Tamaki Hayashi

Unresponsiveness to factor VIII inhibitor bypassing agents during haemostatic treatment for life-threatening massive bleeding in a patient with haemophilia A and a high responding inhibitor.

Summary.   We report a case of haemophilia A with a high responding inhibitor of factor VIII (FVIII) who had a serious retroperitoneal haematoma caused by penetration of a duodenal ulcer. Inhibitor‐bypassing therapy was commenced immediately on admission. On the 17th day of treatment with activated prothrombin complex concentrate (APCC; FEIBA®), re‐bleeding occurred and thrombelastography (TEG) demonstrated resistance to therapy. Treatment was changed to recombinant activated factor VII (rFVIIa; NovoSeven®) and resulted in clinical improvement together with an improvement in TEG parameters. On the 10th day of continuous infusion with NovoSeven®, however, TEG again showed resistance to therapy. FEIBA® infusions were re‐introduced and TEG results remained satisfactory for 7 days. On day 34, however, further retroperitoneal bleeding was evident and a decline in the haemostatic efficiency of FEIBA® was recorded by TEG. NovoSeven® was again successfully administered for 7 days. There were no laboratory findings to indicate disseminated intravascular coagulation (DIC), hypercoagulability or abnormal fibrinolysis. The plasma‐based clotting tests did not show any additional prolongation on the occasions when the TEG demonstrated unresponsiveness to FEIBA® or NovoSeven®. These findings suggested that some component of whole blood, other than plasma might have governed the TEG data. The long‐term use of APCC such as FEIBA® or rFVIIa, requires careful monitoring in terms of FVIII inhibitor bypassing activity as well as the tendency to DIC.

Correlations between global clotting function tests, duration of operation, and postoperative chest tube drainage in pediatric cardiac surgery.

Background:  Systemic coagulation disorders after cardiac surgery represent serious postoperative complications. There have been few reports, however, identifying preoperative coagulation tests that predict postoperative bleeding. The aim of the present study was to investigate the relationship between postoperative hemorrhage and coagulation parameters determined by global coagulation assays, to define potential predictive markers.

Combined amiodarone and low‐dose carvedilol treatment for severe heart failure in childhood

The patient had lived in a protective care home from 3 years of age because of parental abuse. When she was 8 years old she developed appetite loss, and subsequently had vomiting and edema. Her aspartate aminotransferase and alanine aminotransferase were elevated, and a low left ventricular ejection fraction (LVEF) was detected on 2-D echocardiography (2-DE). She was transferred to the National Cardiovascular Center. On admission her height and weight were 123 cm and 26.5 kg, respectively, she was edematous and had hepatomegaly. Her BNP level was 1070 pg/mL. Chest X-ray indicated a cardiothoracic ratio of 73% and her 12-lead electrocardiogram showed a flat T wave in V6 and poor r waves in V1–4. The peak velocity of tricuspid regurgitation was 4.0 m/s and she had moderate mitral regurgitation on 2-D Doppler (2-DD). She was diagnosed as having dilated cardiomyopathy (DCM). Diuretics, milrinone and dobutamine hydrochloride were administered with oxygen inhalation therapy. The left ventricular end-diastolic volume (LVEDV) was 188 mL with an LVEF of 10% measured on Tc quantitative electrocardiogramgated myocardial single-photon emission computed tomography (QGS) on the third hospital day (Table 1). Bodyweight decreased to 22.0 kg by the fourth hospital day. Dobutamine was stopped and enalapril started on the seventh hospital day. Anticoagulant therapy with coumadin was started. We discontinued milrinone on the sixth hospital day. One month after admission, her BNP had decreased to 347 pg/mL and we performed cardiac catheterization. The mean pulmonary arterial pressure was 25 mmHg, with a left ventricular end-diastolic pressure (LVEDP) of 14 mmHg and her cardiac index on thermodilution was 3.8 L/ min/m. Biopsy of the right ventricular myocardium showed moderate myocardial hypertrophy with mild interstitial fibrosis. Selective coronary angiograms confirmed that both coronary arteries were normal. Left ventriculography was not performed. She was assigned to non-beta-blocker therapy in an ongoing clinical trial of beta-blocker therapy after consent was obtained from her mother. Her LVEDV was 202 mL with an LVEF of 15% on QGS 4 months after admission. After 5 months in hospital she was discharged on furosemide and spironolactone, 3 mg/kg per day per os. At that time her BNP was 234 pg/mL. She was re-admitted 16 months later because of severe heart failure following a common cold. Edema and hepatomegaly were present and her weight was 23 kg. Cardiothoracic ratio was 73% on chest X-ray (Fig. 1a). Her heart rate at rest was 120 beats/min and her BNP had increased to 3344 pg/mL (Fig. 2). On 2-DD the peak velocity pf tricuspid regurgitation was 3.9 m/s, and severe mitral regurgitation was present with a left ventricular enddiastolic diameter (LVDd) of 69 mm (169% of normal) and an LVEF of 19%. I.v. milrinone and diuretics were started, and oral digoxin was administered. BNP decreased to approximately 1000 pg/mL, and induction of carvedilol was tried in a dose of 0.004 mg/kg per day (Fig. 2). But carvedilol had to be stopped because BNP increased and the LVDd increased to 75 mm. The LVEDV was 280 mL and LVEF 15% on QGS. Furthermore, because sustained VT developed, amiodarone was started at a dose of 2 mg/kg per day, unfortunately there was a further increase in BNP and amiodarone had to be stopped. Loss of consciousness due to VT occurred twice when the BNP was >1000 pg/mL. The patient recovered on direct current shock. The hospital committee decided against heart transplantation for social reasons especially the lack of family support. Pimobendan was started at a dose of 0.05 mg/kg per day, together with amiodarone, which was restarted at an increased dose of 4 mg/kg per day. The blood concentration of amiodarone was 0.5–0.7 mg/mL. Induction of carvedilol was re-attempted at 0.004 mg/kg per day, when the BNP was <400 pg/mL 2 months after re-starting amiodarone. The carvedilol dose was increased by 0.003–0.004 mg/kg per 1–2 weeks guided by BNP levels; at a carvedilol dose of 0.05 mg/kg, the BNP fell to <200 pg/mL with an LVEDV of 232 mL and an LVEF of 28%. Her New York Heart Association class improved from IV to II. Although the patient had slow VT Correspondence: Etsuko Tsuda, MD, Department of Pediatrics, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita-shi, Osaka 565-8565, Japan. Email: etsuda@hsp.ncvc.go.jp Received 22 July 2007; revised 11 September 2008; accepted 12 November 2008. Pediatrics International (2010) 52, e39–e42 doi: 10.1111/j.1442-200X.2009.02993.x

A ductal aneurysm rapidly developing into coarctation of the aorta

A newborn boy was referred to us with an aortic anomaly. Computed tomography showed a large ductal aneurysm, 14.6 mm in diameter (Fig. 1). On the 13th day, it had shrunk to a diameter of 1.6 mm (Fig. 2). Coarctations are a rare complication of ductal aneurysms. These changes took place within a short period. Figure 1: A view from the back: a large ductal aneurysm is seen. Figure 2: A view from the back: the ductal aneurysm has developed to coarc-tation of the aorta.

Barth syndrome associated with triple mutation

A full-term male infant weighing 2,582 g was born to a 33-year-old healthy mother. Both pregnancy and delivery were uneventful. Three hours after birth, he was transferred to the present hospital because of dyspnea, mixed respiratory-metabolic acidosis, and decreased left ventricle (LV) function on transthoracic echocardiography. Gallop rhythm, low oxygen saturation (86%), and auxocardia with cardiothoracic ratio 66% on chest X-ray were noted. Echocardiography showed globally decreased LV function with an ejection fraction of 25%, and enlarged LV dimension in diastole (158% of normal). The LV was highly and globally trabeculated (Fig. 1b). The ratio of non-compacted to compacted myocardium was >2.0 in all the segments. Electrocardiography showed LV hypertrophy and depressed ST segment in leads II, III, aVF, and V4–6. He was diagnosed with acute heart failure from LV non-compaction (LVNC) and dilated cardiomyopathy (DCM). He was intubated, and carvedilol was also later given along with the inotropic drugs. Although he was discharged at the age of 5 months, he had repeated acute aggravation of chronic heart failure, ventricular tachyarrhythmia, and reduced muscle mass. At 28 months of age, he had already lost weight and weighed 3.3 kg ( 7.8 SD). He did not have neutropenia nor monocytosis but developed 3-methylglutaconic aciduria at 6 months of age (3-methylglutaconic acid level, +4.1 SD). With regard to family history, his elder brother had died suddenly 17 h after birth, and his maternal grandmother had experienced two spontaneous abortions (Fig. 1a). The genetic analysis was approved by the Medical Research Ethics Committees in the institutions that participated, and written informed consent was obtained from infant’s parents. Targeted sequencing of the cardiomyopathy-associated genes confirmed that the patient had novel rare variants in tafazzin (TAZ), succinate dehydrogenase complex flavoprotein subunit A (SDHA), and a-dystrobrevin (DTNA). These variants were identified in exon 6 of TAZ, c.469C>T (p.Leu157Phe); exon 10 of SDHA, c.1351_1355delCGCCT (p. Arg451 fs); and exon 19 of DTNA, c.1763G>A (p.Ser588Asn; Fig. 1d–f). On in silico analysis these rare variants may be disease causing. In addition to the frameshift mutation in SDHA, the TAZ mutation was categorized as possibly damaging by Polyphen-2 (score 0.995), damaging by SIFT (score 0), and disease causing by Mutation Taster. On genetic analysis of TAZ, the patient was diagnosed with Barth syndrome. The DTNA mutation was categorized as possibly damaging by Polyphen-2 (score 0.486), tolerable by SIFT (score 0.007), and disease causing by Mutation Taster. On further sequencing analyses of genes from the patient’s parents, his mother was found to have the same TAZ mutation, while his father had the SDHA and DTNA mutations, all of which were hemior heterozygous in nature. The proband was confirmed to have both maternal and paternal mutations and was therefore considered as triple hemior heterozygote. His parents and living siblings had no clinical evidence of cardiomyopathy, but his father was suspected to have LVNC with normal cardiac function (Fig. 1c).

Rare Anomaly of Great Arteries

A full-term male infant was transferred to our neonatal intensive care unit because of tachypnea and mild hypoxia. Right atrium and right ventricle enlargement were suspected in the prenatal examination. Echocardiography was performed, and a rare combination of anomalies was observed. The ascending aorta and the main pulmonary artery joined together at the level of the innominate artery over the bridging vessel. The branching patterns of the pulmonary artery and the aorta were normal. There was a very small perimembranous ventricular septal defect. Computed tomography was performed to confirm the diagnosis (Figs. 1, 2). The observed combination had not been reported previously. It was not truncus arteriosus because the orifices of the pulmonary artery and the aorta were separated (Fig. 3). Two diagnoses for this rare combination were considered. The first diagnosis defines it as a variant of the aortopulmonary window. This diagnosis is not correct because the bridging part is not a window but rather a large tube. The second diagnosis defines it as a variant of the right aortic arch and the left-side patent ductus arteriosus. This diagnosis is not appropriate because the innominate artery arises from the bridging vessel. If this vessel is patent ductus arteriosus, there should not be branching. Although the diagnosis was not clear, we thought the spontaneous improvement of pulmonary hypertension could lead to systemic collapse. Ligation of the bridging vessel was performed to avoid such a situation. However, the pulmonary hypertension did not improve after surgery. The ventricular septal defect was so small that the reason for pulmonary hypertension was not clear. Catheter examination showed that although the resistance of the pulmonary artery was high, it responded to oxygen inhalation. The patient was discharged with pulmonary hypertension therapy.