Novel molecular defect in the platelet ADP receptor P2Y12 of a patient with haemorrhagic diathesis

Remijn, Jasper A.; IJsseldijk, Martin J. W.; Strunk, Annuska; Abbes, A. P.; Engel, Henk; Dikkeschei, Bert D.; Dompeling, Ellen C; Groot, Philip G. de; Slingerland, Robbert J.

doi:10.1515/cclm.2007.036

Cited by 46 publications

(34 citation statements)

References 9 publications

(8 reference statements)

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“…[22][23][24] Our recent study of a novel heterozygous P2Y 12 defect and its association with bleeding in a family with type 1 VWD supports a contribution from other loci to the bleeding tendency in patients with type 1 VWD and provides further evidence for locus heterogeneity in this disorder. 19 In this present study we have identified a patient with type 1 VWD and heterozygous for the P341A mutation.…”

Section: Discussionmentioning

confidence: 67%

An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human platelets

Nisar

Daly

Federici

et al. 2011

Blood

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Section: Discussionmentioning

confidence: 67%

An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human platelets

Nisar

Daly

Federici

et al. 2011

Blood

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“…Inactivating mutations in P2Y 12 are responsible for bleeding disorders in humans and dogs (Hollopeter et al, 2001;Cattaneo et al, 2003Cattaneo et al, , 2005Shiraga et al, 2005;Remijn et al, 2007;Daly et al, 2009;Fontana et al, 2009;Boudreaux and Martin, 2011). With significant relevance in pathophysiology, P2Y 12 is also the major target of the antithrombotic drugs ticlopidine and clopidogrel.…”

Section: Introductionmentioning

confidence: 99%

Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y₁₂

et al. 2012

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The ADP receptor P2Y 12 belongs to the superfamily of G protein-coupled receptors (GPCRs), and its activation triggers platelet aggregation. Therefore, potent antagonists, such as clopidogrel, are of high clinical relevance in prophylaxis and treatment of thromboembolic events. P2Y 12 displays an elevated basal activity in vitro, and as such, inverse agonists may be therapeutically beneficial compared with antagonists. Only a few inverse agonists of P2Y 12 have been described. To expand this limited chemical space and improve understanding of structural determinants of inverse agonist-receptor interaction, this study screened a purine compound library for lead structures using wild-type (WT) human P2Y 12

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“…However, as with the dog in this report, a bleeding tendency has also been documented in people heterozygous for P2Y12 mutations. 9,10 Heterozygosity for a P258T substitution was associated with a lifelong history of severe epistaxis, easy bruising, and excessive posttraumatic hemorrhage in one patient. 10 A bleeding tendency has also been noted in a family that included 3 members heterozygous for a different P2Y12 variant, a K174E mutation, that had been previously diagnosed with type 1 von Willebrand disease (VWD).…”

Section: Discussionmentioning

confidence: 98%

“…9,10 Heterozygosity for a P258T substitution was associated with a lifelong history of severe epistaxis, easy bruising, and excessive posttraumatic hemorrhage in one patient. 10 A bleeding tendency has also been noted in a family that included 3 members heterozygous for a different P2Y12 variant, a K174E mutation, that had been previously diagnosed with type 1 von Willebrand disease (VWD). 9 Therefore, in light of the possibility of VWD occurring with a P2Y12 gene mutation and contributing to the bleeding tendency noted in the dog of this report, plasma VWF:Ag concentration was evaluated 3 times.…”

Section: Discussionmentioning

confidence: 98%

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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Novel molecular defect in the platelet ADP receptor P2Y12 of a patient with haemorrhagic diathesis

Abstract: We conclude that perfusion studies with patient blood are of added value in the diagnostic process, which resulted in identification of a novel molecular defect in the P2Y(12) gene of a patient with haemorrhagic diathesis.

Cited by 46 publications

References 9 publications

An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human platelets

An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human platelets

Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y₁₂

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

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Novel molecular defect in the platelet ADP receptor P2Y12 of a patient with haemorrhagic diathesis

Abstract: We conclude that perfusion studies with patient blood are of added value in the diagnostic process, which resulted in identification of a novel molecular defect in the P2Y(12) gene of a patient with haemorrhagic diathesis.

Cited by 46 publications

References 9 publications

An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human platelets

An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human platelets

Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y12

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

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Identification of Determinants Required for Agonistic and Inverse Agonistic Ligand Properties at the ADP Receptor P2Y₁₂