Prior blood clot raises risk of future thrombosis, PNH registry study finds

Recent use of blood thinners also not seen to diminish higher risk

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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People with paroxysmal nocturnal hemoglobinuria (PNH) who had a prior blood clot-related event are more likely to have such events again, regardless of whether they recently used blood thinners, a real-life registry study found.

Other factors that appeared to increase their likelihood in PNH patients not on Soliris (eculizumab) or Ultomiris (ravulizumab) when they entered a registry included high numbers of a certain type of immune cell and high disease activity.

“These findings will aid physicians by providing important clinical and laboratory risk factors that can be used to identify and manage patients with PNH who are at risk of developing [blood clot-related events],” the researchers wrote.

The study, “Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case–control study in the International PNH Registry,” was published in Annals of Hematology.

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In PNH, thrombosis is considered a serious disease complication

Red blood cells become liable in PNH to an attack by the complement system, a domino-like chain of proteins that work with the immune system to clean up damaged cells and protect the body against infection.

The attack causes red blood cells to break down. As a result, symptoms of PNH include anemia (low numbers of red blood cells) and thrombosis, or blood clots forming within blood vessels.

A blood clot-related event, or a thromboembolic event (TE), is a complication of thrombosis that occurs when a blood clot travels through the bloodstream to another location in the body, where it can block blood flow.

Such complications are serious, but early intervention with complement inhibitors — approved PNH treatments such as Soliris and Ultomiris — can reduce the risk of thrombosis. However, this type of medication does not entirely eliminate the risk.

Therefore, “it is important to identify and characterize risk factors predictive of TE because they can assist in improved monitoring and early intervention, which may lead to better outcomes for patients,” the researchers wrote.

An international team of researchers, along with scientists at Alexion, AstraZeneca Rare Disease, drew on data from the International PNH Registry (NCT01374360), an ongoing observational study looking at how PNH progresses and the outlook for treated and untreated patients.

The registry is sponsored by Alexion, which markets both Soliris and Ultomiris.

Among the 2,541 patients not being treated with either Soliris or Ultomiris at the time of enrollment, 77 experienced a TE during follow-up. Among this group, 57 patients were paired with 189 age-, sex-, and country-matched untreated patients who did not experience a TE as a control group.

“Demographics and patient characteristics were similar between [the 57] TE cases and controls,” the researchers wrote, adding that most patients (77.6%) were European and over half (54.5%) were men. Their mean age was 47.

9 times higher thrombosis risk in PNH patients recently on anticoagulants

Among patients who took blood thinners or anticoagulants, a larger proportion of TE cases had a previous TE than those in the control group (33% vs. 23.8%). Most had started an anticoagulation medication before their most recent blood clot-related event.

Symptoms experienced more often by TE cases than controls were fatigue (52.6% vs. 37.6%), high levels of the blood-carrying protein hemoglobin in the urine, known as hemoglobinuria (28.1% vs. 12.7%), abdominal pain (24.6% vs. 6.3%), and difficulty breathing (24.6% vs. 13.8%).

Statistical analyses accounting for a single variable indicated that an increased TE risk was significantly associated with abdominal pain and hemoglobinuria, “which may be symptomatic markers of [red blood cell destruction],” the team wrote.

Further analyses accounting for several concurrent factors showed that patients with a history of TE and using anticoagulants, or blood thinners, within the past six months had a nearly nine times higher likelihood of a TE than those without a history of TE not taking blood thinners.

Having a history of TE alone also increased by five times the odds of having another TE.

This suggests that a prior history of TE increased the chances of having a TE regardless of anticoagulation use.

For patients recently on anticoagulants despite no history of TE, the odds of experiencing a blood clot-related event were about nine times higher compared with those without a history of TE and not taking blood thinners.

“This is expected, likely reflecting prescribing decisions based on physician assessment of increased TE risk and the use of [preventive anticoagulant treatment], rather than adversely contributing to risk itself,” the researchers wrote, adding that this result “should be interpreted accordingly.”

Notably, only the link between recent anticoagulant treatment with no TE history and a higher risk of TE reached statistical significance.

Higher number of GPI-negative granulocytes, an immune cell, also raised risk

A proportion of GPI-negative granulocytes, a type of immune cell, of at least 30% also increased the odds of a TE by up to nearly five times. GPI is a molecule found at low or undetectable levels in people with PNH, aiding in diagnosing the disease.

Patients who met four or more criteria for high disease activity and had high blood levels of lactate dehydrogenase, a marker of red blood cell destruction, were about three times as likely to have a TE as those who did not meet these criteria.

Again, none of these associations reached statistical significance.

Still, “this retrospective analysis from the International PNH Registry identified likely risk factors associated with TE, the most serious complication and leading cause of death for patients with PNH,” the team wrote.

“These results provide important clinical and laboratory risk factors that can be used to identify and manage patients with PNH who are at risk of developing TE,” the researchers noted.

Further research “to identify and monitor risk factors for TE in patients with PNH is warranted to better inform treatment decisions and improve patient outcomes,” they added.