Page 366 - Essential Haematology

352 / Chapter 26 Coagulation disorders

contact sports are to be avoided, or undertaken with like that of prothrombin, factor VII, factor X and
extra prophylaxis. protein C, is vitamin K - dependent. Carrier detec-
tion and antenatal diagnosis is performed as for

haemophilia A. The principles of replacement
Gene t herapy
therapy are similar to those of haemophilia A.
Because it is only necessary to maintain factor levels Bleeding episodes are treated with high - purity factor
> 1% to prevent most of the mortality and morbid- IX concentrates. Because of its longer biological half -

ity of factor VIII or IX deficiency, there is great life, infusions do not have to be given as frequently
interest in gene - based therapy. Various viral vectors as do factor VIII concentrates in haemophilia A.
(retroviral, adeno - associated) as well as non - viral Recombinant factor IX is preferred, but higher doses
vectors are being explored. Phase 1 trials are being are needed than with plasma - derived factor IX to
carried out for both haemophilia A and B. attain the same response. Also the distribution and

kinetics of clearance differ from the natural product,
Inhibitors but it is certainly safe and eff ective.
One of the most serious complications of haemo-
philia is the development of antibodies (inhibitors)
Laboratory fi ndings (Table 26.2 )

to infused factor VIII which occurs in 30 – 40% of
severely effected patients, usually within the fi rst 50 The following tests are abnormal:

days of exposure. This renders the patient refractory
1 APTT;
to further replacement therapy. Immunosuppression
2 Factor IX clotting assay.
and immune tolerance regimens have been used in
an attempt to eradicate the antibody with success As in haemophilia A, the PFA - 100 (and bleeding
(at great cost) in about two - thirds of cases. time) and PT tests are normal.
Recombinant activated factor VII (VIIa) and acti-
vated prothrombin complex concentrates (FEIBA
Von Willebrand d isease
– factor VIII inhibitor bypassing activity) can be
useful in the treatment of bleeding episodes. In this disorder there is either a reduced level or
Factor VIIa complexes with tissue factor exposed abnormal function of von Willebrand factor (VWF)
at the site of injury and produces local haemostasis. resulting from a missense mutation or null muta-

The process is independent of factor VIII or IX and tion. VWF is produced in endothelial cells and

is not affected by their inhibitors. Factor VIIa has a megakaryocytes. It has two roles (see Chapter 24 ).

short half - life and therefore frequent doses may be It promotes platelet adhesion to subendothelium at
needed. In the longer term, immunosuppression high shear rates and it is the carrier molecule for
with cyclophosphamide, rituximab, intravenous factor VIII, protecting it from premature destruc-
immunoglobulin and high - dose factor VIII has also tion. The latter property explains the reduced factor

been successful. VIII levels found in VWD.
Chronic elevation of VWF is part of the acute
phase response to injury, infl ammation, neoplasia
Factor IX d eficiency (Haemophilia B,

or pregnancy. VWF is synthesized as a large 600 -
Christmas disease)
kDa dimeric protein which then forms multimers
6

The inheritance and clinical features of factor IX up to 20 × 10 Da in weight which are the largest

deficiency (Christmas disease, haemophilia B) are molecules in blood. Three types of VWD have been
identical to those of haemophilia A. Indeed, the two described (Table 26.3 ). Type 2 is divided into four
disorders can only be distinguished by specifi c coag- subtypes depending on the type of functional
ulation factor assays. The incidence is one - fi fth that defect. Type 1 accounts for 75% of cases.

of haemophilia A. Factor IX is coded by a gene close VWD is the most common inherited bleeding
to the gene for factor VIII near the tip of the long disorder. Usually, the inheritance is autosomal dom-

arm of the X chromosome at Xq2.6. Its synthesis, inant. The severity of the bleeding is highly variable