Thrombocytopathy leading to impaired in vivo haemostasis and thrombosis in platelet type von Willebrand disease

Thromb Haemost. 2017 Feb 28;117(3):543-555. doi: 10.1160/TH16-04-0317. Epub 2016 Dec 22.


Platelet defects due to hyper-responsive GPIbα causing enhanced VWF interaction, counter-intuitively result in bleeding rather than thrombosis. The historical explanation of platelet/VWF clearance fails to explain mechanisms of impaired haemostasis particularly in light of reported poor platelet binding to fibrinogen. This study aimed to evaluate the defects of platelets with hyper-responsive GPIbα and their contribution to impaired in vivo thrombosis. Using the PT-VWD mouse model, platelets from the hTgG233V were compared to control hTgWT mice. Platelets' pro-coagulant capacity was evaluated using flowcytometry assessment of P-selectin and annexin V. Whole blood platelet aggregation in response to ADP, collagen and thrombin was tested. Clot kinetics using laser injury thrombosis model and the effect of GPIbα inhibition in vivo using 6B4; a monoclonal antibody, were evaluated. Thrombin-induced platelet P-selectin and PS exposure were significantly reduced in hTgG233V compared to hTgWT and not significantly different when compared to unstimulated platelets. The hTgG233V platelets aggregated normally in response to collagen, and had a delayed response to ADP and thrombin, when compared to hTgWT platelets. Laser injury showed significant impairment of in vivo thrombus formation in hTgG233V compared to hTgWT mice. There was a significant lag in in vitro clot formation in turbidity assay but no impairment in thrombin generation was observed using thromboelastography. The in vivo inhibition of GPIbα facilitated new - unstable - clot formation but did not improve the lag. We conclude platelets with hyper-responsive GPIbα have complex intrinsic defects beyond the previously described mechanisms. Abnormal signalling through GPIbα and potential therapy using inhibitors require further investigations.

Keywords: GPIbα inhibition; hyperresponsive GPIbα; platelet activation; platelet bleeding disorders; thrombin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Diphosphate / pharmacology
  • Animals
  • Blood Coagulation Tests
  • Blood Platelet Disorders / blood
  • Blood Platelet Disorders / complications*
  • Blood Platelet Disorders / diagnosis
  • Blood Platelet Disorders / genetics
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism*
  • Collagen / pharmacology
  • Disease Models, Animal
  • Genetic Predisposition to Disease
  • Hemostasis*
  • Humans
  • Kinetics
  • Mice, Transgenic
  • Mutation
  • Phenotype
  • Platelet Activation* / drug effects
  • Platelet Glycoprotein GPIb-IX Complex / genetics
  • Platelet Glycoprotein GPIb-IX Complex / metabolism*
  • Signal Transduction
  • Thrombin / metabolism
  • Thrombosis / blood
  • Thrombosis / diagnosis
  • Thrombosis / etiology*
  • von Willebrand Diseases / blood
  • von Willebrand Diseases / complications*
  • von Willebrand Diseases / diagnosis
  • von Willebrand Diseases / genetics


  • Platelet Glycoprotein GPIb-IX Complex
  • adhesion receptor
  • Adenosine Diphosphate
  • Collagen
  • Thrombin

Supplementary concepts

  • Von Willebrand disease, platelet type