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(Circulation Research. 1995;77:645-650.)
© 1995 American Heart Association, Inc.

Articles

Thrombin and Proliferation of Vascular Smooth Muscle Cells

Gunnar Fager

From the Wallenberg Laboratory for Cardiovascular Research, Sahlgren's Hospital, S-413 45 Göteborg, Sweden.

Correspondence to Gunnar Fager, MD, PhD, Wallenberg Laboratory for Cardiovascular Research, Sahlgren's Hospital, S-413 45 Göteborg, Sweden.

Key Words: thrombin • transcription factor • platelet-derived growth factor • fibroblast growth factor • smooth muscle cells

	Introduction

Top Introduction Enzymatic Properties of Thrombin Cellular Effects of {alpha}... Human Thrombin Cell Surface... Activation of the Thrombin... Intracellular Signaling Pathways Differential Regulation of Proto... Thrombin Inhibitors and Cell... Concluding Remarks References

 
Thrombin is a well-established promoter of vascular SMC proliferation in vitro. A similar role has been suggested but not yet proven in vivo. The effect is mediated via selective receptors expressed on vascular SMCs in vitro. Activation of the thrombin receptor leads to a number of intracellular signaling events as well as to stimulation of endogenous PDGF–A chain and bFGF production. The proto-oncogenes c-fos and c-myc, which code for nuclear proteins needed for the induction of proliferation, are induced by PDGF and bFGF. Both growth factors activate protein kinase C. Thrombin rapidly induces only PLC and c-fos but does not activate protein kinase C.

Thrombin-induced receptor activation and intracellular signaling are prevented by substances that block the catalytic and/or receptor binding domains of thrombin. These substances also block thrombin-induced expression of PDGF and bFGF. Furthermore, thrombin-induced proliferation of vascular SMCs is blocked by antibodies to PDGF and FGF. Thus, the possibility must be considered that thrombin influences proliferation of susceptible SMCs by inducing an autocrine or paracrine stimulation via PDGF and/or bFGF.

	Enzymatic Properties of Thrombin

Top Introduction Enzymatic Properties of Thrombin Cellular Effects of {alpha}... Human Thrombin Cell Surface... Activation of the Thrombin... Intracellular Signaling Pathways Differential Regulation of Proto... Thrombin Inhibitors and Cell... Concluding Remarks References

 
Thrombin has important roles in wound healing: promoting the coagulation of blood, accumulation of inflammatory cells, and proliferation of mesenchymal cells.

Enzymatically active thrombin (-thrombin) is formed from the circulating precursor prothrombin by hydrolytic cleavage (reviewed in Reference 1¹ ). This hydrolysis is initially slow and catalyzed only by factor Xa. Subsequently, -thrombin activates factor V, which operates as a cofactor to factor Xa and accelerates the formation of -thrombin. Furthermore, factor VIII is activated by -thrombin to participate in the production of more factor Xa.

-Thrombin belongs to the superfamily of serine proteases and cleaves its target proteins C-terminally to R (one-letter code for arginine) residues. Structural studies (reviewed in Reference 2² ) have revealed a sequence in -thrombin in which the catalytic site containing an S-H-D motif lies immediately distal to arginine's guanidine side-chain binding site (the arginine side-chain pocket) (Fig 1). Flanking these domains are regions involved in specific hydrophobic and ionic interactions: proximal to the arginine side-chain pocket is an apolar binding site, and distal to the catalytic site is an anion-binding site (exosite).

View larger version (31K): [in this window] [in a new window]   Figure 1. Schematic showing thrombin and its cell surface receptor. One-letter codes are used to indicate functionally important amino acid sequences. Arrow indicates where thrombin cleaves the receptor.

By its apolar and anion-binding sites, -thrombin specifically binds fibrinogen via hydrophobic and ionic interactions.² The Aa and Bb chains of the three-chain fibrinogen molecule bind with slightly different amino acid motifs and are hydrolyzed at the R¹⁶ and R¹⁴ residues, respectively, at different rates. The enzymatic removal of the N termini (fibrinopeptides A and B, respectively) creates active fibrin monomers that polymerize into the fibrin mesh of the developing blood clot.

-Thrombin is eliminated by proteolytic degradation and by binding to inactivator molecules. A number of proteases are involved in the formation of the inactive metabolites ß- and -thrombin. AT III is the most important native inactivator of -thrombin in plasma. -Thrombin binds slowly to AT III to form the TAT complex, which is neither a procoagulant nor a cell stimulator. Heparin binds AT III specifically and significantly facilitates the subsequent binding to -thrombin. This explains part of the anticoagulant activities of heparin.

	Cellular Effects of -Thrombin

Top Introduction Enzymatic Properties of Thrombin Cellular Effects of {alpha}... Human Thrombin Cell Surface... Activation of the Thrombin... Intracellular Signaling Pathways Differential Regulation of Proto... Thrombin Inhibitors and Cell... Concluding Remarks References

 
Apart from its central role in blood coagulation, thrombin has a number of cellular effects. Thrombin activates platelets^{3 4} to adhere, aggregate, and release serotonin, thromboxane A₂, platelet factor 4, PDGF, and several procoagulant substances (fibrinogen, factor V, and phospholipid membranes). It stimulates vascular endothelial cells to produce platelet-activating factor,⁵ prostacyclin,⁶ plasminogen activator-inhibitor,⁷ and PDGF.⁸ Thrombin is also chemotactic for monocytes⁹ and mitogenic for lymphocytes.¹⁰ Furthermore, thrombin has been associated with proliferation of mesenchymal cells, including vascular SMCs.^{11 12} A cell surface receptor that accounts for these cellular effects has been identified.

	Human Thrombin Cell Surface Receptor

Top Introduction Enzymatic Properties of Thrombin Cellular Effects of {alpha}... Human Thrombin Cell Surface... Activation of the Thrombin... Intracellular Signaling Pathways Differential Regulation of Proto... Thrombin Inhibitors and Cell... Concluding Remarks References

 
A functional human cell surface receptor for thrombin was recently cloned and expressed in Xenopus oocytes by microinjection of a size-selected cDNA library from megakaryocyte-like Dami cells.¹³ The deduced 425–amino acid sequence discloses a new member of the seven-transmembrane-domain receptor family by the presence of repeated hydrophobic domains (Fig 1). A disulfide bond is proposed between extracellular loops I (C¹⁷⁵) and II (C²⁵⁴). The extracellular N-terminal domain contains a sequence (L³⁸-D³⁹-P⁴⁰-R⁴¹-S⁴²) very similar to the thrombin cleavage site in zymogen protein C (LDPRI). Activation of protein C by thrombin is associated with a proteolytic cleavage after the R residue.¹⁴ Twelve residues further downstream, there is a highly acidic sequence (E⁵³-P⁵⁴-F⁵⁵-W⁵⁶-E⁵⁷-D⁵⁸-E⁵⁹-E⁶⁰-K⁶¹-N⁶²-E⁶³-S⁶⁴), reminiscent of similar sequences in hirudin (DFEEIPEE) and hirugen (NGDFEEIPEEYL). The latter sequences have been suggested as binding sites for the anion-binding exosite of thrombin.^{15 16 17 18}

Platelets, macrophages, arterial endothelial cells, and SMCs express thrombin receptor transcripts. The human receptor was originally cloned from megakaryocyte-like cells and then found in human platelets¹⁹ and endothelial cells.¹³ Human blood–derived monocytes (activated as well as inactive) exhibit trace levels of mRNA for the human receptor, whereas human alveolar and atherosclerotic intimal macrophages show an abundance of transcripts.²⁰ In grossly normal areas of human arterial specimens, only endothelial cells show significant signals from receptor protein and mRNA by immunohistochemistry and in situ hybridization. In atherosclerotic areas, however, endothelial cells as well as intimal (not medial) SMCs and macrophages show positive signals for receptor protein and mRNA.²⁰ These results are not unequivocal and need corroboration. However, they raise the possibility that the expression of thrombin receptors is transcriptionally upregulated among growth-stimulated intimal SMCs and activated macrophages.

Indeed, Zhong et al,²¹ who recently cloned the rat thrombin receptor, found that it was expressed in growth (bFGF)–stimulated but not in growth-arrested rat vascular SMCs in vitro. bFGF and thrombin have synergistic effects in vascular SMCs,²² but antibodies to bFGF rendered these cells insusceptible to thrombin (but not to PDGF) stimulation.²³ Consequently, it cannot be currently excluded that SMCs are rendered susceptible to the growth-promoting effects of thrombin by mitogens like FGF via induction of thrombin receptors.

	Activation of the Thrombin Receptor

Top Introduction Enzymatic Properties of Thrombin Cellular Effects of {alpha}... Human Thrombin Cell Surface... Activation of the Thrombin... Intracellular Signaling Pathways Differential Regulation of Proto... Thrombin Inhibitors and Cell... Concluding Remarks References

 
Thrombin cuts C-terminally to arginine residues. Indeed, the LDPRS sequence of the thrombin receptor is cleaved at the R residue in analogy with protein C. Substitution of alanine for arginine R⁴¹ by site-directed mutagenesis of the thrombin receptor cDNA in Xenopus oocytes results in a receptor (R41A) that fails to respond to thrombin with mobilization of intracellular Ca²⁺, as evaluated with fluor indo 1 and flow cytometry.¹³ The corresponding substitutions for the other two extracellular arginines (R⁴⁶ and R⁷⁰) do not influence receptor function. In another mutant (S42P), serine residue 42 is substituted by proline, creating a thrombin-resistant arginine-proline bond. This mutant is resistant to thrombin activation, demonstrating that thrombin-induced proteolytic cleavage at arginine residue 41 is indeed involved in activation of the wild-type thrombin receptor. This activation creates an irreversible change in the receptor, which explains the desensitization of cells to repeated thrombin challenges.^{19 24 25}

Proteolytic cleavage at arginine residue 41 yields a new N terminus to the receptor (NH₃-S⁴²-F⁴³-L⁴⁴-L⁴⁵-). A synthetic oligopeptide containing this sequence, but not the variant oligopeptide (NH₃-F-S-L-L-), is able to induce maximum mobilization of intracellular Ca²⁺ in oocytes expressing the wild-type thrombin receptor.¹³ Although resistant to thrombin activation, oocytes expressing the mutant receptors R41A or S42P are fully sensitive to stimulation with the SFLL-containing oligopeptide. This shows that proteolytic cleavage of the receptor by thrombin generates a new N-terminal sequence that is able to activate the receptor intrinsically. For the activation of trypsinogen, a similar mechanism, by which a proteolytic cleavage unmasks an internal ligand that folds and binds within the trypsin molecule, has been shown. This induces a conformational change resulting in active trypsin.^{26 27} Conceivably, the liberated intrinsic ligand sequence folds and binds to a binding site within the external domain of the thrombin receptor, inducing the receptor-mediated cellular response. Brass et al²⁸ showed that active thrombin is also necessary for the appropriate folding of the tethered ligand and the subsequent internalization of the thrombin receptor.

A synthetic heptapeptide (NH₃-S-F-F-L-R-N-P-COOH), which is the hamster homologue to the human SFLL-sequence,²⁹ is as efficient as but less potent than -thrombin in stimulating a number of subcellular events in CCL39 hamster fibroblasts.¹⁹ Anything shorter than the pentapeptide (NH₃-S-F-F-L-R-COOH) is, however, completely inefficient. These results indicate a novel mechanism for receptor activation consisting of a specific proteolytic unraveling of a tethered endogenous ligand sequence.

The importance of the anion exosite binding domain of the receptor is suggested indirectly by experiments with Xenopus oocytes expressing the wild-type thrombin receptor.¹³ Hirudin and hirugen, known to bind to the anion exosite of thrombin without completely blocking hydrolysis of small-substrate molecules (ie, without blocking the catalytic site),¹⁷ inhibit activation of the receptor. Proteolytically inactive thrombin (mutant S205A) carrying an intact receptor-binding motif fails to stimulate oocytes expressing the receptor. The same is true for -thrombin, which is inactivated by binding to the catalytic site-blocker PPACK, which leaves the acid motif free. Likewise, the natural thrombin inhibitor AT III also blocks thrombin-induced receptor stimulation and human arterial SMC proliferation.³⁰

	Intracellular Signaling Pathways

Top Introduction Enzymatic Properties of Thrombin Cellular Effects of {alpha}... Human Thrombin Cell Surface... Activation of the Thrombin... Intracellular Signaling Pathways Differential Regulation of Proto... Thrombin Inhibitors and Cell... Concluding Remarks References

 
Stimulation of thrombin receptors induces an array of intracellular events (Table). In confluent rat aortic SMC cultures, -thrombin induces rapid acidification and subsequent gradual alkalinization that is dependent on the Na⁺-H⁺ exchanger (Reference 31³¹ and reviewed in Reference 32³² ). Within seconds, -thrombin also activates PLC and induces the hydrolysis of phosphoinositides into inositol-3 and inositol-2 phosphates and, subsequently, the production of prostaglandin I₂.^{6 33} This is a likely explanation for the equally rapid increase in intracellular free Ca²⁺ as well as the subsequent activation of the Na⁺-H⁺ exchanger. Phosphorylation of the cytosolic domain of the thrombin receptor by G protein–coupled kinases seems to be an initiating event.³⁴ The number of phosphorylated thrombin receptors depends on the concentration of -thrombin and the subsequent PLC activity in turn on the cumulative number of stimulated receptors.³⁵

View this table: [in this window] [in a new window]   Table 1. Intracellular Signal Events After Stimulation With -Thrombin, PDGF, and FGF

-Thrombin, bFGF,^{36 37} and PDGF^{38 39} activate MAPks. Thrombin induces two bursts of MAPk activity. Only the later burst is blocked by pertussis toxin, suggesting a G protein–coupled receptor mechanism.^{37 39} bFGF and PDGF induce only the late burst of MAPk via their tyrosine kinase–coupled receptors. This burst of activity is necessary for cell proliferation.^{39 40}

-Thrombin dose-dependently inhibits forskolin-stimulated adenylate cyclase activity, with a subsequent decrease in intracellular cAMP levels in human SMCs⁴¹ as well as in hamster fibroblasts.¹⁹ The effect of -thrombin is counteracted by pertussis toxin, suggesting that suppression of adenylate cyclase activity is mediated by G proteins.

In hamster fibroblasts, oligopeptides corresponding to five or more amino acids of the N terminus of the tethered ligand sequence (NH₃-S-F-F-L-R-) are, alone, as efficient as -thrombin in influencing PLC and adenylate cyclase activities.¹⁹ However, only in the presence of added conventional growth factors does the activation of the receptor result in DNA synthesis.¹⁹ Furthermore, the same tethered ligand–derived oligopeptides activate human platelets in vitro to release of ¹⁴C-serotonin.

	Differential Regulation of Proto-oncogene and Growth Factor Expression

Top Introduction Enzymatic Properties of Thrombin Cellular Effects of {alpha}... Human Thrombin Cell Surface... Activation of the Thrombin... Intracellular Signaling Pathways Differential Regulation of Proto... Thrombin Inhibitors and Cell... Concluding Remarks References

 
-Thrombin induces a concentration-dependent transient increase in c-fos mRNA in bovine,⁴² rat,³¹ and human⁴¹ SMCs. An increase is evident within 30 minutes, peaks after 60 minutes, and vanishes within 6 hours (Fig 2). This increase depends on alkalinization by Na⁺-H⁺ exchange, since the exchange-blocking amiloride derivative DMA inhibits this increase.³¹ Furthermore, the intracellular Ca²⁺ chelator quin 2-AM/EGTA prevents the upregulation of c-fos, suggesting the importance of intracellular Ca²⁺ mobilization for the process. Berk et al³¹ suggested that -thrombin stimulates intracellular protein synthesis but not DNA synthesis or cell proliferation in rat SMCs. However, this is at variance with the conclusions of others, who have found DNA synthesis^{19 43} as well as cell proliferation^{12 41 42 44} after stimulation with -thrombin. In human SMCs in culture, -thrombin induces transient expressions of c-fos and c-myc.⁴¹ The former peaks after 15 minutes. This delay is comparable to that after stimulation with PDGF. However, c-myc peaks only at 8 hours after stimulation with -thrombin. In contrast, stimulation with PDGF induces a transient expression of both proto-oncogenes within minutes (reviewed in Reference 45⁴⁵ ).

View larger version (31K): [in this window] [in a new window]   Figure 2. Schematic showing temporal events of thrombin- and PDGF-induced mitogenesis.

In the presence of exogenous PDGF, human SMCs proliferate and exhibit a proliferative morphology without contractile protein filaments in vitro.^{46 47 48 49 50 51} In the absence of PDGF, they become growth-arrested and express contractile filaments. PDGF has been implicated as a critical mitogen in occlusive arterial diseases (reviewed in References 52 and 53^{52 53} ). However, there are a number of other cytokines known to influence the properties of SMCs that might be important in this context. In the rat carotid balloon injury model, bFGF has recently been suggested to be an inducer of proliferation among mature medial SMCs, and PDGF has been cited as a chemoattractant and secondary mitogen among these initiated SMCs.⁵⁴ Consequently, bFGF may induce the expression of thrombin receptors,^{21 22 23} with thrombin subsequently inducing the expression of endogenous PDGF. Indeed, human SMCs respond to thrombin stimulation in vitro by a transcriptionally regulated secretion of PDGF–A chain homodimers and epidermal growth factor.⁵⁵

Using Northern blot hybridization, Okazaki et al⁴³ showed that -thrombin induces an upregulation of PDGF–A chain but not –B chain mRNA in rat SMCs in vitro. Simultaneously, they noticed a suppression of PDGF - and ß-receptor mRNA. These effects were maximal after 6 hours and inhibited by PPACK. The suppression of PDGF receptor mRNA may be a primary result of stimulation with -thrombin. It could be speculated, however, that it is related to the downregulation of PDGF receptors after stimulation by PDGF in vitro (reviewed in References 45, 52, and 53^{45 52 53} ). Therefore, these findings may only indicate that the -receptors were indeed stimulated by endogenous PDGF–A chain homodimers.

The latter interpretation is consistent with observations in vivo. Up to 6 hours after balloon injury to the brachial artery of baboons, there is an increase in PDGF–A chain transcripts in total RNA prepared from the injured arterial tissue.⁴³ However, this increase is significantly reduced if PPACK is administered in conjunction with the trauma. Arterial injury did not suppress PDGF ß-receptor mRNA in these experiments.

These data suggest the possibility that -thrombin induces expression of PDGF that stimulates cell proliferation by induction of both proto-oncogenes c-fos and c-myc (reviewed in References 45, 52, and 53^{45 52 53} ). Consistent with this is the observation that DNA synthesis peaks 20 to 28 hours after stimulation with PDGF but 10 to 20 hours later in human⁴¹ as well as rat¹² SMCs after stimulation with -thrombin. Consequently, -thrombin may induce cell proliferation via the induction of PDGF and, subsequently, c-myc expression. Wilson et al⁵⁶ found that rat vascular SMCs in vitro that were subjected to cyclic mechanical strain in the presence of -thrombin synthesized more DNA and exhibited a transcriptional upregulation of PDGF production. This DNA synthesis was inhibited by antibodies to PDGF.

Apart from similarities discussed above, there seem to be important differences between thrombin and PDGF stimulation regarding intracellular signaling events (Table). Stimulation of thrombin receptors has no effect on protein kinase C but decreases adenylate cyclase and as a consequence the production of cAMP and prostaglandin I₂.¹⁹ In contrast, stimulation of PDGF receptors increases adenylate cyclase and probably protein kinase C.^{45 57} Activation of appropriate kinases within the PDGF receptor by tyrosine phosphorylation is a prerequisite for mitogenic stimulation with PDGF.^{58 59} As discussed earlier, PDGF rapidly induces proto-oncogenes c-fos and c-myc, followed by DNA synthesis. In contrast, thrombin rapidly induces only c-fos. Induction of c-myc and DNA synthesis follow much later after thrombin stimulation and only after the endogenous PDGF–A chain production has been upregulated. It cannot be excluded that the controversy regarding whether SMCs are susceptible to thrombin stimulation in the absence of exogenous growth factors (see above) may relate to the varying contributions of endogenous growth factors.

Less seems to be known about the intracellular events following FGF stimulation than after PDGF or -thrombin stimulation (Table). However, the FGFs seem to operate via partly different signaling pathways. The FGFs increase protein kinase activities^{60 61} but not cAMP production^{61 62} and increase cytosolic Ca²⁺-dependent c-fos^{63 64 65} and c-myc⁶⁴ expression and the proliferation of glomerular mesangial SMCs⁶⁶ and bovine endothelial⁶⁷ cells. bFGF activates phospholipase D but does not induce the breakdown of phosphoinositides.⁶⁸

-Thrombin also upregulates mRNA for the bFGF in rat vascular endothelial cells⁶⁹ and dermal fibroblasts.⁷⁰ Weiss and colleagues^{22 23} have shown a synergistic mitogenic effect of -thrombin and bFGF in rat vascular SMCs in vitro. They have also shown a rapid increase in cytosolic bFGF and that the mitogenic response to -thrombin was inhibited by antibodies to bFGF. Consequently, it cannot be excluded that -thrombin induces an expression of endogenous FGF and PDGF that may be the direct stimuli to cell proliferation.

	Thrombin Inhibitors and Cell Proliferation

Top Introduction Enzymatic Properties of Thrombin Cellular Effects of {alpha}... Human Thrombin Cell Surface... Activation of the Thrombin... Intracellular Signaling Pathways Differential Regulation of Proto... Thrombin Inhibitors and Cell... Concluding Remarks References

 
Several thrombin inhibitors have been shown to block not only fibrin formation but also receptor-mediated cellular responses. Hirudin and hirugen, which bind to the anionic exosite of the thrombin receptor, leaving the catalytic site free to hydrolyze only some small substrate molecules,¹⁷ block cellular responses. Hirudin prevents restenosis after balloon angioplasty in rabbits,⁷¹ but this may be due to factors other than intimal SMC hyperplasia.⁷² PPACK blocks the catalytic site of thrombin but leaves the binding exosites free. PPACK inhibited DNA synthesis in human arterial SMCs in vitro⁴¹ and PDGF expression in SMCs after balloon injury in baboons.⁴³ In vitro, the natural thrombin inhibitor AT III inhibited proliferation of human arterial SMCs in the presence of -thrombin.³⁰

	Concluding Remarks

Top Introduction Enzymatic Properties of Thrombin Cellular Effects of {alpha}... Human Thrombin Cell Surface... Activation of the Thrombin... Intracellular Signaling Pathways Differential Regulation of Proto... Thrombin Inhibitors and Cell... Concluding Remarks References

 
The evidence that thrombin is a direct mitogen is not unequivocal. It cannot be excluded that it operates via induction of conventional growth factors like PDGF and FGF. In the injured arterial wall, PDGF and bFGF from different sources may stimulate cell proliferation. At present, there is no way of grading the importance of these different mitogen sources. Therefore, the growth-inhibitory effects of thrombin inhibitors must be appraised on the basis of their ability to prevent the thrombin-induced simultaneous release of PDGF and bFGF from these sources.

First, locally adhering and agglutinating platelets lyse and release preformed PDGF from their alpha granules. This process is likely suppressed if thrombin is prevented from stimulating its platelet receptor.

Second, endothelial cells expressing thrombin receptors constitutively respond to -thrombin stimulation by bFGF production. This may in turn stimulate thrombin receptor expression in SMCs.

Third, such SMCs would be likely to respond to -thrombin by PDGF production and proliferation. SMCs in the intima of atherosclerotic lesions express transcripts for the PDGF–A chain.⁷³ Although rat vascular SMCs in vitro express bFGF,^{22 23} it is presently unclear whether this occurs in human atherosclerotic lesions. Stimulation of thrombin receptors present on growth factor–stimulated intimal SMCs leads to the endogenous production of PDGF and, possibly, bFGF. Medial differentiated SMCs are insusceptible to thrombin stimulation, suggesting that they must first be rendered susceptible by factors other than thrombin. Only the thrombin-dependent part of the endogenous PDGF and bFGF production is likely blocked by the thrombin inhibitors.

	Selected Abbreviations and Acronyms

 

AT III = antithrombin III bFGF = basic FGF factor Xa = activated factor X FGF = fibroblast growth factor MAPk = mitogen-activated protein kinase PDGF = platelet-derived growth factor PLC = phospholipase C PPACK = phenylalanyl-prolyl-arginine chloromethyl ketone SMC = smooth muscle cell TAT = thrombin–AT III complex

	Acknowledgments

 
Dr Fager was supported by grants from the Swedish Medical Research Council (project Nos. 4531 and 8708) and the Swedish Heart and Lung Foundation, and this is gratefully acknowledged.

Received May 23, 1994; accepted May 11, 1995.

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Top Introduction Enzymatic Properties of Thrombin Cellular Effects of {alpha}... Human Thrombin Cell Surface... Activation of the Thrombin... Intracellular Signaling Pathways Differential Regulation of Proto... Thrombin Inhibitors and Cell... Concluding Remarks References

 
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