RESUMEN
This study evaluated shedding of the platelet collagen receptor, glycoprotein VI (GPVI) in human plasma. Collagen or other ligands induce metalloproteinase-mediated GPVI ectodomain shedding, generating approximately 55-kDa soluble GPVI (sGPVI) and approximately 10-kDa platelet-associated fragments. In the absence of GPVI ligands, coagulation of platelet-rich plasma from healthy persons induced GPVI shedding, independent of added tissue factor, but inhibitable by metalloproteinase inhibitor, GM6001. Factor Xa (FXa) common to intrinsic and tissue factor-mediated coagulation pathways was critical for sGPVI release because (1) shedding was strongly blocked by the FXa-selective inhibitor rivaroxaban but not FIIa (thrombin) inhibitors dabigatran or hirudin; (2) Russell viper venom that directly activates FX generated sGPVI, with complete inhibition by enoxaparin (inhibits FXa and FIIa) but not hirudin; (3) impaired GPVI shedding during coagulation of washed platelets resuspended in FX-depleted plasma was restored by adding purified FX; and (4) purified FXa induced GM6001-inhibitable GPVI shedding from washed platelets. In 29 patients with disseminated intravascular coagulation, mean plasma sGPVI was 53.9 ng/mL (95% confidence interval, 39.9-72.8 ng/mL) compared with 12.5 ng/mL (95% confidence interval, 9.0-17.3 ng/mL) in thrombocytopenic controls (n = 36, P < .0001), and 14.6 ng/mL (95% confidence interval, 7.9-27.1 ng/mL) in healthy subjects (n = 25, P = .002). In conclusion, coagulation-induced GPVI shedding via FXa down-regulates GPVI under procoagulant conditions. FXa inhibitors have an unexpected role in preventing GPVI down-regulation.
Asunto(s)
Coagulación Sanguínea/fisiología , Plaquetas/metabolismo , Factor Xa/fisiología , Glicoproteínas de Membrana Plaquetaria/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Coagulación Sanguínea/efectos de los fármacos , Pruebas de Coagulación Sanguínea , Plaquetas/efectos de los fármacos , Coagulación Intravascular Diseminada/sangre , Coagulación Intravascular Diseminada/metabolismo , Coagulación Intravascular Diseminada/patología , Enoxaparina/farmacología , Factor Xa/metabolismo , Femenino , Fibrinolíticos/farmacología , Hirudinas/farmacología , Humanos , Técnicas In Vitro , Masculino , Metaloproteasas/metabolismo , Persona de Mediana Edad , Trombina/farmacologíaAsunto(s)
Inhibidores del Factor Xa/sangre , Pirazoles/sangre , Piridonas/sangre , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Pruebas de Coagulación Sanguínea/normas , Compuestos Cromogénicos , Inhibidores del Factor Xa/normas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Pirazoles/normas , Piridonas/normas , Reproducibilidad de los ResultadosRESUMEN
Platelet function defects are frequently found in patients with chronic myeloid leukaemia. Major clinical bleeding, however, is a rare and infrequently reported complication. Platelet function abnormalities have also not been previously correlated with molecular monitoring of BCR-ABL in chronic myeloid leukaemia. We report a case of a patient with major clinical bleeding as a presenting feature of chronic myeloid leukaemia. The patient developed compartment syndrome of the thigh secondary to a haematoma developing after minor trauma. Fasciotomy was complicated by severe bleeding requiring massive transfusion. Haemostasis was only obtained after activated recombinant factor VII was administered. Laboratory investigations revealed a platelet function defect with reduced platelet aggregation to collagen, epinephrine and arachidonic acid. As imatinib therapy commenced, molecular response was associated with near-normalization of platelet function, which subsequently became significantly abnormal with molecular relapse. Electron microscopy demonstrated normal platelet ultrastructure. We conclude that dysregulated Abelson kinase plays a pathogenic role in platelet function defects associated with chronic myeloid leukaemia, and discuss the management of clinically significant bleeding in patients with platelet function defects associated with myeloproliferative disorders.