New perspectives on the thrombotic complications of haemolysis

Abstract

SummaryMany clinical settings are associated with haemolysis, from rare conditions, such as paroxysmal nocturnal haemoglobinuria, to common interventions, such as mechanical circulatory support and blood transfusion. The toxic effects of circulating free haemoglobin, haem, and iron are becoming increasingly understood and include an increased risk of thrombotic complications. This review summarizes the epidemiological evidence for an association between haemolysis and thrombosis and explores potential underlying mechanisms. New insights into the role haem plays in inflammatory signalling and in generating neutrophil extracellular traps (NETs) may provide useful strategies for managing pathological states associated with severe haemolysis. A better understanding of the toxic effects of haemolysis will result in better therapies to prevent the side effect of thrombosis.

The prothrombotic state in paroxysmal nocturnal hemoglobinuria: a multifaceted source

“…These clearing mechanisms are overwhelmed in PNH and lead to the accumulation of high levels of free hemoglobin in the plasma, resulting in the scavenging and depletion of nitric oxide (NO). 23 The subsequent excess of hemoglobin leads to the visible hemoglobinuria, while the depletion of NO, a potent vasodilator, results in vasoconstriction, decreased regional blood flow and muscular contraction, causing chest and abdominal pain, amongst other symptoms. 3 Moyo et al reported significant differences in the proportion of PNH cells in patients with symptoms of abdominal pain, hemoglobinuria and esophageal spasm (causing chest pain and dysphagia).…”

“…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.…”

“…69 The now activated endothelial cells recruit inflammatory cells, promoting thrombus formation at the vessel wall. 23 This can be further enhanced by pro-inflammatory cytokines and chemokines which have been observed as being over-expressed in other hemolytic disorders. 70 It is still unknown whether bone marrow-derived endothelial cells in PNH patients harbor the GPI-AP deficiency.…”

“…Free hemoglobin has also been demonstrated to produce reactive oxygen species (ROS) via two mechanisms: 23 the amphipathic heme interacts with the phospholipid membrane, and via the Fenton reaction catalyzes the production of ROS, 78 and extracellular hemoglobin autoxidizes to methemoglobin catalyzed by peroxidase enzymes which further generates ROS. 79 A study by Amer et al has also shown that PNH cells have a higher oxidative status when compared to normal cells.…”

“…80 It is not clear if this is as a result of free hemoglobin, platelet hyperactivity (as previously discussed) or a pre-existing defect in PNH cells that exacerbates these pathologies, thus, further research into this area is necessary. The formation of ROS is well-documented to produce phospholipid disorganisation, induce cytotoxicity and promote inflammation, 23,81 and studies have also shown that ROS can directly enhance platelet activation. 82 The Fenton reaction also activates protein kinase C as well as ROS which have been demonstrated to activate platelets.…”