review

Molecular mechanisms of fibrinolysis
Gabriela Cesarman-Maus and Katherine A. Hajjar Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York-Presbyterian Hospital, New York, NY, USA

Summary
The molecular mechanisms that finely co-ordinate fibrin formation and fibrinolysis are now well defined. The structure and function of all major fibrinolytic proteins, which include serine proteases, their inhibitors, activators and receptors, have been characterized. Measurements of real time, dynamic molecular interactions during fibrinolysis of whole blood clots can now be carried out in vitro. The development of genetargeted mice deficient in one or more fibrinolytic protein(s) has demonstrated expected and unexpected roles for these proteins in both intravascular and extravascular settings. In addition, genetic analysis of human deficiency syndromes has revealed specific mutations that result in human disorders that are reflective of either fibrinolytic deficiency or excess. Elucidation of the fine control of fibrinolysis under different physiological and pathological haemostatic states will undoubtedly lead to novel therapeutic interventions. Here, we review the fundamental features of intravascular plasmin generation, and consider the major clinical syndromes resulting from abnormalities in fibrinolysis. Keywords: Plasminogen, plasminogen activators, plasminogen activator inhibitor-1, annexin 2, thrombin-activatable fibrinolysis inhibitor.

Basic concepts of fibrinolysis
Under physiological conditions, both coagulation and fibrinolysis are precisely regulated by the measured participation of substrates, activators, inhibitors, cofactors and receptors. Molecular links between these systems permit localized, timely removal of ongoing or acutely induced fibrin deposits (Table I). These co-ordinated molecular events insure blood fluidity while preventing blood loss (Esmon et al, 1999; Degen, 2001; Hajjar, 2003a; Kolev & Machovich, 2003).

Correspondence: Dr Katherine A. Hajjar, Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York-Presbyterian Hospital, 1300 York Avenue, Box 45, New York, NY 10021, USA. E-mail: khajjar@med.cornell.edu

Activation of coagulation ultimately generates thrombin, which results in thrombus formation by conversion of fibrinogen to fibrin and by platelet activation. Plasmin is the major fibrinolytic protease (Fig 1). Plasminogen (PLG), a circulating plasma zymogen, can be converted to plasmin by both tissue PLG activator (tPA) as well as by urokinase (uPA). Through a positive feedback mechanism, plasmin cleaves both tPA and uPA, transforming them from single chain to more active two-chain polypeptides. Fibrin, the major plasmin substrate, regulates its own degradation by binding both PLG and tPA on its surface, thereby localizing and enhancing plasmin generation. While tPA is a weak activator of PLG in the absence of fibrin, its catalytic efficiency for PLG activation is enhanced by at least two orders of magnitude in the presence of fibrin. The affinity between tPA and PLG is low in the absence of fibrin, but increases significantly in its presence. Once formed, plasmin cleaves fibrin, generating soluble degradation products, and exposing carboxy-terminal lysine (Lys) residues (Fig 2). ‘Kringles’ 2 of tPA and 1 and 4 of PLG contain lysine-binding sites, which mediate further binding to fibrin, leading to enhanced plasmin generation and fibrin removal. Binding can be blocked by Lys analogues, such as epsilon aminocaproic acid and tranexamic acid, as well as by the recently characterized, thrombin-activatable fibrinolysis inhibitor (TAFI). When activated by thrombin, TAFI removes carboxy-terminal Lys residues, thereby attenuating plasmin generation, stabilizing fibrin thrombi, and establishing a regulatory connection between coagulation and fibrinolysis. Fibrin dissolution is also regulated by inhibitors of PLG activation, such as PLG activator inhibitor-1 (PAI-1), and by inhibitors of plasmin itself, such as a2-plasmin inhibitor (a2-PI). In addition, plasmin bound to fibrin is protected from a2-PI, due to occupancy of its lysine-binding sites. TAFI, on the other hand, decreases this protection by deleting plasminbinding Lys residues on fibrin. In addition, diverse cell types promote plasmin generation through their expression of cell surface receptors (Hajjar, 2003b). Endothelial cells, monocytes, macrophages, neutrophils and some tumour cells, all bind PLG, as well as tPA and/or uPA. Their receptors localize cell surface fibrinolytic activity, serve as cofactors in acute or ongoing plasmin generation, and provide specialized environments that are protected from circulating inhibitors.

ª 2005 Blackwell Publishing Ltd, British Journal of Haematology, 129, 307–321

doi:10.1111/j.1365-2141.2005.05444.x

308 ª 2005 Blackwell Publishing Ltd. 1991). 2003b). plasmin. and is activated 10–20 times more rapidly than Glu-PLG (Markus et al. Components of the fibrinolytic system. known collectively as amino-terminal lysine (Lys) PLG (Wallen & Wiman. Hydrolysis of the Lys77-Lys78 peptide bond gives rise to a conformationally modified form of the zymogen that more readily binds fibrin. Once plasmin is generated. Lys-PLG does not normally Fig 1. gives rise to the active protease. 307–321 . with a half-life of about 2 d (Hajjar. 1986. through the action primarily of two-chain tissue plasminogen activator (tc-tPA) or two-chain urokinase (tc-uPA). amino-terminal glutamic acid (Glu) PLG. 1970. and may also specify its physiological degradation pathway (Hajjar.Review Table I. and exhibits substrate specificity not limited to fibrin (Saksela. Holvoet et al. and to a lesser extent by a2-macroglobulin (a2-MG). Posttranslational modification of PLG results in two glycosylation variants (forms 1 and 2). 1972). monocyte/macrophages. or endothelial cells respectively. British Journal of Haematology. 1980). a2-PI (Hajjar et al. Inhibitors are indicated by red boxes. PAI-2) C1-esterase inhibitor Protease nexin Attenuator Thrombin-activatable fibrinolysis inhibitor (TAFI) Major receptors Activating Annexin 2 aMb2 integrin Urokinase receptor (uPAR) Clearance Low-density lipoprotein receptor-related protein (LRP) Mannose receptor Components of the fibrinolytic system Plasminogen Synthesized primarily in the liver (Raum et al. and from renal epithelium. a2-plasmin inhibitor (a2-PI). 1985). Activation of PLG. displays two. The carbohydrate portion of PLG regulates its affinity for cellular receptors. is readily converted by limited proteolysis to several modified forms. The circulating form of PLG. Plasmin contains a typical serine protease catalytic triad (His 602. Asp 645 and Ser 740). a Mr c. 1985). Both tPA and uPA can be inhibited by plasminogen activator inhibitor-1 (PAI). 1988). 1985). These activators are secreted as single-chain (sc-tPA and scuPA) forms from endothelial cells. 1987). The lysine-binding domains of PLG mediate its specific interactions with fibrin. plasmin (Table I). including its circulating inhibitor. 2003b). PLG. cell surface receptors and other proteins. 92 000 single-chain proenzyme. 16 of which give rise to five homologous triple loop structures called ‘kringles’ (Forsgren et al. 1982. Hoylaerts et al. it converts single chain tPA and uPA to double chain forms. by cleavage of a single Arg-Val peptide bond at position 560–561 (Holvoet et al. 129. while plasmin is inhibited by its major inhibitor. Overview of the fibrinolytic system. The first (K1) and fourth (K4) of these 80 amino acid structures impart high and low affinity Lys binding respectively (Miles et al. 1Æ5 lmol/l. 1979. Zymogen Plasminogen (N-terminal glutamic acid and lysine variants) Plasminogen activators Tissue plasminogen activator (tPA) Urokinase (uPA) Inhibitors Plasmin inhibitors a2-plasmin inhibitor (a2-PI) a2-macroglobulin (a2-MG) Protease nexin Plasminogen activator inhibitors Plasminogen activator inhibitor-1 and -2 (PAI-1. Miles & Plow. Its 791 amino acids are cross-linked by 24 disulphide bridges.to threefold higher avidity for cellular receptors. circulates in plasma at a concentration of c. It is then rapidly inhibited unless it remains bound to fibrin or to its cell surface receptors. The zymogen plasminogen is converted to the active serine protease.

Urokinase (uPA) acts independently of fibrin. such as a2-PI. cleaves lysine residues and attenuates fibrin dissolution by decreasing the fibrin-binding sites (K) for fibrinolytic enzymes. 1990). but has been identified on cell surfaces (Hajjar. This glycoprotein contains five structural domains. Apolipoprotein(a) and PLG are more distantly related to other kringle-containing proteins such as tPA. rectum. including a fibronectin-like ‘finger’.and receptor-enhanced plasmin generation. 1987). The gene is closely linked and structurally related to that of apolipoprotein(a). Thrombin-activatable fibrinolysis inhibitor (TAFIa). which results in further exposure of carboxy-terminal lysines and. (B) Annexin 2 is present on the endothelial cell surface as a heterotetramer with the S100 family protein p11. Fibrin-associated plasmin and tPA are protected from their major inhibitors. 1989. These results suggest that PLG is not strictly required for normal development. Plasminogen activators Tissue plasminogen activator. are fertile. Both types contain high mannose carbohydrate on Asn117. British Journal of Haematology. This trimolecular assembly greatly enhances plasmin (PN) generation. complex oligosaccharide on Asn448 and an O-linked a-fucose residue on Thr61 (Harris et al. Spanning 52Æ5 kb of DNA on chromosome 6q26. 2003b). 1987. 1998). Mr c. both forms demonstrate equivalent activity when fibrin bound (Tate et al. 1985). they display a predisposition to vascular occlusion with spontaneous thrombi appearing in the liver. 129. the gene for human tPA consists of 14 exons spanning a total of 36Æ6 kb (Degen et al. serving as a cofactor for plasmin generation. 307–321 . Fig 1). 1984). and ulcerative lesions in the gastrointestinal tract and rectum. uPA receptor (uPAR) may also bind uPA. and survive to adulthood (Bugge et al. the PLG gene consists of 19 exons (Murray et al. While single-chain tPA is less active than two-chain tPA in the fluid phase. Ichinose. uPA. two-chain form (Pennica et al. a2-plasmin inhibitor (a2-PI) and plasminogen activator inhibitor-1 (PAI) respectively. The two glycosylation forms of tPA are distinguishable by the presence (type 1) or absence (type 2) of a complex N-linked oligosaccharide moiety on Asn184 (Hajjar. One of two major endogenous PLG activators. (A) Tissue plasminogen activator (tPA). two ‘kringle’ structures homologous to those of PLG and a serine protease domain. Fibrin deposition is seen in the liver. 1986). 1983. lung and pancreas. an epidermal growth factor-like cassette. a plasma carboxypeptidase. Cleavage of the Arg275-Ile276 peptide bond by plasmin converts tPA to a disulphide-linked. Fibrin. but is ª 2005 Blackwell Publishing Ltd. circulate in plasma (Holvoet et al. These mice undergo normal embryogenesis and development. Annexin 2 binds both PLG and tPA.Review Fig 2. ultimately. essential for maintenance of postnatal fibrin homeostasis in both intra. In vitro. regulate its binding to cell surface receptors and specify degradation pathways. many agents exert small effects on 309 Characterization of plasmin(ogen) function The diverse physiological roles of plasmin have become evident with the development of gene-targeted PLG-deficient mice (Table II). 1995a). 1987).and extra-vascular settings. colon. in fibrin degradation. Located on chromosome 8q11 (Ny et al. 72 000 tPA consists of 527 amino acids (Pennica et al. hepatocyte growth factor and macrophagestimulating protein (Nakamura et al. However. and protecting plasmin from circulating inhibitors. 1983). The carbohydrate moieties of tPA may modulate its functional activity. bind fibrin through lysine residues (K). 1992). 1991). 2003b). in addition to runting and ligneous conjunctivitis (Drew et al. Petersen et al. and plasminogen (PLG). stomach. serving as a cofactor for plasmin generation. (C) Integrin aMb2 on leucocytes binds both PLG and uPA. The significance of the latter two proteins to fibrinolysis remains to be determined. an apoprotein associated with the highly atherogenic low-density lipoprotein (LDL)-like particle lipoprotein(a) (McLean et al.

1985. especially at branch points. such as thrombin. Kasai et al. 2003b). 1985). femoral vein. Goldsmith et al. Lijnen et al. These include kallikrein. ligneous conjunctivitis Impaired monocyte recruitment Impaired neointima formation after electrical injury Impaired dissemination of Borrelia burgdorferi Reduced excitotoxic neuronal cell death in brain Plasminogen activators tPA)/) Reduced lysis of fibrin clot Increased endotoxin-induced thrombosis Occasional fibrin in liver/intestine uPA)/) Rectal prolapse. The release of tPA is governed by a variety of stimuli. carotid artery or aorta (Levin & del Zoppo. histamine. a single PLG-like kringle and a classical serine protease catalytic triad (His204. A second endogenous PLG activator. ears Reduced macrophage degradation of fibrin Increased endotoxin-induced thrombosis uPA)/)/tPA)/) Reduced growth. has been reported to decrease synthesis of both tPA and PAI-1 (Hajjar. ulcers of eyelids. exercise. and is an effective PLG activator in both the presence and the absence of fibrin (Gurewich et al. 5 min). cachexia Fibrin deposits in liver. thrombin-activatable fibrinolysis inhibitor. In contrast.5-monophosphate (cAMP) levels. acetylcholine. but its in vivo role remains to be determined (Romisch et al. proteases that are traditionally classified within the intrinsic arm of the coagulation cascade have been shown to activate PLG directly. postcapillary venules and vasa vasora. the expression of tPA mRNA. retinoids. Factor VII-activating protease has also been reported to serve as an in vitro activator of single-chain PLG activators. Hajjar. much less expression is seen in endothelial 310 ª 2005 Blackwell Publishing Ltd. face. respectively. 1968. fertility and lifespan. only the high-molecular weight form binds to the uPA receptor (uPAR. 129. The tPA is synthesized and secreted primarily by endothelial cells. uPA has much lower affinity for fibrin than tPA. single-chain uPA or prourokinase. Asp255. 1984. Two-chain uPA occurs in both high (Mr: c. the membrane type 1 matrix metalloproteinase (MT1-MMP) appears to exert fibrinolytic activity in the absence of PLG. 307–321 . Arg vasopressin. skin. tPA appears to be the major intravascular activator of PLG (Hajjar. 1985). factor XIa and factor XIIa (Colman. is a Mr c. However. PAI-1. Genotype* Plasminogen PLG)/) Phenotype Spontaneous thrombosis. 2003b). venous occlusion and shear stress. runting. macrophages. 33 000) forms that differ by the presence or absence. uPA possesses an epidermal growth factor-like domain. premature death Fibrin in liver. gonadotropins. Although expressed by extravascular cells. 2003b). but relatively few enhance tPA synthesis without also augmenting PAI-1 synthesis. plasminogen. In the mouse lung. gonads. Under certain conditions. bradykinin. which are beyond the scope of this review. expression of tPA appears to be restricted to 7–30 nm diameter precapillary arterioles. uPAR. *Several examples of combined gene deletion mouse models exist. 1986). uPA. From Hajjar et al (2005). arterial levels of shear stress and dexamethasone. plasminogen activator inhibitor-1. In addition. Located on chromosome 10q26. Interestingly. PLG. British Journal of Haematology. Forskolin. LRP. Accessory activators and fibrinolysins. of a 135-residue aminoterminal fragment released by plasmin cleavage between Lys135 and Lys136. 1999). which increases intracellular cyclic adenosine 3. single-chain uPA has considerable fibrin specificity. low-density lipoprotein receptor-related protein. tPA. Ser356. rectal prolapse Impaired clot lysis Inhibitors PAI-1)/) Mildly increased lysis of fibrin clot Resistance to endotoxin-induced thrombosis LRP)/) Embryonic lethal day 13Æ5 postconception TAFI)/) Essentially normal Receptors uPAR)/) Essentially normal Reduced macrophage PLG activation in vitro Normal matrix degradation Annexin 2)/) Mild runting. Urokinase. and is expressed by endothelial cells. yet an intrinsic PLG activating capacity of <1% of that observed for two-chain uPA (Hajjar. tissue plasminogen activator. Agents that regulate tPA gene expression independently of PAI-1 include histamine. adrenaline. Reproduced with permission from the McGraw-Hill Companies. urokinase plasminogen activator receptor. its circulating half-life is exceptionally short (c. the human uPA gene is encoded by 11 exons spanning 6Æ4 kb. TAFI. urokinase plasminogen activator. stomach. This may reflect a conformational change in PLG upon binding to fibrin. bronchial artery endothelial cells express tPA antigen. gastric ulcers Impaired wound healing. while pulmonary blood vessels are generally negative. activation of Glu-PLG by two-chain uPA is increased in the presence of fibrin by about 10-fold. 1978). lungs Ulcers in intestine. 54 000) and lowmolecular weight (Mr: c. even though uPA does not bind to fibrin. renal epithelial cells and some tumour cells (Holmes et al. 2003a). fibrin deposition in microvasculature Impaired clearance of arterial thrombi Impaired postnatal neoangiogenesis cells of the femoral artery. butyrate. but normally account for no more than 15% of total plasmingenerating activity in plasma (Hajjar. ears. Cleavage of the Lys158-Ile159 peptide bond by plasmin or kallikrein converts single-chain uPA to a disulphide-linked two-chain derivative. 1994). lungs. 54 000 glycoprotein consisting of 411 amino acids (Table I).Review Table II. and may explain the unexpectedly mild phenotype observed in PLG-deficient mice (Hiraoka et al. Riccio et al. Some gene deletion mouse models relevant to intravascular fibrinolysis. 2003a). Although both forms are capable of activating PLG. 1998).

or both. but it is less effective towards single-chain tPA. on the other hand. 2003b). 1987). secreted by leucocytes and fibrosarcoma cells. 1987). The upstream regulatory region of the human PAI-1 gene contains a strong endothelial cell/fibroblast-specific element. Several additional proteins can act as plasmin or PAIs (Table I). spans 16Æ5 kb. Release of PAI-1 is stimulated by many cytokines. viability. 1987. The PAI-1 is the most important and most rapidly acting physiological inhibitor of both tPA and uPA. 1990. also known as a2-antiplasmin. Mottonen et al. and found in platelet a-granules. Because there are no published clinical examples of complete deficiency of tPA or uPA in humans. and show no evidence of haemorrhage (Carmeliet et al. the protein level. Protease nexin may function as a non-circulating cell surface inhibitor of trypsin. with extensive fibrin deposition in the liver. 1996). and consists of 452 amino acids with two disulphide bridges (Holmes et al. 52 000 single chain. This non-serpin forms non-covalent complexes with plasmin. Activity of this labile serpin is stabilized by complex formation with vitronectin. thrombin. Table I). The gene is located on chromosome 18q21. a glucocorticoid-responsive enhancer and transforming growth factor (TGF)-b responsive elements (Hajjar. Functionally. 70 000. Doubly deficient (tPA)/). Fig 1). 1988. These findings demonstrate that tPA and uPA are not essential for normal embryologic development. 307–321 . clot lysis is markedly impaired. The most ubiquitous of the two major PAIs is PAI-1 (Table I). 1983. 1989).Review Physiological function of plasminogen activators. In humans. and occasional fibrin deposition in tissues. 1988). The promoter region of the a2-PI gene contains a hepatitis B virus-like enhancer element that directs tissue-specific expression in the liver (Holmes et al. These observations contrast with the moderately severe bleeding disorder observed in a human patient with complete PAI-1 deficiency (Fay et al. runting and cachexia. plasma (Huisman et al. endotoxin-induced thrombosis is significantly enhanced. and contains 10 exons distributed over 16 kb of DNA (Hirosawa et al. 0Æ9 nmol/l) with a plasma half-life of about 2Æ4 d. exhibit normal fertility. spanning 12Æ2 kb on chromosome 7q21 (Loskutoff et al. PAI-2 exists as both a Mr c. uPA)/)) mice exhibit rectal prolapse. thrombin and phorbol esters (Etingin et al. tissue histology and development. is immediately neutralized by a2-PI. lipoprotein(a). following proteolytic cleavage of the inhibitor by the target protease. a2-PI contains about 13% carbohydrate by mass. a2-Macroglobulin is a Mr 725 000 dimeric protein synthesized by endothelial cells and macrophages. 1992). 1978a). Transgenic mice that overexpress PAI-1 exhibit thrombotic occlusion of tail veins and swelling of hind limbs within 2 weeks of birth (Erickson et al. C1-esterase inhibitor may serve as an inhibitor of tPA in ª 2005 Blackwell Publishing Ltd. 1985). was originally purified from human placenta (Ye et al. 60 000 glycosylated form. Plasminogen activator inhibitors Plasminogen activator inhibitor-1. but are crucial to thrombolysis and fibrinolytic surveillance in the adult. Both uPA and tPA null mice exhibit normal fertility and embryonic development. urokinase or plasmin (Scott et al. 1986. cysteine (Cys)-less glycoprotein is released by endothelial cells. non-healing ulcerations of the face and eyelids. on the other hand. include the inflammatory cytokines lipopolysaccharide. growth factors and lipoproteins common to the global inflammatory response (Hajjar. 129. 1990). have a normal spontaneous phenotype. the gene is located on chromosome 18q21– 22. However. 2003b). and does not inhibit prourokinase. and contains eight exons (Ye et al. factor Xa. uPA)/) mice developed rectal prolapse. which is cleared in the liver. resulting in protease–inhibitor complexes that are endocytosed via a specific nexin receptor (Hajjar. All serpins form an irreversible complex with the active site serine of the target protease. 1990. gonads and lung. The PAI-1 gene consists of nine exons. 2003a). Significant levels of PAI-2 are found in human plasma only during pregnancy. This Mr c. A single-chain glycoprotein of Mr c. a component of both plasma and pericellular matrix (Declerck et al. tPA-deficient mice. intestine. British Journal of Haematology. and then forms a lysine-binding site-dependent a2-PI–plasmin complex. Both protease and inhibitor lose their activity. Plasminogen activator inhibitor-2. Plasminogen activator inhibitor-2. 1995). Hajjar. hepatocytes. Not surprisingly. TGF-b. non-healing ulceration. Mice deficient in PAI-1. angiotensin II. basic fibroblast growth factor (bFGF). very LDL. 311 Inhibitors and attenuators of fibrinolysis Plasmin inhibitors The action of plasmin is negatively modulated by a family of serine protease inhibitors known as the serpins (Travis & Salvesan. although rates of pulmonary clot lysis are normal. 2003b). a2PI is also a constituent of platelet a-granules (Plow & Collen. PAI-2 inhibits both two-chain tPA and two-chain uPA with comparable efficiency. Table II). but have less efficient lysis of artificially induced pulmonary thrombi. a2-PI. 1994. 1981). without affecting tPA synthesis. 1992). the most compelling studies of the physiological functions of PLG activators derive from gene disruption in mice (Carmeliet et al. as well as enhanced thrombus formation in response to endotoxin. 10% of the efficiency exhibited by a2-PI (Aoki et al. StikoRahm et al. 1993a). plasmin released into flowing blood or in the vicinity of a platelet-rich thrombus. adipocytes and platelets (Ny et al. tumour necrosis factor-a. interleukin-1. a2-PI is cleaved at its Arg364-Met365 peptide bond. 1987). monocytes. Agents that have been shown to enhance expression of PAI-1 at the message level. Thus. 47 000 non-glycosylated intracellular form and a Mr c. circulates in plasma at high concentration (c. macrophages. Samad et al. a 393 amino acid member of the serpin family. and inhibits its activity with c.

2002). leads to enhanced thrombin generation. The uPAR is expressed on monocytes. myeloid cells. reduction of TAFIa. activated protein C (APC). is also known as procarboxypeptidase B (Eaton et al. 1991). neuroblastoma cells. Thus. while they lose their adhesion to fibronectin (Wei et al. A member of the annexin superfamily of calciumdependent. 1994). Neutrophils express integrin aMb2. 2003). 2003). TAFIa functions as a potent attenuator of fibrinolysis. Okamoto et al. PAI-1. On the contrary. 1994). British Journal of Haematology. uPAR is anchored to the plasma membrane through glycosylphosphatidylinositol linkages (Ploug et al. Activation receptors Plasminogen receptors. plasmin can also activate TAFI. more variable N-terminal ‘tail’. Nesheim. increased TAFI activation and blockade of fibrinolysis. phospholipid-binding proteins. the presence of the factor V Leiden mutation. 1995). and also associates with caveolin. 35 000. Zn-dependent carboxypeptidase with specificity for carboxy-terminal Arg and Lys residues. uPAR. Table I). 1991). 1990. 1999). amphoterin. 1995). 1991). and uPAR-transfected renal epithelial cells acquire enhanced adhesion to vitronectin. 40 nmol/l) and PLG (Kd: c. 2002). 1 nmol/l) in a dose-dependent. The urokinase receptor. saturable manner. Wei et al. procarboxypeptidase U (unstable) and procarboxypeptidase R (for Arg). either by direct inhibition or by blockade of intrinsic pathway generation of thrombin. Its gene. spans 11 exons. contributing to the degradation of fibrinrich thrombi (Pluskota et al. 2004). aMb2 binds both uPA (Kd: c. an additional risk factor for thrombosis (Antovic & Blomback. results in enhanced endogenous clot lysis in a rabbit jugular vein model of thrombolysis (Minnema et al. 1998). platelets. Annexin 2. co-localizes with integrins in focal contacts and at the leading edge of migrating cells (Xue et al. 1996). The gene consists of seven exons distributed over 23 kb of genomic DNA. Casey et al. 1995. a aMb2 ligand. 1997). glycoprotein IIb/IIIa complex. TAFI is expressed by the liver and is present in platelets (Nesheim. Thus. TAFI. 100 nmol/l (6 lg/ml. 60 000 polypeptide circulates in plasma at concentrations of c. endothelial cells and a variety of tumour cells (Hajjar. 129. Integrin aMb2. however. These binding proteins commonly interact with the kringle structures of PLG through carboxyl-terminal Lys residues (Miles et al. Its activation by thrombin is accelerated in the presence of thrombomodulin by about 1250-fold. uPAR binds the adhesive glycoprotein vitronectin at a site distinct from the uPAbinding domain (Waltz & Chapman. expressed primarily on monocytoid cells. 1994. 1995. Formation of the uPA–PAI-1 complex appears to hasten clearance of uPA by hepatic or monocytoid cells (Hajjar. Certain polymorphisms enhance its half-life. leucocytes and endothelial cells respectively (Hajjar. renal epithelial cells. also decreases TAFI activation. This Mr c. uPAR appears to integrate cellular adhesion with proteolysis. 1993. structures abundant in endothelial cells and thought to participate in signalling events (Anderson. fibroblasts. 1995). monocyte/macrophages. and a smaller. 1995). have an essentially normal baseline phenotype (Nagashima et al. the Heymann nephritis antigen. cell surface fibrinolytic receptors can be classified into two groups whose integrated actions are likely to be essential for homeostatic control of plasmin activity (Hajjar. 1995). furthermore. encodes a protein of 313 amino acids with a 21-residue signal peptide. and places this glycoprotein within the Ly-1/elapid venom toxin superfamily of Cys-rich proteins (Behrendt et al. ‘Activation’ receptors localize and potentiate PLG activation. TAFI null mice. Activated TAFI (TAFIa) is a Mr c. 1990). macrophages. Cellular receptors Although structurally diverse. All annexin family members have in common a large conserved C-terminal ‘core’ region. the coagulation and fibrinolytic pathways are closely linked. which was cloned and sequenced from a human fibroblast cDNA library (Roldan et al. Attenuation of thrombin generation by the natural anticoagulant. Table I). 1994). 1995. annexin 2 is highly conserved and abundantly expressed on endothelial cells. 1990). At high concentrations. Reported receptors include a-enolase. 1995b). integrin aMb2 and annexin 2. 2003). which confers resistance to APC. The uPAR cDNA. Unstable at body temperature. Plasminogen receptors are a diverse group of proteins expressed on a wide array of cell types (Hajjar. a major component of caveolae. Because these residues are binding sites for PLG and for tPA on fibrin and on annexin 2 (Redlitz et al. resulting in greater clot protection from fibrinolysis (Nesheim. Stahl & Mueller. The human annexin 2 gene consists of 13 exons distributed over 40 kb of genomic DNA on chromosome 15q21 (Spano et al. Protein levels frequently correlate with polymorphisms in the promoter and 3¢-untranslated region (Bajzar et al. and also release uPA. while ‘clearance’ receptors eliminate plasmin and PLG activators from the blood or focal microenvironments. developing neuronal cells and some tumour cells (Hajjar & Krishnan. thus explaining APCs reported profibrinolytic effect. uPAR deficiency in mice is associated with normal fertility. In the same manner. circulating TAFI has a half-life of about 8 min. 1998). located on chromosome 13q14. uPAR appears to regulate cellular signalling and adhesion (Chapman. development and haemostasis (Bugge et al.Review Thrombin-activatable fibrinolysis inhibitor The single-chain plasma glycoprotein. which are 312 ª 2005 Blackwell Publishing Ltd. uPAR-bound uPA maintains its activity and susceptibility to the physiological inhibitor. This results in a 50-fold acceleration of plasmin generation. 307–321 .

Despite these studies. p11 (Deora et al. 2000). uPA and tPA together and annexin 2. fibrin deposition in the microvasculature and angiogenic defects in a variety of tissues (Ling et al. Lys307 appears to be crucial for the effective interaction of PLG with annexin 2 (Hajjar et al. For example. In vitro. 1989). 2001). but not uPA. a value close to the upper limit of normal for HC in plasma (10 lmol/l). vitamin B12. but not tPA. British Journal of Haematology. 1994). but not uPA (Hajjar & Hamel. 39 000 ‘receptor-associated protein’ co-purifies with LRP and may regulate the binding ª 2005 Blackwell Publishing Ltd. 1994). and sometimes paradoxical. 129. 1994). competes with PLG for binding to annexin 2 in vitro (Hajjar et al. LRP ‘knock-out’ embryos undergo developmental arrest by 13Æ5 d after conception. plasmin and its parent molecules appear to be crucial for vascular remodelling and angiogenesis (Lijnen. The annexin 2 heterotetramer. 1991) or an a-fucose-specific receptor (Hajjar & Reynolds. Similarly. Brown et al. Several studies suggest a physiological role for annexin 2 in fibrin homeostasis. while neither PAI-1 nor a2-PI deficiency in the mouse leads to overt bleeding (Carmeliet et al. Knowles & Maeda. lipoprotein(a). 1994). on the other hand. the same human deficiencies are associated with a haemorrhagic state (Hajjar. methylenetetrahydrofolate reductase. and uptake of LRP ligands. uPA alone. for example. or in inherited abnormalities of cystathionine b-synthase. the mannose receptor (Otter et al. An additional Mr c. 1995). arterial thrombosis can be significantly attenuated by pretreatment with intravenous annexin 2 (Ishii et al. thus preventing its interaction with t-PA (Hajjar et al. Pepper. a thiol-containing amino acid that accumulates in association with nutritional deficiencies of vitamin B6. In rats. 1989. roles of the fibrinolytic system in diverse physiological processes. 1998). In vitro. HC impairs the intrinsic fibrinolytic system of the endothelial cell by c. 1994). 1992). or methionine synthase. 2001. prevented cardiac rupture following experimental myocardial infarction (Carmeliet & Collen. native human placental annexin 2 stimulates the catalytic efficiency of tPA-dependent PLG activation by 60-fold (Cesarman et al. Hajjar. 2002). Furthermore. This sequence is a target for homocysteine (HC). or PAI-1 and (iii) loss of uPA. Additional investigations have illustrated the far-reaching. The atherogenic LDL-like particle. 1991). in vivo studies in mice suggest that LRP and the mannose receptor play a dominant role in tPA clearance (Narita et al. 1999). at least in the mouse under resting conditions. This complex interaction requires both growth factor and finger domains of tPA. suggesting that regulation of serine protease activity is crucial for early embryogenesis (Herz et al. and is associated with atherothrombotic disease (Refsum et al. 2001). while tPA may function in neuronal plasticity and may protect against demyelination following nerve crush injury. 1991). 11 lmol/l HC. annexin 2 is translocated to the endothelial cell surface through a mechanism that requires phosphorylation of tyrosine 23 and the accessory protein. reducing cell surface plasmin generation. 2000. it also appears to mediate excitatory neuronal cell death (Strickland. In a purified-protein system. or folic acid. 1998). For example. tPA binding to annexin 2 requires residues 8–13 (Leu-Cys-Lys-Leu-Ser-Leu) within the receptor’s aminoterminal tail domain (Hajjar et al. Interestingly. similarly. 2004). Plasminogen and tPA bind to distinct annexin 2 domains. suggests that these molecules may be dispensable. The complex roles of the fibrinolytic system in cardiovascular disease are illustrated by studies in which (i) postinjury arterial neointima formation required uPA and PLG. The absence of fibrin deposition in the tPA and uPAR knockouts. may have even greater stimulatory effects on tPA-dependent plasmin generation (Kassam et al. 2004). 307–321 . which removes basic carboxyl-terminal amino acids. The half-maximal dose of HC for inhibition of tPA binding to annexin 2 is c. established a central role for these molecules in regulating baseline fibrin homeostasis. The discovery of fibrin deposition in mice deficient in PLG. 114 nmol/l) and tPA (Kd: c. is required for leucocyte recruitment to sites of inflammation. Although several PAI-1-independent clearance pathways for tPA have been proposed involving the large LRP subunit (Bu et al. 50% (Hajjar. (ii) atherosclerotic plaque development was accelerated by deficiency of PLG. which consists of two annexin monomers and two p11 subunits. 1992). Lijnen et al. it is important to note those instances in which the murine fibrinolytic function may depart from that of the human (Lijnen et al. 1998). 30 nmol/l). but not tPA or uPAR. 1993) by forming a covalent derivative with Cys9. Mice with total deficiency of annexin 2 display impaired clearance of artificial arterial thrombi. but may also be co-opted from a host organism by bacteria during the invasive phase of infection (Plow & Hoover-Plow. while the impact of PAI-1 on experimental intimal hyperplasia seems to depend upon the model system employed (Fay. tPA. Although it lacks a classical signal peptide.Review Annexin 2 possesses binding affinity for both PLG (Kd: c. PLG. This effect is completely inhibited in the presence of Lys analogues or upon treatment of annexin 2 with the TAFI-like enzyme carboxypeptidase B. 1990. 2000). Beiseigel et al. 2003b). 2004). 1993b. while ligneous conjunctivitis is the major manifestation of PLG 313 Clearance receptors Both uPA and tPA are cleared from the circulation via the liver (Bu et al. 1998). 2004). clearance of tPA–PAI-1 complexes appears also to be mediated by a large two-chain receptor called the LDL receptor-related protein (LRP. Mouse models of fibrinolysis Much of what we understand about fibrinolytic function in humans reflects pioneering studies conducted in genetically engineered mouse models (Poplis & Castelino.

giving rise to fragments D. 2003). Bb and fragment fibrinopeptide B (FPB)] from the C. arthritis and toxic neuronal death (Hajjar. Plasmin can both activate and inactivate coagulation factors V and IX. When plasma antiplasmin activity is overwhelmed. with permission from Elsevier. as when PLG activators are used for the treatment of thrombosis. Plasmin degradation of fibrin leads to a distinct set of molecular products (Fig 3. circulating fibrinogen may be degraded by plasmin (Fig 3). 2003b).and N-termini of fibrinogen’s three polypeptide chains. such as the collagens. giving rise to fibrin degradation products such as D-dimer. which give rise to fragments [Aa.and b-chains within the D-domain. 2003b). cross-linked by factor XIII. Subsequently. laminin. When fibrin. suggesting possible roles in inflammation. neurodevelopment and prohormone activation in vivo. 129. aggrecan and tenascin C. embryogenesis. The resulting Mr c. Subsequently. are readily degraded by plasmin in vitro. When degrading cross-linked fibrin. laminin. In addition. chemotaxis and immune modulation (Hajjar. and in a series of subsequent reactions. plasmin cleaves the three polypeptide chains that connect the D. (Top panel) Plasmin initially cleaves the C-terminal regions of the a. plasmin initially cleaves the C-terminal region of the a. tumour cell invasion. 314 ª 2005 Blackwell Publishing Ltd. Additional fibrin breakdown products are formed and may have biological activities. 2003b).and Bb-fragments. some of the connecting regions between the D. thereby facilitating the degradation of matrix proteins. vitronectin. the phenotype of complete TAFI deficiency in the mouse is normal (Bouma & Meijers. releasing the Aa. a fragment-containing fibrinopeptide B (FPB) from the N-terminal region of the b-chain is also released. The fibrinolytic actions of plasmin Degradation of fibrin and fibrinogen Fibrinogen. The non-fibrinolytic actions of plasmin A large number of in vitro studies suggest a role for plasmin in tissue remodelling. Fibrin is ultimately solubilized upon hydrolysis of additional peptide bonds within the central portions of the coiled-coil connectors. Impaired wound Fig 3. Some of these fragments inhibit the spontaneous polymerization of fibrinogen (Hajjar. Assays for cross-linked D-dimer fragments are employed clinically to identify disseminated intravascular coagulation-like states associated with excessive plasmin-mediated fibrinolysis. 2003b). such as thrombospondin. Degradation of fibrinogen and cross-linked fibrin by plasmin. Fibrinogen possesses distinct proteolytic cleavage sites for plasmin. Adapted from Hajjar (2003b).and E-domains. fibronectin. fragments known as D-dimers are released (Hajjar. fibronectin and fibrinogen. Basement membrane proteins. including inhibition of platelet function. While elevated plasma TAFI levels in humans may be associated with venous thromboembolism. Y and E. 250 000 molecule is termed fragment X and represents a clottable form of fibrinogen. Additional cleavage events may release other peptides. potentiation of the hypotensive effects of bradykinin. 307–321 . 2003). Pizzo et al. giving rise to the intermediate fragment known as ‘fragment X’. is degraded by plasmin. plasmin may further cleave the three polypeptide chains that connect the D. (Bottom panel) Fibrinogen can also be polymerized by thrombin to form fibrin.and b-chains within the D-domain of fibrinogen. ovulation. Fibrin.and E-domains are severed. elastin. British Journal of Haematology. 1973). Plasmin also activates MMPs 1 and 3. it is seen only in PLG knockout mice with specific genetic backgrounds (Schuster & Seregard.and E-domains.Review deficiency in humans.

Fibrinolytic activity during pregnancy and puerperium Pregnancy is a prothrombotic. 50% of those observed in ª 2005 Blackwell Publishing Ltd. kringle 5 of PLG was found to be an even more potent inhibitor of growth factor-stimulated endothelial cell proliferation (Cao et al. Interestingly. as cells that invade the developing plaque may require plasmin activity for their directed migration (Lyons et al. by converting latent TGF-b to its physiologically relevant active state (Lyons et al. 1999). accompanied by an increase in PAI-1 levels to three times their normal level. In the absence of PAI1. a carrier protein that may limit PLG’s interaction with fibrin. In pre-eclampsia. compared with adult values. there is less neointima formation and reduced luminal stenosis. a marker of placental function. The role of the fibrinolytic system in vascular remodelling during atherosclerosis is complex (Hajjar et al. Although the amino acid composition and apparent molecular mass of neonatal PLG are indistinguishable from those of the adult protein. Hajjar. kainate-induced excitotoxicity and attendant neuronal cell dropout in the hippocampus is not observed in PLG knockout mice but does occur in fibrinogendeficient animals (Chen & Strickland. 307–321 . In other studies. Fibrinolytic deficiency and thrombosis Partial human PLG deficiency was first described in a man with a history of repeated episodes of thrombophlebitis. and in the blood vessel’s proliferative response to injury. sepsis and Argentine haemorrhagic fever because of decreased synthesis and/or increased catabolism. In contrast. the plasmin-generating potential in the newborn is significantly less than that of the adult (Hajjar. 1997. are reduced by 50–80% in healthy. levels of histidine-rich glycoprotein. adults. the haemostatic and fibrinolytic imbalances seen in pregnancy are further exaggerated.Review healing is observed in the PLG ‘knockout’ (Romer et al. less readily activated by tPA. Atherogenesis appears to be a response to vascular insult (Ross. intracranial and mesenteric venous thrombosis. Bugge et al. the prevalence of PLG deficiency was 1Æ9%. 1996. are reduced during pre-eclampsia compared with normal pregnancy. PLG in the neonate is heavily glycosylated. 1990. The cellular target or receptor for angiostatin is unknown although an endothelial cell-binding site distinct from annexin 2 has been proposed. 1991). Carmeliet et al. 2003b). 38 000 polypeptide is identical to kringles 1. and inhibits bFGF-stimulated endothelial cell proliferation in vitro. and pulmonary embolism (Aoki et al. deposition of intravascular fibrin and organization of a thrombus occurs. as may occur in liver disease. 1990). Reduced plasma PLG activity (50% of normal) resulted from an Ala601Thr point mutation. 2005). term newborns (Hajjar. which is reversed upon simultaneous deletion of fibrinogen (Table II. Angiostatin appears to blocks new blood vessel formation in both the chick chorioallantoic membrane and mouse cornea assays. 1996). 1996). Plasmin may play a role in the activation of growth factors. 129. and fibrin deposition is seen in glomerular capillaries and spiral arteries of the placenta. 2. possibly due to more rapid resolution of fibrin. 1995). 3 and 4 of PLG. has frequently been associated with thrombotic vascular occlusion. may have tPA antigen levels that are increased by up to eightfold. non-stressed state. 2003b). As the injury heals. but this predilection may be reversed under conditions of physiological stress (Hajjar. In type I. Acquired PLG deficiency. both concentrations of both PAI-1 and PAI-2 decrease. 1978b). reduced fibrinolytic activity may contribute to the thrombogenic state commonly observed in the newborn. Additional patients with this defect or related substitutions have now been described (Ichinose et al. This Mr c. the principal plasmin inhibitors undergo only minimal change from birth to adulthood. possibly by inducing apoptosis. however. In areas of the vasculature where injury is not associated with fibrin deposition. 1997). 1997). circulating PAI-1 levels exceed those in normal pregnancy. Angiostatin and related plasminogen fragments Angiostatin is a circulating inhibitor of angiogenesis originally isolated from the urine of Lewis lung carcinoma-bearing mice (O’Reilly et al. hypofibrinolytic state. tPA antigen and activity levels are also reduced by c. and increased fibrin deposition is suggested by increasing D-dimer levels throughout pregnancy (Hellgren. Thus. they return to normal levels within 3–5 d. 70%. as reflected in euglobulin lysis activity. is reduced. In this disorder. absence of PAI-1 may lead to enhanced lesion formation. Approximately half of these individuals had other 315 Developmental regulation and disorders of plasmin generation Developmental regulation of the fibrinolytic system In the resting. In contrast. while PAI-2 levels rise to 25 times their level in early pregnancy. fibrin participates in plaque growth and luminal narrowing. levels of PAI-2. Within 1 h of delivery. Coleman et al. 2003b). Plasma concentrations of PLG in the neonate are c. Less dramatic increases in both uPA and tPA levels are also observed. 2003b). 1997). Overall fibrinolytic activity. 2003b). such as those with severe congenital heart disease or respiratory distress syndrome. In the evolution of an injury to the endothelial cell lining of blood vessels. and only weakly bound to the endothelial cell surface. Interestingly. In a study of consecutive patients with thrombophilia. the concentration of immunoreactive PLG is reduced in parallel with functional activity. and this decrease correlates with intrauterine growth retardation of the fetus (Hajjar. British Journal of Haematology. Both PLG and fibrinogen levels in plasma increase by 50–60% in the third trimester. Congenital PLG deficiency has been classified into two types. Stressed infants.

with subsequent excessive fibrinolysis (Nesheim. Although the specific mechanisms leading to plasmin generation are common to both intravascular and extravascular settings. increased levels of PAI-1 have been associated with deep vein thrombosis in patients undergoing hip replacement surgery and in individuals with insulin resistance. Recently. defects in PLG activator release from the vessel wall. In a child with complete loss of PAI-1 expression. In addition. 27% of individuals with dysplasminogenaemia reported a clinical history of thrombosis. 129. While primary genetic disorders of fibrinolysis are uncommon. 2003b). which eliminates expression of annexin 2 through a transcriptional mechanism. the prevalence of thrombosis was 24%. an infant with <1% of normal PLG antigen and activity presented with hydrocephalus. 1991). In a study of a Japanese cohort. TAFI. have been associated with a twofold higher risk for recurrence of an initial venous thromboembolism. 1999). the physiological and pathophysiological effects of plasmin generation are context-dependent and sometimes unexpected. Increased circulating PAI-1 appears to represent an independent risk factor for vascular re-occlusion in young survivors of myocardial infarction (Hamsten et al. protein C. leading to suboptimal activation of TAFI. or during thrombolytic therapy. 2004). However. disseminated intravascular coagulation as result of consumption. Therefore. 2003). However. Premature lysis may reflect insufficient thrombin generation during the clotting process. 2003a). When clotted in vitro in the presence of tPA. or protein S. lyse substantially faster than normal plasma. high plasma levels (‡75th percentile) of the fibrinolytic attenuator. The latter resolved completely upon infusion of Lys-PLG (Schott et al. 1985). we must bear in mind the differences between murine and human fibrinolysis. In their study. tumour progression. poor wound healing.Review risk factors. which induces excessive utilization of the inhibitor. and thus may not be directly responsible for the observed prothrombotic tendency (Hajjar. while 3% and 1% had Val355Phe and Asp676Asn mutations respectively (Tsutsumi et al. and underscores the role of PLG deficiency as a relatively weak predisposing risk factor for thrombosis. bleeding in patients with haemophilia may be due to both a failure of clot formation and a failure of TAFI activation. Patients with acute promyelocytic leukaemia frequently develop severe bleeding accompanied by accelerated plasmin generation and a2-antiplasmin depletion. as well as increased inhibition of tPA by PAI-1. In this disorder. In this study. a twofold increase risk of deep venous thrombosis was seen in individuals with clot lysis times above the 90th percentile of levels present in the healthy population (Listman et al. or resistance to APC. the Leiden Thrombophilia Study (LETS) showed that plasma hypofibrinolysis is a risk factor for venous thrombosis. Mice deficient in many of these molecules have been developed. and a higher risk of recurrence was observed among patients with high levels of both TAFI and one of these factors (Eichinger et al. 2005). c. but only in the setting of trauma or surgery (Fay et al. nephrotic syndrome as a result of urinary losses. VIII and IX. 1998). Mutations in tPA or urokinase have not been clinically linked to thrombophilia. PAI-1 is itself an acute phase reactant. In type II PLG deficiency. The major proteins involved in PLG activation have been identified and characterized at the molecular level. leukaemic blasts overexpress annexin 2 and support enhanced cell surface plasmin generation (Menell et al. 1996). Acquired a2-PI deficiency may be seen in patients with severe liver disease because of decreased synthesis. A number of additional PLG polymorphisms and clinically significant dysplasminogenaemias have also been reported (Robbins. British Journal of Haematology. immunoreactive protein is normal while functional activity is reduced (Ichinose et al. angiogenesis and host defence. recurrent respiratory infections and severe ligneous conjunctivitis (fibrinous membrane over the eyes). In one well-documented case of type I PLG deficiency. This patient exhibited severe haemorrhage. Challenge of genetically engineered mice has illustrated the broad activities of this system relating to haemostasis. Bleeding resolves upon initiation of all-trans-retinoic acid therapy. These findings suggest that the function of PAI-1 in humans may be limited to regulation of fibrinolysis. have both been associated with a thrombotic diathesis. While such studies will illuminate our understanding of human physiology. Among 93 patients with type I heterozygous PLG deficiency. This case illustrates the importance of PLG in extravascular fibrinolysis. or 9% when the propositi were excluded (Hajjar. vascular remodelling. 94% of 129 families with type II dysplasminogenaemia had the Ala601Thr mutation. Conclusions Fibrinolysis is a highly regulated system that integrates with the coagulation system through several direct molecular links. The association of arterial thrombosis with elevated TAFI levels or that of particular TAFI polymorphisms with venous thrombosis has not yet been clearly established. IX (haemophilia B). such as deficiency of antithrombin III. central nervous system malformations. 1990). an autosomal recessive frame-shift mutation induced a premature stop codon in exon 4. In a large prospectively studied cohort of individuals. providing insight into their functional roles in vivo. 1992). Patients with high TAFI levels had significantly higher levels of coagulation factors XI. 1988). inflammation. plasmas deficient in intrinsic pathway factors VIII (haemophilia A). they have ª 2005 Blackwell Publishing Ltd. 307–321 . 316 Enhanced fibrinolysis and bleeding Enhanced fibrinolysis because of congenital or acquired loss of fibrinolytic inhibitor activity is associated with a bleeding diathesis. and early thrombus dissolution. Patients with congenital deficiency of a2-PI also have premature lysis of the haemostatic plug (Saito.

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