Kelly A. Machovec

The procoagulant properties of purified fibrinogen concentrate are enhanced by carbon monoxide releasing molecule-2

INTRODUCTION Fibrinogen concentrate has been demonstrated to enhance coagulation in vitro and in several clinical settings of coagulopathy. We have recently demonstrated that carbon monoxide releasing molecule-2 (tricarbonyldichlororuthenium (II) dimer; CORM-2) enhances fibrinogen as a substrate for thrombin via an attached heme. The objective of this study was to determine if CORM-2 modified fibrinogen concentrate would enhance coagulation more effectively than CORM-2 naïve fibrinogen concentrate. MATERIALS AND METHODS In the first series of experiments, fibrinogen concentrate (final concentration 300mg/dl) was exposed to 0, 50 or 100μM CORM-2 for 5min at 37°C prior to being added to citrated, fibrinogen depleted plasma. In another series of experiments, citrated plasma obtained from 12 normal subjects was 50% diluted with crystalloid to which was added fibrinogen concentrate (final concentration 300mg/dl) exposed to 0 or 100μM CORM-2. Coagulation was activated with tissue factor (n=8 per condition). Thrombus growth was monitored with thrombelastography for 15min. RESULTS AND CONCLUSIONS CORM-2 modification of fibrinogen concentrate significantly enhanced the velocity of clot formation (30-50%) and strength (15-31%) in fibrinogen deficient plasma. Similarly, while diluted plasma-derived thrombi demonstrated a marked decrease in velocity of formation (54%) and strength (61%), fibrinogen concentrate significantly enhanced velocity (217%) and strength (171%); however, CORM-2 modified fibrinogen concentrate significantly increased velocity (303%) and strength (205%) to a greater extent. Additional in vitro investigation and in vivo preclinical assessments of the hemostatic efficacy of CORM-2 modified fibrinogen concentrate are warranted.

Carbon monoxide releasing molecule-2 enhances α2-antiplasmin activity.

The objective of this study was to determine whether carbon monoxide releasing molecule (tricarbonyldichlororuthenium (II) dimer, CORM-2) directly affects α2-antiplasmin activity. For this purpose, purified α2-antiplasmin was exposed to 0 or 100 μmol/l CORM-2 for 5 min at 37°C and then placed in α2-antiplasmin-deficient plasma (25 μg/ml α2-antiplasmin and 3.3 μmol/l CORM-2 final concentrations). In a second series of experiments, α2-antiplasmin and deficient plasma were combined and then exposed to 0 or 100 μmol/l CORM-2. Coagulation was activated with tissue factor and fibrinolysis initiated with tissue-type plasminogen activator (n = 8 per condition). Thrombus growth/disintegration kinetics were monitored with thrombelastography until clot lysis time occurred. Samples containing α2-antiplasmin preexposed to 100 μmol/l CORM-2 demonstrated no changes in the velocity of clot growth, but had a significant prolongation of the time to maximum rate of lysis, clot lysis time, and a significant decrease in the maximum rate of clot lysis compared with samples preexposed to 0 μmol/l CORM-2. In sharp contrast, addition of 100 μmol/l CORM-2 to premixed α2-antiplasmin in its deficient plasma resulted in significant, marked increases in the velocity of clot growth and the strength with concurrent antifibrinolytic effects as in the first series. In conclusion, CORM-2 exerts its antifibrinolytic effects by direct enhancement of α2-antiplasmin activity. It appears that combined modification of both fibrinogen and α2-antiplasmin are responsible for the robust procoagulant/antifibrinolytic effects of CORM-2 in the fibrinolytic environment.

3-Factor Prothrombin Complex Concentrates in Infants With Refractory Bleeding After Cardiac Surgery

From the *Department of Anesthesiology, Duke Children’s Pediatric and Congenital Heart Center, Duke University, Durham, NC; †Department of Anesthesiology, Duke University, Durham, NC; ‡Department of Surgery, Division of Cardiovascular and Thoracic Surgery, Duke Children’s Pediatric and Congenital Heart Center, Duke University, Durham, NC; and §Department of Anesthesiology, Division of Adult Cardiothoracic Anesthesiology and Critical Care Medicine, Duke University, Durham, NC. Address reprint requests to Edmund Jooste, MBChB, Department of Pediatric Anesthesiology, Duke University Medical Center Box 3094, Durham, NC, 27710. E-mail: Edmund.jooste@duke.edu

A change in anticoagulation monitoring improves safety, reduces transfusion, and reduces costs in infants on cardiopulmonary bypass

An immature coagulation system coupled with the hypothermia and hemodilution associated with cardiopulmonary bypass (CPB) in infants makes the activated clotting time (ACT) an ineffective monitor for anticoagulation in this population. The Medtronic HMS Plus Hemostasis Management System (HMS; Medtronic, Inc., Minneapolis, MN, USA) is shown to decrease thrombin generation and blood product requirements.

Reduction in blood transfusion in a cohort of infants having cardiac surgery with cardiopulmonary bypass after instituting a goal-directed transfusion policy

Background: Current trends in pediatric cardiac surgery and anesthesiology include goal-directed allogeneic blood transfusion, but few studies address the transfusion of platelets and cryoprecipitate. We report a quality improvement initiative to reduce the transfusion of platelets and cryoprecipitate in infants having cardiac surgery with cardiopulmonary bypass (CPB). Methods: Data from 50 consecutive patients weighing four to ten kilograms having cardiac surgery with CPB were prospectively collected after the institution of a policy to obtain each patient’s platelet and fibrinogen levels during the rewarming phase of CPB. Data from 48 consecutive patients weighing four to ten kilograms having cardiac surgery with CPB prior to the implementation of the policy change were retrospectively collected. Demographics, laboratory values and blood product transfusion data were compared between the groups, using the Chi-square/Fisher’s exact test or the T-Test/Wilcoxon Rank-Sum test, as appropriate. Results: The results showed more total blood product exposures in the control group during the time from bypass through the first twenty-four post-operative hours (median of 2 units versus 1 unit in study group, p=0.012). During the time period from CPB separation through the first post-operative day, 67% of patients in the control group received cryoprecipitate compared to 32% in the study group (p=0.0006). There was no difference in platelet exposures between the groups. Conclusion: Checking laboratory results during the rewarming phase of CPB reduced cryoprecipitate transfusion by 50%. This reproducible strategy avoids empiric and potentially unnecessary transfusion in this vulnerable population.

Natural history of nonimmune‐mediated thrombocytopenia and acute kidney injury in pediatric open‐heart surgery

Thrombocytopenia and acute kidney injury (AKI) are common following pediatric cardiac surgery with cardiopulmonary bypass (CPB). However, the relationship between postoperative nadir platelet counts and AKI has not been investigated in the pediatric population. Our objective was to investigate this relationship and examine independent predictors of AKI.

Cardiopulmonary Bypass Strategy for a Cyanotic Child With Hemoglobin SC Disease

Hemoglobin SC (HbSC) disease is a hemoglobinopathy that may produce sickling under conditions of hypoxemia, dehydration, and acidosis. We present a case of HbSC disease and tricuspid atresia, type IB. We describe management by cardiopulmonary bypass CPB using exchange transfusion at initiation of bypass and fractionation of collected blood, allowing platelet and plasma apheresis, as an option for patients unable to undergo this procedure off pump.

Ventricular pacing for induced hypotension in a toddler.

Cerebral aneurysm clipping may require periods of hypotension to facilitate dissection and clip application. We describe the use of rapid ventricular pacing to facilitate establishment of controlled hypotension for an 18-month-old child during clipping for giant basilar artery aneurysm. This technique is an alternative to pharmacologic means of inducing hypotension for neurosurgical procedures and has not been previously described in children.

Percutaneous endoscopic gastrostomy vs surgical gastrostomy in infants with congenital heart disease

Infants with congenital heart disease often require feeding tube placement to supplement oral intake. Gastrostomy tubes may be placed by either surgical or percutaneous endoscopic methods, but there is currently no data comparing outcomes of these procedures in this population.

Double-Blind, Randomized, Placebo-Controlled Trial Comparing the Effects of Antithrombin Versus Placebo on the Coagulation System in Infants with Low Antithrombin Undergoing Congenital Cardiac Surgery.

OBJECTIVES To determine whether precardiopulmonary bypass (CPB) normalization of antithrombin levels in infants to 100% improves heparin sensitivity and anticoagulation during CPB and has beneficial effects into the postoperative period. DESIGN Randomized, double-blinded, placebo-controlled prospective study. SETTING Multicenter study performed in 2 academic hospitals. PARTICIPANTS The study comprised 40 infants younger than 7 months with preoperative antithrombin levels <70% undergoing CPB surgery. INTERVENTIONS Antithrombin levels were increased with exogenous antithrombin to 100% functional level intraoperatively before surgical incision. MEASUREMENTS AND MAIN RESULTS Demographics, clinical variables, and blood samples were collected up to postoperative day 4. Higher first post-heparin activated clotting times (sec) were observed in the antithrombin group despite similar initial heparin dosing. There was an increase in heparin sensitivity in the antithrombin group. There was significantly lower 24-hour chest tube output (mL/kg) in the antithrombin group and lower overall blood product unit exposures in the antithrombin group as a whole. Functional antithrombin levels (%) were significantly higher in the treatment group versus placebo group until postoperative day 2. D-dimer was significantly lower in the antithrombin group than in the placebo group on postoperative day 4. CONCLUSION Supplementation of antithrombin in infants with low antithrombin levels improves heparin sensitivity and anticoagulation during CPB without increased rates of bleeding or adverse events. Beneficial effects may be seen into the postoperative period, reflected by significantly less postoperative bleeding and exposure to blood products and reduced generation of D-dimers.