Catherine S. Manno, M.D.

Associations between intracranial haemorrhage and prescribed prophylaxis in a large cohort of haemophilia patients in the United States
Witmer, Char; Presley, Rodney; Kulkarni, Roshni; Soucie, J Michael; Manno, Catherine S; Raffini, Leslie
2011 Jan;152(2):211-216, British journal of haematology
Intracranial haemorrhage (ICH) is the most serious type of bleeding for patients with haemophilia. Prior published reports regarding ICH predate the widespread provision of prophylaxis. Our study objectives were to determine risk factors for ICH and whether prophylaxis reduces ICH occurrence. We performed a nested case-control study of persons with haemophilia, >/=2 years of age enrolled in the Centers for Disease Control and Prevention Universal Data Collection project. Of 10 262 patients 199 (1.9%) experienced an ICH for an incidence rate of 390/10 patient years. Head trauma was reported in 44% (88/199). ICH mortality was 19.6% (39/199). Significant risk factors for ICH included a high titre inhibitor [odds ratio (OR) = 4.01, 95% confidence interval (2.40-6.71)], prior ICH [OR = 3.62 (2.66-4.92)] and severe haemophilia [OR = 3.25 (2.01-5.25)]. Prophylaxis was associated with a significant risk reduction for ICH occurrence in patients with severe haemophilia who were negative for human immunodeficiency virus or an inhibitor, with an OR of 0.52 (0.34-0.81) and 0.50 (0.32-0.77) respectively. The most significant risk factors for ICH included the presence of an inhibitor, prior ICH, severity of haemophilia and reported head trauma. This is the first study to demonstrate that prescribed prophylaxis conferred a protective effect against ICH in patients with uncomplicated severe disease
— id: 138280, year: 2011, vol: 152, page: 211, stat: Journal Article,

Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study
Seif, Alix E; Manno, Catherine S; Sheen, Cecilia; Grupp, Stephan A; Teachey, David T
2010 Mar 18;115(11):2142-2145, Blood
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by dysregulation of the Fas apoptotic pathway. Clinical manifestations of ALPS include autoimmune cytopenias, organomegaly, and lymphadenopathy. These findings overlap with Evans syndrome (ES), defined by presence of at least 2 autoimmune cytopenias. We hypothesized a subset of patients with ES have ALPS and tested 45 children at 22 institutions, measuring peripheral blood double-negative T cells (DNTs) and Fas-mediated apoptosis. ALPS was diagnosed in 47% of patients tested. Markedly elevated DNTs (> or = 5%) were a strong predictor of ALPS (positive predictive value = 94%), whereas no patients with DNTs less than 2.5% had ALPS on apoptosis testing. Severity of cytopenias and elevated immunoglobulin levels also predicted ALPS. This is the largest published series describing children with ES and documents a high rate of ALPS among pediatric ES patients. These data suggest that children with ES should be screened for ALPS with DNTs
— id: 115318, year: 2010, vol: 115, page: 2142, stat: Journal Article,

Dose of prophylactic platelet transfusions and prevention of hemorrhage
Slichter, Sherrill J; Kaufman, Richard M; Assmann, Susan F; McCullough, Jeffrey; Triulzi, Darrell J; Strauss, Ronald G; Gernsheimer, Terry B; Ness, Paul M; Brecher, Mark E; Josephson, Cassandra D; Konkle, Barbara A; Woodson, Robert D; Ortel, Thomas L; Hillyer, Christopher D; Skerrett, Donna L; McCrae, Keith R; Sloan, Steven R; Uhl, Lynne; George, James N; Aquino, Victor M; Manno, Catherine S; McFarland, Janice G; Hess, John R; Leissinger, Cindy; Granger, Suzanne
2010 Feb 18;362(7):600-613, New England journal of medicine
BACKGROUND: We conducted a trial of prophylactic platelet transfusions to evaluate the effect of platelet dose on bleeding in patients with hypoproliferative thrombocytopenia. METHODS: We randomly assigned hospitalized patients undergoing hematopoietic stem-cell transplantation or chemotherapy for hematologic cancers or solid tumors to receive prophylactic platelet transfusions at a low dose, a medium dose, or a high dose (1.1x10(11), 2.2x10(11), or 4.4x10(11) platelets per square meter of body-surface area, respectively), when morning platelet counts were 10,000 per cubic millimeter or lower. Clinical signs of bleeding were assessed daily. The primary end point was bleeding of grade 2 or higher (as defined on the basis of World Health Organization criteria). RESULTS: In the 1272 patients who received at least one platelet transfusion, the primary end point was observed in 71%, 69%, and 70% of the patients in the low-dose group, the medium-dose group, and the high-dose group, respectively (differences were not significant). The incidences of higher grades of bleeding, and other adverse events, were similar among the three groups. The median number of platelets transfused was significantly lower in the low-dose group (9.25x10(11)) than in the medium-dose group (11.25x10(11)) or the high-dose group (19.63x10(11)) (P=0.002 for low vs. medium, P<0.001 for high vs. low and high vs. medium), but the median number of platelet transfusions given was significantly higher in the low-dose group (five, vs. three in the medium-dose and three in the high-dose group; P<0.001 for low vs. medium and low vs. high). Bleeding occurred on 25% of the study days on which morning platelet counts were 5000 per cubic millimeter or lower, as compared with 17% of study days on which platelet counts were 6000 to 80,000 per cubic millimeter (P<0.001). CONCLUSIONS: Low doses of platelets administered as a prophylactic transfusion led to a decreased number of platelets transfused per patient but an increased number of transfusions given. At doses between 1.1x10(11) and 4.4x10(11) platelets per square meter, the number of platelets in the prophylactic transfusion had no effect on the incidence of bleeding. (ClinicalTrials.gov number, NCT00128713.)
— id: 115317, year: 2010, vol: 362, page: 600, stat: Journal Article,

Treatment with sirolimus ameliorates tacrolimus-induced autoimmune cytopenias after solid organ transplant
Teachey, David T; Jubelirer, Tracey; Baluarte, H Jorge; Wade, Amanda; Manno, Catherine S
2009 Dec;53(6):1114-1116, Pediatric blood & cancer
The development of autoimmune blood cell cytopenias is a potentially life-threatening complication of solid organ transplantation, resulting from T-cell dysregulation from immunosuppressive medications. Conventional treatment with corticosteroids and IVIgG is often unsuccessful as these therapies are unlikely to overcome the T-cell dysregulation. We describe two patients who developed severe autoimmune cytopenias after solid organ transplantation. They had limited response to conventional medications, but had complete resolution of autoimmunity upon transition of immunosuppression from tacrolimus to sirolimus. Altering the immunosuppressive regimen to modify T-cell dysregulation may be beneficial for patients who develop post-transplant autoimmune disease and allow continued preservation of allograft
— id: 115319, year: 2009, vol: 53, page: 1114, stat: Journal Article,

Incidence of bleeding complications in pediatric patients with type 1 von Willebrand disease undergoing adenotonsillar procedures
Witmer, Char M; Elden, Lisa; Butler, Regina B; Manno, Catherine S; Raffini, Leslie J
2009 Jul;155(1):68-72, Journal of pediatrics
OBJECTIVE: To review the incidence of postoperative bleeding in children with type 1 von Willebrand disease (VWD) who were treated with a single institution protocol. STUDY DESIGN: We performed a retrospective study to determine the postoperative hemorrhage rate in pediatric patients with type 1 VWD who were treated via the Children's Hospital of Philadelphia institutional protocol. This protocol utilizes intravenous desmopressin (DDAVP), oral aminocaproic acid, and overnight observation. RESULTS: Between the years of 2000 to 2006, 41 children with type 1 VWD underwent an adenotonsillar procedure and were treated with this protocol. Seven patients (17%) experienced delayed (>24 hours after surgery) postoperative hemorrhage requiring intervention. Five of the 7 patients required cautery to control the bleeding, and the remaining 2 patients responded to DDAVP and aminocaproic acid alone. Older age and lower VW antigen levels were associated with postoperative hemorrhage (P = .05). CONCLUSIONS: Despite therapeutic intervention to decrease the risk of postoperative hemorrhage, the incidence of hemorrhage was higher in pretreated patients with type 1 VWD than in children without bleeding disorders. Further prospective studies are necessary to determine the optimal treatment to reduce bleeding complications in these patients
— id: 115321, year: 2009, vol: 155, page: 68, stat: Journal Article,

The clinical management of hemophilia and head trauma: a survey of current clinical practice among pediatric hematology/oncology physicians
Witmer, Char M; Manno, Catherine S; Butler, Regina B; Raffini, Leslie J
2009 Sep;53(3):406-410, Pediatric blood & cancer
BACKGROUND: Determining the appropriate evaluation for a pediatric patient with hemophilia and head trauma is a diagnostic challenge with no neuroimaging guidelines and limited clinical evidence to direct care. PROCEDURE: A questionnaire, with two case scenarios, was emailed to members of the American Society of Pediatric Hematology/Oncology. The case scenarios involved asymptomatic toddlers with severe hemophilia who had either fallen from a height (case 1) or from standing (case 2). Respondents were asked to select from six management options. The case scenarios were then altered to include: a large palpable hematoma, prophylactic factor infusion 24 hr prior, the trauma occurred 48 hr prior, wearing a soft helmet, or emesis. RESULTS: The completed response rate was 23% (252/1,077). Computed tomography (CT) was selected by 68.9% (#1) and 56.4% (#2) of respondents. In both case scenarios the presence of a palpable bruise resulted in a statistically significant increase in CT usage to 83.7% and 82.8% (P < 0.001). The use of prophylaxis did not result in a statistically significant decrease in CT usage. Duration of factor replacement was variable ranging from 1 to 4 days. CONCLUSION: Physician self reported management of pediatric patients with hemophilia and head trauma is diverse. The use of CT imaging for mild head trauma in patients without signs or symptoms of intracranial hemorrhage was very common. The use of prophylaxis did not reduce the use of head CT imaging. This variation in clinical practice demonstrates the lack of evidence regarding the management of head trauma in patients with hemophilia
— id: 115320, year: 2009, vol: 53, page: 406, stat: Journal Article,

A prospective observational study of IVC filters in pediatric patients
Raffini, Leslie; Cahill, Anne Marie; Hellinger, Jeffrey; Manno, Catherine
2008 Oct;51(4):517-520, Pediatric blood & cancer
BACKGROUND: The use of inferior vena cava (IVC) filters to prevent pulmonary embolism (PE) has increased with the advent of retrievable filters (Crowther: Am J Med 120: S13-S17, 2007). Both permanent and retrievable filters have been used in the pediatric population, though reports describing such patients and their outcomes are limited. PROCEDURE: Our center has established a longitudinal prospective cohort study of consecutive patients with acute venous thromboembolism (VTE) at our pediatric tertiary care institution. Data collection in this study includes medical history, risk factors, radiologic and laboratory studies, therapy, and follow-up. RESULTS: Two hundred ten patients were enrolled into this cohort from January 2003 to January 2007. IVC filters were percutaneously placed into 11 patients, ranging in age from 6.8 to 23.4 years. The primary reason for filter placement was a VTE and a contraindication to anticoagulation. Nine patients had retrievable filters placed and two received permanent filters. Seven of the nine retrievable filters were removed 21-97 days (median 37 days) after placement. In the remaining two patients, thrombus prevented removal in one, and the filter was electively retained in the other. One patient with a permanent filter died from malignancy. The three patients who are alive and well with IVC filters have had them for 25-60 months. No patient with an IVC filter developed a subsequent PE. CONCLUSIONS: Approximately 5% of patients in this pediatric thrombosis cohort received an IVC filter. The placement and removal of these devices is technically feasible in children
— id: 90491, year: 2008, vol: 51, page: 517, stat: Journal Article,

CD8(+) T-cell responses to adeno-associated virus capsid in humans
Mingozzi, Federico; Maus, Marcela V; Hui, Daniel J; Sabatino, Denise E; Murphy, Samuel L; Rasko, John E J; Ragni, Margaret V; Manno, Catherine S; Sommer, Jurg; Jiang, Haiyan; Pierce, Glenn F; Ertl, Hildegund C J; High, Katherine A
2007 Apr;13(4):419-422, Nature medicine
Hepatic adeno-associated virus (AAV)-serotype 2 mediated gene transfer results in transgene product expression that is sustained in experimental animals but not in human subjects. We hypothesize that this is caused by rejection of transduced hepatocytes by AAV capsid-specific memory CD8(+) T cells reactivated by AAV vectors. Here we show that healthy subjects carry AAV capsid-specific CD8(+) T cells and that AAV-mediated gene transfer results in their expansion. No such expansion occurs in mice after AAV-mediated gene transfer. In addition, we show that AAV-2 induced human T cells proliferate upon exposure to alternate AAV serotypes, indicating that other serotypes are unlikely to evade capsid-specific immune responses
— id: 87024, year: 2007, vol: 13, page: 419, stat: Journal Article,

Utility of computed tomography of the head following head trauma in boys with haemophilia
Witmer, C M; Raffini, L J; Manno, C S
2007 Sep;13(5):560-566, Haemophila
The most serious site of bleeding for patients with haemophilia is the central nervous system. Intracranial haemorrhage (ICH) in patients with haemophilia can occur spontaneously or following mild head trauma however no guidelines exist for the approach to these patients. The goal of this review was to determine the utility of screening computed tomography (CT) of the head for patients with haemophilia who experience head trauma and to determine if the use of clinical criteria could allow a selective approach to radiographic imaging. In a retrospective study we reviewed the management of head trauma in a cohort of paediatric patients with haemophilia in a single institution. The cohort included males, ages birth to 18 years with haemophilia A or B who were followed at the haemophilia treatment center at The Children's Hospital of Philadelphia from 1994 to 2005. Between the years of 1994 and 2005, 97 patients were evaluated for head trauma for a total of 374 emergency department visits. There were 295 head CT scans performed to identify 9 (3%) episodes of intracranial bleeding. Fifty-six per cent of the patients with intracranial bleeding had no clinical signs or symptoms. The clinical outcome was excellent in all cases with no deaths or reported morbidity. In this cohort, a lack of symptoms and a normal neurological exam did not exclude ICH, especially in patients with severe haemophilia who were evaluated soon after a mild head trauma event suggesting the utility of early head CT imaging
— id: 87023, year: 2007, vol: 13, page: 560, stat: Journal Article,

Evidence of multiyear factor IX expression by AAV-mediated gene transfer to skeletal muscle in an individual with severe hemophilia B
Jiang, Haiyan; Pierce, Glenn F; Ozelo, Margareth C; de Paula, Erich V; Vargas, Joseph A; Smith, Peter; Sommer, Jurg; Luk, Alvin; Manno, Catherine S; High, Katherine A; Arruda, Valder R
2006 Sep;14(3):452-455, Molecular therapy
In a phase I study, administration of an AAV2-FIX vector into the skeletal muscle of eight hemophilia B subjects proved safe and achieved local gene transfer and FIX expression for at least 10 months after vector injection, the last time point assessed by muscle biopsy. In hemophilia B dogs we have demonstrated FIX in both muscle biopsies and circulation >4 years following AAV2-FIX injection. Because circulating FIX levels remained less than 1% of normal in human subjects from the study, the duration of AAV2-mediated transgene expression in humans is unknown. We sought to determine if FIX gene transfer and expression persisted locally at injection sites. Muscle biopsies were obtained from one subject 3.7 years following treatment and revealed transgene FIX DNA and protein by quantitative PCR, DNA fluorescence in situ hybridization, and immunohistochemistry for FIX. These results demonstrate, for the first time, multiyear FIX expression by AAV2 vector in humans and suggest that improved muscle delivery provides effective treatment for protein deficiencies or muscle-specific diseases
— id: 87025, year: 2006, vol: 14, page: 452, stat: Journal Article,

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response
Manno, Catherine S; Pierce, Glenn F; Arruda, Valder R; Glader, Bertil; Ragni, Margaret; Rasko, John J; Ozelo, Margareth C; Hoots, Keith; Blatt, Philip; Konkle, Barbara; Dake, Michael; Kaye, Robin; Razavi, Mahmood; Zajko, Albert; Zehnder, James; Rustagi, Pradip K; Nakai, Hiroyuki; Chew, Amy; Leonard, Debra; Wright, J Fraser; Lessard, Ruth R; Sommer, Jurg M; Tigges, Michael; Sabatino, Denise; Luk, Alvin; Jiang, Haiyan; Mingozzi, Federico; Couto, Linda; Ertl, Hildegund C; High, Katherine A; Kay, Mark A
2006 Mar;12(3):342-347, Nature medicine
We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 x 10(12) vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of approximately 8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression
— id: 87028, year: 2006, vol: 12, page: 342, stat: Journal Article,

Cystic fibrosis as a risk factor for recurrent venous thrombosis at a pediatric tertiary care hospital
Raffini, Leslie J; Raybagkar, Deepti; Blumenstein, Marilyn S; Rubenstein, Ronald C; Manno, Catherine S
2006 May;148(5):659-664, Journal of pediatrics
OBJECTIVE: To evaluate risk factors for recurrent thrombosis in pediatric patients. STUDY DESIGN: This prospective observational cohort study enrolled 120 patients with acute venous thromboembolism from January 2003 to April 2005. Data collection included medical and family history, radiologic and laboratory studies, therapy, and follow-up. RESULTS: The overall prevalence of recurrent thrombosis in our cohort was 19/120 (15.8%). Patients with recurrence were older, with a median age of 14.8 years (range 2 weeks-23.6 years), compared with 10.1 years (range newborn 23.4 years) in patients without recurrence (P = .03). Six of the 19 patients with recurrent thrombosis had cystic fibrosis (CF), compared with 0/101 without recurrence (P < .001). Five of these 6 patients were colonized with Burkholderia cepacia in their sputum. Central venous catheters were associated with most, but not all, of the thromboses in patients with CF. CONCLUSIONS: In this study, patients with CF had a high risk of recurrent venous thrombosis, as well as a high prevalence of colonization with B cepacia. The cause of this risk has not been defined. This observation may have important implications for thromboprophylaxis, particularly in the setting of central venous catheters
— id: 87027, year: 2006, vol: 148, page: 659, stat: Journal Article,

Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)
Teachey, David T; Obzut, Dana A; Axsom, Kelly; Choi, John K; Goldsmith, Kelly C; Hall, Junior; Hulitt, Jessica; Manno, Catherine S; Maris, John M; Rhodin, Nicholas; Sullivan, Kathleen E; Brown, Valerie I; Grupp, Stephan A
2006 Sep 15;108(6):1965-1971, Blood
Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of abnormal lymphocyte survival caused by defective Fas-mediated apoptosis, leading to lymphadenopathy, hepatosplenomegaly, and an increased number of double-negative T cells (DNTs). Treatment options for patients with ALPS are limited. Rapamycin has been shown to induce apoptosis in normal and malignant lymphocytes. Since ALPS is caused by defective lymphocyte apoptosis, we hypothesized that rapamycin would be effective in treating ALPS. We tested this hypothesis using rapamycin in murine models of ALPS. We followed treatment response with serial assessment of DNTs by flow cytometry in blood and lymphoid tissue, by serial monitoring of lymph node and spleen size with ultrasonography, and by enzyme-linked immunosorbent assay (ELISA) for anti-double-stranded DNA (dsDNA) antibodies. Three-dimensional ultrasound measurements in the mice correlated to actual tissue measurements at death (r = .9648). We found a dramatic and statistically significant decrease in DNTs, lymphadenopathy, splenomegaly, and autoantibodies after only 4 weeks when comparing rapamycin-treated mice with controls. Rapamycin induced apoptosis through the intrinsic mitochondrial pathway. We compared rapamycin to mycophenolate mofetil, a second-line agent used to treat ALPS, and found rapamycin's control of lymphoproliferation was superior. We conclude that rapamycin is an effective treatment for murine ALPS and should be explored as treatment for affected humans
— id: 87026, year: 2006, vol: 108, page: 1965, stat: Journal Article,

Use of recombinant factor VIIa for refractory hemorrhage during extracorporeal membrane oxygenation
Dominguez, T E; Mitchell, M; Friess, S H; Huh, J W; Manno, C S; Ravishankar, C; Gaynor, J W; Tabbutt, S
2005 May;6(3):348-351, Pediatric critical care medicine
OBJECTIVE: To describe the outcome and treatment of two patients with recombinant factor VIIa (rFVIIa) for severe hemorrhage associated with extracorporeal membrane oxygenation (ECMO). DESIGN: Case report. SETTING: A 38-bed pediatric intensive care unit and 20-bed pediatric cardiac intensive care unit at a tertiary care children's hospital. Patient: Two patients with life-threatening hemorrhagic complications associated with ECMO requiring massive transfusion of blood products. INTERVENTIONS: Administration of repeated doses of rFVIIa at 90 microg/kg/dose. MEASUREMENT AND MAIN RESULTS: Patient 1 was an 11-yr-old male with a dilated cardiomyopathy who had undergone an orthotopic heart transplant treated with venoarterial ECMO postoperatively for right ventricular dysfunction. Patient 2 was a 13-yr-old male treated with venoarterial ECMO for cardiopulmonary failure from necrotizing staphylococcal pneumonia. Both patients had severe hemorrhage from the cannulation sites and thoracostomy tubes requiring massive transfusion to maintain intravascular blood volume and replace clotting factors. Both patients were treated with rFVIIa every 2-4 hrs and attained hemostasis. Patient 1 was administered three doses and Patient 2 was administered ten doses. No evidence of abnormal thrombus formation was noted in their respective ECMO circuits. CONCLUSIONS: The efficacy of rFVIIa in reducing intractable bleeding postcardiac surgery and in other coagulopathic states is being investigated. Despite theoretical concerns of thrombosis, these cases illustrate that there may be a role for the cautious use of rFVIIa in treating severe and intractable hemorrhage associated with ECMO
— id: 87031, year: 2005, vol: 6, page: 348, stat: Journal Article,

Management of bleeding disorders in children
Manno, Catherine S
2005 ;:416-422, Hematology (American Society of Hematology. Education Program)
Diagnosis and management of congenital and acquired bleeding disorders in children requires not only an understanding of the unique characteristics of pediatric hemostasis but also the natural course of bleeding disorders in children, which may differ substantially from the course observed in adult patients. In this article, three bleeding disorders of great importance to the pediatric hematologist are reviewed: neonatal alloimmune thrombocytopenia (NAIT), hemophilia and immune-mediated thrombocytopenic purpura (ITP). Current aspects of management are outlined. The unique physiology of transplacental transfer of maternally derived anti-platelet antibodies can result in neonatal immune thrombocytopenia, a significant cause of morbidity and mortality from bleeding in affected infants. For patients with hemophilia, approaches to treatment have shifted over the past decade from on-demand therapy to prophylaxis, either primary of secondary, resulting in delay of onset or complete avoidance of hemophilic arthropathy. Hemophilic inhibitors often develop in young children, prompting the need for a thorough understanding of the use of bypassing agents as well as immune tolerance induction in the young child. Finally, although several management strategies for ITP of childhood have been shown to improve the platelet count, side effects associated with corticosteroids, IVIg, anti-D and splenectomy force the practitioner to also consider the option of carefully observing, but not treating, the child with ITP
— id: 87029, year: 2005, vol: , page: 416, stat: Journal Article,

Therapeutic choices in the current millennium: hemophilia workshop highlights
Mathew, Prasad; Manno, Catherine S; Aledort, Louis M
2005 Oct 15;45(5):611-615, Pediatric blood & cancer
Many issues affect hemophilia care providers when managing bleeding episodes in individuals with hemophilia. A diverse group of hemophilia providers from the United States met at two workshops to discuss the issues influencing treatment choices in the current millennium and to learn about current advances in treatment of hemophilia. This paper provides a summary of the discussions at these workshops. Despite the progress made in the management of patients with hemophilia, the workshop highlighted the fact that there were still many unanswered questions
— id: 87030, year: 2005, vol: 45, page: 611, stat: Journal Article,

Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS)
Teachey, David T; Manno, Catherine S; Axsom, Kelly M; Andrews, Timothy; Choi, John K; Greenbaum, Barbara H; McMann, Joseph M; Sullivan, Kathleen E; Travis, Susan F; Grupp, Stephan A
2005 Mar 15;105(6):2443-2448, Blood
Autoimmune lymphoproliferative syndrome (ALPS) is a rare disorder of disrupted lymphocyte homeostasis. Clinical manifestations of ALPS vary but typically include autoimmune cytopenias, organomegaly, lymphadenopathy, and increased risk of malignancies. A similar spectrum of symptoms may be seen in some patients with Evans syndrome (ES), a hematologic disorder defined by autoimmune destruction of at least 2 hematologic cell types. We hypothesized that a subset of patients diagnosed with ES may have ALPS. We screened 12 children with ES by flow cytometric analysis for CD4-/CD8- (double negative) T cells (DNTs) and with the definitive test for ALPS, defective in vitro Fas-mediated apoptosis. Six of the patients had elevated DNTs, suggestive of ALPS and also had defective Fas-mediated apoptosis. The other 6 patients displayed normal T-cell apoptosis; 5 of whom had normal DNTs, and 1 had a borderline result. Thus, 7 (58%) of 12 patients with ES had elevated DNTs suggestive of ALPS, with functional confirmation in 6 of 7. This suggests that analysis of DNTs may be a sensitive first-line screening test, serving as a marker of patients who should undergo definitive testing for ALPS. Our data further suggest that a number of patients with ES may have ALPS, a novel finding with important therapeutic implications
— id: 87032, year: 2005, vol: 105, page: 2443, stat: Journal Article,

Emerging and receding risks of therapeutic regimens for haemophilia
Farrugia, A; Manno, C S; Evatt, B L
2004 Oct;10 Suppl 4:47-54, Haemophila
During the past two decades, the improvement of therapeutic agents for the management of haemophilia has created the opportunity for individuals with haemophilia to live normal lives. However, in some instances, the progress made has been accompanied by emergence of unexpected risks and other new complications. A number of viruses have either emerged, or become greater risks to people with haemophilia. In addition, the drive of many countries towards self-sufficiency in blood products may in fact be endangering people with haemophilia by restricting blood donation to a pool of donors with high infection risk, discouraging commercial interests from developing safer products, and discouraging use of 'foreign' products even where that may be the safer option. Gene therapy for haemophilia, although an encouraging new treatment, has brought with it a number of adverse events, including risk of virus infection and development of carcinomas. The risk of inhibitors is still the most important problem for people with haemophilia, and a recent report showed that the type of factor concentrate does not impact significantly on this risk. Despite the advent of new and promising treatments for haemophilia, heathcare providers must be alert to new risks posed by them
— id: 87033, year: 2004, vol: 10 Suppl 4, page: 47, stat: Journal Article,

HIV infection presenting as severe autoimmune hemolytic anemia with disseminated intravascular coagulation in an infant
Rheingold, Susan R; Burnham, Jon M; Rutstein, Richard; Manno, Catherine S
2004 Jan;26(1):9-12, Journal of pediatric hematology/oncology
Autoimmune hemolytic anemia is rare in children. It is generally diagnosed in relation to a viral or bacterial infection but has also been described in association with drugs, autoimmune disease, malignancy, and immunodeficiency. The authors describe a 5-month-old infant who presented with severe autoimmune hemolytic anemia and disseminated intravascular coagulation as his initial manifestation of HIV infection
— id: 87034, year: 2004, vol: 26, page: 9, stat: Journal Article,

The promise of third-generation recombinant therapy and gene therapy
Manno, Catherine S
2003 Jul;40(3 Suppl 3):23-28, Seminars in hematology
Recombinant factor VIII and IX products have well-established efficacy and safety records. However, concerns about the possibility of viral transmission have prompted efforts to develop recombinant products that are free of added human and animal proteins. The currently licensed second-generation recombinant factor VIII concentrates were introduced in 2000. Two new third-generation products, manufactured without any human- or animal-derived materials, are currently in development and clinical testing. As an alternative to exogenous factor replacement, gene therapy is under investigation for use in the treatment of hemophilia. Gene therapy involves the stable insertion of a functional gene for long-term expression and secretion of endogenous factor VIII or IX protein. Methods used to date have been based on retroviral, adenoviral, and adeno-associated viral vectors, as well as nonviral electroporation. Three phase I trials using these approaches have been completed as of 2002, and one more is ongoing. This article reviews the results of recent clinical studies investigating third-generation recombinant products and gene-based approaches to hemophilia treatment
— id: 87035, year: 2003, vol: 40, page: 23, stat: Journal Article,

AAV-mediated factor IX gene transfer to skeletal muscle in patients with severe hemophilia B
Manno, Catherine S; Chew, Amy J; Hutchison, Sylvia; Larson, Peter J; Herzog, Roland W; Arruda, Valder R; Tai, Shing Jen; Ragni, Margaret V; Thompson, Arthur; Ozelo, Margareth; Couto, Linda B; Leonard, Debra G B; Johnson, Frederick A; McClelland, Alan; Scallan, Ciaran; Skarsgard, Erik; Flake, Alan W; Kay, Mark A; High, Katherine A; Glader, Bertil
2003 Apr 15;101(8):2963-2972, Blood
Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (F.IX). Previously, we established an experimental basis for gene transfer as a method of treating the disease in mice and hemophilic dogs through intramuscular injection of a recombinant adeno-associated viral (rAAV) vector expressing F.IX. In this study we investigated the safety of this approach in patients with hemophilia B. In an open-label dose-escalation study, adult men with severe hemophilia B (F.IX < 1%) due to a missense mutation were injected at multiple intramuscular sites with an rAAV vector. At doses ranging from 2 x 10(11) vector genomes (vg)/kg to 1.8 x 10(12) vg/kg, there was no evidence of local or systemic toxicity up to 40 months after injection. Muscle biopsies of injection sites performed 2 to 10 months after vector administration confirmed gene transfer as evidenced by Southern blot and transgene expression as evidenced by immunohistochemical staining. Pre-existing high-titer antibodies to AAV did not prevent gene transfer or expression. Despite strong evidence for gene transfer and expression, circulating levels of F.IX were in all cases less than 2% and most were less than 1%. Although more extensive transduction of muscle fibers will be required to develop a therapy that reliably raises circulating levels to more than 1% in all subjects, these results of the first parenteral administration of rAAV demonstrate that administration of AAV vector by the intramuscular route is safe at the doses tested and effects gene transfer and expression in humans in a manner similar to that seen in animals
— id: 87036, year: 2003, vol: 101, page: 2963, stat: Journal Article,

Transfusion of the patient with congenital coagulation defects
Shusterman, Suzanne; Manno, Catherine S
Blood banking and transfusion medicine : basic principles and practice Philadelphia PA : Churchill Livingstone, 2003,
— id: 5472, year: 2003, vol: , page: ?, stat: Chapter,

Pediatric transfusion therapy
Herman, Jay H; Manno, Catherine Scott
Bethesda MD : AABB Press, 2002,
— id: 2201, year: 2002, vol: , page: , stat: ,

Gene therapy for bleeding disorders
Manno, Catherine S
2002 Nov;9(6):511-515, Current opinion in hematology
The goal of gene therapy for bleeding disorders is to provide stable insertion and expression of a particular gene whose absence is responsible for a particular disease. The bleeding disorders for which the most basic and clinical research has been completed are the hemophilias factor VIII deficiency and factor IX deficiency. These X-linked diseases are caused by single-gene mutations; replacement of the defective gene has not only resulted in clinical and biochemical improvement in animal models but also provided promising results in phase I clinical trials. An ideal gene transfer approach to the treatment of hemophilia would require a minimally invasive procedure for gene delivery, have minimal associated morbidity, and result in long-term transgene expression, ideally yielding factor levels in the therapeutic range. Multiple approaches to gene transfer in the hemophilias are currently under investigation
— id: 87038, year: 2002, vol: 9, page: 511, stat: Journal Article,

Guidelines for assessing appropriateness of pediatric transfusion
Roseff, Susan D; Luban, Naomi L C; Manno, Catherine S
2002 Nov;42(11):1398-1413, Transfusion
— id: 87037, year: 2002, vol: 42, page: 1398, stat: Journal Article,

Does red-cell T activation matter?
Eder, A F; Manno, C S
2001 Jul;114(1):25-30, British journal of haematology
— id: 87041, year: 2001, vol: 114, page: 25, stat: Journal Article,

Hemoglobinopathies: an opportunity to study cardiac disease
Manno, C S; Jessup, M
2001 Oct 1;111(5):407-408, American journal of medicine
— id: 87040, year: 2001, vol: 111, page: 407, stat: Journal Article,

Complex regional pain syndrome in pediatric patients with severe factor VIII deficiency
Norris, C F; Bingham, P M; Butler, R B; Manno, C S
2001 Dec;23(9):620-622, Journal of pediatric hematology/oncology
Two boys with severe factor VIII deficiency that initially presented with acute onset of joint pain and swelling consistent with an uncomplicated hemarthrosis are reported. When appropriate management failed to provide resolution of symptoms, alternate diagnoses were considered. Both boys ultimately had complex regional pain syndrome (CRPS) diagnosed. The delay in diagnosis contributed to prolonged patient discomfort and lack of appropriate therapy. Complex regional pain syndrome encompasses a group of disorders that are characterized by pain severity or duration disproportionate to that expected. It is uncommon in the pediatric population. Because early diagnosis and appropriate treatment may improve outcome, it is important for practitioners to consider CRPS in the differential diagnosis of persistent pain in children with hemophilia
— id: 87039, year: 2001, vol: 23, page: 620, stat: Journal Article,

Distinguished Career Award of the American Society of Pediatric Hematology/Oncology for 2000
Cohen, A; Manno, C
2000 Jul-Aug;22(4):296-298, Journal of pediatric hematology/oncology
— id: 115325, year: 2000, vol: 22, page: 296, stat: Journal Article,

Neonatal lupus erythematosus with microvascular hemolysis
Hariharan, D; Manno, C S; Seri, I
2000 Jul-Aug;22(4):351-354, Journal of pediatric hematology/oncology
A female, term newborn born to a mother with a history of idiopathic thrombocytopenic purpura and antinuclear antibodies, single-stranded A antibody, and IgM anticardiolipin antibodies presented with immune thrombocytopenia, disseminated intravascular coagulation (DIC), microangiopathic hemolytic anemia, and a characteristic lupus rash in the periorbital areas. She responded to combined treatment with dexamethasone and intravenous immunoglobulin (IVIG). At age 9 months, she was readmitted with severe thrombocytopenia, DIC, and microangiopathic hemolytic anemia. She again responded to IVIG. This suggests that microangiopathic hemolysis can be a presenting symptom in neonatal lupus erythematosus and that reoccurrence of the microangiopathic hemolysis may occur even after the disappearance of lupus antibodies
— id: 87042, year: 2000, vol: 22, page: 351, stat: Journal Article,

Evidence for gene transfer and expression of factor IX in haemophilia B patients treated with an AAV vector
Kay, M A; Manno, C S; Ragni, M V; Larson, P J; Couto, L B; McClelland, A; Glader, B; Chew, A J; Tai, S J; Herzog, R W; Arruda, V; Johnson, F; Scallan, C; Skarsgard, E; Flake, A W; High, K A
2000 Mar;24(3):257-261, Nature genetics
Pre-clinical studies in mice and haemophilic dogs have shown that introduction of an adeno-associated viral (AAV) vector encoding blood coagulation factor IX (FIX) into skeletal muscle results in sustained expression of F.IX at levels sufficient to correct the haemophilic phenotype. On the basis of these data and additional pre-clinical studies demonstrating an absence of vector-related toxicity, we initiated a clinical study of intramuscular injection of an AAV vector expressing human F.IX in adults with severe haemophilia B. The study has a dose-escalation design, and all patients have now been enrolled in the initial dose cohort (2 x 10(11) vg/kg). Assessment in the first three patients of safety and gene transfer and expression show no evidence of germline transmission of vector sequences or formation of inhibitory antibodies against F.IX. We found that the vector sequences are present in muscle by PCR and Southern-blot analyses of muscle biopsies and we demonstrated expression of F.IX by immunohistochemistry. We observed modest changes in clinical endpoints including circulating levels of F.IX and frequency of FIX protein infusion. The evidence of gene expression at low doses of vector suggests that dose calculations based on animal data may have overestimated the amount of vector required to achieve therapeutic levels in humans, and that the approach offers the possibility of converting severe haemophilia B to a milder form of the disease
— id: 87044, year: 2000, vol: 24, page: 257, stat: Journal Article,

Blood transfusion support in pediatric cardiovascular surgery
Kwiatkowski, J L; Manno, C S
1999 Aug;21(1):63-72, Transfusion science
The majority of children who undergo open-heart surgery with cardiopulmonary bypass (CPB) require perioperative blood transfusion. Blood product requirements are affected by factors such as patient age, underlying cardiac disease, complexity of the surgical procedure, and hemostatic alterations induced by CPB. Transfusion support may include the use of whole blood and/or individual blood components with transfusion practices varying widely based on individual preferences and blood product availability. Approaches to limit allogeneic blood exposure include the use of modified ultrafiltration and smaller bypass circuits, preoperative autologous blood donation and intraoperative blood salvage, and adjunctive antifibrinolytic agents. Potential advantages and disadvantages of the different blood products and pharmacological agents must be considered in managing the pediatric cardiac surgery patient
— id: 87043, year: 1999, vol: 21, page: 63, stat: Journal Article,

Treatment options for bleeding episodes in patients undergoing immune tolerance therapy
Manno, C S
1999 Sep;5 Suppl 3:33-41, Haemophila
Inhibitors to factor VIII develop in 4-20% of haemophilia A patients, with the percentage rising to 52% in certain subpopulations. The management of inhibitor patients is directed toward stopping acute haemorrhages, providing short-term haemostasis before and after surgery, and inducing immune tolerance to factor VIII (immune tolerance therapy or ITT). Several different protocols have been used for ITT, but they are all centred around ongoing exposure to high doses of factor VIII. High responders (those patients with a large increase in inhibitor level after exposure to factor VIII) are the prime candidates for ITT, but low responders may also benefit from this treatment. It is often necessary to treat bleeding episodes during ITT, because elimination of inhibitors may require many years of therapy. Treatment of haemorrhages in inhibitor patients is reviewed for both low and high responders during ITT and in the absence of ITT. The choice of clotting agent for inhibitor patients who have not yet responded to ITT depends on current and past inhibitor levels, the severity of the haemorrhage, the site of the haemorrhage or the setting in which it occurs (e.g. surgical), and the extent of inhibitor cross-reactivity with porcine factor VIII. Patients with high-titre inhibitors experiencing a critical haemorrhage are generally best managed with bypassing agents (AUTOPLEX T or FEIBA VH), porcine factor VIII or rFVIIa
— id: 87045, year: 1999, vol: 5 Suppl 3, page: 33, stat: Journal Article,

Transfusion practices in infants receiving assisted ventilation
Cohen, A; Manno, C
1998 Mar;25(1):97-111, Clinics in perinatology
Controversies about medical practices usually arise from lack of definitive scientific studies. In the presence of continuing controversy about the appropriate hemoglobin level for ventilated (or nonventilated) infants, we can attempt to derive as much useful information as possible. In this article, the authors focus on four subjects: the physiologic role of red cells, the clinical effects of anemia and the proposed clinical benefit of red cell transfusions in preterm infants, the risks associated with transfusions, and the use of recombinant erythropoietin as an alternative to transfusion therapy
— id: 115324, year: 1998, vol: 25, page: 97, stat: Journal Article,

Prevalence of the factor V leiden mutation in children and neonates with thromboembolic disease
Hagstrom, J N; Walter, J; Bluebond-Langner, R; Amatniek, J C; Manno, C S; High, K A
1998 Dec;133(6):777-781, Journal of pediatrics
OBJECTIVE: Resistance to activated protein C (APC) has been identified as a risk factor for thrombotic disease in adults. In over 90% of cases, the basis for the APC resistance is a mutation in the coagulation factor V gene (factor V Leiden) that renders the protein more resistant to inactivation by APC. We sought to determine the prevalence of the factor V Leiden (FVL) mutation in neonates and children who had experienced an arterial or venous thromboembolic event.Study design: We retrospectively analyzed the clinical records of 33 neonates and 52 children with thromboembolic disease. Screening for the FVL mutation was performed by DNA analysis, allowing for identification of patients as normal, heterozygous, or homozygous. RESULTS: Of the 85 patients studied, 12 (14.1%) were heterozygous for FVL; none were homozygous. Of the 47 patients who had arterial central nervous system events, 8 (17%) were positive for the FVL mutation, including 6 of 22 (27%) neonates. Of those patients who had a venous thrombosis, 4 of 32 (12.5%) were FVL positive. None of the 85 patients had protein C deficiency, 3.5% had protein S deficiency, 1.2% had antithrombin III deficiency, and 16.5% had anti-phospholipid antibodies. CONCLUSION: These data suggest that the FVL mutation plays a role in the development of arterial and venous thrombotic events in neonates and children
— id: 87046, year: 1998, vol: 133, page: 777, stat: Journal Article,

Diagnosis and management of iron-induced heart disease in Cooley's anemia
Jessup, M; Manno, C S
1998 Jun 30;850:242-250, Annals of the New York Academy of Sciences
Patients with homozygous beta-thalassemia are chronically transfused and, if not assiduously chelated, are at risk for cardiac dysfunction. Available data suggest that even in optimally chelated patients, cardiac pathology is abnormal secondary to iron deposition, fibrosis, hypertrophy, and the structural effects of chronic anemia. Evidence of myopericarditis may also be found. Cardiac performance is usually only subtly affected, primarily with diastolic abnormalities not routinely detected on echocardiograms or nuclear scan. In poorly chelated patients, severe heart failure occurs and is easily predictable but invariably fatal, despite treatment with diuretics, vasodilators, inotropes, and antiarrhythmics. Based on successful prevention of heart failure with ACE inhibitors in other forms of cardiomyopathy, we suggest multicenter trials to explore methods to stabilize cardiac function in patients at risk for iron-induced heart disease. Long-term adverse effects of iron deposition, diastolic dysfunction, and abnormal hormone regulation need to be quantitated in patients reaching their third and fourth decades when the potential for ischemic cardiac disease could compound cardiac dysfunction
— id: 87047, year: 1998, vol: 850, page: 242, stat: Journal Article,

Clinical impact of anti-D in intravenous immunoglobulin
Friedman, D F; Lukas, M B; Larson, P J; Douglas, S D; Manno, C S
1997 Apr;37(4):450-452, Transfusion
— id: 87050, year: 1997, vol: 37, page: 450, stat: Journal Article,

Superior in vivo response of recombinant factor VIII concentrate in children with hemophilia A
Kelly, K M; Butler, R B; Farace, L; Cohen, A R; Manno, C S
1997 Apr;130(4):537-540, Journal of pediatrics
OBJECTIVE: Our previous experience with highly purified plasma-derived factor VIII (pdFVIII) concentrates showed that adult dosage recommendations were not applicable to children. In this study, we compared the in vivo response and recovery of recombinant factor VIII (rFVIII) with those of highly purified pdFVIII concentrate in children with hemophilia A. STUDY DESIGN: Ten boys with severe factor VIII deficiency and no concurrent bleeding episodes participated in a masked, prospective, crossover study comparing factor VIII coagulant activity after infusion of 50 units of pdFVIII and rFVIII products per kilogram of body weight. RESULTS: Mean peak factor VIII response with rFVIII was 1.91% +/- 0.14%, significantly better than the response observed with highly purified pdFVIII of 1.5% +/- 0.15% (p = 0.007). Mean peak factor VIII recovery was 100.5% with rFVIII versus 78.7% with pdFVIII (p = 0.007). Positive correlations between response to rFVIII and body surface area (r = 0.734, p = 0.015), body weight (r = 0.762, p = 0.01), and plasma volume (r = 0.659, p = 0.03) were observed. CONCLUSIONS: Infusion of rFVIII produced a significantly better response and recovery in vivo than infusion of highly purified pdFVIII in children. The response in children after infusion of rFVIII was similar to the response previously observed in adults
— id: 87051, year: 1997, vol: 130, page: 537, stat: Journal Article,

The presurgical management with erythrocytapheresis of a patient with a high-oxygen-affinity, unstable Hb variant (Hb Bryn Mawr)
Larson, P J; Friedman, D F; Reilly, M P; Kattamis, A C; Asakura, T; Fortina, P; Cohen, A R; Kim, H C; Manno, C S
1997 Jul;37(7):703-707, Transfusion
BACKGROUND: Hemoglobin (Hb) Bryn Mawr is an unstable Hb variant resulting in congenital hemolytic anemia. This variant Hb also has an increased affinity for oxygen. The perioperative transfusion management of this disorder is described, and the first genomic analysis of this Hb variant is given. CASE REPORT: An 11-year-old boy, heterozygous for Hb Bryn Mawr, was referred for cholecystectomy. Sequence analysis of genomic DNA confirmed that the patients was heterozygous for a T-->C transition in the codon for amino acid 85, causing a substitution of serine for phenylalanine in the beta-globin chain. On the basis of whole-blood O2 dissociation studies, projected tissue O2 delivery would have been suboptimal during general anesthesia; therefore, a partial red cell exchange transfusion was performed to lower variant Hb and prevent tissue hypoxia during surgery. The red cell mass to be exchanged (50%) was determined from the calculated increase in O2 delivery capacity required to maintain an O2 extraction of 4 to 5 mL of O2 per dL of whole blood. The p50 of whole blood from the patients immediately after the exchange transfusion was 16.0 torr. At the time of surgery, the p50 was normal (25.9 torr). The patient's whole blood 2,3 DPG levels were 4.70 mmol per mL of red cells (before transfusion) (normal range = 4.8 +/- 0.3 mmol/mL red cells), 4.07 mmol per mL of red cells (immediately after transfusion), and 4.55 mmol per mL of red cells (48 hours after transfusion). CONCLUSION: This patient with Hb Bryn Mawr was prepared for surgery with a partial exchange transfusion to prevent tissue hypoxia during anesthesia. Decreased 2,3 DPG levels immediately after transfusion resulted in increased O2 affinity of whole blood; however, 48 hours after exchange transfusion, a normal p50 (due to both removal of variant Hb and regeneration of 2,3, DPG) was observed. Partial exchange transfusion is useful in the preoperative management of patients with Hb variants characterized by increased O2 affinity
— id: 87048, year: 1997, vol: 37, page: 703, stat: Journal Article,

Screening for hereditary spherocytosis by use of automated erythrocyte indexes
Michaels, L A; Cohen, A R; Zhao, H; Raphael, R I; Manno, C S
1997 Jun;130(6):957-960, Journal of pediatrics
OBJECTIVE: To determine whether the mean corpuscular hemoglobin concentration (MCHC) or other erythrocyte indexes, as determined by automated cell counters, remains a useful screening test for identifying patients with hereditary spherocytosis (HS). METHODS: Erythrocyte indexes from 112 children with HS who had not undergone splenectomy were compared with those measured in an equal number of healthy, age-matched children. All indexes were derived from measurements obtained by aperture impedance. RESULTS: Mean corpuscular hemoglobin concentration in the HS group was 35.9 gm/dl, significantly higher than in normal control subjects (34.3 gm/dl; p < 0.001). Mean erythrocyte distribution width also was significantly higher in patients with HS (19.3 vs 12.6; p < 0.001). The MCHC distinguishes individuals with HS, with an area under the receiver operating characteristic curve of 0.86. Although not disease specific, an erythrocyte distribution width > 14 has 85% sensitivity and 97% specificity and an area under the receiver operating characteristic curve of 0.92. An MCHC > 35 gm/dl has a sensitivity of 70% and a specificity of 86%. Combining the MCHC and erythrocyte distribution width increases the area under the receiver operating characteristic curve to 0.97. Specificity is 100% and likelihood ratio is infinite when both the MCHC and erythrocyte distribution width are elevated. CONCLUSIONS: The automated MCHC is an effective screening test to identify children with HS. An elevated erythrocyte distribution width adds additional specificity and is itself a powerful screening tool. The combination of the two tests is an excellent predictor for the diagnosis of HS
— id: 87049, year: 1997, vol: 130, page: 957, stat: Journal Article,

Alloimmunization to platelets in heavily transfused patients with sickle cell disease
Friedman, D F; Lukas, M B; Jawad, A; Larson, P J; Ohene-Frempong, K; Manno, C S
1996 Oct 15;88(8):3216-3222, Blood
Bone marrow transplantation (BMT) is now an option for some patients with sickle cell disease (SCD). Many SCD patients are multiply transfused with red blood cells (RBCs), and may be immunized to alloantigens other than erythrocyte antigens. Because platelet refractoriness is a significant complication during BMT, we wished to determine the prevalence of alloimmunization to platelets in transfused SCD patients. Sera collected from 47 transfused and 14 untransfused SCD patients were screened for HLA and platelet-specific antibodies. Transfusion and RBC antibody histories were reviewed. A subset of the patients were rescreened 1 year later. Eighty-five percent of patients with at least 50 RBC transfusions (22 of 26), 48% of patients with less than 50 transfusions (10 of 21), and none of 14 untransfused patients demonstrated platelet alloimmunization (P < .05). Platelet alloimmunization was more prevalent than RBC alloimmunization (20% to 30%). Half of the platelet reactivity was chloroquine-elutable. Eighteen of 22 patients (82%) on chronic RBC transfusion remained platelet-alloimmunized 11 to 22 months after initial testing. In summary, 85% of heavily transfused SCD patients are alloimmunized to HLA and/or platelet-specific antigens. These patients may be refractory to platelet transfusion, a condition that would increase their risk during BMT. Leukodepletion in the transfusion support of SCD patients should be considered to prevent platelet alloimmunization
— id: 87054, year: 1996, vol: 88, page: 3216, stat: Journal Article,

Delayed hemolytic transfusion reaction due to anti-Go(a), an antibody against the low-prevalence Gonzales antigen
Larson, P J; Lukas, M B; Friedman, D F; Manno, C S
1996 Dec;53(4):248-250, American journal of hematology
Go(a) (D(Cor)) is a low-frequency antigen in the Rh system found on red cells lacking part of the D mosaic (category IVa). Anti-Go(a) has not been previously reported to cause hemolytic transfusion reactions. A 27-year-old African American male with sickle-cell disease, maintained on chronic transfusion, was noted to have dark plasma during an erythrocytapheresis, procedure, and the pretransfusion hemoglobin was noted to be 1 g/dl lower than 4 weeks before (with hyperbilirubinemia and a significantly increased LDH). Polyspecific direct antiglobulin test (DAT) was weakly positive (C3-weak, IgG-weak), and indirect antiglobulin tests (IATs) performed on the serum (pre- and posttransfusion reaction) and a red blood cell (RBC) eluate from the postreaction sample were negative. A segment from one of the four implicated units from the prior month's transfusion was strongly reactive at 37 degrees C and using anti-human globulin (AHG) when crossmatched with the postreaction serum and the eluate. The postreaction serum, screened with a panel of red cells positive for low-prevalence antigens, reacted with three Go(a+) cells. The implicated unit was reactive with a previously identified anti-Go(a) serum
— id: 87052, year: 1996, vol: 53, page: 248, stat: Journal Article,

What's new in transfusion medicine?
Manno, C S
1996 Jun;43(3):793-808, Pediatric clinics of North America
The safety of the blood supply has increased tremendously in the past decade. Donor screening and improved infectious disease testing of units for transfusion have contributed to the decreased risk of transfusion-transmitted diseases. Reduction of the number of passenger leukocytes from RBC and platelet transfusions decreases the rate of febrile transfusion reactions and alloimmunization. Irradiation of cellular products helps prevent TA-GVHD. The practice of obtaining an informed consent prior to transfusion helps patients and families understand the risks and benefits of and alternatives to transfusion therapy
— id: 87055, year: 1996, vol: 43, page: 793, stat: Journal Article,

Recombinant human erythropoietin reduces the need for erythrocyte and platelet transfusions in pediatric patients with sarcoma: a randomized, double-blind, placebo-controlled trial
Porter, J C; Leahey, A; Polise, K; Bunin, G; Manno, C S
1996 Nov;129(5):656-660, Journal of pediatrics
OBJECTIVE: To evaluate the effect of recombinant human erythropoietin (EPO) and iron supplementation on transfusion requirements in pediatric patients with sarcoma who were receiving chemotherapy, we performed a double-blind, placebo-controlled, randomized trial. METHODS: Twenty-four pediatric patients with malignant solid tumors were randomly assigned to receive either placebo (saline solution) or EPO for a 16-week study period. The starting dose was 150 IU/kg per dose three times a week and was escalated by 50 IU/kg per dose increments monthly until packed red blood cell (PRBC) transfusion independence was achieved or a dosage of 300 IU/kg per dose was reached. Iron supplementation was prescribed at a dose of 6 mg of elemental iron per kilogram daily. The primary study end point was the comparison of PRBC transfusion requirements in the two groups. RESULTS: Of 24 patients, 20 were evaluable for response. The median PRBC transfusion requirement during the 16-week period was 23 ml/kg in EPO-treated patients versus 80 ml/kg in placebo patients (p = 0.02). The median number of single-donor platelet units transfused was zero in the EPO-treated patients compared with four in the placebo group (p = 0.005). No statistical difference in the intensity of bone marrow suppression was seen, as measured by the median number of complete blood cell counts with an absolute neutrophil count of < 1000 cells/microliter. CONCLUSIONS: Treatment with EPO and iron significantly reduces PRBC transfusions in pediatric patients receiving concomitant chemotherapy for malignant sarcomas. A decrease in the number of platelet transfusions was also seen and deserves further study
— id: 87053, year: 1996, vol: 129, page: 656, stat: Journal Article,

Treatment of refractory Evans syndrome with alternate-day cyclosporine and prednisone
Rackoff, W R; Manno, C S
1994 May;16(2):156-159, American journal of pediatric hematology-oncology
PURPOSE: We report that the use of alternate-day cyclosporine and prednisone improved the clinical course of a 6-year-old child with severe Evans syndrome. Before the use of cyclosporine the child had experienced life-threatening episodes of hemolytic anemia despite the use of multiple therapeutic modalities. METHODS: Cyclosporine was given at a dose of 10 mg/kg/day divided into two doses on alternate days. RESULTS: The use of cyclosporine resulted in increased hemoglobin levels, increased platelet counts, and the reduction of the patient's prednisone dose from 2 mg/kg/day to as low as 1 mg/kg every other day. With this regimen, the patient had less severe hemolytic anemia, was less thrombocytopenic, and had fewer hospitalizations. No major toxic effects were associated with cyclosporine therapy. CONCLUSION: The regimen of alternate-day cyclosporine and prednisone may prove to be useful in the treatment of other patients with refractory Evans syndrome
— id: 87056, year: 1994, vol: 16, page: 156, stat: Journal Article,

Use of acetyl chloride/methanol for assumed selective methylation of plasma nonesterified fatty acids results in significant methylation of esterified fatty acids
Hallaq, Y; Becker, T C; Manno, C S; Laposata, M
1993 Apr;28(4):355-360, Lipids
The albumin-bound nonesterified fatty acid pool in plasma, which represents a very small percentage of total plasma fatty acids, has previously been quantitated by a variety of methods. In the present study we determined that the nonesterified fatty acid concentrations in the plasma, quantitated by a popular method using acetyl chloride and methanol which is reported to be specific for methylation of nonesterified fatty acids in the presence of esterified fatty acids (i.e., without prior isolation of the plasma nonesterified fatty acids), were significantly overestimated due to cleavage and methylation of esterified fatty acids. Quantitation of the contaminating fatty acid from the esterified pool demonstrated that the amount of fatty acid cleaved from the esterified pool was enough to exceed the entire mass of nonesterified fatty acids. As an established method for comparison, we isolated nonesterified fatty acids from the plasma by thin-layer chromatography prior to methylation, using a number of simple precautions to limit oxidation. By performing all thin-layer chromatography steps in an atmosphere of nitrogen and by including fatty acid standards in the plasma with 0, 1, 2 or 4 double bonds, we were able to accurately and reproducibly determine the concentration of nonesterified fatty acids in the plasma, including arachidonate. We demonstrated that no oxidation occurred in the thin-layer chromatographic isolation of nonesterified fatty acids and that the coefficients of variation for repeat measurements of the same sample were < 11% using our reference method. Our data indicate that the use of acetyl chloride and methanol for assumed selective methylation of plasma nonesterified fatty acids results in significant methylation of esterified fatty acids
— id: 87059, year: 1993, vol: 28, page: 355, stat: Journal Article,

Coagulation defects in neonates during cardiopulmonary bypass
Jobes, D R; Nicolson, S C; Steven, J M; Manno, C S
1993 May;55(5):1283-1284, Annals of thoracic surgery
— id: 87058, year: 1993, vol: 55, page: 1283, stat: Journal Article,

Desmopressin does not decrease bleeding after cardiac operation in young children
Reynolds, L M; Nicolson, S C; Jobes, D R; Steven, J M; Norwood, W I; McGonigle, M E; Manno, C S
1993 Dec;106(6):954-958, Journal of thoracic & cardiovascular surgery
Young children undergoing complex cardiac operation lose more blood after cardiopulmonary bypass than do older patients. This study was designed to investigate the effect of desmopressin on blood loss during the first 24 hours after cardiac operation in children undergoing principally complex surgical procedures. The study consisted of a randomized, blinded comparison of 112 pediatric patients who received either desmopressin 0.3 microgram/kg or saline solution placebo after cardiopulmonary bypass. A coagulation profile including bleeding time, quantitation of von Willebrand factor, and qualitative analysis of the factor VII:von Willebrand factor complex was performed before, 30 minutes after, and 3 hours after the operation. Blood loss and blood replacement were recorded for the first 24 hours after the operation. The surgeon classified the technical difficulty of each procedure as simple or complex. Statistical analysis was performed with Student's unpaired t test and chi 2 analysis. Significance was defined as p < 0.05. Results are listed as mean +/- standard deviation. Data collection was completed for 95 patients. The mean age of all patients was 26 +/- 40 months, and the mean weight was 10 +/- 11 kg, with 84% undergoing complex procedures. There were no differences between the desmopressin and placebo groups with respect to age, weight, or surgical complexity. Twenty-four-hour blood loss and replacement between the desmopressin and placebo groups were not different (blood loss: desmopressin 30 +/- 33 ml/kg, placebo 35 +/- 36; blood replacement: desmopressin 65 +/- 43 ml/kg, placebo 64 +/- 46 ml/kg). Coagulation profiles between the desmopressin and placebo groups were not different at any time. We conclude that desmopressin does not reduce blood loss or blood replacement in young children after cardiopulmonary bypass for either simple or complex cardiac surgical procedures
— id: 87057, year: 1993, vol: 106, page: 954, stat: Journal Article,

Diffuse chondrolytic arthritis in sickle cell disease
Schumacher, H R Jr; Van Linthoudt, D; Manno, C S; Cuckler, J M; Athreya, B H
1993 Feb;20(2):385-389, Journal of rheumatology
A young black man with sickle cell disease with recurrent painful vasoocclusive crises developed at 16 years of age a rapid disabling polyarticular chondrolysis leading to a bilateral hip arthroplasty in 1 year. Light microscopy showed erosion and chondrocyte loss with deep clones in the cartilage and congested vessels with extravasation of red blood cells and mononuclear cells in the synovium. Electron microscopy of the synovium disclosed partially occluded blood vessels and phagocytic cells containing red blood cell debris and crystalline hemoglobin-like material. These observations suggest a role for the phagocytic cells in the joint destruction
— id: 87060, year: 1993, vol: 20, page: 385, stat: Journal Article,

Low recovery in vivo of highly purified factor VIII in patients with hemophilia
Manno, C S; Butler, R B; Cohen, A R
1992 Nov;121(5 Pt 1):814-818, Journal of pediatrics
To assess whether the response and recovery of highly purified factor VIII products approach the levels predicted by use of manufacturers' suggestions, we studied response in vivo and percentage of recovery in boys and men with hemophilia after infusion of 50 IU of an immunoaffinity-purified factor VIII preparation (Hemofil M) per kilogram of body weight. We also studied dose response and percentage of recovery in the same boys after infusion of a factor VII concentrate prepared by solvent detergent treatment and gel filtration (Koate-HP). For boys the difference between mean peak factor VIII response with Hemofil M (1.02% +/- 0.07%) and the response with Koate-HP (1.21% +/- 0.10%) was not significant (p = 0.10), but the response of both products was considerably less than the predicted response of 2.0%. The response to Hemofil M in men (1.38% +/- 0.12%) was significantly better than the response in boys (p = 0.004) but, again, fell short of the anticipated response of 2.0%. In boys the percentage of recovery of Hemofil M was 38.4% +/- 2.1%, compared with Koate-HP recovery, which was 47.0% +/- 3.6% (p = 0.034). The percentage of recovery in men was 47.5% +/- 2.8%. The better response observed in men appears to be, in part, a function of larger body size. We conclude that peak factor VIII response and recovery in boys and men who receive highly purified factor VIII concentrates are lower than those predicted by use of current prescribing recommendations
— id: 87061, year: 1992, vol: 121, page: 814, stat: Journal Article,

Difficult pediatric diagnoses. Bruising and bleeding
Manno, C S
1991 Jun;38(3):637-655, Pediatric clinics of North America
An approach to the evaluation of a child who presents to the pediatrician with bruising is outlined. Important clues in the history and physical examination that suggest disorders of platelet number and function or coagulation abnormalities are presented. A scheme for using screening tests of coagulation and platelet function is followed by a brief summary of currently available therapies appropriate for bleeding episodes in children
— id: 87062, year: 1991, vol: 38, page: 637, stat: Journal Article,

Comparison of the hemostatic effects of fresh whole blood, stored whole blood, and components after open heart surgery in children
Manno, C S; Hedberg, K W; Kim, H C; Bunin, G R; Nicolson, S; Jobes, D; Schwartz, E; Norwood, W I
1991 Mar 1;77(5):930-936, Blood
In a double-blind study, we compared the postoperative (post-op) blood loss in 161 children undergoing open heart surgery with cardiopulmonary bypass whose immediate post-op transfusion requirements were met with either very fresh whole blood (VFWB), 24- to 48-hour-old whole blood or reconstituted whole blood (packed red blood cells, fresh frozen plasma [FFP], and platelets). Assignment to treatment groups was not strictly random but dependent, in part, on the ability of families to provide directed donors for fresh blood. The three patient groups were comparable with respect to patient age, pre-op coagulation profiles (bleeding time, prothrombin time, activated partial thromboplastin time, platelet count, fibrin split products, fibrinogen, and platelet aggregation tests) difficulty of operative procedures and time spent on CPB. Mean 24-hour post-op blood loss in milliliters per kilogram was 50.9 +/- 9.3 in the VFWB group, 44.8 +/- 6.0 in the 24- to 48-hour-old group, and 74.2 +/- 8.9 in the reconstituted group (p = .03). When blood loss was compared in the 93 children less than 2 years of age, mean blood loss was 52.3 +/- 10.8 in the VFWB group, 51.7 +/- 7.4 in the 24- to 48-hour-old group, and 96.2 +/- 10.7 in the reconstituted group (P = .001). For subjects who had received reconstituted blood, 30-minute and 3-hour post-op platelet aggregation responses to adenosine diphosphate (10 mumol/L) and 30-minute aggregation response to epinephrine (2.5 mumol/L) were more depressed than in the VFWB and 24- to 48-hour groups (P less than .001, P = .005, and P = .02). Comparison of other post-op coagulation tests could not explain the increased blood loss in the reconstituted group. We conclude that the transfusion of less than 48 hours old whole blood is associated with significantly less post-op blood loss than the transfusion of packed red blood cells, FFP, and platelets in children under 2 years old who underwent complex cardiac surgery. The blood losses associated with the transfusion of VFWB and 24- to 48-hour-old blood are comparable and may be, in part, due to better functioning platelets
— id: 87063, year: 1991, vol: 77, page: 930, stat: Journal Article,

Splenectomy in mild hereditary spherocytosis: is it worth the risk?
Manno, C S; Cohen, A R
1989 Fall;11(3):300-303, American journal of pediatric hematology-oncology
Patients with mild hereditary spherocytosis (HS) often undergo splenectomy for the sole purpose of preventing gallstone formation. Splenectomy carries a surgical risk as well as the risk of postsplenectomy sepsis. Gallstones develop in less than half of mild HS patients and do not always cause symptomatic biliary tract disease. Using decision analysis, a quantitative approach to problem solving under conditions of uncertainty, we have compared the likelihood of surviving the complications of gallstones with the likelihood of surviving routine splenectomy. Probability figures for critical events were obtained from the medical literature; final outcome is recovery (utility = 1.0) or death (utility = 0.0). Our analysis shows that expectant management of gallstones is the preferred choice, being associated with a higher utility than is routine splenectomy (0.9980 vs 0.9755, respectively). The utility values for the two choices become equivalent only when the risk of postsplenectomy sepsis is lowered from 0.022 to 0.0001
— id: 87064, year: 1989, vol: 11, page: 300, stat: Journal Article,

Rapid excretion of gallium-67 isotope in an iron-overloaded patient receiving high-dose intravenous deferoxamine
Baker, D L; Manno, C S
1988 Dec;29(4):230-232, American journal of hematology
A 23 year-old black male with homozygous sickle cell disease (Hb SS disease) and transfusional iron overload was admitted for evaluation of response to intravenous deferoxamine (DFO) therapy. Soon after admission, the patient suffered an intraventricular hemorrhage and during his subsequent hospitalization developed a persistent fever of undetermined origin (f.u.o.). Included in the diagnostic evaluation of fever was a gallium 67 scan (Ga-67), which was initially nondiagnostic because of Ga-67 citrate's preferential chelation by DFO. After DFO was discontinued, a repeat scan demonstrated a lesion above the left kidney. To our knowledge the unusual interaction in vivo of DFO with Ga-67 citrate has not been reported in the clinical literature. With the anticipated increased use of chelation therapy for patients with transfusional iron overload, this interaction may be encountered more frequently. DFO should be discontinued before the use of Ga-67 scanning in this clinical situation, or an alternative isotopic scan, such as indium-labelled white cells, should be considered
— id: 87065, year: 1988, vol: 29, page: 230, stat: Journal Article,

Sickle cell anemia and cholelithiasis
Manno, C S; Cohen, A R; Schwartz, E
1988 ;18(2):178-178, Pediatric radiology
— id: 87066, year: 1988, vol: 18, page: 178, stat: Journal Article,

Update on hemoglobinopathies
Liebhaber, S A; Manno, C S
1983 Jul;29(10):1-74, Disease-a-month
— id: 87068, year: 1983, vol: 29, page: 1, stat: Journal Article,

Biventricular function in sickle-cell anemia: radionuclide angiographic and thallium-201 scintigraphic evaluation
Manno, B V; Burka, E R; Hakki, A H; Manno, C S; Iskandrian, A S; Noone, A M
1983 Sep 1;52(5):584-587, American journal of cardiology
Left ventricular (LV) and right ventricular (RV) function were evaluated at rest and during exercise using radionuclide ventriculography in 10 patients, aged 19-53 years, with sickle-cell anemia (SCA). Seven patients were in New York Heart Association functional class I and 3 were in class II. The resting LV ejection fraction (EF) was normal in 9 patients and the resting RVEF was normal in 4. LV dilation and high cardiac output were observed in 6 patients at rest. The LVEF during exercise was normal in all 10 patients, whereas only 2 patients had normal RVEF at rest and during exercise. The LVEF was lower in patients with SCA at rest (54 +/- 4% versus 61 +/- 6%, p less than 0.001) and exercise (66 +/- 4% versus 74 +/- 6%, p less than 0.001) than in 42 age-matched normal subjects. Rest thallium-201 images from 9 patients showed abnormal RV uptake in 8 and normal LV uptake in 8. Thus, in adult patients with SCA, LV function was normal during exercise in all patients and at rest in all but 1 patient. The LVEF, however, was lower than that in age-matched normal subjects. RV function was abnormal in most patients at rest and during exercise. RV thallium-201 uptake suggested pressure or volume overload (or both), most likely due to pulmonary vaso-occlusive complications of the disease
— id: 87067, year: 1983, vol: 52, page: 584, stat: Journal Article,