Download PDF
Thromb Haemost 2000; 84(02): 195-203
DOI: 10.1055/s-0037-1613996
Review Article
Schattauer GmbH

Local and Systemic Effects of Intra-arterial Desmopressin in Healthy Volunteers and Patients with Type 3 von Willebrand Disease

Role of Interleukin-6
David E. Newby
1   From the Clinical Pharmacology Unit and Research Centre, Edinburgh, UK
2   Cardiovascular Research, Department of Cardiology, Edinburgh, UK
,
Andrew Stewart
3   Department of Haematology, University of Edinburgh, Western General Hospital, Edinburgh, UK
,
Fraser N. Witherow
2   Cardiovascular Research, Department of Cardiology, Edinburgh, UK
,
Susan Grieve
2   Cardiovascular Research, Department of Cardiology, Edinburgh, UK
,
Pamela Dawson
3   Department of Haematology, University of Edinburgh, Western General Hospital, Edinburgh, UK
,
Keith A. A. Fox
2   Cardiovascular Research, Department of Cardiology, Edinburgh, UK
,
David J. Webb
1   From the Clinical Pharmacology Unit and Research Centre, Edinburgh, UK
,
Christopher A. Ludlam
3   Department of Haematology, University of Edinburgh, Western General Hospital, Edinburgh, UK
› Author AffiliationsThis work was supported by the British Heart Foundation. DJW is supported by a Research Leave Fellowship from the Wellcome Trust (WT 0526330).
Further Information

Publication History

Received 26 January 2000

Accepted after revision 16 March 2000

Publication Date:
14 December 2017 (online)

    Permissions and Reprints

Summary

Intra-arterial desmopressin caused dose and time dependent increases (p <0.001 for all) in forearm blood flow (all doses) and plasma tissue plasminogen activator (t-PA) concentrations (desmopressin ≥70 ng/min). Although plasma t-PA concentrations rose in both forearms, there was a modest local release of t-PA in the infused forearm (14 ng/100 mL of tissue/min, p <0.05). At desmopressin doses ≥300 ng/min, plasma von Willebrand factor (vWf) and Factor VIII:C concentrations rose in both forearms (p <0.001) and correlated with the rise in interleukin-6 concentrations (r = 0.92, p <0.001; r = 0.85, p = 0.002 respectively). Neither desmopressin nor substance P caused t-PA, vWf or Factor VIII:C release in the patients, although desmopressin increased plasma interleukin-6 concentrations as in healthy volunteers. We conclude that desmopressin releases t-PA, vWf and Factor VIII:C predominantly via systemic mechanisms, possibly mediated by cytokine release. Patients with type 3 vWD appear to have a generalised failure to release t-PA acutely despite a normal interleukin-6 response to desmopressin infusion.

Keywords

Plasminogen activators - desmopressin - von Willebrand factor - interleukin-6 - factor VIII:C
 

  • References

  • 1 Cash JD, Gader AMA, de Costa J. The release of plasminogen activator and factor VIII by LVP, AVP, DDAVP, AT III, and OT in man. Br J Haematol 1974; 27: 363-4.
    PubMedGoogle Scholar
  • 2 Mannucci PM, Åberg M, Nilsson IM, Robertson B. Mechanism of plasminogen activator and factor VIII increase after vasoactive drugs. Br J Haematol 1975; 30: 81-93.
    CrossrefPubMedGoogle Scholar
  • 3 Mannucci PM. Treatment of von Willebrand disease. Haemophilia 1998; 04: 661-4.
    CrossrefPubMedGoogle Scholar
  • 4 Castaman G, Lattuada A, Mannucci PM, Rodeghiero F. Factor VIII:C increases after desmopressin in a subgroup of patients with autosomal recessive severe von Willebrand disease. Br J Haematol 1995; 89: 147-51.
    CrossrefPubMedGoogle Scholar
  • 5 Hashemi S, Tackaberry ES, Palmer DS, Rock G, Ganz PR. DDAVP-induced release of von Willebrand factor from endothelial cells in vitro: the effect of plasma and blood cells. Biochim Biophys Acta 1990; 1052: 63-70.
    CrossrefPubMedGoogle Scholar
  • 6 Hashemi S, Palmer DS, Aye MT, Ganz PR. Platelet-activating factor secreted by DDAVP-treated monocytes mediates von Willebrand factor release from endothelial cells. J Cell Physiol 1993; 154: 496-505.
    CrossrefPubMedGoogle Scholar
  • 7 Grant MB, Guay C, Lottenberg R. Desmopressin stimulates parallel norepinephrine and tissue plasminogen activator release in normal subjects and patients with diabetes mellitus. Thromb Haemost 1988; 59: 269-72.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Cash JD, Gader AMA, Mulder JL, Cort JH. Structure-activity relations of the fibrinolytic response to vasopressins in man. Clin Sci Mol Med 1978; 54: 403-9.
    PubMedGoogle Scholar
  • 9 Newby DE, Sciberras DG, Ferro CJ, Gertz BJ, Sommerville D, Majmadar A, Lowry RC, Webb DJ. Substance P induced vasodilatation is mediated by the neurokinin type 1 receptor but does not contribute to basal vascular tone in man. Br J Clin Pharmacol 1999; 48: 336-44.
    PubMedGoogle Scholar
  • 10 Jern S, Selin L, Bergbrant A, Jern C. Release of tissue-type plasminogen activator in response to muscarinic receptor stimulation in human forearm. Thromb Haemost 1994; 72: 588-94.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 11 Wall U, Jern S, Tengborn L, Jern S. Evidence of a local mechanism for desmopressin-induced tissue-type plasminogen activator release in human forearm. Blood 1998; 91: 529-37.
    PubMedGoogle Scholar
  • 12 Newby DE, Wright RA, Ludlam CA, Fox KAA, Boon NA, Webb DJ. An in vivo model for the assessment of the acute fibrinolytic capacity of the endothelium. Thromb Haemost 1997; 78: 1242-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Newby DE, Wright RA, Dawson P, Ludlam CA, Fox KAA, Boon NA, Webb DJ. The L-arginine:nitric oxide pathway contributes to the acute release of tissue plasminogen activator in vivo in man. Cardiovasc Res 1998; 38: 485-92.
    CrossrefPubMedGoogle Scholar
  • 14 Newby DE, Wright RA, Labinjoh C, Ludlam CA, Fox KAA, Boon NA, Webb DJ. Endothelial dysfunction, impaired endogenous fibrinolysis and cigarette smoking: a mechanism for arterial thrombosis and myocardial infarction. Circulation 1999; 99: 1411-5.
    CrossrefPubMedGoogle Scholar
  • 15 Sporn LA, Marder VJ, Wagner DD. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell 1986; 46: 185-90.
    CrossrefPubMedGoogle Scholar
  • 16 Nusinow SR, Federici AB, Zimmerman TS, Curd JG. Increased von Willebrand factor antigen in the plasma of patients with vasculitis. Arthritis Rheum 1984; 27: 1405-10.
    CrossrefPubMedGoogle Scholar
  • 17 Kahaleh MB, Osborn I, LeRoy EC. Increased factor VIII/von Willebrand factor antigen and von Willebrand factor activity in scleroderma and in Raynaud’s phenomenon. Ann Intern Med 1981; 94: 482-4.
    CrossrefPubMedGoogle Scholar
  • 18 Blann AD, McCollum CN. von Willebrand factor, endothelial cell damage and atherosclerosis. Eur J Vasc Surg 1994; 08: 10-5.
    CrossrefPubMedGoogle Scholar
  • 19 Haverkate F, Thompson SG, Duckert F. Haemostasis factors in angina pectoris; relation to gender, age and acute phase reaction results of the ECAT angina pectoris study group. Thromb Haemost 1995; 73: 561-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo 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: 635-41.
    CrossrefPubMedGoogle Scholar
  • 21 Stirling D, Hannant WA, Ludlam CA. Transcriptional activation of the factor VIII gene in liver cell lines by interleukin-6. Thromb Haemost 1998; 79: 74-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Wegenka UM, Buschmann J, Lutticken C, Heinrich PC, Horn F. Acutephase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the post-transcriptional level. Mol Cell Biol 1993; 13: 276-88.
    CrossrefPubMedGoogle Scholar
  • 23 Webb DJ. The pharmacology of human blood vessels in vivo. J Vasc Res 1995; 32: 2-15.
    CrossrefPubMedGoogle Scholar
  • 24 Benjamin N, Calver A, Collier J, Robinson B, Vallance P, Webb D. Measuring forearm blood flow and interpreting the responses to drugs and mediators. Hypertension 1995; 25: 918-23.
    CrossrefPubMedGoogle Scholar
  • 25 Wiinberg N, Walter-Larson S, Eriksen C, Nielsen PE. An evaluation of semi-automatic blood pressure manometers against intra-arterial blood pressure. J Ambulatory Monitoring 1988; 01: 303-9.
    PubMedGoogle Scholar
  • 26 Kluft C, Verheijen JH. Leiden fibrinolysis working party: blood collection and handling procedures for assessment of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Fibrinolysis 1990; 04 (Suppl. 02) 155-61.
    PubMedGoogle Scholar
  • 27 Olsen JD, Brockway WJ, Fass DN. Evaluation of ristocetin – von Willebrand factor assay and ristocetin-induced platelet aggregation. Am J Clin Path 1975; 63: 210-8.
    CrossrefPubMedGoogle Scholar
  • 28 Kerslake DMcK. The effect of the application of an arterial occlusion cuff to the wrist on the blood flow in the human forearm. J Physiol (Lond) 1949; 108: 451-7.
    CrossrefPubMedGoogle Scholar
  • 29 Labinjoh C, Newby DE, Dawson P, Johnston NR, Ludlam CA, Boon NA, Webb DJ. Fibrinolytic actions of intra-arterial angiotensin II and bradykinin in vivo in man. Cardiovasc Res. 2000 in press..
    PubMedGoogle Scholar
  • 30 Medina P, Segarra G, Vila JM, Chuan P, Domenech C, Lluch S. V-receptor-mediated relaxation of human renal arteries in response to desmopressin. Am J Hypertens 1999; 12: 188-93.
    PubMedGoogle Scholar
  • 31 Aldasoro M, Medina P, Vila JM, Otero E, Martinez-Leon JB, Lluch S. Endothelium-dependent relaxation of human saphenous veins in response to vasopressin and desmopressin. J Vasc Surg 1997; 25: 696-703.
    CrossrefPubMedGoogle Scholar
  • 32 Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Büller HR, van Deventer SJH, Hack E, ten Cate JW, Rosenberg RD. Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue antibody in chimpanzees. J Clin Invest 1994; 93: 114-20.
    CrossrefPubMedGoogle Scholar
  • 33 Biemond BJ, Levi M, ten Cate H, van der Poll T, Büller HR, Hack CE, ten Cate JW. Plasminogen activator and plasminogen activator inhibitor 1 release during experimental endotoxaemia in champanzees: effect of interventions in the cytokine and coagulation cascades. Clin Sci 1995; 88: 587-94.
    CrossrefPubMedGoogle Scholar
  • 34 Kruithof EKO, Mestries JC, Gascon MP, Ythier A. The coagulation and fibrinolytic responses of baboons after in vivo thrombin generation – effect of interleukin 6. Thromb Haemost 1997; 77: 905-10.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 35 van der Poll T, Levi M, Büller HR, van Deventer SJH, de Boer JP, Hack E, ten Cate JW. Fibrinolytic response to tumour necrosis factor in healthy subjects. J Exp Med 1991; 174: 729.
    CrossrefPubMedGoogle Scholar
  • 36 van Hinsbergh VWM, Bauer KA, Kooistra T, Kluft C, Dooijewaard G, Sherman ML, Nieuwenhuizen W. Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products. Blood 1990; 76: 2284-9.
    PubMedGoogle Scholar
  • 37 Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissue of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 1998; 83: 847-50.
    PubMedGoogle Scholar
  • 38 Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin JS, Klein S, Coppack SW. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo. J Clin Endocrinol Metab 1997; 82: 4196-200.
    PubMedGoogle Scholar
  • 39 Ludlam CA, Peake IR, Allen N, Davies BL, Furlong RA, Bloom AL. Factor VIII and fibrinolytic response to deamino-8-d-arginine vasopressin in normal subjects and dissociate response in some patients with haemophilia and von Willebrand disease. Br J Haematol 1980; 45: 499-511.
    CrossrefPubMedGoogle Scholar
  • 40 Wieczorek I, Ludlam CA, MacGregor IR. Study of endothelial t-PA and vWf in normal subjects and in von Willebrand disease. Blood Coagul Fibrinolysis 1994; 05: 329-34.
    PubMedGoogle Scholar
  • 41 Nilsson IM, Vilhardt H, Holmberg L, Astedt B. Association between factor VIII related antigen and plasminogen activator. Acta Med Scand 1982; 211: 105-12.
    PubMedGoogle Scholar