Mild hemophilia A with factor VIII assay discrepancy: using thrombin generation assay to assess the bleeding phenotype.
BACKGROUND
In some patients with mild hemophilia A, there are discrepancies between 1-stage (1-st) and 2-stage (2-st) factor VIII (FVIII) clotting assays, and also chromogenic assays for FVIII activity (FVIII:C). We examined whether thrombography could provide a better evaluation of the hemostatic status of these patients.


METHODS
Two families with such discrepancies and markedly contrasting clinical histories were studied. Family X had no serious bleedings, in contrast to family Y. Sixty-one moderate/mild hemophiliacs without discrepancy and 15 healthy subjects served as controls. Calibrated automated thrombography was performed with platelet-rich plasma after one freeze-thawing cycle and low tissue factor concentration.


RESULTS
The chromogenic FVIII:C levels were higher (0.90 +/- 0.15 and 0.47 +/- 0.13 IU mL(-1)) than the 1-st clotting ones (0.14 +/- 0.05 and 0.10 +/- 0.05 IU mL(-1)) in family X and Y, respectively (P < 0.001). Mean endogenous thrombin potential (ETP) was 1579 +/- 359 nM min(-1) and 1060 +/- 450 for healthy controls and hemophilic controls, respectively. For members of family X, the ETP values were 1188, 1317 and 2277 nM min(-1), whereas for those of family Y they ranged from 447 to 1122 nM min(-1). Two novel missense point mutations were evidenced: p.Ile369Thr in family X and p.Phe2127Ser in family Y. In family X, we postulate that the mutation is responsible for a delayed but non-deleterious FVIII activation.


CONCLUSIONS
Our results suggest that the hemostatic phenotype assessed by thrombography may be clinically relevant in moderate/mild hemophilic patients with discrepant FVIII:C results.
Trossaërt
M
M
Centre Régional de Traitement de l'Hémophilie - Laboratoire d'Hématologie, Centre Hospitalier Universitaire, Nantes, France. marc.trossaert@chu-nantes.fr
Regnault
V
V
Sigaud
M
M
Boisseau
P
P
Fressinaud
E
E
Lecompte
T
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D001331:Automation; D002138:Calibration; D016022:Case-Control Studies; D005169:Factor VIII / Q000096:biosynthesis*; D006467:Hemophilia A / Q000097:blood* / Q000175:diagnosis*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D013917:Thrombin / Q000378:metabolism*
D005169:Factor VIII; D013917:Thrombin