Relation Between Mutations in FVIII Gene and Response to Desmopressin in Patients with Hemophilia A

Hemophilia A is a rare X-linked bleeding disorder caused by a variety of mutations in the factor VIII (FVIII) gene resulting in lowered levels of FVIII. Desmopressin causes a 2- to 6-fold rise of FVIII in patients with mild (>5%FVIII) or moderate (1–5% FVIII) hemophilia A. To prevent bleeding during surgical procedures, FVIII levels should rise above 0.50 IU/ml. The response to desmopressin is known to have a great inter-individual variation. It is unknown if there is a relation between the type of FVIII gene mutation and the response to desmopressin.

To assess the response to desmopressin in patients with mild or moderate hemophilia A and known mutations of the FVIII gene.

Patients with mild or moderate hemophilia from the Erasmus University Medical Center Rotterdam were retrospectively included. Inclusion criteria: male, age ≥12 years, known mutation in FVIII gene, previous intravenous or intranasal administration of desmopressin, FVIII levels available at baseline and at peak level after desmopressin. Desmopressin response was defined as complete if FVIII ≥0.50 IU/ml, partial if ≥0.30 but <0.50 IU/ml or none <0.30 IU/ml. Response was determined 1 hour (peak level) and 3–4 hours (sustained response) after desmopressin administration. Fold increase over baseline was calculated as FVIII peak level / FVIII baseline level. Five groups of mutations were composed: Arg2169His, Arg612Cys, Asn637Ser, Pro149Arg and 1 residual group containing all other mutations.

Eighty-three male patients were included; 70 patients with mild and 13 with moderate hemophilia A. The mean age was 33 years (range 12–86). The median FVIII baseline level was 0.16 IU/ml (IQR 0.08–0.25), median FVIII peak level 0.58 IU/ml (IQR 0.38–0.86) and median fold increase over baseline was 4.15 (IQR 3.11–5.50). Of the 83 patients, 51 (61%) had a complete response. FVIII levels 3–4 hours after desmopressin were available in 58 of 83 patients and the response sustained in 28 (48%) patients. Of the 21 patients with mutation Arg2169His, 8 (38%) showed a complete response after 1 hour. In only 1 (9%) patient the complete response sustained. A partial response was seen in 6 (29%) patients and in 5 (46%) of 11 patients the response sustained. Seven (33%) patients had no response. None of the patients with mutation Pro149Arg achieved a complete response after 1 hour. Four (67%) of 6 patients had a partial response, after 3–4 hours 2 (50%) of 4 patients sustained. Two (33%) patients did not respond at all (Table 1). Mutation Arg2169His and Pro149Arg had significant lower FVIII levels at baseline, peak and 3–4 hours after desmopressin, compared to Arg612Cys, Asn637Ser and the group with other mutations. Fold increase over baseline was highest in Arg2169His (5.3 fold) and lowest in Asn637Ser (3.4 fold) (p=0.047) (Table 2).

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Although desmopressin caused a 4–5 fold increase over baseline in hemophilia A patients with mutation Arg2169His or Pro149Arg, the clinical utility is limited. A complete response at peak level did not sustain in most of the patients with Arg2169His and a complete response in patients with Pro149Arg was not seen. Therefore if patients with hemophilia A and mutation Arg2169His or Pro149Arg are treated with desmopressin, it should only be used to prevent bleeding during minor and not major surgery. A desmopressin challenge with measurement of the sustained response should be performed in all patients prior to surgery.

No relevant conflicts of interest to declare.