CONTENTS  •  Volume 13  Number 3   1998

Editorial

Original Articles

87    Risk of and Prophylaxis for Venous Thromboembolism in Hospital Patients
Second Thromboembolic Risk Factors (THRiFT II) Consensus Group

98    The Effect of Compression on Venous Haemodynamics Assessed by Quantitative Photoplethysmography 
A. Fronek, M. Goldman and K. Fronek

102   Effect of Compression Stockings on Leg Volume in Patients with Varicose Veins 
U. Müller-Bühl, B, Heim, U. Fischbach, J. Windeler, Th. Finkenstädt and M. Schläfer

107   Design of Randomized Controlled Trials in the Treatment of Leg Ulcers:  More Answers with Fewer Patients
R. J. Prescott, E. A. Nelson, J. J. Dale, D. R. Harper and C. V. Ruckley

113   Expression and Distribution of Laminin, Fibronectin and Tenascin is Stage Dependently Modulated in the Skin of Chronic Venous Insufficiency
M. Peschen, A. Schild, B. Brand-Saberi, A. A. Rogers, M. Augustin, E. Schöpf and W. Vanscheidt

120   Higher Migratory Activity of Arterial Smooth Muscle Cells than of Venous Smooth Muscle Cells on Different Collagen Matrices
S. Jimi, S. Takebayashi, S. Ryu, K. Saku and N. Sakata

Obituary

Letters

Book Review

Philip D. Coleridge Smith

Another consensus document on DVTs and their prevention I hear you say? Do we need this? I believe we do! Technology marches on and we are encouraged to base our use of treatment on hard clinical evidence obtained from controlled clinical trials. The development of low molecular weight heparins (LMWHs) has necessitated the conduct of more clinical trials to assess the efficacy of these drugs in comparison to unfractionated heparin. Many large trials have been undertaken to study infrequent events, such as pulmonary embolism. Advantages have been shown for the new generation of heparins in a number of areas. In particular, orthopaedic surgery prophylaxis shows advantages for the LMWHs. Fewer DVTs occur with the new generation of heparins. The advantages of these drugs have yet to be clearly demonstrated in the case of general surgery. Of course, our medical colleagues also have problems with DVTs following treatment of their patients, especially following strokes and myocardial infarction. The frequency of these events have been investigated but few studies in the prevention of venous thrombosis have been performed. Where patients have had a stroke there is concern about the use of anticoagulants in the minds of many physicians. This has yet to be studied in detail in a clinical trial. The cost of developing a new drug is substantial, perhaps US$300 million. Therefore it is not surprising that new drugs are expensive following their initial launch. However, prices of LMWHs have fallen since their initial marketing and are now in widespread use. Perhaps one advantage is that prophylaxis may be given once a day. Hard pressed healthcare systems, for example in the UK, find it difficult to recruit sufficient nurses to care for patients in hospitals and therefore any advance which reduces the demands on the level of nursing care is seen as an advantage.

So when should we replace the old drugs with new ones? Who should decide which is the best course of action? The pharmaceutical industry tries to persuade us that any new drug is a major advance, which is the line that they hold with the regulatory authorities. For drugs such as cimetidine and ranitidine for the management of peptic ulceration there is little doubt that these were a major advance, and the number of patients subjected to surgery for these conditions has fallen dramatically as a result. In the case of DVT prevention, where there are sometimes voices that call into doubt the need for prophylaxis at all [11, then the evidence must be reviewed carefully. This has been undertaken in the THRiFT document by a panel who have read much of the world literature in this area and reached an informed opinion. What is the need for the ‘improved’ heparin and how will it modify our surgical practice? Whilst unfractionated heparin reduced the risk of DVT and pulmonary embolism it certainly did not totally eliminate the risk of these complications. Surgical procedures such as lower limb arthroplasty where the risks are highest would benefit most of all from new prophylactic drugs. Orthopaedic surgeons are concerned about the risk of haematoma following operation which might lead to loss of the prosthetic joint. An improved drug here would be of tangible benefit. To my mind, one of the greatest advantages of LMWHs is their use in the treatment of established DVT. There is growing evidence that the use of too little heparin in the initial phases of treatment is associated with a worse outcome (more recurrences of DVT) than no treatment at all! When unfractionated heparin is given by IV infusion, the anticoagulation has to be monitored by blood tests. There is a tendency to under-anticoagulation. With LMWHs the drug may be given subcutaneously on a weight adjusted basis ensuring adequate anticoagulation without the need for blood tests. This seems more likely to ensure that initial under-anticoagulation is avoided. These issues are not discussed in the THRiFT document but remain important in the use of LMWHs.

The authors of the THRiFT document are recognized experts in their field, but perhaps they are influenced by the might of the pharmaceutical industry. Examination of the document confirms that their conclusions and advice are based on the results of clinical trials and that these are clear cut. Where no published data is available to answer a particular point this is acknowledged and recommendations made on the basis of available data. The major conclusions from the document are that DVTs and pulmonary embolism remain a problem and that this would best he addressed by a local policy of management of patients in hospital to ensure that patients are not omitted from consideration for prophylaxis, which seems

to be the most common reason for failure of prophylaxis. Readers are recommended to study the THRiFT document and extract those parts of it relevant to their clinical practice and consider how their current methods could be revised.

1. Murray AW, Britton AR. Bulstrode CJ. Thromboprophlaxis and death after total hip replacement. J Bone Joint Surg 1996;78:863-70.

Contents

Second Thromboembolic Risk Factors (THRiFT II) Consensus Group*
(*The Thromboembolic Risk Factors Consensus Group comprised: J. Scurr, Lister Hospital, London; T. Baglin, Addenbrooke’s NHS Trust, Cambridge; H. Burns. Department of Public Health Glasgow: R. V. Clements, Harley Street, London: 1. Cooke. Royal Infirmary, Glasgow; M. de Swiet. Queen Charlotte’s & Chelsea Hospital, London; E. Paxton Dewar, Airedale General Hospital. Keighley; C. Forbes, Ninewells Hospital, Dundee; S. Frostick, Royal Liverpool University Hospital. Liverpool: I. Greer, Royal Infirmary, Glasgow: R. Hobbs, University of Birmingham: T. Jenkins, Stoke Mandeville Hospital, Aylesbury; L. Klein, South Cheshire Health Authority; D. Lanigan. Bon Secours Hospital, Cork, Ireland; G. Lowe, Royal Infirmary. Glasgow;  D. Warwick, Avon Orthopaedic Centre, Bristol; J. Wilson, Heatherwood & Wexham Park Hospital, Wexham)

Objective: To review the published clinical data on prophylaxis for thromboembolism in order to develop general guidelines to encourage the establishment of local protocols for management.

Data sources: Published papers on thromboembolism over the period 1991—1997 were identified by Medline search and/or from the authors’ personal literature collections and reviewed.

Study selection: A total of 981 studies were identified. Only those papers reporting randomized studies with clearly defined diagnostic methods and clear end-points were included in this review.

Data extraction: The available evidence for each specialty was summarized and reviewed by the authors responsible for each specialty, prior to presentation and discussion of their findings within the group. Where a consensus opinion was achieved in a speciality, general guidelines for thromboprophylaxis were summarized. Where a consensus could not be agreed, recommendations for further work were made.

Data synthesis: There is evidence to support the preferred use of low-molecular-weight heparins (LMWHs) over unfractionated heparin (UFH) in orthopaedic surgery. major trauma and general surgery. However, the ideal duration of thromboprophylaxis has yet to be defined. The use of once daily subcutaneous administration of LMWH offers major practical advantages and may have significant cost saving implications. Further work is required to investigate the use of thromboprophylaxis in minimal access surgery, trauma, elective lower limb surgery, hip fracture and pregnancy; to compare the efficacy of LMWH and mechanical prophylaxis: and to investigate extended prophylaxis after discharge.

Conclusions: There is overwhelming evidence that thromboembolic prophylaxis reduces the incidence of postoperative deep vein thrombosis and pulmonary embolism. Recommendations concerning the management of these patients when stratified into low, moderate and high risk are made with the suggestion that hospitals develop their own guidelines for the treatment of’ these patients.

Keywords: Deep vein thrombosis; Guidelines; Lowmolecular-weight heparin; Prophylaxis for thromboembolism: Pulmonary embolism

correspondence and offprint requests to: Mr John Scurr. Department of Surgery, Lister Hospital. Chelsea Bridge Road, London SW 1W 8RH. UK.

Contents

A. Fronek^1,2, M. Goldman³ and K. Fronek²
Departments of ¹Surgery. ²Bioengineering and Dermatology, University of California San Diego, La Jolla, California, USA

Background: The purpose of this study was to examine quantitatively the effect of compression stockings on venous haemodynamics at the level of the ankle.

Methods: To obtain quantifiable results, a computer-controlled photoplethysmographic system was used to measure the displacement of local blood volume induced by exercise (exercise displacement volume, EDV) and by tilting the subject (tilt displacement volume. TDV). The test was repeated after application of class I compression stockings 20-30 mmHg). The ratio EDV/TDV is considered to represent the efficiency of the veno-muscular pump. Three groups of subjects were studied: a control group (n = 8), patients with telangiectases (n = 10) and a group with large varices (n = 11).

Results: The application of external compression had a quantifiable and beneficial effect on venous haemodynamics and was most significantly documented by an increase in veno-muscular efficiency (EDV/TDV) from 28% to 44% in the varicose vein patients. Statistically significant increases of EDV/TDV could also be identified in the telangiectatic patients and normal subjects. EDV also showed an increase with compression stockings; however, statistical significance was only reached in the varicose vein group.

Conclusion: External compression (class 1 compression stockings) significantly improved venous haemodynamic indices, especially in patients with varicose veins. Quantitative photoplethysmography used in this study permits a fast, non-invasive and quantifiable evaluation of venous haemodynamics of the lower extremities.

Keywords: Compression therapy: Quantitative photoplethysmography; Venous haemodynamics

correspondence and offprints requests to: A. Fronek. MD. PhD.
Department of Surgery, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093—0643. USA.

Contents

U. Müller-Bühl¹, B. Helm¹, U. Fischbach². J. Windeler³, Th. Finkenstädt⁴ and M. Schläfer⁵
Departments of ¹General Medicine and ³Mcdical Biometry, University of Heidelberg. ²Department of Physics, University of Wuppertal, and ⁴Federal School for Orthopaedic Technology and ⁵Federal Society of Orthopaedic Technologies, Dortmund, Germany

Objective: To evaluate the effect of thigh-length compression stockings on the venous blood pool and interstitial oedema in patients with varicose veins.

Setting: Department of General Medicine. University of Heidelberg. Germany.

Patients: Forty-six patients with unilateral long saphenous varicose veins.

Main outcome measures: The effects of compression stockings on optoelectronically measured volumes of normal legs and legs with varicose veins in supine and upright positions.

Results: Changing body position from a supine to an upright position leads to an increased leg volume by venous blood pooling (236.5 ml and 255.5 ml, respectively, p<0.001). The volume difference between normal legs and legs with varicose veins in the supine position was 172.5 ml, and in the upright position 187.0 ml (p<0.00l). After putting on compression thigh-length stockings. The volume of both normal legs and legs with varicose veins decreased by 314.5 ml and 358.0 ml (acute compression effect). Elastic compression for 8 h produced no significant additional reduction in the leg volumes. Wearing the stockings for 7 successive days failed to reduce the volume in the normal legs. whereas a further reduction in the legs with varicose veins was measured (supine position 61.0 ml. p<0.05; upright position 72.0 nil, p <0.05) (long-term compression effect).

Conclusions: Wearing compression stockings rapidly reduces venous blood pools of the legs. Long-term wear is necessary to mobilize the interstitial limb oedema in patients with superficial venous insufficiency.

Keywords: Compression stockings; Leg volume measurement; Oedema quantification; Varicose veins

Correspondence and offprint requests to: Uwe Müllcr-BühI, MD.
Department of General Medicine. University of Heidelberg. Bergheimer Str. 147. 69115 Heidelberg, Germany. 

Contents

Design of Randomized Controlled Trials in the Treatment of Leg Ulcers: More Answers with Fewer Patients

R. J. Prescott¹, E. A. Nelson². J. J. Dale³. D. R. Harper⁴ and C. V. Ruckley^3
1Medical Statistics Unit, University of Edinburgh, Edinburgh, ²Dcpartment of Health Sciences and Clinical Evaluation. University of York, York, ³Vascular Surgery Unit, Royal Infirmary of Edinburgh. Edinburgh and ⁴Department of Surgery.  Falkirk and District Royal Infirmary, Falkirk, UK

Objective: To illustrate the benefit of the factorial design in randomized controlled trials of leg ulcers.

Design: A 2 x 2 x 2 factorial design.

Setting: Hospital leg ulcer clinics in Edinburgh and Falkirk.

Patients: Adults with at least one unhealed leg ulcer of determined origin, present for at least 2 months and greater than 1 cm in diameter.

Interventions: Pentoxifylline (Trental) 400 mg, three times daily. versus placebo; single-layer versus multi-layer bandage; a hydrocolloid versus knitted viscose dressing.

Main outcome measure: Complete healing of all ulcers within 24 weeks.

Results: Of 525 patients screened, 200 pure venous ulcers were randomized (58.5% healed by 24 weeks), 45 complex venous ulcers were randomized (57.8% healed) and 41 arterial patients were randomized (excluding bandaging comparisons) (19.5% healed). There were no interactions between treatments.

Conclusion: The factorial design was feasible to administer and allowed three therapeutic questions to be investigated using the same resources as would have been needed to answer a single question.

Keywords: Bandages; Dressings: Drug therapy; Factorial design; Leg ulcer; Randomized controlled trials; Research design; Treatment protocols

Correspondence and offprint requests to: R. J. Prescott, Medical Statistics Unit. University of Edinburgh, Medical School. Teviot Place, Edinburgh EH8 9AG. UK.

Contents

M. Peschen¹, A. Schild¹, B. Brand-Saberi², A. A. Rogers³. M. Augustin¹, E. Schöpf¹ and W. Vanscheidt¹
Departments of ¹Dermatology and ²Anatomy, University of Freiburg, Germany and ³Convatec Wound Healing Research Institute, Deeside. UK

Objective: The regulation of tissue remodelling is a function of extracellular matrix (ECM) deposition. Our aim was to determine the expression and distribution pattern of the ECM proteins laminin, fibronectin and tenascin in all stages of chronic venous insufficiency (CVI) from telangiectases to ulceration.

Methods: In punch biopsies of 25 patients with various stages of CVI and five healthy volunteers, ECM proteins were stained using indirect immunofluroescence. The staining pattern in the affected skin was evaluated by two independent, double-blinded investigators by microscopic examination.

Results: In specimens of healthy skin or skin with telangiectases or pigmentation. a faint and partly inhomogeneous ECM staining pattern was detected in the upper dermis. In venous eczema, lipodermatosclerosis and venous leg ulcers, an increased expression and a wide-meshed distribution pattern throughout the dermis was observed for laminin, fibronectin and tenascin. Fragmentation of ECM components was first observed in venous eczema, persisting in the more severe stages of CVI. Laminin staining revealed unusual streak-like distributions in the papillary dermis, pronounced in pigmentation and lipodermatosclerosis and diminished in leg ulcers.

Conclusions: Our results indicate an important role of laminin, fibronectin and tenascin, and in particular of their proteolytic fragments, in the early phases of CVI, such as venous eczema, by creating permissive environments for cell migration and differentiation. essential for wound healing.

Keywords: Chronic venous insufficiency; Extracellular matrix; Fibronectin; Laminin; Microcirculation; Tenascin

Correspondence and offprint requests to: M. Peschen, Department of Dermatology, University of Freihurg, Hauptstr. 7, 79104 Freiburg, Germany.

Tel; 49-761-270’6701; Fax: 49.761-270-6818; c-mail:  Peschen@haut.ukl.uni-freiburg.de

Contents

S. Jimi, S. Takebayashi. S. Ryu, K. Saku and N. Sakata
Departments of Pathology and Internal Medicine, School of Medicine. Fukuoka University. Fukuoka, Japan

Design: Migratory activities of porcine arterial and venous smooth muscle cells (SMCs) were compared by a modified Boyden chamber method using coated filters with type 1, III, IV and V collagens.

Results: At the basal level of migration activity without stimulation, arterial SMCs showed greater migratory activity than venous SMCs in all of the substrata. When platelet-derived growth factor was added to the lower wells, all of the migration activities increased, and arterial SMCs showed significantly higher activity than venous SMCs. When cell-associated fibronectin was determined by an enzyme-linked immunoassay and immunohistochemistry, arterial SMCs secreted significantly more cell-associated fibronectin than venous SMCs. Type IV collagen had the greatest positive effect, and also induced the lowest level of cell-associated fibronectin.

Conclusion: These in-vitro results indicate that fibronectin secreted by vascular smooth muscle is an important regulatory protein for cell migration even when SMCs migrate on collagen substrates. Arterial SMCs have higher migratory activities than venous SMCs as a result of their lower production of fibronectin.

Keywords: Artery; Collagen; Fibronectin: Migration; Smooth muscle cells; Vein

Tel: +81-92-801-1011 (ext. 3285); Fax: +81-92-863-8383; e-mail:   mm036938@msat.fukuoka-u.ac.jp

Contents

Copyright © 2000 Philip Coleridge Smith