The prothrombin 20210A allele influences clinical manifestations of hemophilia A in patients with intron 22 inversion and without inhibitors.
OBJECTIVE
The modulation of disease severity in hemophilia A (HA) patients may be related to the co-inheritance of mutations in genes with a known thrombotic effect such as factor V Leiden (FVL) and prothrombin. In the Spanish population, the prothrombin 20210A (PT20210A) allele is the most prevalent genetic risk factor for venous thromboembolism.


METHODS
We investigated the presence of both mutations in a cohort of 265 hemophiliac patients divided into two groups: I) 140 unrelated patients with moderate and mild HA and II) 125 unrelated patients with severe HA (83 carrying an inversion of intron 22).


RESULTS
In group I, 4 patients had the FVL (2.8% vs. 2.98% controls) and 5 had the PT20210A (3.6% vs. 6.46% controls). In group II, two patients with inversion had the FVL (1.6%) and PT20210A was found in 10 patients (8%), five of them with inversion of intron 22 without inhibitors. One of these patients had the FVL and PT20210A mutations concomitantly. In the subgroup of patients with inversion who were carriers of the PT20210A, three parameters i.e. spontaneous bleeding (p=0.008), factor VIII utilization (p=0.016) and number of hemophilic arthropathies (p<0.0005) were significantly lower than in a subgroup of 11 age-matched non-PT20210A severe HA patients with inversion and without inhibitors.


CONCLUSIONS
These results indicate that the inheritance of PT20210A could be a protective factor that mitigates the clinical severity of HA.
Tizzano
Eduardo F
EF
Servei de Genètica, Hospital de Sant Pau, Padre Claret 167, 08025, Barcelona, Spain. etizzano@hsp.santpau.es
Soria
José Manuel
JM
Coll
Immaculada
I
Guzmán
Blanca
B
Cornet
Mónica
M
Altisent
Carmen
C
Martorell
Marta
M
Domenech
Montserrat
M
del Río
Elisabeth
E
Fontcuberta
Jordi
J
Baiget
Montserrat
M
D000293:Adolescent; D000328:Adult; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D007446:Chromosome Inversion; D005165:Factor V / Q000032:analysis; D005820:Genetic Testing; D006467:Hemophilia A / Q000175:diagnosis* / Q000235:genetics* / Q000276:immunology; D006470:Hemorrhage / Q000097:blood / Q000209:etiology / Q000235:genetics; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D007518:Isoantibodies / Q000097:blood; D015995:Prevalence; D011516:Prothrombin / Q000032:analysis / Q000235:genetics*
D007518:Isoantibodies; C095381:factor V Leiden; D005165:Factor V; D011516:Prothrombin