Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome

Miha Furlan, Rodolfo Robles, Miriam Galbusera, Giuseppe Remuzzi, Paul A. Kyrle, Brigitte Brenner, Manuela Krause, Inge Scharrer, Volker Aumann, Uwe Mittler, Max Solenthaler, Bernhard Lämmle

Research output: Contribution to journalArticle

1368 Citations (Scopus)

Abstract

Background Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevalence of von Willebrand factor-cleaving protease deficiency in patients with familial and nonfamilial forms of these disorders. Methods Plasma samples were obtained from 53 patients with thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome. Von Willebrand factor-cleaving protease was assayed in diluted plasma samples with purified normal von Willebrand factor as the substrate. The extent of the degradation of von Willebrand factor was assessed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. To determine whether an inhibitor of von Willebrand factor-cleaving protease was present, we measured the protease activity in normal plasma after incubation with plasma from the patients. Results We examined 30 patients with thrombotic thrombocytopenic purpura and 23 patients with the hemolytic- uremic syndrome. Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor found in 20 of these patients was shown to be IgG in five of five tested plasma samples. Of 13 patients with nonfamilial hemolytic- uremic syndrome, 11 had normal levels of activity of von Willebrand factor- cleaving protease during the acute episode, whereas in 2 patients, the activity was slightly decreased. All 6 patients with familial thrombotic thrombocytopenic purpura lacked von Willebrand factor-cleaving protease activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was normal in all 12 patients. Conclusions Nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of von Willebrand factor-cleaving protease, whereas the familial form seems to be caused by a constitutional deficiency of the protease. Patients with the hemolytic- uremic syndrome do not have a deficiency of von Willebrand factor-cleaving protease or a defect in von Willebrand factor that leads to its resistance to protease.

Original languageEnglish
Pages (from-to)1578-1584
Number of pages7
JournalNew England Journal of Medicine
Volume339
Issue number22
DOIs
Publication statusPublished - Nov 26 1998

Fingerprint

Thrombotic Thrombocytopenic Purpura
Hemolytic-Uremic Syndrome
von Willebrand Factor
Peptide Hydrolases
ADAMTS13 Protein
Blood Platelets
Immunoblotting

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. / Furlan, Miha; Robles, Rodolfo; Galbusera, Miriam; Remuzzi, Giuseppe; Kyrle, Paul A.; Brenner, Brigitte; Krause, Manuela; Scharrer, Inge; Aumann, Volker; Mittler, Uwe; Solenthaler, Max; Lämmle, Bernhard.

In: New England Journal of Medicine, Vol. 339, No. 22, 26.11.1998, p. 1578-1584.

Research output: Contribution to journalArticle

Furlan, M, Robles, R, Galbusera, M, Remuzzi, G, Kyrle, PA, Brenner, B, Krause, M, Scharrer, I, Aumann, V, Mittler, U, Solenthaler, M & Lämmle, B 1998, 'Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome', New England Journal of Medicine, vol. 339, no. 22, pp. 1578-1584. https://doi.org/10.1056/NEJM199811263392202
Furlan, Miha ; Robles, Rodolfo ; Galbusera, Miriam ; Remuzzi, Giuseppe ; Kyrle, Paul A. ; Brenner, Brigitte ; Krause, Manuela ; Scharrer, Inge ; Aumann, Volker ; Mittler, Uwe ; Solenthaler, Max ; Lämmle, Bernhard. / Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. In: New England Journal of Medicine. 1998 ; Vol. 339, No. 22. pp. 1578-1584.
@article{ad039762c08940259af674d057b80bf3,
title = "Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome",
abstract = "Background Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevalence of von Willebrand factor-cleaving protease deficiency in patients with familial and nonfamilial forms of these disorders. Methods Plasma samples were obtained from 53 patients with thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome. Von Willebrand factor-cleaving protease was assayed in diluted plasma samples with purified normal von Willebrand factor as the substrate. The extent of the degradation of von Willebrand factor was assessed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. To determine whether an inhibitor of von Willebrand factor-cleaving protease was present, we measured the protease activity in normal plasma after incubation with plasma from the patients. Results We examined 30 patients with thrombotic thrombocytopenic purpura and 23 patients with the hemolytic- uremic syndrome. Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor found in 20 of these patients was shown to be IgG in five of five tested plasma samples. Of 13 patients with nonfamilial hemolytic- uremic syndrome, 11 had normal levels of activity of von Willebrand factor- cleaving protease during the acute episode, whereas in 2 patients, the activity was slightly decreased. All 6 patients with familial thrombotic thrombocytopenic purpura lacked von Willebrand factor-cleaving protease activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was normal in all 12 patients. Conclusions Nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of von Willebrand factor-cleaving protease, whereas the familial form seems to be caused by a constitutional deficiency of the protease. Patients with the hemolytic- uremic syndrome do not have a deficiency of von Willebrand factor-cleaving protease or a defect in von Willebrand factor that leads to its resistance to protease.",
author = "Miha Furlan and Rodolfo Robles and Miriam Galbusera and Giuseppe Remuzzi and Kyrle, {Paul A.} and Brigitte Brenner and Manuela Krause and Inge Scharrer and Volker Aumann and Uwe Mittler and Max Solenthaler and Bernhard L{\"a}mmle",
year = "1998",
month = "11",
day = "26",
doi = "10.1056/NEJM199811263392202",
language = "English",
volume = "339",
pages = "1578--1584",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "22",

}

TY - JOUR

T1 - Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome

AU - Furlan, Miha

AU - Robles, Rodolfo

AU - Galbusera, Miriam

AU - Remuzzi, Giuseppe

AU - Kyrle, Paul A.

AU - Brenner, Brigitte

AU - Krause, Manuela

AU - Scharrer, Inge

AU - Aumann, Volker

AU - Mittler, Uwe

AU - Solenthaler, Max

AU - Lämmle, Bernhard

PY - 1998/11/26

Y1 - 1998/11/26

N2 - Background Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevalence of von Willebrand factor-cleaving protease deficiency in patients with familial and nonfamilial forms of these disorders. Methods Plasma samples were obtained from 53 patients with thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome. Von Willebrand factor-cleaving protease was assayed in diluted plasma samples with purified normal von Willebrand factor as the substrate. The extent of the degradation of von Willebrand factor was assessed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. To determine whether an inhibitor of von Willebrand factor-cleaving protease was present, we measured the protease activity in normal plasma after incubation with plasma from the patients. Results We examined 30 patients with thrombotic thrombocytopenic purpura and 23 patients with the hemolytic- uremic syndrome. Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor found in 20 of these patients was shown to be IgG in five of five tested plasma samples. Of 13 patients with nonfamilial hemolytic- uremic syndrome, 11 had normal levels of activity of von Willebrand factor- cleaving protease during the acute episode, whereas in 2 patients, the activity was slightly decreased. All 6 patients with familial thrombotic thrombocytopenic purpura lacked von Willebrand factor-cleaving protease activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was normal in all 12 patients. Conclusions Nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of von Willebrand factor-cleaving protease, whereas the familial form seems to be caused by a constitutional deficiency of the protease. Patients with the hemolytic- uremic syndrome do not have a deficiency of von Willebrand factor-cleaving protease or a defect in von Willebrand factor that leads to its resistance to protease.

AB - Background Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome are severe microvascular disorders of platelet clumping with similar signs and symptoms. Unusually large multimers of von Willebrand factor, capable of agglutinating circulating platelets under high shear stress, occur in the two conditions. We investigated the prevalence of von Willebrand factor-cleaving protease deficiency in patients with familial and nonfamilial forms of these disorders. Methods Plasma samples were obtained from 53 patients with thrombotic thrombocytopenic purpura or hemolytic-uremic syndrome. Von Willebrand factor-cleaving protease was assayed in diluted plasma samples with purified normal von Willebrand factor as the substrate. The extent of the degradation of von Willebrand factor was assessed by electrophoresis in sodium dodecyl sulfate-agarose gels and immunoblotting. To determine whether an inhibitor of von Willebrand factor-cleaving protease was present, we measured the protease activity in normal plasma after incubation with plasma from the patients. Results We examined 30 patients with thrombotic thrombocytopenic purpura and 23 patients with the hemolytic- uremic syndrome. Of 24 patients with nonfamilial thrombotic thrombocytopenic purpura, 20 had severe and 4 had moderate protease deficiency during an acute event. An inhibitor found in 20 of these patients was shown to be IgG in five of five tested plasma samples. Of 13 patients with nonfamilial hemolytic- uremic syndrome, 11 had normal levels of activity of von Willebrand factor- cleaving protease during the acute episode, whereas in 2 patients, the activity was slightly decreased. All 6 patients with familial thrombotic thrombocytopenic purpura lacked von Willebrand factor-cleaving protease activity but had no inhibitor, whereas all 10 patients with familial hemolytic-uremic syndrome had normal protease activity. In vitro proteolytic degradation of von Willebrand factor by the protease was studied in 5 patients with familial and 7 patients with nonfamilial hemolytic-uremic syndrome and was normal in all 12 patients. Conclusions Nonfamilial thrombotic thrombocytopenic purpura is due to an inhibitor of von Willebrand factor-cleaving protease, whereas the familial form seems to be caused by a constitutional deficiency of the protease. Patients with the hemolytic- uremic syndrome do not have a deficiency of von Willebrand factor-cleaving protease or a defect in von Willebrand factor that leads to its resistance to protease.

UR - http://www.scopus.com/inward/record.url?scp=0032569884&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032569884&partnerID=8YFLogxK

U2 - 10.1056/NEJM199811263392202

DO - 10.1056/NEJM199811263392202

M3 - Article

C2 - 9828245

AN - SCOPUS:0032569884

VL - 339

SP - 1578

EP - 1584

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 22

ER -