Fibrinolysfs 8 Profeo/ys~s (1999) 13 (4/5). 155416 0 Harcourl Publishers Lld 1999
Fibrinolysis aneurysm A. Holmberg,’ ‘Department 2Depariment
01 Surgery, of Medical
in open surgery
6. Westman,’ Umversity Sciences,
Hospital Uppsala, Unit of Coagulation
S-751 65 Uppsala. Sweden Disorders, Clinical Chemistry,
Summary Objective: Does open surgery for abdominal aortic aneurysm (AAA) influence fibrinolysis? Setting: University Hospital. Materials: Twenty-three consecutive patients underwent open AAA surgery. Blood from the cubital vein was sampled pre-, intra- and postoperatively. lntraoperatively blood was also sampled from the femoral vein. Main outcome Measures: ELISA-methodology was used for quantitative determination of tissue plasminogen activator (tPA) and human cross-linked fibrin degradation product (D-dimer) antigens as well as for quantification of plasminogen activator inhibitor-l (PAI-1) activity. Results: Preoperatively D-dimer in AAA patients were higher than in 20 healthy age-matched controls (p
Elective repair of asymptomatic infrarenal abdominal aortic aneurysms according to open standard procedure carries a 30 day mortality of 4-8%, primarily because of myocardial infarction. ‘.2 Moreover, there are a high incidence of serious non-lethal complications including myocardial infarction, congestive heart failure, respiratory insufficiency, acute renal failure and stroke.3f4 A substantial part of the complications mentioned may have thromboembolic aetiology. Also, in connection with aortic clamping and declamping, with a subsequent ischaemia-reperfusion injury, one may assume that an inflammatory reaction involving various cytokines may induce an acute phase reaction5 Received:
1998 28 April 1999
Correspondence to: Anders Holmberg University Hospital, S-751 65 Uppsala
MD, Department Sweden.
Tel.: (46) 16 66 46 26; fax: (46) 16 66 46 32
In patients with abdominal aortic aneurysm (AAA) the coagulation system is activated already preoperatively. A further activation occurs during aneurysm repair, especially in blood draining ischaemic and reperfused tissues leading to an extensive thrombin generation and, consequently, fibrin production.6 The activity returns to almost preoperative but still supranormal levels I week postoperatively.6-8 Degradation of fibrin in the blood vessels is the principal function of the fibrinolytic system, thus limiting the effects of coagulation. The central component is the agreessive proteolytic enzyme plasmin formed from plasminogen.g Since the intravascular fibrinolytic system is mainly regulated by the balance between tissue plasminogen activator &PA) and its primary inhibitor, plasminogen activator inhibitor-l (PAI-l),1o these two substances are generally accepted as markers of the fib+ nolytic activity. Some investigators have used plasmin%antiplasmin complex (PAP) as a measure of fibrinolytic activity in AAA patients” and in connection with hepatic 155
Holmberg et al.
resection.12 In spite of promising results, the experience of PAP measurements are limited and there are still no studies of correlation between PAP, tPA and PAI-1. Plasmin cleaves cross-linked fibrin into fragments D and E with a subsequent release of D-dimer which, thus, is a marker of both fibrin production (coagulation) and degradation (fibrinolysis). An impaired fibrinolytic function is a frequent observation in patients with thromboembolic disease and myocardial infarction.13 There are, however, few studies of the fibrinolytic activity in patients undergoing AAA surgery. The aims of this study were, therefore, to evaluate the activity of the fibrinolytic system in response to abdominal aortic aneurysm surgery both in the systemic circulation and in the ischaemic and reperfused part of the body, distal to aortic clamping. In order to study the influence of the operative trauma and age versus ischaemia-reperfusion injury, comparisons were made with the activity during major non-vascular surgery of similar magnitude as well as in healthy unoperated agematched controls.
Approval for this study was obtained from the research Ethics Committee, Faculty of Medicine, University of Uppsala. Patients and control subjects gave their approval in a written informed consent. AAA patients
Twenty-three consecutive patients with AAA were operated on electively according to standard open procedure. The median aneurysmal diameter was 60mm (range 43-75). All patients were men with a median age of 72 years (range 54-83). Exclusion criteria were concomitant chronic inflammatory disease (except for one inflammatory aneurysm), malignancy and recent fracture. Five were suffering from intermittent claudication, with a median ankle bra&al pressure index (ABPI) of 0.6 (range 0.4-0.8). Three had diabetes mellitus, six had hypertension, ten had a previous history of myocardial infarction and three had a history of stroke. Eleven were current smokers. After standard premeditation and general anaesthesia, the patients were operated on with an open exclusion of the aneurysm and insertion of a dacron graft. Four bifurcated tube and 19 grafts were inserted. Prior to aortic clamping 5000 units. of unfractionated heparin were administered intravenously. One hundred and fifty to 200ml of Mannitol were rapidly infused intravenously approximately 20 min before aortic clamping. The median Fibrinolysis
operation time was 172 min (range 60-340), median aortic clamping time 70 min (range 22-166) and intraoperative haemorrhage 3200ml (range 500-12000). One patient with a previous history of myocardial infarction and cerebrovascular disease died on the 25th postoperative day because of myocardial reinfarction and multiorgan failure. He had a negative laparatomy 1 week before death because of suspicion of intestinal ischaemia. Two patients had non-fatal myocardial infarction and one was reoperated with a left hemicolectomy and colostomy according to Hartmann because of colon ischaemia. Postoperatively, a daily subcutaneous injection of 40 mg of enoxaparin was routine in all patients. Controls
Eleven patients, five men and six women, with a median age of 49 years (range 19-77), operated on with stabilization of the cervical and/or lumbar vertebral column, served as operated control subjects (OC) because of a large operative trauma without vascular involvement. Indication for surgery was non-traumatic instability of the vertebral column. They had no clinical signs of cardiovascular disease, malignancy, chronic inflammatory diseases or recent fractures. The median operation time was 175 mm (range 85-300) and the median intraoprative blood loss was 2500ml (range 200-6200). No heparin was administered pre- or intraoperatively. Daily subcutaneous administration of 40 mg enoxaparin 1 week postoperatively was routine in all patients. All patients were postoperatively mobilized without restrictions. However, two had to stay in bed for 3 and 4 days respectively because of CSF leakage secondary to injury of the spinal dura mater. Twenty healthy persons, 16 men and four women, with a median age of 72 years (range 66-79), without clinical signs of cardiovascular, malignant or inflammatory diseases, served as agematched controls (AMC) for baseline data since the operated controls were significantly younger than the AAA patients and the reference values from the manufacturers were not given for the relevant age group. Blood
In AAA patients, 2 x 4.5 ml of blood were sampled in tubes containing 0.5 ml of 0.129 M citrate each (Becton Dickinson VACUTAINER Systems Eur. B.P. 37 38241 Myelan Cedex, France) from the cubital vein the day before surgery (baseline), intraoperatively 20 min after aortic clamping (ischaemia), intraoperatively 20 min after aortic declamping (reperfusion) and 1 week postoperatively. On the intraoperative occasions blood was also sampled from the femoral vein reflecting alterations in the ischaemic and reperfused part of the body. 0 Harcourt
L td 1999
Fibrinolysis in open abdominal aortic aneurysm surgery
Table 1 AAA patients. manufacturer: 4-78). Values
tPA in nglml (reference interval given by the manufacturer: 3-lo), PAI- in units/ml (reference value given by the mean 12.8+12.1; [SD] median: 9.6), D-dimer in rig/ml (reference range given by the manufacturer [2.5-97.5 percentile]: are expressed as median (min-max).
Baseline Aortic clamping, cubital vein Aortic clamping, femoral vein Aortic declamping, cubital vein Aortic declamping, femoral vein 1 week postoperatively ns=non significant; ‘=pcO.O5; “=pc0.01; “‘=pcO.OOl (Wilcoxon signed Significances were calculated
10.2 6.8 8.6 8.4 9.9 16.3
rank test) with respect
(4.9-24.2) (1.1-11.6)“’ (4.4-l 6.8)ns (2.6-19.5)’ (2.2-26.5)ns (8.3-28.4)”
OC patients. tPA in q/ml (reference interval given manufacturer mean: 12.8 f 12.1 [SD]; median: 9.6), D-dimer 4-78. Values are expressed as median (min-max).
by the manufacturer: in nglml (reference
7.2 (2.3-l 0.4) 6.7 (l.&9.4)ns 7.4 (2.4-13.6)ns
ns= non significant; ‘=pcO.O5; “=p
rank test) with respect
571 579 782 484 525 1146
(60-1515) (19-6000)ns (76-6000)’ (65-6000)ns (132-6000)ns (491-6000)“’
given by the percentile):
7.2 (2-80.6) 3.4 (2-33.1)’ 2.8 (2-30)’
17 (10-85) 21 (11-81)ns 259 (65-638)”
In the 00, blood was sampled from the cubital vein the day before surgery (baseline), intraoperatively after exposure of the posterior portion of the vertebral column immediately before osteotomy and finally 1 week postoperatively. In the AMCs blood from the cubital vein was sampled in c&rated tubings. The interpretations were based on data that were not corrected for haemodilution in AL4 and OC patients. Immediately after blood sampling, the plasma was separated by centrifugation at 2500 rpm for 15 min, froozen in -70°C and stored. Enzyme immunoassay for quantitative determination of tissue plasminogen activator antigen @PA)was performed (ImulyseTh’ tPA, Biopool, UmeA, Sweden), reference interval given by the manufacturer was 3 to 10 rig/ml with lower values for younger people. The intra- and inter-assay variation is 8 and 10% respectively. Quantitative determination of active human plasminogen activator inhibitor, type l(PAI-1) was performed by using a bioimmunoassay (Biopool Chromolize TM,Biopool, Umed Sweden). Reference interval given by the manufacturer based on 367 subjects between 20 and 59 years was 12.8k12.1 (SD) IU/mL (median 9.6 tits/ml).14 The intra- and interassay variation is 2.6-3.70/o and 3.6-16.90/o respectively. Human cross-linked fibrin degradation product (D-dimer) was Publishers
(2.0-33.1) (2.0-42.0)ns (2.0-45.l)ns (1.5-151.7)” (2.0-146.3)“’ (2.0-26.0)ns
3-lo), PAIin units/ml (reference value range given by the manufacturer (2.5-97.5
Baseline lntraoperatively 1 week postoperatively
3.5 4.9 3.4 18.4 16.7 3.2
quantitatively determined by using a sandwich enzyme immunoassay ([email protected]
D-Dimer micro, Behring Behring Diagnostics GmbH, MarburgKermany), reference range given by the manufacturer was 4-78 ng/mI. (2.5925 percentile range). Irma- and interassay variation is 2.4-4.40/o and 12.3-15.40/o respectively. Statistics
Data were analysed using SPSSfor Windows release 6.0. Variables were presented as median (min-max) unless otherwise stated. A values were calculated as an intraoperative value minus baseline value. Differences between repeated measurements within groups were analysed with the Wilcoxon signed rank test. Differences between groups concerning absolute as well as A values were analysed with the Kruskal-Wallis one-way ANOVA. Covariations between pre- as well as intraoperative parameters and the absolute values were studied with multiple linear stepwise regression test. Correlation between age and baseline values in the operated controls and agematched controls was analysed with the Spearman rank correlation test. Significance tests were two-tailed and considered significant if ~10.05. Fibrinolysis
Holmberg et al.
18 16 14
In AAA patients tPA did not differ from the AMC preoperatively (Km&al-Wallis one-way ANOVA). tPA decreased significantly during aortic clamping in cubital (p(O.001) but not in femoral blood, was still significantly decreased in cubital blood after aortic declamping (p(O.05) and became sign&army increased 1 week postoperatively (~K0.01) compared to the baseline level (see Table 1) (Wilcoxon signed rank test). When the values during aortic clamping and after aortic declamping were compared, tPA values both in cubital and femoral blood were significantly lower during aortic clamping 60.05 and 60.001 respectively) (Wilcoxon signed rank test). Moreover, tPA was signihcantly lower in cubital than in femoral blood during aortic clamping (~KO.001) (Wilcoxon signed rank test). In AAA patients, preoperative PAI-I activity did not differ from the AMC subjects (Kruskal-Wallis one-way ANOVA). PAI-I was unaltered during aortic clamping, increased significantly after aortic declamping in cubital as well as in femoral blood (~K0.0 1 and 60.00 1 respectively) and returned to baseline levels 1 week postoperatively (see Table 1) (Wilcoxon signed rank test). PAIactivity was significantly lower during aortic clamping than after aortic declamping in cubital as well as in femoral blood (~K0.01 and p
In AMC the median level of tPA was 9.4 ng/mL (range 2.9-19.0), PAI- 4.7IU/mL (range 2-30.9) and D-dimer 32 ng/mL (range 10536; two persons had higher values than the reference interval). Thus, median values for all three markers were within the normal reference interval (see above). Fibrinolysis
Fig. 1 Levels of tPA before, versus OC patients. ns= non significant “=p
and 1 week
In OC patients tPA was preoperatively significantly lower than in AMC subjects QKO.01) (Kruskal-Wallis one-way ANOVA). Pre-, intra- as well as postoperatively tPA was within the reference interval given by the manufacturer. No significant changes were observed during surgery (see Table 2) (Wilcoxon signed rank test). PAI- activity did preoperatively not differ from AMC (Km&al-Wallis one-way ANOVA) and was within the reference interval given by the manufacturer pre-, intraand postoperatively. However, a significant decrease intra-as well as postoperatively was observed QKO.05 for both) (see Table 2) (Wilcoxon signed rank test). D-dimer did not differ from AMC preoperatively (Kruskal-Wallis one-way ANOVA) and was within the reference interval given by the manufacturer pre- and intraoperatively without any significant intraoperative change while 1 week postoperatively a significant increase wO.01) (Wilcoxon signed rank test) to a higher level than the reference interval was observed (see Table 2). AAA versus OC
Levels in cubital blood were compared using Kruskal-Wallis one-way ANOVA. tPA levels pre- and postoperatively were higher in AAA than in OC @
Fibrinolysis in open abdominal aortic aneurysm surgery
20 1 16 14
” ’ Base
line ’ aorta
Fig. 2 Levels of PAIbefore, AAA versus OC patients. ns= non significant; ‘=p
and one week
Fig. 3 Levels of D-dimer AAA versus OC patients. ‘=p
1 week 1 week
D-dimer levels were higher in AAA than OC preoperatively (~K0.00 l), intraoperatively during sot-tic clamping @
After aortic declamping tPA in cubital blood showed a significant positive co-variation with aortic clamping time (~K0.01). Intraoperative values of PAI- in AAA patients co-varied significantly with blood loss and aortic clamping time o(O.001 and 60.01 respectively). No co-variation was found between D-dimer levels and parameters of operative trauma in AAA patients. When OC patients and AhK subjects were pooled (-3 1) baseline tPA showed a significant correlation with age (Ml.49, p
This study showed that AAA patients had an increased fibrinolytic activity preoperatively. During AAA surgery there were signs of a fibrinolytic inhibition. The intraoperative inhibition of fibrinolysis was more profound after aortic declamping and more profound in the systemic circulation than locally, distal to aortic clamping. The AAA patients seemed to be in a condition of high fibrinolytic activation relative base line 1 week postoperatively owing to high tPA and D-dimer levels and low PAI-1 activity. The activity of the fibrinolytic system may covary with variables reflecting the magnitude of the operative trauma and seems to be age dependent. When comparing plasma protein concentrations between repeated measurements, the effects of haemodilution - that is blood volume changes, blood loss and osmolality alterations - may influence the results as well as synthesis, metabolism and excretion. This question is of vital importance especially when decreases in plasma concentrations occurs as in tPA. In order to rule out the influence of haemodilution, correction for erythrocyte volume fraction (EVF) ratio has been suggested. However, van Beaumont claimed that EVF is not directly related to plasma volume and showed in a mathematical example that an increase of 3 EVF units gave a plasma volume decrease of 11.40/0.‘~Thus, using EVF ratio to correct for haemodilution has been criticized because it may overestimate postdilution concentrations in plasma and the error increases as the degree of volume change increases. Instead, it has been suggested both mathematically and experimentally that the plasma dilution factor (PDF), accounting for the influence of any blood loss and change in plasma osmolality, would predict the influence of haemodilution more accurately. However, PDF does not correct for blood transfusion.~6 Therefore, we initially used both EVF- and PDF-corrected data as well as uncorrected data. EVF showed generally higher and PDF lower values than the uncorrected data (data not shown). Furthermore, as tPA has a half-live in plasma of just a few minutes one may assume that haemodilution should not influence this value. We, therefore, chose to present the uncorrected data. The AAA patients and the operated controls were well matched according to the size of operative trauma with respect to blood loss and operation time. However, a methodological problem was that the AAA patients were older than the operated controls and age is a factor known to correlate with tPA and D-dimer levels as well as with PAI- activity.17-20 In order to compensate for this age-missmatch at baseline, a healthy age-matched control group was chosen. When the control groups were pooled the analyses could confirm a positive correlation between age and tPA as well as D-dimer. However, the ideal control group would have been age matched with respect to AAA Fibrinolysis
Holmberg et al.
patients, undergoing major non-vascular surgery on other indications than malignancy, chronic inflammatory diseases and fracture since haemostatic factors are inlluenced by malignancy,21 chronic inflammation22~3 and fracture.24z25No such control group seemed to exist. There are studies where the influence of surgical trauma on fibrinolysis have been studied, such as laparotomy12.26.27and hip arthroplasty. 28,2gHowever, these patients were young, suffered from malignancies or underwent osteotomy, thus, all factors known to influence fibrinolysis. The observed elevation of the fibrinolytic activity in patients suffering from symptomatic peripheral arterial occlusive disease (PAOD)3s34may be caused by activating processes in arteriosclerotic vessels35and may correlate with the angiographic extent of the occlusive disease.36 In our study, there was no correlation between a decreased ankle brachial pressure index - as a parameter of PAOD - and the fibrinolytic parameters. However, in our sample there were only five patients with PAOD and, therefore, the contribution by PAOD to the fibrinolytic response could not be established. Preoperative hyperfibrinolysis has been reported earlier,37 especially in patients with a large mural intraaneurysmal thrombus,6 and parallels with high baseline activity of the coagulation system.6-8 The observations of tPA accumulation in the aneurysmal wall by scintigraphy38 as well as the findings of increased levels of both fibrinogen and D-dimer, 3gindicate a connection between the occurrence of AAA and activation of the fibrinolytic system. Probably this is due to a high fibrin turnover within the aneurysmal thrombus. AAA but not OC patients got 5000 units of unfractionated heparin intravenously during surgery. tPA levels have been shown to increase secondary to heparin administration40 and high-dose therapy for acute deep vein thrombosis decreases D-dimer levels,4’.42therefore, the observed differences between AAA and OC might have been underestimated. In connection with AAA surgery, a,-antiplasmin and plasminogen have been reported to decrease intraoperatively“3 as well as immediately postoperatively.7 Also, PAI1 has been found to decrease intraoperatively and increase immediately postoperatively.37 These findings may indicate an intraoperative activation of the fibrinolytic system but can also be interpreted as a consumption of a,-antiplasmin and thus indicate an inhibition. m the present study an intraoperative decrease in tissue plasminogen activator could be established. Also, there was an intraoperative increase of PAI-1. Moreover, no major increase in D-dimer was observed in spite of an extensive coagulation activation seen in another study by our group.6 Taken together, these observation constitutes strong evidence for an intraoperative fibrinolytic shut-down during AAA surgery. Fibrinotysis
The reaction patterns concerning tPA and PAI- may correlate to an activation of the inflammatory system, and increment of interleukind levels shown in a previous work by our group.44 PAI- has been found to behave like an acute phase reactant in vivo,45 and cytokines as well as endotoxin stimulate PAI- and inhibit tPA release by endothelial cells. 46.47 When these data are put together a connection between the inilammatoty response and the activity of fibrinolytic system may be suggested. When combining these data suggesting a fibrinolytic inhibition with the increased activity of the coagulation system previously shownh AAA patients seem to be in a strong prothrombotic as well as proinflammatory state during open aneurysmal repair. No difference between a,-antiplasmin levels in central and femoral venous blood was reported by Sommoggy et aLJ3 We found lower tPA and D-dimer levels in the systemic circulation than in femoral blood during aortic clamping. This may indicate a stronger fibrinolytic inhibition in the systemic circulation than in the lower part of the body distal to aortic clamping. The plasma levels of D-dimer and tPA in AAA patients increased relative base line values 1 week after surgery, while the PAI-1 levels returned to preoperative values within the reference interval. The D-dimer levels in OC patients also increased, but not to comparable values. High D-dimer levels have been observed 1 week after AAA [email protected]
after hepatic resection.” A possible interpretation of our results may be that the fibrinolytic system in AAA patients was activated 1 week postoperatively. In conclusion, an intraoperative tPA decrease, PAIincrease and only slightly influenced D-dimer, in spite of an extensive thrombin generation shown in an earlier study, strongly suggests an inhibition of the fibrinolytic system in AAA patients. The same reaction was not seen in OC patients. Thus, an ischaemia-reperfusion induced inhibition of the fibrinolytic activity may be suggested which may, in part, explain why patients undergoing open AAA repair are prone to thromboembolic complications. ACKNOWLEDGEMENTS
This study was financially supported by the Swedish Medical Research Council, U568-Ol A and 00759 as well as Swedish Heart and Lung Foundation and Uppsala University. We thank Birgitta Fahlstrom, Margareta Gulin and Dr Jie Chen for excellent technical assistance as well as Dietrich von Rosen for statistical advise and assistance. REFERENCES 1. Akkersdijk GJM, Craaf Y van der, Bockel JH van, Vries AC de, Eikelboom BC. Mortality rates associated with operative treatment of infrarenal abdominal aortic aneurysm in Netherlands. Br J Surg 1994; 8 I : 706-709.
Fibrinolysis in open abdominal aortic aneurysm surgery
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