Bleeding Tendency of Carriers of Hemophilia A – Dependent on the Age of the Carriers?

Dependent on the Age of the Carriers?

W. Miesbach, J. Oldenburg, I. Stier-Brück, T. Vigh and I. Scharrer

Carriers of hemophilia A often present with normal clotting factor VIII levels but occasionally also report a considerable tendency to bleeding. Recently it was shown that reduced concentrations of factor VIII and IX in carriers of hemophilia A and B are associated with favorable effects on blood coagulation and hemostasis which contributes to cardiovascular protection and a decreased mortality of ischemic heart disease. [1]

Hemophilia A is an X-linked recessive bleeding disorder of variable severity that is caused by a deficiency of factor VIII (FVIII). The disease results from mutations in the FVIII gene which are heterogeneous both in type and position within the gene.

The frequency of hemophilia A is 1–2 in 10 000 male births in all ethnic groups.

Because carriers have usually one unaffected allele the FVIII concentration is often of about 50 % of normal. But symptomatic carriers of hemophilia A can pre- sent with bleeding symptoms like a male patient with mild hemophilia A. A small number of carriers may have very low levels of FVIII [2] due to co-inheritance of a variant von Willebrand factor allele (i.e. von Willebrand’s disease Normandy), homozygosity for hemophilia gene [3] or extreme lyonization.

The daughters of men with hemophilia are obligate carriers and carriers have a 50:50 chance of passing on the condition to a son and a 50:50 chance that a daugh- ter will be a carrier.

Members of the same family usually have the same FVIII level and the severity of hemophilia within a family remains constant.

Over the last 20 years the advances in molecular biology and prenatal diagnos- tic techniques have faciliated the diagnosis of hemophilia.

The gene for factor VIII was cloned in 1984 [4-6]. The FVIII gene is 186 kb in size and contains 26 exons.

The factor VIII mutations causing hemophilia A are heterogeneous. In hemo- philia A patients many mutations in the FVIII gene have been identified including deletions, point mutations or mutations resulting in stop codons [7]. In about 5 % of the patients with hemophilia A there are large (more than 100 nucleotides) dele- tions in the FVIII gene [8]. Deletions almost always produce severe hemophilia A.

Small deletions or insertions in the coding region of the factor VIII gene that result in frameshifts may cause severe hemophilia A, too. FVIII gene inversion mutations were identified in 45 % of severe hemophilia [9].

I. Scharrer/W. Schramm (Ed.)

34^thHemophilia Symposium Hamburg 2003

” Springer Medizin Verlag Heidelberg 2005

It is not always possible to exclude carrier status by measuring a women’s FVIII level. These levels fluctuate in normal people under stress, during pregnancy and for those under oral contraceptives. Thus, for this tests calculations are made after taking blood samples on several separate occasions. Carrier detection in hemophi- lia A can give definite answers in 80–90% of cases after DNA analysis. The tests sometimes require blood samples from other members of the family, particularly the person with hemophilia and an unaffected male.

The aim of this investigation was to document the occurrence of bleedings in carriers of hemophilia A and to study the genotype and phenotype correlation as well as the dependency of the bleeding events on the age of the carriers.

Material and Methods

The subjects included in this study were carriers of hemophilia A who attended the Hemophilia Ambulance of the University Hospital Frankfurt/Main, Germany.

The fact that they were carriers was confirmed in all cases by analysis of the fac- tor VIII gene mutation (done by PD Dr. J. Oldenburg,Würzburg/Frankfurt).

42 carriers were questioned about their tendency to bleedings.

The following symptoms were noted: easy bruising, nose bleeding, gum bleed- ing, bleeding after small or larger traumata, bleeding after surgical procedures, long or heavy menstrual bleedings.

Measurement of factor VIII was carried out by an one-stage clotting assay (Instrument ACL 300, normal range: 64 %–167 %) with FVIII-deficient plasma from Instrumentation Laboratory (IL).

To exclude the additional presence of a von Willebrand syndrome the von Willebrand antigen was measured in all carriers by an home-made ELISA.

Results

The median age of the carriers was 43 years (16–75 years).

In all carriers the FVIII mutation could be detected. Nine carriers had an intron- 22-inversion, one carrier a small deletion and the majority of the carriers (32 car- riers) a point mutation.

The median FVIII concentration of all carriers was 54.5 % (4–136 %).

Divided into two age-dependent groups, the younger patients (median age 32 years, range 16–43 years) had a lower FVIII concentration (median 53 %, range 4–120 %), the older patients (median age 57 years, range 43–75 years) had a higher FVIII con- centration (median 62 %, range 16–136 %) (Table 1).

28/42 carriers (67 %) reported on the occurrence of bleeding events.

The following bleeding symptoms were noted (Fig. 1).

The most frequently mentioned events were bleedings after traumata or opera-

tions (24/28, 86 %). Tendency for bruising was reported by 11/28 carriers (39 %),

strikingly long and heavy menstrual bleeding by 3/28 (11 %), and frequently gum

bleeding by 2/28 (7 %) carriers.

14/42 (33 %) carriers reported that they did not remember any tendency to bleed- ing.

In the 28/42 carriers who presented with bleeding tendency the FVIII concentration was lower (median factor VIII 51 %, 4–136 %) than in 14/42 carriers without any bleeding tendency (median factor VIII 66 %, 30–120 %) (Table 2).

Table 1. Characteristics of the carriers

Median age 43 years (16–75)

Factor VIII-activity, median 54.5 % (4–136 %) Factor VIII –gene mutation

Intron-22-Inversion 9 carriers

Point Mutation 32 carriers

Small Deletion 1 carrier

Factor VIII concentration – dependent on the age of the carriers?

Median age Factor VIII-activity

32 years (16–43, n = 21) 53 % (4–120 %) 57 years (43–75, n = 21) 62 % (16–136 %)

Postoperative Easy bruising Menstrual Gum 7

11

38

83

%

Fig. 1. Type of bleeding events

Table 2. Association of bleeding tendency to the FVIII concentration and the age of the car- riers

Bleeding tendency yes no

Carriers 28 / 42 (67 %) 14 / 42 (33 %)

Factor VIII-activity 51 % (4 % - 136 %) 66 % (30 % - 120 %)

Age 47 years (21–73) 32 years (16–75 J.)

The age of the 28/42 carriers with bleeding tendency was median 47 years (21–73 years).

The age of the 14/42 carriers without any bleeding tendency was median 32 years (16–75 years).

By separation the carriers into two age-groups from 16 to 43 years (21 carriers, factor VIII: 53 %, 4–120 %) and from 43 to 75 years (21 carriers, factor VIII: 62 %, 16–136 %) it could be shown that in the group of younger carriers 50 % of them had so far no bleedings in comparison with only 20 % of the carriers with older age al- though in these carriers factor VIII levels were higher (Table 3).

Discussion

Mostly not enough attention is paid to the bleeding history of carriers of hemo- philia A.

Recurrent bleeding events however are a frequent symptom in carriers of hemo- philia A. Bleedings after traumata or operations are the most frequent manifes- tations of this. Bruising or prolonged menstrual bleeding occur markedly less.

Recently we have demonstrated that the incidence of bleeding symptoms is cor- related to the activity of FVIII and the underlying FVIII gene mutation. Carriers with low levels of FVIII are at risk of excessive bleeding from surgery or other inva- sive procedures. [10]

In this investigation we studied the dependency of the bleeding events on the age of the carriers.

It could be shown that in the group of younger carriers less carriers had a history of bleeding events in comparison to the older carriers. The younger age of the carriers who could not remember any tendency to bleeding is striking. This cor- relation was in inverse proportion to the FVIII concentration. Although we demon- strated a correlation between the age of the carriers and the level of FVIII before [10], in this case the bleeding tendency correlated to the age of the carriers and not to the FVIII level.

Although their factor VIII levels were lower, younger carriers were less likely to report a tendency to bleeding. Older carriers with higher concentrations of FVIII reported more common bleeding events.

This may be due to the fact that the diagnosis of a carrier was made earlier in younger carriers and that frequently postoperative bleeding was dealt by prophy- lactic treatment.

Finally it can be postulated that carriers were less likely to report a tendency for bleeding when timely diagnosis and treatment for carriers of hemophilia A can pre- vent the tendency to bleeding.

Table 3. Bleeding tendency of two age-dependent groups of carriers

Median age Bleeding tendency

32 years (16–43, n = 21) 52 % (11 / 21)

57 years (43–75, n = 21) 81 % (17 / 21)

References

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