Fibrinolysis during liver transplantation in humans: role of tissue- type plasminogen activator

Abstract Human liver transplantation is frequently associated with a coagulopathy and bleeding diathesis developing during the anhepatic phase of surgery. The hemostatic defect has been attributed in part to accelerated fibrinolysis. In this study we evaluated changes in specific blood fibrinolytic parameters occurring in eight adult patients undergoing first-time orthotopic liver transplantation. Five of the eight patients experienced moderate to severe systemic fibrinolysis as reflected by alpha 2-antiplasmin consumption and fibrinogen degradation with the concomitant appearance of fibrin(ogen) degradation products. In association with these changes, an increase in tissue-type plasminogen activator (t-PA) activity and t-PA antigen levels was also observed. Fibrinolysis was most pronounced during the anhepatic phase of surgery and decreased after revascularization of the grafted liver. Three additional patients who underwent the same procedure manifested much less evidence of systemic fibrinolytic activation and had minimal elevation of t-PA antigen levels or activity. Urokinase-type plasminogen activator levels, although elevated in three patients, were disassociated from increased t-PA levels and concomitant systemic fibrinolysis. The operative course of those patients developing t-PA-associated fibrinolysis was characterized by shock, acidosis, generalized bleeding, and a need for substantially greater blood product support during surgery. These findings suggest that the observed fibrinolytic defect is related to increased circulating plasma levels of t-PA, presumably resulting from a combination of increased intravascular release and decreased hepatic clearance of t-PA. These observations may have implications for intraoperative therapy for the transplant-related coagulopathy and its associated bleeding.

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Fibrinolysis during liver transplantation in humans: role of tissue- type plasminogen activator

Blood ◽

10.1182/blood.v71.4.1090.bloodjournal7141090 ◽

1988 ◽

Vol 71 (4) ◽

pp. 1090-1095

Author(s):

WH Dzik ◽

CF Arkin ◽

RL Jenkins ◽

DC Stump

Keyword(s):

Liver Transplantation ◽

Plasminogen Activator ◽

Degradation Products ◽

Hepatic Clearance ◽

Tissue Type ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Anhepatic Phase ◽

Fibrinolytic Parameters

Human liver transplantation is frequently associated with a coagulopathy and bleeding diathesis developing during the anhepatic phase of surgery. The hemostatic defect has been attributed in part to accelerated fibrinolysis. In this study we evaluated changes in specific blood fibrinolytic parameters occurring in eight adult patients undergoing first-time orthotopic liver transplantation. Five of the eight patients experienced moderate to severe systemic fibrinolysis as reflected by alpha 2-antiplasmin consumption and fibrinogen degradation with the concomitant appearance of fibrin(ogen) degradation products. In association with these changes, an increase in tissue-type plasminogen activator (t-PA) activity and t-PA antigen levels was also observed. Fibrinolysis was most pronounced during the anhepatic phase of surgery and decreased after revascularization of the grafted liver. Three additional patients who underwent the same procedure manifested much less evidence of systemic fibrinolytic activation and had minimal elevation of t-PA antigen levels or activity. Urokinase-type plasminogen activator levels, although elevated in three patients, were disassociated from increased t-PA levels and concomitant systemic fibrinolysis. The operative course of those patients developing t-PA-associated fibrinolysis was characterized by shock, acidosis, generalized bleeding, and a need for substantially greater blood product support during surgery. These findings suggest that the observed fibrinolytic defect is related to increased circulating plasma levels of t-PA, presumably resulting from a combination of increased intravascular release and decreased hepatic clearance of t-PA. These observations may have implications for intraoperative therapy for the transplant-related coagulopathy and its associated bleeding.

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Evolution of Urokinase-Type Plasminogen Activator (u-PA) and Tissue-Type Plasminogen Activator (t-PA) in Orthotopic Liver Transplantation (OLT)

Thrombosis and Haemostasis ◽

10.1055/s-0038-1651548 ◽

1993 ◽

Vol 69 (01) ◽

pp. 056-059 ◽

Cited By ~ 2

Author(s):

G Himmelreich ◽

G Dooijewaard ◽

P Breinl ◽

W O Bechstein ◽

P Neuhaus ◽

...

Keyword(s):

Liver Transplantation ◽

Plasminogen Activator ◽

Orthotopic Liver Transplantation ◽

Tissue Type ◽

Bleeding Complications ◽

Activity Levels ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Anhepatic Phase

SummaryIn orthotopic liver transplantation (OLT) hyperfibrinolysis seems to be of causative importance for intra- and postoperative bleeding. Although recently hyperfibrinolysis has been successfully reduced by intraoperative aprotinin treatment, small increases of fibrinolysis still remain during OLT. Originally, tissue-type plasminogen activator (t-PA) was considered to be responsible for the increases, but the efficacy of aprotinin which inhibits besides plasmin also kallikrein and urokinase-type plasminogen activator (u-PA) suggested also a role for the intrinsic and contact system-dependent plasminogen activators. We investigated the role of u-PA. From 29 patients undergoing OLT with intraoperative aprotinin infusion arterial blood samples were taken at 7 different time points. The preoperative median values for u-PA antigen (u-PA Ag) and plasmin-activatable single-chain u-PA (scu-PA) levels, which were more than 2-fold above normal (both: p <0.01), decreased slightly during the preanhepatic phase and remained unchanged during the anhepatic phase. With reperfusion of the graft liver the two levels decreased significantly (p = 0.0003 and p = 0.006, respectively) to almost normal values, probably due to clearance by the graft liver. Active two-chain u-PA (tcu-PA) was preoperatively 2-fold above the detection limit, remained stable during the preanhepatic phase and increased 2-fold in the anhepatic phase (p = 0.0018). As expected tcu-PA also relapsed upon reperfusion, but to the preoperatively enhanced level, possibly caused by sustained activation of scu-PA by cathepsin B. t-PA activity levels were at the upper end of the normal range preoperatively, slightly increased during preanhepatic and anhepatic phases and decreased significantly with reperfusion. The increases in tcu-PA and t-PA activities during the anhepatic phase coincided with greatly increased fibrinolysis as demonstrated by thrombelastography, indicating that both u-PA and t-PA are involved in the development of fibrinolysis during OLT.One patient was excluded from statistical evaluations because preoperative u-PA Ag, scu-PA, tcu-PA and t-PA activity levels were much higher than in the other 28 patients. In the investigated group this patient was the only one with diffuse peritonitis intraoperatively and severe bleeding complications postoperatively which made retransplantation mandatory.

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CHANGES IN FIBRINOLYTIC PARAMETERS AFTER DELIVERY

10.1055/s-0038-1644843 ◽

1987 ◽

Author(s):

J C Kirch-heimer ◽

H Kölbl ◽

G Christ ◽

G Tatra

Keyword(s):

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Tissue Type ◽

Functional Assay ◽

Hormonal Changes ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Fibrinolytic Parameters ◽

Activator Inhibitor

Recent studies by Astedt et al. have shown increasing levels of plasminogen activator inhibitor during pregnancy, but the origin of the inhibitor is unknown. Levels of fibrinolytic parameters were determined in plasma collected from 18 females (age 22.7 ± 3.2, mean ± SD) after a normal medically controlled pregnancy at the time of delivery and on the following 5 days. Tissue-type plasminogen activator (tPA) antigen was measured by enzyme immunoassay, urokinase type plasminogen activator (uPA) antigen by a radioimmunoassay and plasminogen activator inhibitor (PAI ) by a functional assay. The results are summarized in the following table:Postpartal changes in tPA antigen and PAI have been found to be significant, both decreasing after delivery and reaching normal control values for tPA on day 2 and for PAI on day 1 while uPA antigen remained normal. Since tPA levels before delivery have been found to be normal, increased levels at delivery might be caused by a release or by hormonal changes, while the decrease in PAI might again be caused by hormonal changes or by removal of the placenta.

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Depression of Tissue-Type Plasminogen Activator and Enhancement of Urokinase-Type Plasminogen Activator as an Expression of Local Inflammation

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656345 ◽

1992 ◽

Vol 68 (02) ◽

pp. 180-184 ◽

Cited By ~ 22

Author(s):

Emile J P Brommer ◽

Gerard Dooijewaard ◽

Ben A C Dijkmans ◽

Ferdinand C Breedveld

Keyword(s):

Plasminogen Activator ◽

Tissue Type ◽

Plasminogen Activation ◽

Single Chain ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Healthy Donors ◽

Urokinase Type Plasminogen Activator ◽

Knee Trauma ◽

Fibrinolytic Parameters

SummaryInflammatory processes are accompanied by extravascular deposition and breakdown of fibrin. We measured fibrinolytic parameters in synovial fluid (SF) and in plasma of 36 patients with rheumatoid arthritis (RA). As a control, SF of 13 patients with blunt knee trauma, and plasma of 17 healthy volunteers were studied. In RA patients, extravascular t-PA mediated plasminogen activation was depressed: mean SF tissue-type plasminogen activator (t-PA:Ag) concentration (2.1 ± 1.6 ng/ml) was four-fold lower, and plasminogen activator inhibitor (PAI) activity (284 ± 212%) four-fold higher than the plasma values of the same patients or of healthy donors. In contrast, u-PA related plasminogen activation was strongly enhanced: urokinase-type plasminogen activator (u-PA) antigen (23.1 ±12.4 ng/ml) was more than four-fold higher, single-chain u-PA (scu-PA) (5.3 ± 1.9 ng/ml) three-fold higher than in plasma of the same patients or of healthy donors, and active two-chain u-PA (tcu-PA) was detected in 14 of the 36 SF samples of RA patients. All of these changes in extravascular fibrinolytic parameters correspond with those induced by inflammatory mediators in cell cultures. In joint effusions of patients with a blunt knee trauma, the effects were intermediate: u-PA related parameters showed moderate changes in the same direction as in arthritis; t-PA antigen was also decreased. The only exception was that PAI was not increased. We conclude that the findings in traumatic effusions reflect transient effects as a reaction to trauma. In joint inflammation, the depressed t-PA mediated plasminogen activation, although more than compensated by the enhanced u-PA mediated plasminogen activation, results in protraction of fibrin removal. Besides, the enhanced u-PA activation might lead to proteolytic damage of the cartilage.

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Enhanced Effective Fibrinolysis following the Neutralization of Heparin in Open Heart Surgery Increases the Risk of Post-Surgical Bleeding

Thrombosis and Haemostasis ◽

10.1055/s-0038-1645202 ◽

1990 ◽

Vol 63 (02) ◽

pp. 241-245 ◽

Cited By ~ 49

Author(s):

Jørgen Gram ◽

Thomas Janetzko ◽

Jørgen Jespersen ◽

Hans Dietrich Bruhn

Keyword(s):

Blood Loss ◽

Plasminogen Activator ◽

Heart Surgery ◽

Degradation Products ◽

Open Heart Surgery ◽

Tissue Type ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator ◽

Chest Tube Drain ◽

Median Blood Loss

SummaryThe tissue-type plasminogen activator related fibrinolytic system was studied in 24 patients undergoing cardiopulmonary bypass surgery. The degradation of fibrinogen and fibrin was followed during and after surgery by means of new sensitive and specific assays and the changes were related to the blood loss measured in the chest tube drain during the first 24 postoperative hours. Although tissue-type plasminogen activator was significantly released into the circulation during the period of extracor-poreal circulation (p <0.01), constantly low levels of fibrinogen degradation products indicated that a systemic generation of plasmin could be controlled by the naturally occurring inhibitors. Following extracorporeal circulation heparin was neutralized by protamine chloride, and in relation to the subsequent generation of fibrin, there was a short period with increased concentrations of fibrinogen degradation products (p <0.01) and a prolonged period of degradation of cross-linked fibrin, as detected by increased concentrations of D-Dimer until 24 h after surgery (p <0.01). Patients with a higher than the median blood loss (520 ml) in the chest tube drain had a significantly higher increase of D-Dimer than patients with a lower than the median blood loss (p <0.05).We conclude that the incorporation of tissue-type plasminogen activator into fibrin and the in situ activation of plasminogen enhance local fibrinolysis, thereby increasing the risk of bleeding in patients undergoing open heart surgery

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Pharmacokinetics and Effects on Fibrinolytic and Coagulation Parameters of Two Doses of Recombinant Tissue-Type Plasminogen Activator in Healthy Volunteers

Thrombosis and Haemostasis ◽

10.1055/s-0038-1661592 ◽

1986 ◽

Vol 56 (01) ◽

pp. 001-005 ◽

Cited By ~ 53

Author(s):

M Verstraete ◽

C A P F Su ◽

P Tanswell ◽

W Feuerer ◽

D Collen

Keyword(s):

Healthy Volunteers ◽

Plasminogen Activator ◽

Degradation Products ◽

Plasma Concentrations ◽

State Level ◽

Compartment Model ◽

Tissue Type ◽

Maximum Plasma ◽

Tissue Type Plasminogen Activator ◽

Type Plasminogen Activator

SummaryPharmacokinetics and pharmacological effects of two intravenous doses of recombinant tissue-type plasminogen activator (rt-PA) (40 and 60 mg over 90 min) were determined in healthy volunteers. Mean maximum plasma concentrations were 1080 and 1560 ng/ml respectively. The steady state level during subsequent maintenance infusion of 30 mg over 6 h was 250 ng/ml. The pharmacokinetics of rt-PA showed a bi-exponential disappearance from plasma consistent with a 2-compartment model of t½α = 5.7 min, a t½β = 1.3 h and a total clearance of 380 ml/min.Mean fibrinogen levels at the end of the infusions of 40 mg or 60 mg rt-PA over 90 min, measured in thawed plasma samples collected on citrate/aprotinin, decreased to 74% and 57% of the preinfusion values respectively. Plasminogen fell to 55% and 48%, and α2-antiplasmin to 28% and 18% of initial values. No further decrease of these parameters was observed during the infusion of 30 mg rt-PA over 6 h. Only 2% of the preinfusion fibrinogen levels could be recovered as fibrinogen-fibrin degradation products. This moderate extent of systemic fibrinogenolysis is much less than that reported for therapeutic i.v. infusions of streptokinase.

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