PNH phenotypes and their genesis

The phrase Paroxysmale H€amoglobinurie was coined in 1882 by Paul Str€ ubing (Str€ ubing, 1882), to describe an acquired haemolytic anaemia that seemed to have unique features [the adjective nocturnal was added later (Enneking, 1928): rather unfortunately, since paroxysms can occur at any time of the day or night]. For decades, paroxysmal nocturnal haemoglobinuria (PNH) has been a source of fascination to those aficionados who are passionate about the mechanism of complement-mediated intravascular haemolysis (Rosse & Dacie, 1966; Dacie, 1999); we must however admit that, for a long time, within haematology as a whole, PNH remained a Cinderella disease. This humble status has changed in a rather spectacular way since the hope of few, that complement blockade could curb intravascular haemolysis became, with the successful introduction of eculizumab (Hillmen et al., 2006), a reality for all. The Leeds group led by Peter Hillmen was pivotal to this major shift (Hillmen et al., 2004) and for years this group has also been provided with sound laboratory diagnostic support by Steve Richards (Richards et al., 2000); in this issue of the British Journal of Haematology they give an overview of an impressively large set of data (Richards et al., 2020). There are two groups of patients in their study. One group consisted of over 300 patients who have PNH – namely, the clinical picture was dominated by haemolysis, or thrombosis, or both. Within this group, some interesting observations have emerged – for instance, thrombosis correlated to some extent with the proportion of ‘PNH II’ red cells [a cell population that has partial rather than total lack of glucosyl-phosphatidyl-inositol (GPI)-anchored proteins]. Although this correlation is not yet explained, it does highlight the fact that, unlike the mechanism of haemolysis, the mechanism of thrombosis in PNH – despite much investigation (reviewed by Hill et al., 2013) – still remains elusive. In most cases, we really don’t know why only some patients suffer thrombosis recurrently (Araten et al., 2005), or why a patient may only have the first episode of thrombosis ten years or more after the onset of the disease. However, the Leeds group has recently confirmed that thrombosis can occur in PNH patients who have a relatively low rate of haemolysis (Griffin et al., 2019), suggesting that GPI-deficient white cells and/or platelets may play a significant role. The majority of patients (n = 699) reviewed by Richards et al. (2020) were classified as cytopenic by the haematologists who sent samples – they had a GPI-deficient blood cell population, but they did not have PNH. In most of these cases, the provisional diagnosis was probably aplastic anaemia (AA) – the fact that flow cytometry analysis was requested is positive evidence of increasing awareness about the close link between AA and PNH. Initially the link was mainly clinical (Lewis & Dacie, 1967), in that an original diagnosis of AA for some patients then ‘turned into’ PNH and, more rarely, the opposite happened. Subsequently, once the clonal origin of PNH was proven [exactly 50 years ago (Oni et al., 1970)], it became possible to visualise pathogenetic mechanisms. It was hypothesised (Rotoli & Luzzatto, 1989) that PNH arises in a hypoplastic/aplastic bone marrow because the mutant clone has a conditional selective advantage. The sequence AA-PNH would thus be the rule rather than the exception. In a PNH patient, haematopoiesis can be supported almost entirely and for a long time by the PNH clone (Nishimura et al., 2002), but if the clone becomes exhausted – possibly through telomere attrition (Karadimitris et al., 2003) – the picture of AA can appear (or re-appear). This model of PNH pathogenesis has been corroborated through many lines of evidence (Luzzatto & Risitano, 2018) and has become widely accepted (Young, 2005; Shen et al., 2014). Richards et al. (2020) now show that the distribution of the quantity of GPI-negative (PNH-like) blood cells in over 1000 patients with AA and PNH, over a range from 0 1% to over 90%, is a continuum. This is in keeping with the model (see Fig 1), and with the notion that in nearly all patients with PNH, the background is AA. Indeed, a patient with AA may or may not develop PNH depending on whether (i) the GPI-negative cells arise from a bona fide PIGA mutant stem cell, and (ii) patient bone marrow failure Correspondence: Lucio Luzzatto, Department of Haematology and Blood Tranfusion, Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania. E-mail: lluzzatto@blood.ac. tz commentary