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Ann Thorac Surg 1998;66:1837-1844
© 1998 The Society of Thoracic Surgeons

How to do it

Measures to control blood activation during assisted circulation

Christophe Baufreton, MD, PhDa, Matthias Kirsch, MDa, Daniel Y. Loisance, MDb

a Department of Thoracic and Cardiovascular Surgery, CNRS URA 1431, Association Claude Bernard, Hôpital Henri Mondor, Créteil, France
b Centre de Recherches Chirurgicales, Hôpital Henri Mondor, Créteil, France

Address reprint requests to Dr Loisance, Centre de Recherches Chirurgicales, Faculté de Médecine, 8, rue du Général Sarrail, 94000 Créteil, France
e-mail: (loisance{at}univ-paris12.fr)


   Abstract
Top
 Abstract
Introduction
 What is blood activation?...
 The specific setting of...
 Methods to control blood...
 Conclusions
 References
 
Major improvements in heart assist devices have allowed prolonged mechanical circulatory support with successful subsequent weaning or heart transplantation. The contact of blood with biomaterials used in life-sustaining devices and numerous biomaterial-independent factors elicit a systemic inflammatory response, which involves activation of various plasma protein systems and blood cells. Prolonged mechanical circulatory support elicits a systemic inflammatory response and hemostatic perturbations similar to that reported during cardiopulmonary bypass. However, in the setting of prolonged assistance, time has a complex and ill-known influence on blood activation. Methods to reduce blood activation during prolonged assisted circulation are derived from cardiopulmonary bypass investigations. Improving the biocompatibility of artificial devices can be achieved either by biomaterial surface modifications, by inhibition of biologic cascades leading to blood activation, or by controlling end points of biologic cascades. However, the necessity to respect the integrity of the organism during prolonged assistance precludes most systemic interventions and limits the control of blood activation to the area of the device.


   Introduction
Top
 Abstract
 Introduction
What is blood activation?...
 The specific setting of...
 Methods to control blood...
 Conclusions
 References
 
Devices used for assisted circulation have been sufficiently improved to allow some patients to be fully rehabilitated for cardiac transplantation or weaning, whereas others will be discharged from the hospital under wearable circulatory support. However, hemostasis disturbances and infections remain of major importance in the daily practice of assisted circulation. The conflict of blood with biomaterials appears to be the Achilles’ heel of circulatory support, especially in prolonged procedures. This clinical challenge more or less parallels the whole-body inflammatory response associated with cardiopulmonary bypass (CPB), which has been recognized since the early 1980s. The knowledge of mechanisms involved in the blood activation initiated by CPB and available methods to minimize pathophysiologic aspects may thus appear to be very helpful. The goal of controlling blood activation during assisted circulation is a compromise between inducing local thromboresistance and immune tolerance without inhibiting clotting and self-nonself discrimination outside the vessels.


   What is blood activation? lessons learned from the CPB experience
Top
 Abstract
 Introduction
 What is blood activation?...
The specific setting of...
 Methods to control blood...
 Conclusions
 References
 
Extracorporeal circulation acts as the interface of a blood–artificial surface conflict that takes place at a distance from the internal circulation. Because fluidity and integrity are essential features of the vascular system, the whole body generates hemostasis disturbances and an inflammatory response when the blood–endothelium barrier is altered. Many plasma and cellular systems of the organism are involved in blood activation cascades. However, mainly the contact phase, the complement system, platelets, and monocytes are affected, whereas other systems are subsequently activated [1]. Some reactions are followed preferentially by hemostasis disturbances whereas others lead to an inflammatory response. However, most of these cascades are so closely related that they are affecting both of these two major pathways. For that reason, it may appear easier to classify blood activation as biomaterial-dependent and biomaterial-independent (eg, patient-dependent).

When blood first contacts with artificial surfaces, the contact phase of coagulation is activated, resulting in the production of factor XIIa and kallikrein, which are involved together within an amplification loop [2]. The contact phase activation has been believed for a long time to initiate the intrinsic pathway of coagulation, thus resulting in the production of thrombin, which is involved in clotting. On the other hand, the extrinsic pathway is activated because the surgical wound (a patient-dependent factor) exposes blood to tissue factor expressed by subendothelial cells. This takes an important place in clot formation because blood returns to CPB by way of suckers. There is growing evidence that extrinsic coagulation might be predominant [3]. Indeed, patients missing one factor of the extrinsic pathway are at higher risk for bleeding than those missing one factor of the intrinsic pathway. Moreover, high doses of heparin used to prevent clotting during CPB cannot suppress the production of thrombin as reflected by the detected levels of fibrinopeptide 1 + 2 or thrombin–antithrombin complexes [4, 5]. Thus, it has been speculated that the extrinsic pathway is responsible for the initiation of coagulation and that the intrinsic pathway factors are required for growth that and maintenance of clot formation once coagulation has been initiated [3].

The fibrinolytic system regulates the increasing clotting by accelerating the degradation of fibrinogen and fibrin [3]. This pathway acts under the control of plasmin generated from plasminogen interacting with tissue plasminogen activator (tPA). Kallikrein and bradykinin from the contact phase are potent agonists of urokinase plasminogen activator, which potentiates tPA production. At rest tPA is stored in the endothelial cells and is inhibited by plasminogen-activator inhibitor (PAI-1). This inhibition is partly reinforced by lipopolysaccharides and cytokines such as interleukin-1 or tumor necrosis factor-{alpha} (TNF-{alpha}), thus explicating the promotion of thrombosis [3]. Nevertheless, these complex mechanisms are not totally elucidated as their manifestations are widely variable from patient to patient [3].

Once CPB is initiated, platelets are promptly activated by contact with adsorbed fibrinogen that covers the extracorporeal circuit. Activated platelets will change shape and adhere to biomaterials [1]. Whether their glycoprotein IIB/IIIa or glycoprotein Ib receptors are predominantly involved in this attachment to artificial surfaces remains incompletely explained. However, because thrombin is a potent agonist of platelets, the surface of platelets appears to be the milieu where humoral components of coagulation are concentrated.

Different inflammatory pathways are activated after CPB: the complement system, the polymorphonuclear neutrophils, and the mononuclear cells leading to cytokine release. Complement activation plays a major role in contact activation secondary to CPB [6]. The degree of this humoral response, as measured by concentrations of the anaphylatoxins C3a and terminal complement complex C5b-9, has been associated with the incidence of postoperative cardiac, pulmonary, and renal dysfunction [7–9]. The alternative pathway is the pathway that is predominantly activated by contact of blood with most artificial surfaces, whereas the classic pathway is initiated by antigen–antibody complex formation and heparin–protamine complexes. The anaphylatoxins C3a and C5a are responsible for the release of inflammatory mediators such as lysosomal enzymes and reactive oxygen species in the vicinity of smooth muscle and endothelial cells, leading to muscle contraction and increased vascular permeability. On the other hand, endotoxemia, which originates from the splanchnic area under impaired conditions of gut perfusion, also participates in blood activation during CPB as a biomaterial-independent factor [10] by activating the complement system [11] and stimulating the expression of tissue factor [12] and cytokines by monocytes [13]. These inflammatory cytokines, such as TNF-{alpha}, interleukin-6 (IL-6), and interleukin-8 (IL-8), stimulate the expression of endothelial adhesion molecules such as ELAM-1 (endothelial–leukocyte adhesion molecule) and ICAM-1 (intercellular adhesion molecule) interacting with receptors expressed on activated neutrophils. This interaction enables the attachment of neutrophils to endothelial cells and the release of neutrophil-derived cytotoxic factors (oxygen free radicals, leukotrienes, and proteolytic enzymes). Neutrophils may therefore contribute to the reperfusion injury either by occluding the microvasculature or by producing oxygen free radicals.


   The specific setting of assisted circulation: different patients, different systems
Top
 Abstract
 Introduction
 What is blood activation?...
 The specific setting of...
Methods to control blood...
 Conclusions
 References
 
For several reasons, assisted circulation cannot be considered simply as the prolongation of CPB. Assisted circulation offers more therapeutic options than CPB because indications vary from postcardiotomy recovery, cardiac resuscitation, bridge to cardiac transplantation or expected weaning, or permanent implant. The profile of patients differs before implantation. Assisted circulation is performed when patients are in end-stage cardiac insufficiency or in acute cardiogenic shock, eventually complicated by multiorgan failure. Signs of systemic inflammation have been detected even before implantation of an assist device as reflected by elevated levels of IL-8, IL-6, and sE-selectin [14, 15]. Patients who undergo cardiac operations that include CPB are simultaneously exposed to an anesthetic and a surgical stress. These two factors contribute to the inflammatory response observed during CPB. Although these stresses exist initially during the implantation of an assist device, they are no longer present in the setting of prolonged assistance. Furthermore, although hypothermia is often used during CPB for cardioprotective reasons, prolonged assisted circulation has to be performed under normothermic conditions. The influence of temperature on the inflammatory response during CPB has been reported [16]. The flow regimen used during CPB is nonpulsatile or slightly pulsatile and at low pressure, whereas assisted circulation is performed in most cases using pulsatile flow at higher pressure. The relative hypoperfusion of the gut generated by CPB induces endotoxemia, whereas the flow regimen and elevated maximum rate of increase of left ventricular pressure provided by some electrically or pneumatically driven left ventricular assist devices (LVAD) might interfere with coagulation. Indeed, it has been experimentally observed that high shear stresses generated by a parallel-plate perfusion chamber device decrease the antithrombogenicity afforded by aspirin on platelets [17]. Contact of blood with artificial surfaces occurs in both CPB and assisted circulation. However, the artificial surface area in contact with blood is much smaller in circulatory assist devices because no gas- or heat-exchangers are used. On the other hand, the implantation of the assist device in the extraperitoneal space leads to a foreign body response and the subsequent development of a fibrous capsule around the pump housing [18]. Although this fibrous capsule formation is considered a normal host response and may help guard against infection, it probably contributes to the systemic inflammatory response.

However, most LVADs require the use of CPB during implantation. Therefore, the immediate postoperative inflammatory response observed in LVAD recipients is the result of a complex interaction between patient-related variables (circulatory shock, end-stage cardiac failure), acute blood–biomaterial interactions on CPB and LVAD surfaces, and a multitude of biomaterial-independent variables (anesthesia, surgical procedures, hypothermia, hemodynamic alterations, ischemia-reperfusion injury, drugs, and blood products) (Fig 1). On the other hand, at some distance from implantation, most biomaterial-independent factors are no longer present and the main initiating factors are represented by chronic blood–biomaterial interactions and eventual infections. Thus, in the setting of prolonged mechanical circulatory support, the inflammatory response has to be considered as a time-dependent phenomenon. Therefore, the pathophysiologic process induced by assisted circulation needs to be partly redefined.



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  		Fig 1. Main initiating factors of the systemic inflammatory response (IR) during mechanical circulatory support (MCS) and their modifications over time.

 
It has been recently reported that LVAD selectively absorbs and activates dendritic cells and monocytes (Fig 2) [19]. Activation of these cells results in enhanced adhesion molecules and tissue factor expression and release of cytokines (IL 1-ß, TNF-{alpha}), thus providing a sustained proinflammatory or prothrombotic stimulus [19]. Furthermore, activation of phagocytic cells on the surface of LVADs leads to enhanced antigen presentation to T cells and a subsequent polyclonal B-cell activation [20]. Individuals expressing the HLA-DR3 phenotype are particularly prone to the development of anti-HLA antibodies, the occurrence of which is associated with adverse outcome after heart transplantation [21]. Hummel and colleagues [22] have asked the question of the clinical relevance of cytokine production during assisted circulation. Although monitoring serum cytokine values (IL-6 and IL-8) may be helpful in selecting patients with fatal outcome [22], they provided evidence that the persistence of cytokines is not caused by blood–surface conflict [14]. Infections are frequent complications during LVAD support and thus represent a major confounding factor in the evaluation of the inflammatory response associated with assisted circulation.



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  		Fig 2. Adsorption and activation of circulating monocytes and dendritic cells on left ventricular assist device (LVAD) textured surfaces. Activation of these cells results in a sustained proinflammatory and prothrombic stimulus secondary to enhanced cytokine release and expression of tissue factor and adhesion molecules. Increased antigen presentation activity by these cells leads to a polyclonal B-cell activation. (IL1-ß = interleukin-1ß; TNF-alpha = tumor necrosis factor-{alpha}; NF-{kappa}B = nuclear factor kappa B; VCAM-1 = vascular cell adhesion molecule-1; ICAM-1 = intercellular adhesion molecule.)

 
Moreover, we have to focus on mechanisms involved in thromboembolic events occurring during prolonged assisted circulation although heparin is usually administered and the tissue pathway of coagulation is not continually stimulated once the operation is completed. The LVAD Dacron grafts have been reported to harbor surface thrombin activity, which is resistant to low heparin anticoagulation that may be a primary source for LVAD thrombogenicity [23]. Detailed study of the inflow and outflow conduits of LVADs implanted for a long time have shown active tissue remodeling on the inner surface (Loisance and colleagues, unpublished data). Basically, LVAD is complicated by hemorrhages in the early postoperative period (the first 2 weeks) and by thromboembolisms in the later course [24]. Only a few extended hematologic studies have been performed in patients with LVADs. All of them provided evidence of platelet activation, excessive fibrinolysis, and hypercoagulable state [25–28]. However, routine coagulation assays are not conclusive [25]. Therefore plasma and cellular activation markers are required. In more detail, major alterations of the contact system associated with fibrinolytic activation have been detected in the early postoperative period [26]. Later on, a shift to a procoagulant state with sustained prothrombin and platelet activation has been observed despite the administration of dipyridamole and aspirin [26]. Spanier and associates [28] have revealed that markers of thrombin generation and fibrinolysis are significantly elevated during implantation, return to near-normal values by days 5 to 7 after the operation, and then rise in a time-dependent manner, peaking at approximately day 35 of LVAD therapy, an effect that is subsequently sustained. The monocyte activation pathway seems to be a promising approach as it has been recently reported that in LVAD ongoing complement activation may trigger monocyte-dependent coagulation (tissue factor expression) and subsequent cell aggregate formation [12].

Thus, patients with LVADs require sophisticated laboratory monitoring and individualized treatment for hemostasis disturbances [25] and inflammatory response while waiting for more hemocompatible biomaterials.


   Methods to control blood activation
Top
 Abstract
 Introduction
 What is blood activation?...
 The specific setting of...
 Methods to control blood...
Conclusions
 References
 
Methods to reduce blood activation during assisted circulation are derived from CPB investigations. Improving the biocompatibility of artificial devices can be achieved either by surface modifications, by inhibition of the biologic cascades leading to blood activation, or by controlling end points of biologic cascades.

Surface modifications
Polyurethanes have excellent mechanical and physical properties and constitute the linings of most intermediate and long-term circulatory support devices [29]. Polyurethane surface modifications have been attempted by numerous investigators and include different approaches: physical modification, chemical modification by grafting a hydrophilic component, inclusion of a bioactive agent, biomembrane mimicry, and endothelial cell seeding or lining.

Physical modification
The majority of circulatory assist devices currently use smooth-surfaced polyurethanes. However, microscopic imperfections, seams and junctions between device components, and fatigue-induced cracklings on the surface might lead to thrombosis. An alternative approach is to use rough surfaces [30]. These include textured polyurethanes and textured metals. Textured surfaces encourage the development of a tightly adherent pseudoneointima, thus covering surface irregularities and eliminating direct contact between the device and blood. The TCI HeartMate LVAD (Thermo Cardiosystems Inc, Woburn, MA) [31] has been specifically designed with textured blood-contacting surfaces: sintered titanium microspheres are used on the pump housing and conduits, and integrally textured polyurethane is used on the flexing pusher-plate diaphragm [32]. Studies of explanted LVADs have demonstrated that this surface modification enables considerable cellular entrapment [32, 37]. However, there are conflicting data about the presence of endothelial cells and their recovery within the textured surface of the LVAD [33, 34, 36]. The positive immunoreactivity using von Willebrand factor observed in the lining by Frazier and colleagues [34] does not definitively prove that endothelial cells are present, because platelets also express this factor. Other studies have revealed that the cells trapped by the polyurethane surface, titanium housing, and Dacron grafts are biologically active [23]. Therefore, Spanier and associates [28] postulated that these entrapped cells may become activated and contribute to the initiation and propagation of further blood activation. Despite apparently normal platelet count, prothrombin, and activated partial thromboplastin times, thrombin formation and subsequent fibrinolysis are occurring and these abnormalities are attributable to the LVAD rather than to end-stage cardiac failure [28]. These investigators concluded that the TCI HeartMate LVAD had the potential to exacerbate bleeding or clotting when clinically relevant disorders, such as operation, infection, or inflammatory stress, occurred.

Chemical modification by grafting a hydrophilic component
The first event that occurs after blood contacts a polymer surface is the adsorption of plasma proteins and the formation of a protein layer at the blood–polymer interface [38, 39]. It has been shown that the type of protein adsorbed greatly influences the thrombogenicity of the surface. Albuminated surfaces have been found to reduce platelet adhesion and thrombogenesis, whereas fibrinogen and gamma globulins greatly enhance thrombogenesis. Adsorbed albumin changes the surface from hydrophobic to hydrophilic, which virtually completely prevents platelet adhesion. Despite the enhanced biocompatibility of adsorbed albumin, it is rapidly desorbed from the surface when exposed to circulating blood. Recently, Ryu and coworkers [40] have immobilized human serum albumin onto a polyurethane surface by stable covalent bonds. In vitro evaluation of this albumin-immobilized polyurethane has shown reduced thrombogenicity when compared with polyurethane alone [40]. However, this surface modification has not been evaluated under prolonged flow conditions.

Surface modification by inclusion of a bioactive component
Heparin coating seems to be a promising approach to improve biocompatibility of polyurethanes. The presence of heparinlike molecules (heparan sulfate) with anticoagulant activity has been demonstrated on the luminal surface of the microvasculature endothelium [41]. Numerous techniques have been used to immobilize heparin onto synthetic surfaces to mimic the interface between blood and endothelial cells. Mainly two of these technics were retained by the industry: ionically bonded heparin and covalently bonded heparin [42]. Heparin-coated extracorporeal circuits have been assessed in clinical protocols as they have been commercially available for a few years in routing CPB. Recent research has provided evidence that heparin coating reduces the contact phase activation as reflected by lower release of C1-inhibitor–kallikrein complexes [43]. Although reducing the contact phase activation, heparin coating does not reduce the thrombin formation nor the fibrinolytic activity even with full systemic heparinization [4, 5, 43]. For these reasons, it has been considered dangerous to reduce systemic heparinization when using heparin-coated extreacorporeal circuits for CPB [5, 44]. The capacity of heparin coating to decrease complement activation has been documented by many authors. This consistent benefit is mediated through inhibition of the amplification of the alternative complement pathway and subsequent terminal complement complex [45, 46]. The activation of the classic pathway after protamine administration is also reduced by heparin coating [4]. However, the protective mechanism remains unknown. Recent results of heparin-coated LVAD have been published [47, 49]. One of the main cautions was about the stability of heparin coating throughout the duration of prolonged implant. Indeed, it has been demonstrated that about 10% of the ionically bonded heparin is rapidly washed out, even during short-term CPB [42]. Kaufmann and associates [49] have recently confirmed the importance of this leaching effect and demonstrated the stability of the inner layer treatment thereafter. Moreover these investigators provided evidence that coating the Berlin Heart LVAD with heparin results in a very significant reduction in surface deposits [49]. However, extensive studies of heparin-coated LVADs reporting plasma and cellular activation markers are still missing.

Biomembrane mimicry
The concept of biomembrane mimicry is based on the attachment of polymeric phospholipids to mimic the lipidic composition of the outer surface of blood cells [50, 51]. Von Segesser and colleagues [50, 51] have shown in a bovine left heart bypass model that phospholipid surface coating significantly reduces surface deposits after 6 hours of perfusion. Improved biocompatibility of phospholipid surfaces was similar to that achieved by heparin-coated surfaces [50, 51].

Cellular seeding and lining
Appreciation of the central role played by living endothelial cells in maintaining a thrombus-free surface in normal vessels has quite logically stimulated efforts to produce a similar antithrombotic lining in cardiovascular prostheses. The seeding with autologous endothelial cells of the blood-contacting surfaces of vascular prostheses has had conflicting results [52]. In most instances, cells have sloughed off under flow conditions. Although the feasibility of endothelialization of artificial hearts has been shown [53], the high shear stresses and the extended movements of the driving membrane in circulatory assist devices seem to be major obstacles. Therefore, the ability of seeded cells to adhere and resist high shear forces needs to be improved. Furthermore, it remains to be established conclusively that seeded cells will maintain their anticoagulant and other favorable biologic functions. In contrast to endothelial cells, smooth muscle cells form strong attachments to the surface of textured LVADs [54]. However, smooth muscle cells have thrombogenic cell surfaces and exhibit high proliferative activity. Transfecting smooth muscle cells with DNA vectors containing genes for nitric oxide synthase allowed controlled proliferation and reduced platelet adhesion [54, 55]. Modification of cell phenotype and function using recombinant gene technology will probably revolutionize the field of biocompatibility during the next several decades [56, 57].

Inhibition of initial events leading to blood activation
To inhibit the biologic cascades leading to the systemic inflammatory response and hemostatic disturbances, it seems logical to concentrate efforts on controlling the initial events of blood–surface interaction. From the knowledge coming from the literature, it appears essential that we must control the activation pathways of the platelets, contact phase, complement system, and monocytes [58].

Platelet "anesthesia."
Reversible platelet anesthesia is mandatory during assisted circulation. However, in the context of an "internal artificial organ" such as LVAD, platelet adhesion needs to be protected while reversibly abolishing platelet aggregation [58]. The reason is because platelets are vital to the maintenance of vascular integrity that is required for prolonged assisted circulation whereas total abolition of platelet function is only acceptable for a while in the condition of CPB [58]. Therefore, prostanoids and analogs, such as iloprost, are not convenient for using with assisted circulation because they decrease platelet adhesion and aggregation [58]. Furthermore, prostanoids are potent vasodilators [58]. Reversible inhibitors of platelet GP IIb/IIIa receptors are promising pharmacologic agents for cardiology because they prevent platelet adhesion and aggregation. For that reason, and also because these agents do not prevent activation of platelet thrombin receptors, inhibitors of GP IIb/IIIa receptors are not the solution for assisted circulation [58]. On the other hand, aspirin and ticlopidine are not reversible antiplatelet agents. The ideal platelet inhibitor should reversibly restore the GP Ib receptor while selectively inhibiting GP IIb/IIIa receptors. The GP Ib receptor is the main platelet receptor for the formation of the hemostatic plug at high shear stress although patients missing the platelet GP IIb/IIIa receptor are not usually prone to spontaneously bleeding [58].

Contact phase inhibition
There are many inhibitors of the contact phase. The most well studied is aprotinin, which is currently used in aspirin-treated and redo patients undergoing CPB. It has been widely reported that this drug reduces postoperative blood loss and the need for transfusion [59]. Aprotinin is a serine protease inhibitor derived from bovine lung acting as a reversible inhibitor of plasmin, mainly, and kallikrein. We recently demonstrated in vivo that aprotinin reduces the contact phase activation after CPB initiation [60]. We observed that aprotinin decreases the thrombin formation as reflected by reduced levels of fibrinopeptide 1 + 2, thus acting as a potent anticoagulant. Because it has been reported that the extrinsic pathway of coagulation is likely the main trigger of thrombin production during CPB [3], the possibility that aprotinin also prevents activation of the extrinsic coagulation pathway has emerged and is open for debate [60]. Additionally, aprotinin has been proved to reserve the platelet surface glycoprotein Ib receptors when platelet activation occurs [61]. Thus, aprotinin might be an ideal pharmacologic agent for assisted circulation. However, the capacity of aprotinin to decrease complement and neutrophil activation remains controversial [6, 62].

During the early postoperative period, using aprotinin seems to be of great interest for patients undergoing LVAD support [63–65]. Perioperative use of aprotinin, by reducing postoperative blood loss and need for transfusion, results in less secondary right ventricular failure and subsequent lower mortality [64]. The relationship between postoperative bleeding and development of right-sided cardiac failure may be explained by the influence of hemorrhage and resuscitation on cytokine production, subsequent heart and lung injury, and pulmonary hypertension [66, 67]. Moreover, the need for secondary right ventricular assist device is thus decreased as well as the risk of alloimmunization as a result of polytransfusion before heart transplantation [68].

Prolonged administration of aprotinin has not been investigated in patients undergoing long-term circulatory support. However, aprotinin has to be administered intravenously, which is not compatible with full rehabilitation of the patient under circulatory support. Furthermore, repeated or prolonged administration of aprotinin might expose the patient to allergic reactions and renal insufficiency. Other inhibitors of the contact phase such as nafamostat or ecotin have been proposed. Nafamostat mesylate has recently been shown to significantly reduce blood activation during in vitro and in vivo CPB [69]. Ecotin has not been assessed in the setting of CPB [58].

Complement inhibition
Besides heparin coating, several pharmacologic methods have been proposed to inhibit complement activation. Corticosteroids inhibit the formation of C3 and C5, but clinical impact is conflicting [6]. Dexamethasone prophylaxis suppresses the TNF-{alpha} release and improves myocardial performance [70]. However, the fear of emerging bacterial or fungal infections and induced "steroid-diabetes" [70] limits the interest in using corticosteroids for prolonged assisted circulation. The protease inhibitor FUT-175 (nafamostat mesylate) has been proved to reduce complement activation, mainly the classic pathway [71]. Because the alternative pathway is highly predominant in blood activation induced by biomaterials, this drug is of limited interest [6]. Recently, the low-molecular-weight heparin, enoxaparin, has been discovered to inhibit terminal complement complex and elastase release [72]. However, this unexpected benefit has no clear explanation.

Monocyte inhibition
The control of monocyte activation has been poorly documented in cardiosurgical patients. Actually, heparin coating seems to be the main therapeutic option associated with the reduction of cytokine production [73, 74] and procoagulant tissue factor from monocytes [75]. Prostanoids have also been proposed for this issue [58], but the vasodilation they induce is a limiting factor. Recently, Spanier and coworkers [76] have shown that activation of the DNA transcription factor nuclear kappa B (NF-{kappa}B) is involved in the activation of cells on the surface of a textured LVAD. Antiinflammatory interventions targeted against NF-{kappa}B (like acetylsalicylic acid or pentoxyphyline) might be an effective approach to reduce cellular activation on the surface of assist devices [76].

End point inhibition of biologic cascades
Another strategy to reduce blood activation is to control end points of biologic cascades.

Antifibrinolytic drugs
Tranexamic acid and {epsilon}-aminocaproic acid inhibit the distal process of fibrinolytic activity by inhibiting the conversion of plasminogen into plasmin. McKellar and associates [77] have recently evaluated {epsilon}-aminocaproic acid as an alternative to aprotinin treatment in an LVAD population. They reported a similar benefit on hemostasis with both drugs. Furthermore, morbidity was lower with {epsilon}-aminocaproic acid as reflected by reduced renal insufficiency [77].

Modulation of neutrophil-mediated injury
An elegant approach to the problem of neutrophil–endothelium interactions is to use monoclonal antibodies against adhesion molecules [6]. The goal of such a therapy is to block the adherence of the cells and the release of proteolytic enzymes and oxygen free radicals in the vicinity of endothelial cells. Such a method has been associated to a marked decrease in pulmonary injury [78]. However, one major limitation of this therapy is that the treatment has to cover the time frame of molecule expression. To achieve optimal efficacy, it would require a mixture of agents able to neutralize each variety of surface adhesion molecules [11]. Moreover, this immunosuppressive attitude exposes the patient to the risk of infection that is of major importance in the case of assisted circulation. On the other hand, reduced circulation plasma levels of E-selectin have been reported in patients undergoing heparin-coated CPB [74]. Whether it is a consequence of the reduction of previous inflammatory reactions or a direct effect of heparin coating on neutrophil–endothelium interaction remains to be established.


   Conclusions
Top
 Abstract
 Introduction
 What is blood activation?...
 The specific setting of...
 Methods to control blood...
 Conclusions
References
 
Prolonged mechanical circulatory support elicits a systemic inflammatory response and hemostatic perturbations similar to that reported during CPB. However, in the setting of prolonged assistance, the variable "time" adds a new dimension to the problem. A better understanding of the time-dependent modifications of the inflammatory response is crucial for the development of efficient therapeutic interventions. Early implantation of the device might prevent degradation of the recipient’s condition and the related inflammatory response. During the immediate postoperative period, a multisystem approach combining anticoagulant, antiaggregant, antifibrinolytic, and antiinflammatory therapy seems to be useful to control blood activation. However, to respect the integrity of the organism during prolonged assistance, it appears that the control of blood activation has to be limited to the area of the device rather than applied to the whole body. Reduced shear stresses by optimal device design, and patient-device synchronization, and improved biocompatibility of devices are mandatory to successful long-term mechanical circulatory support [35, 48].


   References
Top
 Abstract
 Introduction
 What is blood activation?...
 The specific setting of...
 Methods to control blood...
 Conclusions
 References
 

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