Natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays

Abstract

Summary Paroxysmal nocturnal haemoglobinuria (PNH) is an uncommon, acquired disorder of blood cells caused by mutation of the phosphatidylinositol glycan class A (PIG‐A) gene. The disease often manifests with haemoglobinuria, peripheral blood cytopenias, and venous thrombosis. The natural history of PNH has been documented in retrospective series; but there has only been one study that correlated the more sensitive and specific flow cytometric assays that have become available in the last decade with severe symptoms associated with PNH. In a retrospective analysis of 49 consecutive patients with PNH evaluated at Johns Hopkins, large PNH clones were associated with an increased risk for thrombosis as well as haemoglobinuria, abdominal pain, oesophageal spasm, and impotence. Of the 14 (29%) patients that developed thrombosis, nine died; six of these from complications related to thromboses. According to logistic regression modelling, for a 10% change in PNH clone size, the odds ratio for risk of thrombosis was estimated to be 1·64. No patient with <61% PNH granulocytes developed a thrombosis, whereas 12 of 22 patients (54·5%) with ≥61% PNH granulocytes manifested with thrombosis. These data not only confirm that the size of the PNH clone correlates with the risk for thrombosis, but they also suggest a correlation of PNH clone size to more symptomatic PNH.

The prothrombotic state in paroxysmal nocturnal hemoglobinuria: a multifaceted source

“…27 Through logistical regression, Moyo et al calculated the increase in odds ratio for thrombosis to be 1.64 for each 10% increase in the proportion of PNH cells. 24 These findings correlate with other studies which have shown that the occurrence of thrombosis is noticeably elevated in PNH patients with a proportion of PNH cells as low as 10% when compared to normal population controls.…”

“…The mean proportion of PNH granulocytes in patients with these symptoms was at least twice that of patients who did not possess these clinical manifestations. 24 As previously described, thrombosis is the most serious complication associated with PNH. Thrombotic events are reported to be of venous origin in 85% of cases, arterial in 15% of cases and involve more than one site at the same time in 20.5% of cases.…”

“…54,57 The scavenging mechanisms described above can become saturated resulting in increased levels of free hemoglobin in the circulation, leading to a prothrombotic state in addition to other symptoms. 23,24 There is increasing evidence supporting possible prothrombotic effects of free hemoglobin on platelets and the vascular endothelium. 58 A recent study by Belcher et al showed that heme rapidly stimulates the release of Weibel-Palade bodies (WPBs) from the vascular endothelium.…”

“…Upon intravascular hemolysis, free hemoglobin is rapidly bound to the serum protein haptoglobin expressed on monocytes/macrophages forming a complex which is then endocytosed and degraded by CD163. 24,54,55 The oxygen binding component of hemoglobin, ferrous heme, can be oxidised to ferric heme, resulting in rapid binding to hemopexin. 56 The resulting reaction has vasodilatory, antiproliferative, anti-inflammatory, and antioxidant properties through the release of carbon monoxide, the biliverdin metabolite biliverdin reductase, and the uptake of anti-inflammatory interleukin-10 and heme oxygenase into circulating monocytes.…”

The role of paroxysmal nocturnal hemoglobinuria in idiopathic habitual abortion

“…(15). Two large studies have shown that in all patients with thrombosis, the PNH clone in granulocytes was greater than 50% and 61% respectively (15,16). However, in some studies, PNH clones have been reported at much lower levels in patients with thrombosis.…”