A study of prospective surveillance for inhibitors among persons with haemophilia in the United States.

Inhibitors are a rare but serious complication of treatment of patients with haemophilia. Phase III clinical trials enrol too few patients to adequately assess new product inhibitor risk. This project explores the feasibility of using a public health surveillance system to conduct national surveillance for inhibitors. Staff at 17 U.S. haemophilia treatment centres (HTC) enrolled patients with haemophilia A and B into this prospective study. HTC staff provided detailed historic data on product use and inhibitors at baseline, and postenrolment patients provided monthly detailed infusion logs. A central laboratory performed inhibitor tests on blood specimens that were collected at baseline, annually, prior to any planned product switch or when clinically indicated. The central laboratory also performed genotyping of all enrolled patients. From January 2006 through June 2012, 1163 patients were enrolled and followed up for 3329 person-years. A total of 3048 inhibitor tests were performed and 23 new factor VIII inhibitors were identified, 61% of which were not clinically apparent. Infusion logs were submitted for 113,205 exposure days. Genotyping revealed 431 distinct mutations causing haemophilia, 151 of which had not previously been reported elsewhere in the world. This study provided critical information about the practical issues that must be addressed to successfully implement national inhibitor surveillance. Centralized testing with routine monitoring and confirmation of locally identified inhibitors will provide valid and representative data with which to evaluate inhibitor incidence and prevalence, monitor trends in occurrence rates and identify potential inhibitor outbreaks associated with products.

Successful treatment of autoimmune neutropenia with recombinant human granulocyte-colony stimulating factor (R-metHuG-CSF).

Autoimmune neutropenia (AIN) is characterized by antibody mediated peripheral destruction of neutrophils. Since there is no effective treatment, antibiotics have to be used frequently for recurrent infections. Five selected patients with serologically proven AIN were treated with r-metHuG-CSF at 5-8 micrograms/kg body weight (300-480 micrograms) daily; the dose and frequency of r-metHuG-CSF was reduced after neutrophil counts above 1.0 x 10(9)/l were obtained. R-metHuG-CSF is effective in AIN and causes a sustained rise in ANC which can be maintained on a low dose administered twice or thrice weekly.

Uncomplicated stereotactic and open neurosurgical procedures in patients with factor VII deficiency.

Factor VII deficiency is characterized by epistaxis, bruising, hemarthrosis, menorrhagia, gastrointestinal bleeding, hematuria, and intracranial hemorrhage during infancy. Causes of acquired factor VII deficiency include liver disease, Vitamin K deficiency, and warfarin administration. Congenital factor VII deficiency is an autosomal recessive disorder, with the homozygotes having a severe deficiency and the heterozygotes a moderate deficiency of factor VII. Orthopedic, gynecological, cardiothoracic, and abdominal surgical procedures have been successfully performed in patients with factor VII deficiency both with and without factor VII replacement. We present two patients with moderate and moderately severe factor VII deficiency who successfully underwent intracranial procedures using plasma during the perioperative period for factor VII replacement. One patient successfully underwent stereotactic placement of mesial temporal lobe depth electrodes and subdural strip electrodes followed by anterior temporal lobectomy for medically refractory seizures. The second patient successfully underwent craniotomy for an olfactory groove meningioma. No bleeding complications were encountered with any of the three intracranial procedures performed. These cases represent the first reported cases of successful intracranial procedures in patients with factor VII deficiency, other than shunting procedures performed for intraventricular hemorrhage during infancy.

alpha-Interferon treatment for idiopathic hypereosinophilic syndrome.

Idiopathic hypereosinophilic syndrome (HES) is a poorly understood disorder characterized by a markedly elevated peripheral blood eosinophil count in the absence of known associated causes of hypereosinophilia. Idiopathic hypereosinophilic syndrome is associated with eosinophil-induced organ damage, including endomyocardial and pulmonary fibrosis, stroke, and gastrointestinal disease. Treatment of idiopathic HES is centered on the reduction of peripheral circulating eosinophils in an effort to diminish tissue infiltration and destruction. Multiple cytotoxic agents have been tried, with variable results. Prednisone and hydroxyurea have remained the therapies of choice in long term treatment of idiopathic HES. We report here the successful 2 year treatment of aggressive idiopathic HES, refractory to hydroxyurea and prednisone, with alpha-interferon.

Angiodysplasia and von Willebrand's disease type IIB treated with estrogen/progesterone therapy.

The association between angiodysplasia and von Willebrand's disease was first reported in 1967. The cases reported to date have involved patients with type I and IIA von Willebrand's disease. We report a patient with type IIB von Willebrand's disease who suffered gastrointestinal bleeding attributable to gastric angiodysplasia. The patient underwent endoscopic electrocautery acutely and has been treated long-term with estrogen/progesterone therapy. She has suffered no recurrent gastrointestinal bleeding at over 11 months of follow-up. We suggest hormonal therapy as an alternative to repeated blood product transfusion or extensive surgical resection in patients with von Willebrand's disease and gastrointestinal bleeding from angiodysplasia.

Fine mapping of monoclonal antibody epitopes on human von Willebrand factor using a recombinant peptide library.

A recombinant human von Willebrand factor (vWF) cDNA fragment library was constructed in lambda gt11 for the localization of anti-vWF monoclonal antibody epitopes. Twelve of 21 monoclonal antibodies screened identified epitopes expressed in lambda gt11 as beta-galactosidase fusion proteins. By sequence analysis, these antigenic determinants were localized to segments ranging from 17 to 105 amino acids in length. Four epitopes apparently shared by more than one antibody were identified, suggesting the presence of immuno-dominant epitopes within vWF. Monoclonal antibody C3, which blocks factor VIII (FVIII) binding to vWF, bound to the same epitope previously identified by a second monoclonal antibody which also blocks this function, suggesting that this region may be at or near the vWF/FVIII binding domain. Three antibodies recognize the same region within the vWF A2 repeat. Mutations near this region appear to be responsible for Type IIA von Willebrand's disease. The co-localization of these antibodies suggests that this domain might be exposed on the surface of vWF, consistent with its apparent increased sensitivity to plasma proteases.

S100-positive, T-cell chronic lymphoproliferative disease: an aggressive disorder of an uncommon T-cell subset.

S100-positive T lymphocytes account for less than 3% of peripheral blood T cells. Rare cases of S100-positive T-cell lymphoma have been previously described. We report four such cases of S100-positive T-cell chronic lymphoproliferative disease. In all cases, hepatosplenomegaly was observed, without prominent lymphadenopathy. Central nervous system (CNS) involvement by the leukemic cells was suggested in three cases by physical symptoms and confirmed in two cases by cerebrospinal fluid studies. Despite treatment, three patients died at 3, 6, and 8 months after diagnosis. Although there was a leukemic presentation, only minimal bone marrow infiltration was evident. Splenectomy showed red pulp infiltration. Liver and lymph node biopsies showed sinusoidal leukemic involvement. In all cases, the leukemic cells expressed mature T-cell- and natural killer cell-associated antigens. Cytoplasmic S100 was detected in the leukemic cells in the blood, spleen, liver, and lymph node. Southern blot studies in two cases showed T-beta, T-gamma, and T-delta gene rearrangements. RNA Northern blots showed T-alpha and T-beta chain transcripts with no T-gamma or T-delta RNA identified. Southern blot analysis showed no hybridization to probes specific for Epstein-Barr virus, cytomegalovirus, human immunodeficiency virus-1, or human T-cell lymphotropic virus type-1. These findings show that S100-positive T-cell chronic lymphoproliferative disorder is an aggressive, extramedullary-based disease frequently associated with CNS involvement and characterized by short survivals.

Molecular basis of human von Willebrand disease: analysis of platelet von Willebrand factor mRNA.

von Willebrand disease (vWD), the most common inherited bleeding disorder in humans, can result from either a quantitative or a qualitative defect in the adhesive glycoprotein, von Willebrand factor (vWF). Molecular studies of vWD have been limited by the large size of the vWF gene and difficulty in obtaining the vWF mRNA from patients. By use of an adaptation of the polymerase chain reaction, vWF mRNA was amplified and sequenced from peripheral blood platelets. A silent vWF allele was identified, resulting from a cis defect in vWF mRNA transcription or processing. In two type IIA vWD patients, two different but adjacent missense mutations were identified, the locations of which may identify an important vWF functional domain. Expression in heterologous cells of recombinant vWF containing one of these latter mutations reproduced the characteristic structural abnormality seen in type IIA vWD plasma.