Robert A. Castro

Procoagulant and anticoagulant factor abnormalities following the fontan procedure: increased factor VIII may predispose to thrombosis

OBJECTIVE Using age-matched controls, this study prospectively evaluated coagulation factor abnormalities and hemodynamic variables in children who had undergone the Fontan operation. METHODS Coagulation factors were assayed in 20 children (mean age 6.4 +/- 2.9 years), at a mean 3.7 +/- 2.3 years after the Fontan procedure; 24 healthy children (mean age 6.8 +/- 2.8 years) were assayed as controls. Concentration of factors II, V, VII, VIII, IX, X; ATIII; plasminogen; proteins C and S; fibrinogen; serum albumin; and liver enzymes were measured. Normal reference intervals based on the control patients were determined using 95% confidence limits. Patient demographic, hemodynamic variables, and elapsed time after the Fontan procedure were evaluated as possible predictors of coagulation abnormalities. RESULTS Concentrations of protein C; factors II, V, VII, X; plasminogen; and ATIII were significantly lower in Fontan patients compared with age-matched controls (P <.01); factor VIII was significantly elevated in 6 patients (35%), 2 of whom had a thromboembolic event. A higher superior vena cava pressure was predictive of an elevated factor VIII level (P =.003). No other specific hemodynamic variables were predictive of a procoagulant or anticoagulant abnormality. CONCLUSION Procoagulant and anticoagulant factor levels were significantly lower in patients after the Fontan operation independent of hemodynamic variables peculiar to the Fontan circulation. Increased factor VIII level requires further evaluation as a cause of thrombosis in patients with Fontan physiology and may also indicate a subset of these patients in whom anticoagulation is indicated.

Prospective longitudinal study of coagulation profiles in children with hypoplastic left heart syndrome from stage I through Fontan completion

OBJECTIVE The risk for thrombosis is increased after the Fontan operation. It is unknown whether children with univentricular heart disease have an intrinsic coagulation anomaly or acquire a defect in coagulation during the course of the staged repair. This prospective, longitudinal study evaluated changes in coagulation profiles in a cohort of patients with hypoplastic left heart syndrome from stage I palliation through completion of the Fontan operation. METHODS Thirty-seven patients with hypoplastic left heart syndrome were enrolled prospectively, and the concentration of factors II, V, VII, VIII, IX, X, proteins C and S, fibrinogen, antithrombin, serum albumin, and liver enzymes were measured before stage I palliation (mean age 4 +/- 2 days), before bidirectional Glenn (mean age 5.9 +/- 1.8 months), before the Fontan procedure (mean age 27.1 +/- 6.6 months), and after the Fontan procedure (mean age 49 +/- 17.6 months). Healthy children were used as age-matched controls for coagulation factors. Demographic, hemodynamic variables, and elapsed time after the Fontan procedure were evaluated as possible predictors of coagulation abnormalities. RESULTS Significantly lower levels of both procoagulation and anticoagulation factors were demonstrated through to completion of the Fontan procedure. After the Fontan procedure, there was a significantly higher factor VIII level (P < .005) but no correlation with hemodynamic variables or liver function. CONCLUSION This longitudinal study in patients with identical cardiac disease and staged surgical procedures confirms the increase in factor VIII level after the Fontan procedure. This is an acquired defect, and although the cause remains to be determined, monitoring factor VIII levels after the Fontan operation could indicate a subset of patients at risk for thrombosis.

Coagulation factor abnormalities in patients with single-ventricle physiology immediately prior to the fontan procedure

BACKGROUND Coagulation abnormalities have been reported following the Fontan operation and have been attributed to various aspects of Fontan-associated physiology. Using age-matched controls, this study evaluated coagulation abnormalities in children who had undergone a bidirectional Glenn procedure to test the hypothesis that coagulation abnormalities are present before the Fontan operation. METHODS Coagulation factors were assayed in 38 children (mean age 34.4 +/- 15 months) immediately before the Fontan operation; 37 healthy children (mean age 33 +/- 17 months) were assayed as controls. Concentration of factors II, V, VII, VIII, IX, and X and of antithrombin III, plasminogen, proteins C and S, fibrinogen, serum albumin, and liver enzymes were measured. Normal reference intervals based on the control patients were determined using 95% confidence limits. Patient demographic data, hemodynamic variables, and elapsed time after the Glenn procedure were evaluated as possible predictors of coagulation abnormalities. RESULTS Concentrations of protein C; factors II, V, VII, and X; plasminogen; and antithrombin III were significantly lower before the Fontan operation compared with age-matched controls (p < 0.01); no specific hemodynamic variables were predictive of a pro- or anticoagulant deficiency. There were significant positive correlations between patients who had abnormally low factor VII, protein S, and protein C levels and a longer interval between the bidirectional Glenn procedure and the Fontan operation (p < 0.001). CONCLUSIONS Coagulation abnormalities that could predispose patients to increased risk for clotting or bleeding are evident early in the course of staged single-ventricle repair.

Hemostatic consequences of a non‐fresh or reconstituted whole blood small volume cardiopulmonary bypass prime in neonates and infants

Objectives:  Despite aggressive measures to miniaturize the cardiopulmonary bypass (CPB) circuit in neonates and infants, the CPB prime volume is often at least as large as the patients’ blood volume. We conducted an observational study to characterize the hemostatic consequences of a CPB prime consisting of either non‐fresh or reconstituted whole blood.

The effect of milrinone on platelet activation as determined by TEG platelet mapping.

BACKGROUND: Milrinone is a phosphodiesterase III inhibitor that increases intracellular cyclic adenosine monophosphate resulting in improved ventricular function and vasodilation. Increased intracellular levels of cyclic adenosine monophosphate also inhibit adenosine diphosphate (ADP) and arachidonic acid (AA)-induced platelet aggregation. We hypothesized that inhibition of ADP and AA-induced platelet activation by therapeutic blood concentrations of milrinone could be quantified using TEG® Platelet Mapping™. METHODS: Blood was taken from 15 healthy adults who had not been taking antiplatelet medications. Milrinone was added to whole blood in three clinically relevant concentrations (30, 100, and 300 ng/mL). Conventional thromboelastography (TEG®) and TEG Platelet Mapping were performed on whole blood without milrinone and at each of these three concentrations. RESULTS: Increased blood concentrations of milrinone were associated with increased inhibition of ADP and AA-induced platelet activation (P < 0.0001). Milrinone at a blood concentration of 300 ng/mL markedly impaired the platelet activation response to ADP and AA. CONCLUSIONS: Therapeutic blood concentrations of milrinone exhibit a significant inhibitory effect on ADP and AA-induced platelet activation as determined by TEG Platelet Mapping, without affecting the conventional kaolin-activated TEG. We suggest that TEG Platelet Mapping results be interpreted with caution in patients being treated with milrinone, and other drugs that modify platelet cyclic nucleotide concentrations.

Premature chromosome condensation as a predictive indicator of relapse in children and adolescents with acute leukemia: initial observations.

Premature chromosome condensation has been used to determine a proliferative potential index (PPI) in a study of children in leukemia remission at varying times during the disease. Values 35% and greater were considered predictive of relapse. Such values preceded relapse with a mean of 5 months in acute lymphoblastic leukemia (ALL) patients who had previously relapsed and in myeloid leukemia patients. ALL patients followed from diagnosis and children off therapy had fluctuating and false predictive PPI values preceding long courses of continued remission. This study suggests that the PPI as a predictive indicator for relapse may be useful for patients with ALL who have previously relapsed and for patients with myeloid leukemias. Future exploration to further evaluate this mechanism of prediction is to be attempted by investigating the ability to obtain similar and more detailed information through the use of peripheral blood rather than bone marrow samples.

Methodology of premature chromosome condensation and its potential for relapse prediction in acute leukemia of children and adolescents

Premature chromosome condensation has been examined as a method for measuring the proliferative potential of bone marrow cells derived from children with acute leukemia with the intention of finding a predictor of relapse. A proliferative potential index (PPI) has been determined for patients with active disease at diagnosis and relapse, as well as at onset of remission and at extramedullary relapse. A modification of the technique established by Hittelman is described, which can be easily performed by the leukemia cytogeneticist. A PPI of 35% or greater is usually obtained for patients at diagnosis or in relapse. At the onset of remission, the PPI declines to values significantly below 35% and during extramedullary relapse the value of the PPI is near normal (12%). The method for the determination of the PPI is given in detail.

EVALUATION OF THE COAGULATION SYSTEM IN CHILDREN WITH TWO-VENTRICLE CONGENITAL HEART DISEASE

BACKGROUND Multiple coagulation factor abnormalities involving both procoagulant and anticoagulant proteins have been described in children with single-ventricle physiology. This study used age-matched controls to evaluate coagulation factors in children with two-ventricle congenital heart disease (CHD). METHODS Coagulation factors were assayed in 120 patients with CHD, divided into four age groups: group 1, 0 to 3 months; group 2, 3 to 12 months; group 3, 12 to 48 months; and group 4, older than 48 months. Healthy children without CHD were assayed as controls. Concentration of factors II, V, VII, VIII, IX, and X; protein C and S, plasminogen, and antithrombin III, were measured by standard assays. Normal ranges were determined by the empirical 95% confidence intervals. RESULTS Significant reductions were found in mean levels of both procoagulant and anticoagulant factors in patients in groups 1, 2, and 3 compared with controls, but no differences were found in group 4. In group 1, all variables had significantly lower concentrations except fibrinogen and protein S; in group 2, all variables had significantly lower concentrations except for fibrinogen, factors VIII and IX, and plasminogen and protein S; and in group 3, all variables had significantly lower concentrations except fibrinogen, factors VIII and IX, and antithrombin III, plasminogen, and protein S. CONCLUSIONS Neonates and infants with two-ventricle CHD have lower levels of procoagulant and anticoagulant factors compared with aged-matched controls approaching normal levels in children aged older than 4 years. These coagulation factor abnormalities are similar to those described in patients with single-ventricle physiology.