Propensity score method for analyzing the effect of labor induction in prolonged pregnancy.

INTRODUCTION: There is an ongoing debate on the optimal time of labor induction to reduce the risks associated with prolonged pregnancy. MATERIAL AND METHODS: Registry-based study of 212 716 term, singleton cephalic deliveries between 2006 and 2012 in Finland comparing the outcomes of labor induction with those of expectant management in five, three-day gestational age periods between 40 and 42 weeks (group 1: 40+0 -40+2 ; group 2: 40+3 -40+5 ; group 3: 40+6 -41+1 ; group 4: 41+2 -41+4 ; group 5: 41+5 -42+0 ). Using Poisson regression, induced deliveries in each of the gestational age periods were compared with all ongoing pregnancies. Propensity score matching was applied to reduce confounding by indication. RESULTS: In the gestational age groups 1 and 2, labor induction significantly decreased the risk of meconium aspiration syndrome [relative risk (RR) 0.40, 95% confidence interval (CI) 0.18-0.91 (group 1), RR 0.44, 95% CI 0.21-0.91 (group 2)] but increased the risk for prolonged hospitalization of a neonate [RR 1.30, 95% CI 1.10-1.54 (group 1) and RR 1.23, 95% CI 1.03-1.47 (group 2)]. In groups 3 and 4, labor induction significantly increased the risk for emergency cesarean section [RR 1.17, 95% CI 1.06-1.28 (group 3) and RR 1.19, 95% CI 1.09-1.29 (group 4)] but still reduced the risk for meconium aspiration syndrome. In group 5, labor induction did not affect the risk for any of the studied outcomes (operative delivery, obstetric trauma, neonatal mortality, respirator treatment, Apgar <7). CONCLUSIONS: Propensity score matching is a novel approach to studying the effect of labor induction. It highlighted the conflicting maternal and neonatal risks and benefits of the intervention, and supported expectant management as a valid option, at least until close to 42 weeks.

Coordinated responses of natural anticoagulants to allogeneic stem cell transplantation and acute GVHD - A longitudinal study.

BACKGROUND: Allogeneic stem cell transplantation (SCT) enhances coagulation via endothelial perturbation and inflammation. Role of natural anticoagulants in interactions between coagulation and inflammation as well as in acute graft-versus-host disease (GVHD) are not well known. The purpose of this study was to define changes in natural anticoagulants over time in association with GVHD. PATIENTS AND METHODS: This prospective study included 30 patients who received grafts from siblings (n = 19) or unrelated donors (n = 11). Eight patients developed GVHD. Standard clinical assays were applied to measure natural anticoagulants, represented by protein C (PC), antithrombin (AT), protein S (PS), complex of activated PC with its inhibitor (APC-PCI) and by markers of endothelial activation: Factor VIII coagulant activity (FVIII:C) and soluble thrombomodulin (s-TM) at 6-8 time points over three months. RESULTS: Overall, PC, AT and FVIII:C increased in parallel after engraftment. Significant correlations between PC and FVIII:C (r = 0.64-0.82, p<0.001) and between PC and AT (r = 0.62-0.81, p<0.05) were observed at each time point. Patients with GVHD had 21% lower PC during conditioning therapy and 55% lower APC-PCI early after transplantation, as well as 37% higher values of s-TM after engraftment. The GVHD group had also increases of PC (24%), FVIII: C (28%) and AT (16%) three months after transplantation. CONCLUSION: The coordinated activation of natural anticoagulants in our longitudinal study indicates the sustained ability of adaptation to endothelial and inflammatory activation during allogenic SCT treatment. The suboptimal control of coagulation by natural anticoagulants at early stage of SCT may contribute to onset of GVHD.

Activated protein C retards recovery from coagulopathy in severe acute pancreatitis.

OBJECTIVES: Activated protein C (APC), an endogenous anticoagulant, has antithrombotic, fibrinolytic and anti-inflammatory properties. We recently conducted a controlled study (APCAP, activated protein C in severe acute pancreatitis) of APC treatment of patients with severe acute pancreatitis (SAP). Here we studied the effect of APC on the pivotal coagulation parameters of the surviving patients in the APCAP study. METHODS: The study consisted of 20 patients of whom 10 patients had received APC and 10 patients had received placebo. Coagulation parameters, physiological anticoagulants, thrombograms and circulating levels of IL-6 and CRP were determined on admission and at days 1, 3-4 and 6-7. RESULTS: During follow-up, the temporal levels of prothrombin time (PT) decreased and the temporal levels of thromboplastin time (TT) increased in placebo group (p< 0.001 for both), but not in APC group. The temporal levels of antithrombin (AT) increased less in APC group than in placebo group (p = 0.011). The shapes of the SAP patients' thrombograms were strongly deranged and were marginally affected by APC treatment. CONCLUSIONS: Coagulopathy in SAP, a complex phenomenon, is not alleviated by APC treatment. Rather, the patients receiving APC are heading toward normal homeostasis of coagulation slower than patients receiving placebo.

Antenatal betamethasone associates with transient immunodepression in very low birth weight infants.

BACKGROUND: Antenatal betamethasone (BM) treatment for mothers at risk for premature delivery is effective in reducing neonatal morbidity. Immunodepression, defined as monocyte human leukocyte antigen (HLA)-DR expression <60%, is common in patients in intensive care. In very low birth weight (VLBW) infants, immunodepression correlates with gestational age and may predispose to infections. OBJECTIVES: To evaluate whether timing of antenatal BM associates with immunodepression in VLBW infants. METHODS: We determined monocyte HLA-DR expression by flow cytometry and measured 13 cytokines, cortisol, and BM in plasma from 56 VLBW infants. We calculated total glucocorticoid index as the sum of BM and cortisol at the ratio 33.3:1. RESULTS: HLA-DR expression both in cord (R(2) = 0.175, p = 0.033, n = 26) and on day 1 (R(2) = 0.125, p = 0.011, n = 51) showed an association with timing of BM. A short interval from BM to birth induced more pronounced and prolonged immunodepression, with lower HLA-DR% on postnatal day 7. On day 3, 25 infants (45%) met the criteria of immunodepression. HLA-DR expression correlated negatively with total glucocorticoid index (cord: R(2) = -0.573, p = 0.003, n = 13; day 1: R(2) = -0.213, p = 0.008, n = 32). Elapsed time from maternal BM correlated positively with concentrations of cytokines IL-6 and IL-10 on day 1. CONCLUSIONS: In VLBW infants, antenatal BM associated with transient immunodepression in a time-dependent manner. Suppression of both anti- and proinflammatory cytokines occurred. These effects may lead to an increased risk for later infections.

Coordinated release of tissue factor and tissue factor pathway inhibitor in VLBW infants.

AIM: Tissue factor (TF), a mediator between coagulation and inflammation, is upregulated in alveolar compartment and circulation in very low birthweight (VLBW) infants. We investigated the contribution of TF to systemic regulation of coagulation in VLBW infants. METHODS: We measured TF, total and free tissue factor pathway inhibitor (TFPIt, TFPIf), prothrombin fragment (F1 + 2), and thrombin-antithrombin complexes (TAT) in plasma from 51 VLBW infants during their first week of life. RESULTS: F1 + 2 in cord plasma was high (1385 pmol/mL) and decreased postnatally to 17% (p = 0.002). TAT decreased from a high cord concentration to 3% postnatally (p < 0.001). Plasma TF increased and peaked on day 3, showing no correlation with F1 + 2 or TAT. TFPIt and TFPIf increased postnatally, correlating with TF (day 1 TFPIf: R = 0.595, p < 0.001, day 3 TFPIf: R = 0.582, p < 0.001). Based on the TF/TFPIf ratio, a relative excess of plasma TF over TFPIf probably prevailed on day 3. CONCLUSIONS: In VLBW infants plasma TF fails to associate with thrombin formation. This is partly explained by release of TFPI. Despite TFPI, the newborn VLBW infant is subjected to a substantial circulating pool of TF with potential proinflammatory effects.

Low monocyte HLA-DR expression as an indicator of immunodepression in very low birth weight infants.

BACKGROUND: As a protective response to an inflammatory stimulus, the antigen-presenting molecules (human leukocyte antigen-DR (HLA-DR)) on monocytes are downregulated. If severe, the response may lead to immunodepression or immunoparalysis, associated with an increased rate of morbidity and mortality in adults. In very low birth weight (VLBW) infants, birth and intensive care present major immunological challenges. METHODS: We measured monocyte HLA-DR expression by flow cytometry and determined 13 plasma cytokines in 56 VLBW infants (gestational age (GA): 23.7-31.8 wk) and 25 controls (GA: 34.1-41.4 wk). RESULTS: HLA-DR expression decreased postnatally both in VLBW and in control infants. In VLBW infants, GA and respiratory distress syndrome (RDS) both showed associations with HLA-DR nadir on day 3, when 45% of them met the criteria of immunodepression. HLA-DR expression was lower in those infants subsequently developing infection (74 vs. 49% (day 3) and 85 vs. 68% (day 7); both P = 0.002). Interleukin (IL)-6 on day 1 was a predictor of the HLA-DR nadir. CONCLUSION: VLBW infants are in a state of immunodepression postnatally. This immunodepression correlated with GA and was a predisposing factor for late infections. The downregulation of HLA-DR during RDS probably indicates an RDS-induced antigen load on the immune system.

Thrombin formation and effect of unfractionated heparin during pediatric cardiac catheterization.

OBJECTIVES: To assess the strength of thrombin formation and determine the effects of unfractionated heparin (UFH) in children during cardiac catheterization. BACKGROUND: UFH reduces the thrombotic risk related to catheterization but the effects of UFH on the coagulation system in children, and proper monitoring of UFH remain unclear. METHODS: We studied 42 patients aged 3-12 years undergoing catheterization. Twenty-seven received UFH (group A) and 15 patients did not (group B). Anticoagulation was assessed by measurements of plasma prothrombin fragment F1 + 2, thrombin-antithrombin (TAT) complexes, D-dimer, activated partial thromboplastin time (APTT), anti-FXa, and prothrombinase-induced clotting time (PiCT). RESULTS: Markers of thrombin generation remained low during catheterization in group A. In group B, both F1 + 2 and TAT had increased significantly (P < 0.05) by the end of the procedure versus baseline and versus respective levels in group A. In group A, 15 min after heparinization, APTT was over 180 sec (in all patients), anti-FXa 1.4 U/ml (1.1-2.4 U/ml) and PiCT 1.5 U/ml (1.3-2.4 U/ml). Anti-FXa and PiCT were correlated (R = 0.84, P < 0.0001). CONCLUSIONS: Thrombin generation was enhanced in patients who did not receive UFH, which may increase the risk of thrombotic complications. In group A, routine heparinization seemed excessive by all monitoring methods. UFH prevented an increase in prothrombin to thrombin conversion, resulting in unaltered fibrin formation. The current UFH protocol seemed to have no effect on postprocedural activation of coagulation. Further studies are needed to clarify adequate heparin dosing for children during cardiac catheterization to prevent thrombotic complications without predisposing the patient to bleeding complications.

Enhanced thrombin generation and depressed anticoagulant function in children with pneumonia.

AIMS: To clarify the status of the coagulation system in children with community-acquired pneumonia. METHODS: Coagulation activation markers (prothrombin fragment F1 + 2, thrombin-antithrombin complexes, D-dimer), the natural anticoagulants (antithrombin, protein C and S) and tissue factor were measured in 28 consecutive children with pneumonia on admission to the hospital. Patients were divided into those with either bacterial-type pneumonia (at least two of the following three criteria: plasma C-reactive protein (CRP) >80 mg/L, white blood cell count >15 × 10(9) /L and alveolar infiltrates on the chest radiograph) or viral-type pneumonia. RESULTS: The majority of the patients (79%) showed elevation of at least one of the three coagulation activation markers. Plasma CRP concentration correlated with F1 + 2 (R = 0.44, p < 0.05) and D-dimer (R = 0.71, p < 0.0001). Patients with bacterial-type pneumonia (n = 17) had higher D-dimer levels (p < 0.05) and lower levels of antithrombin (p = 0.005) and protein C (p = 0.08) than the patients with viral-type pneumonia. CONCLUSIONS: Children with community-acquired bacterial-type pneumonia show distinctive changes in their coagulation system. The finding of coagulation system activation and depressed function of natural anticoagulants in uncomplicated pneumonia helps to understand the rapid and unpredictable changes observed in the coagulation status in patients with more severe forms of disease.

High tissue factor in lungs and plasma associates with respiratory morbidity in preterm infants.

AIM: In preterm infants, inflammation and intra-alveolar fibrin formation characterize respiratory distress syndrome (RDS). Tissue factor (TF) is a link between inflammation and coagulation pathways. We investigated the relationship between TF and cytokines in preterm infants to gain information of the role of TF in the inflammatory response. METHODS: We measured TF in plasma and in tracheal aspirates and analysed TF on monocytes by flow cytometry and 13 cytokines from plasma, in 56 preterm infants (birthweight 600-1500 g) during their first week. RESULTS: Plasma TF increased and peaked on day 3 and correlated with both RDS and inversely with paO2/FIO2. On day 1, TF in tracheal aspirates was 10-fold higher than in plasma and correlated with plasma TF (4888 vs. 506 pg/mL, R = 0.692, p = 0.013, n = 12). Of main pro-inflammatory cytokines, plasma TF correlated post-natally with IL-8 and IL-6 but not with IL-1 or TNF-α. CONCLUSIONS: Respiratory morbidity associates with high TF in lungs and plasma. In sick newborn infants, upregulation of TF may be mediated by IL-6 and IL-8. High TF and pro-inflammatory cytokines may together participate in the pathogenesis of pulmonary and extrapulmonary injury in preterm infants through pro-inflammatory mechanisms.

Inflammation and coagulation. An overview.

Inflammation and coagulation are two main host-defence systems that interact with each other. Inflammation activates coagulation and coagulation modulates the inflammatory activity in many ways. The contributing molecular pathways are reviewed. Thrombin and activated protein C (APC) and its receptor EPCR constitute a major physiological regulatory system to control vascular wall permeability during sepsis. Pro-inflammatory cellular effects of coagulation proteases as well as the anti-inflammatory effects of APC/EPCR are mediated by signaling via protease activated receptors PAR on mononuclear cells, endothelial cells, platelets, fibroblast, and smooth muscle cells. The beneficial effects of APC in sepsis are mainly dependent on the PAR-mediated cell-protective properties rather than the anticoagulant protease function on coagulation cofactors FV/Va and FVIII/VIIIa. Animal experiments with signaling selective APC-variants show promise in improving the therapeutic efficacy and safety of APC in sepsis.

Increased preoperative thrombin generation and low protein S level associated with unfavorable postoperative hemodynamics after coronary artery bypass grafting.

In a previous study, preoperative levels of activated protein C (APC) were associated with unfavorable postoperative hemodynamics after coronary artery bypass grafting (CABG). Protein C is activated by thrombin. Protein S, the cofactor of activated protein C, has activated protein C-independent anticoagulant activity and cytoprotective effects. Therefore, the objective of this study was to test whether preoperative, baseline levels of either thrombin or protein S were associated with hemodynamic performance or markers of myocardial damage after CABG. One hundred patients undergoing elective on-pump CABG were prospectively studied. Prothrombin fragment F1+2 (a marker of thrombin generation) and free protein S were measured preoperatively and cardiac index, systemic vascular resistance index (SVRI), and pulmonary vascular resistance index (PVRI) were measured serially thereafter at fixed time points. Cardiac biomarkers CK-MBm and TnT were measured postoperatively. There was an inverse correlation between preoperative F1+2 and free protein S levels (r= -0.30, p=0.003). High preoperative F1+2 and low preoperative protein S levels were associated with a less favorable hemodynamic profile postoperatively. Patients with F1+2 in the highest decile (≥0.85 nmol/l) and patients with preoperative protein S in the lowest decile (≤63%) had lower CI values, and higher pulmonary and systemic vascular resistance index values postoperatively than comparison patients. Preoperative F1+2 or protein S did not correlate with postoperative cardiac biomarker levels. Baseline activation of coagulation and the balance between pro-coagulant and anti-coagulant factors preoperatively might have implications for postoperative hemodynamic recovery after CABG.

Thrombin generation in vitro and in vivo, and disturbed tissue factor regulation in patients with acute pancreatitis.

BACKGROUND: Being a central link between inflammation and coagulation, tissue factor (TF) and its inhibitor (TFPI) might be associated with the severity of acute pancreatitis (AP) and the development of organ failure (OF). METHODS: The study comprises 9 severe AP patients with OF and 24 reference patients (11 mild AP and 13 severe AP without OF). Plasma samples were collected on admission. TF-induced thrombin generation in plasma samples was studied using the thrombogram method. In vivo thrombin generation was estimated by prothrombin fragment F1+2. Free and total TFPI levels were measured. To evaluate coagulation status the activated partial thromboplastin time, prothrombin time, platelet count, D-dimer, fibrinogen, antithrombin (AT) 3 and protein C (PC) were determined. RESULTS: There was no significant difference in F1+2 levels between the patient groups. Patients with severe AP tended to show low platelet counts, PC and AT3 levels, and high D-dimer levels. In 11 patients the standard TF stimulation did not trigger thrombin generation in the thrombogram. All deaths occurred in these patients. Free TFPI levels and free/total TFPI ratios were significantly higher in these patients and in non-survivors. CONCLUSION: Failure of TF-initiated thrombin generation in the thrombogram assay explained by high levels of circulating free TFPI may be associated with OF and mortality in AP. and IAP.

Thrombin in myocardial ischemia-reperfusion during cardiac surgery.

Thrombin is a multifunctional protease with procoagulant, pro-inflammatory, and pro-apoptotic effects. Thrombin has direct potentially adverse effects on the endothelium and on cardiomyocytes, which are independent of its procoagulant effects, and it has emerged as a possible mediator of ischemia-reperfusion injury. Several lines of experimental evidence specifically implicate thrombin to be involved in myocardial ischemia-reperfusion injury. Cardiopulmonary bypass increases thrombin generation progressively, but reperfusion after myocardial ischemia induces an additional distinct and rapid increase in thrombin generation. Clinical studies have shown that thrombin formation during cardiac surgery, especially during myocardial reperfusion, is involved with myocardial damage and impaired hemodynamic recovery. Therefore, strategies to improve thrombin control during cardiopulmonary bypass might be beneficial.

Intragraft coagulation events and delayed graft function in clinical renal transplantation.

BACKGROUND: Cold preservation, reperfusion damage, immunosuppressive drugs, and uremia-induced acquired thrombophilias increase the risk of thrombotic complications in renal transplantation. Intragraft fibrin deposition may be associated with delayed graft function. METHODS: We studied coagulation and fibrinolysis in 45 patients of a larger trial in renal transplantation: perioperative antithymocyte globulin (group A, n=15), perioperative basiliximab (group B, n=16), and conventional triple therapy (group C, n=14). Blood samples for prothrombin fragment F1+2, plasminogen activator inhibitor (PAI)-1, d-dimer, tPA antigen, tPA activity, and platelet counts were obtained simultaneously at 1 and 5 min after reperfusion from iliac artery and graft vein for calculation of transrenal changes. Because antithymocyte globulin activates coagulation and fibrinolysis, group A was analyzed separately. Groups B and C were pooled (group BC). RESULTS: In group BC, transrenal D-dimer release occurred at 1 min, tPA-antigen release at 1 and 5 min, and transrenal PAI-1 uptake at 5 min postreperfusion. tPA activity increased marginally only at 1 min. High graft tPA-antigen release at 5 min and D-dimer release at 1 min were associated with delayed graft function. In group A, transrenal tPA-antigen release occurred at 1 and 5 min and D-dimer release at 1 min. There were no transrenal F1+2 changes in either group. CONCLUSION: Although graft PAI-1 uptake inhibits tPA activity, graft releases D-dimer at early reperfusion without concomitant F1+2 release. Data suggest thrombin and fibrin formation already before cold preservation during donor care and organ retrieval. This fibrin deposition increases risk of delayed graft function.

Monitoring high-dose heparinization during cardiopulmonary by-pass--a comparison between prothrombinase-induced clotting time (PiCT) and two chromogenic anti-factor Xa activity assays.

Heparinization requires monitoring, but optimal methods for measuring the anticoagulant effects of heparin remain to be determined. We compared prothrombinase-induced clotting time (PiCT) and two chromogenic anti-factor Xa activity (anti-Xa) assays in monitoring high-dose heparinization during cardiopulmonary by-pass (CPB). Heparin effects were serially measured with PiCT and two anti-Xa assays in 100 patients. Antithrombin and protein C activities were measured preoperatively, and antithrombin activity was measured during CPB. Activation of coagulation was assessed with measurements of prothrombin fragment F1+2, soluble fibrin complexes, and D-dimer before, during, and after CPB. During CPB mean ranges of PiCT and of anti-Xa heparin levels measured with (anti-Xa A) and without (anti-Xa B) dextran sulfate and antithrombin supplementation were 5.0-5.2, 4.7-5.0, and 4.5-4.9 IU/ml, respectively. There was poor agreement between PiCT and anti-Xa and between the two anti-Xa assays (r = 0.32-0.65 and broad limits of agreement). Patients with low preoperative antithrombin or protein C levels had lower PiCT (p = 0.028 and p = 0.01) and anti-Xa A (both p<0.001) levels during CPB than others. Patients with the lowest heparin activities during CPB (lowest deciles of PiCT and anti-Xa A) had higher subsequent F1+2 after CPB (p = 0.002 and p = 0.02), and patients with high heparin levels required fewer transfusions of packed red blood cells than others. In conclusion, in the challenging setting of CPB there is poor agreement between anti-Xa assays and PiCT. However, coagulation-based PiCT could provide an alternative to the chromogenic anti-Xa assays. Higher heparin levels during CPB were confirmed to associate with reduced transfusion requirements.

Thrombophilic variables do not increase the generation or procoagulant activity of thrombin during cardiopulmonary bypass.

BACKGROUND: The generation of thrombin and its procoagulant activity are upregulated during cardiopulmonary bypass (CPB). Thrombophilia associates with increased basal thrombin generation and might therefore propagate thrombin generation during CPB. The objective of this study was to test whether preoperative thrombophilic variables associate with increased generation of thrombin or its procoagulant activity during and after CPB. METHODS: Comprehensive thrombophilia screening was performed in patients (n = 100) before elective coronary artery bypass grafting (CABG) with CPB. Markers of thrombin generation (prothrombin fragment F1+2), its procoagulant activity (soluble fibrin complexes), and a marker of fibrin degradation (D-dimer) were measured serially at eight time points before, during, and after CABG. RESULTS: Abnormal thrombophilia screening was common (44%). While patients with thrombophilic variables had higher preoperative prothrombin fragment F1+2 than others (median [interquartile range] 0.55 [0.34] vs 0.45 (0.21) nmol/L, p = 0.009) they did not have higher F1+2, D-dimer, or soluble fibrin complex levels during CPB or postoperatively than patients without thrombophilic variables. CONCLUSIONS: Preoperative thrombophilic variables do not associate with perioperative thrombin generation or its procoagulant activity in patients undergoing CABG. Our results do not support routine thrombophilia screening before CABG.

Inhibition of thrombin during reperfusion improves immediate postischemic myocardial function and modulates apoptosis in a porcine model of cardiopulmonary bypass.

OBJECTIVE: Transient left-ventricular dysfunction because of myocardial reperfusion injury is a significant problem after cardiac surgery, but the underlying complex pathophysiology is still poorly understood. The authors studied early functional recovery of the postischemic myocardium and explored potential effects of thrombin inhibition on procoagulatory, proinflammatory, and proapoptotic features of myocardial ischemia-reperfusion injury. DESIGN: A randomized, blinded study. SETTING: University research laboratory. SUBJECTS: Porcine model. INTERVENTIONS: Twenty pigs undergoing 60 minutes of aortic clamping and 75 minutes of normothermic cardiopulmonary bypass (CPB) received an intravenous bolus of r-hirudin (10 mg, 0.4mg/kg, n = 10) or placebo (n = 10) 15 minutes before aortic declamping, followed by a 135-minute intravenous infusion of r-hirudin (3.75 mg, 0.15 mg/kg/h) or placebo. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters were measured before CPB, after weaning from CPB, and at 30, 60, 90, and 120 minutes after aortic declamping. Blood was sampled, and myocardial biopsies were taken before CPB, just before aortic declamping, during reperfusion, and after 120 minutes of reperfusion to measure thrombin antithrombin complexes and to quantitate leukocyte infiltration (myeloperoxidase activity) for histologic evaluation and detection of apoptosis with caspase-3 and the TUNEL method. The r-hirudin group showed significantly higher stroke volume and cardiac output than the control group at 60 minutes and at 90 minutes after aortic declamping (p < 0.05). Microthrombosis was not observed in either group, indicating sufficient anticoagulation and excluding intravascular clots as explanations for LV dysfunction in the current experiment. Instead, ample myocardial activation of inflammation was present, but only a trend of r-hirudin-associated anti-inflammatory effect was observed. Compared with the controls, TUNEL-positive myocytes were detected significantly less frequently in the r-hirudin group (0.05 +/- 0.06 v 0.13 +/- 0.07 TUNEL-positive nuclei %, p = 0.042). CONCLUSIONS: The improved cardiac recovery in the r-hirudin group during reperfusion after cardioplegia-induced cardiac arrest was associated with significant differences in cardiomyocyte apoptosis and anti-inflammatory effects. Thus, in clinical cardiac surgery, inhibition of reperfusion- induced thrombin may offer beneficial effects by mechanisms other than direct anticoagulation.

Activation of protein C and hemodynamic recovery after coronary artery bypass surgery.

OBJECTIVES: Activated protein C is a physiologic anticoagulant that is activated by thrombin and upregulated during coronary artery bypass grafting. We studied the balance between thrombin generation and activated protein C levels during coronary artery bypass grafting and hypothesized that protein C activation during reperfusion is associated with hemodynamic recovery or postoperative myocardial damage. METHODS: One hundred patients undergoing elective on-pump coronary artery bypass grafting were prospectively studied. Activated protein C, protein C, prothrombin fragment F1+2 (a marker of thrombin generation), and D-dimer (a marker of fibrinolysis) levels were measured preoperatively and at 7 time points during cardiopulmonary bypass and reperfusion and postoperatively. Hemodynamic parameters were measured serially. Cardiac biomarkers (mass of the Mb fraction of creatine kinase and troponin T) were measured postoperatively. RESULTS: Reperfusion induced a significant increase in thrombin generation. Activated protein C levels peaked after heparin neutralization, when they increased more than 3-fold. Activated protein C levels correlated with F1+2 and D-dimer levels during cardiopulmonary bypass and reperfusion. Even though this correlation peaked during early reperfusion (r = 0.55, P < .001), the ratio of activated protein C to F1+2 decreased during surgical intervention and early reperfusion by 70% from the preoperative level, indicating a marked delay in protein C activation in relation to thrombin generation. Patients in the highest quintile of activated protein C levels during this period had a higher postoperative cardiac index (mean, 3.1 vs 2.5 L x min(-1) x m(-2); P < .05) and lower systemic vascular resistance (mean, 2137 vs 2429 dyne x s x cm(-5) x m(-2); P < .05). Conversely, levels of preoperative activated protein C and activated protein C measured after heparin neutralization were associated with unfavorable hemodynamic recovery postoperatively. Activated protein C or protein C levels were not associated with increased postoperative cardiac biomarkers. CONCLUSIONS: Reperfusion caused significant thrombin generation that was followed by activation of protein C. The balance of activated protein C with thrombin is associated dynamically with postoperative hemodynamic recovery.