title: Combined in vivo depletion of glycoprotein VI and C-type lectin-like receptor 2 severely compromises hemostasis and abrogates arterial thrombosis in mice.
abstract: OBJECTIVE
  Platelet inhibition is a major strategy to prevent acute ischemic cardiovascular and cerebrovascular events, which may, however, be associated with an increased bleeding risk. The (hem)immunoreceptor tyrosine activation motif-bearing platelet receptors, glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2), might be promising antithrombotic targets because they can be depleted from circulating platelets by antibody treatment, leading to sustained antithrombotic protection, but only moderately increased bleeding times in mice.
  
  
  RESULTS
  We investigated whether both (hem)immunoreceptor tyrosine activation motif-bearing receptors can be targeted simultaneously and what the in vivo consequences of such a combined therapeutic GPVI/CLEC-2 deficiency are. We demonstrate that isolated targeting of either GPVI or CLEC-2 in vivo does not affect expression or function of the respective other receptor. Moreover, simultaneous treatment with both antibodies resulted in the sustained loss of both GPVI and CLEC-2, while leaving other activation pathways intact. However, GPVI/CLEC-2-depleted mice displayed a dramatic hemostatic defect and profound impairment of arterial thrombus formation. Furthermore, a strongly diminished hemostatic response could also be reproduced in mice genetically lacking GPVI and CLEC-2.
  
  
  CONCLUSIONS
  These results demonstrate that GPVI and CLEC-2 can be simultaneously downregulated in platelets in vivo and reveal an unexpected functional redundancy of the 2 receptors in hemostasis and thrombosis. These findings may have important implications of the potential use of anti-GPVI and anti-CLEC-2-based agents in the prevention of thrombotic diseases.
authors: University Hospital Würzburg and Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine, University of Würzburg, Würzburg, Germany.
authors: Markus
authors: M
authors: Bender
authors: Frauke
authors: F
authors: May
authors: Viola
authors: V
authors: Lorenz
authors: Ina
authors: I
authors: Thielmann
authors: Ina
authors: I
authors: Hagedorn
authors: Brenda A
authors: BA
authors: Finney
authors: Timo
authors: T
authors: Vögtle
authors: Katharina
authors: K
authors: Remer
authors: Attila
authors: A
authors: Braun
authors: Michael
authors: M
authors: Bösl
authors: Steve P
authors: SP
authors: Watson
authors: Bernhard
authors: B
authors: Nieswandt
mesh_terms: D000818:Animals; D006487:Hemostasis; D037181:Lectins, C-Type / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D013927:Thrombosis / Q000517:prevention & control*
chemical_list: C529518:CLEC-2 protein, mouse; D037181:Lectins, C-Type; D010980:Platelet Membrane Glycoproteins; C098341:platelet membrane glycoprotein VI