British Medical Bulletin (1978) Vol. 34, No. 2, pp. 201-207



materials that prevent thrombosis and also to therapeutic substances that prevent deposition of fibrin or formed elements on the thrombogenic surface.


1 Historical Review In early research into blood coagulation, William Hewson suggested in 1772 that the solidification of the "coagulable lymph" was initiated by exposure to air (see Gulliver, 1846), a view which was extended by Thackrah (1819) who postulated a "vital influence" in the vessel wall which prevented clotting. This was confirmed, experimentally, by BrQcke (1857) using turtle blood which rapidly clotted in a glazed basin but remained fluid if kept in the isolated heart. In 1863, Joseph Lister, working in Glasgow, confirmed the importance of the type of surface in contact with the blood by allowing blood to clot in an India rubber and glass tube. He then extended these observations in vivo by cannulating the jugular vein of a sheep with a loop of vulcanized India rubber tubing. He recorded that the blood did not coagulate and obstruct the lumen but did form a lining membrane. On the arterial side he also showed that the insertion of a silver wire into the carotid artery of a horse resulted in the formation of a coagulum. These are the earliest recorded in-vivo experiments of the effect of a foreign surface on blood clotting. The elucidation of the contact mechanism of blood coagulation resulted from the work of Margolis (1956), Shaftir & de Vries (1956) and Waaler (1959). They showed that initiation of coagulation was due to a particular plasmatic factor or factors. This was confirmed by the discovery by Ratnoff & Colopy (1955) of a patient (Mr Hageman) whose blood did not clot in a glass tube and whose plasma lacked the specific protein. In addition three other factors have been described that are necessary for the production of contact product: plasma thromboplastin antecedent (PTA) (Rosenthal et al. 1953), Fletcher factor (Hathaway et al. 1965) and Fitzgerald factor (Waldmann & Abraham, 1974). Numerous foreign surfaces have been described which activate the contact mechanism. Almost all of them have negative surface charges, but total surface charge (C. potential) and clot-promoting activity do not necessarily correlate.

CHARLES D FORBES MD FRCP COLIN R M PRENTICE MD FRCP University Department of Medicine Royal Infirmary, Glasgow 1 2 3 4 5

Historical review The normal endothelium Adsorption of proteins to artificial surfaces Adhesion of platelets to artificial surfaces Polymer surface modification and blood compatibility a Surface charge and biocompatibility b Heparin binding c Prostaglandin binding d Albumin coating e Modification to improve blood compatibility 6 Clinical application of artificial surfaces a Prosthetic heart valves b Cardiopulmonary by-pass c Artificial heart d Haemodialysis e Haemoperfusion / Prosthetic blood-vessels g Arteriovenous shunts h Catheters 7 Tests to evaluate haemostasis during artificial surface contact References

Over the past 20 years development of artificial organs and devices to maintain life functions has stimulated research into the problems of the compatibility of blood with the foreign surfaces used. Blood compatibility may be defined as the inability of an artificial surface to activate the intrinsic blood coagulation system or to attract or alter platelets or leucocytes (Mason et al. 1976). An immense literature has been generated in a variety of clinical situations, as thrombus formation has become a major complication of vascular catheters, cardiopulmonary oxygenators, dialysis membranes, vascular grafts and charcoal columns used in haemoperfusion. There is a wide range of thrombogenic effect varying from complete occlusion to a degree of consumption of the blood clotting factors or formed elements. To date, the factors that initiate such a thrombogenic response and the mechanisms in the blood responsible have not been accurately defined and no synthetic material has been produced that is totally free from this effect. Ideal materials should not activate clotting factors, cause platelet aggregation, or cause local damage to the surrounding tissues. It is the induction of thrombosis which has limited the development and use of artificial internal organs and devices. Despite many recent advances by biomedical engineers, the ideal blood-compatible surface of endothelium has not been matched in its non-thrombogenic properties by any artificial material (Salzman, 1975). To overcome such problems research has been directed towards production of

2 The Normal Endothelium The unique property of normal endothelium is its total compatibility with blood. Endothelial cells are capable of metabolic processes which actively discourage thrombus formation. Endothelium is a rich source of plasminogen activator (Todd, 1959) and apparently prevents platelet aggregation by the production of substances such as prostaglandins (Gimbrone & Alexander, 1975) and, in particular, prostacyclin (Moncada et al. 1977)1. Heparin and related mucopolysaccharides are synthesized by many mammalian cultured cells (Kraemer, 1971). The non-thrombogenic properties of normal endothelium, recently reviewed by Gimbrone (1976), are sustained by a series of elaborate metabolic processes, and clearly it will tax the ingenuity of the ablest bioengineers to produce surfaces suitable for long-term perfusion after implantation of artificial surfaces. > See Moncada & Vine, pp. 129-135 of thij Bulletin.—ED.

201 VoL 34 No. 2

THROMBUS FORMATION AND ARTIFICIAL SURFACES 3 Adsorption of Proteins to Artificial Surfaces


there is a need to study the relative affinity of thrombin for polymers and for its major inhibitor, antithrombin m .

Plasma proteins, either in whole blood or in purified form, are easily adsorbed to artificial surfaces in varying degrees. This process has been shown by a number of physical and chemical methods including eUipsometry, ^-potential measurement, radioactive labelling and immunological identification. Protein adsorption occurs rapidly on contact with the artificial surface (Mason et al. 1976) and it is probable that fibrinogen, factor VBI and the contact factors are of major importance in the development of a fibrin clot In particular, the adsorbed fibrinogen monolayer apparently mediates platelet adhesion (Zucker & Vroman, 1969) and from these components a small fibrin-platelet thrombus may develop. In addition, a variety of other proteins are adsorbed and rapidly denatured (Lee & Hairston, 1971). This material may then produce emboli as well as influence the adhesion of platelets and leucocytes (Wallace et al. 1975). It is possible that adsorption of protein to artificial surfaces may significantly alter the circulating levels of certain plasma proteins and may also alter their functional or immunological characters. The adsorption of plasma proteins on to artificial surfaces is influenced both by the specific surface properties and by the presence of different species of proteins in the mixture (Brash & Lyman, 1969). Protein molecules are adsorbed to artificial surfaces to form a monolayer coat, and it is possible that this process involves a change in tertiary structure. In human blood, in addition to fibrinogen, the following proteins may be adsorbed: albumin, a, [} and y globulins, transferrin, caeruloplasmin, thrombin, and factors XH, XL, V and Vin. With time, there are changes in the composition of the adsorbed protein coating. Prior binding of heparinoids to a surface alters its ability to adsorb protein. It is probable that the formation of a protein layer precedes the adhesion of blood platelets. The adsorption of albumin to artificial surfaces is of practical importance, because albumin-coated surfaces reduce platelet adhesion (Lyman et al. 1968; Salzman et al. 1969). In the field of haemoperfusion, collodion and albumin-coated charcoal granules have been used with success for clinical detoxication (Chang et al. 1971; Chang, 1974). The proteins causing most platelet adhesion contain the greatest proportion of carbohydrate, and the efficacy of albumin may result from the fact that it contains no carbohydrate (Lee & Kim, 1974). In general, proteins interact more strongly with hydrophobic surfaces than with hydrophilic ones (Hoffman, 1974) and hydrophilic surfaces seem to adsorb less protein than hydrophobic surfaces (Brash & Lyman, 1969). Reversibility of the physical bond is an important factor determining the state of equilibrium of the protein on the surface (Yroman et al. 1971). It seems likely that adsorption and activation of clotting factors from the intrinsic coagulation pathway is of major importance. Factor XII (Hageman factor) is readily adsorbed to most artificial surfaces and is rapidly activated. Thrombin, also, can be adsorbed on to artificial surfaces (Waugh & Baughman, 1969) and this may initiate local thrombus formation. This view is supported by the recent evidence that release of fibrinopeptide A, and presumably also thrombin formation, occur fairly frequently (Nossel, 1977). Clearly

4 Adhesion of Platelets to Artificial Surfaces The adhesion of platelets to artificial surfaces usually involves the interaction of platelets with a layer of plasma protein adsorbed to the surface (Falb et al. 1966; Dutton et al. 1969; Salzman, 1971). In in-vitro experiments, purified plasma proteins adsorbed to a surface have different effects on platelet adhesion. Adsorption of fibrinogen and y globulins markedly increases platelet adhesion (Evans & Mustard, 1968; Lyman et al. 1968) but adsorption of albumin has little or no effect (Vroman & Adams, 1969). It has been suggested that the carbohydrate component of adsorbed proteins is involved in the reaction with platelet receptors in a manner similar to the platelet-collagen reaction (Jamieson, 1973) and probably also with surface-charged groups such as Ar-acetylneuraminic acid (Seaman, 1975). From the clinical standpoint, interaction of platelets with artificial surfaces is invariable and this may be manifested in three ways (Scarborough, 1971): i. Thrombus formation may interfere with function. ii. Small thrombi which are formed may embolize off the surface, iii. Accelerated consumption of platelets with production of a haemostatic defect may occur. Following exposure of the surface to blood, platelets are seen to adhere rapidly, either as a monolayer or as aggregates, and these may also have an associated fibrin meshwork (Dutton et al. 1969). The initial phase of protein adsorption and the subsequent platelet adhesion are influenced by a combination of factors, including surface smoothness, surface charge, wettability and surface tension. In addition, surface texture and flow may determine whether platelet thrombi are removed as emboli. Interaction between platelets and many synthetic materials is clearly of low affinity as compared with collagen or basement membrane. The initial rate of platelet attachment to a variety of artificial surfaces under controlled flow conditions is similar, indicating a comparatively non-specific reaction (Friedman & Leonard, 1971). It is well known that materials vary in thrombogenicity and it would seem that the release reaction and aggregation must be important. The exact biochemical pathway of this reaction is not clear but may be associated with the increased synthesis of prostaglandin E2, which in turn inhibits the enzyme adenylate cyclase and leads to a fall in cyclic AMP within the platelet (Berger et al. 1974). Yet another factor is the reaction of platelets to shear stress. Brown et al. (1975) and Goldsmith et al. (1975) have shown, by measurement of release of acid phosphatase or serotonin (5-hydroxytryptamine), platelet destruction at a threshold shear stress of approximately 15N/m2. Turbulent flow caused higher levels of damage at higher shear rates, and Klose et al. (1975) report that platelet aggregates form in a cone-in-plate viscosimeter with a shear-strain rate of 25-115/s. Examples of platelet, red-cell and white-cell adhesion to a foreign surface are shown in Plate III: Aa-Ac. It is of interest that the fall in platelet count occurs immediately after contact with the foreign surface, indicating that the initial interaction between the platelet and the artificial surface is of primary importance (Plate IV: Ba, Bb). 202 Br. Med. Bull. 1978




Aa-Ac. Adhesion of protein, platelets, and red and white cells to strands of Dacron wool which had been inserted as a filter into a closed-loop system containing heparinized blood. (Photographs by courtesy of Dr Rosemary Wilkinson, Department of Bioengineering, University of Strathclyde, Glasgow.) (el«ccron microf raphs; m*f nKication x 3000)






250 Number of platelets

~»n zo ° 150



Platelet adhesiveness (%) ( mean ± s. D. )




, 10


4 hours

Minutes Time

Ba, Bb. The fall in platelet count (mean + s.o. of eight experiments; P < 0.025) during experiments carried out in vivo. Hepariniied blood was circulated through a test system containing a filter of Dacron wool (Swank filter). In Ba, the arrow indicates the time at which filtration was performed, A the readings immediately before the blood was passed through the filter, and B the readings immediately after. It can be seen that immediately on passage through the filter the platelet count fell, but rapidly returned to normal In Bb, the two tracings show that the platelet function, as measured by ADP-induced aggregation in atypical patient, was altered. (C: prefiltratlon; D: postfiltration)


heparinized surface (Olsson et al. 1977). It is interesting that the heparinized surfaces adsorb proteins to a greater extent than do untreated ones (Larsson et al. 1977), and it is possible that these proteins may include antithrombin HI and factors DC, X and XI, which have an affinity for heparin (Gentry & Alexander, 1973; Lee et al. 1974).

5 Polymer Surface Modification and Blood Compatibility In order to provide guides to the selection of a suitable polymer structure, numerous attempts have been made to establish a relationship between the blood compatibility of a polymer and some particular property of the polymer, such as surface charge, surface-free energy, and the ability of the polymer to interact with proteins and blood platelets.

c Prostaglandin Binding In view of the current interest in prostaglandins and their precursors as agents that reduce platelet adhesion and aggregation to normal endothelium (Moncada et al. 1977), these compounds would seem a good choice for incorporation into polymer membranes. Grode et al. (1974) have already shown that immobilization of prostaglandins on surfaces reduces platelet aggregation.

a Surface Charge and Biocompatibility The importance of surface charge on thrombogenicity of a material is not clear. In 1953, Sawyer & Pate observed the formation of a thrombus at the anode when a current was passed across a blood-vessel. There is still no agreement as to the optimal ratio of positive to negative charges desirable or as to the density of these charges. It is generally agreed that surfaces that are predominantly positively charged are poorly compatible with blood (Milligan et al. 1968; Salzman, 1971) and surfaces that contain nearly equal mixtures of positively and negatively charged groups have a fairly high compatibility with blood (Mason, 1972). It is possible that the ability of normal endothelium to resist thrombus formation results from the negative charge on its surface, and reversal of this may be a factor in atherogenesis (Sawyer et al. 1953). A reduced C potential has been described in blood-vessels with atherosclerosis (Sawyer & Srinivasan, 1967). Various attempts have been made to produce a surface with antithrombotic properties by the incorporation of negative charges, e.g. fixed anionic groups (Bixler et al. 1969), neutral polymers with negative £ potential (Leininger et al. 1966), and electrets with a fixed negative charge (Sharp et al. 1968). However, there is little agreement in this area, since DePalma et al. (1972) found no correlation of relative surface charge with thromboresistance in several metals, and Ross et al. (1961) failed to find a correlation with £ potential and thrombus formation. It is probable that surface charge alters rapidly with adsorption of plasma proteins (Weiss, 1971).

d Albumin Coating It is thought that albumin coating of surfaces may improve blood compatibility of the surface (Chang, 1974). Platelet adhesion to surfaces is reduced by prior coating with albumin (Packham et al. 1969). e Modification to Improve Blood Compatibility An alternative to heparin incorporation is to modify the polymer coating so that blood compatibility is improved. The selection and design of the polymer coating naturally depend on its intended purpose, for instance, whether it is to be used as flat sheets for oxygenators or haemodialysis membranes, or whether it is designed to coat activated charcoal. An attractive solution may be the use of copolymer systems, in which one monomer contributes to film strength and the other to film reactivity. One such successful combination has been a copolymer of dimethylaminoethyl methacrylate (DMAEMA) and methyl methacrylate (MMA) (Courtney et al. 1977). Polymerization of DMAEMA gives rise to water sensitivity and cationic properties. The incorporation of DMAEMA into polymers enables heparin to be bonded ionically (Falb et al. 1967; Idezuki et al. 1975), and a successful clinical evaluation of an acrylonitrile-DMAEMA film bonded with heparin has been made by Lindsay et al. (1976).

b Heparin Binding One of the commonest methods of improving the blood compatibility of polymers is by treatment with heparin. Commercial heparin represents a family of compounds of varying chain length, having similar saccharide repeating units and functional groups. The heparins can be regarded as polyanions, possessing aminosulphate and carboxyl groups2. Most methods of bonding heparin to polymers to make nonthrombogenic artificial surfaces are based on achieving ionic attachment of the molecule by methods such as pre-treatment of the polymer with graphite and a cationic surfactant or with a quaternary ammonium salt (Falb et al. 1967; Bruck et al. 1973; Chawla & Chang, 1974). Although heparin bound ionically to membranes undergoes leaching in the presence of blood or plasma with loss of effect, treatment of the heparinized surface with glutaraldehyde reduces this problem (Lagergren & Eriksson, 1971; Larsson et al. 1977). The heparinized surfaces appeared to inhibit platelet adhesion to a greater extent than non-heparinized surfaces (Lagergren et al. 1974; Lindsay et al. 1977; Olsson et al. 1977), and also to prevent platelet aggregation in the blood exposed to the

6 Clinical Application of Artificial Surfaces a Prosthetic Heart Valves Replacement of damaged or diseased heart valves has been extensively practised since 1951 when Hufnagel described the ball check valve. Despite changes in design and materials used, thrombo-embolism remains the most serious complication following implantation of such a valve. In addition, infection, haemolysis, endocardial thickening and valve detachment may occur. The incidence of detectable thromboembolism may be as high as 50%, depending on the valve design and construction (Gadboys et al. 1967). Most detectable emboli are those in the cerebral vessels and result in permanent neurological dysfunction. It seems from clinical experience that the mitral valve is more likely to give rise to embolism than the aortic valve (Stanford et al. 1972). The presence of shortened platelet survival may be of value to predict which patients are prone to thrombo-embolism

> See Bammdifie tt al, pp. 143-1 JO of thli Bulletin.—ED.

203 VoL34No.2




TABLE I. Agents inhibiting platelet adhesion to artificial surfaces

(Harker & Slichter, 1970; Weily et al. 1974) and to assess the effect of antithrombotic therapy. A significant reduction in thrombo-embolism may occur with oral anticoagulants. It seems likely in such patients that platelet deposition on the ring or the valve flap or ball is the initiating factor. Measurement of platelet survival shows significant shortening, and scanning electron micrographs of removed valves show platelet aggregates. In addition, a combination of the antiplatelet agent dipyridamole with established warfarin therapy leads to a further significant reduction in embolism (Sullivan et al. 1968). A similar observation was made with sulphinpyrazone (Weily & Genton, 1970). Covering the exposed parts of the prosthetic valve with cloth leads to rapid coagulation in the interstices. As the blood flow is so rapid, propagation of the thrombus does not occur and the surface soon undergoes endothelialization and is inert (Braunwald et al. 1972).

Amitriptyllne Androjterone Chlorpromazlne Cloflbnte Colchlclne Dextrin 70 Dlcoumarol Dihomo--j-llnolenlc acid Dipyridamole Ethylenediamlnetetra-acetlc add

Ethyloestrenol Heparin p-Hydroxymercuribenioate Imipramlne Nlalamlde Promethazine Prostagiandln E Sulphinpyrazone Vlnblastlne VIncrlitlne

c Artificial Heart Much research is now being directed to development of the artificial heart (Kolff, 1977). The goal is to produce an implantable heart capable of long-term operation without thrombogenic complications. In the meantime, cardiac pumps used for left ventricular assist are already capable of dealing with the potentially reversible circulatory failure following cardiopulmonary by-pass. Most of these assist devices contain a flexible polyurethane bladder lined by polyester fibres on which a compatible neointima develops, containing fibrin, platelets, erythrocytes and leucocytes (Norman, 1977). Norman (1977) and colleagues have found, from animal experiments, thatfibrin-derivedpannus occurs at the junction of the polyolefin rubber pump and the artificial valves. The use of natural valves in the artificial heart may circumvent this problem (Kolff, 1977). Many of the thrombotic problems associated with the artificial heart are probably related to the design of the chamber and to flow patterns through it rather than to the nature of the surface.

b Cardiopulmonary By-Pass Cardiopulmonary support systems after 20 years of use are still limited in their application by the serious complication of haemorrhage, which may occur in 5-25% of cases (Gralnick & Fischer, 1971; Verska et al. 1972; Heiden et al. 1975). The platelet count decreases to almost zero after a prolonged period of by-pass when a bubble oxygenator is used (Bloom et al. 1974; Fong et al. 1974). With new types of machines (non-gas interface systems), thrombocytopenia is less marked, but during prolonged use haemostatic problems still occur (Bartlett, 1974; Zapol et al. 1975). The main abnormalities have been reviewed ably by Bick (1976). There is increasing evidence that platelet-protein interaction with the oxygenator surface is responsible for many of the undesirable haemostatic consequences of by-pass surgery. The initial thrombocytopenia may be partly related to platelets sticking to the membrane surface, but mainly to platelet aggregates, formed as a result of the platelet-surface interaction, which are then sequestered within the body. Such platelet micro-emboli may cause a rise in pulmonary pressure and pulmonary vascular resistance (Birek et al. 1976). Additionally, the serious neurological abnormalities, such as dysphasia and disorientation, may result from platelet microemboli in the cerebral vessels causing micro-infarcts (Swank et al. 1963; Branthwaite, 1972). These abnormalities and some of the clinical neurological sequelae may be prevented by inserting micropore filters into the return line of the oxygenator (Ashmore et al. 1972; Branthwaite, 1975). These filters, on scanning-electron-microscopical examination, contain masses of debris, including platelets, red cells and denatured protein. Ocular defects due to retinal vessel obstruction have also been reported (Williams, 1971). Further problems may arise because of the release of biologically active substances, such as serotonin, from the disrupted platelets (Hollenberg et al. 1963; Lindsay et al. 1977). In addition to improvement of membrane oxygenator design, attempts have been made to prevent platelet-surface interaction by the use of drugs that depress platelet function. This topic has been recently extensively reviewed (Turpie, 1977) and a list of some drugs that have been used is shown in Table I. Sulphinpyrazone (Birek et al. 1976) and dipyridamole (Becker, 1973; Nuutinen & Mononen, 1975) are apparently promising in this respect, but aspirin is less effective (Mielke et al. 1973).

d Haemodialysis Haemodialysis with the earlier types of dialysers was associated with significant blood loss, from the regular dialysis patient, of 2.0-4.5 litres per annum. This was mostly because of thrombus formation initiated by contact with the Cuprophane membrane of the dialyser (Lindsay et al. 1973a). The most striking changes occur in platelet number and this can best be demonstrated with 31Cr-labelled platelets and with scanning electron micrographs. In addition fluoresceinlabelled anti-fibrinogen antiserum shows the presence of fibrin deposition (Lindsay et al. 1972a). There may also be a postdialysis rise in activity of factors V and VHr, with a shortening of the partial thromboplastin time. These changes could be reduced by administration of aspirin and RA 233, a dipyridamole analogue (Lindsay et al. 1972b). Recent changes in the chemical and physical properties of dialysis membranes have now overcome some of the above problems (Lindsay et al. 1973b). It is of interest that heparin tends to aggravate platelet retention in this situation. This is in keeping with the observation that, in vitro, heparin enhances platelet aggregation and adhesiveness (Thomson et al. 1973), but this undesirable effect may be diminished by use of sulphinpyrazone and aspirin (Winchester et al. 1977a). Many of the recently designed dialysers are of the capillary or hollow-fibre type, rather than the flat-bed or coiled parallel flow type, and these do not appear to produce major haemostatic or thrombotic problems. 204 Br. Med. Bull. 1978


insertion (Kuruvila & Beven, 1971; Ozeran et al. 1972). The venous side of the system is more likely to be the site of the thrombus. Surgical procedures or fibrinolytic agents may be of value in salvaging shunts. The cause of thrombosis is probably multifactorial and may be associated with vasospasm, phlebitis and mechanical factors. In addition, changes occur in the platelet count, platelet reactivity is increased, and the level of factor VTII increases, these changes all favouring thrombosis; and, in addition, fibrinolysis is impaired. It is possible with the use of antiplatelet agents such as aspirin, dipyridamole and sulphinpyrazone to correct the reduced platelet survival in such patients, but this does not seem to reduce substantially the incidence of thrombosis (Mustard et al. 1967). Such shunts still have a place in the short term but are rarely of value beyond 12 months, and in chronic dialysis they have been replaced by a variety of arteriovenous fistulae.

e Haemoperfusion

Haemoperfusion involves the passage of anticoagulated blood from the patient's circulation through a device containing activated charcoal or ion-exchange polystyrene-based resins, with a view to removing unwanted substances, e.g. urea or poisons (Chang et al. 1971). As blood is in contact with a large area of artificial surface, major changes may occur in the haemostatic mechanism. However, these effects are reduced when albumin-coated charcoal is used. In addition to reduction of platelet retention, the coating on activated charcoal reduces attrition of the charcoal and subsequent small-particle release (Courtney et al. 1976). In the UK most experience has been gained from acrylic-hydrogel-coated charcoal in the treatment of poisoning, liver failure and uraemia (Fennimore et al. 1974; Gazzard et al. 1974; Winchester et al. 1976). Invariably there is a fall in the platelet count, with minor changes in clotting factors, when coated charcoal is used. Usually the fall in platelet count is to a level which does not prejudice the haemostatic state of the patient (Winchester et al. 1977b).

h Catheters Intravenous or intra-arterial catheters have become a keystone of modern medical investigation and treatment. Inflammation of the vessel wall and thrombo-embolism are the two important complications. By use of special radiological techniques it is possible to demonstrate platelet-fibrin emboli in 40% of cases following arteriography (Siegelman et al. 1968). Usually such emboli are transient and of trivial clinical importance but they may, on occasions, lead to ischaemic necrosis of a digit or limb and on occasion to death (Moore et al. 1970). On the venous side, fibrin deposition may occur on the outer surface of the catheter and eventually lead to occlusion of the vein. Embolization may also occur as the fibrin is stripped off when the catheter is removed. Superficial thrombophlebitis is invariably present if a catheter is left in

f Prosthetic Blood-Vessels

For 25 years tubes fashioned from a variety of substances have been used to replace diseased arteries (Voorhees et al. 1952). The incidence of thrombosis depends on a variety of physical and chemical factors, e.g. (i) material used, (ii) the smoothness of its surface, (iii) the flow characteristics once it is implanted, and (iv) the diameter of the tube used. When the graft size falls below 6mm there is a high incidence of thrombotic occlusion, e.g. in femoro-popliteal grafts. In this situation only autologous vein is consistently successful. Numerous studies are now available in a variety of grafting materials and it seems clear that platelets are the initiating factor in thrombosis, as evidenced by reduced platelet survival and number and by scanning-electronmicroscopical pictures of removed grafts (Slichter et al. 1972). The surfaces of many prostheses become coated with a cellular neointima, and many of the artificial blood-vessels, such as woven Dacron or velour, rely on this mechanism for their non-thrombogenic properties (DeBakey*/ al. 1964). The advantage to the patient is that the new intima is formed from his own endothelium. As endothelial cells contain histocompatibility antigens (Vetto & Burger, 1972), there are problems of allograft rejection during blood-vessel or organ transplantation. Conventional anticoagulants such as heparin and warfarin do not prolong graft patency and their use is not recommended (Salzman, 1965; Evans & Irvine, 1966). Newer materials such as porous woven Dacron that is preclotted, expanded microporous polytetrafluoroethylene and glutaraldehyde-treated human femoral artery all seem to have better thrombo-resistant surfaces and meet many of the criteria laid down by Sauvage et al. (1974).

TABLE II. Tests to evaluate thrombogenesis on artificial surfaces Radiological tests Electron microscopy Function Coagulation tests

Fibrinolytic activity

g Arteriovenous Shunts

The use of tubes of synthetic polymers for long-term venous access has theoretical attractions in diseases such as uraemia, aplastic anaemia and genetic coagulation defects. Such arteriovenous shunts were originally described by Quinton et al. (1960) and a massive literature has grown up about them and their variants. Thrombosis is the most common complication, followed by infection and bleeding at the site of

Platelet function

205 Vol. 34 No. 2


f Conventional angiography \Radionudlde angiography Scanning of prosthesis after removal Deterioration of performance Partial thrombopiastln time: in sillcone Prothrombln time Thrombin time Assay of flbrlnogen and factors II, V, VIII, XI and XII 'Eugiobulin lysis time Plasmlnogen level Fibrin plates Radioactive fibrin clot Flbrlnogen-flbrin polymers Platelet count Platelet adhesiveness Platelet aggregation (ADP, collagen, noradren*llne, serotonin) Platelet survival Release of platelet constituents Test cells containing the materials under study Artificial circulations with the material substituted Arteriovenous anastomosis by tubes of the material under study Estimation of the number and site of emboli following Implantation of a foreign substance

THROMBUS FORMATION AND ARTIFICIAL SURFACES situ for 5 days or more and this may represent local infection, chemical phlebitis from the infusion fluid, chemical or mechanical phlebitis from the r^nnnln, or local thrombosis (Frazer et al. 1977). As on the arterial side, fatal complications have been recorded following prolonged use of indwelling venous catheters, usually for measurement of central venous pressure or for cardiac pacing (Adar & Mozes, 1971). Attempts to reduce the incidence of embolic complications by coating catheters with heparin and systemic heparinization have been generally unsuccessful. It would seem wise in high-risk patients to administer an antiplatelet agent during the time the catheter remains in situ. 7

displayed in Table n and a selection of these can be chosen to illustrate properties of materials under test The easiest, cheapest and most widely reported test is the platelet count. The test giving most information is platelet survival using a radionuclide marker.

In this account, we have attempted to summarize the main factors involved in the interaction between artificial surfaces and components of the haemostatic mechanism. It is clearly impossible to imitate exactly the complex functions of the normal endothelium which prevent the initiation of thrombosis, and the success of many of the present prostheses is that they allow the formation of a neointima. However, progressive advances are being made in the production of new biocompatible materials, in laboratory and animal tests to assess their suitability, and in the development of antiplatelet agents to prevent the surface-platelet interaction. These innovations will lead to a rapid increase in the help we can gain from artificial materials when facing the problems caused by human disease.

Tests to Evaluate Haemostasia during Artificial Surface Contact

Tests to evaluate haemostatic defects have recently been 1976; Winchester et

the thrombogenic potential induced by artificial-surface adequately reviewed (Fekete al. 1976). A variety of such


and the exposure & Bick, tests are


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Br. Med. Bull. \

Thrombus formation and artificial surfaces.

British Medical Bulletin (1978) Vol. 34, No. 2, pp. 201-207 THROMBUS FORMATION AND ARTIFICIAL SURFACES CDForbes&CRMPrentice materials that prevent...
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