Low levels of the blood clotting factor fibrinogen in adults with secondary hemophagocytic lymphohistiocytosis (sHLH) are linked to an increased risk of mortality, a study suggested.
That finding supports fibrinogen’s potential prognostic role in this inflammatory disease, the researchers said.
The study, “The prognostic role of plasma fibrinogen in adult secondary hemophagocytic lymphohistiocytosis,” was published in the journal Orphanet Journal of Rare Diseases.
Blood clotting (coagulation) disorders are common in people with sHLH, occurring in up to 60% of patients, according to the researchers. One of the condition’s hallmarks is low levels of the clotting factor fibrinogen (Factor I) — a protein in the blood that is broken down to fibrin by the enzyme thrombin to form blood clots.
Studies have confirmed that between 50% and 80% of sHLH patients have very low levels of the blood clotting factor (hypofibrinogenemia), the researchers said, with levels less than or equal to 1.50 g/L (normal range 2-4 g/L). Furthermore, evidence suggests that fibrinogen levels below this value may be a predictive measure for increased mortality (risk of death).
While some studies have reported a prognostic role of fibrinogen in adult sHLH, these studies were limited by small numbers of participants and a lack of follow-up data. Moreover, the relationship between fibrinogen and the risk of mortality has not been assessed.
Thus, whether reduced blood fibrinogen is associated with an increased risk of mortality independent of conventional risk factors is unclear.
To address this question, researchers at The First Affiliated Hospital of Nanjing Medical University, in China, analyzed the medical records of 293 adults with a primary diagnosis of secondary HLH. The team focused on data regarding circulating levels of fibrinogen and survival.
The study population had a mean age of 53 years (range 41-64) and 62.5% were men. The mean follow-up was 52 days. A total of 169 (57.7%) had malignant disorders causing sHLH, while 124 (42.3%) had non-malignant sHLH.
Overall, the median fibrinogen level was 1.50 g/L in the overall group.
Based on fibrinogen levels, the patients were divided into three groups: T1 for individuals with 1.20 g/L or less (99 patients), T2 for those between 1.21 and 1.97 g/L (inclusive; 97 patients), and T3 for patients with more than 1.97 g/L (97 patients).
During follow-up, 208 deaths were reported, including 137 patients with malignant sHLH and 71 people with non-malignant sHLH.
Survival curves showed patients with higher fibrinogen levels (T2 and T3) had a similar survival rate, whereas those below 1.20 g/L (T1 group) had a significantly worse survival than those with higher fibrinogen levels.
This result remained valid after adjusting for confounding factors, including age, platelet count, ferritin (iron stores), Epstein-Barr virus infection (EBV), malignant sHLH or non-malignant sHLH, and treatments prescribed.
A statistical analysis found a significant relationship between blood fibrinogen levels and survival, in which sHLH patients with levels of 1.76 g/L or below had a 32% decrease in the odds of survival relative to those above this value, whose survival odds did not change significantly with increased fibrinogen.
No significant links were found between fibrinogen and survival across different categories of age, sex, ferritin, EBV infection, underlying causes, and sCD25. sCD25 is a protein that is increased in activated immune cells.
However, worse survival in patients with low fibrinogen was more likely in those with younger age, men, those who had ferritin equal to or lower than 10,000 micrograms/L, with an EBV infection, and non-malignant sHLH.
“To our knowledge, this is the largest cohort study assessing the prognostic role of fibrinogen in adult sHLH,” the researchers wrote.
The team hypothesized that low fibrinogen levels might reflect a more severe form of HLH, with high immune activation. These patients “may reach a certain threshold of excessive activated immune cells and overwhelming systemic inflammation,” the researchers said.
“Early identification of these patients may prompt earlier consideration of alternative therapeutic strategies, including intensive immunotherapies,” the team suggested.
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