Coagulation disorders may be inherited or acquired. The inherited disorders are uncommon and usually involve deficiency of one factor only. The acquired disorders occur more frequently and almost always involve several coagulation factors.
Deficiencies of all factors have been described. They are rare apart from haemophilia A (factor VIII deficiency), haemophilia B (factor IX deficiency) and von Willebrand’s disease.
In haemophilia A, the level of factor VIII:C is reduced but the level of factor VIII:vWF is normal. It is inherited as an X-linked recessive. The incidence of haemophilia A varies from 1 in 5000 to 1 in 10000 of the male population.
The human factor VIII gene was cloned in 1984. The gene is enormous, constituting about 0.1% of the X chromosome, encompassing 186 kilobases of DNA. Various genetic defects have been found, including deletions, point mutations and insertions. There is a high mutation rate with one-third of cases being apparently sporadic with no family history of haemophilia.
The clinical features depend on the level offactor VIII:C. Levels of less than 1% are associated with frequent spontaneous bleeding from early life. Haemarthroses are common and may lead to joint deformity and crippling if adequate treatment is not given. Bleeds into muscles are also common.
Levels of less than 5% are associated with severe bleeding, following injury and occasional spontaneous episodes, and levels above 5% with milder disease usually with post-traumatic bleeding only.
The most frequent cause of death in patients with severe haemophilia is AIDS. HIV was transmitted to many patients by coagulation factor concentrates in the 1980s.
The main laboratory features of haemophilia A are shown in Table 6.23. The abnormal findings are a prolonged PTTK and a reduced level offactor VIII:C; the PT, bleeding time and factor VIII :vWF level are normal.
Bleeding is treated by administration of factor VIII concentrate by intravenous injection. For minor bleeding the factor VIII level should be raised to 20-30% of normal, and for severe bleeding episodes it should be raised to at least 50%. For major surgery the level should be raised to 100% preoperatively and maintained above 50% until healing has occurred.
Factor VIII has a half-life of 12 hours and therefore must be administered twice daily to maintain the required therapeutic leveL Factor VIII concentrate may be stored in domestic refrigerators and so may be administered by the patient immediately after bleeding has started, reducing the likelihood of chronic damage to joints and the need for inpatient care. High purity factor VIII concentrates are now preferred to intermediate purity concentrates. Factor VIII:C produced by recombinant DNA technology is undergoing clinical trials.
DDAVP (i.v.) produces a rise in factor VIII proportional to the initial level of factor VIII. It avoids the complications associated with blood products and is useful for treating bleeding episodes in mild haemophiliacs and as prophylaxis before minor surgery.
All haemophiliacs should be registered at haemophilia centres, who take responsibility for their full medical care, including social and psychological support. Each haemophiliac carries a special medical card giving details of the defect and treatment.
About 10% of severe haemophiliacs develop antibodies to factor VIII:C. Inhibitors develop almost exclusively in patients with no detectable VIII:C. Management of such patients may be very difficult, and extremely high doses of factor VIII may be needed to produce a rise in the plasma level of factor VIII:C. Alternative treatment includes recombinant factor VIla, purified porcine factor VIII which may not cross-react with the patient’s antibody, and some factor IX concentrates containing activated factor X, which may ‘bypass’ the inhibitor and stop the bleeding. Following numerous transfusions there is a high risk of acquiring transfusion-transmitted infections, particularly hepatitis and HIV. The risk has been reduced by excluding high risk blood donors, testing all donations for HBsAg and HIV antibody, and by including steps to inactivate viruses during the preparation of concentrates. The use of recombinant factor VIII will avoid the risk of transfusion-transmitted infection; preliminary data suggest that it is safe and effective but there is a similar incidence of inhibitor development as with plasmaderived factor VIII. Carrier detection and antenatal diagnosis Determination of carrier status in females used to depend on detailed information from the family history and results of coagulation factor assays. Carriers could be diagnosed with reasonable confidence if the level of factor VIII:C was 50% of that expected from the level of factor VIII :vWF but often no clear-cut answer was provided by this method.
Carrier detection can now be carried out using DNA analysis either by direct detection of mutations within the factor VIII gene or by indirect detection of the abnormal gene using DNA polymorphisms within or adjacent to the factor VIII gene as markers of the abnormal gene. Antenatal diagnosis may be carried out by DNA analysis of fetal tissue obtained by chorionic villus biopsy at 9-11 weeks’ gestation or by using ultrasound-guided fetal blood sampling to detect low plasma levels in a fetus at 18-20 weeks of gestation.
Haemophilia B (Christmas disease) Haemophilia B is caused by a deficiency of factor IX. The inheritance and clinical features are identical to haemophilia A, but the incidence is only about 1:30 000 males. It is treated with factor IX concentrates.
von Willebrand’s disease (vWD) In vWD, there is defective platelet function as well as factor VIII:C deficiency and both are due to a deficiency or abnormality of factor VIII:vWF . Factor VIII:vWF plays a role in platelet adhesion to damaged subendothelium as well as stabilizing factor VIII:C in plasma.
The VIII:vWF gene is on chromosome 12 and numerous mutations of the gene have been identified. vWD has been classified into three types: TYPE I is characterized by a mild reduction in factor VIII :vWF and is inherited as an autosomal dominant.
TYPE II is due to a decrease in the proportion of high molecular weight multimers and is also inherited as an autosomal dominant.
TYPE III is recessively inherited and patients have barely detectable levels of factor VIII:vWF (and therefore factor VIII:C).
The clinical features of vWD are variable. Type I and type II patients usually have mild clinical features. Bleeding follows minor trauma or surgery and epistaxis and menorrhagia often occur. Haemarthroses are rare. Type III patients have clinical features resembling haemophilia A. Characteristic laboratory findings are shown . These also include defective platelet aggregation with ristocetin.
Treatment depends on the severity of the condition and may be similar to that of mild haemophilia, including the use of DDAVP for minor surgery. Factor VIII concentrates should be used to treat bleeding or to cover surgery in patients with severe vWD. Cryoprecipitate should be avoided because of the greater risk of transfusiontransmitted infection.