Monitoring Hemostasis During Extracorporeal Life Support.

To balance the risk of bleeding versus circuit thrombosis during extracorporeal life support (ECLS), it is important to monitor anticoagulants and hemostasis. We evaluated the prothrombin time (PT), partial thromboplastin time (PTT), activated clotting time (ACT), and antifactor Xa heparin activity (aXa) correlation with changes in coagulation factor and heparin levels using in vitro and in vivo samples. aXa correlated with heparin (r = 0.

A Prospective Study of the Causes of Bruises in Premobile Infants.

Objective: This study had 2 objectives. First, to determine the behavior of physicians evaluating premobile infants with bruises. Second, and most importantly, to learn whether infants with unexplained bruising who had been initially evaluated by primary care and emergency department (ED) physicians are as likely to have their bruises attributed to child abuse as those children evaluated by child abuse physicians.

The use of antifibrinolytics in pediatric patients with hypoproliferative thrombocytopenia.

Despite the use of evidence-based platelet transfusion therapy during periods of hypoproliferative thrombocytopenia, a large proportion of pediatric hematology/oncology patients continue to suffer from clinically significant bleeding. Antifibrinolytic (AF) drugs have been shown in certain surgical and trauma settings to decrease bleeding, blood transfusion, and improve survival. We conducted a retrospective assessment of the safety of using AF drugs in pediatric patients with hypoproliferative thrombocytopenia at our center as well as the impact on bleeding occurrence and severity.

T cells from hemophilia A subjects recognize the same HLA-restricted FVIII epitope with a narrow TCR repertoire.

Factor VIII (FVIII)-neutralizing antibodies ("inhibitors") are a serious problem in hemophilia A (HA). The aim of this study was to characterize HLA-restricted T-cell responses from a severe HA subject with a persistent inhibitor and from 2 previously studied mild HA inhibitor subjects. Major histocompatibility complex II tetramers corresponding to both of the severe HA subject's HLA-DRA-DRB1 alleles were loaded with peptides spanning FVIII-A2, C1, and C2 domains.

Eltrombopag for the treatment of children with persistent and chronic immune thrombocytopenia (PETIT): a randomised, multicentre, placebo-controlled study.

Background: The oral thrombopoietin receptor agonist eltrombopag is approved for treatment of adults with chronic immune thrombocytopenia. In the PETIT trial, we aimed to investigate the efficacy and safety of eltrombopag in children with persistent or chronic immune thrombocytopenia.

Methods: PETIT was a three-part, randomised, multicentre, placebo-controlled study done at 22 centres in the USA, UK, Canada, Spain, France, and the Netherlands.

Hemolytic disease of the fetus and newborn: managing the mother, fetus, and newborn.

Hemolytic disease of the fetus and newborn (HDFN) affects 3/100 000 to 80/100 000 patients per year. It is due to maternal blood group antibodies that cause fetal red cell destruction and in some cases, marrow suppression. This process leads to fetal anemia, and in severe cases can progress to edema, ascites, heart failure, and death.

Factor VIII gene variants and inhibitor risk in African American hemophilia A patients.

African American hemophilia A (HA) patients experience a higher incidence of neutralizing anti-factor VIII (FVIII) antibodies ("inhibitors") vis-à-vis white patients. Nonsynonymous single-nucleotide polymorphisms (ns-SNPs) in the F8 gene encoding FVIII-H484, FVIII-E1241, and FVIII-V2238 are more prevalent in African Americans. This study tested the hypothesis that immune responses to these sites provoke inhibitors.

Antithrombin concentrates use in children on extracorporeal membrane oxygenation: a retrospective cohort study.

Objective: To investigate whether receipt of any antithrombin concentrate improves laboratory and clinical outcomes in children undergoing extracorporeal membrane oxygenation for respiratory failure during their hospitalization compared with those who did not receive antithrombin.

Design: Retrospective cohort study.

Setting: Single, tertiary-care pediatric hospital.

Inherited disorders of platelet function.

Inherited platelet function disorders are of variable severity and unknown frequency and may be difficult to diagnose. Nevertheless, they are increasingly recognized as an important cause of bleeding in pediatrics, particularly in adolescent girls with menorrhagia, where they may be more common than von Willebrand disease. This article reviews the presentation of these disorders, summarizes the most common types of platelet function disorders, discusses the challenges in diagnostic testing, and details treatment and supportive care options.

Fanconi anemia-like presentation in an infant with constitutional deletion of 21q including the RUNX1 gene.

We describe a newborn female with a de novo interstitial deletion of chromosome 21q21.1-22.12 including the RUNX1 gene who had developmental delay, multiple congenital anomalies, tetralogy of Fallot, anemia, and chronic thromobocytopenia requiring frequent platelet transfusions from birth.

Successful unrelated donor cord blood transplantation for Glanzmann's thrombasthenia.

GT, a rare disorder of platelet function, can lead to life-threatening bleeding, particularly following the development of antiplatelet antibodies. Curative therapy includes HCT but previous reports are limited predominantly to matched siblings and have excluded CBT. Delayed or non-engraftment of platelets because of antiplatelet antibodies might be particularly concerning after CBT for GT.

Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.

We conducted a study to estimate the maximum tolerated dose (MTD) of (131)I-anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation.

Pretargeted radioimmunotherapy using anti-CD45 monoclonal antibodies to deliver radiation to murine hematolymphoid tissues and human myeloid leukemia.

Radioimmunotherapy (RIT) for treatment of hematologic malignancies frequently fails because of disease recurrence. We therefore conducted pretargeted (P)RIT studies to augment the efficacy in mice of therapy using a pretargeted anti-human (h)CD45 antibody (Ab)-streptavidin (SA) conjugate followed by a biotinylated clearing agent and radiolabeled 1,4,7,10-tetraazacylodode cane N,N',N",N'''-tetraacetic (DOTA)-biotin. Tumor-to-blood ratios at 24 hours were 20:1 using pretargeted anti-hCD45 RIT and <1:1 with conventional RIT.

Inferior vena cava thrombosis causing acute cauda equina syndrome. Case report.

The authors report a case of a 16-year-old girl who presented with a 1-week history of progressive low-back pain, buttock paresthesias, and bilateral lower extremity pain and weakness. Magnetic resonance (MR) imaging and MR venography studies of her lumbar spine revealed engorgement of the epidural venous plexus and mild compression of the cauda equina. A lower extremity and pelvic venogram revealed occlusive thrombosis of the femoral and iliac veins as well as of the inferior vena cava (IVC).

131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission.

In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a phase 1/2 study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/mL) and cyclophosphamide (CY; 120 mg/kg). Fifty-two (88%) of 59 patients receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ.

Biodistribution of yttrium-90-labeled anti-CD45 antibody in a nonhuman primate model.

Purpose: Radioimmunotherapy may improve the outcome of hematopoietic cell transplantation for hematologic malignancies by delivering targeted radiation to hematopoietic organs while relatively sparing nontarget organs. We evaluated the organ localization of yttrium-90-labeled anti-CD45 ((90)Y-anti-CD45) antibody in macaques, a model that had previously predicted iodine-131-labeled anti-CD45 ((131)I-anti-CD45) antibody biodistribution in humans.

Experimental Design: Twelve Macaca nemestrina primates received anti-CD45 antibody labeled with 1 to 2 mCi of (90)Y followed by serial blood sampling and marrow and lymph node biopsies, and necropsy.

Conditionally cleavable radioimmunoconjugates: a novel approach for the release of radioisotopes from radioimmunoconjugates.

One of the limitations of therapy with radiolabeled monoclonal antibodies (mAbs) is that significant toxicities can arise from circulating non-tumor-bound radiolabeled conjugate. Here, we describe a new method to reduce systemic radiation exposure from radiolabeled mAbs involving the attachment of the radioisotope through a linker that can be cleaved by an administered enzyme. To demonstrate the feasibility of this approach, we prepared a conditionally cleavable radioimmunoconjugate (RIC) composed of (131)I-labeled cephalosporin conjugated to Tositumomab, a mAb against the CD20 antigen.

High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: a multivariable cohort analysis.

We performed a multivariable comparison of 125 consecutive patients with follicular lymphoma (FL) treated at our centers with either high-dose radioimmunotherapy (HD-RIT) using 131I-anti-CD20 (n = 27) or conventional high-dose therapy (C-HDT) (n = 98) and autologous hematopoietic stem cell transplantation. The groups were similar, although more patients treated with HD-RIT had an elevated pretransplantation level of lactate dehydrogenase (41% versus 20%, P =.03) and elevated international prognostic score (41% versus 19%, P =.

Use of radiolabeled antibodies in the treatment of childhood acute leukemia.

Despite advances in therapy for acute leukemia, relapse continues to be the major cause of treatment failure. Hematopoietic stem cell transplant can rescue some patients after relapse, but the ability to escalate the intensity of preparative regimens is limited by toxicity to normal organs. Radiolabeled monoclonal antibodies against hematopoietic antigens have emerged as an alternative to deliver targeted supplemental radiation to sites of leukemic involvement while relatively sparing normal organs.

Comparison of anti-CD20 and anti-CD45 antibodies for conventional and pretargeted radioimmunotherapy of B-cell lymphomas.

Radiolabeled anti-CD20 antibodies produce responses in 60% to 95% of patients with relapsed non-Hodgkin lymphoma (NHL); however, absorbed radiation ratios between tumors and normal organs are relatively low, and many patients have relapses. In this study we compared the abilities of anti-CD45 (BC8) and anti-CD20 (1F5) antibodies to target human Ramos lymphoma xenografts in athymic mice. When direct radioiodination was performed with conventional methods, BC8 delivered 2- to 4-fold more radioiodine to tumors than 1F5, with tumor-to-normal organ ratios as high as 20:1 using radiolabeled BC8 compared with a maximal ratio of 9.

Antibody-based therapy of human leukemia.

During the past decades, monoclonal antibodies have been used as vehicles to deliver targeted therapy to sites of leukemic involvement. Anti-CD33 antibodies have been used alone-and more effectively, attached to chemotherapy agents or radioisotopes-to treat those with acute myeloid leukemia. Anti-CD45 antibodies have demonstrated an antileukemic effect when used either unconjugated or attached to radioactive iodine.

High-dose chemo-radioimmunotherapy with autologous stem cell support for relapsed mantle cell lymphoma.

Relapsed mantle cell lymphoma is a radiation-sensitive malignancy that is unlikely to be cured by treatment with conventional high-dose therapy and autologous stem cell transplantation. We tested the safety and efficacy of using a CD20-specific monoclonal antibody conjugated with (131)I to deliver high-dose radiation selectively to all lymphoma sites. Patients with relapsed or refractory mantle cell lymphoma received infusions of (131)I-labeled CD20-specific monoclonal antibody (Tositumomab).