Identical twin marrow transplantation for venous thrombosis in paroxysmal nocturnal hemoglobinuria; long-term complete remission as assessed by flow cytometry

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal defect in bone marrow-derived cells and is clinically associated with intravascular hemolysis, hemoglobinuria, and an increased frequency of venous thrombosis. The common denominator of PNH-affected blood cells appears to be a defect in the membrane attachment of proteins normally anchored by glycosyl-phosphatidylinositol (GPI). We report here that the cellular receptor for urokinase-type plasminogen activator (u-PAR) is deficient on affected peripheral blood monocytes and granulocytes from four individuals with PNH as evidenced by chemical cross-linking analysis as well as by immunofluorescence flow cytometry using a monoclonal anti-u-PAR antibody. In contrast, on normal blood monocytes and granulocytes we find significant amounts of u-PAR, which is attached to the plasma membrane by a GPI-anchor as defined by its sensitivity towards a specific phospholipase treatment. By two-color flow cytometry it was shown that deficiency of u-PAR expression paralleled that of another GPI-anchored protein. As u-PAR is involved in the initiation of pericellular proteolysis, the reduced expression of u-PAR on PNH-affected leukocytes led to an overall reduction in the capacity for plasminogen activation by cell-surface-bound urokinase. Whereas the abnormal susceptibility of PNH-affected erythrocytes to lysis by autologous complement has been related to the low expression of three GPI-anchored complement regulatory proteins on the cell surface, we now propose that lack of u-PAR expression on the surface of peripheral blood leukocytes may be causally related to the high incidence of venous thrombosis observed in PNH patients.

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Long-Term Survival After Marrow Transplantation for Paroxysmal Nocturnal Hemoglobinuria with Aplastic Anemia

Annals of Internal Medicine ◽

10.7326/0003-4819-101-2-193 ◽

1984 ◽

Vol 101 (2) ◽

pp. 193 ◽

Cited By ~ 32

Author(s):

JEFFREY SZER

Keyword(s):

Aplastic Anemia ◽

Marrow Transplantation ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Term Survival ◽

Long Term Survival

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Treatment of hemophagocytic lymphohistiocytosis with chemotherapy and bone marrow transplantation: a single-center study of 22 cases

Blood ◽

10.1182/blood.v78.1.51.51 ◽

1991 ◽

Vol 78 (1) ◽

pp. 51-54 ◽

Cited By ~ 84

Author(s):

S Blanche ◽

M Caniglia ◽

D Girault ◽

J Landman ◽

C Griscelli ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Complete Remission ◽

Hemophagocytic Lymphohistiocytosis ◽

Marrow Transplantation ◽

Allogeneic Bone Marrow Transplantation ◽

Long Term Results ◽

Intrathecal Methotrexate ◽

Allogeneic Bone

Abstract Twenty-two children with hemophagocytic lymphohistiocytosis were treated with a chemotherapy regimen consisting of VP16–213, corticosteroids, and intrathecal methotrexate. A sustained clinical and biologic complete remission was obtained in 15 children and a partial remission in one child; six children died early of opportunistic infection (n = 4) or of disease progression (n = 2). Of the 16 children who were placed in first remission, 10 received maintenance chemotherapy alone, while six underwent bone marrow transplantation (HLA matched in five, HLA mismatched in one). Of the children who received chemotherapy alone, only two are in long-term remission after cessation of treatment. The remaining eight patients relapsed after a mean period of 5.4 months (range 2 to 8 months). Further treatment using the same regimen induced second remissions of short duration; death occurred after a median period of 2.3 months (range 0.5 to 6 months). A total of nine patients received allogeneic bone marrow transplantation (BMT). Among the six children transplanted in remission, four are in long-term unmaintained remission, 1 to 6 years after HLA-matched BMT. However, the relapse that occurred in one patient 1 year post BMT is difficult to interpret because the donor, the patient's 5-year-old sister, also developed the disease 1 year later. An HLA-nonidentical BMT resulted in unmaintained remission for 1 year, with autologous hematologic reconstitution followed by disease relapse. HLA-nonidentical BMT failed in three other patients with active disease at time of transplant. The poor long-term results of chemotherapy alone justify the use of related HLA-matched BMT in complete remission.

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The receptor for urokinase-type plasminogen activator is deficient on peripheral blood leukocytes in patients with paroxysmal nocturnal hemoglobinuria

Blood ◽

10.1182/blood.v79.6.1447.1447 ◽

1992 ◽

Vol 79 (6) ◽

pp. 1447-1455 ◽

Cited By ~ 92

Author(s):

M Ploug ◽

T Plesner ◽

E Ronne ◽

V Ellis ◽

G Hoyer-Hansen ◽

...

Keyword(s):

Flow Cytometry ◽

Cell Surface ◽

Venous Thrombosis ◽

Peripheral Blood ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Blood Monocytes ◽

Peripheral Blood Leukocytes ◽

Blood Leukocytes ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal defect in bone marrow-derived cells and is clinically associated with intravascular hemolysis, hemoglobinuria, and an increased frequency of venous thrombosis. The common denominator of PNH-affected blood cells appears to be a defect in the membrane attachment of proteins normally anchored by glycosyl-phosphatidylinositol (GPI). We report here that the cellular receptor for urokinase-type plasminogen activator (u-PAR) is deficient on affected peripheral blood monocytes and granulocytes from four individuals with PNH as evidenced by chemical cross-linking analysis as well as by immunofluorescence flow cytometry using a monoclonal anti-u-PAR antibody. In contrast, on normal blood monocytes and granulocytes we find significant amounts of u-PAR, which is attached to the plasma membrane by a GPI-anchor as defined by its sensitivity towards a specific phospholipase treatment. By two-color flow cytometry it was shown that deficiency of u-PAR expression paralleled that of another GPI-anchored protein. As u-PAR is involved in the initiation of pericellular proteolysis, the reduced expression of u-PAR on PNH-affected leukocytes led to an overall reduction in the capacity for plasminogen activation by cell-surface-bound urokinase. Whereas the abnormal susceptibility of PNH-affected erythrocytes to lysis by autologous complement has been related to the low expression of three GPI-anchored complement regulatory proteins on the cell surface, we now propose that lack of u-PAR expression on the surface of peripheral blood leukocytes may be causally related to the high incidence of venous thrombosis observed in PNH patients.

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Treatment of hemophagocytic lymphohistiocytosis with chemotherapy and bone marrow transplantation: a single-center study of 22 cases

Blood ◽

10.1182/blood.v78.1.51.bloodjournal78151 ◽

1991 ◽

Vol 78 (1) ◽

pp. 51-54 ◽

Cited By ~ 1

Author(s):

S Blanche ◽

M Caniglia ◽

D Girault ◽

J Landman ◽

C Griscelli ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplantation ◽

Complete Remission ◽

Hemophagocytic Lymphohistiocytosis ◽

Marrow Transplantation ◽

Allogeneic Bone Marrow Transplantation ◽

Long Term Results ◽

Intrathecal Methotrexate ◽

Allogeneic Bone

Twenty-two children with hemophagocytic lymphohistiocytosis were treated with a chemotherapy regimen consisting of VP16–213, corticosteroids, and intrathecal methotrexate. A sustained clinical and biologic complete remission was obtained in 15 children and a partial remission in one child; six children died early of opportunistic infection (n = 4) or of disease progression (n = 2). Of the 16 children who were placed in first remission, 10 received maintenance chemotherapy alone, while six underwent bone marrow transplantation (HLA matched in five, HLA mismatched in one). Of the children who received chemotherapy alone, only two are in long-term remission after cessation of treatment. The remaining eight patients relapsed after a mean period of 5.4 months (range 2 to 8 months). Further treatment using the same regimen induced second remissions of short duration; death occurred after a median period of 2.3 months (range 0.5 to 6 months). A total of nine patients received allogeneic bone marrow transplantation (BMT). Among the six children transplanted in remission, four are in long-term unmaintained remission, 1 to 6 years after HLA-matched BMT. However, the relapse that occurred in one patient 1 year post BMT is difficult to interpret because the donor, the patient's 5-year-old sister, also developed the disease 1 year later. An HLA-nonidentical BMT resulted in unmaintained remission for 1 year, with autologous hematologic reconstitution followed by disease relapse. HLA-nonidentical BMT failed in three other patients with active disease at time of transplant. The poor long-term results of chemotherapy alone justify the use of related HLA-matched BMT in complete remission.

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Idiopathic venous thrombosis

Hämostaseologie ◽

10.1055/s-0037-1616877 ◽

2006 ◽

Vol 26 (01) ◽

pp. 52-54 ◽

Cited By ~ 3

Author(s):

P. A. Kyrle

Keyword(s):

Chronic Disease ◽

Venous Thrombosis ◽

Vitamin K ◽

Clinical Benefit ◽

Plasma Levels ◽

Vitamin K Antagonists ◽

Antithrombin Deficiency ◽

Optimal Duration ◽

Risk Of Treatment

SummaryVenous thrombosis is a chronic disease with a recurrence rate of approximately 30% within 5-8 years. The optimal duration of secondary thromboprophylaxis in these patients entails balancing the risk of recurrence against the risk of treatment-associated bleeding. There is agreement that patients with a first idiopathic venous thrombosis should receive vitamin K antagonists for at least 3-6 months. Convincing trials showing a clinical benefit in terms of morbidity or mortality with respect to expansion of anticoagulation beyond 6 months are lacking. Nevertheless, some subgroups of patients with venous thrombosis may benefit from indefinite anticoagulation. Thus, patients with antithrombin deficiency, combined or homozygous defects, more than one unprovoked episode of thrombosis, the lupus anticoagulant or high factor VIII plasma levels are good candidates for long-term prevention.

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Faculty Opinions recommendation of Long-term outcome of patients given transplants of mobilized blood or bone marrow: A report from the International Bone Marrow Transplant Registry and the European Group for Blood and Marrow Transplantation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1060722.512638 ◽

2007 ◽

Author(s):

Ginna Laport

Keyword(s):

Bone Marrow ◽

Bone Marrow Transplant ◽

Marrow Transplantation ◽

Marrow Transplant ◽

Term Outcome ◽

Long Term Outcome ◽

Blood And Marrow Transplantation ◽

Transplant Registry ◽

European Group

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Long-term follow-up of differentiated thyroid carcinoma in children and adolescents

Journal of Pediatric Endocrinology and Metabolism ◽

10.1515/jpem-2020-0194 ◽

2020 ◽

Vol 33 (11) ◽

pp. 1431-1441

Author(s):

Montserrat Negre Busó ◽

Amparo García Burillo ◽

Marc Simó Perdigó ◽

Pere Galofré Mora ◽

Maria Boronat de Ferrater ◽

...

Keyword(s):

Complete Remission ◽

Thyroid Carcinoma ◽

Children And Adolescents ◽

Differentiated Thyroid Carcinoma ◽

Radioiodine Treatment ◽

Persistent Disease ◽

Stage 4 ◽

Long Term Follow Up

AbstractObjectivesThe aims were to analyze the clinical features, response to treatment, prognostic factors and long-term follow-up of children and adolescents with differentiated thyroid carcinoma (DTC).MethodsEighty patients with DTC were studied retrospectively. All underwent total or near-total thyroidectomy, and in 75 cases, ablative iodine therapy was recommended. Patients were assessed periodically by tests for serum thyroglobulin levels and whole-body iodine scans. Age, gender, initial clinical presentation, histology, tumor stage, postoperative complications, radioiodine treatment protocol, treatment response, thyroglobulin (Tg), recurrence and long-term disease progression were evaluated.ResultsSeventy patients completed >2 years of follow-up (23 males, 47 females; median age: 14 years; range: 3–18 years). Sixty-two patients showed papillary DTC and eight, follicular DTC. Sixty-five percent presented nodal metastasis and 16%, pulmonary metastasis at diagnosis. Six months after first radioiodine treatment, 36.2% of patients were free of disease. Seven recurrences were documented. At the end of follow-up, overall survival was 100%, and 87.2% of patients were in complete remission. Nine patients had persistent disease. We found a significant association between stage 4 and persistent disease. Hundred percent of patients with negative Tg values at 6 months posttreatment were documented free of disease at the end of the follow-up. The analysis of disease-free survival based on radioiodine treatment protocols used showed no statistically significant differences.ConclusionsDTC in children and adolescents is frequently associated with presence of advanced disease at diagnosis. Despite this, complete remission was documented after treatment in most cases, with a good prognosis in the long-term follow-up. Negative posttreatment thyroglobulin and stage 4 at diagnosis were significant prognostic variables.

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