Decreased Factor V Ameliorates Bleeding Diathesis in Patients with Combined Deficiency of Factor V and Factor VIII

Combined factor V (FV) and factor VIII (FVIII) deficiency (F5F8D) is a rare autosomal recessive bleeding disorder caused by mutations in LMAN1 and MCFD2 gene. Though characterized with deficiencies of both FV and FVIII, it failed to lead to more severe bleeding than single defect of FVIII in similar degree. Our study on F5F8D patients revealed that mild decrease of FV and FVIII had counteractive effect on blood coagulation. Out of 5 subjects investigated, three showed potent thrombin generation as observed in thrombin generation assay (TGA), with peak heights ranging from 138 nM to 166 nM, compared with 81 nM in normal plasma when coagulation was initiated with 1pM TF. The same trend was seen when the TF concentration was increased to 5 pM.

Supplement of FV and FVIII, however, demonstrated distinct impact in TGA, with FVIII addition inducing more thrombin generation whereas higher FV level failed to further boost thrombin generation despite the shortened lag time.

FV is a Janus-faced protein and suppresses blood coagulation by protecting TFPI from degradation.Similar to patients with severe FV deficiency, both total and free TFPI levels also decreased slightly in F5F8D patients. Total TFPI levels decreased from healthy donors (65.95±8.35 ng/mL) to F5F8D patients (65.79±12.99 ng/mL), to severe FV-deficient patients (51.30±11.15 ng/mL, P=0.037). A more pronounced trend was observed for free TFPI levels, as free TFPI in healthy controls were 12.68±2.91 ng/mL, higher than those in F5F8D (4.73±1.31 ng/mL, P=0.004), and in severe FV-deficient patients (3.81±1.03 ng/mL, P=0.004).The lowered TFPI in patients with F5F8D may neutralize the impact of FV and FVIII deficiency on blood coagulation.

Desmopressin (DDAVP) increases endogenous FVIII and is used in the management of mild hemophilia A patients. In current study, 4 patients with F5F8D were treated with DDAVP. The administration of DDAVP saw no elevation of FV yet the increase of FVIII. The mean basal FV and FVIII levels were 11.5±3.4% and 15.1±4.8% respectively. The peak value of FVIII levels rose to 66.1±20.5% 30 minutes after the administration, and was sustained at two-folds of the baseline four hours post administration.

The distinctive changes brought by combined FV and FVIII deficiencies on blood coagulation functions indicates the lone FVIII replacement without FV supplement might be sufficient in bleeding management of patients with F5F8D. DDAVP can be considered as a potential substitute for FVIII concentrate in the treatment of F5F8D patients.