Thromb Haemost 1992; 67(02): 203-208
DOI: 10.1055/s-0038-1648413
Original Articles
Schattauer GmbH Stuttgart

A Randomised, Double-Blind, Placebo-Controlled Trial of Dermatan Sulphate for Prevention of Deep Vein Thrombosis in Hip Fracture

Giancarlo Agnelli
1   The istituto di Semeiotica Medica, Perugia, Italy
,
Benilde Cosmi
1   The istituto di Semeiotica Medica, Perugia, Italy
,
Paolo Di Filippo
2   Istituto di Ortopedia e Traumatologia, Perugia, Italy
,
Valeria Ranucci
1   The istituto di Semeiotica Medica, Perugia, Italy
,
Franca Veschi
1   The istituto di Semeiotica Medica, Perugia, Italy
,
Mauro Longetti
1   The istituto di Semeiotica Medica, Perugia, Italy
,
Cinzia Renga
1   The istituto di Semeiotica Medica, Perugia, Italy
,
Francesco Barzi
3   Istituto di Radiologia, Università di Perugia, Perugia, Italy
,
Francesco Gianese
4   Medical Department, Mediolanum Farmaceutici, Milan, Italy
,
Luciano Lupattelli
3   Istituto di Radiologia, Università di Perugia, Perugia, Italy
,
Emanuele Rinonapoli
2   Istituto di Ortopedia e Traumatologia, Perugia, Italy
,
Giuseppe G Nenci
1   The istituto di Semeiotica Medica, Perugia, Italy
› Author Affiliations
Further Information

Publication History

Received 25 June 1991

Accepted after revision 09 September 1991

Publication Date:
02 July 2018 (online)

Summary

Dermatan sulphate (MF 701) is a natural glycosaminoglycan that catalyses thrombin inhibition by heparin cofactor II. The aim of the study was to evaluate the efficacy and safety of MF 701 for prevention of deep vein thrombosis (DVT) in patients with hip fracture. A randomised, double-blind, placebo-controlled design was used to assess two dose regimens of MF 701 in two consecutive study phases. Treatment was started within 48 h from the trauma and continued for 14 days for non-operated patients or until the 10th postoperative day. Bilateral mandatory venography was used to assess the end-point. Eighty patients were included in the first phase (40 MF 701, 40 placebo). MF 701, 100 mg IM b. i. d., did not reduce incidence of DVT from that on placebo and did not induce any bleeding. In the second phase 126 patients were included, with a randomisation ratio of 2:1 (84 MF 701, 300 mg IM b.i.d., 42 placebo). Bilateral venography was obtained for 110 patients. The incidence of DVT was 64% (23/36) in the placebo group and 38% (28/74) in the MF 701 group (p = 0.01; odds ratio [OR] = 0.34, 95% confidence limits [CL] = 0.15-0.80); proximal DVTs were 42% (15/36) and 20% (15/74), respectively (p = 0.02; OR = 0.36, CL = 0.15-0.89). No significant differences were found in haemorrhagic complications (2.4% in each group), blood loss from drains, blood transfusions, haemoglobin and haematocrit values. This study is the first demonstration that dermatan sulphate is a clinically effective antithrombotic agent without bleeding effects. It also provides evidence of the biological role of heparin cofactor II.

 
  • References

  • 1 Gallus AS. Anticoagulants in the prevention of venous thromboembolism. In: Antithrombotic Therapy. Hirsh J. (ed). Bailliere’s Clinical Haematology. 1990. 3 No. 03 651-684
  • 2 Consensus Conference. Prevention of venous thrombosis and pulmonary embolism. JAMA 1986; 256: 744-749
  • 3 Paiement GD, Wessinger SJ, Harris WH. Survey of prophylaxis against venous thromboembolism in adults undergoing hip surgery. Clin Orthop Rel Res 1987; 223: 188-193
  • 4 Tollefsen DM, Majerus DW, Blank K. Heparin cofactor II: purification and properties of a heparin-dependent inhibitor of thrombin in human plasma. J Biol Chem 1982; 257: 2162-2169
  • 5 Tollefsen DM, Petska CA, Monafo WJ. Activation of heparin cofactor II by dermatan sulfate. J Biol Chem 1983; 258: 6713-6716
  • 6 Fernandez F, Van Ryn J, Ofosu FA, Hirsh J, Buchanan MR. The haemorrhagic and antithrombotic effects of dermatan sulphate. Br J Haematol 1986; 64: 309-317
  • 7 Merton RE, Thomas DP. Experimental studies on the relative efficacy of dermatan sulphate and heparin as antithrombotic agents. Thromb Haemostas 1987; 58: 839-842
  • 8 Maggi A, Abbadini N, Pagella PG, Borowska A, Pangrazzi J, Donati MB. Antithrombotic properties of dermatan sulphate in a rat venous thrombosis model. Haemostasis 1987; 17: 329-335
  • 9 Van Ryn-McKenna J, Gray E, Weber E, Ofosu FA, Buchanan MR. Effects of sulfated polysaccharides on inhibition of thrombus formation initiated by different stimuli. Thromb Haemostas 1989; 61: 7-9
  • 10 Van Ryn-McKenna J, Ofosu FA, Gray E, Hirsh J, Buchanan MR. Effects of dermatan sulfate and heparin on inhibition of thrombus growth “in vivo”. Ann NY Acad Sci 1989; 556: 304-312
  • 11 Agnelli G, Longetti M, Cosmi B, Lupattelli L, Barzi F, Levi M, Nenci GG. Diagnostic accuracy of computerized impedence plethysmography in the diagnosis of symptomatic deep vein thrombosis: a controlled venographic study. Angiology 1990; 41: 559-564
  • 12 Rabinov K, Paulin S. Roentgen diagnosis of venous thrombosis in the leg. Arch Surg 1972; 104: 134-144
  • 13 Hirsh J, Hull RD, Raskob GE. Diagnosis of pulmonary embolism. J Am Coll Cardiol 1986; 8: 128B-36B
  • 14 Dol F, Houin G, Rostin M, Montastruc JL, Dupouy D, Gianese F, Sié P, Boneu B. Pharmacodynamics and pharmacokinetics of dermatan sulfate in humans. Blood 1989; 74: 1577-1582
  • 15 Pocock SJ. Clinical Trials: A Practical Approach. J. Wiley & Sons; Chichester: 1983
  • 16 Dixon WJ. BMDP Statistical Software. University of California Press; Berkeley, CA: 1985
  • 17 Cruickshank MK, Levine MN, Hirsh J, Turpie AGG, Powers P, Jay R, Gent M. An evaluation of impedance plethysmography and 125I-fibrinogen leg scanning in patients following hip surgery. Thromb Haemostas 1989; 62: 830-834
  • 18 Paiement GD, Bell D, Wessinger SJ, Harris WH. New advances in the prevention, diagnosis and cost effectiveness of venous thromboembolic disease in patients with total hip replacement. In: The Hip. Brand RA. (ed). The CV Mosby Company; St. Louis, MO: 1987. pp 94-119
  • 19 Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. N Engl J Med 1988; 318: 1162-1173
  • 20 Moskovitz PA, Ellenberg SS, Feffer HL, Kenmore PI, Neviaser RJ, Rubin BE, Varma VM. Low-dose heparin for prevention of venous thromboembolism in total hip arthroplasty and surgical repair of hip fractures. J Bone Joint Surg (Am) 1978; 60: 1065-1070
  • 21 Sevitt S, Gallagher NG. Prevention of Venous thrombosis and pulmonary embolism in injured patients: a trial of anticoagulant prophylaxis with phenindione in middle-aged and elderly patients with fractured necks of femur. Lancet 1959; 2: 981-989
  • 22 Borgstrom S, Greitz T, van der Linden W, Molin J, Rudies I. Anticoagulant prophylaxis of venous thrombosis in patients with fractured neck of the femur. Acta Chir Scand 1965; 129: 500-508
  • 23 Eskeland G, Solheim K, Skiorten F. Anticoagulant prophylaxis, thromboembolism and mortality in elderly patients with hip fractures. Acta Chir Scand 1966; 131: 16-29
  • 24 Hamilton HW, Crawford JS, Gardiner JH, Wiley AM. Venous thrombosis in patients with fracture of the upper end of the femur: a phlébographie study of the effect of prophylactic anticoagulation. J Bone Joint Surg (Br) 1970; 52: 268-269
  • 25 Morris GK, Mitchell JRA. Warfarin sodium in prevention of deep venous thrombosis and pulmonary embolism in patients with fractured neck of femur. Lancet 1976; 2: 869-872
  • 26 Powers PJ, Gent M, Jay RM, Julian DH, Turpie AGG, Levine M, Hirsh J. A randomized trial of less intense postoperative warfarin or aspirin therapy in the prevention of veneous thromboembolism after surgery for fractured hip. Arch Intern Med 1989; 149: 771-774
  • 27 Kakkar W, Flanc C, Howe CT, Clarke MB. Natural history of postoperative deep vein thrombosis. Lancet 1969; 2: 230-232
  • 28 Dorfman GS, Froehlich JA, Cronan JJ, Urbanek PJ, Herndon JH. Lower-extremity venous thrombosis in patients with acute hip fractures: determination of anatomic location and time of onset with compression sonography. AJR 1990; 154: 851-855