Radical prostatectomy has been shown to improve disease-specific survival in randomized trials and represents the most common therapeutic option for the curative treatment of localized prostate cancer . Despite important advances in surgical techniques during the last 25 yr and introducing vessel- and nerve-sparing methods, intra- and postoperative bleeding is still one of the most important complications associated with this operation [2,3]. The risk of bleeding has been related to the surgical trauma of the prostatic dorsal venous plexus and to the activation of the fibrinolytic system. The high concentration of tissue type plasminogen activator (t-PA) in the prostate gland, in combination with the constant flow of urine containing urokinase over the prostatic cavity both promoting the formation of plasminogen is believed to be the rationale for local and systemic activation of the fibrinolytic system .
When antifibrinolytic drugs became clinically available about 20 yr ago, several authors studied the efficacy of administering them to reduce massive haemorrhage in the perioperative period of prostatic surgery [5-7]. However, those results were conflicting and many have debated whether antifibrinolytic therapy increases the risk of postoperative thromboembolism . General concerns about the use of antifibrinolytic drugs rose due to the report of an elevated rate of renal and cardiovascular complications after the use of aprotinin in cardiovascular surgery . Routine use of antifibrinolytic drugs in patients undergoing surgery of the prostate nowadays is not recommended .
Patients for oncological surgery are generally believed to be at high risk for thromboembolic complications . Recently, the procedure of prostatectomy itself has been associated with a hypercoagulable state. So Bell and colleagues [12,13] demonstrated the activation of coagulation and a consequent hypercoagulable state after transurethral prostatectomy for both malignant and benign prostatic disease. The American College of Chest Physicians classified retropubic prostatectomy as a category 1 (high risk) procedure for venous thromboembolism . On the other hand, fearing an increased risk of haemorrhagic complications, prophylactic low-dose subcutaneous heparin is not routinely used everywhere, and patients on low-dose aspirin are often made to stop the therapy perioperatively [15,16].
Testing of the complete coagulation status would be useful to balance the individual risk of bleeding with that of hypercoagulation resulting in a higher risk of cardiac complications. Thromboelastography (TEG®; Haemoscope Corporation, Skokie, IL, USA) is a sensitive method which measures thrombus formation, the stability and firmness of the clot, as a function of platelet–fibrin interaction and fibrin polymerization, as well as fibrinolysis. Thus it provides overall information of the coagulatory and fibrinolytic status, whereas the single parameters prothrombin time (PT), a partial thromboplastin time (aPTT) or fibrinogen is performed on centrifuged plasma without taking into consideration platelets and red blood cells . The presumed superiority of TEG® over conventional coagulation tests relies on the real-time availability, whereas basic homeostasis testing in central laboratories may easily be longer than 1 h. Despite its obvious advantages, TEG® has always caused some debate because it has never undergone all the validation procedures mandatory for conventional haemostasis tests and its use is not fully standardized. Nevertheless TEG® can be found in many operating departments, especially in the field of cardiac surgery and liver transplants where it helps to guide transfusion of blood products or the use of antifibrinolytic therapy [18-21]. However, little is known about the use of TEG® to monitor the tendency towards fibrinolysis or hypercoagulation during urologic surgery .
We conducted this prospective, observational multi-centre study to assess changes in the coagulation status and define the degree of systemic fibrinolysis or hypercoagulation in the perioperative period. We studied serial changes in standard laboratory values such as PT, international normalized ratio (INR), PTT, fibrinogen, D-dimers and platelet count and in TEG® parameters including lysis at 30 and 60 min (LY-30, LY-60), alpha-angle (α) and maximum amplitude (MA). Furthermore, we looked to see if the standard coagulation indices showed a correlation with the TEG® values.
Following approval by the local Ethics Committees of five Italian University hospitals, and with the patients' written, informed consent, 49 patients, aged 62 ± 5 yr (BMI: 26.3 ± 3.2) undergoing radical retropubic prostatectomy were prospectively included. Patients with abnormal preoperative coagulation screening (PT, international normalized ratio (INR), PTT and platelet count), known coagulopathies or hepatic disorders were excluded from the study. Atraumatic antecubital venous whole-blood samples were taken using a two-syringe technique to avoid bias by locally released t-PA. Native whole-blood samples for TEG measurements were analysed within 6 min after venesection using a thrombelastograph Haemoscope 5000 (Haemoscope Corporation).
Blood samples were taken before surgery (T1), at removal of the prostate (T2), 4–6 h after surgery (T3) and then 1 day after surgery (T4). All patients received ampicillin/sulbactam 3 g i.v. half an hour before the start of the operation. Radical prostatectomy was performed under general anaesthesia induced with propofol (2 mg kg−1), fentanyl (2 μg kg−1), muscle relaxation with atracurium (0.5 mg kg−1) and maintenance with sevoflurane in oxygen and air. No epidural catheters were placed to avoid interaction between the local anaesthetic and the calcium channels of platelets, which could hamper the aggregation of thrombocytes .
All patients were covered with a forced air warming system (Bair Hugger, Arizant, Eden Prairie, MN, USA) and fluids were warmed before infusion.
Perioperative thromboembolic prophylaxis with low-molecular-weight heparin (LMWH) 2500–5000 IU was routinely performed from the day before surgery onwards.
Statistical analysis was performed using SPSS version 15.0 (SPSS, Chicago, IL, USA). The distribution of data was first evaluated using the Kolmogorov–Smirnov test. To compare continuous parametric data with normal distribution, analysis of variance for repeated measures was used; a Tukey's test was used for posthoc analysis. Non-normally distributed data were analysed with the non-parametric test of Friedman; a Dunnett's test was used for posthoc analysis. Correlation and linear regression analysis have also been used where indicated.
Continuous variables are presented as mean ± SD and/or 95% CI for normally distributed data, or median (range) for non-normally distributed data. Categorical variables are presented as numbers. A value of P < 0.05 was considered significant.
As shown in Figure 1a, b, we found no evidence of hyperfibrinolysis (TEG LY-30 >8%; LY-60 >15%) at any stage. LY-30 and LY-60 values decreased intraoperatively and returned in the following period until T4 to a value slightly higher than baseline. Similarly, for fibrinogen an initial decline followed by a rise was observed (Fig. 1e). We saw a marked decrease of fibrinogen intraoperatively (P < 0.01), but it was still within the normal range. A correlation was seen between fibrinogen and LY-60 (P = 0.001). There was no relevant variation in values of α-angle or MA, which remained within the normal range throughout the whole period (Fig. 1c, d). Both parameters showed a high correlation with aPTT values (P < 0.001). MA values were also significantly associated with the fibrinogen values (P < 0.05). D-dimers increased significantly above the normal range until T3 (P < 0.01) and then decreased to the 1.7-fold basal value within the upper level of the normal range at T4 (Fig. 1f). PT values peaked above normal values intraoperatively and decreased slowly to a still significantly higher value at T4 than the preoperative mean value (P < 0.01, respectively) (Fig. 1g). Preoperative PTT values were elevated, indicating hypocoagulation (Fig. 1h). The PTT mean fell significantly during surgery and then increased again at the following sample points without reaching the mean preoperative value. Median (range) platelet count decreased constantly from 209 × 103 μL−1 (149 – 259 × 103 μL−1) to 170 × 103 μL−1 (119 – 270 × 103 μL−1) (P < 0.001).
In this study, we did not see any clinically relevant activation of fibrinolysis at any stage. Intraoperatively we found more activation of blood coagulation with the consumption of fibrinogen and a reduced TEG® percentage clot lysis. The elevated preoperative PTT values, which might be due to the first dose of LMWH given the evening before surgery, also fell significantly during surgery indicating a shift to a more hypercoagulable state. Enhanced intraoperative coagulation might be not only an effect of the stress response induced by surgery but also a result of haemodilution. Intraoperatively, 3100 ± 800 mL of crystalloids were infused and haematocrit levels fell from 44.3 ± 2.8% to 31.6 ± 5.4% (Fig. 1i). Crystalloid haemodilution has been widely described to enhance the coagulation onset , and Ruttman and colleagues  found a correlation of this effect within the duration of haemodilution.
Only at the first postoperative sample point did we see a trend to a more fibrinolytic state indicated by increasing PTT, LY-30 and LY-60 values and a peak of the fibrin degradation product D-dimers. This is consistent with a normal reaction to the hypercoagulable state before and is unlikely to be due to an intraoperative t-PA release. Activation of fibrinolysis in the context of prostate manipulation should be seen within 1 h after organ removal as t-PA has a serum half-life of 5 min and its effects on the clot persist only for an hour .
We found no evidence for an uncontrolled activation of fibrinolysis on the day after surgery either. On the contrary, α-values that indicate the rate of clot formation and increase during hypercoagulation showed the tendency to rise slightly compared with the preoperative value. Also the MA value, which reflects the qualitative and quantitative properties of the clot-forming components, firstly decreased slightly then returned to an insignificantly higher value the day after surgery.
Platelets showed a constant reduction probably due to consumption and haemodilution, but never fell below the critical level of 30 000 μL−1. The mean blood loss was 1200 ± 800 mL. In all, 90% of the patients needed to be transfused with a median of 2 (0–6) units of whole blood. We had no major problems of postoperative bleeding requiring re-intervention in our study. In all, seven patients (14%) were transfused with 1 unit within the 24 h after surgery.
Our results are in accordance with the results of the TEG evaluation of coagulation in transurethral prostatectomy reported by Bell and colleagues [12,13]. Systemic activation of fibrinolysis did not appear to be of any clinical relevance; however, it might appear locally at the denuded prostatic cavity [4,26].
In contrast, the hypercoagulable prothrombotic state associated with prostatectomy seems to have an important impact on the outcome after retropubic prostatectomy. Three large case series [27-29] have examined causes of death within 30 days of radical prostatectomy and showed that cardiovascular diseases (in particular myocardial infarction) and pulmonary embolism were the most common causes of death. In our study, we had no case of cardiovascular complication such as myocardial infarction, pulmonary embolism or clinically evident deep venous thrombosis. The reported incidence of postoperative cardiac mortality within 30 days is about 0.18%, the rate of pulmonary embolism ranges between 0.06–0.6% and 0.21–2.1% for deep venous thrombosis, so these complications may not be present among a study group of 49 patients [15,27,28,30].
To balance the individual risk of bleeding with that of cardiac complications, it would be important to analyse the overall coagulation state of every single patient. This could help decide adequate anti-thromboembolic therapy with LMWH, the re-administration of aspirin in cardiac patients or consider alternative prophylaxis such as sequential compression devices in patients at risk of bleeding. TEG®, which provides a rapid assessment of the global coagulation state, could also help monitor the effect of drugs that affect coagulation. Its use to control therapy with LMWH has been demonstrated while there is no clear evidence for good control of aspirin-induced effects [31,32].
In conclusion, neither standard coagulation parameters nor TEG® values showed a significant activation of fibrinolysis or of hypercoagulation in the perioperative period. Nevertheless, hypercoagulation seems to have a substantial clinical impact resulting in fatal cardiovascular complications. Our study showed that TEG® values give a good estimation of the blood coagulation/fibrinolysis state during and in the first 24 h after retropubic prostatectomy. TEG® deserves a new evaluation as an easy to perform near-patient test of haemostasis for non-hepatic and non-cardiac surgery.
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