2 Proteins May Help Predict Acute Joint Bleeding in Severe Hemophilia A, Study Suggests

Blood levels of two proteins — C-reactive protein (CRP) and vascular endothelial growth factor (VEGF) — involved in inflammation and blood vessel formation are significantly associated with, and may help predict, acute bleeding in the joints of people with severe hemophilia A, a study has found.

The study, “Diagnostic Values of Inflammatory and Angiogenic Factors for Acute Joint Bleeding in Patients With Severe Hemophilia A,” was published in the journal Clinical and Applied Thrombosis/Hemostasis.

Hemophilia A is an inherited bleeding disorder caused by the lack of factor VIII, a blood clotting protein. While some progress has been made in its treatment, patients often experience joint bleeding, which can result in joint damage and disability.

Currently, the risk of bleeding is assessed by measuring levels of blood clotting factors, but studies suggest that inflammatory molecules and proteins involved in blood vessel formation (angiogenic factors) also play a key role in joint bleeding.

In an effort to develop better tools to predict joint bleeding and improve hemophilia treatment, researchers in China examined the levels of inflammatory and angiogenic factors, and determined their association with joint bleeding.

Their analysis included 144 male patients with severe hemophilia A and 90 healthy volunteers, average age 22 years, who were recruited between October 2015 and August 2018. Among those with hemophilia, 66 experienced acute joint bleeds.

Blood samples from patients and volunteers were assessed for a panel of leukocytes (white blood cells), platelets, blood clotting proteins, and angiogenic and inflammatory factors.

Results showed that levels of plasminogen, implicated in the breakdown of blood clots, were significantly increased in people with hemophilia A compared to controls, and in patients with joint bleeding compared to those without. Similar differences were seen with fibrin/fibrinogen degradation products — and their specific fragment called d-dimer. (Fibrinogen is converted into fibrin during coagulation).

Likewise, leukocytes and inflammatory markers such as CRP, ferritin, and macrophage migration inhibitor were all higher in hemophilia patients, and particularly increased in those with joint bleeding.

As for angiogenic factors, only VEGF was significantly elevated in people with severe hemophilia A compared to healthy volunteers, and in those with bleeding compared to those without joint bleeding.

A statistical analysis then showed that only CRP and VEGF levels could independently predict the risk of acute joint bleeding.

CRP, in particular, had an accuracy of 83% at discriminating hemophilia patients with and without joint bleeding, being able to correctly identify 88% of patients with joint bleeding (sensitivity) and 68% of those without joint bleeding (specificity).

In turn, VEGF accurately identified 76% of patients, including 83% of those with joint bleeding and 68% of patients without bleeding.

“Our analysis demonstrates that the levels of inflammatory and angiogenesis factors increase in patients with severe hemophilia A,” the researchers wrote, adding that CRP and VEGF “may be used as diagnostic markers to predict joint bleeding.”

Additional studies in a larger number of patients and with longer follow-up periods are warranted to validate the prognostic value of these two factors.