Faculty Opinions recommendation of Inhibition of von Willebrand factor-platelet glycoprotein Ib interaction prevents and reverses symptoms of acute acquired thrombotic thrombocytopenic purpura in baboons.

Abstract The pathophysiology of thrombotic thrombocytopenic purpura (TTP) can be explained by the absence of active ADAMTS13, leading to ultra-large von Willebrand factor (UL-VWF) multimers spontaneously interacting with platelets. Preventing the formation of UL-VWF–platelet aggregates therefore is an attractive new treatment strategy. Here, we demonstrate that simultaneous administration of the inhibitory anti-VWF monoclonal antibody GBR600 and the inhibitory anti-ADAMTS13 antibody 3H9 to baboons (prevention group) precluded TTP onset as severe thrombocytopenia and hemolytic anemia were absent in these animals. In addition, partial VWF inhibition was not enough to prevent thrombocytopenia, demonstrating the specificity of this therapeutic strategy. GBR600 treatment of baboons during acute TTP (treatment group) resulted in a rapid recovery of severe thrombocytopenia similar to the platelet count increases observed in TTP patients treated by plasma exchange. Baboons in the control group only injected with 3H9 developed early stages of TTP as previously described. Hence, inhibiting VWF-GPIb interactions is an effective way to prevent and treat the early symptoms of acquired TTP in baboons.

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Investigation of the role of von Willebrand factor in thrombotic thrombocytopenic purpura

Blood ◽

10.1182/blood.v66.5.1219.1219 ◽

1985 ◽

Vol 66 (5) ◽

pp. 1219-1221 ◽

Cited By ~ 15

Author(s):

EC Lian ◽

FA Siddiqui

Keyword(s):

Platelet Aggregation ◽

Thrombotic Thrombocytopenic Purpura ◽

Von Willebrand Factor ◽

Platelet Glycoprotein ◽

Plasma Samples ◽

Thrombocytopenic Purpura ◽

Von Willebrand ◽

Induced Aggregation ◽

Willebrand Factor

Abstract Von Willebrand factor (vWF) has been implicated to function as a cofactor in platelet aggregation induced by thrombotic thrombocytopenic purpura (TTP) plasma. To investigate further this role of vWF, we have used rabbit monospecific anti-FVIII/vWF antibodies and a monoclonal antibody to platelet glycoprotein Ib (GP Ib) that blocks the ristocetin- induced platelet aggregation. The monoclonal anti-platelet GP Ib antibody inhibited the platelet aggregation induced by ristocetin in the presence of normal plasma, but not that by any of the five TTP plasma samples. The TTP plasma samples from five patients were incubated with the monospecific antibodies to FVIII/vWF. In all of the samples, the FVIII/vWF:Ag was drastically reduced; however, there was almost no effect on the platelet-aggregating activity. Therefore, it is concluded that vWF is unlikely to play a major role in platelet aggregation induced by majority of TTP plasmas and that the site of platelet GP Ib, to which vWF binds in the presence of ristocetin, is not involved in TTP plasma-induced aggregation.

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Investigation of the role of von Willebrand factor in thrombotic thrombocytopenic purpura

Blood ◽

10.1182/blood.v66.5.1219.bloodjournal6651219 ◽

1985 ◽

Vol 66 (5) ◽

pp. 1219-1221

Author(s):

EC Lian ◽

FA Siddiqui

Keyword(s):

Platelet Aggregation ◽

Thrombotic Thrombocytopenic Purpura ◽

Von Willebrand Factor ◽

Platelet Glycoprotein ◽

Plasma Samples ◽

Thrombocytopenic Purpura ◽

Von Willebrand ◽

Induced Aggregation ◽

Willebrand Factor

Von Willebrand factor (vWF) has been implicated to function as a cofactor in platelet aggregation induced by thrombotic thrombocytopenic purpura (TTP) plasma. To investigate further this role of vWF, we have used rabbit monospecific anti-FVIII/vWF antibodies and a monoclonal antibody to platelet glycoprotein Ib (GP Ib) that blocks the ristocetin- induced platelet aggregation. The monoclonal anti-platelet GP Ib antibody inhibited the platelet aggregation induced by ristocetin in the presence of normal plasma, but not that by any of the five TTP plasma samples. The TTP plasma samples from five patients were incubated with the monospecific antibodies to FVIII/vWF. In all of the samples, the FVIII/vWF:Ag was drastically reduced; however, there was almost no effect on the platelet-aggregating activity. Therefore, it is concluded that vWF is unlikely to play a major role in platelet aggregation induced by majority of TTP plasmas and that the site of platelet GP Ib, to which vWF binds in the presence of ristocetin, is not involved in TTP plasma-induced aggregation.

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Glycoprotein Ib Can Mediate Endothelial Cell Attachment to a von Willebrand Factor Substratum

Thrombosis and Haemostasis ◽

10.1055/s-0038-1653770 ◽

1995 ◽

Vol 73 (02) ◽

pp. 309-317 ◽

Cited By ~ 16

Author(s):

Dorothy A Beacham ◽

Miguel A Cruz ◽

Robert I Handin

Keyword(s):

Endothelial Cell ◽

Von Willebrand Factor ◽

Cell Attachment ◽

Umbilical Vein ◽

Single Amino Acid ◽

Cell Surface Expression ◽

Platelet Glycoprotein ◽

Glycoprotein Ib ◽

Von Willebrand ◽

Willebrand Factor

SummaryIntroduction of single amino acid substitutions into the C-terminal Arg-Gly-Asp-Ser (RGDS) site of von Willebrand Factor, referred to as RGD mutant vWF, selectively abrogated vWF binding to platelet glycoprotein IIb/IIIa (GpIIb/IIIa, αIIbβ3 and abolished human umbilical vein endothelial cell (HUVEC) spreading, but not attachment, to RGD mutant vWF (Beacham, D. A., Wise, R. J., Turci, S. M. and Handin, R. I. 1992. J. Biol. Chem. 167, 3409-3415). These results suggested that in addition to the vitronectin receptor (VNR, αvβ3), a second endothelial membrane glycoprotein can mediate HUVEC adhesion to vWF. HUVEC attachment to wild-type (WT) and RGD-mutant vWF was reduced by two proteins known to block the vWF-platelet glycoprotein Ib/IX (GpIb/IX) interaction, the monoclonal antibody AS-7 and the recombinant polypeptide, vWF-A1. The addition of cytochalasin B or DNase I to disrupt potential GPIbα-cytoskeletal interactions enhanced the immunoprecipitation of endothelial GPIbα, caused HUVEC to round up, and increased HUVEC adhesion to RGD mutant vWF. These results indicate that while the VNR is the primary adhesion receptor for vWF, endothelial GPIbα can mediate HUVEC attachment to vWF. GpIb-dependent attachment could contribute to HUVEC adhesion under conditions when cell surface expression of the VNR is downregulated, and VNR-dependent adhesion is reduced.

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