Polyphosphate binds to human von Willebrand factor in vivo and modulates its interaction with glycoprotein Ib

Abstract

Summary. Background: Polyphosphate, a phosphate polymer released by activated platelets, has recently been described as a potent modulator of blood coagulation and fibrinolysis. In blood plasma, polyphosphate binds to and alters the biological functions of factor XII, fibrin(ogen), thrombin and factor VII activating protease. Objectives: The aim of the present study is to investigate whether polyphosphate also binds to von Willebrand factor (VWF) and alters some of its activities. Methods/Results: When studying patients with type 1 von Willebrand disease (VWD) and their healthy relatives, we discovered a significant correlation between von Willebrand factor (VWF) and platelet polyphosphate levels. We have also found polyphosphate in preparations of VWF isolated from normal platelets and plasma. Surface plasmon resonance and electrophoretic mobility assays indicated that polyphosphate interacts with VWF in a dose-and time-dependent manner. Treatment of normal plasma with active exopolyphosphatase decreased the VWF ristocetin cofactor (VWF:RCo) activity, a functional measure of VWF binding to platelet glycoprotein receptor Ib. VWF collagen binding and multimerization were unaltered after polyphosphate depletion. Moreover, addition of polyphosphate increased the deficient VWF:RCo activity presented by plasma from patients with type 1 VWD. Conclusions: Our results reveal that a new role is played by polyphosphate in hemostasis by its interaction with VWF, and suggest that this polymer may be effective in the treatment of some types of VWD.

Novel Family of Insect Salivary Inhibitors Blocks Contact Pathway Activation by Binding to Polyphosphate, Heparin, and Dextran Sulfate

“…They are also known to inhibit the activity of tissue factor pathway inhibitor by stimulating the activation of FV, 19 stabilize fibrin clots, 19 and modulate the interaction between von Willebrand factor and the platelet receptor glycoprotein1b. 49 PdSP15 proteins inhibit the activation of FXII and FXI, as well as the cleavage of FXI by FXIIa or thrombin, and would be expected to inhibit any anionic surface–mediated reaction. Mast cell proteases such as tryptase occur as heparin complexes, with heparin being essential for stabilization of the tetrameric structure of the enzyme.…”

Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels

“…Although fibrinogen binding to integrin a IIb b 3 is normal in Ip6k1 2/2 platelets, it is possible that vWF function is compromised due to lowered levels of polyP. 12 Trafficking of cargo to dense granules is dependent on the adaptor protein complex AP3, the function of which is compromised in IP6K1 knockout MEFs. 29 It is possible that the decrease in platelet polyP in Ip6k1 2/2 mice is secondary to an AP3-dependent trafficking defect.…”

“…49 PolyP also reversed a defect in vWF-dependent platelet agglutination in patients of type I von Willebrand disease. 12 Hermansky-Pudlak syndrome is a form of dSPD in which patients display dysfunctional biogenesis of lysosomerelated organelles including platelet dense granules, leading to prolonged bleeding time in addition to other clinical features such as albinism. Lengthened plasma clotting time in Hermansky-Pudlak syndrome patients can be rescued by the addition of polyP.…”

“…11 It was recently shown that platelet a-granules also contain polyP at 500-fold lower levels than dense granules. 12 PolyP in a-granules is bound to von Willebrand factor (vWF) and enhances vWF-dependent platelet aggregation. PolyP also acts as a proinflammatory agent, as demonstrated by stimulation of bradykinin generation in human plasma by synthetic polyP 4 and by polyP derived from acid-rich granules of mast cells.…”

Polyphosphate

“…Ruiz et al [7] reported that platelet dense granules are essentially acidocalcisomes, containing abundant polyP inside the granules. Platelet alpha granules also contain polyP, but at markedly lower concentrations [30]. Platelet polyP is smaller and much less heterodisperse than microbial polyP, with lengths of approximately 60 to 100 phosphate units [7, 21].…”