Ashraf M. Aly

Histocompatibility antigen patterns in haemophilic patients with factor VIII antibodies.

Summary A number of studies suggest that there is a genetic basis for the formation by some haemophilia A patients of antibodies that inactivate factor VIII. In our study, human leucocyte antigen (HLA)‐A, B. C, DR and DQ typing was carried out for 44 haemophilia A patients, including 16 who had developed an antibody to factor VIII. In contrast to previous reports, we found no association between HLA‐DR antigens and haemophilia A per se or the formation of a factor VIII inhibitor. However, there was an absence of HLA‐Cw5 in the 16 haemophilic patients who had formed an antibody to factor VIII. This finding, consistent with a previous report, identified a statistically significant difference in HLA‐Cw5 frequency when the inhibitor patient group was compared to multi‐transfused haemophilic patients who had no inhibitor (11/28).

TWIN PRETERM NEONATES WITH CARDIAC TOXICITY RELATED TO LOPINAVIR/RITONAVIR THERAPY

We report twin neonates who were born prematurely at 32 weeks of gestation to a mother with human immunodeficiency virus infection. One of the twins developed complete heart block and dilated cardiomyopathy related to lopinavir/ritonavir therapy, a boosted protease-inhibitor agent, while the other twin developed mild bradycardia. We recommend caution in the use of lopinavir/ritonavir in the immediate neonatal period.

Cysteamine enhances the procoagulant activity of Factor VIII-East Hartford, a dysfunctional protein due to a light chain thrombin cleavage site mutation (arginine-1689 to cysteine).

We have recently identified the molecular defect responsible for cross-reacting material-positive hemophilia A in two unrelated patients in which the substitution of cysteine for arginine-1689 (Factor VIII-East Hartford[FVIII-EH]) abolishes a critical Factor VIII light chain thrombin cleavage site. As other mutant proteins with a cysteine for arginine substitution have been modified in the presence of cysteamine, we have determined the effect of this and other reducing agents on FVIII-EH function. Cysteamine concentrations between 0.1 and 10 mM caused dose- and time-dependent increases in FVIII-EH VIII:C activity, as much as 14-fold (to 35 and 62 U/dl for the two patients tested). Comparable data were obtained in a standard one-stage VIII:C coagulation assay and in a chromogenic substrate assay measuring Factor Xa generation. Thrombin cleavage of the FVIII-EH light chain in the presence of cysteamine was documented by immunoadsorption and analysis. Cystamine and cysteamine-S-phosphate, similar compounds that do not possess a free thiol group, had no effect. Cysteamine augmentation of FVIII-EH VIII:C was abolished by the simultaneous addition of N-ethyl maleimide or iodoacetamide, but these sulfhydryl blocking agents did not prevent the VIII:C increase and light chain cleavage by thrombin if the plasma samples were dialyzed to remove the inhibitors before adding the cysteamine. However, incubation with DTT before iodoacetamide prevented the cysteamine effect after dialysis. These data suggest that when isolated from patient plasma, FVIII-EH cysteine-1689 is present in a disulfide bond. This bond is cleaved by cysteamine to form a new mixed disulfide, a pseudolysine that restores a thrombin cleavage site that is essential for procoagulant function.

Factor VIII-East Hartford (arginine 1689 to cysteine) has procoagulant activity when separated from von Willebrand factor.

Factor VIII East Hartford (FVIII-EH) procoagulant activity is reduced because the substitution of cysteine for arginine 1689 abolishes an essential Factor VIII light chain thrombin cleavage site. Incubation of FVIII-EH plasma with penicillamine or DTT causes a five- to sixfold increase in FVIII-EH VIII:C, at 80 and 1 mM, respectively. While there is no FVIII-EH light chain cleavage when thrombin is added in the presence of penicillamine or DTT, these reducing agents disrupt the FVIII-vWf complex. For example, the addition of 5 mM DTT to normal or FVIII-EH plasma causes a 50% reduction in Factor VIII binding to vWf. These observations suggested that DTT increases FVIII-EH VIII:C by partial dissociation of FVIII-EH from vWf. This was verified by showing that vWf-free FVIII-EH had VIII:C activity of 21 U/dl, while the starting plasma level was 2.5 U/dl. Removal of other FVIII-EH plasma proteins by agarose gel filtration had no effect on VIII:C activity. The demonstration that this mutant Factor VIII has cofactor function when separated from vWf indicates that the dissociation of Factor VIII from vWf is an essential effect of Factor VIII light chain cleavage at arginine-1689.

Absent pulmonary valve syndrome with left hemitruncus.

Absent pulmonary valve syndrome (APVS) is a rare congenital heart defect, usually associated with tetralogy of Fallot (TOF), although other associations have been described. A pregnant woman was referred to fetal echocardiography clinic from the Maternal Fetal Medicine department due to abnormal findings on routine antenatal ultrasound, showing a pulsatile cystic mass above the left atrium and a suspected TOF. A fetal echocardiogram confirmed the presence of TOF/APVS. The pulsatile cystic mass was the aneurysmally dilated main pulmonary artery. The exact origin of the left pulmonary artery (LPA) was not clearly established prenatally. A postnatal echocardiogram of the neonate showed an abnormal origin of the LPA from the ascending aorta (hemitruncus). The neonate subsequently underwent surgical repair with a good outcome. We present a novel case of a TOF/APVS associated with an abnormal origin of the LPA from the ascending aorta.

Dilated Cardiomyopathy Induced by Chronic Starvation and Selenium Deficiency

Protein energy malnutrition (PEM) has been rarely documented as a cause of cardiovascular abnormalities, including dilated cardiomyopathy. Selenium is responsible for antioxidant defense mechanisms in cardiomyocytes, and its deficiency in the setting of PEM and disease related malnutrition (DRM) may lead to exacerbation of the dilated cardiomyopathy. We report a rare case of a fourteen-year-old boy who presented with symptoms of congestive heart failure due to DRM and PEM (secondary to chronic starvation) along with severe selenium deficiency. An initial echocardiogram showed severely depressed systolic function consistent with dilated cardiomyopathy. Aggressive nutritional support and replacement of selenium and congestive heart failure medications that included diuretics and ACE inhibitors with the addition of carvedilol led to normalization of the cardiac function within four weeks. He continues to have significant weight gain and is currently completely asymptomatic from a cardiovascular standpoint.

Unusual presentation of unroofed coronary sinus with cyanosis after ventricular septal defect closure

Cyanosis after surgical closure of ventricular and/or atrial septal defect is very unusual. We report a case of unroofed coronary sinus in a six-month-old boy who developed cyanosis after surgical closure of ventricular and atrial septal defects. Clinical presentation, diagnosis, and management are discussed.

Maternal use of cyclobenzaprine (Flexeril) may induce ductal closure and persistent pulmonary hypertension in neonates

Abstract A full-term male infant presented shortly after birth with respiratory distress. An echocardiogram done within the first hour of life showed an elevated pulmonary artery pressure, an associated right ventricular hypertrophy without a patent ductus arteriosus. The patient was treated for persistent pulmonary hypertension with favorable response. Maternal history was unremarkable except for chronic low back pain treated with cyclobenzaprine (Flexeril®). A proposed mechanism for cyclobenzaprine includes inhibition of norepinephrine and serotonin reuptake, factors known to inhibit prostaglandin and nitric oxide. These two factors are the leading causes of in-utero ductal closure. This report is the first to indicate that cyclobenzaprine use during late pregnancy should be considered a potential cause of early ductal closure.

High-sensitivity troponin T in preterm infants with a hemodynamically significant patent ductus arteriosus

ObjectiveTo investigate if a hemodynamically significant patent ductus arteriosus (hsPDA) leads to elevated high-sensitivity troponin T (hsTnT) and NTproBNP levels in serum.Study designInfants <34 weeks and <1500 g were prospectively enrolled, except those with major congenital or chromosomal anomalies. An echocardiogram (ECHO) was performed and hsTnT and NTproBNP were measured within 5 days of life and repeated after treatment of hsPDA. Clinical, ECHO, and hsTnT data were analyzed using Student t-test, two proportion z-test, and regression analysis.ResultsSeventy infants were enrolled. Infants in the hsPDA group had lower gestation and birth weight. Mean hsTnT and NTproBNP levels in the hsPDA group were higher compared to the group without an hsPDA, with levels being 251.54 vs 161.6 pg/ml, p < 0.01 for hsTnT and 18181.02 vs 3149.23 pg/ml, p < 0.001 for NTproBNP.ConclusionHsPDA leads to increased hsTnT and NTproBNP levels in preterm infants without affecting cardiac function.

NTproBNP as a surrogate biomarker for early screening of pulmonary hypertension in preterm infants with bronchopulmonary dysplasia

ObjectivePulmonary hypertension (PH) is a known complication of bronchopulmonary dysplasia (BPD). This study aimed to determine the utility of serial N-Terminal pro-Brain Natriuretic Peptide (NTproBNP) levels in the screening of BPD associated PH (BPD-PH) in preterm infants.Study designInfants with birth weight <1500 g and <30 week corrected gestational age (CGA) were followed with serial NTproBNP levels and echocardiograms (ECHO). They were divided into control, BPD and BPD-PH groups. Statistical analyses included repeated measures analysis of variance and receiver operator curve (ROC) generation.ResultsInfants in the BPD-PH and BPD group had significantly elevated NTproBNP levels as compared to the control group. ROC curves for NTproBNP at 28 weeks CGA provided a cut-point of 2329 pg/ml and 578.1 pg/ml for detection of BPD-PH and BPD, respectively.ConclusionsNTproBNP appears to be a good screening tool to determine the onset of BPD-PH as early as 28 weeks CGA.