Study Reveals Risk Factors for Future Bleeds in Hemophilia Patients

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by Patricia Inácio, PhD |

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The levels of blood clotting factors, physical activity, and bleeding history are all potential risk factors for future bleeds in hemophilia patients under preventive therapy, a small review study from Canada suggests.

“These and other risk factors for bleeding could be combined in a risk assessment model (RAM) for the prediction of bleeds in [people with hemophilia],” particularly those receiving regular prophylaxis, the researchers wrote.

“The identification of patients at high risk of bleeding is an important first step in lowering the risk,” the team wrote, adding, “This is particularly important now that new non-clotting factor therapies … are available or are about to enter the market (e.g., gene therapy).”

The study, “Risk factors for bleeding in people living with hemophilia A and B treated with regular prophylaxis: A systematic review of the literature,” was published in the Journal of Thrombosis and Haemostasis.

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Hemophilia is a genetic blood disorder that affects the body’s ability to form blood clots to prevent excessive bleeding. In hemophilia A, which accounts for 80% of all disease cases, this blood clotting inability is caused by the lack of a specific clotting protein, called factor VIII (FVIII). The lack of another protein, called factor IX (FIX), causes hemophilia B.

In both cases, prophylactic or preventive treatments — which provide the missing clotting factors for each hemophilia type — are considered the gold standards to prevent spontaneous bleeding episodes.

But patients’ responses to such preventive treatment can vary. This can be due to the fact that preventive therapies are administered based on a person’s weight. According to researchers, this can lead to either under- or overdosing.

Assessing the bleeding risks of hemophilia patients could be informative to aid both patients and physicians in minimizing this risk.

“Patients, physicians, and policy makers might benefit from knowing the risk of bleeding of individual patients,” the researchers wrote.

The team, led by researchers at McMaster University, in Ontario, now conducted a systematic review of studies reporting risk assessment tools and risk factors for bleeding in hemophilia patients on preventive therapy.

First, a search was conducted for studies published through Aug. 21, 2019, across four Canadian databases: Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Cochrane Database of Systematic Reviews (CDSR).

From more than 1,800 potential studies, researchers evaluated 152 and selected 10 that met the inclusion criteria to be included in their analysis. All studies reported risk factors linked to bleeding. No study, however, was designed to develop or evaluate a potential risk assessment tool.

Five of the selected studies included only hemophilia A patients, while one involved only hemophilia B patients. Four studies included patients with both types of hemophilia. Most studies were conducted in North America and/or Europe, and the number of patients analyzed ranged from 32 to 286. Patient follow-up ranged from six months to six years.

According to researchers, all of the studies except one had a high risk of bias.

Six studies assessed the link between clotting factor levels in the blood and the risk of bleeding. Blood clotting factor levels were not measured directly, but instead based on pharmacokinetic estimates and patients’ treatment regimens. Pharmacokinetics refers to the movement of medicines into, through, and out of the body.

All studies, but one, reported that higher clotting factor levels were associated with a lower risk of bleeding, although the risk varied across studies. Complete adherence to preventive therapy reduced the risk of bleeds, particularly in patients ages 10–65, according to one study.

Physical activity involving contact sports was linked to an increased bleeding risk — ranging from 1.7 to 7.3 times higher — according to one study. In another study, the link between physical activity involving contact sports and bleeding was not conclusive.

A bleeding history, even of nonsevere bleeds, was linked to an increased risk of future bleeds. One study reported the risk of a severe bleed — ones requiring a change in treatment, hospitalization, transfusion, or surgical intervention — increased by 21 times for patients with a history of nonsevere bleeds. Another study estimated that bleeding episodes in the previous 12 months also was a risk factor for future bleeds.

Additional parameters, including age, body mass index (a measure of body fat), antithrombotic therapy, year season, and some laboratory tests, were only evaluated in a single study each, which, according to researchers, was highly biased.

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Overall, the results of this small study suggest that blood “factor levels, physical activity, and bleeding history are important risk factor for bleeding and ideally should be considered in the derivation of a RAM [risk assessment models],” the researchers wrote.

Simply put, according to the researchers, “the risk for bleeding was increased when factor levels were lower and in people with a significant history of bleeding or who engaged in physical activities involving contact.”

The role of additional factors, such as obesity, still requires further investigation, the team noted.

The findings of this review could be useful in developing a risk assessment model for people with hemophilia, the scientists said.

“We believe that deriving and validating … a RAM would be of value. Factor levels, physical activity, and bleeding history appear to be the most important risk factors to be included in such a model,” they concluded.