Joanna Dubis, Wojciech Witkiewicz
The Role of Thrombin-Activatable Fibrinolysis Inhibitor
in the Pathophysiology of Hemostasis
Rola inhibitora fibrynolizy aktywowanego trombiną
w patofizjologii hemostazy
Regional Specialist Hospital in Wrocław, Research and Development Center, Poland
Abstract
The fibrinolytic system is responsible for the enzymatic degradation of fibrin and participates in a wide vari-ety of physiological and pathological processes, such as hemostatic balance, tumor invasion, angiogenesis, tissue remodeling, and reproduction. The balance between clot formation and fibrinolysis is controlled by the molecular components of the hemostatic system, including thrombin-activatable fibrinolysis inhibitor (TAFI). Several stud-ies indicate an important role for plasma TAFI in the regulation of fibrinolysis. It is activated by thrombin during blood clotting and is a link between coagulation and fibrinolysis. Moreover, TAFI plays a pivotal role in inflamma-tion. In this review, recent basic and clinical findings that demonstrate the role of TAFI in regulating the crosstalk between coagulation, fibrinolysis, and inflammation are summarized (Adv Clin Exp Med 2010, 19, 3, 379–387).
Key words: thrombin-activatable fibrinolysis inhibitor, hemostasis.
Streszczenie
Układ fibrynolizy jest odpowiedzialny za enzymatyczną degradację fibryny, a także uczestniczy w wielu procesach fizjologicznych i patologicznych, takich jak: hemostaza, migracja komórek nowotworowych, angiogeneza, przebu-dowa tkanek, rozród. Równowaga między procesem powstawania skrzepu a fibrynolizą jest precyzyjnie kontrolowa-na przez czynniki układu hemostazy, w tym przez inhibitor fibrynolizy aktywowany trombiną (TAFI). Wykazano, że osoczowe stężenie TAFI ma znaczący wpływ na proces fibrynolizy w stanach patologicznych. Inhibitor TAFI jest aktywowany przez trombinę i jest czynnikiem wiążącym między procesem koagulacyjnym a fibrynolizą. TAFI pełni także ważną rolę w procesie zapalenia. W pracy przedstawiono najnowsze wyniki badań podstawowych i kli-nicznych na temat roli TAFI w regulacji powiązań między procesami krzepnięcia krwi, fibrynolizy i zapalenia (Adv Clin Exp Med 2010, 19, 3, 379–387).
Słowa kluczowe: inhibitor fibrynolizy aktywowany trombiną, hemostaza.
Adv Clin Exp Med 2010, 19, 3, 379–387 ISSN 1230-025X
REvIEWS
© Copyright by Wroclaw Medical University
In the course of hemostasis, vascular wall, platelets, and the coagulation system together with fibrinolysis provide for the proper functioning of mechanisms responsible for fluidity of blood in the vascular bed and prevention of its loss after vessel damage. Only the proper activity of the main ele-ments of hemostasis and efficient functioning of the mechanisms controlling them protect the body against pathological conditions which may appear, such as hemorrhagic diathesis, thrombi, and relat-ed complications. The fibrinolytic system is also engaged in many other physiological processes. Proteolytic enzymes of this system participate in
such processes as cell migration, tissue remodel-ing, angiogenesis, and reproduction. Fibrinolytic system disorders contribute to thrombosis, ath-erosclerosis, endometriosis, complications in the course of pregnancy, and the development of neo-plastic disease [1].
vascular cells, whereas uPA is produced in vari-ous organs, for example the kidneys. These factors are activated in the blood plasma by kallikrein and also by plasmin itself. Under normal conditions, fibrinolysis, i.e. the process in which an intravas-cular thrombus is dissolved under the influence of proteolytic enzymes, takes place mainly on the surface of, for example, endothelial cells thanks to appropriate cellular receptors. These receptors bind plasminogen, uPA, and annexin II, which may form a complex with plasminogen and tPA. Proteolytic degeneration of the fibrin network takes place in the blood only under pathological conditions [2, 3].
There are generally two main mechanisms inhibiting fibrinolysis: inhibition of plasmin with α-anitiplasmin and inhibition of tPA and uPA. The key inhibitors are PAI-1 (plasminogen activa-tor inhibiactiva-tor type 1, produced in endothelial cells, liver, and megakaryocytes) and PAI-2 (plasmino-gen activator inhibitor type 2, isolated from pla-centa). PAI-1 mainly inactivates tPA in plasma, whereas PAI-2 is responsible for tPA and uPA inactivation. Relatively recently a new plasma factor, TAFI (thrombin-activatable fibrinolysis inhibitor) was discovered. It participates in the regulation of fibrinolysis by the coagulation sys-tem. TAFI is activated by thrombin, an enzyme of the coagulation system which inhibits the produc-tion of plasmin. TAFI is therefore often described as a plasma factor binding coagulation and fibrin-olysis. Description of the physiological function of TAFI in hemostasis facilitates the understanding of the regulatory relations between coagulation and fibrinolysis [4].
The role of TAFI was initially described chiefly in tPA-induced exogenous fibrinolysis. Currently, its role is discussed in the regulation of endoge-nous fibrinolysis related to the activation of plas-minogen [5]. Since TAFI plasma factor was iden-tified independently by different research teams, there are differences in terminology in the litera-ture. The nomenclature of the enzyme was par-tially unified by Bajar and associates in 1995 after discovering its activity in fibrinolysis inhibition, and it is currently described in the literature with the acronym TAFI [6]. Active TAFI appears in the literature as TAFIa, carboxypeptidase B (CPB), carboxypeptidase U (CPU), and carboxypeptidase R (CPR). On the other hand, the inactive form of enzyme (proenzyme) is described as TAFI, procar-boxypeptidase U (pro-CPU), procarprocar-boxypeptidase B CPB), and procarboxypeptidase R (pro-CPR) [7].
TAFI deserves particular attention because apart from its antifibrinolytic property, it possess-es the ability to inactivate inflammation mediators
such as C3a and C5a, bradykinin, osteopontin, and anexin II [8]. It was shown that the inhibitor plays a significant role in cardiovascular diseases, thrombotic complications, and the pathogeneses of sepsis and disseminated intravascular coagula-tion [9–11].
Structure and Activation
of the Enzyme
Structural examination showed that TAFI is a glycoprotein with a molecular mass of 60 kDa (402 aa) which circulates in the blood as an inac-tive enzyme precursor [6,7]. The inhibitor is built up of a catalytic domain with Zn2+ in the active
center and a 92-amino-acid-long activating pep-tide (Fig. 1). As most plasma factors, TAFI is pro-teolytically activatable. It is activated by cleavage of the activating peptide, which obscures the active center of the enzyme. This results in the forma-tion of the active form of the inhibitor, TAFIa. Biochemical studies have shown that hydrolysis of the activating peptide can take place with the par-ticipation of thrombin, thrombin/thrombomodu-lin (IIa/TM) complex, plasmin, as well as trypsin [12].
TAFI is a metallocarboxypeptidase which has the activity of a carboxypeptidase, hydrolyzes the carboxylic bond, and splits off the lysine and argi-nine residues from the C-terminal of the amino-acid chain [6, 13].
The activity of TAFI depends on temperature. The half-life of this enzyme at 37°C is 10 min-utes, at 22°C 1–2 hours, and at 4°C a few hours. Inactivation of the factor under the influence of
Fig. 1. The structure of thrombin-activatable fibrinoly-sis inhibitor (TAFI). TAFI is a single-chain zymogen that consists of an activation peptide and a catalytic domain. Thrombin cleaves the zymogen and releases a 92-amino-acid N-terminal activation peptide which obscures the active center of the enzyme (NH2–). The
active site with Zn2+ is shown
Ryc. 1. Budowa inhibitora fibrynolizy aktywowanego trombiną (TAFI). TAFI jest zymogenem, który składa się z peptydu aktywacyjnego i domeny katalitycznej. Trombina rozszczepia zymogen i uwalnia N-końcowy peptyd aktywacyjny (NH2–), który przesłania centrum
temperature changes is caused by changes in the protein’s conformation, which has a direct influ-ence on its enzymatic activity [14–16]. It should be emphasized that in plasma there is an enzyme with a similar activity to TAFI, i.e. carboxypeptidase N, which has the ability to remove residues of lysine and arginine but which does not demonstrate prop-erties of fibrinolysis inhibition. Carboxypeptidase N, in contrast to TAFI, is constitutively active and it is not inhibited in vitro by potato tuber carboxy-peptidase inhibitor (PTCI) [17].
Mechanisms of Fibrinolysis
Inhibition by TAFIa
In correctly proceeding fibrinolysis, the acti-vation of plasminogen by tPA and the forming of plasmin is the main stage in dissolving a
throm-bus and this plays a key role in maintaining the patency of blood vessels. The activation of plas-minogen and the simultaneous increase in blood fibrinolytic activity is most efficient (200–400 times quicker) when plasminogen is in complex with tPA and fibrin. This complex can be formed only when fibrin is partially degraded and there are free residues of lysine in its amino-acid chain. Specific interactions of the lysine-binding sites in plasminogen and tPA with C-terminal lysine residues in partially degraded fibrin result in the formation of a ternary complex and catalytic effi-ciency of plasmin formation. Consequently, as a result of the presence of an ever greater concen-tration of plasmin, fibrinolysis leaves the initiation phase and quickly increases its potential [3]. As a result of the enzymatic activity of TAFI, lysine is hydrolytically split off from the C-terminal of the fibrin amino-acid chain (Fig. 2). In this way, fibrin
Fig. 2. Mechanism of fibrinolysis inhibition with the participation of TAFI. During the initiation phase of fibrinolysis, a small amount of plasmin is produced which, although insufficient for efficient thrombolysis, enables fibrinolysis to enter the next phase. Due to the limited proteolysis of the fibrin network, residues of lysine (fibrin-C-lys) at the C-terminals of digested amino-acid chains appear in the initial phase of the process. These residues are necessary to bind fibrin, plasminogen, and tPA. The Lys-plasminogen formed is a better substrate for tPA. TAFI, activated by thrombin (IIa) at a high concentration or thrombin complexed with thrombomodulin (IIa/TM), splits off residues of lysine at the C-terminals of fibrin, thereby preventing its binding of tPA and plasminogen. As a result there is a decrease in catalytic efficiency of the production of plasmin from plasminogen. In this way, TAFI inhibits fibrynoly-sis and stabilizes the forming thrombus
Ryc. 2. Schemat przedstawiający mechanizm hamowania procesu fibrynolizy z udziałem czynnika TAFI. Podczas inicjacyjnej fazy fibrynolizy powstaje niewielka ilość plazminy, która nie jest wystarczająca do skutecznej lizy skrzepu, ilość ta umożliwia jednak fibrynolizie wejście w następny etap. Na skutek ograniczonej proteolizy fibrynowej sieci we wczesnej fazie procesu pojawiają się na C-końcach trawionych łańcuchów aminokwasowych reszty lizyny (fibryna-C-Lys). Reszty te są konieczne do związania się z fibryną plazminogenu oraz aktywatora tPA. Utworzony Lys-
becomes more resistant to fibrinolysis initiated by tPA released from endothelial cells under the influ-ence of thrombin. The lack of plasmin prevents fibrin from further degradation, which efficiently protects a thrombus against lysis. The carboxypep-tidase TAFI prolongs the lysis of thrombus acti-vated by tPA and uPA in vivo [18].
TAFI is activated by thrombin, but the most efficient activation occurs when thrombin is in complex with thrombomodulin (IIa/TM) [12]. The IIa/TM complex is known as an activator of protein C, which actively participates in coagula-tion processes. The regulacoagula-tion of fibrinolysis with the participation of TAFI, similarly to the case of protein C, depends on the amount of TM [4]. The activation of TAFI by the thrombin/thrombomod-ulin complex couples the coagulation-induced inhibition of fibrinolysis and the profibrinolytic effect of activated protein C.
The activity of TAFI depends on the concen-tration and activity of thrombin, the most impor-tant enzyme in the coagulation system. Thrombin is responsible for the production of fibrin and it also regulates fibrinolysis [19]. Studies have shown that in people with hyperhomocysteinemia and a genetically conditioned high level of prothrom-bin, there is lower fibrinolytic activity of plasma together with an increased TAFI level [20].
There are two physiological activation path-ways of TAFI. The first is very efficient, with the participation of thrombin at a relatively low con-centration but in the presence of thrombomodulin (TM), and the second is with the sole participa-tion of thrombin (IIa), which occurs at a very high concentration as a result of the activated coagu-lation pathways. When the concentration level of thrombin in plasma is low, the clot is built of dense coarse-grained fibrins, which can be easily degrad-ed by plasmin [21]. In the presence of the endothe-lial cell receptor thrombomodulin, the activation of TAFI is independent of thrombin generation. Compared with the activation of the proenzyme by thrombin itself, the IIa/TM complex catalyses the reaction of TAFI → TAFIa about 1250 times more quickly. If there is a relatively high level of thrombin in plasma, a thrombus with a structure resistant to fibrinolysis is formed. Thrombin acti-vates factor XIII to form additional bonds between the molecules of fibrin and enables the binding of α2-antiplasmin (plasmin inhibitor) with fibrin. On the other hand, thrombin activates TAFI to stabi-lize the fibrin clot [12]. The activation of TAFI by thrombin is an inefficient process and requires a relatively high concentration of thrombin.
The activation of TAFI starts at the moment of coagulation initiation when thrombin appears and is sensitive to the coagulation dynamics. The
half-life of the active form of the inhibitor is very short and, probably due to this, the activity of TAFI, and also fibrinolysis, may be effectively controlled by the coagulation system. The short half-life of active TAFI guarantees a specific way of regulating enzyme activity and makes the enzyme effective at a given place and in a specified time [15]. On the basis of recent studies on the mechanisms respon-sible for the inhibition of exogenous fibrinolysis, there are now two independent ways of regulat-ing this process, i.e. a pathway with PAI-1 and a pathway with TAFI. PAI-1 is a strong fibrinolysis inhibitor that binds tPA and uPA, forming with them inactive complexes. This leads to inhibition of the main reaction of the fibrinolytic system, i.e. the transformation of plasminogen to plasmin. TAFI, on the other hand, prevents the binding of tPA and plasminogen to fibrin [5].
Polymorphism of the Gene
Encoding TAFI
The mechanism of thrombus formation in vessels under pathological conditions may depend on the change in activity of one or more factors taking part in hemostasis. This is often caused by polymorphisms in genes encoding proteins par-ticipating in coagulation and fibrinolysis. Several polymorphisms have been identified in the TAFI gene and some of them are strongly associated with plasma TAFI levels [22, 23].
carriers have a higher risk of developing deep vein thrombosis (DvT) [25]. The 438G/A polymor-phism of the promoter region of the gene for TAFI was also linked to the risk of thrombosis develop-ment [24].
Genetic studies suggest a multi-gene inheri-tance model of TAFI factor activity. It has been suggested that CPB2 gene is responsible for the concentration and activity levels of TAFI, but in connection with other, not yet discovered, genes. These are genes that are probably jointly respon-sible for the appearance of chronic diseases which are caused by hemostatic disorders coexisting with reduced plasma fibrinolytic activity.
Physiological Role of TAFI
TAFI is synthesized in the liver and from there it is transported to the circulatory system and tis-sues. Similarly to many other proteins active in coagulation processes and fibrinolysis, TAFI also appears in blood platelets’ α-granules, and simi-larly to them the factor is released to plasma after platelet activation in coagulation [7]. It has been demonstrated that the plasma concentration of TAFI of healthy people amounts to 70–100 nM and increases with age in women, but not in men [9, 26].TAFI is a carboxypeptidase with a wide spec-trum of substrate specificity and its role is not lim-ited to participation in fibrinolysis; the enzyme is also an active factor participating in inflammation in response to tissue injury or infection. TAFIa is an effective inactivator of major inflammatory mediators, i.e. the anaphylatoxins C3a and C5a of the complement system, bradykinin, and osteopon-tin. The inactivation of inflammatory mediators with the participation of TAFIa consists in cleav-age of lysine and arginine residues from amino-acid chains of protein C-terminals [8, 27]. At the moment of inflammation, the level of inflamma-tory mediators increases significantly and there is a release of neutrophil granules and strengthening of phagocytosis. The potent chemoattractants C3a and C5a are formed directly at the site of inflam-mation, where their activity must be precisely con-trolled. The expression of TAFI rises significantly in the liver in response to the presence of endo-toxins in the body. In the course of inflammation, this factor is released to the circulatory system as an acute-phase protein. There is a very close rela-tionship between the coagulation and fibrinolysis systems and the complement system. The anaphy-latoxins C3 and C5 may be activated by the main proteolytic enzymes of the hemostatic process, thrombin and plasmin, and complement may
induce both the coagulation system and fibrinoly-sis. Complement is an integral part of nonspecific immunity and plays a significant role in bacterial infections. It is also engaged in processes caused by acute and chronic inflammatory diseases [28].
The mechanism of TAFI activity in the inflam-matory process (similarly to fibrinolysis) is based on thrombin activity and thrombin/thrombo-modulin complexes. Thrombin is produced at an endothelial injury site and immediately activates hemostatic and anti-inflammatory mechanisms by bonding to retinoic acid receptors (RARs) on endothelial cells, monocytes, and smooth muscle cells. When thrombin appears in plasma, TAFI factor is activated as well. The formed throm-bin/TM complexes (IIa/TM) located on the sur-face of uninjured endothelium activate TAFI and protein C, which has strong anticoagulative and anti-inflammatory properties. Activated protein C (APC) and TAFI are physiological substrates for IIa/TM and play complementary functions in the regulation of inflammation; APC inhib-its the coagulation cascade by lowering the level of thrombin produced, whereas TAFI inactivates post-inflammatory factors [4, 29].
In addition to plasminogen (Pg) activation in the fluid phase, Pg is activated by plasminogen activators (tPA, uPA) on the surface of a variety of cells. Pericellular proteolysis contributes to several cellular functions, such as cell migration, angio-genesis, and tissue repair. In vivo, TAFI is a modu-lator of basic functions of plasminogen (Plg) con-nected with pericellular fibrinolysis necessary for hepatocyte proliferation and plays a role in liver regeneration [30].
A lower level of TAFI can be observed in patients with inflammatory diseases, for example inflammatory bowel disease and Behçet disease [31, 32]. Lower concentration levels of TAFI were also described in patients with hyperthyroidism and cirrhosis of the liver [33, 34]. A higher level of TAFIa in plasma may result in the risk of develop-ment of deep vein thrombosis, coronary disease, and ischemic stroke [9, 29, 35, 36]. A decreased level of TAFIa in people with atherosclerosis is a death risk factor due to the development of this disease [10].
TAFI and the Danger
of Thrombosis
of thrombosis is very complex due to its multifac-toral nature. The coagulation system comprises numerous pro- and anti-coagulative factors whose concentrations are maintained in strict balance thanks to relevant hemostatic regulatory mecha-nisms. At the moment of, for example, vessel inju-ry, coagulation is activated. Promptly thereafter the balance of the concentration levels of the fac-tors participating in the process is restored. Under pathological conditions, thrombi posing a threat of embolism are formed in vessels. Defects of the coagulation system, for example protein C and protein S deficiency as well as a high activity of prothrombin, are responsible for the pathomecha-nism of thrombosis. Thromboembolism may also result from fibrinolytic system defects. Thus 10 out of 100 fibrinogen mutations as well as genetic plas-minogen deficiencies have been directly linked to the development of thrombotic complications [37]. Although the role of TAFI in the regulation of the fibrinolytic system is well documented, it has been impossible to prove that its activity is wholly related to hemostatic abnormalities. No severe hemostatic disorders have been observed in mice deprived of the gene encoding TAFI protein; therefore the role in the regulatory mechanisms of hemostasis which bind the coagulation process and fibrinolysis is attributed to TAFI [38].
The increased concentration of tPA inhibi-tor (PAI-1) is related to recurrent coronary artery thrombosis, which may lead to myocardial infarc-tion. Due to TAFI’s function in the process of thrombus stabilization, it may have a substantial influence on the risk of developing hemostatic complications. A high level of TAFI significantly lengthens clot lysis time and suppresses fibrinoly-sis, and it strengthens procoagulative tendencies in the blood, which may lead to thrombosis [9, 14, 32]. The most recent clinical studies suggest that the inhibitor, participating in the regulation of coagulation processes, may be responsible for the pathomechanism of thrombosis development. Studies conducted on an animal model indicate a significant role of TAFI in the pathomechanism of caval vein thrombosis development. TAFI defi-ciency in mice evidently protects these animals from this disorder [38]. Moreover, clinical stud-ies revealed that carriers of the 505G allele with lower TAFI levels showed an increased risk of deep vein thrombosis (DvT) [25]. In people with the G20210A prothrombin gene polymorphism and with hyperprothrombinemia, a lower plasma fibrinolytic potential and a significantly increased prothrombin concentration were observed, which is an independent risk factor of thrombosis occur-rence. In patients with hyperprothrombinemia, an increased TAFI level in blood is observed as well.
In this condition, a pathomechanism that results in thrombosis takes place with the participation of TAFI, which, activated by thrombin, takes part in the inhibition of fibrinolytic processes by throm-bus stabilization [20].
Hemostatic dysfunctions and complications connected with the formation of clots or hemor-rhagic diathesis develop in patients with infec-tions, cardiovascular diseases, sepsis, hyperthy-roidism, and tumors. Inflammation and coagu-lation together with fibrinolysis are parallel process that occur in blood under pathological conditions. Significantly higher TAFI and PAI-1 levels compared with healthy people have been described in patients with Behçet disease (with systemic vasculitis), in which a main complica-tion is deep vein thrombosis. There was a higher TAFI level in patients with thrombosis than in those patients without thrombotic complications [39]. Patients withhyperthyroidism have a higher concentration PAI-1, but lower concentrations of TAFI. The inverse correlation between TAFI and PAI-1 antigen levels in patients with hyperthy-roidism may be associated with activation of the TAFI pathway during coagulation [33]. The lat-est research in the field of cardiovascular diseases has shown a link between plasma TAFI levels and the risk of complications in the course of coro-nary artery disease. Elevated levels of the active form of TAFI (TAFIa) is associated with the risk of cardiovascular death in patients with coronary artery disease [10, 24].
TAFI in Neoplastic Disease
Disorders of the coagulation system and fibrin-olysis are observed in most patients with neoplas-tic disease. Hemostaneoplas-tic abnormalities develop in the bloodstream as a result of processes directly and indirectly connected with cancer develop-ment and may be the consequence of therapeutic procedures [41]. Hemostatic disorders may lead to such complications as thromboembolic incidents. Clinically, they occur as coagulopathy, thrombo-sis, and DIC. These complications are one of the main causes of death in patients with diagnosed neoplastic disease.The role of TAFI in the pathogenesis and development of neoplastic disease is still unknown. In vivo studies conducted on a mouse model (animals deprived of TAFI gene) have shown that lack of TAFI gene directly influences neither tumor growth nor metastasis [42]. The plasminogen system plays an important role in cancer tumor growth, invasion, and metastasis [2]. Thus the negative regulator of plasmino-gen pathway, TAFIa, may be involved in cancer development.
Thrombosis is a frequent complication during the course of lung cancer. The results of in vitro
studies showed that TAFI is secreted by human lung cancer cell lines [43]. Moreover, increased TAFI is observed in the plasma of patients with the lung cancer compared with healthy subjects [43, 44]. In patients with small-cell carcinoma there is a higher level than in the plasma of patients with adenocarcinoma and squamous cell carcinoma [43]. Plasma TAFI concentration does not depend on the age or sex of patients with lung squamous cell carcinoma or on the disease development stage. Patients with lung cancer have hypercoagu-lability, which is caused by multiple factors, and a higher plasma level of TAFI may be one of the factors contributing to the formation of thrombi [43, 44]. Thus TAFI probably plays a role in the pathogenesis of thrombotic disorders in patients with lung cancer. Increased levels of circulating TAFI is observed in patients with lung carcinoma, while reduced TAFI activity is detected in
bleed-ing patients sufferbleed-ing from acute promyelocytic leukemia (APL) [45]. This finding suggests that hemorrhage diathesis in patients with leukemia is a consequence of disturbances in clot stabilization during fibrinolysis.
Low TAFI levels in a patient is genetically determined and may be associated with the risk for cancer development. Recent genetic studies revealed that individuals with the 1040T/T allele (T/T homozygotes) have an increased risk of oral cancer [16]. The clinical relevance of TAFI in developing cancer is not yet understood and larger studies will be required to investigate the possible link between TAFI and neoplasic disease.
Conclusions
Thrombin-activatable fibrinolysis inhibitor is a one of the components of the hemostatic system which, after activation, down-regulates fibrinolysis and determines clot stability. Together with factor XIII, TAFI stabilizes the fibrin clot and makes it more resistant to fibrinolysis. TAFI plays a pivotal role in the regulation of the fibrinolytic system, but its effect on hemostasis remains unclear due to its poorly proved clinical impact. On the basis of the latest data it is possible to assert that the physiological function of TAFI is not restricted to fibrinolysis. TAFI modulates the proinflammatory processes connected with bradykinin, comple-ment, and thrombin-cleaved osteopontin and may have other so far unidentified functions.
Current clinical studies revealed an associa-tion between plasma levels of TAFI and hemo-static disturbances which may determine throm-boembolic events. TAFI’s potential for clot sta-bilization opens further possibilities for rational drug design. Selective inhibition of TAFIa may be helpful in enhancing fibrinolysis by tissue plasmi-nogen activator (tPA) and may be of benefit in the treatment of ischemic stroke. Intravenous admin-istration of a tPA is used in the treatment of acute ischemic stroke patients [46]. On the other hand, enhancement of the TAFIa pathway may be help-ful in patients with coagulopathies.
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Address for correspondence:
Joanna Dubis
Regional Specialist Hospital in Wrocław Kamieńskiego 73a
51-124 Wrocław Tel.: +48 71 327 04 56 Poland
E-mail: [email protected]
Conflict of interest: None declared
