Hemophilia A natural history, complications and prognosis: Difference between revisions
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{{Hemophilia A}} | {{Hemophilia A}} | ||
{{CMG}}{{AE}}{{FNY}} | {{CMG}}{{AE}}{{FNY}} {{VE}} | ||
==Overview== | ==Overview== | ||
[[Hemophilia A|Hemophilia]] presentation varies depending on the stage of the disease.<ref>Severity of Hemophilia – World Federation of Hemophilia. Available at http://www.wfh.org/en/page.aspx?pid=643. Accessed on July 30,2016 </ref> 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]]<ref name="pmid11307831">{{cite journal| author=White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J et al.| title=Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. | journal=Thromb Haemost | year= 2001 | volume= 85 | issue= 3 | pages= 560 | pmid=11307831 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11307831 }}</ref>. | [[Hemophilia A|Hemophilia]] presentation varies depending on the stage of the disease.<ref>Severity of Hemophilia – World Federation of Hemophilia. Available at http://www.wfh.org/en/page.aspx?pid=643. Accessed on July 30,2016 </ref> People with mild hemophilia (5-40% of [[factor VIII]]/ [[Factor IX|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]]<ref name="pmid11307831">{{cite journal| author=White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J et al.| title=Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. | journal=Thromb Haemost | year= 2001 | volume= 85 | issue= 3 | pages= 560 | pmid=11307831 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11307831 }}</ref>. | ||
It is proposed that there are many other determinants beyond factor levels that influence the severity of the disease; these include type of genetic defects, fibrinolytic potential, alterations of other genes involved in hemostasis and inflammatory processes, and age of the patient at the first joint bleeding episode<ref name="pmid24026911">{{cite journal| author=Pavlova A, Oldenburg J| title=Defining severity of hemophilia: more than factor levels. | journal=Semin Thromb Hemost | year= 2013 | volume= 39 | issue= 7 | pages= 702-10 | pmid=24026911 | doi=10.1055/s-0033-1354426 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24026911 }}</ref>. | It is proposed that there are many other determinants beyond factor levels that influence the severity of the disease; these include type of genetic defects, fibrinolytic potential, alterations of other genes involved in hemostasis and inflammatory processes, and age of the patient at the first joint bleeding episode<ref name="pmid24026911">{{cite journal| author=Pavlova A, Oldenburg J| title=Defining severity of hemophilia: more than factor levels. | journal=Semin Thromb Hemost | year= 2013 | volume= 39 | issue= 7 | pages= 702-10 | pmid=24026911 | doi=10.1055/s-0033-1354426 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24026911 }}</ref>. | ||
For many years it was believed that Hemophilia B is practically indistinguishable from Hemophilia A; However, several Recent studies proposed that Hemophilia B is much less severe disease than Hemophilia A when equal factor measures present<ref name="pmid21342368">{{cite journal| author=Nagel K, Walker I, Decker K, Chan AK, Pai MK| title=Comparing bleed frequency and factor concentrate use between haemophilia A and B patients. | journal=Haemophilia | year= 2011 | volume= 17 | issue= 6 | pages= 872-4 | pmid=21342368 | doi=10.1111/j.1365-2516.2011.02506.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21342368 }}</ref><ref name="pmid21042678">{{cite journal| author=Klamroth R, Orlovic M, Kubicek-Hofman C, Gottstein S| title=[Haemophilia A and haemophilia B. Are there relevant clinical differences?]. | journal=Hamostaseologie | year= 2010 | volume= 30 Suppl 1 | issue= | pages= S26-7 | pmid=21042678 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21042678 }}</ref><ref name="pmid19357395">{{cite journal| author=Tagariello G, Iorio A, Santagostino E, Morfini M, Bisson R, Innocenti M et al.| title=Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders. | journal=Blood | year= 2009 | volume= 114 | issue= 4 | pages= 779-84 | pmid=19357395 | doi=10.1182/blood-2009-01-195313 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19357395 }}</ref><ref name="pmid11012692">Ludlam CA, Lee RJ, Prescott RJ, Andrews J, Kirke E, Thomas AE et al. (2000) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11012692 Haemophilia care in central Scotland 1980-94. I. Demographic characteristics, hospital admissions and causes of death.] ''Haemophilia'' 6 (5):494-503. PMID: [https://pubmed.gov/11012692 11012692]</ref>. These studies indicate on lower frequency of bleeding episodes and need for regular prophylaxis and joint arthroplasty surgeries in Hemophilia B patients compared to Hemophilia A. It is of note that the current data still remains inconclusive and more evidence is needed to draw a definite conclusion about this issue<ref name="pmid23517072">{{cite journal| author=Mannucci PM, Franchini M| title=Is haemophilia B less severe than haemophilia A? | journal=Haemophilia | year= 2013 | volume= 19 | issue= 4 | pages= 499-502 | pmid=23517072 | doi=10.1111/hae.12133 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23517072 }}</ref>. | For many years it was believed that [[Hemophilia B]] is practically indistinguishable from Hemophilia A; However, several Recent studies proposed that Hemophilia B is much less severe disease than Hemophilia A when equal factor measures present<ref name="pmid21342368">{{cite journal| author=Nagel K, Walker I, Decker K, Chan AK, Pai MK| title=Comparing bleed frequency and factor concentrate use between haemophilia A and B patients. | journal=Haemophilia | year= 2011 | volume= 17 | issue= 6 | pages= 872-4 | pmid=21342368 | doi=10.1111/j.1365-2516.2011.02506.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21342368 }}</ref><ref name="pmid21042678">{{cite journal| author=Klamroth R, Orlovic M, Kubicek-Hofman C, Gottstein S| title=[Haemophilia A and haemophilia B. Are there relevant clinical differences?]. | journal=Hamostaseologie | year= 2010 | volume= 30 Suppl 1 | issue= | pages= S26-7 | pmid=21042678 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21042678 }}</ref><ref name="pmid19357395">{{cite journal| author=Tagariello G, Iorio A, Santagostino E, Morfini M, Bisson R, Innocenti M et al.| title=Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders. | journal=Blood | year= 2009 | volume= 114 | issue= 4 | pages= 779-84 | pmid=19357395 | doi=10.1182/blood-2009-01-195313 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19357395 }}</ref><ref name="pmid11012692">Ludlam CA, Lee RJ, Prescott RJ, Andrews J, Kirke E, Thomas AE et al. (2000) [https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11012692 Haemophilia care in central Scotland 1980-94. I. Demographic characteristics, hospital admissions and causes of death.] ''Haemophilia'' 6 (5):494-503. PMID: [https://pubmed.gov/11012692 11012692]</ref>. These studies indicate on lower frequency of bleeding episodes and need for regular [[prophylaxis]] and joint [[arthroplasty]] surgeries in Hemophilia B patients compared to Hemophilia A. It is of note that the current data still remains inconclusive and more evidence is needed to draw a definite conclusion about this issue<ref name="pmid23517072">{{cite journal| author=Mannucci PM, Franchini M| title=Is haemophilia B less severe than haemophilia A? | journal=Haemophilia | year= 2013 | volume= 19 | issue= 4 | pages= 499-502 | pmid=23517072 | doi=10.1111/hae.12133 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23517072 }}</ref>. | ||
==Natural History== | ==Natural History== | ||
| Line 25: | Line 25: | ||
Many of the long-term sequelae of hemophilia are either related to the morbidity of severe bleeds, or from side effects of frequent [[transfusions]] | Many of the long-term sequelae of hemophilia are either related to the morbidity of severe bleeds, or from side effects of frequent [[transfusions]] | ||
*Recurrent episodes of hemarthroses can cause [[arthritis]] and eventual destruction of the joint space, bones and cartilages. | *Recurrent episodes of hemarthroses can cause [[arthritis]] and eventual destruction of the joint space, bones and cartilages. | ||
*Frequent transfusions have resulted in high profile cases of hemophiliacs becoming infected with blood-borne viruses (i.e. [[HIV]] and [[Hepatitis C]]). This issue was became very important to the extent that some decades ago, the leading cause of death among Hemophilia patients was AIDS and liver failure due to hepatitis. With improved screening of blood products, the risks of these infections is substantially reduced.<ref>NHF – Guardian of the Nation’s Blood Supply | National Hemophilia Foundation. Available at https://www.hemophilia.org/Bleeding-Disorders/Blood-Safety/NHF-Guardian-of-the-Nations-Blood-Supply. Accessed on Sept 20, 2016 </ref> | *Frequent transfusions have resulted in high profile cases of hemophiliacs becoming infected with blood-borne viruses (i.e. [[HIV]] and [[Hepatitis C]]). This issue was became very important to the extent that some decades ago, the leading cause of death among Hemophilia patients was [[AIDS]] and [[liver failure]] due to [[hepatitis]]. With improved screening of blood products, the risks of these infections is substantially reduced.<ref>NHF – Guardian of the Nation’s Blood Supply | National Hemophilia Foundation. Available at https://www.hemophilia.org/Bleeding-Disorders/Blood-Safety/NHF-Guardian-of-the-Nations-Blood-Supply. Accessed on Sept 20, 2016 </ref> | ||
*Spontaneous intracranial hemorrhage, although rare, is considered a medical emergency that can occur as a complication of hemophilia. | *Spontaneous intracranial hemorrhage, although rare, is considered a medical emergency that can occur as a complication of hemophilia. | ||
*Most important iatrogenic complication of Hemophilia is development of inhibitor antibodies against factor VIII or IX concentrates which are prescribed for prophylaxis and treatment. The development of these inhibitors is reported much more frequently in Hemophilia A rather than B<ref name="pmid29925096">{{cite journal| author=Santoro C, Quintavalle G, Castaman G, Baldacci E, Ferretti A, Riccardi F et al.| title=Inhibitors in Hemophilia B. | journal=Semin Thromb Hemost | year= 2018 | volume= | issue= | pages= | pmid=29925096 | doi=10.1055/s-0038-1660817 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29925096 }}</ref>. | *Most important iatrogenic complication of Hemophilia is development of inhibitor antibodies against factor VIII or IX concentrates which are prescribed for prophylaxis and treatment. The development of these inhibitors is reported much more frequently in Hemophilia A rather than B<ref name="pmid29925096">{{cite journal| author=Santoro C, Quintavalle G, Castaman G, Baldacci E, Ferretti A, Riccardi F et al.| title=Inhibitors in Hemophilia B. | journal=Semin Thromb Hemost | year= 2018 | volume= | issue= | pages= | pmid=29925096 | doi=10.1055/s-0038-1660817 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=29925096 }}</ref><ref name="pmid23818083">{{cite journal| author=Zimmerman B, Valentino LA| title=Hemophilia: in review. | journal=Pediatr Rev | year= 2013 | volume= 34 | issue= 7 | pages= 289-94; quiz 295 | pmid=23818083 | doi=10.1542/pir.34-7-289 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23818083 }}</ref>. | ||
==Prognosis== | ==Prognosis== | ||
With appropriate assistance and education, patients with Hemophilia A 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 replacement therapy. | With appropriate assistance and education, patients with Hemophilia A 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 replacement therapy. | ||
Patients with hemophilia A have approximately twice the mortality rate of healthy male population. Patients with severe hemophilia A have a mortality rate about 4-6 times higher<ref>Hemophilia A | Genetic and Rare Diseases Information Center (GARD) - an NCATS Proggram. Available at https://rarediseases.info.nih.gov/diseases/6591/hemophilia-a#diseasePrognosisSection. Accessed on March 27, 2017 </ref> | Patients with hemophilia A have approximately twice the mortality rate of healthy male population. Patients with severe hemophilia A have a mortality rate about 4-6 times higher<ref>Hemophilia A | Genetic and Rare Diseases Information Center (GARD) - an NCATS Proggram. Available at https://rarediseases.info.nih.gov/diseases/6591/hemophilia-a#diseasePrognosisSection. Accessed on March 27, 2017 </ref> | ||
Latest revision as of 09:19, 29 January 2019
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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] Vahid Eidkhani, M.D.
Overview
Hemophilia presentation varies depending on the stage of the disease.[1] 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[2].
It is proposed that there are many other determinants beyond factor levels that influence the severity of the disease; these include type of genetic defects, fibrinolytic potential, alterations of other genes involved in hemostasis and inflammatory processes, and age of the patient at the first joint bleeding episode[3].
For many years it was believed that Hemophilia B is practically indistinguishable from Hemophilia A; However, several Recent studies proposed that Hemophilia B is much less severe disease than Hemophilia A when equal factor measures present[4][5][6][7]. These studies indicate on lower frequency of bleeding episodes and need for regular prophylaxis and joint arthroplasty surgeries in Hemophilia B patients compared to Hemophilia A. It is of note that the current data still remains inconclusive and more evidence is needed to draw a definite conclusion about this issue[8].
Natural History
- Clinical features are usually related to abnormal or spontaneous bleeding, and can be separated into internal bleeds and external bleeds.[9][10]
- Internal bleeding sites include:
- Hematuria (bleeding from kidneys or bladder)
- Melena or hematochezia (bleeding into the GI tract)
- Hemarthroses and hematomas (bleeding into joints and muscle). this sign is emphasized to be the hallmark of Hemophilia disease.
- Bleeding into the brain (potentially catastrophic)
- External bleeding sites include:
- Heavy bleeding from a minor cut
- Excessive bleeding from surgical or traumatic wound
- Epistaxis or bleeding in gums (though not as commonly seen as in platelet disorders)
- Internal bleeding sites include:
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
- Recurrent episodes of hemarthroses can cause arthritis and eventual destruction of the joint space, bones and cartilages.
- Frequent transfusions have resulted in high profile cases of hemophiliacs becoming infected with blood-borne viruses (i.e. HIV and Hepatitis C). This issue was became very important to the extent that some decades ago, the leading cause of death among Hemophilia patients was AIDS and liver failure due to hepatitis. With improved screening of blood products, the risks of these infections is substantially reduced.[11]
- Spontaneous intracranial hemorrhage, although rare, is considered a medical emergency that can occur as a complication of hemophilia.
- Most important iatrogenic complication of Hemophilia is development of inhibitor antibodies against factor VIII or IX concentrates which are prescribed for prophylaxis and treatment. The development of these inhibitors is reported much more frequently in Hemophilia A rather than B[12][13].
Prognosis
With appropriate assistance and education, patients with Hemophilia A 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 replacement therapy. Patients with hemophilia A have approximately twice the mortality rate of healthy male population. Patients with severe hemophilia A have a mortality rate about 4-6 times higher[14]
References
- ↑ Severity of Hemophilia – World Federation of Hemophilia. Available at http://www.wfh.org/en/page.aspx?pid=643. Accessed on July 30,2016
- ↑ White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J; et al. (2001). "Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis". Thromb Haemost. 85 (3): 560. PMID 11307831.
- ↑ Pavlova A, Oldenburg J (2013). "Defining severity of hemophilia: more than factor levels". Semin Thromb Hemost. 39 (7): 702–10. doi:10.1055/s-0033-1354426. PMID 24026911.
- ↑ Nagel K, Walker I, Decker K, Chan AK, Pai MK (2011). "Comparing bleed frequency and factor concentrate use between haemophilia A and B patients". Haemophilia. 17 (6): 872–4. doi:10.1111/j.1365-2516.2011.02506.x. PMID 21342368.
- ↑ Klamroth R, Orlovic M, Kubicek-Hofman C, Gottstein S (2010). "[Haemophilia A and haemophilia B. Are there relevant clinical differences?]". Hamostaseologie. 30 Suppl 1: S26–7. PMID 21042678.
- ↑ Tagariello G, Iorio A, Santagostino E, Morfini M, Bisson R, Innocenti M; et al. (2009). "Comparison of the rates of joint arthroplasty in patients with severe factor VIII and IX deficiency: an index of different clinical severity of the 2 coagulation disorders". Blood. 114 (4): 779–84. doi:10.1182/blood-2009-01-195313. PMID 19357395.
- ↑ Ludlam CA, Lee RJ, Prescott RJ, Andrews J, Kirke E, Thomas AE et al. (2000) Haemophilia care in central Scotland 1980-94. I. Demographic characteristics, hospital admissions and causes of death. Haemophilia 6 (5):494-503. PMID: 11012692
- ↑ Mannucci PM, Franchini M (2013). "Is haemophilia B less severe than haemophilia A?". Haemophilia. 19 (4): 499–502. doi:10.1111/hae.12133. PMID 23517072.
- ↑ 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
- ↑ NHF – Guardian of the Nation’s Blood Supply | National Hemophilia Foundation. Available at https://www.hemophilia.org/Bleeding-Disorders/Blood-Safety/NHF-Guardian-of-the-Nations-Blood-Supply. Accessed on Sept 20, 2016
- ↑ Santoro C, Quintavalle G, Castaman G, Baldacci E, Ferretti A, Riccardi F; et al. (2018). "Inhibitors in Hemophilia B." Semin Thromb Hemost. doi:10.1055/s-0038-1660817. PMID 29925096.
- ↑ 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.
- ↑ Hemophilia A | Genetic and Rare Diseases Information Center (GARD) - an NCATS Proggram. Available at https://rarediseases.info.nih.gov/diseases/6591/hemophilia-a#diseasePrognosisSection. Accessed on March 27, 2017