Download PDF
Thromb Haemost 1997; 77(02): 387-393
DOI: 10.1055/s-0038-1655973
Original Article
Schattauer GmbH Stuttgart

Acute von Willebrand Factor Secretion from the Endothelium In Vivo: Assessment through Plasma Propeptide (vWf:AgII) Levels

Ulrich M Vischer
1   Division de Biochimie Clinique, HCUG, Geneva, Switzerland
,
Jørgen Ingerslev
2   Hemophilia Center and Coagulation Laboratory, University Hospital Aarhus/Skejby, Aarhus, Denmark
,
Claes B Wollheim
1   Division de Biochimie Clinique, HCUG, Geneva, Switzerland
,
Jean-Claude Mestries
3   CRSSA, La Tronche, France
,
Dimitrios A Tsakiris
4   University Hospital Basel, Basel, Switzerland
,
Walter E Haefeli
4   University Hospital Basel, Basel, Switzerland
,
Egbert K O Kruithof
5   Division d’Angiologie et d’Hémostase, Department of Internal Medicine, HCUG, Geneva, Switzerland
› Author Affiliations
Further Information

Publication History

Received 01 August 1996

Accepted after revision 24 October 1996

Publication Date:
10 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Elevated plasma concentrations of von Willebrand factor (vWf) are increasingly recognized as a cardiovascular risk factor, and are used as a marker of endothelial activation. However, the factors which determine the rate of vWf release from the endothelium in vivo have not been defined clearly. In addition, vWf plasma levels may also be influenced by adhesion of vWf to the vascular wall or to platelets, and by its rate of degradation. The propeptide of vWf (also called vWf:AgII) is stored and released in equimolar amounts with vWf. In the present study we attempted to determine whether this propeptide could be a more reliable marker of endothelial secretion than vWf itself. To accomplish this we developed an ELISA based on monoclonal antibodies. The propeptide levels in normal plasma were found to be 0.7 µg/ml, more than 10 times lower than vWf itself. Administration of desmopressin (DDAVP) induced a rapid relative increase in propeptide (from 106 to 879%) and in vWf (from 112 to 272%). However, the increases in vWf and propeptide were equivalent when expressed in molar units. A time course study indicated a half-life of the propeptide of 3 h or less. In a baboon model of disseminated intravascular coagulation (DIC) induced by FXa, vWf increased by less than 100%, whereas the propeptide concentrations increased by up to 450%. In view of the massive thrombin generation (as assessed by fibrinogen depletion), the increases in vWf are small, compared to the strong secretory response to thrombin and fibrin previously observed in vitro. Our results suggest that due to its rapid turnover, the propeptide could provide a sensitive plasma marker of acute endothelial secretion.

 

  • References

  • 1 Thompson SG, Kienast J, Pyke SDM, Haverkate F, van deLoo JCW. for the European concerted action on thrombosis and disabilities angina pectoris study group. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995; 332: 635-641
    CrossrefPubMedGoogle Scholar
  • 2 Jansson JH, Nilsson TK, Johnson o. von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J 1991; 66: 351-355
    CrossrefPubMedGoogle Scholar
  • 3 Pedrinelli R, Giampietro O, Carmassi F, Melillo E, Dell’Omo G, Catapano G, Matteucci E, Talarico L, Morale M, De NegriF, Di BelloV. Microalbuminuria and endothelial dysfunction in essential hypertension. Lancet 1994; 344: 14-18
    CrossrefPubMedGoogle Scholar
  • 4 Jensen T, Bjerre-Knudsen J, Feldt-Rasmussen B, Deckert T. Features of endothelial dysfunction in early diabetic nephropathy. Lancet 1989; 01: 461-463
    PubMedGoogle Scholar
  • 5 Stehouwer CDA, Fischer HRA, van KuijkAWR, Polack BCP, Donker AJM. Endothelial dysfunction precedes development of microalbuminuria in IDDM. Diabetes 1995; 44: 561-564
    CrossrefPubMedGoogle Scholar
  • 6 Gris JC, Branger B, Vecina F, al-Sabadani B, Fourcade J, Schved JF. Increased cardio-vascular risk factors and features of endothelial activation and dysfunction in dialyzed uremic patients. Kidney Int 1994; 46: 807-813
    CrossrefPubMedGoogle Scholar
  • 7 Wagner DD. Cell biology of von Willebrand factor. Ann Rev Cell Biol 1990; 06: 217-246
    CrossrefPubMedGoogle Scholar
  • 8 Bowie EJW, Solberg LA, Fass DN, Johnson CM, Knutson GJ, Stewart ML, Zoecklein LJ. Transplantation of normal bone marrow into a pig with severe von Willebrand disease. J Clin Invest 1986; 78: 26-30
    CrossrefPubMedGoogle Scholar
  • 9 Birch KA, Pober JS, Zavoico GB, Means AR, Ewenstein BM. Calcium/ calmodulin transduces thrombin-stimulated secretion:studies in intact and minimally permeabilized human umbilical vein endothalial cells. J Cell Biol 1992; 118: 1501-1510
    CrossrefPubMedGoogle Scholar
  • 10 Ribes JA, Francis CW, Wagner DD. Fibrin induces release of von Willebrand factor from endothelial cells. J Clin Invest 1987; 79: 117-123
    CrossrefPubMedGoogle Scholar
  • 11 Hamilton KK, Sims PJ. Changes in cytosolic Ca2+associated with von Willebrand factor release in human endothelial cells exposed to histamine. J Clin Invest 1987; 79: 600-608
    CrossrefPubMedGoogle Scholar
  • 12 Foreman KE, Vaporciyan AA, Bonish BK, Jones ML, Johnson KJ, Glovsky MM, Eddy SM, Ward PA. C5a-induced expression of P-selectin in endothelial cells. J Clin Invest 1994; 94: 1147-1155
    CrossrefPubMedGoogle Scholar
  • 13 Rickies FR, Hoyer LW, Rick ME, Ahr DJ. The effects of epinephrine infusion in patients with von Willebrand ’s disease. J Clin Invest 1976; 57: 1618-1625
    CrossrefPubMedGoogle Scholar
  • 14 Eyster ME, Ballard JO, Prager D. Comparison of factor VIII levels after adrenalin in classic hemophilia and von Willebrand’s disease. Thromb Haemost 1978; 39: 657-662
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Mannucci PM. Desmopressin:a nontransfusional form of treatment for congenital anad acquired bleeding disorders. Blood 1988; 72: 1449-1455
    PubMedGoogle Scholar
  • 16 Ingerslev J. A sensitive ELISA for von Willebrand factor (vWf:Ag). Scand J Lab Clin Med 1987; 47: 143-149
    PubMedGoogle Scholar
  • 17 Sporn LA, Marder VJ, Wagner DD. Differing polarity of the constitutive and regulated secretory pathways for von Willebrand factor in endothelial cells. J Cell Biol 1989; 108: 1283-1289
    CrossrefPubMedGoogle Scholar
  • 18 Stel HV, Sakariassen KS, de GrootPG, van MourikJA, Sixma JJ. von Willebrand factor in the vessel wall mediates platelet adherence. Blood 1985; 65: 85-90
    PubMedGoogle Scholar
  • 19 Moake JL, Turner NA, Stathopoulos NA, Nolasco LH, Heliums JD. Involvement of large plasma von Willebrand factor multimers and unusually large vWf forms derived from endothelial cells in shear stress-induced platelet aggregation. J Clin Invest 1986; 78: 1456-1461
    CrossrefPubMedGoogle Scholar
  • 20 Silveira AM, Elgue G, Hamsten A, Blomback M. von Willebrand factor in plasma and urine of men with premature coronary artery disease. Thromb Haemost 1992; 67: 161-165
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Gill JC, Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR. The effect of ABO blood group on the diagnosis of von Willebrand disease. Blood 1987; 69: 1691-1695
    CrossrefPubMedGoogle Scholar
  • 22 Matsui T, Fujimura Y, Nishida S, Titani K. Human plasma α2-macroglobulin and vonWillebrand factor possess covalently linked ABO (H) blood group antigens in subjects with corresponding ABO phenotype. Blood 1993; 82: 663-668
    PubMedGoogle Scholar
  • 23 Montgomery RR, Coller BS. von Willebrand disease. In: Coleman RW, Hirsch J, Marder VJ, Salzman EW. eds. Hemostasis and thrombosis:basic principles and clinical practice, 3d Edition. Lippincott Company; Philadelphia: 1994. p 134
    Google Scholar
  • 24 Vischer UM, Wagner DD. von Willebrand factor proteolytic processing and multimerization preceed the formation of Weibel-Palade bodies. Blood 1994; 83: 3536-3544
    CrossrefPubMedGoogle Scholar
  • 25 Wagner DD, Fay PJ, Spom LA, Sinha S, Lawrence SO, Marder VJ. Divergent fates of von Willebrand factor and its propolypeptide (von Willebrand antigen II) after secretion from endothelial cells. Proc Natl Acad Sci 1987; 84: 1955-1959
    CrossrefPubMedGoogle Scholar
  • 26 McCarroll DR, Ruggeri ZM, Montgomery RR. Correlation between circulating levels of von Willebrand’s antigen II and von Willebrand factor:discrimination between type I and Type II von Willebrand’s disease. J Lab Clin Med 1984; 103: 704-711
    PubMedGoogle Scholar
  • 27 Wagner DD, Lawrence SO, Ohlsson-Wilhelm BM, Fay PJ, Marder VJ. Topology and order of formation of interchain disulfide bonds in von Willebrand factor. Blood 1987; 69: 27
    CrossrefPubMedGoogle Scholar
  • 28 Vischer UM, Wagner DD. CD63 is a component of Weibel-Palade bodies of human endothelial cells. Blood 1993; 82: 1184
    PubMedGoogle Scholar
  • 29 Fay PJ, Smudzin TM. Topography of the human factor VUI-von Willebrand factor complex. J Biol Chem 1990; 265: 6197
    PubMedGoogle Scholar
  • 30 Vischer UM, Jomot L, Wollheim CB, Theler JM. Reactive oxygen intermediates induce regulated secretion of von Willebrand factor from cultured human vascular endothelial cells. Blood 1995; 85: 3164-3172
    PubMedGoogle Scholar
  • 31 Tsakiris DA, Haefeli WE, Linder L, Steiner B, Marbet GA. Platelet surface activation markers after DDAVP infusion in healthy subjects. Thromb Haemost 1995; 74: 991-992
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Spom LA, Marder VJ, Wagner DD. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell 1986; 46: 185-190
    CrossrefPubMedGoogle Scholar
  • 33 Ewenstein BM, Warhol MJ, Handin RI, Pober JS. Composition of the von Willebrand factor storage organelle (Weibel-Palade body) isolated from cultured human umbilical vein endothelial cells. J Cell Biol 1987; 104: 1423-1433
    CrossrefPubMedGoogle Scholar
  • 34 Mayadas TN, Johnson RC, Raybum H, Hynes RO, Wagner DD. Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 1993; 74: 541-554
    CrossrefPubMedGoogle Scholar
  • 35 Hattori R, Hamilton KK, Fugate RD, McEver RP, Sims PJ. Stimulated secretion of endothelial von Willebrand factor is accompanied by rapid redistribution to the cell surface of the intracellular granule membrane protein GMP140. J Biol Chem 1989; 264: 7768-7671
    PubMedGoogle Scholar
  • 36 McCarroll DR, Ruggeri ZM, Montgomery RR. The effect of DDAVP on plasma levels of von Willebrand antigen II in normal individuals and patients with von Willebrand’s disease. Blood 1984; 63: 532-535
    PubMedGoogle Scholar