Haemophilia A

Haemophilia A
Deficiency in coagulation factor VIII is the cause of haemophilia A.
Classification and external resources
Specialty	Hematology
ICD-10	D66
ICD-9-CM	286.0
OMIM	306700
DiseasesDB	5555
MedlinePlus	000538
eMedicine	emerg/239
Patient UK	Haemophilia A

Haemophilia A is a genetic deficiency in clotting factor VIII,^[1] which causes increased bleeding and usually affects males. About 70% of the time it is inherited as an X-linked recessive trait, but around 30% of cases arise from spontaneous mutations.

Genetics

Haemophilia A is inherited as an X-linked recessive trait, and thus occurs in males and in homozygous females. However, mild haemophilia A (and B) is known to occur in heterozygous females due to X-inactivation, so it is recommended that levels of factor VIII and IX be measured in all known or potential carriers prior to surgery and in the event of clinically significant bleeding.^[2]

5-10% of patients with haemophilia A are affected because they make a dysfunctional version of the factor VIII protein (qualitative deficiency), while the remainder are affected because they produced factor VIII in insufficient amounts (quantitative deficiency).^[2] Of those who have severe deficiency (defined as <1% activity of factor VIII), 45-50% have the same mutation, an inversion within the factor VIII gene that results in total elimination of protein production.^[2] However, since both forms of haemophilia can be caused by a variety of different mutations, initial diagnosis and classification is done by measurement of protein activity rather than by genetic tests, though genetic tests are recommended for testing of family members once a known case of haemophilia B is identified.^[2]

Approximately 30% of patients have no family history; their disease is presumably caused by new mutations.^[3]

Severity

There are numerous different mutations which cause haemophilia A. Due to differences in changes to the gene involved (and the subsequent resulting protein), patients with haemophilia often have some level of active clotting factor. Individuals with less than 1% active factor are classified as having severe haemophilia, those with 1–5% active factor have moderate haemophilia, and those with mild haemophilia have between 5–40% of normal levels of active clotting factor.^[4]recessive X-linked involve in functional factor IX

Signs and symptoms

Characteristic symptoms vary with severity. In general symptoms are internal or external bleeding episodes, which are called "bleeds".^[5]^[6] Patients with more severe haemophilia suffer more severe and more frequent bleeds, while patients with mild haemophilia typically suffer more minor symptoms except after surgery or serious trauma. Moderate haemophiliacs have variable symptoms which manifest along a spectrum between severe and mild forms.

If forceps or vacuum extraction are used in vaginal births, the first signs of haemophilia may be severe head bruising or haematomas or even intracranial haemorrhage.^[7] Prolonged bleeding from a circumcision wound or a venepuncture or heelprick is another common early sign of haemophilia. These signs may lead to blood tests which indicates haemophilia. In other patients, especially those with moderate or mild haemophilia a later trauma will lead to the first serious bleed.

Haemophilia leads to a severely increased risk of prolonged bleeding from common injuries, or in severe cases bleeds may be spontaneous and without obvious cause. Bleeding may occur anywhere in the body. Superficial bleeding such as those cause by abrasions, or shallow lacerations may be prolonged and the scab may easily be broken up due to the lack of fibrin, which may cause re-bleeding. While superficial bleeding may be troublesome, by far the most serious sites of bleeding are:

Muscle and joint haemorrhages - or haemarthrosis - are indicative of haemophilia, while digestive tract and cerebral haemorrhages are also germane to other coagulation disorders.

Though typically not life-threatening, joint bleeds are one of the most serious symptoms of haemophilia. Repeated bleeds into a joint capsule can cause permanent joint damage and disfigurement resulting in chronic arthritis and disability. Joint damage is not a result of blood in the capsule but rather the healing process. When blood in the joint is broken down by enzymes in the body, the bone in that area is also degraded. Therefore, this exerts massive amounts of pain upon the person afflicted with the disease.

Diagnosis

The diagnosis may be suspected as coagulation testing reveals an increased PTT in the context of a normal PT and bleeding time. PTT tests are the first blood test done when haemophilia is indicated. However, the diagnosis is made in the presence of very low (<10 IU) levels of Factor VIII.

A family history is frequently present, although not essential. Recently, genetic testing has been made available to determine an individual's risk of attaining or passing on hemophilia.

Diagnosis of haemophilia A also includes a severity level which can range from mild to severe based on the amount of active and functioning factor VIII detected in the blood. Factor VIII levels do not typically change throughout an individual's life. Severe haemophilia A is the most common form occurring in 60% of patients. Severe haemophilia A is indicated by active Factor VIII levels less than 1 or 2% Severe haemophiliacs have frequent serious bleeds (20+ times per year), these bleeds often occur spontaneously without trauma or injury. Moderate haemophilia is indicated by active Factor VIII levels between 1–5% and a lower, but variable frequency of bleeding episodes, particularly of spontaneous bleeds. Mild haemophilia is indicated by active Factor VIII levels between 5–25%. Patients with mild haemophilia often experience few or no bleeding episodes except in the case of serious trauma (i.e. compound fracture of a bone), tooth extraction, or surgery.

Differential diagnosis

The two most common differential diagnoses are haemophilia B (also known as Christmas disease) which is a deficiency in Factor IX and von Willebrand Disease which is a deficiency in von Willebrand factor needed for the proper functioning of Factor VIII. Haemophilia C is also a possible, but rare, differential diagnosis.

Therapy

Most severe haemophilia patients require regular supplementation with intravenous recombinant or plasma concentrate Factor VIII. The prophylactic treatment regime is highly variable and individually determined. Apart from "routine" supplementation, extra factor concentrate is given around surgical procedures and after trauma. In children, an easily accessible intravenous port (e.g. Port-a-Cath) may have to be inserted to minimise frequent traumatic intravenous cannulation. These devices have made prophylaxis in haemophilia much easier for families because the problems of "finding a vein" for infusion two to three times a week are eliminated. However, there are risks involved with their use, the most worrisome being that of infection. Studies differ but some show an infection rate as high as 50%. These infections can usually be treated with intravenous antibiotics but sometimes the device must be removed. Also, there are other studies that show a risk of clots forming at the tip of the catheter. Still, many families choose to use the device because of the benefits.

Some patients with severe haemophilia and most with moderate and mild haemophilia treat only as needed without a regular prophylactic schedule. Due to risk of permanent disability, prophylactic treatment is always indicated if a "target joint" (a joint that has repeated bleeding episodes) is identified.

Mild haemophiliacs often manage their condition with desmopressin, which releases stored factor VIII from blood vessel walls.

Complications

A particular therapeutic conundrum is the development of "inhibitor" antibodies against factor VIII due to frequent infusions. These develop as the body recognises the "normal form" factor VIII as foreign, as the body does not have its own "copy". The problem is that in these patients, factor VIII infusions are ineffective. Recently activated factor VII (NovoSeven) has become available as a treatment for haemorrhage in patients with haemophilia and factor inhibitors.

Epidemiology

Haemophilia A (incidence) occurs in approximately 1 in 5,000 males.^[2] The incidence of haemophilia B is 1 in 30,000 in male population.^[2] Of these, 85% have haemophilia A and 15% have hemophilia B.^[2]

References

↑ Merck Manual of Diagnosis and Therapy Home Edition Haemophilia
1 2 3 4 5 6 7 Kliegman, Robert (2011). Nelson textbook of pediatrics. (PDF) (19th ed.). Philadelphia: Saunders. pp. 1700–1. ISBN 978-1-4377-0755-7. Retrieved 8 January 2012.
↑ Bowen, D J (2002). "Haemophilia A and haemophilia B: molecular insights". Molecular Pathology 55 (1): 1–18. doi:10.1136/mp.55.1.1. PMC 1187139. PMID 11836440.
↑ Hemophilia A at eMedicine
↑ Types of Bleeds National Hemophilia Federation.
↑ Key facts: what is hemophilia? The Hemophilia Society.
↑ Kelley, L.A. 2007 "Raising a child with hemophilia: a practical guide for parents, 4th edition." LA Kelley Communications, Inc. USA. Sponsored by CSL Behring.

External links

GeneReviews/NCBI/NIH/UW entry on Hemophilia A

Diseases of clotting (D50–69,74, 280–287)

Coagulation/
coagulopathy

↑

Hyper- coagulability	primary: Antithrombin III deficiency Protein C deficiency/Activated protein C resistance/Protein S deficiency/Factor V Leiden Prothrombin G20210A Sticky platelet syndrome acquired:Thrombocytosis essential DIC Purpura fulminans autoimmune Antiphospholipid

↓

Hypo-
coagulability

Thrombocytopenia	Thrombocytopenic purpura: ITP Evans syndrome TM TTP Upshaw Schulman syndrome Heparin-induced thrombocytopenia May–Hegglin anomaly

Platelet function	adhesion Bernard–Soulier syndrome aggregation Glanzmann's thrombasthenia platelet storage pool deficiency Hermansky–Pudlak syndrome Gray platelet syndrome

Clotting factor	Hemophilia A/VIII B/IX C/XI von Willebrand disease Hypoprothrombinemia/II XIII Dysfibrinogenemia Congenital afibrinogenemia

Sex linkage: X-linked disorders

X-linked recessive

Immune	Chronic granulomatous disease (CYBB) Wiskott–Aldrich syndrome X-linked severe combined immunodeficiency X-linked agammaglobulinemia Hyper-IgM syndrome type 1 IPEX X-linked lymphoproliferative disease Properdin deficiency

Hematologic	Haemophilia A Haemophilia B X-linked sideroblastic anemia

Endocrine	Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy KAL1 Kallmann syndrome X-linked adrenal hypoplasia congenita

Metabolic	Amino acid: Ornithine transcarbamylase deficiency Oculocerebrorenal syndrome Dyslipidemia: Adrenoleukodystrophy Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency Pyruvate dehydrogenase deficiency Danon disease/glycogen storage disease Type IIb Lipid storage disorder: Fabry's disease Mucopolysaccharidosis: Hunter syndrome Purine-pyrimidine metabolism: Lesch–Nyhan syndrome Mineral: Menkes disease/Occipital horn syndrome

Nervous system	X-linked mental retardation: Coffin–Lowry syndrome MASA syndrome X-linked alpha thalassemia mental retardation syndrome Siderius X-linked mental retardation syndrome Eye disorders: Color blindness (red and green, but not blue) Ocular albinism (1) Norrie disease Choroideremia Other: Charcot–Marie–Tooth disease (CMTX2-3) Pelizaeus–Merzbacher disease SMAX2

Skin and related tissue	Dyskeratosis congenita Hypohidrotic ectodermal dysplasia (EDA) X-linked ichthyosis X-linked endothelial corneal dystrophy

Neuromuscular	Becker's muscular dystrophy/Duchenne Centronuclear myopathy (MTM1) Conradi–Hünermann syndrome Emery–Dreifuss muscular dystrophy 1

Urologic	Alport syndrome Dent's disease X-linked nephrogenic diabetes insipidus

Bone/tooth	AMELX Amelogenesis imperfecta

No primary system	Barth syndrome McLeod syndrome Smith–Fineman–Myers syndrome Simpson–Golabi–Behmel syndrome Mohr–Tranebjærg syndrome Nasodigitoacoustic syndrome

X-linked dominant

X-linked hypophosphatemia Focal dermal hypoplasia Fragile X syndrome Aicardi syndrome Incontinentia pigmenti Rett syndrome CHILD syndrome Lujan–Fryns syndrome Orofaciodigital syndrome 1 Craniofrontonasal dysplasia

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