Lec.
(18-19)
Inherited Coagulation Disorders
Hereditary deficiencies of each of the coagulation factors have
been described. Haemophilia A (factor VIII deficiency), haemophilia B
(Christmas disease, factor IX deficiency) and von Willebrand disease
(VWD) are the most common; the others are rare.
Haemophilia A
Haemophilia A is the most common of the hereditary clotting
factor deficiencies. The prevalence is of the order of 30-100 per million
population. The inheritance is sex-linked (Fig. 24.1) but up to 33% of
patients have no family history and result from spontaneous mutation.
Clinical features
Infants may suffer from profuse post-circumcision haemorrhage
or develop joint bleeding and excessive bruising.
Recurrent painful haemarthroses may occur .
Prolonged bleeding occurs after dental extractions. Spontaneous
haematuria and gastrointestinal haemorrhage can also occur.
The clinical severity of the disease correlates with the extent of
the factor VIII deficiency.
Laboratory findings (Table 24.2)
The following tests are abnormal:
1- Activated partial thromboplastin time (APTT).
2- Factor VIII clotting assay.
The bleeding time and prothrombin time (PT) tests are normal.
Carriers are now better detected with DNA probes.
1
Carrier detection and antenatal diagnosis
Until recently, carrier detection and antenatal diagnosis were
limited to measuring plasma levels of factor VIII and von Willebrand
factor (VWF). Carriers are now better detected with DNA probes. A
known specific mutation can be identified or restriction fragment length
polymorphisms within or close to the factor VIII gene allows the mutant
allele to be tracked. Chorionic biopsies at 8-10 weeks' gestation provide
sufficient fetal DNA for analysis.
Antenatal diagnosis is also possible following the demonstration of
low levels of factor VIII in fetal blood obtained at 16-20 weeks' gestation
from the umbilical vein by ultrasound-guided needle aspiration.
Factor IX deficiency
The inheritance and clinical features of factor IX deficiency
(Christmas disease, haemophilia B) are identical to those of haemophilia
A.
Indeed, the two disorders can only be distinguished by specific
coagulation factor assays.
The incidence is one-fifth that of haemophilia A. Factor IX is
coded by a gene close to the gene for factor VIII in X chromosome. Its
synthesis is vitamin K-dependent (like that of prothrombin, factor VII,
factor X and protein C).
2
Laboratory findings (Table 24.2)
The following tests are abnormal:
1- APTT prolonged.
2- Factor IX clotting assay low.
As in haemophilia A, the bleeding time and PT tests are normal.
Von Willebrand disease
In this disorder there is either a reduced level or abnormal function
of VWF resulting from a point mutation or major deletion. VWF is
produced in endothelial cells and megakaryocytes.
It has two roles.
1- It promotes platelet adhesion to damaged endothelium and
2- It is the carrier molecule for factor VIII, protecting it from
premature destruction.
Three types of VWD have been described.
Type 2 is divided into four subtypes depending on the type of functional
defect. Type 1 accounts for 75% of cases.
VWD is the most common inherited bleeding disorder.
Usually, the inheritance is autosomal dominant with varying expression.
The severity of the bleeding is variable.
3
Typically, there is mucous membrane bleeding (e.g. epistaxes,
menorrhagia), excessive blood loss from superficial cuts and abrasions.
Haemarthroses and muscle haematomas are rare, except in type 3 disease.
Laboratory findings (Table 24.2
1- The bleeding time can be prolonged.
2- Factor VIII levels are often low. If low, a factor VIII VWF binding
assay is performed.
3- The APTT may be prolonged.
4- VWF levels are usually low.
5- There is defective platelet aggregation by patient plasma in the
presence of ristocetin (VWF: Rco).
Aggregation to other agents (adenosine diphosphate (ADP),
thrombin or adrenaline) is usually normal.
6- Collagen-binding function (VWF: CB) is usually reduced.
7- Multimer analysis is useful for diagnosing different
subtypes.
8- The platelet count is normal except for type 2B disease (where it is
low).
4
Hereditary disorders of other coagulation factors
All these disorders (deficiency of fibrinogen, prothrombin, factors
V, VII, combined V and VIII, factors X, XI, XIII) are rare. In most the
inheritance is autosomal recessive.
Factor XI deficiency is seen mainly in Jews.
Factor XIII deficiency produces a severe bleeding tendency,
characteristically with umbilical stump bleeding.
