Full text of DOI:10.1177/021849230100900203

HEMOSTATIC MARKERS AND RENAL FUNCTION AFTER CARDIOPULMONARY BYPASS
Yılmaz
ORIGINAL CONTRIBUTION
HEMOSTATIC MARKERS AND
RENAL FUNCTION AFTER
CARDIOPULMONARY BYPASS
1
˙
Mustafa Yılmaz, MD, Ibrahim Haznedarog˘lu, MD ,
M S¸anser Ates¸, MD, S¸erafettin Kirazlı, MD, PhD1,
˙
Ilhan Pas¸aog˘lu, MD
Department of Thoracic and Cardiovascular Surgery
1Department of Hematology
Faculty of Medicine
Hacettepe University
Sihhiye, Ankara, Turkey
ABSTRACT
To evaluate coagulation status after cardiopulmonary bypass and its relation to
renal function, thrombin-antithrombin III complex and prothrombin fragment 1+2
were measured as thrombotic markers in 46 patients undergoing coronary artery
bypass grafting. Postoperative serum creatinine values exceeded 20 mg·L–1 in 12
patients, indicating compromised renal function; there was a statistically significant
increase in the postoperative levels of thrombotic markers in these patients. These
data indicate that patients with renal dysfunction after cardiopulmonary bypass
have a thrombotic tendency. Anticoagulant treatment is recommended in such
patients.
(Asian Cardiovasc Thorac Ann 2001;9:86–9)
and VIII, antithrombin III, plasminogen, and alpha-2
INTRODUCTION
antiplasmin decrease during CPB, mainly due to
hemodilution, and they subsequently increase due to
synthesis by the liver. Plasminogen is activated. Fibrinogen
is known to be absorbed onto the circuit surface, which
binds to platelets. The concentration of platelets drops,
their functions alter (they become insensitive to adenosine
diphosphate and epinephrine), and they are activated.
Complement activation through an alternative pathway
has also been demonstrated during CPB.5,6
Cardiopulmonary bypass (CPB) is important in cardio-
vascular surgery. The extracorporeal circulation system
that replaces the functions of the heart and lungs, consists
of a pump, disposable oxygenator, reservoirs, and tubing.
Blood flow, gas exchange, blood-surface interface effects,
and reticuloendothelial function are altered by CPB, with
consequent changes in renal, neurological, hepatic, and
other functions.1–3 The organism is temporarily faced
with unphysiological conditions such as non-pulsatile
flow, anticoagulation, hemodilution, hypothermia, and
relative hypoperfusion. All of these factors affect platelet
function, coagulation, and the fibrinolytic system.1,4–6
Normally, there is continuous fibrin formation on the
endothelial surface, which is balanced by concomitant
It is now possible to evaluate the hemostatic system more
accurately with molecular markers of in-vivo coagulation.
Among these markers are the thrombin-antithrombin III
complex (TAT), a marker of intravascular thrombin
formation, and prothrombin fragment 1+2 (PF 1.2), a
fibrinolysis. If this balance is upset, the clotting mechanism peptide fragment generated when prothrombin is activated
is activated.4 Heparinization is used to prevent blood to thrombin.4 Studies on hemostatic system changes have
coagulation during CPB. Initially, the levels of factors V been carried out in patients undergoing hemodialysis, and
For reprint information contact:
Mustafa Yılmaz, MD Tel: 90 312 476 5533 Fax: 90 312 324 3284 email: myilmazmd88@turk.net
Department of Thoracic and Cardiovascular Surgery, Faculty of Medicine, Hacettepe University, Sihhiye,
Ankara 06100, Turkey.
A
SIAN
C
ARDIOVASCULAR & THORACIC
A
NNALS
86
2001, VOL. 9, NO. 2
Downloaded from aan.sagepub.com at UNIV OF BIRMINGHAM on March 20, 2015

Yılmaz
HEMOSTATIC MARKERS AND RENAL FUNCTION AFTER CARDIOPULMONARY BYPASS
it has been well documented that patients with end-stage grafting in the Department of Thoracic and Cardiovascular
renal failure exhibit thrombotic complications. The aim Surgery, Hacettepe University. Patients with bleeding
of this study was to evaluate hemostatic status in relation diathesis who received salicylic acid, heparin, warfarin,
to renal function in patients undergoing coronary artery nonsteroidal antiinflammatory drugs, or fibrinolytic
bypass grafting with CPB.
medication, were excluded from the study. A Univox
membrane oxygenator, DeBakey roller pump, and Bentley
Duraflo II pump system (Bentley, Irvine, CA, USA) were
used in all patients for CPB. Patients were cooled to 28°C
and cold potassium cardioplegia was applied. The
PATIENTS AND METHODS
The study was carried out on 36 men and 10 women, aged
38 to 67 years, who underwent coronary artery bypass
Table 1. Renal and Hemostatic Parameters in Group 1 and Group 2 (Postoperative Creatinine ≥ 20 mg·L–1)
Preoperative
Postoperative
Parameter
Group 1 (n = 34)
Group 2 (n = 12)
Group 1 (n = 34)
Group 2 (n = 12)
Blood urea nitrogen (mg·L–1)
185.6 ± 22
9.9 ± 1
186.2 ± 19
10.1 ± 1
248.1 ± 29
14.2 ± 2
333.8 ± 4*
23.9 ± 2*
Serum creatinine (mg·L–1
)
Thrombin-antithrombin III (ng·mL–1)
Prothrombin fragment 1+2 (nmol·L–1)
4.37 ± 2.4
2.87 ± 1
3.42 ± 0.9
2.89 ± 1.6
4.46 ± 3.5
3.82 ± 2.5†
13.1 ± 5.4*
5.47 ± 2*†
†
*Significantly higher than group 1. Significantly higher than preoperative values.
Preoperative
Log
Postoperative
Log
Patient No. (n = 34)
Figure 1. Preoperative and postoperative thrombin-antithrombin III complex (TAT) in group 1 (serum creatinine < 20 mg·L–1).
Preoperative
Log
Postoperative
Log
Patient No. (n = 12)
Figure 2. Preoperative and postoperative thrombin-antithrombin III complex (TAT) in group 2 (serum creatinine > 20 mg·L–1).
2001, VOL. 9, N
O
. 2
87
ASIAN CARDIOVASCULAR & THORACIC ANNALS
Downloaded from aan.sagepub.com at UNIV OF BIRMINGHAM on March 20, 2015

HEMOSTATIC MARKERS AND RENAL FUNCTION AFTER CARDIOPULMONARY BYPASS
Yılmaz
perfusion pressure was kept above 40 mm Hg. Bypass Package for Social Sciences, Inc., Chicago, IL, USA)
flow rates were maintained at 2.4 L·m–2·min–1.
Heparin 3 mg·kg–1 (Liquemine; La Roche Ltd, Basel,
Switzerland) was given before cannulation. The activated
clotting time was monitored (Hemachron; Technidyne,
Edison, NJ, USA) and kept at approximately 400 seconds.
Neutralization of heparin after CPB was achieved with
protamine (Protamin; La Roche Ltd, Basel, Switzerland)
administration. Blood samples were obtained before CPB
and 24 hours postoperatively to determine PF 1.2 and
TAT levels. PF 1.2 and TAT concentrations in plasma
were measured using solid-phase sandwich enzyme-linked
immunosorbent assays (Enzygnost F 1+2 and Enzygnost
TAT; Behring, Frankfurt, Germany). Preoperative and
postoperative blood urea nitrogen and serum creatinine
values were also determined.
was used to analyze the data.
RESULTS
Patients were grouped according to their postoperative
serum creatinine values: group 1, n = 34, creatinine
< 20 mg·L–1; and group 2, n = 12, creatinine > 20 mg·L–1.
Plasma concentrations of TAT and PF 1.2, blood urea
nitrogen, and serum creatinine are shown in Table 1 and
Figures 1 to 4. In group 1, preoperative and postoperative
TAT values were not significantly different (p = 0.416),
but PF 1.2 levels were significantly higher postoperatively
(p < 0.05). In addition to blood urea nitrogen and
creatinine, postoperative TAT and PF 1.2 values were
significantly higher in group 2 than in group 1. The PF
1.2 level in group 2 was higher postoperatively than
preoperatively (p < 0.05).
Results were expressed as mean ± standard error of the
mean. Values of p < 0.05 were accepted as significant.
Student’s t test for paired samples was used for comparison
of preoperative and postoperative plasma PF 1.2 and TAT
values. SPSS version 5.01 for Windows (Statistical
DISCUSSION
The coagulation cascade is a series of linked proteolytic
reactions leading to thrombin generation and fibrin
formation. CPB causes hemostatic abnormalities by
Preoperative
Log
Postoperative
Log
Patient No. (n = 34)
Figure 3. Preoperative and postoperative prothrombin fragment 1+2 (PF 1.2) in group 1 (serum creatinine < 20 mg·L–1).
Preoperative
Log
Postoperative
Log
Patient No. (n = 12)
Figure 4. Preoperative and postoperative prothrombin fragment 1+2 (PF 1.2) in group 2 (serum creatinine > 20 mg·L–1).
A
SIAN ARDIOVASCULAR & THORACIC NNALS 2001, VOL. 9, NO. 2
C
A
88
Downloaded from aan.sagepub.com at UNIV OF BIRMINGHAM on March 20, 2015

Yılmaz
HEMOSTATIC MARKERS AND RENAL FUNCTION AFTER CARDIOPULMONARY BYPASS
in extracorporeal circulation. 3rd ed. Oxford: Butterworth-
Heinemann, 1992:144–56.
influencing the coagulation factors, fibrinogen and the
fibrinolytic system, as well as the number and function
of platelets. The coagulation activation markers are useful
for studying coagulation status in vivo.7 PF 1.2, the peptide
fragment generated when prothrombin is activated to
thrombin, is found during the activation of coagulation.
When thrombin is formed, it combines in a complex with
the serine protease inhibitor antithrombin III. These in-
vivo molecular markers of coagulation circulate in the
blood of patients with thrombotic disorders, indicating
hemostatic system activation.4,8
3. Paramo JA, Rifon J, Llorens R, Casares J, Paloma MJ,
Rocha E. Intraoperative and postoperative fibrinolysis in
patients undergoing cardiopulmonary bypass surgery.
Hemostasis 1991;21:58–64.
4. Fareed J, Brick RL, Hoppensteadt DA, Walenga JM,
Messmore HL, Bermes EW Jr. Molecular markers of
hemostatic activation. Implications in the diagnosis of
thrombosis and vascular and thrombotic disorders. Clin
Lab Med 1995;15:39–61.
5. Gormon RC, Ziats NP, Rao AK, Gikakis N, Sun L, Khan
MM, et al. Surface-bound heparin fails to reduce thrombin
formation during clinical cardiopulmonary bypass. J Thorac
Cardiovasc Surg 1996;111:1–12.
The results of this study show that CPB induces thrombin
generation.Although PF 1.2 levels increased slightly when
renal function was not affected (group 1), levels of both
markers showed marked increases when renal function
was compromised (group 2). Further study is required to
determine whether only TAT or both TAT and PF 1.2 are
important in the thrombotic tendency. However, it is well
known that acute renal failure after open heart surgery
correlates with longer durations of CPB and aortic
crossclamping. The correlation between renal failure and
thrombotic tendency has been established.9–14 It seems
that postoperative impairment of renal function gives rise
to a thrombotic tendency.14
6. Horimoto H, Kondo K, Asada K, Sasaki S. Heparin coated
cardiopulmonary circuits in coronary artery bypass surgery.
Artif Org 1994;20:936–40.
7. Khuri SF, Wolfe JA, Josa M, Axford TC, Szymanski I,
Assousa S, et al. Hematologic changes during and after
cardiopulmonary bypass and their relationship to the
bleeding time and nonsurgical blood loss. J Thorac
Cardiovasc Surg 1992;104:94–107.
8. Rifon J, Paramo JA, Prosper F, Collados MT, Sarra J,
Rocha E. Thrombin-antithrombin complexes and
prothrombin fragment 1+2 in aorto-coronary bypass
surgery: relation to graft occlusion. Hematol Pathol 1994;
8:35–42.
The findings in this study suggest that the thrombotic
tendency imposed by CPB is augmented by impairment
of renal function. CPB times in all patients were more
than 60 minutes. Serum creatinine levels were above
20 mg·L–1 in the early postoperative period (24 hours) in
the 12 patients in group 2, but they had decreased to less
than 20 mg·L–1 by the 5th postoperative day in all except
one of them. This suggests that coronary artery bypass
graft patients should be anticoagulated during periods
when creatinine levels are above 20 mg·L–1, to prevent
graft thrombosis. This increased thrombotic tendency is
important in early and long-term graft patency. Therefore,
prophylactic anticoagulation treatment is recommended
when TAT and PF 1.2 values are increased in patients
with renal impairment.
˙
9. Erdem Y, Haznedarog˘lu IC, Kiraz S¸. Increased prothrombin
fragment 1.2 concentrations in hemodialysis patients. Clin
Nephrol 1999;45:69.
10. Koning HM, Koning AJ, Leusink JA. Serious acute renal
failure following open heart surgery. Thorac Cardiovasc
Surgeon 1985;33:283–7.
11. Sagripanti A, CupistiA, Baicchi U, Ferdeghini M, Morelli
E, Barsotti G. Plasma parameters of prothrombotic state
in chronic uremia. Nephron 1993;63:273–8.
12. Zanardo G, Michielion P, Paccagnella A, Rosi P, Calo M,
Salandin V, et al. Acute renal failure in the patient
undergoing cardiac operation. Prevalence, mortality rate,
and main risk factors. J Thorac Cardiovasc Surg 1994;
107:1489–95.
13. Mezzano D, Tagle R, Panes O, Perez M, Downey P,
Munoz B, et al. Hemostatic disorder of uremia: the platelet
defect, main determinant of the prolonged bleeding time,
is correlated with indices of activation of coagulation and
fibrinolysis. Thromb Haemost 1996;76:312–21.
REFERENCES
1. Edmunds LH, Ellison N Jr, Colman RW, Niewiarowski S,
Rao AK, Addonizio VP Jr, et al. Platelet function during
cardiac operation: comparison of membrane and bubble
oxygenators. J Thorac Cardiovasc Surg 1982;83:805–12.
14. Stefanidis I, Frank D, Maurin N. Hemostasis activation
markers in acute renal failure. Ren Fail 1998;20:147–55.
2. Kay PH. Hematological aspect of extracorporeal
circulation. In: Rajah MS, Penny AF, editors. Techniques
2001, VOL. 9, N
O
. 2
89
ASIAN CARDIOVASCULAR & THORACIC ANNALS
Downloaded from aan.sagepub.com at UNIV OF BIRMINGHAM on March 20, 2015