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1.  Use of prothrombin complex concentrate for excessive bleeding after cardiac surgery 
Prothrombin complex concentrates (PCCs) are sometimes used as ‘off label’ for excessive bleeding after cardiopulmonary bypass (CPB). The main objective of this study was to retrospectively evaluate the clinical and biological efficacy of PCC in this setting.
We reviewed the charts of all patients who had undergone cardiac surgery under CPB in our institution for 2 years. Patients treated for active bleeding with haemostatic therapy were identified. Chest tube blood loss was quantified postoperatively in the first 24 h. Coagulation parameters were recorded at intensive care unit admission and in the patient's first 24 h. Thromboembolic complications were also ascertained.
Seventy-seven patients out of the 677 studied (11.4%) were included: PCC was solely administered in 24 patients (group I), fresh frozen plasma in 26 (group II) and both in 27 (group III). The mean dose of PCC was 10.0 UI/kg ± 3.5 for group I vs 14.1 UI/kg ± 11.2 for group III (P = 0.09). Initial blood loss in the first hour was different between the three groups (P = 0.05): 224 ± 131 ml for group I, 369 ± 296 ml for group II and 434 ± 398 ml for group III. Only group I vs group III presented a significant difference (P = 0.02). Variations of blood loss over time were no different according to the treatment groups (P = 0.12). Reductions in blood loss expressed in percentage showed no difference between the three groups after 2 h: 54.5% (68.6–30.8) for group I; 45.0% (81.6–22.2) for group II; 57.6 (76.0–2.1) for group III; (P = 0.89). Re-exploration for bleeding involved 1 patient in group I (4%), 2 in group II (8%) and 10 in group III (37%) (P = 0.002). Except for fibrinogen, variations of prothrombin time, activated partial thromboplastin time and platelets with time were not different according to the treatment groups. Cerebral infarction occurred in one patient in group II.
Administration of low-dose of PCC significantly decreased postoperative bleeding after CPB.
PMCID: PMC3422937  PMID: 22623627
Prothrombin complex concentrates; Bleeding; Cardiopulmonary bypass; Thromboembolic complications
2.  Role of prothrombin complex concentrate in perioperative coagulation therapy 
Prothrombin complex concentrate (PCC) is a term to describe pharmacological products that contain lyophilized, human plasma-derived vitamin K-dependent factors (F), FII, FVII, FIX, FX, and various amounts of proteins C and S. PCCs can be rapidly reconstituted in a small volume (20 ml for about 500 international units (IU)) at bedside and administered regardless of the patient’s blood type. PCCs are categorized as 4-factor PCC if they contain therapeutic amounts of FVII, and 3-factor PCC when FVII content is low. In addition, activated PCC which contains activated FVII and FX with prothrombin is available for factor VIII bypassing therapy in hemophilia patients with inhibitors. Currently, 4-factor PCC is approved for the management of bleeding in patients taking warfarin, but there has been increasing use of various PCCs in the treatment of acquired perioperative coagulopathy unrelated to warfarin therapy and in the management of bleeding due to novel oral anticoagulants. There is also an ongoing controversy about plasma transfusion and its potential hazards including transfusion-related lung injury (TRALI). Early fixed ratio plasma transfusion has been implemented in many trauma centers in the USA, whereas fibrinogen concentrate and PCC are preferred over plasma transfusion in some European centers.
In this review, the rationales for including PCCs in the perioperative hemostatic management will be discussed in conjunction with plasma transfusion.
PMCID: PMC4336276  PMID: 25705417
Coagulation; Fresh frozen plasma; Prothrombin complex concentrate; Recombinant activated factor VII; Factor eight bypassing agent; Thromboelastometry
3.  Prothrombin complex concentrate vs fresh frozen plasma for reversal of dilutional coagulopathy in a porcine trauma model 
BJA: British Journal of Anaesthesia  2009;102(3):345-354.
Fluid resuscitation following traumatic injury causes haemodilution and can contribute to coagulopathy. Coagulation factor replacement may be necessary to prevent bleeding complications of dilutional coagulopathy. Compared with fresh frozen plasma (FFP), prothrombin complex concentrate (PCC) may potentially offer a more rapid and effective means of normalizing coagulation factor levels.
In anaesthetized mildly hypothermic pigs, 65–70% of total blood volume was substituted in phases with hydroxyethyl starch and red cells. Animals were then treated with 15 ml kg−1 isotonic saline placebo, 25 IU kg−1 PCC, or 15 ml kg−1 FFP. Immediately thereafter, either a standardized femur or spleen injury was inflicted, and coagulation function, including thrombin generation, and bleeding were assessed. An additional group received high-dose FFP (40 ml kg−1) before femur injury.
Haemodilution markedly prolonged prothrombin time and reduced peak thrombin generation. PCC, but not FFP, fully reversed those effects. Compared with 15 ml kg−1 FFP, PCC shortened the time to haemostasis after either bone (P=0.001) or spleen (P=0.028) trauma and reduced the volume of blood lost (P<0.001 and P=0.015, respectively). Subsequent to bone injury, PCC also accelerated haemostasis (P=0.003) and diminished blood loss (P=0.006) vs 40 ml kg−1 FFP.
PCC was effective in correcting dilutional coagulopathy and controlling bleeding in an in vivo large-animal trauma model. In light of its suitability for more rapid administration than FFP, PCC merits further investigation as a therapy for dilutional coagulopathy in trauma and surgery.
PMCID: PMC2642652  PMID: 19168856
blood, haemodilution; complications, haemorrhagic disorder; complications, trauma; fresh frozen plasma; prothrombin complex concentrate
4.  Prediction of Post-Weaning Fibrinogen Status during Cardiopulmonary Bypass: An Observational Study in 110 Patients 
PLoS ONE  2015;10(5):e0126692.
After cardiac surgery with cardiopulmonary bypass (CPB), acquired coagulopathy often leads to post-CPB bleeding. Though multifactorial in origin, this coagulopathy is often aggravated by deficient fibrinogen levels.
To assess whether laboratory and thrombelastometric testing on CPB can predict plasma fibrinogen immediately after CPB weaning.
Patients / Methods
This prospective study in 110 patients undergoing major cardiovascular surgery at risk of post-CPB bleeding compares fibrinogen level (Clauss method) and function (fibrin-specific thrombelastometry) in order to study the predictability of their course early after termination of CPB. Linear regression analysis and receiver operating characteristics were used to determine correlations and predictive accuracy.
Quantitative estimation of post-CPB Clauss fibrinogen from on-CPB fibrinogen was feasible with small bias (+0.19 g/l), but with poor precision and a percentage of error >30%. A clinically useful alternative approach was developed by using on-CPB A10 to predict a Clauss fibrinogen range of interest instead of a discrete level. An on-CPB A10 ≤10 mm identified patients with a post-CPB Clauss fibrinogen of ≤1.5 g/l with a sensitivity of 0.99 and a positive predictive value of 0.60; it also identified those without a post-CPB Clauss fibrinogen <2.0 g/l with a specificity of 0.83.
When measured on CPB prior to weaning, a FIBTEM A10 ≤10 mm is an early alert for post-CPB fibrinogen levels below or within the substitution range (1.5–2.0 g/l) recommended in case of post-CPB coagulopathic bleeding. This helps to minimize the delay to data-based hemostatic management after weaning from CPB.
PMCID: PMC4444179  PMID: 26011420
5.  Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital 
Critical Care  2008;12(4):R105.
Major blood loss can often be life-threatening and is most commonly encountered in the settings of surgery and trauma. Patients receiving anticoagulant therapy are also at increased risk of bleeding. We investigated the use of a prothrombin complex concentrate (PCC; Beriplex P/N, CSL Behring, Marburg, Germany) to treat severe bleeding in a variety of settings: cardiac surgery, warfarin therapy and other surgery.
Thirty consecutive patients who had received PCC were identified from blood transfusion records. For cardiac surgery and warfarin reversal, PCC was administered in accordance with hospital protocols. PCC was administered to cardiac and other surgical patients responding poorly to recognized blood products, whereas it was administered first-line to patients with life-threatening bleeds and requiring warfarin reversal, in accordance with British Committee for Standards in Haematology guidelines. We conducted a retrospective analysis of patient records in order to ascertain PCC dose, use of other blood products and response to PCC (clotting screen results before and after PCC administration, haemostasis achievement, and survival).
Six patients (20%) were excluded because of inadequate documentation (n = 5) or acquired haemophilia (n = 1). Therefore, 24 patients were included in the analysis: coronary artery bypass graft (n = 5), mitral/aortic valve replacement (n = 2), other surgery (n = 9) and warfarin reversal (n = 8). Most patients (83.3%) received no more than 1500 IU of Beriplex P/N 500. Considerable reduction in administration of other blood products was seen during the 24 hours after PCC administration. Partial or complete haemostasis was achieved in 14 out of 18 cases (77.8%). In total, 12 out of 24 patients (50%) died during the study; two-thirds of the deaths were considered unrelated to bleeding. No thrombotic complications or adverse drug reactions were observed.
This study emphasizes the value of PCC in reversing the effects of oral anticoagulant therapy in bleeding patients. It also demonstrates the potential value of PCC in controlling bleeding in patients undergoing cardiac and other surgical procedures. The use of PCC in bleeding patients without hereditary or anticoagulation-related coagulopathy is novel, and further investigation is warranted. In the future, it may be possible to use PCC as a substitute for fresh frozen plasma in this setting; adequate documentation is crucial for all blood products.
PMCID: PMC2575594  PMID: 18706082
6.  Time course of haemostatic effects of fibrinogen concentrate administration in aortic surgery 
BJA: British Journal of Anaesthesia  2013;110(6):947-956.
There is currently a contrast between the demonstrated benefits of fibrinogen concentrate in correcting bleeding and reducing transfusion, and its perceived thrombogenic potential. This analysis evaluates the effects of fibrinogen concentrate on coagulation up to 12 days after administration during aortic surgery.
We performed a post hoc analysis of a prospective, randomized, double-blind, controlled trial of fibrinogen concentrate as first-line haemostatic therapy in aortic surgery. After cardiopulmonary bypass (CPB) and protamine administration, subjects with coagulopathic bleeding received fibrinogen concentrate or placebo. The placebo group received allogeneic blood products, including fresh-frozen plasma (FFP; n=32); the fibrinogen concentrate group received fibrinogen concentrate alone (FC; n=14), or fibrinogen concentrate followed by allogeneic blood products (FC+FFP; n=15). Plasma fibrinogen, fibrin-based clotting (ROTEM®-based FIBTEM assay), and peri- and postoperative haematological and coagulation parameters were compared.
Plasma fibrinogen and FIBTEM maximum clot firmness (MCF) decreased ∼50% during CPB but were corrected by FC or FC+FFP. At last suture, the highest values for plasma fibrinogen (360 mg dl−1) and FIBTEM MCF (22 mm) were within normal ranges—below the acute phase increases observed after surgery. In patients receiving only FFP as a source of fibrinogen, these parameters recovered marginally by last suture (P<0.001 vs FC and FC+FFP). All groups displayed comparable haemostasis at 24 h post-surgery. Fibrinogen concentrate did not cause alterations of other haemostasis parameters.
Fibrinogen concentrate provided specific, significant, short-lived increases in plasma fibrinogen and fibrin-based clot firmness after aortic surgery.
PMCID: PMC3657602  PMID: 23388508
blood coagulation tests; cardiopulmonary bypass; fibrin; fibrinogen; plasma
7.  Fibrinogen concentrate administration attributes to significant reductions of blood loss and transfusion requirements in thoracic aneurysm repair 
Repair of thoracic aortic aneurysm (TAA) is often associated with massive hemorrhage aggravated by dilutional coagulopathy with severe hypofibrinogenemia. Although only fresh frozen plasma (FFP) is available for acquired hypofibrinogenemia in Japan, the hemostatic effect of FFP has not been enough for dilutional coagulopathy in TAA surgery. There are increasing reports suggesting that fibrinogen concentrate may be effective in controlling perioperative bleeding and reducing transfusion requirements.
We retrospectively analyzed the hemostatic effect of fibrinogen concentrate compared with FFP in total 49 cases of elective TAA surgery. In 25 patients, fibrinogen concentrate was administered when the fibrinogen level was below 150 mg/dL at the cardiopulmonary bypass (CPB) termination. The recovery of fibrinogen level, blood loss, and transfused units during surgery were compared between cases of this agent and FFP (n = 24).
We observed rapid increases in plasma fibrinogen level and subsequent improvement in hemostasis by administration of fibrinogen concentrate after CPB termination. The average volume of total blood loss decreased by 64% and the average number of transfused units was reduced by 58% in cases of fibrinogen concentrate given, in comparison with cases of only FFP transfused for fibrinogen supplementation.
In patients showing severe hypofibrinogenemia during TAA surgery, timely administration of fibrinogen concentrate just after removal from CPB is effective for hemostasis, and therefore in reducing blood loss and transfused volumes.
PMCID: PMC4067735  PMID: 24884627
Massive hemorrhage; Thoracic aortic aneurysm; Cardiopulmonary bypass; Dilutional coagulopathy; Hypofibrinogenemia
8.  Comparison of single lung transplant with and without the use of cardiopulmonary bypass† 
Many centres avoid using cardiopulmonary bypass (CPB) for lung transplant due to concerns over aggravated lung reperfusion injury and excessive blood loss. We reviewed our 23-years’ experience of single lung transplantation.
A retrospective review of single lung transplants at our institution (1987–2010), examining differences in allograft function and postoperative complications between CPB and non-bypass (non-CPB) cases.
Two hundred and fifty-nine single lung transplants were undertaken. Fifty-three (20.5%) with CPB. There was no difference demographically between the two groups. No difference existed in preoperative PO2/FiO2. At 1 and 24 h, the postoperative PO2/FiO2 ratio was no different (mean 2.95 and 3.24 in non-CPB cases; 3.53 and 3.75 in CPB patients, P = 0.18 and P = 0.34, respectively). Extubation time was not influenced by the use of CPB. Postoperative blood loss was greater in the CPB group. The usage of fresh frozen plasma and platelets was similar (P = 0.64 and 0.41, respectively). More blood was transfused during postoperative care of CPB patients (P = 0.02).
Fears of poor postoperative lung function after CPB appear unfounded. We could detect no difference in function or extubation time. Although the use of CPB increases postoperative bleeding and the need for transfusion, it may be used safely to facilitate lung transplantation.
PMCID: PMC3422961  PMID: 22714587
Lung transplant; Cardiopulmonary bypass
9.  Intraoperative Use of Low-Dose Recombinant Activated Factor VII During Thoracic Aortic Operations 
The Annals of thoracic surgery  2012;93(6):1921-1929.
Numerous studies have supported the effectiveness of recombinant activated factor VII (rFVIIa) for the control of bleeding after cardiac procedures; however safety concerns persist. Here we report the novel use of intraoperative low-dose rFVIIa in thoracic aortic operations, a strategy intended to improve safety by minimizing rFVIIa exposure.
Between July 2005 and December 2010, 425 consecutive patients at a single referral center underwent thoracic aortic operations with cardiopulmonary bypass (CPB); 77 of these patients received intraoperative low-dose rFVIIa (≤60 μg/kg) for severe coagulopathy after CPB. Propensity matching produced a cohort of 88 patients (44 received intraoperative low-dose rFVIIa and 44 controls) for comparison.
Matched patients receiving intraoperative low-dose rFVIIa got an initial median dose of 32 μg/kg (interquartile range [IQR], 16–43 μg/kg) rFVIIa given 51 minutes (42–67 minutes) after separation from CPB. Patients receiving intraoperative low-dose rFVIIa demonstrated improved postoperative coagulation measurements (partial thromboplastin time 28.6 versus 31.5 seconds; p = 0.05; international normalized ratio, 0.8 versus 1.2; p < 0.0001) and received 50% fewer postoperative blood product transfusions (2.5 versus 5.0 units; p = 0.05) compared with control patients. No patient receiving intraoperative low-dose rFVIIa required postoperative rFVIIa administration or reexploration for bleeding. Rates of stroke, thromboembolism, myocardial infarction, and other adverse events were equivalent between groups.
Intraoperative low-dose rFVIIa led to improved postoperative hemostasis with no apparent increase in adverse events. Intraoperative rFVIIa administration in appropriately selected patients may correct coagulopathy early in the course of refractory blood loss and lead to improved safety through the use of smaller rFVIIa doses. Appropriately powered randomized studies are necessary to confirm the safety and efficacy of this approach.
PMCID: PMC3718882  PMID: 22551846
10.  Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial 
Critical Care  2007;11(6):R117.
Extracorporeal circulation induces hemostatic alterations that lead to inflammatory response (IR) and postoperative bleeding. Tranexamic acid (TA) reduces fibrinolysis and blood loss after cardiopulmonary bypass (CPB). However, its effects on IR and vasoplegic shock (VS) are not well known and elucidating these effects was the main objective of this study.
A case control study was carried out to determine factors associated with IR after CPB. Patients undergoing elective CPB surgery were randomly assigned to receive 2 g of TA or placebo (0.9% saline) before and after intervention. We performed an intention-to-treat analysis, comparing the incidence of IR and VS. We also analyzed several biological parameters related to inflammation, coagulation, and fibrinolysis systems. We used SPSS version 12.2 for statistical purposes.
In the case control study, 165 patients were studied, 20.6% fulfilled IR criteria, and the use of TA proved to be an independent protective variable (odds ratio 0.38, 95% confidence interval 0.18 to 0.81; P < 0.01). The clinical trial was interrupted. Fifty patients were randomly assigned to receive TA (24) or placebo (26). Incidence of IR was 17% in the TA group versus 42% in the placebo group (P = 0.047). In the TA group, we observed a significant reduction in the incidence of VS (P = 0.003), the use of norepinephrine (P = 0.029), and time on mechanical ventilation (P = 0.018). These patients showed significantly lower D-dimer, plasminogen activator inhibitor 1, and creatine-kinase levels and a trend toward lower levels of soluble tumor necrosis factor receptor and interleukin-6 within the first 24 hours after CPB.
The use of TA attenuates the development of IR and VS after CPB.
Trial registration number
PMCID: PMC2246206  PMID: 17988379
11.  Angiotensin-Converting Enzyme Inhibition Alters the Inflammatory and Fibrinolytic Response to Cardiopulmonary Bypass in Children 
Many children with a congenital heart defect undergo surgical correction requiring cardiopulmonary bypass (CPB). One sixth of these patients take an angiotensin-converting enzyme inhibitor (ACEi) for heart failure treatment. The effect of ACE inhibition on the fibrinolytic and inflammatory response in children undergoing CPB is unknown. In adults, ACE inhibition attenuates the increase in plasminogen activator inhibitor-1 (PAI-1) following CPB whereas the effect on the interleukin (IL)-6 response is uncertain. This study tests the hypothesis that preoperative ACE inhibition attenuates postoperative PAI-1 and IL-6 expression following CPB in children.
Single center prospective randomized non-blinded study.
University-affiliated pediatric hospital.
Children undergoing elective surgical correction of a congenital heart defect requiring CPB and taking an ACEi.
Children were randomized to continue ACEi until the morning of surgery (ACEi group, N=11) or to discontinue therapy 72 hours prior to surgery (No ACEi group, N=9).
Measurement and Main Results
Blood samples were collected at baseline before CPB, at 30min of CPB, upon arrival to the ICU, and on postoperative day 1 (POD1). Baseline bradykinin concentrations were significantly higher and ACE activity significantly lower in the ACEi group compared to the no ACEi group (P=0.04 and P=0.001 respectively). PAI-1 antigen increased 15-fold following CPB and peaked on POD1 (from 4.6±1.2 to 67.7±9.5 ng/ml; P<0.001). POD1 PAI-1 antigen correlated significantly with CPB time (r2=0.40, P=0.03) and was significantly lower in the ACEi group compared to the no ACEi group (P=0.03). The pro-inflammatory markers IL-6 and IL-8, as well as the anti-inflammatory marker IL-10, increased significantly following CPB (all P<0.001). IL-6 concentrations were significantly higher in the ACEi group following CPB (P=0.02) even after controlling for potential confounding factors such as age, CPB time and transfusion volume.
ACE inhibition attenuates the increase in postoperative PAI-1 but enhances the IL-6 response in children undergoing CPB.
PMCID: PMC3690292  PMID: 20975611
angiotensin converting enzyme; plasminogen activator; interleukin; pediatric surgery; acute kidney injury; cardiopulmonary bypass
12.  Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model 
Critical Care  2014;18(1):R27.
New oral anticoagulants are effective alternatives to warfarin. However, no specific reversal agents are available for life-threatening bleeding or emergency surgery. Using a porcine model of trauma, this study assessed the ability of prothrombin complex concentrate (PCC), activated PCC (aPCC), recombinant FVIIa (rFVIIa) and a specific antidote to dabigatran (aDabi-Fab) to reverse the anticoagulant effects of dabigatran.
Dabigatran etexilate (DE) was given orally for 3 days (30 mg/kg bid) and intravenously on day 4 to achieve consistent, supratherapeutic concentrations of dabigatran. Blood samples were collected at baseline, after oral DE, after intravenous dabigatran, and 60 minutes post-injury. PCC (30 and 60 U/kg), aPCC (30 and 60 U/kg), rFVIIa (90 and 180 μg/kg) and antidote (60 and 120 mg/kg) were added to blood samples ex-vivo. Coagulation was assessed by thromboelastometry, global coagulation assays and diluted thrombin time.
Plasma concentrations of dabigatran were 380 ± 106 ng/ml and 1423 ± 432 ng/ml after oral and intravenous administration, respectively, and all coagulation parameters were affected by dabigatran. Both PCCs and aDabi-Fab, but not rFVIIa, reversed the effects of dabigatran on thromboelastometry parameters and prothrombin time. In contrast, aPTT was only normalised by aDabi-Fab. Plasma concentration (activity) of dabigatran remained elevated after PCC and rFVIIa therapy, but was not measureable after aDabi-Fab.
In conclusion, PCC and aPCC were effective in reducing the anticoagulant effects of dabigatran under different conditions, while aDabi-Fab fully corrected all coagulation measures and decreased the plasma concentration of dabigatran below the limit of detection. No significant effects were observed with rFVIIa.
PMCID: PMC4059479  PMID: 24499559
13.  Impact of experimental haemodilution on platelet function, thrombin generation and clot firmness: effects of different coagulation factor concentrates 
Blood Transfusion  2013;11(3):391-399.
Haemodilution during resuscitation after massive haemorrhage may worsen the coagulopathy and perpetuate bleeding.
Materials and methods
Blood samples from healthy donors were diluted (30 and-60%) using crystalloids (saline, Ringer’s lactate, PlasmalyteTM) or colloids (6% hydroxyethylstarch [HES130/0.4], 5% human albumin, and gelatin). The effects of haemodilution on platelet adhesion (Impact R), thrombin generation (TG), and thromboelastometry (TEM) parameters were analysed as were the effects of fibrinogen, prothrombin complex concentrates (PCC), activated recombinant factor VII (FVIIa), and cryoprecipates on haemodilution.
Platelet interactions was already significantly reduced at 30% haemodilution. Platelet reactivity was not improved by addition of any of the concentrates tested. A decrease in TG and marked alterations of TEM parameters were noted at 60% haemodilution. HES130/0.4 was the expander with the most deleterious action. TG was significantly enhanced by PCC whereas rFVIIa only caused a mild acceleration of TG initiation. Fibrinogen restored the alterations of TEM parameters caused by haemodilution including those caused by HES 130/0.4. Cryoprecipitates significantly improved the alterations caused by haemodilution on TG and TEM parameters; the effects on TG disappeared after ultracentrifugation of the cryoprecipitates.
The haemostatic alterations caused by haemodilution are multifactorial and affect both blood cells and coagulation. In our in vitro approach, HES 130/0.4 had the most deleterious effect on haemostasis parameters. Coagulation factor concentrates did not improve platelet interactions in the Impact R, but did have favourable effects on coagulation parameters measured by TG and TEM. Fibrinogen notably improved TEM parameters without increasing thrombin generation, suggesting that this concentrate may help to preserve blood clotting abilities during haemodilution without enhancing the prothrombotic risk.
PMCID: PMC3729130  PMID: 23058866
haemodilution; coagulation factor concentrates; platelet function; thrombin generation; thromboelastometry
14.  Factors associated with excessive bleeding in cardiopulmonary bypass patients: a nested case-control study 
Excessive bleeding (EB) after cardiopulmonary bypass (CPB) may lead to increased mortality, morbidity, transfusion requirements and re-intervention. Less than 50% of patients undergoing re-intervention exhibit surgical sources of bleeding. We studied clinical and genetic factors associated with EB.
We performed a nested case-control study of 26 patients who did not receive antifibrinolytic prophylaxis. Variables were collected preoperatively, at intensive care unit (ICU) admission, at 4 and 24 hours post-CPB. EB was defined as 24-hour blood loss of >1 l post-CPB. Associations of EB with genetic, demographic, and clinical factors were analyzed, using SPSS-12.2 for statistical purposes.
EB incidence was 50%, associated with body mass index (BMI)< 26.4 (25–28) Kg/m2, (P = 0.03), lower preoperative levels of plasminogen activator inhibitor-1 (PAI-1) (P = 0.01), lower body temperature during CPB (P = 0.037) and at ICU admission (P = 0.029), and internal mammary artery graft (P = 0.03) in bypass surgery. We found a significant association between EB and 5G homozygotes for PAI-1, after adjusting for BMI (F = 6.07; P = 0.02) and temperature during CPB (F = 8.84; P = 0.007). EB patients showed higher consumption of complement, coagulation, fibrinolysis and hemoderivatives, with significantly lower leptin levels at all postoperative time points (P = 0.01, P < 0.01 and P < 0.01).
Excessive postoperative bleeding in CPB patients was associated with demographics, particularly less pronounced BMI, and surgical factors together with serine protease activation.
PMCID: PMC1950484  PMID: 17425777
Cardiopulmonary bypass (CPB) protocols of the baboon (Papio cynocephalusanubis) are limited to obtaining experimental data without concern for long-term survival. In the evaluation of pulmonary artery tissue engineered heart valves (TEHV's), pediatric CPB methods are adapted to accommodate the animals' unique physiology enabling survival up to six months until elective sacrifice.
Aortic access was by a 14F arterial cannula and atrial access by a single 24F venous cannula. The CPB circuit includes a 3.3 L/min flow rated oxygenator, 1/4" X 3/8" arterial-venous loop, 3/8" raceway, and bubble trap. The prime contains 700 ml Plasma-lyte, 700 units heparin, 5 ml of 50% dextrose, and 20 mg amiodarone. Heparinization (200 u/kg) targets an activated clotting time of 350 seconds. Normothermic CPB was initiated at a 2.5 L/M2/min cardiac index with a mean arterial pressure of 55–80 mmHg. Weaning was monitored with transesophageal echo cardiogram. Post-CPB circuit blood is re-infused. Chest tubes were removed with cessation of bleeding. Extubation is performed upon spontaneous breathing. The animals were conscious and upright three hours post-CPB.
Bioprosthetic valves or TEHVs were implanted as pulmonary replacements in 20 baboons: weight = 27.5 ± 5.6 kg, height = 73 ± 7 cm, body surface area = 0.77 m2 ± 0.08, mean blood flow =1.973 ± 0.254 L/min, core temperature = 37.1 ± 0.1°C, CPB time = 60 ± 40 minutes. No acidosis accompanied CPB. Sixteen animals survived, 4 expired. Three died of right ventricular failure and one of an anaphylactoid reaction. Surviving animals had normally functioning replacement valves and ventricles.
Baboon CPB requires modifications to include high systemic blood pressure for adequate perfusion into small coronary arteries, careful CPB weaning to prevent ventricular distention, and drug and fluid interventions to abate variable venous return related to a muscularized spleno-splanchnic venous capacity.
PMCID: PMC3152821  PMID: 21114226
Baboon; Tissue Engineered Heart Valve (TEHV); Right Ventricular Outflow Tract (RVOT); Pulmonary Valve; Cardiopulmonary Bypass (CPB); Subhuman Primates; Homografts; Allografts; Xenografts
16.  The role of plasma gelsolin in cardiopulmonary bypass induced acute lung injury in infants and young children: a pilot study 
BMC Anesthesiology  2014;14:67.
Acute lung injury (ALI) induced by cardiopulmonary bypass (CPB, CPB-ALI) is a common and serious complication after cardiac surgery. And infants and young children are more prone to CPB-ALI. The purpose of this study was to investigate the perioperative changes of plasma gelsolin (pGSN) in patients below 3years of age with cardiac surgeries and CPB, and determine whether pGSN are associated with the occurrence and severity of CPB-ALI.
Seventy-seven consecutive patients ≤3 years of age with congenital heart diseases (CHD) performed on open heart surgery with CPB were finally enrolled, and assigned to ALI and non-ALI groups according to the American-European Consensus Criteria. Plasma concentrations of gelsolin and total protein were measured at following 8 time points: before CPB (a), after CPB (b), 2 hours after CPB (c), 6 hours after CPB (d), 12 hours after CPB (e), 24 hours after CPB (f), 48 hours after CPB (g) and 72 hours after CPB (h).
Twenty-seven (35.1%) patients developed CPB-ALI in the study, including eleven (14.3%) patients with ARDS. The earliest significant drop of pGSN and normalized pGSN (pGSNN) of ALI group both occurred at 6 hours after CPB (p = 0.04 and p < 0.01), which was much earlier than those of non-ALI group (48 hours, p = 0.03 and 24 hours, p < 0.01); PGSN of ALI group before CPB and 6 hours after CPB were both significantly lower than those of non-ALI group (p < 0.01); PGSNN of ALI group before CPB and 6 hours after CPB were both significantly lower than those of non-ALI group (p < 0.01, p = 0.04); PGSN before CPB was the only independent risk factor predicting the occurrence of CPB-ALI (OR, 1.023; 95% CI, 1.007-1.039; p < 0.01) with an AUC of 0.753 (95% CI, 0.626-0.880); The optimal cutoff value of pGSN before CPB was 264.2 mg/L, with a sensitivity of 58.3% and a specificity 94.7%. And lower pGSN before CPB was significantly associated with the severity of CS-AKI (r = −0.45, p < 0.01).
Patients developing CPB-ALI had lower plasma gelsolin reservoir and a much more amount and rapid consumption of plasma gelsolin early after operation. PGSN before CPB was an early and sensitive predictor of CPB-ALI in infants and young children undergoing cardiac surgery, and was negatively correlated with the severity of CPB-ALI.
PMCID: PMC4132929  PMID: 25126004
Plasma gelsolin; Acute lung injury; Cardiac surgery; Cardiopulmonary bypass; Infant; Young children; Congenital heart disease
17.  Emergency reversal of anticoagulation: from theory to real use of prothrombin complex concentrates. A retrospective Italian experience 
Blood Transfusion  2012;10(1):87-94.
Prothrombin Complex Concentrates (PCC) are administered to normalise blood coagulation in patients receiving oral anticoagulant therapy (OAT). Rapid reversal of OAT is essential in case of major bleeding, internal haemorrhage or surgery.
The primary end-point was to evaluate whether PCC in our hospital were being used in compliance with international and national guidelines for the reversal of OAT on an emergency basis. The secondary end-point was to evaluate the efficacy and safety of PCC.
Materials and methods
All patients receiving OAT who required rapid reversal anticoagulation because they had to undergo emergency surgery or urgent invasive techniques following an overdose of oral anticoagulants were eligible for this retrospective observational study.
Forty-seven patients receiving OAT who needed rapid reverse of anticoagulation were enrolled in our study. The patients were divided in two groups: (i) group A (n=23), patients needed haemostatic treatment before neurosurgery after a head injury and (ii) group B (n=24), patients with critical haemorrhage because of an overdose of oral anticoagulants. The International Normalised Ratio (INR) was checked before and after infusion of the PCC. The mean INR in group A was 2.7 before and 1.43 after infusion of the PCC; in group B the mean INR of 6.58, before and 1.92 after drug infusion. The use of vitamin K, fresh-frozen plasma and red blood cells was also considered. During our study 22 patients died, but no adverse effects following PCC administration were recorded.
In our study three-factor-PCC was found to be effective and safe in rapidly reversing the effects of OAT, although it was not always administered in accordance with international or national guidelines. The dose, time of administration and monitoring often differed from those recommended. In the light of these findings, we advocate the use of single standard protocol to guide the correct use of PCC in each hospital ward.
PMCID: PMC3258994  PMID: 22044952
prothrombin complex concentrate; oral anticoagulant therapy; reversal of anticoagulation guidelines
18.  Safety and Effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial 
In cardiopulmonary bypass (CPB) patients, fibrinolysis may enhance postoperative inflammatory response. We aimed to determine whether an additional postoperative dose of antifibrinolytic tranexamic acid (TA) reduced CPB-mediated inflammatory response (IR).
We performed a randomized, double-blind, dose-dependent, parallel-groups study of elective CPB patients receiving TA. Patients were randomly assigned to either the single-dose group (40 mg/Kg TA before CPB and placebo after CPB) or the double-dose group (40 mg/Kg TA before and after CPB).
160 patients were included, 80 in each group. The incident rate of IR was significantly lower in the double-dose-group TA2 (7.5% vs. 18.8% in the single-dose group TA1; P = 0.030). After adjusting for hypertension, total protamine dose and temperature after CPB, TA2 showed a lower risk of IR compared with TA1 [OR: 0.29 (95% CI: 0.10-0.83), (P = 0.013)]. Relative risk for IR was 2.5 for TA1 (95% CI: 1.02 to 6.12). The double-dose group had significantly lower chest tube bleeding at 24 hours [671 (95% CI 549-793 vs. 826 (95% CI 704-949) mL; P = 0.01 corrected-P significant] and lower D-dimer levels at 24 hours [489 (95% CI 437-540) vs. 621(95% CI: 563-679) ng/mL; P = 0.01 corrected-P significant]. TA2 required lower levels of norepinephrine at 24 h [0.06 (95% CI: 0.03-0.09) vs. 0.20(95 CI: 0.05-0.35) after adjusting for dobutamine [F = 6.6; P = 0.014 corrected-P significant].
We found a significant direct relationship between IL-6 and temperature (rho = 0.26; P < 0.01), D-dimer (rho = 0.24; P < 0.01), norepinephrine (rho = 0.33; P < 0.01), troponin I (rho = 0.37; P < 0.01), Creatine-Kinase (rho = 0.37; P < 0.01), Creatine Kinase-MB (rho = 0.33; P < 0.01) and lactic acid (rho = 0.46; P < 0.01) at ICU arrival. Two patients (1.3%) had seizure, 3 patients (1.9%) had stroke, 14 (8.8%) had acute kidney failure, 7 (4.4%) needed dialysis, 3 (1.9%) suffered myocardial infarction and 9 (5.6%) patients died. We found no significant differences between groups regarding these events.
Prolonged inhibition of fibrinolysis, using an additional postoperative dose of tranexamic acid reduces inflammatory response and postoperative bleeding (but not transfusion requirements) in CPB patients. A question which remains unanswered is whether the dose used was ideal in terms of safety, but not in terms of effectiveness.
Current Controlled Trials number
PMCID: PMC3206427  PMID: 21999189
Cardiac surgery; Cardiopulmonary bypass; Fibrinolysis; Tranexamic acid; Inflammatory response; Bleeding
19.  Predictive value of rotational thromboelastometry during cardiopulmonary bypass for thrombocytopenia and hypofibrinogenemia after weaning of cardiopulmonary bypass 
Korean Journal of Anesthesiology  2015;68(3):241-248.
The early detection of coagulopathy helps guide decisions regarding optimal transfusion management during cardiac surgery. This study aimed to determine whether rotational thromboelastometry (ROTEM) analysis during cardiopulmonary bypass (CPB) could predict thrombocytopenia and hypofibrinogenemia after CPB.
We analyzed 138 cardiac surgical patients for whom ROTEM tests and conventional laboratory tests were performed simultaneously both during and after CPB. An extrinsically activated ROTEM test (EXTEM), a fibrin-specific ROTEM test (FIBTEM) and PLTEM calculated by subtracting FIBTEM from EXTEM were evaluated. Correlations between clot amplitude at 10 min (A10), maximal clot firmness, platelet count, and fibrinogen concentrations at each time point were calculated. A receiver operating characteristic analysis with area under the curve (AUC) was used to assess the thresholds of EXTEM, PLTEM and FIBTEM parameters during CPB and for predicting thrombocytopenia and hypofibrinogenemia after weaning of CPB.
The A10 on EXTEM, PLTEM, and FIBTEM during CPB showed a good correlation with platelet counts (r = 0.622 on EXTEM and r = 0.637 on PLTEM; P < 0.0001 for each value) and fibrinogen levels (r = 0.780; P < 0.0001) after CPB. A10 on a FIBTEM threshold of 8 mm during the CPB predicted a fibrinogen concentration < 150 mg/dl (AUC = 0.853) after CPB. Additionally, the threshold level of A10 on EXTEM during CPB for predicting platelet counts < 100,000 /µl after CPB was 42 mm (AUC = 0.768).
EXTEM, PLTEM, and FIBTEM parameters during CPB may be useful for predicting thrombocytopenia and hypofibrinogenemia after weaning of CPB.
PMCID: PMC4452667  PMID: 26045926
Cardiac surgery; Cardiopulmonary bypass; Coagulopathy; Thromboelastometry
20.  A Prospective Study of the Clinical Benefits of Prostacyclin in 554 Cardiopulmonary Bypass Procedures 
Texas Heart Institute Journal  1988;15(2):86-90.
Abnormal bleeding after cardiopulmonary bypass (CPB) may result from incomplete neutralization of heparin, increased fibrinolytic activity, consumption of coagulation factors, or from a reduction in the number of circulating platelets together with impairment of platelet function. Although researchers have reason to believe that hemostasis after CPB could be improved with prostacyclin (PGI2), a potent inhibitor of platelet aggregation, the drug's clear-cut benefits in this respect have not yet been confirmed.
After conducting an initial study concerning the fate of platelets during CPB, in which we determined that PGI2 had a protective effect, we investigated the effects of PGI2 infusion during CPB on postoperative blood loss in 554 open-heart surgery patients, 200 of whom underwent valve replacement, 200 of whom had coronary artery bypass grafting (CABG), and 154 of whom underwent repeat valve replacement or CABG. The patients were divided into 2 groups: 277 patients (the study group) received both heparin and PGI2 during CPB, whereas the remaining 277 patients (the control group) were given heparin alone.
Of the patients who underwent surgery for the first time, those treated with PGI2 had a reduced mean blood loss (p < 0.05 only in CABG patients) in comparison with those who received heparin alone. Of the patients who underwent redo operations, those who received PGI2 had a nonsignificant tendency toward reduced blood loss. The mean difference in blood loss between the study group and the control group had no clinical relevance, however, because it was less than the smallest practical unit of measurement (i.e., 1 unit of blood). (Texas Heart Institute Journal 1988; 15:86-90)
PMCID: PMC324797  PMID: 15227257
Cardiopulmonary bypass; prostaglandins X; platelet aggregation; hemostasis, surgical
21.  Activated Prothrombin Complex Concentrates for the Reversal of Anticoagulant-Associated Coagulopathy 
Pharmacy and Therapeutics  2013;38(11):696-701.
Managing hemorrhaging after the use of warfarin and other anticoagulants is challenging. Although an FDA-approved product, FEIBA, has been used as an off-label anticoagulant-reversal agent, the potential risks of thrombosis associated with activated prothrombin complex concentrates must be carefully weighed.
Prothrombin complex concentrate (PCC) products are emerging as alternative strategies for reversing anticoagulant pharmacotherapy. Factor eight inhibitor bypassing activity (FEIBA, or anti-inhibitor coagulant complex) is an activated PCC (aPCC). Although FEIBA is approved by the FDA to control spontaneous bleeding episodes and to prevent bleeding with surgical interventions in hemophilia A and hemophilia B patients with inhibitors to factor VIII, recent data have suggested that the product may be used off-label as an anticoagulant-reversal agent. To evaluate the safety and efficacy of aPCC products in reversing anticoagulant pharmacotherapy, we searched online databases for English-language publications that discussed this topic.
Data Sources: The EMBASE, MEDLINE, and International Pharmaceutical Abstracts databases were used. We evaluated all articles published in the English language identified from the data sources. We included studies conducted in human subjects and in in vitro and in vivo models in our review.
Current published evidence suggests that the use of an aPCC, compared with fresh-frozen plasma, is associated with a significantly faster correction of supratherapeutic International Normalized Ratios (INRs) secondary to warfarin therapy. Conflicting evidence exists regarding the ability of aPCCs to reverse the prolonged bleeding times caused by the anticoagulant agents dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and fondaparinux (Arixtra).
The theoretical risks of thrombosis associated with PCC products must be carefully considered before they are administered to patients who require coagulation therapy. The use of aPCCs to reverse the anticoagulant effects of warfarin, dabigatran, or rivaroxaban should be limited because of the lack of efficacy and safety data in humans. Moreover, the safety of aPCCs in off-label indications has not been adequately assessed.
PMCID: PMC3875259  PMID: 24391389
FEIBA; activated PCC; hemorrhage; reversal; anticoagulation
22.  Platelet-dependent thrombography gives a distinct pattern of in vitro thrombin generation after surgery with cardio-pulmonary bypass: potential implications 
Thrombosis Journal  2012;10:15.
Bleeding remains a potentially lethal complication of cardio-pulmonary bypass (CPB) surgery. The purpose of this study was to obtain a better insight into in vitro thrombin generation in the context of CPB.
We used Calibrated Automated Thrombography to assess blood coagulation of 10 low-risk patients operated for valve replacement with CPB, under 2 experimental conditions, one implicating platelets as platelet dysfunction has been described to occur during CPB.
Our main finding was that CPB-induced coagulopathy was differently appreciated depending on the presence or absence of platelets: the decrease in thrombin generation was much less pronounced in their presence (mean endogenous thrombin potential change values before and after CPB were -3.9% in the presence of platelets and -39.6% in their absence).
Our results show that experimental conditions have a profound effect in the study of in vitro thrombin generation in the context of CPB.
PMCID: PMC3522546  PMID: 22909275
Cardio pulmonary bypass; Thrombin; Platelets; Thrombography
23.  A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal 
Critical Care  2013;17(1):R4.
Prothrombin complex concentrates (PCC) are haemostatic blood preparations indicated for urgent anticoagulation reversal, though the optimal dose for effective reversal is still under debate. The latest generation of PCCs include four coagulation factors, the so-called 4-factor PCC. The aim of this study was to compare the efficacy and safety of two doses, 25 and 40 IU/kg, of 4-factor PCC in vitamin K antagonist (VKA) associated intracranial haemorrhage.
We performed a phase III, prospective, randomised, open-label study including patients with objectively diagnosed VKA-associated intracranial haemorrhage between November 2008 and April 2011 in 22 centres in France. Patients were randomised to receive 25 or 40 IU/kg of 4-factor PCC. The primary endpoint was the international normalised ratio (INR) 10 minutes after the end of 4-factor PCC infusion. Secondary endpoints were changes in coagulation factors, global clinical outcomes and incidence of adverse events (AEs).
A total of 59 patients were randomised: 29 in the 25 IU/kg and 30 in the 40 IU/kg group. Baseline demographics and clinical characteristics were comparable between the groups. The mean INR was significantly reduced to 1.2 - and ≤1.5 in all patients of both groups - 10 minutes after 4-factor PCC infusion. The INR in the 40 IU/kg group was significantly lower than in the 25 IU/kg group 10 minutes (P = 0.001), 1 hour (P = 0.001) and 3 hours (P = 0.02) after infusion. The 40 IU/kg dose was also effective in replacing coagulation factors such as PT (P = 0.038), FII (P = 0.001), FX (P <0.001), protein C (P = 0.002) and protein S (0.043), 10 minutes after infusion. However, no differences were found in haematoma volume or global clinical outcomes between the groups. Incidence of death and thrombotic events was similar between the groups.
Rapid infusion of both doses of 4-factor PCC achieved an INR of 1.5 or less in all patients with a lower INR observed in the 40 IU/kg group. No safety concerns were raised by the 40 IU/kg dose. Further trials are needed to evaluate the impact of the high dose of 4-factor PCC on functional outcomes and mortality.
Trial registration
Eudra CT number 2007-000602-73.
PMCID: PMC4057510  PMID: 23305460
24.  Does incorporation of thromboelastography improve bleeding prediction following adult cardiac surgery? 
Blood Coagulation & Fibrinolysis  2014;25(6):561-570.
Cardiopulmonary bypass (CPB) coagulopathy increases utilization of allogenic blood/blood products, which can negatively affect patient outcomes. Thromboelastography (TEG) is a point-of-care measurement of clot formation and fibrinolysis. We investigated whether the addition of TEG parameters to a clinically based bleeding model would improve the predictability of postoperative bleeding. A total of 439 patients’ charts were retrospectively investigated for 8-h chest tube output (CTO) postoperatively. For model 1, the variables recorded were patient age, gender, body surface area, clopidogrel use, CPB time, first post-CPB fibrinogen serum level, first post-CPB platelet count, first post-CPB international normalized ratio, the total amount of intraoperative cell saver blood transfused, and postoperative first ICU hematocrit level. Model 2 had the model 1 variables, TEG angle, and maximum amplitude. The outcome was defined as 0–8-h CTO. The predictor variables were placed into a forward stepwise regression model for continuous outcomes. Analysis of variance with adjusted R2 was used to assess the goodness-of-fit of both predictive models. The predictive accuracy of the model was examined using CTO as a dichotomous variable (75th percentile, 480 ml) and receiver operating characteristic curves for both models. Advanced age, male gender, preoperative clopidogrel use for 5 days or less, greater cell saver blood utilization, and lower postoperative hematocrit levels were associated with increased 8-h CTO (P < 0.05). Adding TEG angle and maximum amplitude to model 1 did not improve CTO predictability. When TEG angle and maximum amplitude were added as predictor factors, the predictability of the bleeding model did not improve.
PMCID: PMC4162333  PMID: 24717423
adult; bleeding; cardiac surgery; cardiopulmonary bypass; coagulation; coronary artery bypass graft; thromboelastography; transfusion
25.  A Comparative Study to Determine the Effect of Intravenous Magnesium on Postoperative Bleeding after on Pump CABG in Patients Receiving Pre-Operative Aspirin 
Indian Journal of Anaesthesia  2009;53(2):197-203.
Hypomagnesaemia is a common complication after cardiopulmonary bypass (CPB) and predisposes to the development of cardiac arrhythmias. Previous studies showed that intravenous magnesium reduces the incidence of postoperative cardiac arrhythmias but it also inhibits platelet function. Our aim was to compare the postoperative blood loss in patients not receiving magnesium after CPB with the group who received magnesium and to compare the requirement of blood, fresh frozen plasma (FFP) and platelets within 24 hours after surgery. This prospective randomized controlled study was conducted in 80 adult patients on oral aspirin undergoing elective CABG requiring CPB. Group A patients had not received magnesium infusion after recovery from CPB. Group B patients received magnesium infusion after recovery from CPB. Postoperative bleeding was assessed in both the groups. All the data were statistically analyzed. There was a insignificant increase in 24 hours postoperative drainage in magnesium recipient group compared to control group (p>0.05). Requirements of blood and blood products to maintain haematocrit and coagulation profile revealed insignificant (p > 0.05). Increase in requirement of PRC, FFP and platelets in magnesium recipient patients than the control group. Incidence of atrial fibrillation (Gr A 2.5%, Gr B 2.5%) and atrial extrasystoles (Gr A 2.5%, Gr B 10%) revealed comparable (p > 0.05) between the groups, but incidence of ventricular arrhythmias were significantly (p<0.05) high in the patients of Gr A(17.5%) than Gr B(5%). To conclude, magnesium may be administered to patients who continue pre-operative aspirin to undergo on-pump CABG surgery.
PMCID: PMC2900106  PMID: 20640123
Aspirin; Magnesium; CPB; CABG; Postoperative bleeding

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