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TAFI (thrombin-activable fibrinolysis inhibitor) is a recently described plasma zymogen that, when exposed to the thrombin-thrombomodulin complex, is converted by proteolysis at Arg92 to a basic carboxypeptidase that inhibits fibrinolysis (TAFIa). The studies described here were undertaken to elucidate the molecular basis for the inhibition of fibrinolysis. When TAFIa is included in a clot undergoing fibrinolysis induced by tissue plasminogen activator and plasminogen, the time to achieve lysis is prolonged, and free arginine and lysine are released over time. In addition, TAFIa prevents a 2.5-fold increase in the rate constant for plasminogen activation which occurs when fibrin is modified by plasmin in the early course of fibrin degradation. The effect is specific for the Glu- form of plasminogen. TAFIa prevents or at least attenuates positive feedback expressed through Lys-plasminogen formation during the process of fibrinolysis initiated by tissue plasminogen activator and plasminogen. TAFIa also inhibits plasmin activity in a clot and prolongs fibrinolysis initiated with plasmin. We conclude that TAFIa suppresses fibrinolysis by removing COOH-terminal lysine and arginine residues from fibrin, thereby reducing its cofactor functions in both plasminogen activation and the positive feedback conversion of Glu-plasminogen to Lys-plasminogen. At relatively elevated concentrations, it also directly inhibits plasmin.
Thrombin-activable fibrinolysis inhibitor (TAFI) is a recently described plasma zymogen that can be activated by thrombin to an enzyme with carboxypeptidase B-like activity. The enzyme, TAFIa, potently attentuates fibrinolysis. TAFI activation, like protein C activation, is augmented about 1250-fold by thrombomodulin (TM). In this work, the effects of both soluble and cellular forms of TM on TAFI activation-dependent suppression of fibrinolysis were investigated. Soluble TM included in clots formed from purified components, barium citrate-adsorbed plasma, or normal human plasma maximally increased the tissue plasminogen activator-induced lysis time 2-3-fold, with saturation occurring at 5, 10, and 1 nM TM in the three respective systems. Soluble TM did not effect lysis in the system of purified components lacking TAFI or in plasmas immunodepleted of TAFI. In addition, the antifibrinolytic effect of TM was negated by monoclonal antibodies against either TAFI or TM. The inhibition of fibrinolysis by cellular TM was assessed by forming clots in dialyzed, barium citrate-adsorbed, or normal plasma over cultured human umbilical vein endothelial cells (HUVECs). Tissue plasminogen activator-induced lysis time was increased 2-fold, with both plasmas, in the presence of HUVECs. The antifibrinolytic effect of HUVECs was abolished 66% by specific anti-TAFI or anti-TM monoclonal antibodies. A newly developed functional assay demonstrated that HUVECs potentiate the thrombin-catalyzed, TM-dependent formation of activated TAFI. Thus, endothelial cell TM, in vitro at least, appears to participate in the regulation of not only coagulation but also fibrinolysis.
Recently, it has been shown that Factor XI can be activated by thrombin, and that Factor XIa significantly contributes to the generation of thrombin via the intrinsic pathway after the clot has been formed. This additional thrombin, generated inside the clot, was found to protect the clot from fibrinolysis. A plausible mechanism for this inhibitory effect of thrombin involves TAFI (thrombin-activatable fibrinolysis inhibitor, procarboxypeptidase B) which, upon activation, may inhibit fibrinolysis by removing carboxy-terminal lysines from fibrin. We studied the role of Factor XI and TAFI in fibrinolysis using a clot lysis assay. The lysis time was decreased twofold when TAFI was absent, when TAFI activation was inhibited by anti-TAFI antibodies, or when activated TAFI was inhibited by the competitive inhibitor (2-guanidinoethylmercapto)succinic acid. Inhibition of either TAFI activation or Factor XIa exhibited equivalent profibrinolytic effects. In the absence of TAFI, no additional effect of anti-Factor XI was observed on the rate of clot lysis. We conclude that the mechanism of Factor XI-dependent inhibition of fibrinolysis is through the generation of thrombin via the intrinsic pathway, and is dependent upon TAFI. This pathway may play a role in determining the fate of in vivo formed clots.
The plasminogen activator systems in the blood, the coagulation system, and the complement pathways are reviewed. The review describes the role of the vascular intima in activation of coagulation and fibrinolysis and the interrelations between the complement system and haemostatic mechanisms. Physiological activation of fibrinolysis may be triggered by and limited to fibrin because of a special affinity of plasminogen and plasminogen activators. The binding of plasminogen to fibrin is regulated by histidine-rich glycoprotein, and the primary physiological inhibitor of generated plasmin is alpha 2-antiplasmin and especially the plasminogen-binding form of this immediate plasmin inhibitor. Plasminogen activator inhibitors in the blood, that is, notably plasminogen activator inhibitor type 1 (PAI-1), bind circulating tissue-type plasminogen activator (t-PA). However, local fibrinolysis in vivo mediated by t-PA may be independent of complex formation between plasminogen activator inhibitors and t-PA in the fluid phase. Circulating plasminogen activator inhibitors might regulate fibrinolysis by increasing the clearance of t-PA from the blood. The urokinase-type and factor XII-dependent fibrinolytic proactivator system can be activated following t-PA-mediated generation of plasmin, and could thus serve as an amplification system of t-PA-induced fibrinolysis. It is claimed that the as yet uncharacterized proactivator is essential for optimal generation of plasminogen activator activity by the factor XII-dependent fibrinolytic system. The normal antithrombotic condition of the vascular intima probably results from lack of tissue factor activity and the presence of significant antithrombotic components comprising, among others, antithrombin III and the protein C-protein S system. A number of pathophysiologic stimuli, notably mediators of the acute phase response such as the cytokines interleukin-1 and tumour necrosis factor-alpha (cachectin), have the potential to induce the vascular endothelium to express procoagulant activity. Vascular endothelium promoting coagulant activity releases increased amounts of t-PA antigen and PAI-1 antigen into the circulation, and elevated levels in the blood of both may be regarded as a marker of a generalized procoagulant condition involving the vascular endothelium. In a prospective study in patients with unstable angina pectoris, patients in whom disease progresses and acute myocardial infarction develops, have increased amounts of t-PA antigen and PAI-1 antigen in the blood. This suggests that the procoagulant potential and atherosclerotic process of the vascular intima is more pronounced in the risk group.(ABSTRACT TRUNCATED AT 400 WORDS)
The main complication of totally implantable venous access devices is deep venous thrombosis on catheter. It may dramatically reduce the already limited venous capacity of patients undergoing chemotherapy and obturate catheters, causing pulmonary embolism or functional disorders. These thromboses usually involve veins of the superior vena cava system where the catheters are implanted. Generally, they occur early, are extensive and often asymptomatic. Doppler ultrasonography is the diagnostic investigation of choice, phlebography being reserved for particular cases or to specify the limits of the thrombus. In a series of 412 vein access devices implanted and systematically monitored by Doppler ultrasonography, we found 57 thromboses (13.8%), 15 partial and 42 complete. The lowest thrombosis rate was observed in the right internal jugular vein (10% vs 20 to 23%, p = 0.006). Thirty-two patients received a systemic fibrinolytic treatment, 16 with streptokinase (SK), five with urokinase (UK), four with tissue plasminogen activator (rt-PA) and seven with SK/UK association. No serious side effects were observed. Sixteen repermeabilizations (50% of fibrinolysis) were obtained. There were no significant differences with respect to the fibrinolytic, the initial characteristics of thrombosis or the patients. Patients without fibrinolysis received 3 weeks of low molecular weight heparin (curative doses) then warfarin. Only one patient was repermeabilized with this treatment (significative difference with fibrinolysis: p = 0.009). Fibrinolysis is indicated in symptomatic thrombosis and/or in cases of extension to the innominate vein or the superior vena cava. Systematic monitoring by Doppler ultrasonography and prophylactic anti-thrombotic treatment are recommended in patients with implantable venous access devices in order to decrease the occurrence of thromboses, to detect asymptomatic patients at an early stage and to increase the effectiveness of fibrinolysis.
The effect of purified human activated protein C (APC) on fibrinolysis was studied by using in vitro clot lysis techniques. Clots were formed from citrated blood or plasma (supplemented with 125I-labeled fibrinogen) by adding thrombin and Ca(2+)-ions; lysis of the clots was achieved by the addition of tissue-type plasminogen activator before clot formation. The gradual release of labeled fibrin degradation products from the clot into the supernatant was taken as a measure for the lysis rate. It was demonstrated that the acceleration of clot lysis by APC added before clot formation depends on the presence of Protein S, Ca(2+)-ions and phospholipids. These observations suggest a role of APC as anticoagulant in clot lysis, since the cofactors for the expression of its anticoagulant and profibrinolytic effect are very similar. Indeed, we could demonstrate that the profibrinolytic effect of APC in vitro is associated with reduction of thrombin generation through the coagulation cascade by inactivation of factor VIIIa and factor Va. For instance, APC did not accelerate the lysis of factor X deficient blood clots. More generally, thrombin generation was associated with retarded fibrinolysis in vitro. Consequently anticoagulants such as APC or Heparin are profibrinolytic, whereas pro-coagulants such as phospholipids (in cell-free plasma) inhibit fibrinolysis through the generation of thrombin. Thrombin thus plays a crucial role as a link between coagulation and fibrinolysis. As thrombin is able to inhibit the lysis of blood and plasma clots, and not of purified fibrin clots, we hypothesize that thrombin inhibits lysis through an as yet unidentified mediator in plasma.
BACKGROUND AND AIMS: The bleeding tendency of patients suffering from cirrhosis is in part ascribed to accelerated fibrinolysis. In this study, the role of the recently discovered inhibitor of fibrinolysis, thrombin-activatable fibrinolysis inhibitor (TAFI) in cirrhosis was examined. METHODS: In 64 patients with cirrhosis of varying severity, TAFI antigen levels were measured by enzyme-linked immunosorbent assay and compared with TAFI levels in control subjects. Furthermore, a plasma-based fibrinolysis assay was performed in the presence and absence of a specific inhibitor of activated TAFI. RESULTS: TAFI levels were decreased in cirrhosis. Mean TAFI levels were 66% in Child's A, 55% in Child's B, 47% in Child's C cirrhosis, and 26% in acute liver failure. Decreased TAFI antigen levels were highly correlated with antithrombin and alpha(2)-antiplasmin activity levels. Clot lysis times and clot lysis ratio (defined as ratio between clot lysis time in the absence and presence of a specific inhibitor of activated TAFI) of cirrhotics were not significantly different from healthy controls. CONCLUSIONS: Despite decreased levels of TAFI and other components of the fibrinolytic system, no evidence of increased plasma fibrinolytic potential in cirrhosis is observed using the plasma-based assay of this study. The reduction of antifibrinolytic factors in cirrhosis is compensated by the concomitant reduction in profibrinolytics.
Thrombin-activatable fibrinolysis inhibitor (TAFI) is a 60-kDa plasma protein that has been shown to be identical to plasma carboxypeptidase B (CPB) and carboxypeptidase U (CPU). TAFI is activated by thrombomodulin (TM)-bound thrombin and specifically removes the C-terminal Lys and Arg by its CPB activity. One of its target substrates is the C-terminal Lys residue in the alpha-chain of plasmin-digested fibrin, which is critical for plasminogen binding to fibrin. Thus, its removal seems to be the main mechanism through which TAFI inhibits fibrinolysis. In this article, relevance of C-terminal Lys of plasmin-digested fibrin in fibrinolysis is described, and then possible roles of TAFI and TM-bound thrombin in a cross-talk between coagulation and fibrinolysis are discussed.
Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxy-peptidase B-like proenzyme that after activation by thrombin downregulates fibrinolysis. Thrombomodulin stimulates the activation of both TAFI and protein C whereas activated protein C inhibits the activation of TAFI by downregulation of thrombin formation, a process in which protein S acts as a cofactor. Here we determined the role of protein S in the activation of TAFI and regulation of fibrinolysis. Depletion of protein S from plasma or inhibition of protein S by specific antibodies resulted in an increased rate of TAFI activation and in an increased maximum of TAFIa activity generated. The effect on the rate of TAFI activation could be attributed to the APC-independent anticoagulant function of protein S whereas the effect on the maximum activity could be attributed to the APC cofactor function of protein S. Therefore it is concluded that protein S inhibits TAFI activation in two ways. On one hand, protein S functions as a cofactor for APC which results in a reduction of the maximum induced TAFI activity and on the other hand protein S inhibits the initial thrombin formation independently of APC which results in a decreased rate of TAFI activation. The effect of the APC-independent anticoagulant activity of protein S on the activation of TAFI provides a new mechanism for the regulation of fibrinolysis in the early stages of clot formation.
Thrombin Activatable Fibrinolysis Inhibitor (TAFI) is a relatively recently described glycoprotein (MM 55 KDa) that can be converted into its active form by the thrombin/thrombomodulin complex and potentially inhibits fibrinolysis. Since it represents a link between coagulation and fibrinolysis, TAFI can be expected to play a part in various clinical conditions associated with a thrombotic tendency. Preeclampsia (PE) and intrauterine fetal growth retardation (IUFGR) are fairly common complications of pregnancy that are characterized by hemostatic abnormalities. TAFI antigen and its influence on hemostasis was investigated in 46 women with PE and/or IUFGR and in 16 normal pregnancies. We found a significant decrease of TAFI antigen in the patient group. Using the recently described method Overall Hemostatic Potential (OHP) in plasma we measured clot lysis time (CLT) and overall fibrinolytic potential (OFP). We found that CLT is prolonged and OFP decreased in patients with PE and/or IUFGR. Since OFP did not increase after addition of the specific inhibitor of TAFI (potato tuber carboxypeptidase inhibitor), it seems that TAFI does not contribute to the impairment of fibrinolysis in these patients. Since serum albumin was decreased together with presence of proteinuria and aminotransferases were increased in the patients, it seems that one explanation for the decrease in TAFI could be reduced hepatic synthesis and an increased loss in urine. It an be speculated that this mechanism can prevent more serious thrombotic complications in patients with PE and/or IUFGR.
A 45 years old woman with AL amyloidosis presented with a hypofibrinogenemia (fibrinogen 100 mg/dl) without severe bleeding. There was laboratory evidence of fibrinolysis with shortened euglobulin lysis time, decreased alpha-2 plasmin inhibitor and decreased plasminogen. The mechanism of this primary fibrinolysis remains unclear, since there is no enhancement of the tissue-type plasminogen activator. Analysis of the 8 cases related in the literature of excessive fibrinolysis associated with amyloidosis demonstrated improvement of bleeding manifestations and abnormal fibrinolysis following the administration of antifibrinolytic agents.
BACKGROUND: End-stage renal disease (ESRD) patients, not uncommonly, might exhibit thrombotic complications, as well as they may present with a bleeding diathesis. Changes in vessel wall and/or blood flow in native arteriovenous fistula (AVF) might also augment these disarrangements, as vascular endothelium is predominantly involved in the regulation of haemostatic pathways. OBJECTIVE: This study was designed to evaluate the state of coagulation and fibrinolysis and the role of AVF on haemostatic defects, in ESRD patients on maintenance haemodialysis. METHODS: Plasma samples for prothrombin fragment 1+2, thrombin-antithrombin III complex, plasmin-alpha2 antiplasmin complex, tissue type plasminogen activator antigen, urokinase type plasminogen activator antigen, u-PA activity, plasminogen activity, alpha2-antiplasmin and alpha2-macroglobulin assays were obtained from AVF and contralateral large veins of ESRD patients and from peripheral veins of the control group. RESULTS: Our results indicate a predominant thrombotic state as evidenced by activated coagulation markers and enhanced fibrinolysis in systemic circulation of ESRD patients. However the most novel finding is the probable contribution of AVF on haemostatic activation, as proven by the statistically different and positively correlated concentrations of both coagulation, fibrinolysis, and fibrinolysis inhibitors in AVF when compared to the levels in peripheral venous circulation. CONCLUSION: In addition to systemic derangements of haemostasis in ESRD patients, AVF individually might have a substantial role in the modulation of coagulation and fibrinolytic cascade.
Hyperfibrinolysis is thought to contribute to bleeding associated with advanced cirrhosis. Thrombin activatable fibrinolysis inhibitor (TAFI) is a plasma precursor of a carboxypeptidase (TAFIa) with antifibrinolytic activity and was recently shown to be reduced in cirrhosis. In this study, we evaluated the influence of TAFI deficiency on in vitro fibrinolysis in cirrhotic patients. Fifty-three patients with cirrhosis and 43 healthy controls were studied. TAFI antigen was measured by enzyme-linked immunosorbent assay and TAFI activity by chromogenic assay. Fibrinolysis was evaluated as tissue plasminogen activator-induced plasma clot lysis time in the absence and in the presence of a specific inhibitor of TAFIa. TAFI antigen and activity levels were markedly reduced in cirrhotic patients (P <.0001). In these patients, the lysis time of plasma clots was shorter than in controls (median, interquartile range: 25 minutes, 21-36 minutes vs. 48 minutes, 40-60 minutes, respectively; P <.0001) and was poorly influenced by the TAFIa inhibitor. Accordingly, TAFIa and thrombin activity, generated in cirrhotic samples during clot lysis, were significantly lower than in control samples. Addition of purified TAFI to cirrhotic plasma prolonged the lysis time and enhanced the response to TAFIa inhibitor in a dose-dependent manner. In conclusion, our results indicate that in vitro plasma hyperfibrinolysis in cirrhosis is largely due to a defective TAFIa generation resulting from low TAFI levels and probably from impaired thrombin generation. Impairment of the antifibrinolytic TAFI pathway might contribute to bleeding associated with this disease.
Studies have shown that inhibition of TAFI by small peptides enhances pharmacological effects of tPA in animal models of thrombosis, suggesting that TAFI modulates the fibrinolytic system. In this study, we investigated the effect of activated human TAFI (TAFIa) on endogenous fibrinolysis in a rat model of intravascular fibrin deposition. (125)I-labeled fibrinogen was injected intravenously followed by a bolus injection of batroxobin, a thrombin-like enzyme. Batroxobin cleaved fibrinogen to form insoluble fibrin that was deposited in tissues, including the lungs. This was shown by a decrease of radioactivity in the blood as a result of consumption of (125)I-labeled fibrinogen and an elevation of radioactivity in the lungs 5 min following batrox-obin administration. Endogenous fibrinolysis was detected by a gradual increase in radioactivity in the blood and a decrease in radioactivity in the lungs at 30 min, an indication of radiolabeled fibrin degradation products (FDPs) being released into the circulation from the tissues. Intravenous administration of human TAFIa dose-dependently attenuated the later phase reduction of radioactivity in the lungs. When the dose of TAFIa was 218 micro g/kg, giving a peak plasma level of TAFIa 0.9 +/- 0.05 micro g/ml, the spontaneous fibrinolysis was completely prevented. These results provide direct evidence that an increase in circulating TAFIa impairs endogenous clot lysis in a rat model of fibrin deposition.
Intra-arterial local fibrinolysis was performed in 72 patients (51 men, 21 women, mean age 66.8 years) during the course of 78 angioplasties. 11.1% were stage IIa (Fontaine), 38.9% were stage II b, 27.8% were stage III and 22.2% were stage IV. The methods used were conventional fibrinolysis (15.4%), spray lysis (47.4%) and mechanically accelerated fibrinolysis (37.2%). In 66.7% the urokinase dose was < 600,000 I.U., in 17.9% it was > 1,000,000 I.U. Additional balloon dilatation was performed in 72 cases, percutaneous aspiration of thrombo-embolic material in 41 cases and stent implantation in 7 cases. Angiographically the procedure was successful in 90.7%; the Doppler index rose from 0.47 +/- 0.27 to 0.85 +/- 0.3 (p < 0.001). At discharge, staging was: I = 38.9%, IIa = 38.9%, IIb = 5.6%, III = 1.4%, IV = 15.3%. There were no systemic bleeding complications. In 5.1%, complications had to be treated surgically.
Thrombin generation induced by recombinant factor VIIa (rFVIIa) in patients with haemophilia and/or inhibitors to factor VIII/IX could enhance generation of thrombin-activatable fibrinolysis inhibitor (TAFI), a recently described link between coagulation and fibrinolysis. TAFI is unstable and it is not easy to measure its active form in vivo. Overall haemostatic potential (OHP) is a novel method for haemostasis estimation, based on determination of the fibrin aggregation curve in which tiny amounts of thrombin are used for activation of clotting. We measured OHP in six patients with inhibitors to factor VIII before injection of rFVIIa and 10 and 120 min thereafter. Overall fibrinolytic potential (OFP) and clot lysis time (CLT) analysed by this method could be used for indirect estimation of TAFI generation. We found no change in pro-TAFI and total TAFI antigen before and after treatment with rFVIIa. OHP was almost undetectable before treatment but increased into the range of normal pooled plasma 10 and 120 min after rFVIIa treatment, as did CLT. However, after addition of potato tuber carboxypeptidase inhibitor, a specific inhibitor of TAFI, the shortening of CLT was lower than that in NPP. OFP was increased in patient plasma both 10 and 120 min after treatment compared with NPP. There was a strong positive correlation between pro-TAFI concentration and shortening of CLT after PTCI addition and a negative correlation between pro-TAFI concentration and OFP 10 min after rFVIIa injection. Thus, rFVIIa normalizes OHP and CLT 10 min after injection. While this improvement slightly decreases, but still exists after 2 hours, it suggests efficacy in bleeding prevention using a protocol based on rFVIIa administration every 2 hours.
Ischaemic and haemorrhagic stroke may cause haemostatic abnormalities, apart from concomitant brain damage. In this study, some blood coagulation and fibrinolysis parameters were investigated in 30 patients with ischaemic stroke (atherothrombotic) and 30 with haemorrhagic (20 with intracerebral and 10 with subarachnoid haemorrhage) stroke. The following parameters were determined within the first 24h after stroke: prothrombin time (PT%). activated partial thromboplastin time (aPTT). fibrinogen, activity of FVII, antithrombin. plasmin inhibitor (PI) and fibrin D-dimer. Significant decreases in PT%, FVII activity and antithrombin as well as an increase in fibrinogen and D-dimer were noticed in ischaemic stroke and in both groups of patients with haemorrhagic stroke. PI levels were significantly lower in subarachnoid haemorrhage patients compared with those in controls and those in both the intracerebral haemorrhage and the ischaemic stroke patients. With the exception of this difference, there were no other differences between ischaemic stroke and the two types of haemorrhagic stroke. This could indicate that haemostatic abnormalities are a consequence of brain damage rather than primary haemostatic activation during thrombosis and/or bleeding in the acute phase of stroke. A decrease in the plasmin inhibitor could suggest excessive fibrinolysis in subarachnoid haemorrhage.