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Aplastic anemia was followed by the development of paroxysmal nocturnal hemoglobinuria. Comparative study of the clinical and biological features with the disease paroxysmal nocturnal hemoglobinuria.
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder in which the blood cells demonstrate aberrant interactions with serum complement. In part, this is due to the absence of the complement regulatory protein, decay accelerating factor (DAF). A small number of patients with PNH have gone on to develop acute nonlymphocytic leukemia, which is thought to arise from the injured marrow as a second hematopoietic disorder. We have studied a patient with PNH who developed acute myeloblastic leukemia (AML); the blasts from this patient were found to lack DAF as measured by polyclonal antibody binding and fluorescence flow cytometry as well as by immunoblotting. The blasts from 11 other patients with AML bound anti-DAF antibody in amounts similar to normal mononuclear cells from healthy donors. Cells of the human leukemia cell lines HL-60, K562, U937, and HEL also bound anti-DAF antibody. In addition to DAF deficiency, blasts from the PNH patient had undetectable alkaline phosphatase activity, in contrast to human leukemia cell lines. These data suggest that the leukemic cells of the PNH patient arose out of the PNH clone and that AML in the setting of PNH is not a separate disorder.
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BACKGROUND: Paroxysmal nocturnal hemoglobinuria is a rare, clonal primitive hematopoietic cell disorder, often affecting middle-aged adults, including women of reproductive age. Major morbidity and mortality with this disease are often ascribed to the development of venous thromboembolism. We reviewed the current literature on the risk of venous thrombosis among nonpregnant and pregnant patients, and generated recommendations for the prevention of venous thromboembolism, as well as duration of treatment for affected patients who develop thrombotic disease. METHODS: We searched Medline for papers published between January 1966 and April 1999. We also requested relevant unpublished data from speakers who attended a recent international workshop of paroxysmal nocturnal hemoglobinuria. References from all primary data and review publications were also examined. Only English language publications were included. Event rates for venous thromboembolism and death were pooled using a random effect technique. Reports of paroxysmal nocturnal hemoglobinuria during pregnancy were summarized using descriptive statistics only. RESULTS: Thirteen retrospective studies of paroxysmal nocturnal hemoglobinuria in nonpregnant individuals were found. The rates of venous thrombosis varied considerably, but were reported to affect 14.4% of all individuals [95% confidence interval (CI) 7.6-25.5]. Among patients from western nations, venous thromboembolism seemed to develop at a higher rate (30.3%, 95% CI 26. 1-34.9). The majority of venous thromboembolic events were intra-abdominal, principally within the hepatic and mesenteric veins. The likely cause of death among patients with paroxysmal nocturnal hemoglobinuria was described in nine studies: 22.2% of fatalities were due to venous thrombosis (95% CI 11.8-38.0), more commonly in western countries (event rate 37.2%, 95% CI 21.6-56.0). Another 20 published reports described the outcome of 33 pregnant women with paroxysmal nocturnal hemoglobinuria. Two women developed venous thromboembolism during pregnancy and another 2 during the postpartum state for a combined event rate of 12.1% (95% CI 3.4-25.2), three of which resulted in death. The all-cause mortality rate was 20.8% (95% CI 7.3-39.0). Both anemia (event rate 72.7%, 95% CI 56.5-86.3), and thrombocytopenia (event rate 27.3%, 95% CI 13.7-43.5) were common, often necessitating red cell or platelet transfusions. Almost half of all infants (54.8%, 95% CI 36.1-72.7) were delivered preterm, and had a mean live birth weight of 2,800 g. Three of 34 reported births ended in death (perinatal mortality rate 8.8%, 95% C 1.9-23.7). CONCLUSION: In accordance with the apparently high rate of venous thrombosis among pregnant and nonpregnant individuals with paroxysmal nocturnal hemoglobinuria, especially for fatal thrombosis, we developed practical recommendations for the prevention and treatment of venous thromboembolic disease in these groups.
The erythrocytes of paroxysmal nocturnal hemoglobinuria are abnormally sensitive to complement-mediated lysis because they are deficient in membrane proteins that regulate the functional activity of complement. All the deficient proteins in paroxysmal nocturnal hemoglobinuria share the common structural feature of being anchored to the cell surface by a glycosyl phosphatidylinositol moiety. Recent studies showed that the first intermediate in the pathway of the glycosyl phosphatidylinositol anchor synthesis is not formed in paroxysmal nocturnal hemoglobinuria cells. This observation suggests that the molecular basis of paroxysmal nocturnal hemoglobinuria is due to an abnormality involving a gene that encodes a protein essential for the normal biosynthesis of the first intermediate. By using expression cloning, the complementary DNA (called phosphatidylinositol glycan class A [PIG-A]) that corrects the abnormality in glycosyl phosphatidylinositol-anchor synthesis in paroxysmal nocturnal hemoglobinuria cells was identified. Subsequent studies showed that the PIG-A gene is located on the X chromosome. Together, these studies provided a molecular explanation for paroxysmal nocturnal hemoglobinuria.
Paroxysmal cold hemoglobinuria is a rare and potentially life-threatening acquired hemolytic anemia occurring either as an acute transient anemia following several different viral syndromes, or in a chronic idiopathic form. Episodic hemolysis in paroxysmal cold hemoglobinuria is usually associated with a biphasic (Donath-Landsteiner) IgG cold-reactive complement-fixing autohemolysin with anti-P specificity. Paroxysmal cold hemoglobinuria has not previously been associated with malignancy nor has it been clearly shown to be steroid-responsive. This report describes a patient with steroid-responsive autoimmune hemolytic anemia and immune thrombocytopenia (Evans' syndrome) associated with oat cell carcinoma of the lung and a unique biphasic anti-IgM autohemolysin. This case extends the spectrum of biphasic antibody-mediated immune cytopenias and widens both the clinical and the serologic definition of paroxysmal cold hemoglobinuria.
We describe a 19-year-old male who presented with traumatic hemoglobinuria. We hypothesize that this patient has a genetic haptoglobin variant with a low hemoglobin binding capacity which resulted in hemoglobinuria after physical fraternity hazing. A review of the literature regarding traumatic hemoglobinuria supports the association between decreased baseline plasma haptoglobin levels and hemoglobinuria after trauma.