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PubMed2002

The effect of external pneumatic compression on regional fibrinolysis in a prospective randomized trial.

INTRODUCTION: External pneumatic compression devices (EPC) prevent deep venous thrombosis (DVT) by reducing lower extremity venous stasis. Early studies suggested they also enhance fibrinolytic activity; however, in a recent study, EPC had no effect on systemic fibrinolysis in patients undergoing abdominal surgery. The hypothesis of this study was that EPCs enhance regional fibrinolysis in these subjects. METHODS: Forty-five patients (44 male, one female; mean age, 67 years) undergoing major abdominal surgery (35 bowel procedures, 10 aortic reconstructions) were prospectively randomized to one of three groups for DVT prophylaxis: subcutaneous heparin injections (HEP), thigh-length sequential EPC devices (EPC), or both (HEP+EPC). Prophylaxis was begun immediately before surgical incision and continued until postoperative day 5 or patient discharge. Venous blood samples were collected from the common femoral vein for measurement of regional fibrinolysis after induction of anesthesia but before initiation of prophylaxis, and on postoperative days 1, 3, and 5. A baseline sample was collected the day before surgery. Fibrinolysis was quantified with measurement of the activities of tissue plasminogen activator (tPA; the activator of fibrinolysis) and its inhibitor plasminogen activator inhibitor-1 (PAI-1) with amidolytic technique. RESULTS: tPA activity in all groups was normal at baseline; baseline PAI-1 activity was elevated. Within each prophylaxis group, no significant changes occurred in either tPA or PAI-1 activities after induction of anesthesia or after surgery compared with before surgery (P >.05, analysis of variance with repeated measures). No changes occurred between postoperative samples and after anesthesia within each group. No significant enhancement of fibrinolysis, manifested as either increased tPA activity or decreased PAI-1 activity, occurred in either EPC group compared with the HEP group at any time point (P >.05, analysis of variance with repeated measures). No differences were noted when surgery was performed for malignant disease versus nonmalignant disease. CONCLUSION: In this study, enhanced regional fibrinolysis in the lower extremities could not be detected with the use of EPCs, as measured with tPA and PAI-1 activity in common femoral venous blood samples. EPC devices do not appear to prevent DVT with fibrinolytic enhancement; effective and safe prophylaxis is provided only when the devices are used in a manner that reduces lower extremity venous stasis.

Abdomen↗

PubMed1997

Rheological study of the dynamic process of fibrinolysis.

The dynamic process of fibrinolysis induced by tissue plasminogen activator was examined using a rheological technique. Change in a rheological parameter (logarithmic damping factor) of whole blood and platelet-free plasma during fibrinolysis was largely dependent on the initial concentration of tissue plasminogen activator. Addition of activated partial prothrombin time reagent allowed determination of the time both of onset and end of fibrinolysis without affecting the coagulation process. The changes in the clot structure of fibrin during fibrinolysis were observed with a scanning electron microscope and compared with the time-dependent behavior of the logarithmic damping factor. Differences in the logarithmic damping factor during fibrinolysis were evident in alteration of the network structure of clots. It will be shown that the present rheological technique is useful for examining the concentration dependence of fibrinolytic reagent on fibrinolysis as well as for monitoring the dynamic process of fibrinolysis.

Adult↗

PubMed1993

Baseline plasma fibrinolysis and its correlation with clinical manifestations in patients with Raynaud's phenomenon.

OBJECTIVES: (1) To assess if patients with various forms of Raynaud's phenomenon (RP) have abnormal plasma fibrinolysis that may contribute to diminished digital blood flow; (2) to assess whether patients with RP with evidence of endothelial damage have abnormal plasma fibrinolysis; (3) to determine the clinical relevance of abnormalities, if any, in plasma fibrinolysis in patients with RP. METHODS: One hundred and sixty eight patients with significant RP were studied--46 had primary Raynaud's disease (RD), 32 had suspected Raynaud's syndrome secondary to an undifferentiated connective tissue disorder (undifferentiated CTD), 25 had Raynaud's syndrome associated with atherosclerosis (athero RS), and 65 had an underlying connective tissue disease (CTD RS). All attended in the morning after a low fat light breakfast. After a clinical history was obtained, venous blood samples were collected without stasis for assays of plasma fibrinolysis and factor VIII von Willebrand factor antigen (fVIII vWF Ag). Results were compared with those obtained from normal subjects matched for sex and age. As patients with athero RS were significantly older than the other patients with Raynaud's phenomenon, two groups of control subjects were recruited--namely, 'old' and 'young' control subjects. RESULTS: Patients with CTD RS and athero RS had higher concentrations of fVIII vWF Ag (CTD RS median 174.5 range (45-370)% v 100 (38-202)%, p < 0.001; athero RS 182-5 (100-240)% v 100 (50-158)%, p < 0.001). Both had raised fibrinogen (CTD RS 3.25 (1.9-6.8) g/l v 2.4 (1.2-4.2) g/l, p < 0.001; athero RS 3.4 (2.2-6.2) g/l v 2.5 (1.8-3.9) g/l, p < 0.001) and both had diminished fibrinolysis with reduced plasminogen activator activity (CTD RS 79.5 (31-72) mm2 v 92 (37-197) mm2, p < 0.04; athero RS 73 (45-125) mm2 v 98 (41-197) mm2, p < 0.03). Patients with CTD RS also had raised plasminogen activity (3.3 (2.3-5.8) cU/ml v 2.9 (1.5-5.4) cU/ml, p < 0.001). On the contrary, patients with primary RD and undifferentiated CTD had normal fibrinogen and plasma fibrinolysis. Within each patient group, no significant differences in any of the measured variables were found between those who had RP all year and those who had RP in the winter only, those with RP of the hands only and of hands and feet, or those with and without digital ulcers. CONCLUSION: Diminished plasma fibrinolysis is found in patients likely to have endothelial damage (CTD RS and athero RS). These changes are probably a consequence rather than a cause of the disease.

Arteriosclerosis↗

PubMed1991

Haemostasis in oral surgery--the possible pathogenetic implications of oral fibrinolysis on bleeding. Experimental and clinical studies of the haemostatic balance in the oral cavity, with particular reference to patients with acquired and congenital defects of the coagulation system.

Activation and inhibition of the haemostatic system was reviewed including the interaction between the four biological systems involved in haemostasis: the vessel wall, the platelets, the coagulation system and the fibrinolytic system. The haemostatic mechanism is initiated at the site of injury through local activation of surfaces and release of tissue thromboplastin, resulting in formation and deposition of fibrin. The coagulation process is regulated by physiological anticoagulants. Activation of fibrinolysis is triggered by the presence of fibrin, and the role of tissue-type plasminogen activators (t-PA) at the site of fibrin formation in particular is emphasized. The process is regulated by physiological inhibitors, of which alpha 2-antiplasmin, histidine-rich glycoprotein and plasminogen activator inhibitor are reported to be of major physiological significance. The role of fibrinolysis in the regulation of the dynamic haemostatic balance is discussed, elucidated through examples of congenital deficiencies of the coagulation and the fibrinoytic system. Pharmacological inhibitors of fibrinolysis (i.e. epsilon-aminocaproic acid and tranexamic acid) and their possible effect on the haemostatic system are described. The systemic effects on the fibrinolytic system of surgery and oral surgery is reviewed, and it is concluded, that oral surgery has insignificant effects on blood fibrinolysis. In contrast, oral surgery induces changes of fibrinolysis in the oral environment; initially the fibrinolytic activity of saliva is reduced, due to the presence of inhibitors of fibrinolysis originating from the blood and the wound exudate. When bleeding and exudation cease, the fibrinolytic activity of the saliva will increase. Plasminogen and plasminogen activator, identified as t-PA are present in the oral environment under physiological conditions. Plasminogen is secreted in the saliva and the sources of t-PA include oral epithelial cells and gingival crevicular fluid. The presence of plasminogen and t-PA in the oral environment implies that when fibrin is present (i.e. after surgery), fibrinolysis is triggered. Haemorrhagic complications to oral surgery in patients without known defects of the coagulation system is reviewed. It is concluded that the investigations conducted to the present day do not permit final conclusions with respect to the pathophysiological role of defects in the coagulation and the fibrinolytic systems for the development of bleeding after oral surgery. Further investigations are necessary in order to clarify these aspects, and should include extensive laboratory analyses to reveal rare congenital defects such as factor XIII- and alpha 2-antiplasmin deficiencies.(ABSTRACT TRUNCATED AT 400 WORDS)

Anticoagulants↗

PubMed1988

Fibrinolysis abnormalities in systemic lupus erythematosus and their relation to vasculitis.

Fibrinolysis was evaluated in 16 women with SLE, who were divided into three groups of increasing disease severity according to their past history, and in 10 normal subjects. Fibrinolysis parameters assessed were tissue-type plasminogen activator (t-PA) activity in plasma and in euglobulin fractions and rapid plasminogen activator inhibitor activity. All parameters were evaluated before and after venous occlusion to assess endothelial cell t-PA release in response to localized anoxia. Markers of deficient fibrinolysis were persistently undetectable t-PA activity and increased rapid plasminogen activator inhibitor activity after venous occlusion. Defective fibrinolysis was correlated with disease severity; it was noted only in patients with severe or moderate disease and in no patients with mild disease or in controls. Fibrinolysis abnormalities were independent of disease activity, suggesting that vascular endothelium injuries occurring during flare-ups persist during inactive phases of the disease. No correlation was found between fibrinolysis abnormalities and disease duration, corticosteroid administration, or the presence of lupus anticoagulant or anticardiolipin antibodies. These data support the hypothesis of parallelism between the severity of vascular injuries, suggested by deficient fibrinolysis, and the severity of clinical manifestations in SLE.

Adult↗

PubMed2005

Does diabetes mellitus abolish the beneficial effect of primary coronary angioplasty on long-term risk of reinfarction after acute ST-segment elevation myocardial infarction compared with fibrinolysis? (A DANAMI-2 substudy).

Little is known about the effect of diabetes mellitus on long-term clinical outcome after primary percutaneous coronary intervention (pPCI) compared with fibrinolysis in patients who have acute ST-elevation myocardial infarction. We analyzed 3-year clinical outcome in diabetic patients and nondiabetic patients who had been randomized to fibrinolysis or pPCI in the DANAMI-2 trial to compare long-term clinical outcome. The primary end point was a composite of death, clinical reinfarction, or disabling stroke. Median follow-up was 3.8 years. Among 1,572 consecutive patients who had ST-elevation myocardial infarction and were randomized to pPCI or fibrinolysis, 173 (11.0%) had diabetes mellitus; 60 of these patients received metformin treatment and were excluded. After 3 years no difference was found between diabetic patients who underwent pPCI versus fibrinolysis (combined event p=0.37, reinfarction p=0.06 in favor of fibrinolysis), whereas pPCI was superior to fibrinolysis in nondiabetic patients (combined event p=0.002, clinical reinfarction p<0.001). Three-year incidence of clinical reinfarction analyzed with Cox's regression showed that pPCI compared with fibrinolysis increased the relative risk of clinical reinfarction in diabetic patients (relative risk 2.57, 95% confidence interval 1.48 to 4.46, p <0.001) but decreased the risk in nondiabetic patients (relative risk 0.52, 95% confidence interval 0.36 to 0.74, p<0.001). In conclusion, from the DANAMI-2 trial we hypothesize that diabetes may abolish the beneficial effect of pPCI on long-term risk of clinical reinfarction.

Angioplasty, Balloon, Coronary↗

PubMed1992

Effects of platelets and plasma on fibrinolysis.

The effects of various concentrations of platelets and plasma on in vitro t-PA-induced fibrinolysis were investigated. At t-PA levels between 30 and 70 ng/ml, fibrinolysis proceeded faster in platelet-rich plasma (PRP) than in platelet-poor plasma (PPP). When PRP was serially diluted with PPP and the rate of fibrinolysis compared to PPP, higher platelet counts (up to 300 x 10(9)/l) were associated with increased enhancement of lysis. However, lysis was inhibited when platelets were added to plasma diluted with buffer. Thus, platelets enhance fibrinolysis in undiluted plasma but inhibit lysis in diluted plasma. This is probably because platelets provide a catalytic surface for fibrinolysis but also release inhibitors of fibrinolysis. In undiluted plasma, there would be sufficient fibrinogen and plasminogen to overcome the effect of the platelet inhibitors, but in diluted systems, the inhibitors would predominate, retarding fibrinolysis.

Blood Platelets↗

PubMed2002

Acute thrombosis of renal transplant artery: graft salvage by means of intra-arterial fibrinolysis.

BACKGROUND: Arterial thrombosis in a transplanted kidney is a serious complication that usually leads to graft loss. The purpose of our study was to evaluate intra-arterial fibrinolysis as a treatment of acute renal transplant artery thrombosis and to determine the maximum period of occlusion allowing a reasonable chance of graft salvage. METHODS AND RESULTS: Four patients underwent intra-arterial fibrinolysis for acute transplant artery thrombosis. Transplantations had been performed 29 days to 10 years before the fibrinolysis. Fibrinolysis was carried out by using recombitant tissue plasminogen activator (n=1) or urokinase (n=3). In one patient, anuric for 13 hr at admittance, fibrinolysis could not revascularize the graft artery. In a second patient, anuric for 48 hr at admittance, fibrinolysis did revascularize the graft artery, but dialysis could not be discontinued. In the two remaining patients, anuric for 19 and 20 hr at admittance, the graft artery was successfully revascularized and dialysis could be discontinued 1 week later. One of these two patients returned to dialysis 71 months later because of chronic rejection. Thirty-four months after the acute episode, the remaining patient had a patent artery and did not require dialysis. CONCLUSIONS: Fibrinolysis seems an efficient treatment that may save transplants after up to 24 hr of the arterial occlusion.

Acute Disease↗

PubMed1964

COAGULATION AND FIBRINOLYSIS IN INJURED PATIENTS.

Serial changes in coagulation and fibrinolysis studied among 42 patients admitted to hospital with a wide variety of injuries are reported. The first hours after trauma are dominated by an acceleration of fibrinolysis (clot lysis) and clotting time which are often followed by an abrupt rebound to prolonged fibrinolysis and normal clotting. Evidence is presented that acceleration of fibrinolysis is due to flooding of the circulation by plasminogen activator and that prolongation is probably due to an inhibitor. A prolonged prothrombin time, increased prothrombin consumption index, an acceleration of the heparin-retarded clotting time, and a fall in the platelet count are also frequent during the first hours after injury. There is evidence also of an early deficiency in factor V and the onset of a fall in factor VII and prothrombin. The following days are characterized by continued prolongation of fibrinolysis, a lengthening of clotting time, and an increased prothrombin consumption index suggestive of a defect in thrombo-plastin generation. Subsequent periods of prolonged fibrinolysis may develop. Prothrombin time often continues prolonged for one to three weeks and may vary phasically; plasma prothrombin and factor VII are reduced but there is now little change in factor V. The platelet count continues to fall for one to three days, then a thrombocytosis develops, often with abnormally high platelet levels, a week or so later. Plasma fibrinogen rises within 24 hours to reach a plateau maximum a few days later and levels remain high for prolonged periods in the severely injured. Various changes are related to or influenced by the severity of trauma. Mechanisms are discussed, including thrombosis in vivo, and reference is made to homeostatic significance and its possible breakdown.

Blood Coagulation↗

PubMed2006

Contact activation prolongs clot lysis time in human plasma: role of thrombin-activatable fibrinolysis inhibitor and Factor XIII.

BACKGROUND: Contact activation system proteins (e.g., Factor XII, kallikrein) have been implicated as direct or indirect activators of plasminogen. However, contact activation and Factor XI have enhanced thrombin-activatable fibrinolysis inhibitor (TAFI) activation and decreased fibrinolysis, and Factor XIII (FXIII) also delays fibrinolysis via alpha(2)-anti-plasmin deposition on fibrin polymers. Thus, the goals of this study were to define how fibrinolysis is modulated in human plasma by contact or tissue factor (TF) activation, and what role TAFI and FXIII plays in this system. METHODS: Normal, TAFI-deficient and TAFI-deficient/FXIII-supplemented plasma was exposed to tissue-type plasminogen activator and activated with either celite or TF. Clot growth/disintegration kinetics were documented with thrombelastography. RESULTS: Normal plasma activated with celite had significantly prolonged onset and duration of clot lysis compared with samples activated with TF. TAFI-deficient plasma activated with celite was noted to have a duration of clot lysis not different from samples activated with TF, but a significant difference in time to onset of lysis persisted. Celite activation of TAFI-deficient/FXIII-supplemented plasma showed significantly prolonged onset and duration of clot lysis compared with samples activated with TF. CONCLUSIONS: Primarily TAFI, and to a lesser extent FXIII, contributed to contact system protein-mediated attenuation of fibrinolysis. Clinical investigation of these phenomena is warranted in clinical settings involving contact activation (e.g., intra-aortic balloon pumps and ventricular assist devices) to determine whether these devices modulate fibrinolysis and perhaps contribute to thromboembolic morbidity.

Carboxypeptidase B2↗

PubMed1998

Fibrinolysis-adjusted perioperative low-dose aprotinin reduces blood loss in bypass operations.

BACKGROUND: Postoperative bleeding still remains a serious problem in bypass surgery. This study evaluated fibrinolysis and perioperative low-dose antifibrinolytic regimens adjusted to the time course of fibrinolysis. METHODS: In a prospective, randomized study of 42 patients undergoing bypass grafting, patients received low-dose aprotinin (group A; n = 14) or low-dose tranexamic acid (group TA; n = 14) intraoperatively and postoperatively, respectively, with no antifibrinolytics for comparison (group C; n = 14). Parameters of procoagulation, fibrinolysis, and activated factor VII were measured preoperatively, intraoperatively, and postoperatively. Blood loss was determined up to 24 hours. RESULTS: The level of thrombin-antithrombin III complex was significantly decreased postoperatively in the treatment groups (group A and TA versus C: 25 +/- 14 and 19 +/- 10 microg/L, respectively, versus 40 +/- 21 microg/L; p < 0.05). Levels of plasmin-antiplasmin complexes were significantly decreased postoperatively in group A (607 +/- 231 microg/L) versus group C (825 +/- 225 microg/L) (p < 0.05) but were increased in group TA (1,145 +/- 394 microg/L) versus group C (p < 0.05). At all times intraoperatively and postoperatively, levels of D-dimers were significantly decreased in group A and group TA versus control (p < 0.001), indicating that fibrinolysis persists after the operation. Intraoperatively, the factor VIIa level decreased significantly in group A (20 +/- 8 mU/mL) versus group C (31 +/- 15 mU/mL) (p < 0.05), but not in group TA (32 +/- 15 mU/mL). Blood loss was significantly lower in group A (135 +/- 37 mL) and group TA (155 +/- 71 mL) versus group C (354 +/- 170 mL) (p < 0.001). CONCLUSIONS: This low-dose aprotinin regimen adjusted to perioperative fibrinolysis reduces blood loss significantly in coronary bypass grafting. For further progress in this subject, clinical investigations of individual fibrinolysis-adjusted antifibrinolytic treatment seems warranted.

Aged↗

PubMed1997

The effect of tranexamic acid on local and plasma fibrinolysis during total knee arthroplasty.

The aim of the present study was to investigate aspects of coagulation and fibrinolysis during knee arthroplasties in order to find out. 1. whether an increased fibrinolysis is correlated to an increased blood loss 2. whether there is a difference in markers for coagulation and fibrinolysis in peripheral venous blood compared to those in blood from the wounds 3. whether the administration of tranexamic acid modifies the fibrinolytic response. Twenty-four patients were included. Twelve patients were given tranexamic acid intravenously at the end of the operation. The dose was repeated three hours later. The other 12 patients were given an equivalent amount of placebo. The administration was randomised and double-blind. Levels of prothrombin fragments 1 + 2, D-dimers, plasminogen, alpha 2-antiplasmin, tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI-1) in venous blood were investigated just before the operation, at the end of the operation and three hours later. At the end of the operation blood for analysis was also drawn from the wound. Coagulation and fibrinolysis was activated during and after surgery. The activation was significantly higher in blood from the wounds than in peripheral venous blood. We found no direct correlation between the degree of fibrinolysis and blood loss. The administration of tranexamic acid reduced fibrinolysis in the wounds but not in peripheral venous blood. The postoperative blood loss was reduced by half.

Aged↗

PubMed2001

Acute inhibitory effect of alcohol on fibrinolysis.

In contrast to a reduced risk of coronary heart disease (CHD) with light to moderate alcohol consumption, heavy alcohol intake and binge drinking are associated with increased cardiovascular mortality. Alcohol has an acute and profound effect on fibrinolysis that may be relevant to the pathogenesis of CHD. The short-term effects of a low (two glasses, 250 mL, 20 g ethanol) and a high (six glasses, 750 mL, 60 g ethanol) intake of red wine were studied in male volunteers and compared to the intake of mineral water. To find a threshold for inhibition of fibrinolysis and to study a binge effect, a second experiment was performed comparing the intake of four (500 mL, 40 g ethanol) and eight (1000 mL, 80 g ethanol) glasses of red wine with mineral water. Plasminogen activator inhibitor-1 (PAI-1), tissue-type plasminogen activator (t-PA), plasmin-antiplasmin (PAP) complexes and clot lysis time were measured. In contrast to the circadian rhythm with an enhanced fibrinolysis in the evening that was found in the mineral water group, an intake above four glasses of wine inhibited fibrinolysis significantly. After the intake of two glasses no significant disturbance of the circadian rhythm was observed. Five hours after the consumption of six glasses of wine, a dramatic increase occurred of PAI-1 antigen (77 +/- 42 microg L-1 vs. - 5 +/- 10 microg L-1 in the mineral water controls; P < 0.001) and PAI-1 activity (27 +/- 15 U mL-1 vs. - 2 +/- 3 U mL-1 in mineral water controls; P < 0.001). Despite a rise in t-PA antigen, t-PA activity dropped (- 0.5 +/- 0.2 U mL-1 vs. - 0.1 +/- 0.2 in controls; P < 0.001) as did PAP complexes (- 103 +/- 55 microg L-1 vs. - 26 +/- 57 microg L-1 in controls; P < 0.01). After the consumption of eight glasses of wine, the clot lysis assay indicated continued inhibition of fibrinolysis the following morning. Drinking a large amount of alcohol in the evening results in an acute inhibition of fibrinolysis, persisting the following morning. This may predispose to accelerated atherosclerosis and set the stage for thrombotic coronary events, explaining the higher cardiovascular mortality risk in binge drinkers.

Adult↗

PubMed2003

Thrombin-activatable fibrinolysis inhibitor (TAFI, plasma procarboxypeptidase B, procarboxypeptidase R, procarboxypeptidase U).

Recently, a new inhibitor of fibrinolysis was described, which downregulated fibrinolysis after it was activated by thrombin, and was therefore named TAFI (thrombin-activatable fibrinolysis inhibitor; EC 3.4.17.20). TAFI turned out to be identical to the previously described proteins, procarboxypeptidase U, procarboxypeptidase R, and plasma procarboxypeptidase B. Activated TAFI (TAFIa) downregulates fibrinolysis by the removal of carboxy-terminal lysines from fibrin. These carboxy-terminal lysines are exposed upon limited proteolysis of fibrin by plasmin and act as ligands for the lysine-binding sites of plasminogen and tissue-type plasminogen activator (t-PA). Elimination of these lysines by TAFIa abrogates the fibrin cofactor function of t-PA-mediated plasminogen activation, resulting in a decreased rate of plasmin generation and thus downregulation of fibrinolysis. In this review, the characteristics of TAFI are summarized, with an emphasis on the pathways leading to activation of TAFI and the role of TAFIa in the inhibition of fibrinolysis. However, it cannot be ruled out that TAFI has other, as yet undefined, functions in biology.

Animals↗

PubMed2003

Dynamic changes of fibrin architecture during fibrin formation and intrinsic fibrinolysis of fibrin-rich clots.

Clotting and fibrinolysis are initiated simultaneously in vivo, and fibrinolysis usually occurs without any individualized lysis front (intrinsic fibrinolysis). We have developed a novel model to assess whether morphological changes resulting from intrinsic fibrinolysis are similar to those previously reported at the lysis front using externally applied lytic agents. Fibrin assembly and fibrinolysis were followed in real-time by confocal microscopy using gold-labeled fibrinogen molecules. An increase in fiber absorbance (30%, p < 0.01) and a decrease in fiber diameter (60%, p < 0.01) due to the ongoing accumulation and packing of fibrin molecules were the most significant detectable features occurring during fibrin assembly. Similar features with a similar magnitude were observed during fibrin dissolution, but in the reverse order and with a 3-fold increase in duration. Then, lysing fibers were progressively transected laterally, and thinner fibers were cleaved at a 2.5-fold faster rate than thicker fibers (p < 0.001). Frayed lysing fibers were seen to interact progressively with adjoining fibers (agglomeration), leading to a 76 and 88% increase in the network pore diameter (p < 0.05) and fiber diameter (p < 0.01), respectively. At the maximum decrease in fiber absorbance (46%, p < 0.05), the network suddenly collapsed with the release of large fragments that gradually vanished. Morphological changes of fibrin that occur during intrinsic fibrinolysis are similar as those observed next to the lysis front, although they are not restricted spatially to the clot/surrounding milieu interface but are observed through the entire clot.

Algorithms↗

PubMed2004

The intrinsic threshold of the fibrinolytic system is modulated by basic carboxypeptidases, but the magnitude of the antifibrinolytic effect of activated thrombin-activable fibrinolysis inhibitor is masked by its instability.

Activated thrombin-activable fibrinolysis inhibitor (TAFIa) is intrinsically unstable, a property that complicates the study of its role in regulating fibrinolysis. To investigate the effect of basic carboxypeptidases on fibrinolysis under conditions of constant carboxypeptidase activity, we employed pancreatic carboxypeptidase B (CPB), a homologous, stable basic carboxypeptidase, as a surrogate for TAFIa. Clots formed from TAFI-depleted plasma or from purified components were supplemented with tissue-type plasminogen activator and either CPB or TAFIa. The clot lysis data indicate that the down-regulation of fibrinolysis mediated by basic carboxypeptidases involves a threshold mechanism. At carboxypeptidase concentrations above the threshold, plasminogen activation is maintained in a fully down-regulated state; experiments in plasma showed that fibrinolysis is essentially halted by saturating concentrations of TAFIa and that fibrinolysis can be prolonged more than 45-fold by a stable carboxypeptidase. The threshold carboxypeptidase concentration was dependent on tissue-type plasminogen activator and antiplasmin concentrations, indicating that the threshold is determined by the steady-state plasmin concentration. Although obvious with CPB, the threshold was masked by the intrinsic instability of TAFIa and became apparent only when the effect of TAFIa was investigated over the picomolar concentration range. Because of the threshold effect and the instability of TAFIa, exponential increases in TAFIa concentration generate linear increases in lysis time. A model relating lysis time to TAFIa concentration, TAFIa half-life, and the threshold concentration of TAFIa is provided. The threshold effect has potentially important implications regarding the role of TAFIa and the regulation of clot lysis in vivo.

Carboxypeptidase B↗

PubMed1997

Continuous small-dose tranexamic acid reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation.

Tranexamic acid (TA) is a synthetic drug that inhibits fibrinolysis. It has been administered to decrease the use of blood products during cardiac surgery and orthotopic liver transplantation when infused in larger doses. A small-dose infusion of aprotinin causes a reduction in fibrinolysis and blood product requirement during orthotopic liver transplantation without apparent risk of intravascular thrombosis. This prospective study was designed to investigate whether a small-dose infusion of TA would be equally effective in reducing fibrinolysis and blood product transfusions during orthotopic liver transplantation. A double-blind, controlled study was undertaken to compare the efficacy of a small-dose TA infusion with that of a placebo. Thirty-two consecutive patients were randomized either to the TA group (n = 16), which received an intravenous infusion of 2 mg x kg(-1) x h(-1), or to the control group (n = 16), which received an identical volume of normal saline. Coagulation values were measured, a field rating was made by the surgeon, and a thromboelastogram was produced at four predetermined intervals throughout the case-before TA infusion was started, after portal vein ligation, 10 min after reperfusion, and at the end of surgery. Intraoperative transfusion requirements were recorded during the procedure and for the first 24 h postoperatively. A record was kept of any intraoperative epsilon-aminocaproic acid administered for uncontrolled fibrinolysis. The thromboelastogram clot lysis index was significant for lysis in the control group during both the anhepatic and the neohepatic phases (P < 0.01 and P < 0.05, respectively) when compared with the TA group. Fibrin degradation products were significantly increased (>20 microg/mL) in the control group at reperfusion (P < 0.03) and at the end of surgery (P < 0.01). D-dimers were also significantly increased (>1 mg/L) in the control group at the end of surgery (P < 0.04). Nine of the 16 control patients versus 3 of the 16 TA patients required epsilon-aminocaproic acid rescue for fibrinolysis. There were no other significant differences between groups. Transfusion requirements during surgery and for the first 24 h postoperatively did not differ significantly between the two groups. We conclude that the use of small-dose TA reduces fibrinolysis but not transfusion requirements during orthotopic liver transplantation.

Aminocaproic Acid↗

PubMed2006

Elastic modulus-based thrombelastographic quantification of plasma clot fibrinolysis with progressive plasminogen activation.

Thrombelastographic detection of fibrinolysis has been critical in the identification and treatment of coagulopathy in many perioperative settings. However, the fibrinolytic assessments have been at best non-parametric, amplitude-based determinations (e.g. estimated % lysis, clot lysis time or clot lysis rate). Recognizing this limitation, a methodology was developed to measure the onset, speed and extent of clot disintegration by changes in elastic modulus derived from the amplitude. Using this approach, our goal was to characterize the clot disintegration kinetics of progressive plasminogen activation with tissue plasminogen activator (tPA) and to determine the extent of inhibition of fibrinolysis mediated by tPA with aprotinin and activated factor XIII. While the estimated % lysis and clot lysis time were significantly affected by tPA (0-300 U/ml), elastic modulus-based analyses in a more activity-specific fashion demonstrated significantly decreased onset, increased rate and increased extent of fibrinolysis. Furthermore, aprotinin was found to inhibit the onset, rate and extent of fibrinolysis in an activity-dependent fashion, whereas activated factor XIII was noted to enhance the speed of onset of clot growth and delay the onset of fibrinolysis. In summary, our results serve as the rational basis to utilize this elastic modulus-based approach to quantify the extent of fibrinolysis in clinical and laboratory settings, as well as potentially guiding antifibrinolytic therapy.

Analysis of Variance↗