Abstract

Introduction: Some severe hemophiliacs (FVIII/FIX<1%) exhibit a mild bleeding tendency, but the basis for this heterogeneous clinical expression is poorly understood. This study investigated the relationship between the values of endogenous thrombin potential (ETP) and clinical phenotype in severe hemophiliacs. The impact of FVIII/FIX gene mutations and thrombophilic polymorphisms into the modulation of the phenotype was also evaluated.

Methods: severe hemophiliacs older than 18 years without inhibitor history and treated on demand were eligible for inclusion in the study. Mild bleeders (MB) and severe bleeders (SB), representing the extremes of the clinical spectrum, were defined according to the following criteria: spontaneous bleeding episodes per year ≤2 (MB) or ≥25 (SB) and concentrate consumption <500 (MB) or >2000 (SB) IU/Kg/year. Patients who did not fit these criteria were considered as intermediate bleeders (IB). Plasma samples were obtained after a minimum wash-out period of 5 days. FVIII was measured by chromogenic assay. ETP was measured in platelet-rich plasma after addition of tissue factor.

Results: 22MB, 22SB and 28IB were enrolled. MB showed an older age at first bleed compared to SB (p < 0.005) and p for trend among the 3 groups was also significant (p < 0.05). The prevalence of severe FVIII/FIX gene defects (null mutations) was extremely low in MB (6%). ETP values were higher in MB compared with both IB and SB (p<0.05); p for trend among the 3 groups was also significant (p <0.05).

Conclusions: this study shows that the measurement of thrombin generation in platelet-rich plasma may allow to identify patients with mild bleeding diathesis among severe hemophiliacs, in contrast with the features of conventional functional assays.

SB (#22)IB (#28)MB (#22)P
Age (yr) 38 (21–76) 38 (23–62) 32 (22–73) NS 
Age 1st bleed (yr) 1 (0–4) 2 (0–6) 3 (1–10) < 0.005 
Bleeding episodes/yr 36 (25–60) 10 (3–20) 0 (0–2) < 0.0005 
Factor use (IU/Kg/yr) 2207 (2040–8696) 1068 (207–2400) 60 (25–487) < 0.0005 
Null mutations (%) 59 70 < 0.005 
PTG20210A (%) NS 
FV Leiden (%) NS 
Median ETP (nM) 414 478 850 < 0.05 
SB (#22)IB (#28)MB (#22)P
Age (yr) 38 (21–76) 38 (23–62) 32 (22–73) NS 
Age 1st bleed (yr) 1 (0–4) 2 (0–6) 3 (1–10) < 0.005 
Bleeding episodes/yr 36 (25–60) 10 (3–20) 0 (0–2) < 0.0005 
Factor use (IU/Kg/yr) 2207 (2040–8696) 1068 (207–2400) 60 (25–487) < 0.0005 
Null mutations (%) 59 70 < 0.005 
PTG20210A (%) NS 
FV Leiden (%) NS 
Median ETP (nM) 414 478 850 < 0.05 

Author notes

Disclosure: No relevant conflicts of interest to declare.