Prothrombotic variants as modifiers of clinical phenotype in four related individuals with haemophilia A

Abstract Introduction: By assuming the hypothesis, that a high coinheritance of genetic haemostatic abnormalities influences the clinical phenotype in patients with coagulation disorders, we analysed the bleeding tendency in adult patients with haemophilia A. Patients: A total of 49 patients with haemophilia A (severe:20 patients, moderate:12 patients, mild:17 patients; median age:44 years, range:22–78 years) and 80 sex-matched healthy subjects (median age:26 years, range:16–58 years) were studied in our haemophilia treatment center. Two of this patients have an inhibitor against factor VIII. 10 of 49 patients receive the factor VIII replacement therapy on demand. In addition to factor VIII activity, FV G1691A mutation and the FII G20210A variant were investigated. Results: In our study the prevalence of FV G1691A was significantly higher among patients 6/49 (severe:5, moderate:1) than among control subjects 2/80 [12% vs 2.5%; p=0.03 OR 4.9]. We found no differences in the FII G20210A variant in 2/49 patient (moderate:1, mild:1) as compared to 2/80 among controls [4% vs 2.5%; p=0.62 OR 1.63 ]. In none of our patients both defects together were identified. Within the last year the onset of bleeding was not different in thrombophilic haemophilia patients (n=8) 64 bleeding episodes/year compared with non-carriers (n=41) 284 bleeding episodes/year [8 vs 7 bleeding episodes/year/patient; p=0.72; OR 1.15]. Conclusion: The FV G1691A was found significantly more frequent in the thrombophilic haemophiliacs than in the general population. In our smal study group we could not demonstrate a relevant influence of the FV G1691A and FII G20210A on bleeding tendency. Further studies are needed to confirm whether FV G1691A and FII G20210A plays a role on the influence of bleeding tendency in haemophilia A patients.

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Mutation analysis in 51 patients with haemophilia A: report of 10 novel mutations and correlations between genotype and clinical phenotype

Haemophilia ◽

10.1111/j.1365-2516.2005.01069.x ◽

2005 ◽

Vol 11 (2) ◽

pp. 133-141 ◽

Cited By ~ 24

Author(s):

M. Hill ◽

S. Deam ◽

B. Gordon ◽

G. Dolan

Keyword(s):

Mutation Analysis ◽

Clinical Phenotype ◽

Haemophilia A ◽

Novel Mutations

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Different clinical phenotype in triplets with haemophilia A

Haemophilia ◽

10.1111/j.1365-2516.2006.01396.x ◽

2007 ◽

Vol 13 (2) ◽

pp. 202-205 ◽

Cited By ~ 5

Author(s):

C. BARNES ◽

V. BLANCHETTE ◽

D. LILLICRAP ◽

K. MANN ◽

A. M. STAIN ◽

...

Keyword(s):

Clinical Phenotype ◽

Haemophilia A

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Platelet degranulation and glycoprotein IIbIIIa opening are not related to bleeding phenotype in severe haemophilia A patients

Thrombosis and Haemostasis ◽

10.1160/th13-07-0546 ◽

2014 ◽

Vol 111 (06) ◽

pp. 1022-1030 ◽

Cited By ~ 2

Author(s):

Roger E. G. Schutgens ◽

Kathelijn Fischer ◽

Philip G. de Groot ◽

Mark Roest ◽

Esther R. van Bladel

Keyword(s):

Endothelial Cell ◽

Platelet Activation ◽

Cell Activation ◽

Clinical Phenotype ◽

Platelet Reactivity ◽

Joint Damage ◽

Haemophilia A ◽

Severe Haemophilia ◽

Endothelial Cell Activation ◽

Bleeding Score

SummaryRecently we reported data suggesting that platelets could compensate for the bleeding phenotype in severe haemophilia A (HA). The aim of this study was to confirm these results in a larger population with a detailed characterisation of clinical phenotype. Patients with diagnostic severe HA (FVIII:C <1%) were scored for clinical phenotype by integrating data on age at first joint bleed, joint damage, bleeding frequency and FVIII consumption. Phenotype was defined as onset of joint bleeding-score + arthropathy-score + joint bleeding-score + (2* treatment intensity-score). After a washout period of three days, blood was collected for measurement of basal level of platelet activation, platelet reactivity, endothelial cell activation and presence of procoagulant phospholipids in plasma. Thirty-three patients with severe HA were included, 13 patients with a mild, 12 patients with an average and eight patients with a severe clinical phenotype. No relevant differences in basal level of platelet activation, platelet reactivity, endothelial cell activation and procoagulant phospholipids between all three groups were observed. The mean annual FVIII consumption per kg did not correlate with the platelet P-selectin expression and glycoprotein (GP)IIbIIIa activation on platelets. In conclusion, variability in clinical phenotype in patients with diagnostic severe HA is not related to platelet activation or reactivity, measured as platelet degranulation and platelet GPIIbIIIa opening.

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