Hemophilia A overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fahd Yunus, M.D. [2]
Overview
'''Hemophilia A''' is a blood clotting disorder caused by a mutation of the factor VIII gene, leading to a deficiency in Factor VIII. It is the most common hemophilia. Inheritance is X-linked recessive; hence, males are affected while females are carriers or very rarely display a mild phenotype. 1 in 5,000 males are affected.
"Hemophilia B" is also a blood clotting disorder similar to Hemophilia A to the extent that these two diseases have been considered clinically indistinguishable. Hemophilia B inheritance is also X-linked, however it is caused by the mutation of factor IX gene. The overall clinical severity of Hemophilia B in terms of equal amount of factor deficency is believed to be less severe than Hemophilia A, besides the prevalence of the disease is also lower; 1 in 30,000 males[1].
There is also another type of bleeding disorder related to deficiency of factor XI known as Hemophilia C, it is a rare autosomal disease with usually mild phenotype and is almost exclusively seen in Ashkenazi Jews[2] hence the concentration of our Hemophilia page here is mostly directed towards Hemophilia A and B.
Historical Perspective
Hemophilia is sometimes referred to as “The Royal Disease”, as it affected many members of the English, German, Russian and Spanish monarchies in the 19th and 20th centuries.[3]
In 1947, It was found that blood donations from a Hemophilia patient can cure clotting disorder in another Hemophilia patient. This was the start point to distinguish two major forms of Hemophilia which were later named A and B.
Classification
Hemophilia A and B and C are classified according to the amount of Factor VIII/ IX/ XI present respectively, resulting in either a mild, moderate, or severe form of the disease.[4]
Pathophysiology
Mainly, the pathogenesis of hemophilia A is characterized by genetic deficiency in Factor VIII. And similarly the pathogenesis of hemophilia B is characterized by genetic deficiency in Factor IX. Albeit, not all cases of Hemophilia are genetic disorders and there are several case reports of acquired forms of these diseases.
Causes
Hemophilia A and B are caused by an inherited X-linked recessive trait, with defective genes located on the X chromosome.
Differentiating Hemophilia from Other Diseases
Hemophilia must be differentiated from other diseases that cause abnormal or excessive bleeding.[5]
The most important differential diagnosis of Hemophilia A is that of hemophilia B or von Willebrand disease. The former is usually considered if factor VIII levels are normal in a person with a hemophilia phenotype. The latter is excluded on routine testing for that condition.
Epidemiology and Demographics
The incidence of Hemophilia A is approximately 1 per 5,000 to 10,000 males worldwide. In 2016, it was estimated that 20,000 males in the United States were living with Hemophilia A.The incidence of Hemophilia B is estimated 1 per 30,000 males.[6][1] The incidence of Hemophilia C is populations is estimated to be about 1:1,000,000 worldwide while it is much higher among Ashkenazi Jews (1:450)[2].
Risk Factors
Risk factors for development of Hemophilia include being of male sex and having a positive family history of the disease.
Screening
Screening for Hemophilia revolves around obtaining a thorough family history of bleeding.
Natural History, Complications, and Prognosis
- Hemophilia presentation varies depending on the stage of the disease:[7]
- People with mild hemophilia (5-40% of factor VIII/ IX activity in the blood) generally present with excessive bleeding following surgery (such as a dental procedure) or trauma. They may remain asymptomatic otherwise for long period of time, even into late adulthood
- People with moderate hemophilia (1-5% of factor VIII/ IX activity in the blood) have presentation ranging between mild and severe forms. They present earlier than patients with mild hemophilia, and may bleed following minor trauma
- People with severe hemophilia (less than 1% of factor VIII/ IX in blood) present sooner in life with abnormal bleeding episodes, usually in the first year of life. They are also at risk for spontaneous hemorrhages, i.e. unprovoked bleeding episodes, frequently in the joints and muscles
Natural History
Clinical features are usually related to abnormal or spontaneous bleeding, and can be separated into internal bleeds and external bleeds.[8] [9]
Complications
Many of the long-term sequelae of Hemophilia are either related to the morbidity of severe bleeds, or from side effects of frequent transfusions.
Prognosis
With appropriate assistance and education, patients with Hemophilia can live productive lives, both in terms of longevity and quality of life. The prognosis of these patients is helped greatly with the availability of more effective replacement therapy.
Diagnosis
Diagnostic Criteria
The initial phase of diagnosis is based on clinical findings of bleeding and a positive family history in majority of cases. The diagnosis may be suspected as coagulation testing reveals an increased partial thromboplastin time (PTT) in the context of a normal prothrombin time (PT) and bleeding time.[10] The diagnosis is made in the presence of very low (<10 IU) levels of factor VIII/ IX.
History and Symptoms
Hemophilia leads to a severely increased risk of bleeding from common injuries. Mild hemophilia is usually asymptomatic, unless the patient experiences an injury or undergoes surgery. Bleeding into large joints or muscles is the most common site of bleeding in hemophilia. Though uncommon, spontaneous or traumatic intracranial hemorrhages are the most catastrophic complication of hemophilia.
Physical exam findings in Hemophilia are usually related to the site of bleeding.[11]
Laboratory Findings
The typical coagulation profile of a patient with hemophilia A usually presents as the following:[12]
- Prolonged partial thromboplastin time (PTT)
- Normal prothrombin time
- Normal bleeding time
- Normal fibrinogen level
- Low factor VIII/ IX/ XI
Other laboratory findings consistent with the diagnosis of hemophilia A include correction of the PTT with a 1:1 mixing study (i.e. factor VII/ IX from the normal blood mixed with the hemophiliac blood is able to correct for the coagulation deficit).
Imaging Findings
There are no imaging findings classically associated with Hemophilia.
Other Diagnostic Studies
Genetic testing appears to be a promising means of determining an individual's risk of attaining or passing on Hemophilia.
Treatment
There is no definitive treatment for hemophilia , the mainstay of therapy is supportive and preventative care. It is recommended that patients diagnosed with hemophilia be referred to hemophilia treatment centers (HTC), which provide coordinated care between physicians (usually hematologists), nurses, social workers and other staff who specialize in bleeding disorders.[13]
Medical Therapy
Most Hemophilia patients require regular supplementation with intravenous recombinant factor VIII/ IX, also known as replacement therapy. Apart from "routine" supplementation, extra factor concentrate is given around surgical procedures and after trauma, as well as emergently during any bleeding episode.[14]
Other therapeutic options include cryoprecipitate, fresh frozen plazma (FFP), desmopressin (DDAVP), and anti-fibrinoltytic agents.
Surgery
There is no role for surgery in the routine treatment of Hemophilia. Surgical intervention however may be requ ired in cases where hematomas or bleeds from the disease process cannot be managed conservatively, i.e. with major intracranial hemorrhages
Prevention
There are no established measures for the primary prevention of Hemophilia. Secondary prevention for hemophilia is aimed at preventing spontaneous or excessive bleeds in patients who are high risk, and relies on the use of recombinant clotting factor VIII/ IX administration on a regular basis to prevent bleeding episodes.
References
- ↑ 1.0 1.1 Zimmerman B, Valentino LA (2013). "Hemophilia: in review". Pediatr Rev. 34 (7): 289–94, quiz 295. doi:10.1542/pir.34-7-289. PMID 23818083.
- ↑ 2.0 2.1 Duga S, Salomon O (2013). "Congenital factor XI deficiency: an update". Semin Thromb Hemost. 39 (6): 621–31. doi:10.1055/s-0033-1353420. PMID 23929304.
- ↑ Franchini M, Mannucci PM (2012). "Past, present and future of hemophilia: a narrative review". Orphanet J Rare Dis. 7: 24. doi:10.1186/1750-1172-7-24. PMC 3502605. PMID 22551339.
- ↑ How is Hemophilia Diagnosed? – NHLBI, NIH. Available at http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/diagnosis. Accessed on July 30, 2016
- ↑ Konkle BA, Josephson NC, Nakaya Fletcher S. Hemophilia A. 2000 Sep 21 [Updated 2014 Jun 5]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www-ncbi-nlm-nih-gov.laneproxy.stanford.edu/books/NBK1404/
- ↑ What is Hemophilia? – NHLBI, NIH. Available at http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia. Accessed on Sept 20, 2016
- ↑ Severity of Hemophilia – World Federation of Hemophilia. Available at http://www.wfh.org/en/page.aspx?pid=643. Accessed on July 30,2016
- ↑ What are the signs and symptoms of Hemophilia? – NHLBI, NIH. Available at http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/signs. Accessed on Sept 20, 2016
- ↑ Types of Bleeds | National Hemophilia Foundation. Available at https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeds . Accessed on Sept 20, 2016
- ↑ Cortegiani A, Russotto V, Foresta G, Montalto F, Strano MT, Raineri SM; et al. (2013). "A perioperative uncontrollable bleeding in an elderly patient with acquired hemophilia A: a case report". Clin Case Rep. 1 (1): 3–6. doi:10.1002/ccr3.2. PMC 4184532. PMID 25356200.
- ↑ What are the signs and symptoms of Hemophilia? – NHLBI, NIH. Available at http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/signs. Accessed on Sept 20, 2016
- ↑ Diagnosis | Hemophilia | NCBDDD | CDC. Available at http://www.cdc.gov/ncbddd/hemophilia/diagnosis.html. Accessed on Sept 20, 2016
- ↑ Konkle BA, Josephson NC, Nakaya Fletcher S. Hemophilia A. 2000 Sep 21 [Updated 2014 Jun 5]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: http://www-ncbi-nlm-nih-gov.laneproxy.stanford.edu/books/NBK1404/
- ↑ Treatment of Hemophilia – World Federation of Hemophilia. Available at http://www.wfh.org/en/page.aspx?pid=642. Accessed on Sept 20, 2016