Function of von Willebrand Factor in Children with Diarrhea-Associated Hemolytic-Uremic Syndrome (D+ HUS)

ABSTRACT

Reports on von Willebrand factor (vWF) in hemolytic-uremic syndrome (HUS) are not unequivocal. Because of potential pathogenic implications, we examined the ability of vWF to bind to collagen in vitro, which reflects its function. Plasma vWF antigen (vWF:Ag) and collagen-binding activity (vWF:CBA) were measured by enzyme-linked immunosorbent assay in children with (1) diarrhea-associated (D+) HUS (n = 27), (2) chronic renal insufficiency (CRI) (n = 8), (3) gastroenteritis (GE) not associated with HUS (n = 15), (4) immune thrombocytopenia (ITP) (n = 40) and from controls (n = 35). Structural vWF was evaluated by multimer analysis. Children with D+ HUS had vWF:Ag of 2.53 and vWF:CBA of 1.98 U/mL. The corresponding values for patients with ITP were 1.35 and 1.82 U/mL, with CRI 1.55 and 1.55 U/mL, and with GE 1.68 and 2.10 U/mL; all values were higher than in controls (1.04 and 1.16 U/mL). The mean ratio of vWF:CBA to vWF:Ag ratio in controls was 1.13; only children with HUS had a dysfunctional vWF, as indicated by a low ratio of 0.78; the ratio was elevated in children with ITP (1.36) and GE (1.27) and was normal in those with CRI (1.06). No ultralarge molecular multimers of vWF were detected in any group, including HUS. The very high concentration of plasma vWF:Ag in HUS probably reflects endothelial cell damage or irritation. In contrast to all other groups, only children with HUS had a dysfunctional vWF, caused either by a primary (due to enterohemorrhagic Escherichia coli) or secondary (due to consumption of functionally active vWF) process. This abnormality was not obvious as structural anomaly by multimer analysis.

Hemolytic-uremic syndrome - idiopathic thrombocytopenic purpura - gastroenteritis - chronic renal failure - von Willebrand factor antigen - von Willebrand factor collagen-binding activity

REFERENCES

• 1 Kaplan B S, Cleary T G, Obrig T G. Recent advances in understanding the pathogenesis of the hemolytic uremic syndromes.  Pediatr Nephrol . 1990;  4 276-283
• 2 Van-Geet C, Proesmans W, Arnout J, Vermylen J, Declerck P J. Activation of both coagulation and fibrinolysis in childhood hemolytic uremic syndrome.  Kidney Int . 1998;  54 1324-1330
• 3 Gordjani N, Sutor A H. Coagulation changes associated with the hemolytic uremic syndrome.  Semin Thromb Hemost . 1998;  24 577-582
• 4 van-de-Kar N C, Monnens L A. The hemolytic-uraemic syndrome in childhood.  Baillieres Clin Haematol . 1998;  11 497-507
• 5 Proesmans W. The role of coagulation and fibrinolysis in the pathogenesis of diarrhea associated hemolytic uremic syndrome.  Semin Thromb Hemost . 2001;  27 201-206
• 6 Gordjani N, Sutor A H, Zimmerhackl L B, Brandis M. Hemolytic uremic syndromes in childhood.  Semin Thromb Hemost . 1997;  23 281-293
• 7 Baker K R, Moake J L. Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.  Curr Opin Pediatr . 2000;  12 23-28
• 8 Mannucci P M, Lombardi R, Lattuada A. Enhanced proteolysis of plasma von Willebrand factor in thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome.  Blood . 1989;  74 978-983
• 9 Moake J L. Von Willebrand factor abnormalities in thrombotic thrombocytopenic purpura and the uremic syndrome. In: Kaplan BS, Trompeter RS, Moake JL, eds. Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura New York: Marcel Dekker 1992: 459-471
• 10 Zimmerhackl L B, Thomas K B, Zehenter A. Alteration of the von Willebrand factor in children with hemolytic uremic syndrome. In: Karmali MA, Goglia A, eds. Recent Advances in Verocytotoxin-Producing Escherichia coli Infections Amsterdam: Elsevier Science 1994: 333-336
• 11 Fischer B E, Thomas K B, Schlokat U, Dorner F. Triplet structure of human von Willebrand factor.  Biochem J . 1998;  331 483-488
• 12 Verweyen H M, Karch H, Allerberger F, Zimmerhackl L B. Enterohemorrhagic Escherichia coli (EHEC) in pediatric hemolytic-uremic syndrome: a prospective study in Germany and Austria.  Infection . 1999;  27 341-347
• 13 Bloom A L. Von Willebrand factor: clinical features of inherited and acquired disorders.  Mayo Clin Proc . 1991;  66 743-751
• 14 Berkowitz S D, Ruggeri Z M. The management of von Willebrand disease.  Biomed Prog . 1994;  7 5-10
• 15 Thomas K B, Sutor A H, Altinkaya N. Von Willebrand factor-collagen binding activity is increased in newborns and infants.  Acta Paediatr . 1995;  84 697-699
• 16 Sadler J E. Von Willebrand factor.  J Biol Chem . 1991;  266 22777-22780
• 17 Ruggeri Z M, Ware J. Von Willebrand factor.  FASEB J . 1993;  7 308-316
• 18 Furlan M, Lämmle B. Haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura-new insights into underlying biochemical mechanisms.  Nephrol Dial Transplant . 2000;  15 1112-1114
• 19 Gerritsen H E, Turecek P L, Schwarz H P, Lämmle B, Furlan M. Assay of von Willebrand factor (vWF)-cleaving protease based on decreased collagen binding affinity of degraded vWF: a tool for the diagnosis of thrombotic thrombocytopenic purpura (TTP).  Thromb Haemost . 1999;  82 1386-1389
• 20 Raines G, Aumann H, Sykes S, Street A. Multimeric analysis of von Willebrand factor by molecular sieving electrophoresis in sodium dodecyl sulphate agarose gel.  Thromb Res . 1990;  60 201-212
• 21 Howard M A, Firkin B G. Ristocetin-a new tool in the investigation of platelet aggregation.  Thromb Diath Haemorrh . 1971;  26 362-369
• 22 Favaloro E J. Collagen binding assay for von Willebrand factor (VWF:CBA): detection of von Willebrand's disease (VWD), and discrimination of VWD subtypes, depends on collagen source.  Thromb Haemost . 2000;  83 127-135
• 23 Brown J E, Bosak J O. An ELISA test for the binding of von Willebrand antigen to collagen.  Thromb Res . 1986;  43 303-311
• 24 Thomas K B, Sutor A H, Zieger B. A simple test for the determination of the von Willebrand factor function: the collagen binding activity.  Haemostaseologie . 1994;  14 133-139
• 25 Thomas K B, Choong S C, Jessat U. Von Willebrand factor-collagen binding activity. A comparison of methods able to differentiate von Willebrand disease type I and II. Preliminary results. In:Scharrer I, Schramm W, eds. 24 Hämophilie-Symposion, Hamburg, 1993 Berlin: Springer Verlag 1994: 235-242
• 26 Fischer B E, Thomas K B, Dörner F. Collagen covalently immobilized onto plastic surfaces simplifies measurement of von Willebrand factor-collagen binding activity.  Ann Hematol . 1998;  76 159-166
• 27 Verweyen H M, Karch H, Brandis M, Zimmerhackl L B. Enterohemorrhagic Escherichia coli infections: following transmission routes.  Pediatr Nephrol . 2000;  14 73-83
• 28 Warwicker P, Donne R L, Goodship J A. Familial relapsing haemolytic uraemic syndrome and complement factor H deficiency.  Nephrol Dial Transplant . 1999;  14 1229-1233
• 29 Inward C D, Pall A A, Adu D, Milford D V, Taylor C M. Soluble circulating cell adhesion molecules in haemolytic uraemic syndrome.  Pediatr Nephrol . 1995;  9 574-578
• 30 Sagripanti A, Carpi A, Baicchi U. Plasmatic parameters of coagulation activation in thrombotic microangiopathy.  Biomed Pharmacother . 1996;  50 357-362
• 31 Rose P E, Enayat S M, Sunderland R. Abnormalities of factor VIII related protein multimers in the haemolytic uraemic syndrome.  Arch Dis Child . 1984;  59 1135-1140
• 32 Wagner D D, Bonfanti R. Von Willebrand factor and the endothelium.  Mayo Clin Proc . 1991;  66 621-627
• 33 Zoja C, Remuzzi G. The pivotal role of the endothelial cell in the pathogenesis of HUS. In: Kaplan BS, Trompeter RS, Moake JL, eds. Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura New York: Marcel Dekker 1992: 389-404
• 34 Thomas K B, Zieger B, Jessat U, Sutor A H. The role of platelet von Willebrand factor in patients with Von Willebrand disease. In: Scharrer I, Schramm W, eds. 24 Hämophilie-Symposion, Hamburg, 1993 Berlin: Springer Verlag 1994: 243-248
• 35 Niesvizky R, Calandri C, Patel N D. Von Willebrand factor binding to collagen in patients with end-stage renal disease.  J Lab Clin Med . 1994;  123 137-142