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Elevated fibrinolysis in cardiopulmonary bypass is factor XII dependent
Fibholysis (1994) 8, SuppI 2, 84-85 CJ 1994 Longman Group Ltd
Elevated Fibrinolysis
in Cardiopulmonary
H.I. Chung, J.F. Burman,
B.A. Balogun,
KEY WORDS.
J.C.R.
Bypass is Factor XII Dependent
Lincoln,
J.R. Pepper
Factor XII. Cardiopulmonary bypass. Fibrinolysis
We measured heparin, thrombin-antithrombin complexes (TAT), Prothrombin Fragment 1+2 (F1+2) to assess b viva thrombin generation, and cross-linked fibrin degradation products (XDP), plasmin antiplasmin complexes (PAP), tissue plasminogen activator (t-PA) levels to assess fibrinolysis in two patients with factor XII (FXII) deficiency, who underwent open heart surgery with cardiopulmonary bypass (CPB), one severe (factor XII < 1 iu/dl for correction of atria1 septal defect and a patent ductus arterious) and one mild (factor XII 10 iu/dl for mitral value replacement). Eight patients undergoing elective first time cardiac CPB surgery served as a comparison group.
Elevated fibrinolytic activity during CPB and especially after protamine infusion was reported as early as 1958.’ Von Kaulla et al. reported shortened euglobin lysis times as well as changes in thrombelastography. increased cross-link fibrin Recent reports show degradation products (XDP), tissue plasminogen activator t-PA) and plasmin antiplasmin complex levels during CPB.z-6 In our FXTI deficient patients, there was evidence of thrombin generation during cardiopulmonary bypass, as judged by the activation markers F1+2 and TAT. Levels of these were comparable to those reported during cardiopulmonary bypass in routine cardiac surgery.
Table 1. Sevrr~ FXII deficiency patient
Heparin (iulml) TAT (n&ml) F1+2 (nmol/L) XDP (&ml) t-PA (ag) (q/ml) PAI-I (ag) (nglml) Plasminogen (iu/dl)
Pre op
CPB 15 min
CPB 30 min
CPB end
Protamine + 20 min
0 1.8 1.17 43 7.7 8.7 82.5
4 49 4.08 88 16.2 17.2 43.4
3.5 27 3.48 82 20.0 16.2 41.6
3.3 30 4.20 I21 17.5 19.1 43.2
0 30 3.09 77 6.9 38.3 49.8
Mild FXII deficiency patient
Heparin (h/ml) TAT (ng/ml) F1+2 (nmol/L) XDP (nglml) t-PA (ag) (ng/ml) PAI- (ag) (nglml) Plasminogen (iuldl)
Pre op
CPB 1.5 min
CPB 30 min
CPB end
Protamine + 20 min
0 10.3 1.06 51 7.6 8.3 74.8
3.4 8.8 0.81 56 5.9 15.3 55.7
2.9 28.1 1.51 165 5.4 12.8 44.3
1.9 19.7 1.73 144 6.7 7.3 44.1
0 25.9 2.35 164 6.2 8.6 52.2
Department of Haematology. Royal Brompton National Heart and Lung Hospital, Sydney Street, London SW3 6NP, United Kingdom
84
Fibrinolysis
85
900 600 700
B
4
C
Operative
D
E
A
C
B
Stages
D
Operative
E
Operative
60 16 16
3 E
14
$
12
g
10
z
50
a 5
40
p 7
30
2
20
6 10
6 Ol A
Operative
C
D
Stages
E
.r!‘;; 4
0
4 B
E
Stages
70
22
p
D
C
B
A
Stages
A
B
D
C
Operative
Stages
E
A
B
Operative
C
D
E
Stages
Fig. I Normal (circle) severe FXII deficient patient (square), and mild FXII deficient patient (triangle). Samples were taken at (A) preoperatively, (B) 15 minutes on CPB, (C) 30 minutes on CPB, (D) just prior to end of CPB, (E) 20 minutes post protamine.
In our FXII deficient patients, there is a small rise in XDP levels, but at no time did they exceed normal (< 250 ng/ml). Our comparison patient group shows markedly elevated XDP and plasmin antiplasmin complexes (PAP) level which is consistent with the findings of others. Tanaka et al.’ demonstrated that during CPB, increased t-PA release from endothelial cells coupled with an increase in circulating plasmin antiplasmin complexes is followed by an increased level of XDP. He suggested that activated FXII is the cause of the hypertibrinolytic state seen in CPB. In our comparison CPB patients, the t-PA levels rise ahead of PAI- and at the same time as XDP and PAP supporting the idea of Tanaka et al. However, our severe FXII deficiency patient shows a rise in t-PA level without the corresponding rise in PAP or XDP. In our cases FXII appear to have a key role in fibrinolysis. Whereas, the role of t-PA in hyperfibrinolysis observed in CPB remains unclear.
REFERENCES 1,
van Kaulla K N, Swan H 1958 Clotting deviations in man during cardiac bypass: librinolysis and circulating anticoagulant. J Thor
3_.
3.
4.
5.
6.
7.
surg 36: 5 19-533 Tanaka K, Wada K, Morimoto T, Shomura S, Satoh T, Yada I, Yuasa H, Kusagawa M, Deguchi K 1989 The role of the protein C-system in physiologic anticoagulation during cardiopulmonary bypass. Transact Am Sot Artif Int Organs 35: 373-365 Sato T, Tanaka K, Kondo C, Morimoto T, Yada I, Yuasa H, Kusagawa M, Deguchi K 1991 Nafamostat mesilate administration during cardiopulmonary bypass decreases postoperative bleeding after cardiac surgery. Transact Am SOC Artif Organs 37: M 194-M 195 Wachtfogel Y T, Kucich U, Greenplate J, Gluszko P, Abrams W, Weinbaum G, Wenger R K, Rucinski B, Niewiarowski S, Bdmunds L H, Colman R W 1987 Human neutrophil degranulation during extracorporeal circulation. Blood 69: 324330 Teufelsbauer H, Proidl S, Have1 M, Vukovich T 1992 Early activation of hemostasis during cardiopulmonary bypass: evidence for thrombin mediated hyperlibrinolysis. Thromb Haemostas 68: 250-252 Batios G, de la Pefia A, Izaguirre R 1992 The vascular plasminogen activator as source of the librinolytic potential observed during cardiopulmonary bypass. Thromb Res 67: 579588 Tanaka K. Morimoto T, Yada I, Kusagawa M, Deguchi K 1987 Physiologic role of enhanced bbrinolytic activify during cardiopulmonary bypass in open heart surgery. Transact Am SOC Artif Int Organs 33: 505-509.
Elevated Fibrinolysis
in Cardiopulmonary
H.I. Chung, J.F. Burman,
B.A. Balogun,
KEY WORDS.
J.C.R.
Bypass is Factor XII Dependent
Lincoln,
J.R. Pepper
Factor XII. Cardiopulmonary bypass. Fibrinolysis
We measured heparin, thrombin-antithrombin complexes (TAT), Prothrombin Fragment 1+2 (F1+2) to assess b viva thrombin generation, and cross-linked fibrin degradation products (XDP), plasmin antiplasmin complexes (PAP), tissue plasminogen activator (t-PA) levels to assess fibrinolysis in two patients with factor XII (FXII) deficiency, who underwent open heart surgery with cardiopulmonary bypass (CPB), one severe (factor XII < 1 iu/dl for correction of atria1 septal defect and a patent ductus arterious) and one mild (factor XII 10 iu/dl for mitral value replacement). Eight patients undergoing elective first time cardiac CPB surgery served as a comparison group.
Elevated fibrinolytic activity during CPB and especially after protamine infusion was reported as early as 1958.’ Von Kaulla et al. reported shortened euglobin lysis times as well as changes in thrombelastography. increased cross-link fibrin Recent reports show degradation products (XDP), tissue plasminogen activator t-PA) and plasmin antiplasmin complex levels during CPB.z-6 In our FXTI deficient patients, there was evidence of thrombin generation during cardiopulmonary bypass, as judged by the activation markers F1+2 and TAT. Levels of these were comparable to those reported during cardiopulmonary bypass in routine cardiac surgery.
Table 1. Sevrr~ FXII deficiency patient
Heparin (iulml) TAT (n&ml) F1+2 (nmol/L) XDP (&ml) t-PA (ag) (q/ml) PAI-I (ag) (nglml) Plasminogen (iu/dl)
Pre op
CPB 15 min
CPB 30 min
CPB end
Protamine + 20 min
0 1.8 1.17 43 7.7 8.7 82.5
4 49 4.08 88 16.2 17.2 43.4
3.5 27 3.48 82 20.0 16.2 41.6
3.3 30 4.20 I21 17.5 19.1 43.2
0 30 3.09 77 6.9 38.3 49.8
Mild FXII deficiency patient
Heparin (h/ml) TAT (ng/ml) F1+2 (nmol/L) XDP (nglml) t-PA (ag) (ng/ml) PAI- (ag) (nglml) Plasminogen (iuldl)
Pre op
CPB 1.5 min
CPB 30 min
CPB end
Protamine + 20 min
0 10.3 1.06 51 7.6 8.3 74.8
3.4 8.8 0.81 56 5.9 15.3 55.7
2.9 28.1 1.51 165 5.4 12.8 44.3
1.9 19.7 1.73 144 6.7 7.3 44.1
0 25.9 2.35 164 6.2 8.6 52.2
Department of Haematology. Royal Brompton National Heart and Lung Hospital, Sydney Street, London SW3 6NP, United Kingdom
84
Fibrinolysis
85
900 600 700
B
4
C
Operative
D
E
A
C
B
Stages
D
Operative
E
Operative
60 16 16
3 E
14
$
12
g
10
z
50
a 5
40
p 7
30
2
20
6 10
6 Ol A
Operative
C
D
Stages
E
.r!‘;; 4
0
4 B
E
Stages
70
22
p
D
C
B
A
Stages
A
B
D
C
Operative
Stages
E
A
B
Operative
C
D
E
Stages
Fig. I Normal (circle) severe FXII deficient patient (square), and mild FXII deficient patient (triangle). Samples were taken at (A) preoperatively, (B) 15 minutes on CPB, (C) 30 minutes on CPB, (D) just prior to end of CPB, (E) 20 minutes post protamine.
In our FXII deficient patients, there is a small rise in XDP levels, but at no time did they exceed normal (< 250 ng/ml). Our comparison patient group shows markedly elevated XDP and plasmin antiplasmin complexes (PAP) level which is consistent with the findings of others. Tanaka et al.’ demonstrated that during CPB, increased t-PA release from endothelial cells coupled with an increase in circulating plasmin antiplasmin complexes is followed by an increased level of XDP. He suggested that activated FXII is the cause of the hypertibrinolytic state seen in CPB. In our comparison CPB patients, the t-PA levels rise ahead of PAI- and at the same time as XDP and PAP supporting the idea of Tanaka et al. However, our severe FXII deficiency patient shows a rise in t-PA level without the corresponding rise in PAP or XDP. In our cases FXII appear to have a key role in fibrinolysis. Whereas, the role of t-PA in hyperfibrinolysis observed in CPB remains unclear.
REFERENCES 1,
van Kaulla K N, Swan H 1958 Clotting deviations in man during cardiac bypass: librinolysis and circulating anticoagulant. J Thor
3_.
3.
4.
5.
6.
7.
surg 36: 5 19-533 Tanaka K, Wada K, Morimoto T, Shomura S, Satoh T, Yada I, Yuasa H, Kusagawa M, Deguchi K 1989 The role of the protein C-system in physiologic anticoagulation during cardiopulmonary bypass. Transact Am Sot Artif Int Organs 35: 373-365 Sato T, Tanaka K, Kondo C, Morimoto T, Yada I, Yuasa H, Kusagawa M, Deguchi K 1991 Nafamostat mesilate administration during cardiopulmonary bypass decreases postoperative bleeding after cardiac surgery. Transact Am SOC Artif Organs 37: M 194-M 195 Wachtfogel Y T, Kucich U, Greenplate J, Gluszko P, Abrams W, Weinbaum G, Wenger R K, Rucinski B, Niewiarowski S, Bdmunds L H, Colman R W 1987 Human neutrophil degranulation during extracorporeal circulation. Blood 69: 324330 Teufelsbauer H, Proidl S, Have1 M, Vukovich T 1992 Early activation of hemostasis during cardiopulmonary bypass: evidence for thrombin mediated hyperlibrinolysis. Thromb Haemostas 68: 250-252 Batios G, de la Pefia A, Izaguirre R 1992 The vascular plasminogen activator as source of the librinolytic potential observed during cardiopulmonary bypass. Thromb Res 67: 579588 Tanaka K. Morimoto T, Yada I, Kusagawa M, Deguchi K 1987 Physiologic role of enhanced bbrinolytic activify during cardiopulmonary bypass in open heart surgery. Transact Am SOC Artif Int Organs 33: 505-509.