Enhanced fibrinolytic activity during cardiopulmonary bypass in open-heart surgery in man is caused by extrinsic (tissue-type) plasminogen activator

Fibrinolytic activity is reportedly increased during cardiopulmonary bypass( CPB ), and this increase has been considered to be related to the bleeding complications in open heart surgery. The purpose of this study was to clarify the nature of the fibrinolytic activity duringCPB. Twenty patients with valve replacement or aortocoronary bypass surgery were examined. The following parameters were determined: fibrinogen, plasminogen, fibrinopeptide A( FPA ), fibrinopeptide B β 15-42 ( FPB β15-42 ), and tissue-type plasminogen activator ( t-PA ). For further characterization of the fibrinolytic activity, the fibrin plate method was used. Intrinsic fibrinolytic activity was determined by the assay of the fibrinolytic activity of the kaolin activatedeuglobulin. Extrinsic fibrinolyticactivity was estimated by the assayof Cl-inactivator resistant fibrinolytic activity as well as t-PA. Fibrinogen and plasminogen did not decrease except at the beginning of CPB. FPA was increased significantly during CPB. FPB3 15-42 was also increased to four times the preoperative value at 2 hrs of CPB. The intrinsic fibrinolytic system was activatedonly a short time after the startof CPB. The Cl-inactivator resistant fibrinolytic activity was activated gradually during CPB, reached a maximum level 1 hr after the start of CPB, and returned to the preoperative level within 1 hr after the end of CPB. The changes on t-PA paralleled the course of the Cl-inactivator resistant fibrinolytic activity, indicating that enhanced fibrinolytic activity during CPB is predominantly of extrinsic origin caused by t-PA. We conclude that thrombin activity continues during CPB despite the use of heparin, and thatthe enhanced fibrinolytic activity during CPB is essential because t-PA activates plasminogen predominantly at the sites where fibrin is formed, resulting in the dissolution of the microthrombi formed during CPB.

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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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On the Fibrinolytic System in Aged Rats, and Its Reactivity to Endotoxin and Cytokines

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648525 ◽

1992 ◽

Vol 67 (06) ◽

pp. 697-701 ◽

Cited By ~ 6

Author(s):

J J Emeis ◽

A Brouwer ◽

R J Barelds ◽

M A Horan ◽

S K Durham ◽

...

Keyword(s):

Plasminogen Activator ◽

Fibrinolytic Activity ◽

Fibrinolytic System ◽

Tissue Type ◽

High Dose ◽

Base Line ◽

Aged Rats ◽

Tissue Type Plasminogen Activator ◽

Young Rats ◽

Type Plasminogen Activator

SummaryAged rats are more susceptible to endotoxin-induced effects, including microthrombosis and platelet aggregation, than are young rats. To investigate whether changes in the fibrinolytic system might be involved, we investigated the fibrinolytic activity in plasma euglobulin fractions and tissues (lung and heart) of young (6-months old) and aged (24-months old) rats under baseline conditions and after challenge with endotoxin. Aged rats had lower plasma levels of tissue-type plasminogen activator (t-PA) and of urokinase-type PA (u-PA) activity. PA inhibitor (PAI) activity was higher in the plasma of aged rats, as was t-PA activity in lung and heart.Rats were treated with either a low dose (1 μg/kg) or a high dose (10 mg/kg) of endotoxin. Both treatments induced a transient phase of increased blood fibrinolytic activity, as evidenced by higher levels of tissue-type plasminogen activator (t-PA) activity and decreased levels of PA inhibitor (PAI) activity. Over time, the fibrinolytic activity decreased, probably due to increased levels of PA inhibitor.Both the early increase in t-PA activity, and the subsequent increase in PAI activity, were more pronounced in the aged rats, as compared with the younger rats, after the high dose of endotoxin. The aged rats also responded to an injection of interleukin-1β or tumor necrosis factor-α with a larger increase of PAI activity than did the younger rats.Together the data suggest that, compared to young rats, aged rats have a decreased base-line plasma fibrinolytic activity, while their fibrinolytic system is more responsive to challenge by endotoxin and cytokines.

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