Prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass surgery. A prospective randomised pilot study.

It has been suggested that preoperative fibrinogen plasma concentration is independently associated to postoperative blood loss after cardiac surgery. Theoretically, prophylactic infusion of fibrinogen concentrate may thus reduce postoperative bleeding, but this has not previously been investigated. Twenty elective coronary artery bypass graft (CABG) patients with preoperative plasma fibrinogen levels <3.8 g/l were included in a prospective randomised pilot study. Patients were randomised to receive an infusion of 2 g fibrinogen concentrate (FIB group) or no infusion before surgery (control group). Primary endpoint was safety with clinical adverse events and graft occlusion assessed by multi-slice computed tomography. Predefined secondary endpoints were postoperative blood loss, blood transfusions, haemoglobin levels 24 hours (h) after surgery, and global haemostasis assessed with thromboelastometry, 2 and 24 hours after surgery. Infusion of 2 g fibrinogen concentrate increased plasma levels of fibrinogen by 0.6 +/- 0.2 g/l. There were no clinically detectable adverse events of fibrinogen infusion. Computed tomography revealed one subclinical vein graft occlusion in the FIB group. Fibrinogen concentrate infusion reduced postoperative blood loss by 32% (565 +/- 150 vs. 830 +/- 268 ml/12 h, p=0.010). Haemoglobin concentration was significantly higher 24 h after surgery in the FIB group (110 +/- 12 vs. 98 +/- 8 g/l, p=0.018). Prophylactic fibrinogen concentrate infusion did not influence global postoperative haemostasis as assessed by thromboelastometry. In conclusion, in this pilot study preoperative fibrinogen concentrate infusion reduced bleeding after CABG without evidence of postoperative hypercoagulability. Larger studies are necessary to ensure safety and confirm efficacy of prophylactic fibrinogen treatment in cardiac surgery.

Plasma fibrinogen level, bleeding, and transfusion after on-pump coronary artery bypass grafting surgery: a prospective observational study.

BACKGROUND: Early identification of patients with increased risk of excessive bleeding and transfusion after cardiac surgery offers the possibility to initiate countermeasures. Fibrinogen is a key protein in the coagulation cascade and thus a potential biomarker for bleeding. We investigated the relationship between preoperative fibrinogen plasma concentration and postoperative bleeding and transfusion after coronary artery bypass grafting (CABG). STUDY DESIGN AND METHODS: A total of 170 patients (mean age, 67 +/- 9 years; 75% men) undergoing isolated CABG were included in a prospective observational study. Patient variables (age, sex, operation time, anticoagulation therapy), preoperative laboratory variables (platelet [PLT] count, activated partial thromboplastin time, prothrombin time, and fibrinogen), postoperative bleeding volume, and transfusions during hospital stay were registered. Independent predictors of bleeding volume and transfusion were identified with multiple regression models. RESULTS: Postoperative bleeding volume correlated univariately with preoperative fibrinogen concentration (r = -0.53, p < 0.001) and PLT count (r = -0.26, p = 0.001) but only preoperative fibrinogen concentration was an independent predictor of postoperative bleeding volume. Twenty-nine of the 170 patients (17%) received transfusions with blood products. Independent predictors of transfusion were preoperative fibrinogen concentration (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.1-3.7 per 1-unit decrease; p = 0.027), female sex (OR, 5.0; 95% CI, 1.8-14.7; p = 0.002), and aortic cross-clamp time (OR, 1.03; 95% CI, 1.01-1.06 per minute; p = 0.013). CONCLUSION: The results indicate that preoperative fibrinogen concentration (even within the normal range) is a limiting factor for postoperative hemostasis. Preoperative measurement of fibrinogen concentration provides information about bleeding volume and transfusion requirements after CABG.

Release of PMN elastase, TGF-beta1 and neopterin during blood storage; unfiltered versus filtered blood.

Release of inflammatory mediators from blood cells during prestorage leukocyte filtration may result in recipient immune suppression. To investigate the effects of prestorage leukocyte filtration on the quality of blood components, twenty-four blood units were collected from healthy donors and randomised into 3 groups. Eight units were stored as whole blood, eight units were separated into plasma, red blood cells (RBC) and buffy coat and eight units were collected and filtered through the ASAHI RZ 2000 leukocyte filter and separated into plasma and RBC. The units were stored for 35 days. Samples were collected weekly for analyses of polymorphonuclear elastase (PMN elastase), transforming growth factor-beta1 (TGF-beta1) and neopterin. PMN elastase and neopterin increased during storage of whole blood and RBC. From the beginning and throughout storage, PMN elastase was increased in filtered plasma as compared with unfiltered plasma. Filtration per se did not influence the neopterin concentration in plasma or RBC. TGF-beta1 increased in plasma and RBC during storage. In filtered plasma, an elevation of the TGF-beta1 concentration was observed from the start of storage. The TGF-beta1 levels were higher in filtered plasma compared with unfiltered plasma. Prestorage leukocyte filtration increased the release of PMN elastase and TGF-beta1 in plasma and RBC.

Recombinant activated factor VII in the management of life-threatening bleeding in cardiac surgery.

OBJECTIVE: Massive perioperative bleeding is a potential complication of cardiac surgery, and may persist despite conventional interventions. RFVIIa is being increasingly used as additional therapy, and the aim of the present study was to describe our experience with rFVIIa in the management of life-threatening bleeding in adult cardiac surgery. METHODS: Retrospective chart review of 24 patients undergoing a variety of cardiac procedures was performed at Sahlgrenska University Hospital between January and August 2004. The patients developed life-threatening bleeding during or after surgery despite conventional medical therapy and transfusion of blood products, and received rFVIIa as additional therapy. RESULTS: RFVIIa was administered as a median bolus dose of 60 microg/kg. Nineteen patients received one dose of rFVIIa; the bleeding stopped or decreased in 18 of them. Five patients received repeated doses of rFVIIa. Fifteen patients were reexplored due to massive postoperative bleeding or cardiac tamponade and a surgical source of bleeding was identified in six of these patients. A statistically significant reduction in chest drain losses after administration of rFVIIa was demonstrated. No adverse reactions were noted. CONCLUSIONS: RFVIIa was successfully used as an additional therapy both during and after cardiac surgery, when bleeding was refractory to conventional methods. Bleeding stopped eventually in all patients and none of the patients exsanguinated.

Autologous blood transfusion in radical hysterectomy with and without erythropoietin therapy.

OBJECTIVE: To investigate whether preoperative treatment with erythropoietin facilitates the collection of a sufficient amount of autologous blood in a short period of time. METHODS: Forty-one women scheduled for radical hysterectomy were randomized to preoperative autologous blood donation with or without preoperative recombinant human erythropoietin therapy. All patients were scheduled to deposit three units of blood within 2 weeks before surgery. Hemoglobin, erythrocyte volume fraction, blood cells, iron status, and hemolysis were analyzed before and after surgery. RESULTS: Hemoglobin levels decreased continuously in both groups after the first autologous donation until day 1 postoperatively. With erythropoietin therapy, the erythrocyte volume fraction and hemoglobin levels were significantly higher during precollection and day 1 after surgery. Preoperatively, the drop was 12 g/L less in the erythropoietin-treated group. The additional use of erythropoietin therapy reduced the inability of patients to predeposit blood from 17.8% to 3.4%. CONCLUSION: Most women can predeposit three units of whole blood in only 2 weeks without obtaining severe anemia. By treating women with erythropoietin, one out of seven can be prevented from a hemoglobin level below the 100 g/L limit for donation.

A structured blood conservation programme reduces transfusions and costs in cardiac surgery.

OBJECTIVES: Transfusions of blood products can be lifesaving, but they are also associated with considerable risks and adverse effects, including immune response and infections. In cardiac surgery, transfusions have also been associated with increased mortality. We prospectively studied the effects of a structured programme to reduce transfusions and transfusion-associated costs in cardiac surgery. METHODS: The programme included: (i) education of all staff about the risks and benefits of blood transfusions; (ii) revised guidelines for transfusions; and (iii) a transfusion log where indication for transfusion, status of the patient and prescribing physician were registered. Transfusion prevalence, complications and costs for blood products were registered for all acute and elective cardiac operations during a 12-month period before (n = 1128) and after (n = 1034) the programme was started. The two time periods were compared. In addition, the prevalence of transfusions was registered for 2 more years after the programme was initiated. RESULTS: The first year after the programme was initiated the proportion of patients transfused with red blood cell concentrate decreased by 21.8% (from 58.2 to 45.5%, P <0.001), plasma by 37.4% (from 30.8 to 19.3%, P <0.001) and platelets by 21.0% (from 20.5 to 16.2%, P = 0.010). Reoperations for bleeding (5.8 vs 5.0%), early complication rate and 30-day mortality (2.5 vs 2.6%) were not significantly different before and after the start date. Based on the 2009 institutional prices for red blood cell concentrate (102 €/unit), plasma (35 €/unit) and platelets (290 €/unit), the savings on blood products were €161,623 during the first 12 months after the programme was launched. The proportion of patients transfused with any blood product was 60.9% before the programme was started and 48.3, 54.0 and 50.7% 1-3 years after its start (all P <0.001), respectively. CONCLUSIONS: A structured blood conservation programme reduces transfusions and costs for blood products in cardiac surgery, without any signs of compromised medical safety. The effects of introducing such a programme are maintained over at least 3 years.

Sustained heparin effect contributes to reduced plasma thrombin generation capacity early after cardiac surgery.

INTRODUCTION: Thrombin is a key component in the coagulation cascade, and impaired thrombin generation has been linked to increased bleeding after surgical procedures. The aim was to evaluate postoperative thrombin generation capacity in plasma after cardiac surgery, and its potential associations to activity of individual coagulation factors and heparin. MATERIAL AND METHODS: Forty-eight coronary artery bypass grafting patients were included in a prospective observational cohort study. Thrombin generation capacity was analysed in plasma with calibrated automated thrombogram with tissue factor as activator before (baseline), and 2 h and 24 h after surgery. In addition, plasma activity of coagulation factors II, V, VII, VIII, IX, X, XI, XIII, were determined. Heparin effect was assessed by anti-Xa activity, APTT and thrombin time. RESULTS: Thrombin generation was markedly reduced 2h after surgery compared to baseline. Peak levels decreased with median 74% (interquartile range 52-90), p<0.001, and endogenous thrombin generation potential decreased with 65% (43-86), p<0.001. Postoperative changes in endogenous thrombin generation potential correlated inversely to changes in anti-Xa activity (r=-0.51, p=0.010) and to changes in thrombin time (r=-0.51, p=0.009), but there were no correlations to changes in individual coagulation factor activity. CONCLUSIONS: A marked reduction in thrombin generation potential was observed in the early postoperative phase after cardiac surgery. The decrease was independent of reductions in individual coagulation factor activity but correlated to heparin effects. The results indicate that a sustained heparin effect contributes to the postoperative reduction in thrombin generation capacity.

Prophylactic fibrinogen infusion in cardiac surgery patients: effects on biomarkers of coagulation, fibrinolysis, and platelet function.

OBJECTIVE: We have recently reported that prophylactic fibrinogen infusion reduces bleeding after coronary artery bypass grafting (CABG) surgery. Because fibrinogen for the first time was administered to patients without hereditary fibrinogen deficiency or ongoing bleeding, a detailed analysis of the effects of fibrinogen concentrate on biomarkers of coagulation, fibrinolysis, and platelet function was performed. METHODS: Twenty CABG patients with preoperative plasma fibrinogen levels <3.8 g/L were included in a prospective study. Patients were randomized to preoperative infusion of 2 g fibrinogen concentrate (fibrinogen group) or no infusion (control group). Activated partial thromboplastin time (aPTT), prothrombin time, activated clotting time, and plasma concentrations of fibrinogen, antithrombin, thrombin-antithrombin complex, prothrombin fragment 1.2, and D-dimer, thromboelastometry, platelet count, and platelet aggregometry were analyzed before and 15 minutes after infusion, and 2 and 24 hours after surgery. RESULTS: Fifteen minutes after infusion of fibrinogen concentrate, fibrinogen plasma levels increased by 0.6 ± 0.2 g/L (P < .001 between groups), and induced minimal changes in aPTT and plasma levels of antithrombin, while remaining variables remained unchanged. After surgery, fibrinogen levels no longer differed between groups. D-dimer was significantly higher after surgery in the fibrinogen group (P = .03), while none of the other markers were statistically different between groups. CONCLUSIONS: Infusion of 2 g fibrinogen to cardiac surgery patients, without hereditary or acquired fibrinogen deficiency or ongoing bleeding, results in no or minimal changes in biomarkers reflecting coagulation and platelet function. An increased release of fibrin degradation products was detected after surgery in fibrinogen-treated patients.

Plasma activity of individual coagulation factors, hemodilution and blood loss after cardiac surgery: a prospective observational study.

BACKGROUND: Hemodilution and consumption of coagulation factors during cardiopulmonary bypass has been suggested to contribute to bleeding complications after cardiac surgery. The aim was to describe the activity of individual coagulation factors after CABG in relation to hemodilution and postoperative bleeding. MATERIALS AND METHODS: Plasma concentrations of fibrinogen and plasma activity of FII, FV, FVII, FVIII, FIX, FX, FXI and FXIII adjusted for hemodilution were analysed in 57 CABG patients before, and 2h and 24h after surgery. Postoperative bleeding was registered and correlations to coagulation factor activity were calculated. RESULTS: Adjusted plasma concentration of fibrinogen (-14+/-6%), and plasma activity of FII (-9+/-6%), FV (-13+/-8%), FX (-13+/-7%) and FXIII (-9+/-14%) were reduced two hours after surgery compared to baseline (all p<0.001). FVII (+3+/-12%, p=0.34) and FXI (+1+/-19%, p=0.50) were unchanged, while FVIII (+23+/-44%, p=0.006) and FIX (+23+/-17%, p<0.001) increased. Twenty-four hours after surgery fibrinogen (+45+/-27%), FVIII (+93+/-66%) and FIX (+33+/-26%) were all increased (all p<0.001), while FVII (-37+/-14%, p<0.001), FXI (-4+/-18%, p=0.02) and FXIII (-6+/-15%, p=0.004) were decreased. Median postoperative blood loss was 380 ml/12h. There were significant inverse correlations between postoperative blood loss and fibrinogen concentration 2h after surgery (r=-0.33, p=0.019) and between postoperative blood loss and pre- and postoperative FXIII activity (r=-0.34, p=0.009 and r=-0.41, p=0.003, respectively), but not between blood loss and any of the other factors. CONCLUSIONS: There is a marked dissociation in plasma activity of individual coagulation factors after CABG. Plasma concentration of fibrinogen and factor XIII activity correlates inversely to postoperative blood loss after CABG.