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Blood-Borne Tissue Factor (Including Microparticles)

and .

Minor amounts of biologically active tissue factor (TF) are always constitutively present in circulating blood of healthy individuals. In various diseases, including those underlying the induction of disseminated intravascular coagulation (DIC), the level of circulating TF may be subject to changes due to production or release of the factor from peripheral monocytes or subendothelial structures. Thus TF will emerge on the surface of monocytes upon synthesis induction and become available from the subendothelium subsequent to permeability changes or damage to the endothelium. In subendothelial strata, significant amounts of TF are constitutively present in fibroblasts, pericytes and macrophages.

Several pathophysiological conditions are associated with monocyte activation and ensuing TF expression. The degree to which TF activity is expressed strongly hinges on a P-selectin-dependent interaction between monocytes, platelets and granulocytes. Part of the role of the latter two cell types is believed to entail a decryption process, unfolding to its full potential the TF activity of circulating monocytes, of which otherwise about 80% is encrypted and not available at the cell surface. Monocyte-derived TF-rich microparticles possessing P-selectin glycoprotein ligand-1 (PSGL-1) either bind to activated platelets or to platelet-derived microparticles expressing P-selectin, in the process generating a favorable microenvironment for TF activity expression. Alternatively, selectin-ligand interactions may facilitate the generation of active TF-containing hybrid microparticles of monocyte and platelet origin. The recent reports on TF localized on granulocytes are probably dealing not with TF originating in granulocytes per se, but rather with granulocyte-bound, TF-rich platelet/monocyte-derived microparticles.

Although endothelial cells (EC) have been shown to synthesize large amounts of TF in vitro, it is the opinion of the authors that evidence is pending for any relevance of this observation to the in vivo situation. Rather, the TF observed in association with the endothelium probably corresponds to TF-rich, monocyte-derived microparticles bound to activated endothelial cells. In conclusion, the phenomena observed thus far are best accounted for by monocytes serving as the sole TF-synthesizing cells in the peripheral circulation.


In 1905 Morawitz proposed a three-step theory of blood clotting.1 Platelets were seen as containing tissue thromboplastin (tissue factor, TF) activity that was released at sites of damage to the vessel wall in vivo or upon contact with some foreign surface in vitro. The ensuing step entailed TF activity-promoted conversion of the inert precursor prothrombin to thrombin in a calcium-dependent manner, the generated thrombin eventually cleaving fibrinogen to fibrin.

The discovery of many additional clotting factors, beginning with Owren's identification of a patient with a congenital lack of factor V (FV) in 19432 and followed by a string of reports pertaining to deficiencies in FVII, 3,4 FIX, 5,6 and FX,7 rendered this classical theory obsolete or at the very least grossly incomplete.

Coon8 and Hjort9 showed that FVII formed a complex with TF in the presence of calcium. In 1964, the cascade10 and waterfall11 theories launched the idea of TF-mediated conversion of FVII to an enzyme with a FX-activating potential. Nemerson12 reviewed the notion of an extrinsic FX activator working in a manner analogous to the prothrombin-converting complex, suggesting that the activator was comprised of FVII, TF and calcium ions forming a complex.

The current view of the role of TF is the following. TF forms a complex with FVII/FVIIa, and by way of limited proteolysis the active TF/FVIIa complex converts FIX and FX into the corresponding active forms, FIXa and FXa, respectively.13 Although association of FVIIa and TF is greatly enhanced in the presence of calcium ions and phospholipids,14,15 neither is an absolute prerequisite for the interaction.15,16 This was also shown when FVII was allowed to interact with phospholipids (PL) in the presence of Ca2+, and then exposed to phospholipase C (PLC) or vehicle only. Although the PLC treatment led to gross inactivation of PL, only a 80–90% reduction in FVIIa activity was seen.17 In contrast, FVIIa similarly recombined with PL was not affected by the PLC treatment of PL.

When bound to TF, FVII can be activated by FXa, FIXa, FVIIa, or thrombin.18–20 Part of this activation requires membrane anchoring.21 Although the low amidolytic activity of FVIIa is enhanced up to 100-fold in the presence of TF,22,23 membrane anchoring is not required for this to occur.24,25 In contrast, the activation of FIX and FX is highly dependent on membrane anchoring,26 and is supported by negatively charged phospholipid.27–29

Distribution of TF

An early assessment of the gross distribution of TF was accomplished by testing different tissues for overall TF activity. In this way Astrup30 provided evidence for high levels of TF activity in the brain, lung and kidney. Employing increasingly available specific mono and polyclonal antibodies to TF, detailed immunohistochemical analyses of the actual distribution of TF antigen in various tissues have more recently been brought about. Table 1 summarizes the localization of TF antigen in human tissues. Generally the brain, lung, kidney and placenta are very rich in TF.

Table 1. The distribution of TF in human tissues.

Table 1

The distribution of TF in human tissues.

The realization that TF of blood vessels is predominantly localized in adventitia, deeply hidden away from the vessel lumen, prompted the launching of an “envelope” theory, entailing the notion of TF as a hemostatic envelope encapsulating the vascular bed, already present for setting off blood clotting should the integrity of the vasculature be compromised.31

However, more recently it has become evident that whole blood, even in healthy subjects, may contain active TF as demonstrated by the prolongation of the clotting time of whole blood when anti-TF antibodies are added.32 Such circulating TF is anticipated to derive from circulating monocyes, which may release TF-bearing microparticles to the plasma. This topic is discussed later on in this chapter.

TF in the Endothelium?

In vivo findings do not favor the notion of an important role for TF in activated endothelium per se and are at odds with results emerging from in vitro studies pertaining to the expression of TF in endothelial cells. Endothelial cells isolated from umbilical veins (HUVEC) were shown to generate TF activity when exposed to LPS, thrombin, IL-1b, TNF, etc. (for review, see 33). ECs need to be subjected to relatively harsh treatment, including collagenase digestion, in order that they may become available for in vitro studies, the overall process normally taking 4 days. In this very process the cells must acquire characteristics that are far removed from those of ECs resident in the blood vessel wall, the propensity for TF expression apparently being one such attribute. Thus, saphenous veins and internal mammary arteries from coronary bypass failed to show endothelial TF expression.34 Furthermore, when we subjected isolated saphenous veins to perfusion with buffers containing LPS or thrombin, no induction of TF activity was detected in the ECs,35 whether on intact endothelium or in ECs subsequently isolated.

We also failed in finding TF exposure in ECs from rabbits subjected to Schwartzman reaction by the intravenous injection at 24 hours interval of two doses of LPS.36 Corroborative evidence emerged from another more recent study on rabbits, where dual immunohistochemical staining for TF and vWF revealed no detectable endothelial TF antigen.37 In apparent contradiction to the latter two studies, one study claimed a rise in procoagulant activity (PCA) identified as TF in thoracic aorta harvested from rabbits subjected to endotoxin injection.38 Conceivably this PCA may be of non-endothelial origin, arising from, e.g., TF-bearing, monocyte-derived microparticles that also contain the ligand PSGL-1, facilitating their binding to activated endothelium via the exposed receptor P-selectin. After lethal doses of E. coli had been given intravenously to baboons, a thorough immunohistochemical examination revealed the absence of TF antigen in the endothelium of all tissues of the animal apart from those of the spleen.39

Altogether a notion emerging from a whole range of studies is that the propensity for TF expression of ECs propagated in vitro, as reported by many, hinges on poorly defined cellular traits acquired during the isolation and culturing processes and is hence of an artifactual nature. Our opinion is that in the absence of any injury to the vessel wall, there is no exposure to blood of extraluminal tissue factor except when monocytes become activated, e.g., leading to the tethering of TF-bearing microparticles at the endothelial surface. However, when conditions arise where the endothelial barrier is compromised due to, e.g., EC damage, leading to enhanced barrier permeability, plasma factors may rapidly gain access to TF already present in subendothelial strata, and henceforth thrombin generation is initiated. Such is the state that may pervade the microcirculation of several organs of a patient subject to the DIC syndrome.

Localization of TF in Cells

It is well established that TF activity associated with stimulated cells is strongly encrypted. Thus, in activated monocytes examined for the availability of TF antigen, 75% of the antigen had emerged on the surface, whereas only 10–15% of the TF activity acccessible from lysed cells was available on intact cells.40 More recently, three pools of TF antigen constituting the total TF were quantified in smooth muscle cells following lysis of the cells with β-octyl glucoside.41 It was estimated that about 20% of the total cellular TF is available on the surface, about 30% is intracellular, and some 50% is latent. The intracellular material was found to be associated with sufficient membrane material to be biologically active if released.42 Thus, by subjecting TF-bearing cells to a succession of freeze-thaw cycles, calcium ionophore, or PMA, TF increased markedly without TF mRNA or protein being significantly affected.43,44

In order to explain the encryption phenomenon, a mechanism of clustering of TF molecules in the membrane has been suggested, whereby the activity is kept at a limited lower value and only reaching its full potential when the molecules are dispersed.42 Calcium ionophore has been shown to cause a 100-fold rise in the TF activity of intact cells.45 This effect was blocked by pretreating the cells with calmodulin inhibitors. It was hypothesized that the rise in TF activity upon decryption may stem from the exposure of an essential macromolecular substrate binding site in the TF-VIIa complex, as a direct consequence of some change in TF quarternary structure. More specifically the cryptic form was suggested to be TF dimers which were then converted to active monomers. In a recent study, it was concluded that the calcium ionophore effect in decrypting TF activity is not solely the result of increased availability of exposed phosphatidylserine, and the FVIIa/TF substrate specificity is not altered by the decryption process.46

Interactions of monocytes with other blood cells may therefore not only affect their TF activity at the level of synthesis or degradation, but also at the level of activity encryption or decryption. TF activity expression in blood may be regulated by the profusion of microparticles derived from platelets and monocytes, possibly one of the most efficient and important ways to decrypt monocyte-derived TF activity in vivo.

Cellular Interactions in the Expression of TF in Monocytes

Until quite recently, monocytes were thought to be the only blood cells capable of synthesizing and carrying TF. The question whether neutrophils somehow share the same attribute will be addressed later on in the discussion.

Although it has been claimed that circulating monocytes in healthy individuals are free of TF, only expressing TF upon exposure to some agonist, such as LPS,47 it has become evident that this notion has to be reassessed. In the presence of TF-neutralizing antibodies a prolongation of whole blood clotting time was detected when utilizing sensitive fibrin detection equipment (Ranby and Østerud, unpublished data). Furthermore, TF as monitored by FXa formation could be extracted from whole blood and plasma of healthy subjects.48

Activation of monocytes appears always to be accompanied by the expression of TF. A list of potential agents which may induce or enhance TF in monocytes is presented in Table 2. A series of diseases are currently considered to be associated with the expression of TF in circulating monocytes. These are shown in Table 3. In order to understand the pathophysiology of TF expression in circulating monocytes, it is important to gain insight into how TF is induced as well as how TF synthesis and activity expression are regulated.

Table 2. Agents that induce or enhance monocyte activation.

Table 2

Agents that induce or enhance monocyte activation.

Table 3. Conditions where TF may be an integral part of the pathophysiological roles of the monocyte.

Table 3

Conditions where TF may be an integral part of the pathophysiological roles of the monocyte.

Even before it was established that monocytes produce TF, it was shown that platels enhance the expression of TF in leukocytes.49 This was later confirmed in monocyte cell cultures, the mechanism suggested being an up-regulation of TF by 12-HETE derived from activated platelets.50,51 Correspondingly, we were able to demonstrate a platelet effect in our whole blood ex vivo system.52 This whole blood model, comprising blood anticoagulated with heparin or hirudin and stimulated with low dose LPS (5 ng/ml), revealed that TF activity varied within a wide range between individuals, amounting to a 50-fold difference between the highest and the lowest values.53 Part of this variation was accounted for by individual differences in platelet function. Thus, when platelet-depleted blood cell fractions from the different test subjects each were recombined with homologous platelet-poor plasma (PPP) and platelets from different subjects then added, the platelets from a high responder (expressing high TF activity in stimulated monocytes) up-regulated TF expression in a reconstituted cell/plasma system from a low responder.54

The vital role of cellular interactions for the expression of TF activity in monocytes was further documented by utilizing a more refined system reconstituted from separated fractions of blood cells, i.e., mononuclear cells, granulocytes, PRP and heparinized platelet-poor plasma (PPP). In this ex vivo model system, it was demonstrated that this platelet effect was totally dependent on the simultaneous presence also of granulocytes.55 Considering that LPS is a poor agonist of platelets as well as granulocytes, it was a revealing observation that these cells amplified LPS-induced TF activity in monocytes in a co-dependent manner. The phenomenon may be accounted for by the following scenario: TNF endogeneously generated by the LPS-stimulated monocytes potently activating the granulocytes, leading to production and release of platelet-activating factor (PAF), which in turn has an up-regulating effect on LPS-induced TF activity. This up-regulating effect of PAF has been shown to totally hinge on the presence of platelets.54 Furthermore, a PAF antagonist was found to inhibit LPS-induced TF activity. The cellular interaction between monocytes, platelets and granulocytes is depicted in Fig. 1.

Figure 1. Cellular interactions between monocytes, platelets and granulocytes instrumental in LPS-induced TF expression in monocytes of whole blood.

Figure 1

Cellular interactions between monocytes, platelets and granulocytes instrumental in LPS-induced TF expression in monocytes of whole blood. TNF (not shown) generated during incubation of whole blood with LPS, promotes granulocyte activation. Once activated (more...)

It was shown that anti-CD15 antibodies interfered negatively with the cellular interactions described above, leading to almost total abolishment of the up-regulation of TF activity.55,56 Since CD15 is a leukocyte membrane-bound ligand for P-selectin, a scenario may be suggested where monocytes and granulocytes are bound via P-selectin exposed on the surface of activated platelets, thus leading to a proximity of the cells involved in the up-regulation of monocyte TF by LPS. Further evidence in favor of this hypothesis is the observation that anti-P-selectin antibodies partially inhibited LPS-induced TF activity in monocytes.56

Monitoring TF antigen using ELISA and Western blot techniques and at the same time monitoring the correponding TF activity, we recently showed that the platelet effect was discernable only as enhanced TF activity without any corresponding rise in TF antigen.57 Why this asymmetry occurs has not been sorted out, but conceivably the activity up-regulation may hinge on some platelet-monocyte fusion event involving exchange of available PS. By acquiring PS from the platelet membrane, marginally active TF antigen present in the monocyte membrane may have its specific activity up-regulated. Alternatively, the platelet-dependent rise in TF activity is somehow inherent in the generation of monocyte-derived microparticles with decrypted TF activity. Corroborative evidence for the latter notion is the observation that monocyte-derived, TF-containing microparticles may be associated with platelet microparticles, thus providing a mechanism for platelets to indirectly up-regulate TF activity via its microparticles.58 Whatever the predominant mechanism, evidence is mounting that platelets do play a role in decrypting the activity of TF in monocyte membranes. This is discussed further in the section on microparticles below.

Regulation of TF Expression in Monocytes

Comparing our results from studies using the relatively physiological whole blood system with the like issuing from cell culture studies, there is a striking difference in the way monocytes behave under the two types of conditions. Whereas a protein kinase C (PKC) inhibitor had no effect in the whole blood system (Østerud, not published), it potently inhibited LPS-induced TF in monocyte cell cultures,59 indicating that the PKC system is not launched during LPS-stimulation of monocytes in whole blood. This was corroborated by our findings that PMA or TNF alone both failed in inducing TF expression using the whole blood system,55 in contrast to the results obtained using cultures, where either stimulant turned out a potent inducer of TF expression.59–61 On the other hand, provided LPS was present as a stimulant in the whole blood system, the presence of PMA or TNF enhanced monocyte TF expression another 2–3-fold, indicating that the latter agents only affect already aroused monocytes.55

A reasonable interpretation of the above results would be that isolated and cultured monocytes are already driven into a certain state of activation. This is borne out also by the observation that TF mRNA was expressed in unstimulated PBMC and adherent monocytes, but not in monocytes of whole blood.62 Further evidence to the effect that monocytes behave differently under the two types of conditions was obtained from three types of studies, where the following aspects were investigated: melatonin effects on LPS stimulation, oral contraceptive effects on TF expression, and aspirin effects on TF expression, respectively.

It has been reported that melatonin induced oxygen radicals in monocyte cell cultures through a PKC-dependent reaction.63 In contrast, in our whole blood system the addition of even trace amounts of melatonin (10–100 pg/ml) gave a dose-dependent inhibition of LPS-induced TNF as well as TF in monocytes, an effect that is apparently PKC independent.64 Only when PMA was added in addition to LPS did melatonin further enhance the production of TNF and TF. Thus, melatonin seemed to up-regulate the PKC-system, but PMA was required to initiate the PKC activation.

Recently it was reported that TF expression is enhanced in women using oral contraceptives, based on the measurement of enhanced TF gene transcription following activation of NF-κB in cultured monocytes.65 In contrast, we have shown that LPS-induced TF in monocytes of whole blood was suppressed in women using oral contraceptives.66

Whereas some reports proclaim an inhibitory effect of aspirin (acetylsalicylic acid/ASA) on LPS-stimulation of monocytes in cell cultures,67,68 in our whole blood model we found the opposite to be the case. We showed that prior intake of 300 mg ASA caused a significant enhancement of LPS-induced TF activity in the monocytes of stimulated whole blood.69 Similar enhancement of LPS-induced TF expression was found also in another study testing the effect of sodium salicylate on whole blood.70 Recently, it was shown that humans who had taken in ASA just prior to the injection of a small amount of LPS had enhanced TF associated with the circulating monocytes relative to controls who did not receive ASA, in accordance with our ex vivo model studies.71

Despite the failure of TNF by itself in inducing TF expression in monocytes of whole blood,72 TNF amplified severalfold LPS-induced TF activity in a P-selectin-dependent reaction, where granulocytes and platelets were centrally involved.55 An autocrine effect was demonstrated using TNF-derived peptides.73 Thus, a TNF 78–96 peptide which bound to the TNF receptor(s) without potentiating the same signals as native TNF caused an inhibition of LPS-induced TF activity in monocytes of whole blood. Furthermore, upon injection of TNF in animals, activation of the coagulation system is induced.74

In an attempt to gain further insight into the cellular signal network involved in the expression of TF activity in monocytes, a cocktail mixture comprised of different inhibitors and receptor antagonists was added to heparinized blood stimulated with LPS, the idea being to interfere not only with single signaling steps but also with any crosstalk and synergistic pathways. By systematically deleting single agents or different combinations of two agents from the inhibitory cocktail, it was shown that three substances were responsible for 80% of the total cocktail inhibitory effect on LPS induced TF activity.75 These were the PAF receptor (PAFR) antagonist, the thromboxane A2 (TxA2) receptor antagonist and a protease inhibitor, as illustrated in Figure 2. The PAFR antagonist effect was in accordance with results from our earlier studies.54 The effect of the TxA2-receptor antagonist was a novel and quite interesting finding, considering that ASA failed in preventing atherosclerosis in Apo E-deficient mice (mice strongly disposed for atherosclerosis development), whereas an antagonist to the PAFR significantly decreased aortic root lesions as well as serum ICAM-1 levels.76

Figure 2. Regulation of monocyte activation in whole blood.

Figure 2

Regulation of monocyte activation in whole blood. LPS present in whole blood is forming a complex with LPS binding protein (LBP, not shown). This complex is interacting with the TLR4 receptor on the monocyte surface, invoking a series of reactions ultimately (more...)

Do Neutrophils Synthesize and Express TF?

Since the discovery that TF may be induced in monocytes,47 several attempts have been undertaken in order to resolve whether any of the other blood cells may harbour TF. The first report proclaiming the presence of TF also in neutrophils, derived from a study of TF expression in tissues of animals subjected to LPS. Infiltrating neutrophils in the liver of rabbits with acute obstructive cholangitis (AOC), one of the most fatal causes of sepsis, were demonstrated immunohistochemically using specific anti-TF antibodies.77 The same group later found that in this in vivo animal model PAF plays an important role in neutrophil TF expression.78 These investigators recently claimed that neutrophils accumulating in the liver of monkeys 3 hours after i.v. administration of LPS contained TF antigen as well as TF mRNA.79

However, the most significant contribution to the debate whether neutrophils express TF came from a study identifying TF-containing neutrophils and monocytes immunocytochemically in peripheral blood, using a set-up where native human blood was allowed to flow on collagen-coated glass slides.48 It was suggested that blood-borne TF is deposited on platelets in the nascent thrombus, thereby forming “TF-platelet hybrids”. Although TF-positive neutrophils were repeatedly observed, the authors concluded that they do not as yet know whether the TF harbored by the neutrophils was endogenously synthesized or engulfed exogenous material subsequently transported to the site of thrombus growth.

The question whether human neutrophils themselves are capable of synthesizing and expressing TF was addressed in another study using a whole-blood system as well as isolated blood cell fractions. Isolated granulocytes recombined with heparinized plasma failed to express any significant amounts of TF antigen or activity when stimulated with LPS or LPS in combination with PMA or TNF.57 However, when heparinized whole blood was subjected to LPS + PMA for 24 hours, the isolated granulocytes contained some TF activity as well as antigen. By using techniques to secure the removal of contaminating monocytes from the granulocyte fraction, it was found that the specific activity of TF in granulocytes was about 0.05 mU/106 granulocytes as compared to 150 mU/106 monocytes, and the corresponding levels of TF antigen 0.27 pg/106 granulocytes as compared to 4652 pg/106 monocytes. It was suggested that monocytes are the principal source of TF production in circulating blood, a notion which was later challenged by an editorial commentary.80 The major objection was that only 3 agonists were tested, and that TF synthesis may be induced in these cells by other agonists, possibly under the influence of the conditions of high shear stress that prevail in the circulation and that may affect protein synthesis.

Considering all the reports and evidence that TF may be associated with neutrophils, it is our opinion that the phenomenon may be explained by the generation and dispersal of TF-rich microparticles derived from activated monocytes as discussed below.

Decryption of TF by Platelets and Microparticles

Monocyte shedding of microparticles with membrane-associated procoagulant activities was obtained by LPS-stimulation of monocytes.81 On these microparticles were detected both exposed TF as well as phosphatidylserine, the active template in the coagulation enzyme complex, in addition to the adhesion molecules CD14, CD11a and CD18.

An atherogenic role of microparticles of probably mainly monocyte origin can be indirectly inferred from a study where high levels of shed membrane apoptotic microparticles were detected in extracts from atherosclerotic plaques.82 These microparticles expressed both TF and phosphatidylserine. Microparticles derived from platelets have for many years been known as quite thrombogenic.83,84 They are released from activated platelets and express functional adhesion receptors, including P-selectin, on their surface. Platelet microparticles provide a catalytic surface of phosphatidylserine that accelerates coagulation,85–87 and they can bind to neutrophils and monocytes.88 Platelet microparticles have been shown to be present in various diseases.89–91,82,83,92–94

In a recent study it was found that thrombogenic TF on leukocyte-derived microparticles became incorporated into spontaneous human thrombi.95 It was suggested that monocytes and possibly PMN leukocytes are the source of circulating plasma TF which may be transferred to platelets, in effect producing TF-positive platelets capable of triggering and propagating thrombosis. This transfer process was mediated by the interaction of CD15 with platelets and also by TF, which seems to act as an adhesion molecule.96 This observation is in agreement with our own findings that anti-CD15 antibodies abolish about 80% of LPS-induced TF activity in monocytes of cell suspensions recombined with platelet-rich plasma.55

In another study using monocytes in combination with platelet-rich plasma and incubated for 24 hrs in the presence of LPS plus PMA, only a small amount of monocyte TF activity was generated in the absence of platelets, rising almost twenty-fold when the monocytes had been combined with platelets.58 Furthermore, isolated platelets possessed significant amounts of TF after stimulation of blood with LPS alone for 2 or 6 hrs, whereas no such activity was discernable after 24 hrs incubation. The additional presence of PMA during the stimulation further enhanced the platelet TF obtained after 2 or 6 hours severalfold, the activity level tapering off to a 24-hour value about half of that at 6 hours.

Microparticles isolated from blood stimulated with LPS alone had no detectable TF activity as measured by a sensitive clotting assay, whereas microparticles isolated from blood stimulated with LPS + PMA expressed significant amounts of TF activity at 6 and 24 hrs incubation (highest at 24 hrs).

These results indicate that platelets play a central role in the decryption of TF and transfer of TF from monocytes to microparticles, and the TF reported to be associated with PMNs may probably somehow be accounted for by this mechanism (see Fig. 3.).

Figure 3. Shedding of tightly associated or hybrid microparticles derived from monocytes and platelets.

Figure 3

Shedding of tightly associated or hybrid microparticles derived from monocytes and platelets. Tight interactions between monocytes (Mo) and platelets (plt), mediated by the ligands PSGL-1 and CD15 on monocytes and their conjugate receptors on platelets, (more...)

In Vivo Evidence of Blood-Borne TF

Strong evidence for a central role of hypercoagulable monocytes in the pathophysiology of meningococcal infection was found when this disease was shown to be associated with high levels of TF in circulating monocytes.97 There was a close correlation between TF activity levels in monocytes isolated from the patients' blood on admission to the hospital and the outcome of the disease. High levels of monocyte TF activity, i.e., 60–300- fold or more above that of cells in healthy subjects, always prevailed in patients for whom the disease had a lethal outcome.

During our investigations on blood of patients suspected to be infected by meningococci, a simple centrifugation technique was devised for assessing the extent of blood cell activation.98 When isolating mononuclear cells from normal blood freshly collected in EDTA or heparin by centrifugation on Lymphopaque (Nycomed, Oslo, Norway), no sign of cell clumping in the mononuclear/platelet cell band is apparent using either anticoagulant. A rather different outcome was obtained using blood of severe meningococcocemia patients, the anticipated mononuclear band being virtually cell free or containing small cellular aggregates only, depending on whether heparin or EDTA had been used as anticoagulant. This phenomenon coincided with severely impaired peripheral blood circulation in the patients. The explanation suggested was that the cells were already extensively aggregated when the blood was collected, in a partially calcium ion-dependent fashion, leaving very few cells at the interphase when heparin was present, whereas EDTA dissolved the aggregates sufficiently to allow for a significant retention at the interphase. The aggregates may be formed by way of extensive crosslinking from P-selectin exposed on activated platelets or on platelet-derived microparticles, also known to contain P-selectin, to the corresponding P-selectin glycoprotein ligand-1 (PSGL-1) on granulocytes and monocytes/monocyte microparticles. Being thus strongly associated with granulocytes (Fig. 3.), both monocytes and platelets will sediment to the bottom of the tube. Calcium ions are clearly required for the interaction between P-selectin and PSGL-1, since EDTA is known to reduce the interaction by about 60%.

TF Expression in Microparticles in Meningococcal Disease

Recently it was reported that plasma from patients with fulminant meningococcal sepsis contained microparticles expressing CD14 and TF. Relative to normal control plasmas, there were elevated numbers of microparticles orginating from various cell populations, e.g., endothelial cells, monocytes and granulocytes. Correspondingly, the plasma procoagulant activity was enhanced, as revealed by extreme thrombin generation in vitro.93 Of the seven patients studied, one patient with severe DIC uniquely had an extremely elevated number of endothelial cell-derived microparticles compared to controls. However, 85% of the TF-positive microparticles were also CD14 positive. It was therefore concluded that first and foremost the overall procoagulant activity was due to an increased number of monocyte-derived microparticles.

Experimental evidence and theoretical considerations suggest that granulocyte-derived and endothelial cell-derived microparticles may both be associated with TF, albeit probably only indirectly. Thus, by way of their common expression of the ligand PSGL-1, granulocyte-derived microparticles and TF-containing, monocyte-derived microparticles may be associated via bridging platelet microparticles (or platelets) exposing P-selectin, whereas EC-derived microparticles exposing P-selectin may associate directly with monocyte-derived microparticles. By inference, one may hypothesize that at the site of an injury to the vessel wall, activated and adhered platelets may “sweep” the blood and bind activated monocytes as well as their derived TF-expressing microparticles, in effect invoking a gathering of cells and microparticles of strong thrombotic potential (see Fig. 4.).

Figure 4. Formation of a thrombogenic plug at the site of a vessel wall injury.

Figure 4

Formation of a thrombogenic plug at the site of a vessel wall injury. Platelets (plt) adhering to collagen at the site of an injury and exposing P-selectin are capturing circulating monocytes (M), granulocytes (Grc) and monocyte-derived microparticles (more...)

Since the microparticles in addition to expressing TF also tend to be enriched in phosphatidylserine at their surface, therby providing for high TF activity, it was suggested that microparticles are somehow involved in the pathogenesis of DIC during meningococcal sepsis.93

TF in Plasma

It can be anticipated that microparticles tend to be associated with circulating cells or activated endothelium. Notwithstanding this notion, there have been reports over the last decade on elevated TF antigen in plasma, notably in DIC patients. One such study reported that 40% of the DIC patients expressed high plasma TF levels.99 Probably the high values were mostly derived from truncated soluble TF devoid of biological activity, since TF antigen did not correlate with hemostatic markers typically associated with DIC, such as prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex, FDP, D-dimer, or fibrinogen. Interestingly, serial monitoring of plasma TF antigen revealed that most patients having elevated TF antigen at the moment of presentation of DIC were subject to plasma TF changes running roughly in parallel with the progression of DIC. This may be accounted for by a rise in TF release to the circulation concomitantly with a worsening of the primary disease, in turn promoting aggravation of the DIC condition.

Although significant elevation of plasma TF antigen has been detected in cases of DIC associated with certain types of cancer,100 no such elevation was observed in similar cases associated with other types of cancer. Nor had patients without DIC any significant elevation of TF, except in 4 cases of cancer with later onset episodes of DIC.

The apparent discrepancies issuing from these studies are probably rooted largely in the diversity of DIC states, evident, e.g., in the extent to which the walls of the microvasculature have been damaged. Furthermore, the result may be influenced by poorly standardized and hence variable specificity of TF antigen measurements. Thus some of the assays are probably detecting falsely high levels of plasma TF antigen (Luther, personal communication), the lesson being that data from such antigen measurements should be interpreted with caution.

Biological Activity of Plasma TF?

Despite the observation that plasma TF antigen does not correlate with activation markers of DIC and the failure at detecting biologically active TF after orthopaedic surgery where relatively high amounts of TF antigen are present in plasma,101 a potential role of plasma TF may indirectly be inferred from recent data. Thus, three different groups have reported that TF activity is present in association with activated platelets.102–104 To account for this, one may hypothesise that relatively inactive TF antigen present in plasma may be subject to a binding and fusion process at detergent-like areas at the surface of activated platelets, where the phosphatidylserine-enriched milieu would allow its activity potential to unfold. This scenario might also provide for an alternative explanation to the observation that blood passing over a collagen surface ex vivo may generate TF activity in the platelet plugs evolving on top of the surface.95 On the other hand, since the amount of serum TF antigen did not correlate with the DIC markers, this particular pool of TF may not play an important role in DIC.


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