Emicizumab Associated Rhabdomyolysis in Hemophilia A.

Emicizumab is increasingly the front-line treatment for patients with Hemophilia A with or without inhibitors. Rhabdomyolysis is a syndrome of muscle necrosis and release of intracellular muscle constituents into the circulation. Creatine kinase (CK) levels are typically markedly elevated, and muscle pain and myoglobinuria may be present. The severity of illness ranges from asymptomatic elevations in serum muscle enzymes to life-threatening disease associated with extreme enzyme elevations, electrolyte imbalances, acute kidney injury and disseminated intravascular coagulation. We present a case of an African American male with severe hemophilia A and history of factor VIII inhibitor, maintained on emicizumab prophylaxis, who developed rhabdomyolysis with a symptomatic hyperCKemia. To date, there is no known link between rhabdomyolysis to emicizumab. This report brings to light the possibility of symptomatic rhabdomyolysis as a potential side effect of emicizumab after moderate exertional activity.

Angiomatoid Fibrous Histiocytoma With Paraneoplastic Platelet Storage Pool Deficiency.

Angiomatoid fibrous histiocytoma is a rare soft tissue tumor usually discovered in young individuals. This tumor is often mistaken for a hematoma and typically misdiagnosed. It is commonly found in the extremities and may be associated with a site of recent or previous trauma. Characteristic histology includes nodules of histiocytoid spindle cells with pseudoangiomatoid spaces, fibrous pseudocapsules, and lymphoid cuffing. We describe the case of an 8-year-old girl who presented after incision and drainage of a superficial thigh lesion and experienced subsequent chronic bleeding of her wound. Her initial presentation was concerning for an underlying bleeding disorder, and laboratory analysis uncovered a paraneoplastic platelet function disorder that resolved with therapy of the primary tumor.

Losartan for the nephropathy of sickle cell anemia: A phase-2, multicenter trial.

Nephropathy is a common and progressive complication of sickle cell anemia (SCA). In SCA mice, we found that hyperangiotensinemia in the absence of hypertension underlies nephropathy, and its downregulation by losartan, an angiotensin-II-receptor-1 blocker, reduced albuminuria and progression of nephropathy. Therefore, we performed a phase-2 trial of oral losartan, given for 6 months, to explore whether it reduced albuminuria in children and adults with SCA. Participants were allocated to groups defined by class of baseline urinary albumin-to-creatinine ratio (UACR): no albuminuria (NoA), microalbuminuria (MicroA), and macroalbuminuria (MacroA). The primary endpoint was a ≥25% reduction UACR from baseline. There were 32 evaluable participants (mean age 24 years; NoA = 14, MicroA = 12, MacroA = 6). The primary endpoint was met in 83% of the MacroA group (P < 0.0001) and 58% of the MicroA group (P < 0.0001). Median fold-change in UACR was -0.74 for MacroA and -0.46 for MicroA. In MacroA and MicroA, UACR classification improved in 50% but worsened in 11%. Urine osmolality and estimated glomerular filtration rate (eGFR) did not change significantly. Losartan was discontinued in three participants [leg cramps, N = 1; decline in eGFR >25% (142➝104 mL/minute/1.73 m2 ), N = 1; rise in serum creatinine >50% (0.2➝0.3 mg/dL), N = 1]. Albuminuria was associated with diastolic dysfunction and impaired functional capacity, although cardiopulmonary status was unchanged after 6 months of losartan therapy. In summary, losartan decreased urinary albumin excretion in most participants with albuminuria. Those with macroalbuminuria had the greatest benefit. This study forms the basis for a phase-3, randomized, placebo-controlled trial of losartan for the nephropathy of SCA.

Long-term Erythrocytapheresis Is Associated With Reduced Liver Iron Concentration in Sickle Cell Disease.

BACKGROUND: Erythrocytapheresis procedures are increasingly used in sickle cell disease. Serum ferritin and noninvasive magnetic resonance imaging measurements of liver iron concentration (LIC) are frequently used to monitor iron overload secondary to hypertransfusion. There is a paucity of data describing the impact of long-term erythrocytapheresis (LTE) on LIC. MATERIALS AND METHODS: We measured magnetic resonance imaging liver and cardiac iron on LTE subjects and stratified them into 2 groups: higher LIC (>3 mg/g) and lower LIC (<3 mg/g). χ(2) and t test were used to test for differences between the 2 groups. Logistic regression and generalized linear mixed-effects models were used to test what impacted LIC. RESULTS: None of 29 sickle cell disease subjects maintained on LTE had high cardiac iron concentration. LIC was associated with serum ferritin (r=0.697, P<0.001) but was not associated with the total number of LTE procedures (r=-0.088, P=0.656) or total number of simple transfusions (r=0.316, P=0.108). The total number of LTE procedures was not associated with serum ferritin (r=0.040, P=0.838), the total number of simple transfusions (r=-0.258, P=0.184), or LIC group (r=-0.111, P=0.566). CONCLUSION: There was no significant correlation between duration of LTE maintenance and LIC.

Cerebral oximetry improves detection of sickle cell patients at risk for nocturnal cerebral hypoxia.

We previously used cerebral oximetry to identify low cerebral venous oxygen saturation in waking children with sickle cell disease (SCD). Because arterial oxyhemoglobin desaturation is common during sleep in SCD patients, this study compared both waking and sleeping systemic arterial and cerebral venous oxygenation dynamics in children with and without SCD. Seventeen African-American (AA) children with homozygous SCD [8 (4-15) years; 29% male; normal transcranial Doppler velocities] were compared with a control cohort (CON) comprised of six healthy AA children [9 (4-16) years, 33% male]. Standard all-night polysomnographic recordings were performed, including measurement of arterial oxygen saturation by pulse oximetry (SpO(2)). Regional cerebral oxygen saturation (rSO(2)) was measured non-invasively with cerebral oximetry. Intra-cohort comparisons examined the influence of sleep on SpO(2) and rSO(2) in the subjects. Inter-cohort comparisons of SpO(2), rSO(2,) and the rSO(2)/SpO(2) ratio assessed the impact of SCD on systemic and cerebral oxygenation during wakefulness and sleep. Cohort differences in SpO(2) were not statistically significant in either wakefulness or sleep. However, only in the SCD cohort was the magnitude of SpO(2) change statistically significant (P = 0.002). In contrast, both waking and sleep rSO(2) cohort median values did differ significantly [awake: CON 76 (67-86) vs. SCD 62 (58-71), P = 0.01; sleep: CON 65 (60-77) vs. SCD 55 (48-61), P = 0.01)]. The waking rSO(2)/SpO(2) ratio was also significantly lower in the SCD group [CON 0.78 (0.68-0.88) vs. SCD of 0.66 (0.61-0.72); P = 0.015]. During sleep, the ratio was also significantly lower in the SCD group [CON 0.71 (0.66-0.81) vs. SCD 0.59 (0.52-0.65); P = 0.011]. Our findings suggest that SCD patients may be at increased risk of cerebral hypoxia during both wakefulness and sleep.

Quantitative assessment of ventricular function in sickle cell disease: effect of long-term erythrocytapheresis.

BACKGROUND: Previous studies on cardiac function in patients with sickle cell disease (SCD) demonstrated abnormalities of systolic and diastolic function including elevated left ventricular myocardial performance index (LVMPI) on chronic transfusion protocols. LVMPI has been validated as a useful and easy non-invasive measure of overall cardiac function. Up to now, there are no reported studies on cardiac function in patients with SCD maintained on long-term erythrocytapheresis (LTE). PROCEDURES: We recorded LVMPI in 22 patients with SCD aged 3-20 years and we compared the results between non-transfused patients (NT-SCD) and patients on LTE (T-SCD). RESULTS: Males with SCD had higher mean LVMPI than females (P = 0.04). There were significant differences among T-SCD, severe NT-SCD, and mild NT-SCD patients with respect to hemoglobin (Hb) levels (P = .003) and TR velocity (P = .03). T-SCD patients showed elevated LVMPI compared to NT-SCD patients with severe and mild disease (P = 0.002). Pair-wise comparisons demonstrated that T-SCD patients had LVMPI that was significantly higher than NT-SCD (mild) patients (P = 0.01). CONCLUSIONS: Our study demonstrates that patients SCD on LTE have cardiac dysfunction based on elevated LVMPI. This may be a reflection of the global severity of disease. Our findings merit further investigation with serial monitoring of LVMPI on a larger number of patients with SCD.

Carboplatinum and vincristine chemotherapy for central nervous system gliofibroma: case report and review of the literature.

Gliofibromas are bimorphic tumors of the central nervous system. Although they are composed of astrocytic and fibroblastic elements, their histogenesis is not clear. An attempt has been made to classify the tumors as low- or high-grade based on morphology and proliferative labeling index, but the clinical behavior and the optimal therapeutic strategies remain unknown. Although they are considered benign, the authors' review shows a 23% mortality rate. The authors report the successful use of carboplatinum and vincristine as treatment of this disease.

Second malignant neoplasms in childhood acute lymphoblastic leukemia: primitive neuroectodermal tumor of the chest wall with germline p53 mutation as a second malignant neoplasm.

About 80% of children treated for acute lymphoblastic leukemia (ALL) will be long-term survivors. Second malignant neoplasm (SMNs) are a devastating sequelae observed on these children, with an estimated cumulative risk of 2-3.3% fifteen years after diagnosis. Primitive neuroectodermal tumor of bone (PNET) is rarely observed as a SMN following treatment of childhood ALL. The authors described the occurrence of a chest wall PNET of the bone at the site of a central line placement associated with both germ-line and tumor cell p53 mutation in a 8-year-old boy 1 year after completing therapy for standard risk ALL. A review of the literature of 25,051 children treated for ALL discovered 230 SMNs (0.99%), and only one case of PNET of the bone was noted among this group. The occurrence of a SMN in children treated for ALL is a rare event. Such an occurrence, in particular the development of an unusual SMN, should be evaluated for a germline p53 mutation.