High cortisol levels, being male raise risk of blood clots

Cushing's study calls for clear guidelines for preventive anti-blood clotting treatment

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Being male, having high cortisol levels at the time of Cushing’s diagnosis, and undergoing multiple surgeries were identified as key factors linked to a high risk of blood clots in people with Cushing’s, according to data from a large European registry.

Preventive anti-blood clotting protocols varied across treatment centers, highlighting the “urgent need to develop clear guidelines for patients, since only then can physicians provide high-quality treatment options for their patients and minimize the risk,” the researchers wrote.

Findings were reported in the study “High prevalence of venous thrombotic events in Cushing’s syndrome: data from ERCUSYN and details in relation to surgery,” which was published in the European Journal of Endocrinology.

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Cushing’s syndrome comprises a group of disorders characterized by elevated levels of the hormone cortisol. This frequently is due to the presence of a tumor in the pituitary or adrenal glands.

When the source of the problem is a tumor in the brain’s pituitary gland, the condition is known as Cushing’s disease. In that case, the tumor leads to the excessive production of a signaling molecule called adrenocorticotropic hormone (ACTH), which prompts the adrenal glands to overproduce cortisol. In rare cases, tumors outside the pituitary gland also may produce and release ACTH, leading to excessive cortisol levels — a form of the syndrome known as ectopic Cushing’s syndrome.

People with Cushing’s have a higher risk of developing venous thromboembolism (VTE) when compared with the general population. VTE occurs when blood clots form in the deep veins of the legs, groin, or arms, leading to a condition known as deep vein thrombosis. When blood clots travel and lodge in the lungs, they can block circulation and cause a pulmonary embolism.

This increased risk of VTE can be prompted or further aggravated by surgery to treat or cure Cushing’s.

A retrospective analysis

To identify potential risk factors, a team of international researchers retrospectively analyzed data from patients included in the European Registry on Cushing’s syndrome (ERCUSYN), the largest prospective existing database for patients with Cushing’s syndrome.

The analysis included data from 28 centers located across 16 European countries, collected up to Feb. 7, 2022, and totaling 2,174 Cushing’s patients. Of those, 95 had a VTE.

Men had a 2.11-times higher risk of experiencing a VTE compared with women. Compared to patients with adrenal Cushing’s, those with ectopic Cushing’s were 4.65-times more likely to develop VTE, while those with Cushing’s disease were 2.09-times more likely to experience those events.

The risk of VTE was not influenced by body mass index (a measure of body fat), diabetes, or smoking. It was, however, affected by high blood pressure, which increased VTE risk by nearly twofold.

The number of surgeries also affected VTE risk, with patients who underwent more than one surgical procedure being 2.10-times more likely to experience VTE. In patients who had at least one surgery, nearly half of VTEs occurred in the six months following the procedure.

A multivariate analysis, which takes into account several variables, indicated that gender, 24-hour urinary-free cortisol levels at the time of diagnosis, and the number of surgeries were all independent risk factors for VTE.

Overall, patients experienced their first VTE a mean of 2.73 years after being diagnosed with Cushing’s. At the time VTE was first identified, more than half of the patients (64.2%) were in remission, while 28.4% had high cortisol levels and active disease.

Some were taking anticoagulants

About a third of the patients (30.4%) were being treated with anticoagulants — medications that help reduce the risk of blood clotting — at the time of the VTE. Heparin was used most often (68%). After the VTE, 93.4% of the patients received anticoagulants.

Compression stockings were used in 50.9% of the VTE cases, together with preventive treatment for blood clotting. Treatment length varied from two weeks to lifelong maintenance.

Seven patients died during follow-up. In two of them, the cause of death was linked to VTE — one patient had a pulmonary embolism and the other deep venous thrombosis.

Twenty-six of the 28 centers reported their preventive treatment for blood clotting practices in a survey. Fewer than half (12 centers, 46.2%) used anticoagulants on a routine basis. Among those who did use them, only eight applied the treatment for all types of Cushing’s.

Moreover, the time and circumstances at which preventive treatment was employed varied greatly: 29.1% of the centers used it around the time of surgery, while 25% did so after the diagnosis of Cushing’s. The majority (45.9%) used it only in particular scenarios, such as in high-risk patients.

Overall, these findings show that “in most European endocrine centers protocols for [anti-blood clotting therapy] are not used on a routine basis and the heterogeneity of prophylaxis is excessively large in various centers,” the team wrote.