Page 360 - Essential Haematology

346 / Chapter 26 Coagulation disorders

Hereditary c oagulation d isorders glycosylated B domain which is removed when

factor VIII is activated by thrombin. The protein is

Hereditary deficiencies of each of the coagulation
synthesized in the liver and endothelial cells.
factors have been described. Haemophilia A (factor
The defect is an absence or low level of plasma

VIII deficiency), haemophilia B (Christmas disease,

factor VIII. Approximately half of the patients have

factor IX deficiency) and von Willebrand disease
missense or frameshift mutations or deletions in the
(VWD) are the most frequent; the others are rarer.
factor VIII gene. In others a characteristic ‘ flip - tip ’

inversion is seen in which the factor VIII gene is
Haemophilia A broken by an inversion at the end of the X chromo-

some (Fig. 26.2 ). This mutation leads to a severe
Haemophilia A is the most common of the heredi-
clinical form of haemophilia A.
tary clotting factor defi ciencies. The prevalence is of

the order of 30 – 100 per million population. Th e
inheritance is sex - linked (Fig. 26.1 ) but up to one - Clinical f eatures
third of patients have no family history and result
Infants may develop profuse post - circumcision
from recent mutation.
haemorrhage or joint and soft tissue bleeds and
excessive bruising when they start to be active.
Molecular g enetics Recurrent painful haemarthroses and muscle
haematomas dominate the clinical course of severely
The factor VIII gene is situated near the tip of the

aff ected patients and if inadequately treated lead to
long arm of the X chromosome (Xq2.8 region). It
progressive joint deformity and disability (Figs
is extremely large and consists of 26 exons. Th e
26.3 – 26.6 ). Local pressure can cause entrapment
factor VIII protein includes a triplicated region
neuropathy or ischaemic necrosis. Prolonged bleed-
A 1 A 2 A 3 with 30% homology with each other, a
ing occurs after dental extractions. Spontaneous
duplicated homology region C 1 C 2 and a heavily
haematuria and gastrointestinal haemorrhage,
sometimes with obstruction resulting from intra-

mucosal bleeding, can also occur. The clinical sever-
ity of the disease correlates inversely with the factor
VIII level (Table 26.1 ). Operative and post -
55%* 100% traumatic haemorrhage are life - threatening both in
severely and mildly affected patients. Although not

common, spontaneous intracerebral haemorrhage
occurs more frequently than in the general popula-
1% 100% 100% 50%* 120%
tion and is an important cause of death in patients
with severe disease.
Haemophilic pseudotumours are large encapsu-
lated haematomas with progressive cystic swelling
1% 100% 65%* 35%* 100%
from repeated haemorrhage. They are best visual-

ized by magnetic resonance imaging (MRI) (Fig.
Unaffected female Carrier female

26.5 b). They may occur in fascial and muscle
Unaffected male Affected male planes, large muscle groups and in the long bones,

pelvis and cranium. The latter result from repeated
subperiosteal haemorrhages with bone destruction

Figure 26.1 A typical family tree in a family with

and new bone formation.
haemophilia. Note the variable levels of factor VIII
As a result of human immunodefi ciency virus
activity in carriers ( * ) because of random inactivation
of X chromosome (Lyonization). The percentages (HIV) present in concentrates made from human
show the degree of factor VIII activity as a percentage plasma during the early 1980s, over 50% of haemo-
of normal. philiacs treated in the USA or Western Europe