Paroxysmal Nocturnal Hemoglobinuria: An Historical Overview

Abstract

The clinical hallmark of paroxysmal nocturnal hemoglobinuria (PNH) is episodic hemoglobinuria, and it was this feature that captured the attention of European physicians in the latter half of the 19th century, resulting in careful observational studies that established PNH as an entity distinct from paroxysmal cold hemoglobinuria and march hemoglobinuria. Curiosity about the etiology of the nocturnal aspects of the hemoglobinuria led the German physician Paul Strübing to develop the prescient hypothesis that the erythrocytes of PNH are abnormally sensitive to hemolysis when the plasma is acidified during sleep because of accumulation of carbon dioxide and lactic acid as a result of slowing of the circulation. Investigation of the intricate pathophysiology that underlies the abnormal sensitivity of PNH erythrocytes to hemolysis in acidified serum produced a number of remarkable scientific achievements that involved discovery of the alternative pathway of complement, identification of the membrane proteins that regulate complement, discovery of a novel mechanism for attachment of proteins to the cell surface, and identification of the genetic basis of the disease. These discoveries were made steadily over a period of more than 100 years, and each generation of physicians and scientists made important contributions to the field. The mysteries of PNH have been solved in a particularly satisfying way because the precision and orderliness of the solutions made clearly understandable what had seemed at the times prior to resolution to be problems of nearly insurmountable complexity. The history of PNH is an inspirational reminder of the elegant complexity of nature, the rewards of curiosity and the power and beauty of science.

Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy

“…1 The discoveries began with the seminal observations of Thomas Hale Ham in the late 1930s that suggested a novel, antibody-independent mechanism for complement activation. Subsequently, Ham's observations contributed to elucidation of the properdin pathway (now known as the alternative pathway) by Louis Pillemer while the two were on the faculty at Case Western Reserve University in the 1950s.…”

Paroxysmal nocturnal hemoglobinuria (PNH): An atypical case report

“…[1][2][3][4][5][6] Various mechanisms have been evoked to explain its physio-pathology. It seems that continuous activation of complement at the platelets surface will produce release of thrombinogen particules enriched in phosphatidylserine which can fix factor V and prothombinase complexes.…”

“…[1] This is a rare disease (1.3 cases per million individuals ) expressed predominantly in young (median age 32) caucasian people. Recent studies have shown that the disease was related to an acquired mutation of hematopoietic stem cell on phosphatidyl-inositol glycan (GPI) class A (PIG-A) gene located on X chromosome.…”

Hemoglobinúria paroxística noturna: da fisiopatologia ao tratamento

“…Casos compatíveis com HPN já haviam sido relatados em 1793, porém a descrição da doença como síndrome clínica foi feita apenas em 1882 por Paul Strubing 5 . O epônimo síndrome de MarchiafavaMicheli caiu em desuso pelo relato tardio e pequena contribuição destes autores para o entendimento da doença 6 . O termo hemoglobinúria paroxística noturna refere-se à descrição de destruição de eritró-citos com liberação de hemoglobina na urina, notada principalmente por coloração marrom-escura na primeira urina da manhã 7 .…”