Refined dosing strategies may improve perioperative treatment of patients with hemophilia A

Efforts to refine perioperative Factor VIII dosing for patients with hemophilia A based on blood group, age and other individual characteristics may improve quality of care and cost-effectiveness, according to results of a retrospective observational study.

Hemophilia A — a genetic bleeding disorder caused by a deficiency of coagulation Factor VIII (FVIII) — is treated with IV-administered factor replacement therapy. In severe and some moderate cases, prophylactic treatment is administered to prevent spontaneous and frequent bleeding.

Although prior studies showed FVIII concentrate replacement therapy to be effective, overdoses remain common, according to study background.

In addition, the extent, timing and associated risk factors of overdosing and underdosing have not been established, Hendrika C.A.M. Hazendonk, MD, MSc, of Erasmus University Medical Center-Sophia Children’s Hospital, and colleagues wrote.

“We believe that both underdosing and overdosing can be reduced by alternative dosing strategies that take into account individual patient characteristics, leading to optimization of care and a greater efficacy of consumption of costly factor concentrate,” Hazendonk and colleagues wrote.

Hazendonk and colleagues evaluated 119 males with severe or moderate-severe hemophilia A, defined as FVIII levels less than .05 IU mL¯¹, who underwent surgery between 2000 and 2013.

The study population included 75 adults (median age, 48 years; median body weight, 80 kg) who underwent a combined 140 surgical procedures, as well as 44 children (median age, 4 years; median body weight, 19 kg) who underwent a combined 58 surgical procedures.

All patients received perioperative FVIII concentrate.

The majority (70%) of patients had severe hemophilia A and received prophylactic treatment. About half (51%) of patients were in blood group O. Most adults (61%) underwent major surgery, whereas most children (81%) underwent minor surgery.

On the first day after surgery, 283 of 308 samples (77.3%) revealed FVIII levels outside the target range. Of these, 101 (32.7%) were above the target range (median deviation, 0.23; interquartile range [IQR], 0.1-0.4) and 137 (44.5%) were below the target range (median deviation, 0.17; IQR, .08-.33).

Between 2 and 5 days after surgery, 339 of 510 (66.5%) samples revealed FVIII levels outside the target range. Of these, 303 (59.4%) were above the target range (median deviation, 0.23; IQR, 0.12-0.41) and 36 (7.1%) were below the target range (median deviation, 0.17; IQR, 0.07-0.24).

By 6 or more days after surgery, 383 of 471 (81.3%) samples showed FVIII levels outside the target range. Of these, 343 (74.7%) were above the target range (median deviation, 0.31; IQR, 0.15-0.45) and 40 (8.7%) were below the target range (median deviation, 0.11; IQR, 0.05-0.16).

Researchers reported total FVIII concentration consumption of 6.8 million IU during the perioperative period.

“If target ranges had been adequately maintained, an impressive overall reduction of FVIII consumption of 44% would have been possible,” Hazendonk and colleagues wrote.

Logistic regression analyses showed blood group O (OR = 6.3; 95% CI, 2.7-14.9) and major surgery (OR = 3.3; 95% CI, 1.4-7.9) were predictive of underdosing. In addition, increasing age (OR per year = 1.02; 95% CI, 1.01-1.02) and replacement therapy via bolus infusion (OR = 1.92; 95% CI, 1.45-2.54) were predictive of excessive overdosing.

Patients in blood group non-O also demonstrated a higher risk for overdosing (OR = 1.5; 95% CI, 1.1–1.9).

Results showed 32% of adult surgical procedures and 5% of children’s surgical procedures were complicated by perioperative bleeding.

Patients in blood group O demonstrated more complications than patients with blood group non-O (OR = 2.02; 95% CI, 1–4.09). A higher percentage of blood group O patients than non-blood group O patients experienced severe bleeding complications (33% vs. 18%).

Researchers observed no association between bleeding complications and FVIII plasma level at the time of bleeding in adults or children.

The researchers acknowledged the study was limited by the retrospective nature of the data, the potential overrepresentation of major surgical procedures, and the possibility that use of one-stage laboratory assays to measure FVIII plasma levels led to biased results.

“These data underline that quality of care and cost-effectiveness can be improved by future refining of dosing strategies based on individual patient characteristics, such as ... blood group and mode of infusion,” Hazendonk and colleagues wrote. “However, we also believe that not all variables of influence on dosing and clearance of FVIII concentrate have yet been defined.” – by Kristie L. Kahl

Disclosure: The researchers report no relevant financial disclosures.