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Semin Thromb Hemost 2012; 38(01): 38-46
DOI: 10.1055/s-0031-1300950
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Generation and Breakdown of Soluble Ultralarge von Willebrand Factor Multimers

Nancy Turner
1   Department of Bioengineering, Rice University, Houston, Texas
,
Leticia Nolasco
1   Department of Bioengineering, Rice University, Houston, Texas
,
Joel Moake
1   Department of Bioengineering, Rice University, Houston, Texas
› Author Affiliations
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Publication History

Publication Date:
07 February 2012 (online)

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Abstract

Ultralarge von Willebrand factor (ULVWF) multimeric strings are rapidly secreted by, and anchored to, stimulated endothelial cells (EC), and are hyperadhesive to platelets until cleavage by ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). In ADAMTS-13-deficient familial and autoantibody-mediated thrombotic thrombocytopenic purpura (TTP), there is severely restricted cleavage of EC-anchored ULVWF-platelet strings. The small amount of active enzyme released from their EC cleaves ULVWF strings minimally just above EC surfaces, thus generating soluble ULVWF multimers that are 2.5 to 50 times longer than plasma von Willebrand factor (VWF) forms. Soluble ULVWF multimers (detected in TTP and several other disorders) are also hyperadhesive to platelets and can cause excessive platelet adhesion/aggregation. Without exogenous chemicals or extreme shear stress, soluble ULVWF multimers cannot be cleaved by ADAMTS-13 but can be de-assembled (reduced) in vitro, by a free thiol-containing molecule (>30 kD) present in the cryosupernatant fraction of plasma that is not ADAMTS-13, thrombospondin-1, albumin, cysteine, or glutathione. This reduction may prevent occlusion of the microvasculature by embolic soluble ULVWF multimers (± adherent/aggregated platelets). New inhibitors of platelet adhesion to EC-anchored ULVWF multimeric strings and soluble ULVWF include an aptamer, a nanobody, and N-acetylcysteine.

Keywords

soluble ultralarge von Willebrand factor - ADAMTS-13 - reduction - inhibition
 

  • References

  • 1 Furlan M, Robles R, Galbusera M , et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med 1998; 339 (22) 1578-1584
    CrossrefPubMedGoogle Scholar
  • 2 Furlan M, Robles R, Solenthaler M, Wassmer M, Sandoz P, Lämmle B. Deficient activity of von Willebrand factor-cleaving protease in chronic relapsing thrombotic thrombocytopenic purpura. Blood 1997; 89 (9) 3097-3103
    PubMedGoogle Scholar
  • 3 Tsai HM, Lian EC. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N Engl J Med 1998; 339 (22) 1585-1594
    CrossrefPubMedGoogle Scholar
  • 4 Dong JF, Moake JL, Bernardo A , et al. ADAMTS-13 metalloprotease interacts with the endothelial cell-derived ultra-large von Willebrand factor. J Biol Chem 2003; 278 (32) 29633-29639
    CrossrefPubMedGoogle Scholar
  • 5 Dong JF, Moake JL, Nolasco L , et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions. Blood 2002; 100 (12) 4033-4039
    CrossrefPubMedGoogle Scholar
  • 6 Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347 (8) 589-600
    CrossrefPubMedGoogle Scholar
  • 7 Moake JL, McPherson PD. Abnormalities of von Willebrand factor multimers in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. Am J Med 1989; 87 (3N) 9N-15N
    CrossrefPubMedGoogle Scholar
  • 8 Moake JL, Rudy CK, Troll JH , et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307 (23) 1432-1435
    CrossrefPubMedGoogle Scholar
  • 9 Arya M, Anvari B, Romo GM , et al. Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers. Blood 2002; 99 (11) 3971-3977
    CrossrefPubMedGoogle Scholar
  • 10 Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Hellums JD. Involvement of large plasma von Willebrand factor (vWF) multimers and unusually large vWF forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986; 78 (6) 1456-1461
    CrossrefPubMedGoogle Scholar
  • 11 Turner N, Nolasco L, Tao Z, Dong JF, Moake J. Human endothelial cells synthesize and release ADAMTS-13. J Thromb Haemost 2006; 4 (6) 1396-1404
    CrossrefPubMedGoogle Scholar
  • 12 Feys HB, Liu F, Dong N , et al. ADAMTS-13 plasma level determination uncovers antigen absence in acquired thrombotic thrombocytopenic purpura and ethnic differences. J Thromb Haemost 2006; 4 (5) 955-962
    CrossrefPubMedGoogle Scholar
  • 13 Zhou W, Inada M, Lee TP , et al. ADAMTS 13 is expressed in hepatic stellate cells. Lab Invest 2005; 85: 780-788
    CrossrefPubMedGoogle Scholar
  • 14 Turner NA, Nolasco L, Ruggeri ZM, Moake JL. Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage. Blood 2009; 114 (24) 5102-5111
    CrossrefPubMedGoogle Scholar
  • 15 Dent JA, Galbusera M, Ruggeri ZM. Heterogeneity of plasma von Willebrand factor multimers resulting from proteolysis of the constituent subunit. J Clin Invest 1991; 88 (3) 774-782
    CrossrefPubMedGoogle Scholar
  • 16 Fowler WE, Fretto LJ, Hamilton KK, Erickson HP, McKee PA. Substructure of human von Willebrand factor. J Clin Invest 1985; 76 (4) 1491-1500
    CrossrefPubMedGoogle Scholar
  • 17 Michaux G, Abbitt KB, Collinson LM, Haberichter SL, Norman KE, Cutler DF. The physiological function of von Willebrand’s factor depends on its tubular storage in endothelial Weibel-Palade bodies. Dev Cell 2006; 10 (2) 223-232
    CrossrefPubMedGoogle Scholar
  • 18 Charba D, Moake JL, Harris MA, Hester JP. Abnormalities of von Willebrand factor multimers in drug-associated thrombotic microangiopathies. Am J Hematol 1993; 42 (3) 268-277
    CrossrefPubMedGoogle Scholar
  • 19 Larkin D, de Laat B, Jenkins PV , et al. Severe Plasmodium falciparum malaria is associated with circulating ultra-large von Willebrand multimers and ADAMTS13 inhibition. PLoS Pathog 2009; 5 (3) e1000349
    CrossrefPubMedGoogle Scholar
  • 20 Chen J, Hobbs WE, Le J , et al. The rate of hemolysis in sickle cell disease correlates with the quantity of active von Willebrand factor in the plasma. Blood 2011; 117 (13) 3680-3683
    CrossrefPubMedGoogle Scholar
  • 21 Li Y, Choi H, Zhou Z , et al. Covalent regulation of ULVWF string formation and elongation on endothelial cells under flow conditions. J Thromb Haemost 2008; 6 (7) 1135-1143
    CrossrefPubMedGoogle Scholar
  • 22 Chen J, Reheman A, Gushiken FC , et al. N-Acetylcysteine reduces the size and activity of von Willebrand factor: a potential therapy for thrombotic thrombocytopenic purpura. J Clin Invest 2011; 121 (2) 593-603
    CrossrefPubMedGoogle Scholar
  • 23 Zwicker JI, Peyvandi F, Palla R , et al. The thrombospondin-1 N700S polymorphism is associated with early myocardial infarction without altering von Willebrand factor multimer size. Blood 2006; 108 (4) 1280-1283
    CrossrefPubMedGoogle Scholar
  • 24 Tsai HM. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion. Blood 1996; 87 (10) 4235-4244
    CrossrefPubMedGoogle Scholar
  • 25 Yeh H-C, Zhou Z, Choi H , et al. Disulfide bond reduction of von Willebrand factor by ADAMTS-13. J Thromb Haemost 2010; 8 (12) 2778-2788
    CrossrefPubMedGoogle Scholar
  • 26 Knöbl P, Jilma B, Gilbert JC, Hutabarat RM, Wagner PG, Jilma-Stohlawetz P. Anti-von Willebrand factor aptamer ARC1779 for refractory thrombotic thrombocytopenic purpura. Transfusion 2009; 49 (10) 2181-2185
    CrossrefPubMedGoogle Scholar
  • 27 Jilma-Stohlawetz P, Gorczyca ME, Jilma B, Siller-Matula J, Gilbert JC, Knöbl P. Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura. Thromb Haemost 2011; 105 (3) 545-552
    PubMedGoogle Scholar
  • 28 Ulrichts H, Silence K, Schoolmeester A , et al. Antithrombotic drug candidate ALX-0081 shows superior preclinical efficacy and safety compared with currently marketed antiplatelet drugs. Blood 2011; 118 (3) 757-765
    CrossrefPubMedGoogle Scholar
  • 29 Plaimauer B, Scheiflinger F. Expression and characterization of recombinant human ADAMTS-13. Semin Hematol 2004; 41 (1) 24-33
    CrossrefPubMedGoogle Scholar