<p>The clinical presentation of patients with paroxysmal nocturnal hemoglobinuria (PNH) can vary from patient to patient, with some individuals having asymptomatic disease and others having severe hemolysis and thrombosis. Clone size has a clear role, as do genetic and immune factors, but the exact mechanisms behind the heterogeneity are not fully understood.</p>

I attribute most of the heterogeneity in PNH to clone size, which helps differentiate between clinical presentations. For example, the small PNH clones found in hematologic disorders such as hypoplastic myelodysplastic syndromes and aplastic anemia are usually not very clinically significant. Some patients with PNH can have a large clone size and subclinical disease. In other patients, a large clone size can have a lot of impact on clinical outcomes, particularly due to hemolysis and thrombotic complications.

 

Genetic disorders and modifications can also be a source of PNH heterogeneity. One example is G6PD deficiency, which significantly increases red blood cell sensitivity to oxidative damage, although it has not been mentioned in many discussions or reviews. Sometimes, we may find that the clones that expand in PNH have a G6PD mutation, which may impact the course of disease or response to therapy.

 

Additionally, heterogeneity exists in the development of thrombosis and bone marrow failure syndrome. Thrombosis seems to come from the interactions between the complement system and hemostatic factors such as the coagulation cascade and the close interaction with platelets and the endothelium. The mechanisms involved in the development of bone marrow failure after PNH and the reason(s) some patients develop PNH after bone marrow failure or aplastic anemia are not completely clear.

It is interesting that Dr Afshar-Kharghan mentioned G6PD deficiency because the concept that PNH is an acquired clonal disorder arose after a patient with PNH and G6PD deficiency was described in a case report. If a patient has a massive PNH clone, I think that it may be reasonable to do next-generation sequencing to try to find a mutation that, one day, may be targetable and bring the clone under control.

 

PNH clones can have a partial or complete deficiency of GPI-anchored complement regulatory proteins, particularly CD55 and CD59. Cells with a partial deficiency are type II cells, and those with complete deficiency are type III cells. Patients with mostly type III PNH clones may have more symptoms than those with mostly type II cells.

 

The issue of thrombosis is quite complex, but there is a lot of interaction between the coagulation cascade and the complement cascade. It seems that patients with intravascular hemolysis are much more likely to develop thrombosis than others. This may be, in part, from nitric oxide depletion with intravascular hemolysis or platelet activation, both of which are prothrombotic. Since patients are not thrombosing all the time, and some will not develop thrombosis, there appears to be other triggers.

 

The issue of heterogeneity is interesting because the clinical presentation of PNH is a spectrum from almost asymptomatic disease to severe manifestations and hemolysis. I agree with Dr Afshar-Kharghan and Dr Dingli that clone size and type make a difference. Patients with more type II cells tend to have more bone marrow failure, whereas those with mostly type III cells tend to have more hemolysis.

 

Thrombosis is clearly complement mediated because we see fewer thrombotic episodes when we block complement, but we do not understand what causes thrombosis in some people but not in others. We also do not understand why some patients have more bone marrow failure than others, although evidence points to the immune system and its T-cell component. I think that trying to figure out the clinical heterogeneity of PNH, including the clinical impact of potentially related genetic mutations, will be helpful as time goes on.