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About Bleeding Disorders
Covid 19 and Bleeding Disorders:
Hemophilia:
Definition
Haemophilia is an inherited tendency to bleed caused by a deficiency of FVIII (haemophilia A) or FIX (haemophilia B). Based on the residual function of FVIII or FIX, a distinction is made between severe (residual activity <1%), moderate (residual activity 2–5%) and mild (residual activity >5%) haemophilia with correspondingly different clinical courses.
Genetics
Haemophilia A and B are inherited X‑linked recessively. The F8 gene is located on chromosome Xq28 and comprises 186kb with 26 exons (OMIM database No. 306700). The F9 gene is located on chromosome Xq27.1–27.2 (OMIM database No. 306900). A mother who carries the mutation on an X allele will pass 50% of the mutation on to her offspring. This means that 50% of the sons will receive the mutated allele and suffer from haemophilia and 50% of the daughters as carriers will be able to pass the allele on to their own offspring. About one third of cases of haemophilia A result from spontaneous new mutations of the F8 gene. Molecular genetic diagnosis of the F8 gene is available and in most cases can identify the associated gene mutation that leads to factor deficiency. This enables the clarification of the carriers and prenatal testing of the risk within a family. Various mutations have been described, not all of which lead to a complete loss of function of the protein. The most frequent mutation found in almost half of the families with severe haemophilia A is an inversion of intron 22 with the consequent complete absence of FVIII. An inversion of intron 1 is present in about 3% of severe haemophilia A. Half of the other mutations are large gene alterations, i.e. large deletions or insertions, changes in reading frame or splice site. Mild haemophilia A is more likely caused by missen mutations in exons of the A or C domains. In the freely accessible HAMSTeRS database, short for Haemophilia A Mutation, Structure, Test and Resource Site (http://hadb.org.uk/), the mutations described so far for haemophilia A are compiled. In 2008 the AICE-Genetics haemophilia database was published from Italy, which was able to detect responsible mutations in 90% of patients with haemophilia A. The correlation of genotype to phenotype can provide information about the expected clinical course, in particular the severity of haemophilia and the risk of developing inhibitors. For example, a mutation that leads to a zero allele predisposes to the development of inhibitors in up to 60% of cases, in contrast to Missens mutations with an inhibitor rate of approx. 5%.
Incidence
Haemophilia A affects 1 in 5,000 live-born boys worldwide. There is no difference between countries and races, probably due to the high rate of spontaneous mutations and X‑linked chromosomal inheritance. Haemophilia B is much rarer with an incidence of 1:30’000 boys.
Clinic
The coagulation factors FVIII and FIX are essential components of the plasmatic coagulation cascade and play an important role in secondary hemostasis. Accordingly, the clinical picture of the bleeding tendency is characterized by hematoma tendency, prolonged, renewed bleeding after minor injuries, after tooth extractions or operations.
Children with severe haemophilia A or B are conspicuous from crawling age with large, partly indurated haematomas in exposed body parts, but also in unusual, non-exposed body parts. It is not uncommon for the differential diagnosis to include child abuse in the investigations. More rarely, cerebral haemorrhages are seen, sometimes already neonatal, which are also the main cause of death for haemophiliacs. Long post-bleeding after circumcision of infants is typical. Severe haemophiliacs present from the beginning of the walking age with joint haematomas (preferably knee, hip), which are noticed by limping or sparing a limb. Without the appropriate substitution of the missing coagulation factor, 20–30 bleeding episodes per year can be expected. The course of severe haemophilia is characterized by spontaneous bleeding in joints and muscles. Repeated bleeding into joints leads to haemophilia arthropathy, especially of the large joints. Overall life expectancy is significantly reduced without factor therapy. In developing countries, even today those affected often do not reach adulthood. By optimising factor therapy and patient training, and by reducing the risk of infection with the development of recombinant preparations, life expectancy has increased considerably in industrialised countries in recent decades and is currently over 60 years. The long-term goal of therapy is to prevent or minimize the serious and often disabling haemophilia arthropathy. This requires an interdisciplinary approach with physiotherapists and orthopaedic surgeons.
With moderate and mild haemophilia, the mean age of manifestation is later 5–6 years. The children bleed longer after minor injuries. Sometimes the diagnosis is only made in connection with post-operative bleeding — here again typically circumcision or adenotomy / tonsillectomy — or after accidents, e.g. craniocerebral trauma with unusually heavy bleeding. Spontaneous bleeding rarely occurs in mild haemophilia. The frequency of bleeding varies from 1x per year to 1x in 10 years. In general, bleeding is more common in childhood than in adulthood, which may be related to the pattern of movement and other increased vulnerability of a growing organism.
Diagnostics
In routine tests to determine a bleeding tendency, platelet count, in vitro bleeding time (PFA-100), thrombin time and fibrinogen are normal. The prolonged activated prothrombin time (aPTT) is an indication of the presence of haemophilia A or B, but may be normal in mild haemophilia. The specific factor determination of FVIII or FIX in the presence of a normally high vWF confirms the diagnosis. If the activity of FVIII is borderline 40–80% in the “one-stage” test, a “two-stage” test or chromogenic test can prove the reduced factor activity. In the “one-stage” procedure, different reagents are used with different factor-deficient plasma and different reference plasma samples. The chromogenic test approach is based on a similar principle as the two-stage test and involves a longer preincubation time. Some mutations of the F8 gene lead to a false high result in the “one-stage” test, so that the diagnosis can only be made reliably in the “two-stage” test. In carriers of haemophilia A, a reduced activity of FVIII below 35% is found in about 10%. It should be remembered that FVIII activity may be increased by pregnancy, oral anti-conception, sport or chronic inflammation and that FVIII activity is about 25% lower in people with blood group 0.
Literature:
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