Hemoglobinuria paroxística nocturna. el rol de la anhidrasa carbónica-i urinaria en la hemólisis intravascular / Peroxysmal nocturnal hemoglobinuria: the role of urinary carbonic anhydrase-I in intravascular haemolysis

La Hemoglobinuria Paroxística Nocturna (HPN) se caracteriza por hemólisis intravascular crónica mediada por complemento. Cuando se produce la hemolisis se libera a circulación Anhidrasa Carbónica- I (AC-I), una enzima que se halla en alta concentración en el eritrocito y por su bajo peso molecular filtra por el glomérulo. El objetivo del presente trabajo fue detectar la excreción de la AC-I en orina de pacientes con HPN por Electroforesis Bidimensional de Utilidad Clínica (2D UC), y compararla con otras causas de hemólisis, de origen renal y postrenal. Se evaluaron 8 pacientes con HPN sin tratamiento con eculizumab un inhibidor del C5 del complemento, y 5 de ellos postratamiento, 12 orinas de pacientes con nefritis lúpica y 10 orinas de pacientes con hemólisis postrenal. La AC-I puede estar presente en la orina, en los tres grupos, sin embargo la relación AC-I/Hemoglobina en la hemólisis intravascular está invertida en comparación con la hemolisis glomerular y post-renal. Los pacientes con HPN tratados con eculizumab no presentan AC-I, y sería de utilidad en el seguimiento de los pacientes tratados con el inhibidor del C5, para evidenciar posibles escapes hemolíticos.

Paroxysmal Nocturnal Hemoglobinuria (PNH) is characterized by chronic complement mediated haemolysis. In these conditions it might be expected that carbonic anhydrase-I (AC-I) would be liberated into the plasma and excreted in the urine, by its high concentration in the erythrocyte and low molecular weight. The objective of the present study was to detect the urinary excretion of AC-I from patients with PNH by wodimensional clinical utility electrophoresis (2D UC) and to compare it with other causes of renal and post-renal haemolysis. We evaluated 8 patients with PNH without eculizumab, a complement C5 inhibitor, 5 of them posttreatment, 12 urine of patients with lupus nephritis and 10 urine of patients with post-renal hemolysis. AC-I may be present in the urine, in all three groups, however, the AC-I/Haemoglobin ratio in intravascular haemolysis is reversed compared to glomerular and post-renal haemolysis. Patients with PNH treated with eculizumab do not have AC-I and would be useful in monitoring patients treated with the C5 inhibitor to evidence possible haemolytic leaks.

Haemoglobinuria And Portal Venous Thrombosis In A Young Male.

Paroxysmal nocturnal haemoglobinuria is a non-malignant stem cell disorder due to acquired somatic mutations in cell surface anchored proteins CD55 and CD59. Both have a compliment inhibitory role and their deficiency leads to intravascular haemolysis. This paper reports a challenging case of a 25 years old male who presented with generalized weakness, exertional dyspnoea and episodic early morning haematuria. Recently, he started developing progressive abdominal distention and dull generalized abdominal pain. Investigations revealed haemoglobin 3.5 g/dl with 10% reticulocytes, total bilirubin 54.5 mg/dl, LDH 3155 U/L, negative Coomb's test and erythroid hyperplasia on bone marrow biopsy. Urine complete exam was significant for haemoglobinuria without red blood cells. Doppler scan of abdomen showed portal vein thrombosis. Loss of expression of CD14, CD16, CD55 and CD59 on leukocytes and erythrocytes was seen on PNH analysis, confirming paroxysmal nocturnal haemoglobinuria. He was managed with blood transfusions and was advised folic acid and bone marrow transplant.

Effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) arises from a somatic mutation of the PIG-A gene in a hematopoietic stem cell and the subsequent production of blood cells with a deficiency of surface proteins that protect the cells against attack by the complement system. We tested the clinical efficacy of eculizumab, a humanized antibody that inhibits the activation of terminal complement components, in patients with PNH. METHODS: Eleven transfusion-dependent patients with PNH received infusions of eculizumab (600 mg) every week for four weeks, followed one week later by a 900-mg dose and then by 900 mg every other week through week 12. Clinical and biochemical indicators of hemolysis were measured throughout the trial. RESULTS: Mean lactate dehydrogenase levels decreased from 3111 IU per liter before treatment to 594 IU per liter during treatment (P=0.002). The mean percentage of PNH type III erythrocytes increased from 36.7 percent of the total erythrocyte population to 59.2 percent (P=0.005). The mean and median transfusion rates decreased from 2.1 and 1.8 units per patient per month to 0.6 and 0.0 units per patient per month, respectively (P=0.003 for the comparison of the median rates). Episodes of hemoglobinuria were reduced by 96 percent (P<0.001), and measurements of the quality of life improved significantly. CONCLUSIONS: Eculizumab is safe and well tolerated in patients with PNH. This antibody against terminal complement protein C5 reduces intravascular hemolysis, hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life in patients with PNH.

Propedêutica sequencial da urina nas suspeitas de hematúria / Sequential approach of the urine in the suspected hematuria

Os autores apresentam um caso de hemoglobinúria paroxística noturna cuja suspeita diagnóstica surgiu a partir da análise seqüencial da urina de coloração vermelho-acastanhada em paciente com história de hematúria recorrente. Sugerem que a urinálise pelo nefrologista aumenta as chances de acerto diagnóstico em situações semelhantes, assim como evita a realização desnecessária de exames complementares, como ilustrado no caso apresentado.

The authors present a case of paroxysmal nocturnal haemoglobinuria suspected when the urine was sequentially analyzed in a patient with history of recurrent hematuria. They suggest that the urinalysis done by nephrologists rises the chances of acorrect diagnosis in clinical situations like the one presented, as well as avoid that unnecessary tests to be done, as in the discussed case.

The effect of vitamin E on haemolysis in paroxysmal nocturnal haemoglobinuria: in vitro and in vivo studies.

The administration of vitamin E, a natural antioxidant, to a patient with paroxysmal nocturnal haemoglobinuria (PNH) failed to diminish the urinary excretion of 59-Fe as monitored by 59-Fe whole body counting and urinary loss of isotope. However, in vitro vitamin E corrected the increased sensitivity of PNH red cells to haemolysis by hydrogen peroxide. These results support the concept that the susceptibility of PNH red cells to lipid peroxidation is an in vitro phenomenon bearing little relation to the mechanism of in vivo haemolysis.