Plasmin Cleavage of von Willebrand Factor as an Emergency Bypass for ADAMTS13 Deficiency in Thrombotic Microangiopathy
Background—Von Willebrand factor (VWF) multimer size is controlled through continuous proteolysis by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type I motif, member 13). This prevents spontaneous platelet agglutination and microvascular obstructions. ADAMTS13 deficiency is associated with thrombotic thrombocytopenic purpura (TTP), where life-threatening episodes of microangiopathy damage kidneys, heart and brain. Enigmatically, a complete ADAMTS13 deficiency does not lead to continuous microangiopathy. We hypothesized that plasmin, the key enzyme of the fibrinolytic system, serves as a physiological backup enzyme for ADAMTS13 in the degradation of pathological platelet-VWF complexes.
Methods and Results—Using real-time microscopy, we determined that plasmin rapidly degrades platelet-VWF complexes on endothelial cells in absence of ADAMTS13, after activation by urokinase plasminogen activator (uPA) or the thrombolytic agent streptokinase. Similarly, plasmin degrades platelet-VWF complexes in platelet agglutination studies. Plasminogen directly binds to VWF and its A1 domain in a lysine-dependent manner, as determined by enzyme-linked immunosorbent assay. Plasma levels of plasmin-α2-antiplasmin (PAP)-complexes increase with the extent of thrombocytopenia in patients with acute TTP episodes, independent of ADAMTS13 activity. This indicates that plasminogen activation takes place during microangiopathy. Finally, we show that the thrombolytic agent streptokinase has therapeutic value for Adamts13-/- mice in a model for TTP.
Conclusions—We propose that plasminogen activation on endothelial cells acts as a natural backup for ADAMTS13 to degrade obstructive platelet-VWF complexes. Our findings indicate that thrombolytic agents may have therapeutic value in the treatment of microangiopathies and may be useful to bypass inhibitory antibodies against ADAMTS13 that cause TTP.
- von Willebrand factor
- Received October 5, 2013.
- Revision received November 12, 2013.
- Accepted December 16, 2013.