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Haemophilia A and B


mild.4


Patients with severe haemophilia have no measurable FVIII or FIX (< 0.01 IU/ml) and may bleed spontaneously without preceding trauma. In patients with moderate and mild haemophilia, the plasma FVIII or FIX concentration is between 0.02 and 0.05 IU/ml and 0.06 and 0.40 IU/ml, respectively. In patients with moderate or mild haemophilia, excessive bleeding usually occurs after minor trauma, dental or surgical procedures.


Genetic aspects


The deficiency of FVIII and FIX is due to defects in the respective F8 and F9 genes, which are located on the long arm of the X chromosome. When the F8 or F9 gene sequence is disrupted, this results in reduced or absent synthesis of FVIII or FIX. Alternatively, a less functionally


forceps) should be avoided, as this poses a significant risk for intra- and extracranial bleeding in newborns with haemophilia.


Clinical and laboratory diagnosis The diagnosis of haemophilia can either be established shortly after birth in an affected son (when the mother is a known carrier) or based on unusual bleeding symptoms. Characteristic bleeding symptoms include painful swelling of the joints caused by joint bleeding (haemarthros), post-operative bleeding and extensive subcutaneous bleeding after venapuncture and muscle bleeding, either spontaneously or after intramuscular vaccination.


The diagnosis can be established by haemostatic laboratory testing, including activated partial thromboplastin time


“Medication that impairs haemostasis, such as platelet inhibitors and anticoagulant drugs, should be avoided whenever possible, as these will aggravate bleeding symptoms”


active form of the clotting factor is produced.5–7


A de novo mutation is


present in approximately 30% of patients; the others have a positive family history for haemophilia.


As haemophilia is inherited as an X-linked disease, men are generally affected, because they possess only one X chromosome. Women, who have two X-chromosomes, are carriers of the disease. All daughters of a (male) haemophilia patient are obligate carriers: they must have inherited the X-chromosome with the disrupted F8 or F9 gene sequence from their father. All other female relatives of a person with haemophilia are potential carriers. Carriers may have reduced FVIII of FIX levels, due to inactivation of one X-chromosome per body cell. Approximately 25% of the carriers have plasma FVIII or FIX levels below 0.40 IU/ml. These levels are within the same range as in persons with mild haemophilia and are associated with bleeding symptoms.8


A


normal FVIII or FIX level does not rule out carrier status, which can only be excluded by molecular genetic analysis. Carriers of haemophilia should be offered genetic counselling. Pregnancy and childbirth of carriers should be managed in a haemophilia treatment centre. Instrumental delivery (ventouse and


(PTT), FVIII, FIX and VWF analysis. Patients with haemophilia usually have a prolonged PTT. However, a normal PTT cannot rule out a mild form of haemophilia.


Clotting factor concentrates Bleeding can be either prevented or treated by the intravenous administration of the deficient clotting factor in a concentrated form. At the time of Tsar Nikolaevich, our knowledge of the clotting system and the cause of haemophilia was still limited. In the 20th century, this knowledge rapidly increased and the deficient clotting factors causing haemophilia were identified. This enabled the production of clotting factors in a concentrated form for therapeutic purposes. The first clotting factor concentrates were derived from plasma and became available around 1970. Subsequently, in the 1990s, recombinant FVIII and FIX concentrates were developed. As stated in a recent UK guideline, these are currently the preferred treatment for children in the developed world, and for adult patients in some countries, such as the UK and Sweden.9


A


new generation of recombinant concentrates is presently emerging. These long-acting FVIII and FIX concentrates may enable less frequent dosing and are currently being tested in clinical trials.


The dose of clotting factor depends on the severity and type of bleeding. In the case of major (head) trauma, clotting factor concentrate should always be administered without delay, before diagnostic imaging or other interventions take place. This may be life saving, as supplementation of the deficient clotting factor is essential in stopping haemorrhage in patients with haemophilia. Unfortunately, the need for immediate administration of clotting factor concentrates is not always recognised, resulting in preventable morbidity or death. The dose of clotting factor is calculated based on the target FVIII or FIX plasma level and the body weight of the patient: 1.0 IU/kg body weight of FVIII concentrate increases the FVIII plasma concentration by about 0.02 IU/ml and 1 IU/kg body weight of FIX concentrate increases the FIX plasma concentration by about 0.01 IU/ml. For severe or life-threatening bleeding, the target plasma level is 1.00 IU/ml FVIII or FIX. This is achieved by infusion of 50 IU/kg FVIII concentrate or 100 IU/kg FIX concentrate. The short half-life, ranging from 6–12 hours for FVIII and about 24 hours for FIX, requires repeated administration of clotting factor concentrates to maintain a plasma concentration of FVIII or FIX above the haemostatic threshold of 0.40–0.50 IU/ml. The duration of clotting factor administration depends on the severity of the bleeding. For a joint bleeding, one or two infusions usually suffice, whereas intracranial bleeding requires treatment for up to two weeks. To prevent haemorrhage during surgical or dental procedures, FVIII or FIX levels should be raised to 0.80–1.00 IU/mL immediately prior to surgery and kept above 0.50 IU/ml for 5–14 postoperative days, depending on the type and site of surgery. As haemophilia is a rare disease requiring a multidisciplinary approach, care of these patients should be concentrated in Comprehensive Care Haemophilia Treatment Centres.


Alternative treatments In patients with mild haemophilia A, minor bleeding may be managed by infusion of DDAVP (desmopressin), which can be administered intravenously (0.3 microgram/kg body weight) or intranasally (150 micrograms in children or 300 micrograms in adults). This analogue of the physiological pituitary hormone vasopressin increases the FVIII plasma concentration three-to-five fold by releasing FVIII from an unidentified


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