A reduction of prothrombin conversion by cardiac surgery with cardiopulmonary bypass shifts the haemostatic balance towards bleeding

2016 ◽  
Vol 116 (09) ◽  
pp. 442-451 ◽  
Author(s):  
Yvonne P. J. Bosch ◽  
Saartje Bloemen ◽  
Bas de Laat ◽  
Patrick W. Weerwind ◽  
Bas Mochtar ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
In Silico ◽  
Thrombin Generation ◽  
Coagulation Factor ◽  
Thrombin Inhibition ◽  
Relative Contribution ◽  
Post Surgery ◽  
Heparin Administration ◽  
Thrombotic Complications

SummaryCardiac surgery with cardiopulmonary bypass (CPB) is associated with blood loss and post-surgery thrombotic complications. The process of thrombin generation is disturbed during surgery with CPB because of haemodilution, coagulation factor consumption and heparin administration. We aimed to investigate the changes in thrombin generation during cardiac surgery and its underlying pro- and anticoagulant processes, and to explore the clinical consequences of these changes using in silico experimentation. Plasma was obtained from 29 patients undergoing surgery with CPB before heparinisation, after heparinisation, after haemodilution, and after protamine administration. Thrombin generation was measured and prothrombin conversion and thrombin inactivation were quantified. In silico experimentation was used to investigate the reaction of patients to the administration of procoagulant factors and/or anticoagulant factors. Surgery with CPB causes significant coagulation factor consumption and a reduction of thrombin generation. The total amount of prothrombin converted and the rate of prothrombin conversion decreased during surgery. As the surgery progressed, the relative contribution of α2-macroglobulin-dependent thrombin inhibition increased, at the expense of antithrombin-dependent inhibition. In silico restoration of post-surgical prothrombin conversion to pre-surgical levels increased thrombin generation excessively, whereas co-administration of antithrombin resulted in the normalisation of post-surgical thrombin generation. Thrombin generation is reduced during surgery with cardiopulmonary bypass because of a balance shift between prothrombin conversion and thrombin inactivation. According to in silico predictions of thrombin generation, this new balance increases the risk of thrombotic complications with prothrombin complex concentrate administration, but not if antithrombin is co-administered.

scholarly journals Restoration of Procoagulant Factor Levels after Cardiac Surgery Causes Thrombin Generation to Rise to Thrombotic Levels

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1143-1143
Author(s):  
Romy Kremers ◽  
Yvonne Bosch ◽  
Saartje Bloemen ◽  
Bas De Laat ◽  
Rob Wagenvoord ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Tissue Factor ◽  
In Silico ◽  
Thrombin Generation ◽  
Prothrombin Complex Concentrate ◽  
Coagulation Factor ◽  
Peak Height ◽  
Fresh Frozen Plasma ◽  
Post Surgery ◽  
Fresh Frozen

Abstract Introduction Cardiac surgery with cardiopulmonary bypass (CPB) causes hemodilution and coagulation factor consumption. The administration of unfractionated heparin accelerates thrombin inactivation and leads to elevated consumption of antithrombin (AT). The heparin-mediated release of tissue factor pathway inhibitor (TFPI) from the vessel wall reduces prothrombin activation. CPB surgery thus affects both pro- and anticoagulant processes, which are reflected in changes in a patient's thrombin generation potential. In this study we investigated how cardiac surgery changes thrombin generation (TG), prothrombin conversion and thrombin inactivation. In addition, we studied the consequences of these changes in pro- and anticoagulant processes for transfusion management using in silico experimentation. Methods Thirty patients undergoing cardiac surgery with CPB were included and samples were collected before and after surgery and protamine administration. AT and prothrombin levels were determined and TG was measured at 5 pM tissue factor by calibrated automated thrombinography. Prothrombin conversion and thrombin inactivation were quantified from each TG curve. The effect of transfusion of prothrombin complex concentrate (PCC) was simulated by an in silico increase of prothrombin conversion. The effect of PCC administration in combination with AT was modeled as an increase of prothrombin conversion and antithrombin levels. The effect of in silico transfusion of PCC on coagulation was quantified by TG parameters. Results CPB surgery causes a reduction of plasma coagulation factor levels: AT (47%, p<0.001), prothrombin (63%, p<0.001), and decreases TG peak height by 71% (p<0.001). After surgery prothrombin conversion is significantly impaired (402 ± 218 vs 701 ± 181 nM; p<0.001), which is partly compensated for by lower thrombin inactivation (63%, p<0.001), resulting in a reduction of TG. We modeled the effect of the transfusion of prothrombin complex concentrate with or without added antithrombin on TG. If the prothrombin conversion capacity was increased to pre-surgery levels in the absence of antithrombin, TG peak height increases to 454 ± 72 nM (figure A). A slight increase of prothrombin conversion (up to 83% of the pre-surgery level) brings TG peak height into the normal range (386±61 nM), but the ETP remains elevated (3278 ± 1141 nM). The optimal way to restore thrombin generation is the simultaneous infusion of PCC and antithrombin. Our in silico experiments indicate that this restores both the peak height (362 ± 69 nM) and the ETP (1601 ± 369 nM∙min) to the pre-surgery level (figure B). Conclusions Cardiac surgery with CPB causes the hemostatic balance to shift toward bleeding due to a reduction of prothrombin conversion. This is only partially compensated by a reduction of thrombin inactivation, resulting in reduced TG after surgery. Post-surgery bleeding can be (and often is) remedied by the transfusion of PCC. However, full restoration of the prothrombin conversion capacity results in a TG profile that predicts a prothrombotic state, as an ETP value in the highest quartile is associated with a 5 times elevated thrombosis risk according to Winckers et al. Equilibrated restoration of the hemostatic capacity asks for the simultaneous supplementation of both pro- and anticoagulant factors, i.e. PCC containing AT or fresh frozen plasma. Figure 1. The effect of prothrombin complex concentrate (± antithrombin) transfusion on in silico thrombin generation. ■ Pre-surgery TG, ● Post-surgery TG, □ in silico PCC transfusion (left panel), and ○ in silico PCC and AT transfusion (right panel). Figure 1. The effect of prothrombin complex concentrate (± antithrombin) transfusion on in silico thrombin generation. ■ Pre-surgery TG, ● Post-surgery TG, □ in silico PCC transfusion (left panel), and ○ in silico PCC and AT transfusion (right panel). Disclosures Kremers: Synapse bv: Employment. Bloemen:Synapse bv: Employment. De Laat:Synapse bv: Employment. Wagenvoord:Synapse bv: Employment. Al Dieri:Synapse bv: Employment. Hemker:Synapse bv: Employment.

scholarly journals Impact of 6% balanced hydroxyethyl starch following cardiopulmonary bypass on renal function: a retrospective study

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Ju Yong Lim ◽  
Yun Seok Kim ◽  
Joon Bum Kim
Keyword(s):  
Renal Function ◽  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
Hydroxyethyl Starch ◽  
Early Mortality ◽  
Adverse Outcomes ◽  
Moderate Dose ◽  
Post Surgery ◽  
Randomized Controlled Studies ◽  
Study Results

Abstract Background We aimed to evaluate the effect of limited volume of hydroxyethyl starch (HES) administration on postoperative renal function in patients undergoing cardiac surgery under cardiopulmonary bypass (CPB). Methods One thousand six hundred fifty-seven patients undergoing cardiac surgery under CPB over two years were included. The patients were divided according to the amount of HES administrated during the first 2 days post-surgery; moderate dose HES (≥20 ml/kg) versus low dose HES (< 20 ml/kg). Outcomes were compared by using inverse probability weighting. Results Incidence of acute kidney injury (AKI) was higher in the moderate HES group (p = .02). However, new renal replacement therapy (RRT) (P = .30) and early mortality (p = .97) was similar between the groups. When adjusted, the moderate HES use was associated with AKI (OR, 1.66; 95% CI, 1.12–2.44; p = .01), but did not increase the risk of new RRT (OR, 1.27; 95% CI, 0.71–2.18; p = .40) or early mortality (HR, 0.73; 95% CI, 0.29–1.81; p = .50). Conclusions The moderate dose administration of HES (≥20 ml/kg) in the postoperative period following cardiac surgery might be associated with the risk of AKI. However, it was not associated with serious adverse outcomes such as new RRT or mortality. Further randomized controlled studies are needed to validate study results.

Thrombin Generation during Cardiac Surgery: Is Heparin the Ideal Anticoagulant?

1993 ◽  
Vol 70 (02) ◽  
pp. 259-262 ◽  
Author(s):  
S J Brister ◽  
F A Ofosu ◽  
M R Buchanan
Keyword(s):  
At Risk ◽  
Cardiac Surgery ◽  
Thrombin Generation ◽  
Antithrombin Iii ◽  
Experimental Studies ◽  
High Dose ◽  
Protamine Sulphate ◽  
Elective Cardiac Surgery ◽  
Post Surgery ◽  
Dose Heparin

SummaryBlood samples were collected from 43 patients undergoing elective cardiac surgery to determine the extent of thrombin generation and inhibition in patients when receiving heparin while undergoing cardiopulmonary bypass (CPB). Plasma prothrombin fragment F1 + 2 and thrombin-antithrombin III (TAT) levels were measured as markers of thrombin generation and inhibition, respectively. Both F1 + 2 and TAT levels increased significantly during the course of CPB despite the heparin causing significant systemic anticoagulation, i.e. the activated coagulation time (ACT) was prolonged to greater than 400 s throughout the entire surgical procedure. The extent of thrombin generation increased with time on CPB but did not differ between patients receiving normothermic and hypothermic cardioplegia during CPB. Furthermore, thrombin generation increased following the neutralization of the heparin with protamine sulphate, and continued to be elevated significantly 24 h post surgery. The observation that high dose heparin did not prevent thrombin generation during CPB, is consistent with previous experimental studies demonstrating that thrombin bound to fibrin or other surfaces (e.g. the CPB conduit) is resistant to antithrombin III/heparin inhibition, and thus able to facilitate further thrombin generation. The observation that thrombin generation continued to be elevated post surgery i.e. 24 h after neutralizing the heparin with protamine sulphate, suggests that the high dose heparin did not inhibit effectively all of the thrombin that had been generated. Thus, CPB patients may be at risk not only of bleeding and other side-effects associated with the acute use of high dose heparin, but may also be at risk of further thrombosis-related events either acutely or chronically.

Repletion of factor XIII following cardiopulmonary bypass using a recombinant A-subunit homodimer

2009 ◽  
Vol 102 (10) ◽  
pp. 765-771 ◽  
Author(s):  
Ravi Gill ◽  
Nancy A. Nussmeier ◽  
Peter Olsen ◽  
Henning F. Andersen ◽  
Frank V. McL. Booth ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
Factor Xiii ◽  
Artery Bypass ◽  
Data Monitoring Committee ◽  
Coagulation Factor ◽  
Implantable Defibrillator ◽  
Serious Adverse Events ◽  
A Subunit

SummaryBleeding following cardiac surgery involving cardiopulmonary bypass (CPB) remains a major concern. Coagulation factor XIII (FXIII) functions as a clot-stabilising factor by cross-linking fibrin. Low post-operative levels of FXIII correlate with increased post-operative blood loss. To evaluate preliminary safety and pharmacokinetics of recombinant FXIII (rFXIII-A2) in cardiac surgery, patients scheduled for coronary artery bypass grafting were randomised to receive a single dose of either rFXIII-A2 (11.9,25,35 or 50 IU/kg) or placebo in a 4:1 ratio.Study drug was given post-CPB within 10 to 20 minutes after first protamine dose. Patients were evaluated until day 7 or discharge, with a follow-up visit at weeks 5–7.The primary end-point was incidence and severity of adverse events.Thirty-five patients were randomised to rFXIII-A2 and eight to placebo. Eighteen serious adverse events were reported.These were all complications well recognised during cardiac surgery. Although one patient required an implantable defibrillator, all recovered without sequelae. One myocardial infarction in a patient receiving 35 IU/ kg rFXIII-A2 was identified by the Data Monitoring Committee after reviewing ECGs and cardiac enzymes. No other thromboembolic events were seen. Dosing with 25–50 IU/kg rFXIII-A2 restored levels of FXIII to pre-operative levels, with a tendency towards an overshoot in receiving 50 IU/kg. rFXIII-A2, in doses from 11.9 IU/kg up to 50 IU/kg, was well tolerated. For postoperative FXIII replenishment, 35 IU/kg of rFXIII-A2 may be the most appropriate dose.

Hemostatic Activation and Inflammatory Response during Cardiopulmonary Bypass

2002 ◽  
Vol 97 (4) ◽  
pp. 837-841 ◽  
Author(s):  
Andreas Koster ◽  
Thomas Fischer ◽  
Michael Praus ◽  
Helmut Haberzettl ◽  
Wolfgang M. Kuebler ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
Inflammatory Response ◽  
Thrombin Generation ◽  
Antithrombin Iii ◽  
Clotting Time ◽  
Anticoagulation Management ◽  
Heparin Concentration ◽  
Activated Clotting Time ◽  
Inflammatory System

Background Cardiac surgery involving cardiopulmonary bypass (CPB) leads to fulminant activation of the hemostatic-inflammatory system. The authors hypothesized that heparin concentration-based anticoagulation management compared with activated clotting time-based heparin management during CPB leads to more effective attenuation of hemostatic activation and inflammatory response. In a randomized prospective study, the authors compared the influence of anticoagulation with a heparin concentration-based system (Hepcon HMS; Medtronic, Minneapolis, MN) to that of activated clotting time-based management on the activation of the hemostatic-inflammatory system during CPB. Methods Two hundred elective patients (100 in each group) undergoing standard cardiac surgery in normothermia were enrolled. No antifibrinolytic agents or aprotinin and no heparin-coated CPB systems were used. Samples were collected after administration of the heparin bolus before initiation of CPB and after conclusion of CPB before protamine infusion. Results There were no differences in the pre-CPB values between both groups. After CPB there were significantly higher concentrations ( &lt; 0.05) for heparin and a significant reduction in thrombin generation (25.2 +/- 21.0 SD vs. 34.6 +/- 25.1), d-dimers (1.94 +/- 1.74 SD vs. 2.58 +/- 2.1 SD), and neutrophil elastase (715.5 +/- 412 SD vs. 856.8 +/- 428 SD), and a trend toward lower beta-thromboglobulin, C5b-9, and soluble P-selectin in the Hepcon HMS group. There were no differences in the post-CPB values for platelet count, adenosine diphosphate-stimulated platelet aggregation, antithrombin III, soluble fibrin, Factor XIIa, or postoperative blood loss. Conclusion Compared with heparin management with the activated clotting time, heparin concentration-based anticoagulation management during CPB leads to a significant reduction of thrombin generation, fibrinolysis, and neutrophil activation, whereas there is no difference in the effect on platelet activation. The generation of fibrin even in the presence of high heparin concentrations most likely has to be attributed to the reduced antithrombin III concentrations or reduced inhibition of clot-bound thrombin. Therefore, in addition to maintenance of higher heparin concentrations, monitoring and substitution of antithrombin III should be considered to ensure more efficient antithrombin activity during CPB.

Effects of conventional CPB and mini-CPB on neutrophils CD162, CD166 and CD195 expression

Perfusion ◽  
2016 ◽  
Vol 32 (2) ◽  
pp. 141-150 ◽  
Author(s):  
Drahomira Holmannova ◽  
Martina Kolackova ◽  
Jiri Mandak ◽  
Pavel Kunes ◽  
Zdenka Holubcova ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
Fluorescence Intensity ◽  
Study Groups ◽  
Median Fluorescence Intensity ◽  
The Other ◽  
Blood Samples ◽  
Post Surgery ◽  
The Impact

Objective: Cardiac surgery is known to trigger a systemic inflammatory response. While the use of conventional cardiopulmonary bypass (CPB) results in profound inflammation, modified mini-CPB is considered less harmful. We evaluated the impact of cardiac surgery on the expression of CD162, CD166, CD195 molecules and their association with the type of CPB used. Methods and Results: Twenty-four patients were enrolled in our study. Twelve of them were operated using conventional CPB while the other twelve patients underwent surgery with mini-CPB. Blood samples were analysed by flow cytometry. We observed a significant increase in median fluorescence intensity of CD162 and CD195 that peaked instantly after surgery and normalized to the baseline value on the 1st day post surgery, whereas CD166 was initially down-regulated and its median fluorescence intensity (MFI) value increased to the baseline in the next few days. Conclusion: We observed immediate changes in the expression of CD162, CD166, and CD195 molecules on the neutrophils after surgery in both study groups of patients. The intensity of the observed changes was significantly greater in the group of patients who underwent conventional CPB compared to patients who underwent mini-CPB cardiac surgery.

scholarly journals Different Approaches to Reduce Bleeding of a Hemophilia-A Patient during Cardiac Surgery

2021 ◽  
pp. 1-4
Author(s):  
Kianoush Saberi ◽  
Kianoush Saberi ◽  
Alireza Bakhshandeh ◽  
Shahnaz Sharifi ◽  
Mehrdad Salehi
Keyword(s):  
Congenital Heart Disease ◽  
Cardiac Surgery ◽  
Heart Disease ◽  
Cardiopulmonary Bypass ◽  
Congenital Heart ◽  
Septal Defect ◽  
Hemophilia A ◽  
Coagulation System ◽  
Significant Challenge ◽  
Heparin Administration

A 16-year-old hemophilia-A patient presented with symptomatic atrial septal defect (ASD). Managing bleeding during cardiovascular surgeries is a significant challenge, even for none-hemophilic patients, due to heparin administration, cardiopulmonary bypass (CPB) coagulopathy and surgical complications. This essay is an effort to discuss ASD, CPB effects on the coagulation system, and highlight some approaches to lower bleeding in hemophilic patients with congenital heart disease.

scholarly journals An Exploratory, Observational Cohort Study on the Dynamics of Heparin Binding Protein in Cardiothoracic Surgery Using Cardiopulmonary Bypass

2020 ◽  
Author(s):  
Niklas Sterner ◽  
Jane Fisher ◽  
Louise Thelaus ◽  
Carolin Ketteler ◽  
Špela Lemež ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Cardiopulmonary Bypass ◽  
Organ Dysfunction ◽  
Binding Protein ◽  
Surgical Trauma ◽  
Heparin Binding ◽  
Postoperative Infections ◽  
Heparin Binding Protein ◽  
Heparin Administration ◽  
Protamine Administration

Abstract BackgroundSurgical trauma and cardiopulmonary bypass (CPB) cause an inflammatory response, difficult to differentiate from postoperative infections. Heparin-binding protein (HBP) is released from neutrophils and has been shown to predict infection-related organ dysfunction and disease progression to severe sepsis. In order to explore the potential of HBP as a biomarker for postoperative infections and asess possible confounding effects of concomitant medications, this study aimed to investigate the pre-, intra- and postoperative dynamics of HBP in cardiac surgery with CPB.Methods Thirty patients undergoing cardiac surgery with CPB were included, of which 15 underwent coronary artery bypass grafting (CABG) surgery and 15 underwent complex procedures with longer CPB duration. Ten patients undergoing lung surgery without CPB were also included as a conventional surgery reference group. HBP was measured at nine different perioperative time points.Results Our results showed that HBP levels were not affected by surgical trauma by itself. An increase in HBP levels was observed immediately following heparin administration and further increased during CPB. Prior to protaminization, we measured higher peak HBP-levels in the complex group (345.7 (287.8-472.6) ng/mL) compared with the CABG group (152.7 (85.3-204.0) ng/mL, p<0.001). HBP decreased rapidly following cessation of CPB and simultaneous protamine administration. Delay of protamine administration revealed that protamine, and not the cessation of CPB is primarily responsible for the rapidly reduced HBP concentration. At the arrival to the ICU, the median HBP levels were 24.8 (15.6-38.1) ng/mL for CABG patients compared with 50.5 (36.5-104.6) ng/mL for complex surgery patients (p=0.004). One day after surgery, HBP levels in all three groups were below the proposed cutoff of 30 ng/mL, previously found to predict development of organ dysfunction during infection, while other biomarkers for infections remained elevated.ConclusionsHBP levels are elevated by administration of heparin and the use of CPB but reduced by protamine administration. At postoperative day one, HBP levels were below the threshold for infection with organ dysfunction, indicating that postoperative HBP measurement may be a better screening tool for postoperative infections than other biomarkers of infections that remain elevated after surgery.

Early Heparin Administration Attenuates Tissue Factor-Mediated Thrombin Generation During Simulated Cardiopulmonary Bypass

2013 ◽  
Vol 29 (1) ◽  
pp. 35-40 ◽  
Author(s):  
Sei Morizumi ◽  
Yuji Hiramatsu ◽  
Kanji Matsuzaki ◽  
Yukinobu Goto ◽  
Shoko Sato ◽  
...  
Keyword(s):  
Cardiopulmonary Bypass ◽  
Tissue Factor ◽  
Thrombin Generation ◽  
Heparin Administration
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