ionophore, thrombin, and collagen stimulation. Pedigree studies indicate a likely homozygous recessive inheritance pattern of the defect. These findings confirm the importance of platelet procoagulant activity for in vivo hemostasis and provide a large animal model for studying agonist-induced signal transduction, calcium mobilization, and effector pathways involved in the late platelet response of transmembrane phospholipid movement and membrane vesiculation. (Blood. 2002; 99:2434-2441)

Cellular Mechanisms Underlying the Formation of Circulating Microparticles

“…Although initial studies could not clearly distinguish between a hereditary and an acquired bleeding disorder, recent evidence unequivocally indicates that Scott syndrome has a genetic etiology. 39,43 The hereditary nature of the disorder has been corroborated by the discovery of a single, inbred colony of German shepherd dogs with virtually identical symptoms. 43 In both human patients and affected dogs, a defective floppase activity is considered the core pathophysiological defect of Scott syndrome.…”

“…39,43 The hereditary nature of the disorder has been corroborated by the discovery of a single, inbred colony of German shepherd dogs with virtually identical symptoms. 43 In both human patients and affected dogs, a defective floppase activity is considered the core pathophysiological defect of Scott syndrome. 43,44 Pedigree studies have shown that this defect equally affects males and females, consistent with an autosomal recessive inheritance pattern of the disorder.…”

“…53 In line with our findings in one human Scott patient, 107 tetracaine (a local anesthetic agent that triggers mitochondrial depolarization) induces PS exposure in the canine Scott syndrome to an extent similar to that in canine control platelets. 43 Although platelets from Scott syndrome dogs show a loss of mitochondrial potential following exposure to thrombin and collagen, PS externalization does not occur.…”

“…43 In both human patients and affected dogs, a defective floppase activity is considered the core pathophysiological defect of Scott syndrome. 43,44 Pedigree studies have shown that this defect equally affects males and females, consistent with an autosomal recessive inheritance pattern of the disorder. 42 To date, only 3 documented human cases of Scott syndrome have been reported.…”

Exposure of phosphatidylserine on the cell surface

“…40,93 Canine Scott syndrome, a naturally occurring bleeding disorder, is found in German shepherd dogs. 94 As with human patients, the affected dogs lack procoagulant activity in activated platelets and carry loss-of-function mutations in the TMEM16F gene. 95 Two mouse lines lacking TMEM16F in platelets have been established, by Yang et al 51 and by us.…”