Thrombosis is a common complication in patients with paroxysmal nocturnal hemoglobinuria (PNH). At the 66th American Society of Hematology (ASH) Annual Meeting and Exposition, data were presented from a study attempting to identify genetic determinants of thrombotic risk in patients with PNH.

Following this presentation, featured expert Vahid Afshar-Kharghan, MD, was interviewed by Conference Reporter Medical Director Lauren Weinand, MD. Dr Afshar-Kharghan’s clinical perspectives on these findings are presented here.

While thrombosis is relatively common in patients with PNH, we know that not all patients with PNH will develop clots. In addition, the types of clots that can occur are highly variable. For example, PNH can cause both arterial thrombosis, which can include heart attack and stroke, and venous thrombosis, with deep vein thrombosis in the extremities; pulmonary embolism; and clots in unusual and less frequent sites, such as the splanchnic, portal, superior mesenteric, and cerebral veins, the latter of which includes transverse sinus thrombosis. When a young patient presents with thrombosis in an unusual site, we assess for PNH because that is a common initial presentation.

The question is: Why do patients with PNH develop arterial and venous thrombosis? The short answer is that we do not yet know. One of the things that I have been thinking about is whether a similar situation that happens to red blood cells can also impact platelets, producing hyperactive, more procoagulant platelets because of the complement injury. In addition, the microvesicles generated by the lysis of red blood cells, platelets, and monocytes can also be procoagulants.

We know that increased PNH clone size and a history of thrombosis are risk factors for thrombosis in patients with PNH, but the influence of genetic factors on thrombotic risk is not well understood. To assess the role of genetic variants on thrombotic risk, you can either conduct a wide genetic search (ie, a genome-wide association study) to try to find an association between a mutation and a phenotype or discover the mechanisms behind the development of thrombosis to try to find associated mutations in the proteins in the involved pathways. However, since there are so few patients with PNH, it is very difficult to perform a large cohort study, such as a genome-wide association study, to identify a strong genetic association. This is particularly true because both arterial and venous thrombosis are multifactorial and multigenic processes. Thus, it is difficult to pinpoint 1 or 2 genes that are the cause of PNH-related thrombosis.

An abstract by Carlos Bravo-Perez, MD, and colleagues presented at ASH 2024 sought to evaluate genetic determinants of hypercoagulability in complement and hemostatic systems that may increase thrombotic risk in patients with PNH (abstract 31). The study looked at the frequency of targeted genes, as well as some low-frequency mutations that are not necessarily known to be pathogenic, to determine whether there is a higher frequency of these mutations in patients with PNH who develop thrombosis compared with other patients.

Although the results indicated that there was, in fact, a higher number of these mutations in patients with PNH and thrombosis, the analysis of the exploratory and validation cohorts did not show a significantly higher burden of these defects in patients with aplastic anemia and PNH vs healthy controls. I am not sure what to make of these results, but I think that, overall, this study is a good start in examining other risk factors that may impact the development of thrombosis in PNH. However, we are not yet at a point where we can use genetic information to tell a patient with a certain mutation that they need to start anticomplement therapy sooner or that they need to add anticoagulants. I think that this is an interesting concept and a step closer toward telling people to look at and consider other risk factors in PNH, but the data are not mature enough yet for clinical use. Until we have a better idea of the exact mechanism of thrombosis in PNH, it will be difficult to pinpoint the precise cause and—most importantly—develop better options for prevention and treatment.