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==Overview==
==Overview==
The mainstay of therapy for hemophilia is blood clotting factor replacement therapy.
Clotting factor replacement is the mainstay of hemophilia treatment. [[Blood plasma|Plasma]]-derived factor concentrates and [[Recombinant DNA|recombinant]] factor concentrates are the two types used in the replacement [[therapy]]. Other products used as [[therapy]] include [[Desmopressin acetate (patient information)|desmopressin acetate]], [[Antifibrinolytic|antifibrinolytics]], and [[cryoprecipitate]]. [[Gene therapy]] has the potential to change the course of hemophilia [[therapy]] and [[Medical care|care]].
==Medical Therapy==
==Medical Therapy==
===Blood Clotting factors===
===Clotting Factor Replacement===
*The main treatment for hemophilia is called '''replacement therapy'''. Concentrates of clotting [[factor VIII]] (for hemophilia A) or clotting [[factor IX]] (for [[hemophilia B]]) are slowly dripped or injected into a vein. These infusions help replace the [[clotting factor]] that's missing or low. [[Clotting factor]] concentrates can be made from human blood. The blood is treated to prevent the spread of diseases, such as [[hepatitis]]. With the current methods of screening and treating donated blood, the risk of getting an infectious disease from human clotting factors is very small.
*[[Clotting]] factor replacement is the mainstay of hemophilia treatment
*To further reduce the risk, you or your child can take clotting factor concentrates that aren't made from human blood. These are called '''recombinant clotting factors'''. Clotting factors are easy to store, mix, and use at home—it only takes about 15 minutes to receive the factor.
*The two types of [[clotting]] factor concentrates used as replacement are:
*You may have replacement therapy on a regular basis to prevent bleeding. This is called preventive or prophylactic therapy. Or, you may only need replacement therapy to stop bleeding when it occurs. This use of the treatment, on an as-needed basis, is called '''demand therapy'''. Demand therapy is less intensive and expensive than [[preventive]] therapy. However, there's a risk that bleeding will cause damage before you receive the demand therapy.<ref>{{Cite web | title = NIH Hemophilia Treatment| url =http://www.nhlbi.nih.gov/health/health-topics/topics/hemophilia/treatment}}</ref>
'''1. Plasma-derived factor concentrates'''
*The two main types of [[clotting factor]] concentrates available are:
*It is the primary replacement [[therapy]] in [[Patient|patients]] with hemophilia A in the developing countries.<ref name="pmid30107983">{{cite journal |vauthors=Kevane B, O'Connell N |title=The current and future role of plasma-derived clotting factor concentrate in the treatment of haemophilia A |journal=Transfus. Apher. Sci. |volume=57 |issue=4 |pages=502–506 |date=August 2018 |pmid=30107983 |doi=10.1016/j.transci.2018.07.012 |url=}}</ref><ref name="StonebrakerBrooker2010">{{cite journal|last1=Stonebraker|first1=J. S.|last2=Brooker|first2=M.|last3=Amand|first3=R. E.|last4=Farrugia|first4=A.|last5=Srivastava|first5=A.|title=A study of reported factor VIII use around the world|journal=Haemophilia|volume=16|issue=1|year=2010|pages=33–46|issn=13518216|doi=10.1111/j.1365-2516.2009.02131.x}}</ref>
**'''Plasma-Derived Factor Concentrates''' -Plasma is the liquid part of blood. It is pale yellow or straw colored and contains proteins such as antibodies, [[albumin]] and [[clotting factors]]. Several factor concentrates that are made from human [[plasma proteins]] are available. All blood and parts of blood, such as plasma, are routinely tested for the viruses. The clotting proteins are separated from other parts of the plasma, purified, and made into a freeze-dried product. This product is tested and treated to kill any potential viruses before it is packaged for use.
*Has a lower risk of [[factor VIII]] [[Antibodies|alloantibody]] formation compared to the [[Recombinant DNA|recombinant]] products.<ref name="pmid30107983">{{cite journal |vauthors=Kevane B, O'Connell N |title=The current and future role of plasma-derived clotting factor concentrate in the treatment of haemophilia A |journal=Transfus. Apher. Sci. |volume=57 |issue=4 |pages=502–506 |date=August 2018 |pmid=30107983 |doi=10.1016/j.transci.2018.07.012 |url=}}</ref><ref name="PeyvandiMannucci2016">{{cite journal|last1=Peyvandi|first1=Flora|last2=Mannucci|first2=Pier M.|last3=Garagiola|first3=Isabella|last4=El-Beshlawy|first4=Amal|last5=Elalfy|first5=Mohsen|last6=Ramanan|first6=Vijay|last7=Eshghi|first7=Peyman|last8=Hanagavadi|first8=Suresh|last9=Varadarajan|first9=Ramabadran|last10=Karimi|first10=Mehran|last11=Manglani|first11=Mamta V.|last12=Ross|first12=Cecil|last13=Young|first13=Guy|last14=Seth|first14=Tulika|last15=Apte|first15=Shashikant|last16=Nayak|first16=Dinesh M.|last17=Santagostino|first17=Elena|last18=Mancuso|first18=Maria Elisa|last19=Sandoval Gonzalez|first19=Adriana C.|last20=Mahlangu|first20=Johnny N.|last21=Bonanad Boix|first21=Santiago|last22=Cerqueira|first22=Monica|last23=Ewing|first23=Nadia P.|last24=Male|first24=Christoph|last25=Owaidah|first25=Tarek|last26=Soto Arellano|first26=Veronica|last27=Kobrinsky|first27=Nathan L.|last28=Majumdar|first28=Suvankar|last29=Perez Garrido|first29=Rosario|last30=Sachdeva|first30=Anupam|last31=Simpson|first31=Mindy|last32=Thomas|first32=Mathew|last33=Zanon|first33=Ezio|last34=Antmen|first34=Bulent|last35=Kavakli|first35=Kaan|last36=Manco-Johnson|first36=Marilyn J.|last37=Martinez|first37=Monica|last38=Marzouka|first38=Esperanza|last39=Mazzucconi|first39=Maria G.|last40=Neme|first40=Daniela|last41=Palomo Bravo|first41=Angeles|last42=Paredes Aguilera|first42=Rogelio|last43=Prezotti|first43=Alessandra|last44=Schmitt|first44=Klaus|last45=Wicklund|first45=Brian M.|last46=Zulfikar|first46=Bulent|last47=Rosendaal|first47=Frits R.|title=A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A|journal=New England Journal of Medicine|volume=374|issue=21|year=2016|pages=2054–2064|issn=0028-4793|doi=10.1056/NEJMoa1516437}}</ref><ref name="MakrisKessler2017">{{cite journal|last1=Makris|first1=M.|last2=Kessler|first2=C. M.|title=SIPPET trial: the answers|journal=Haemophilia|volume=23|issue=3|year=2017|pages=344–345|issn=13518216|doi=10.1111/hae.13239}}</ref><ref name="FallonLavin2018">{{cite journal|last1=Fallon|first1=P. G.|last2=Lavin|first2=M.|last3=O'Donnell|first3=J. S.|title=SIPPET: insights into factor VIII immunogenicity|journal=Journal of Thrombosis and Haemostasis|volume=16|issue=1|year=2018|pages=36–38|issn=15387933|doi=10.1111/jth.13886}}</ref>
**'''Recombinant Factor Concentrates'''- Until 1992, all factor replacement products were made from human plasma. In 1992, the U.S. Food and Drug Administration (FDA) approved recombinant [[factor VIII]] (8) concentrate, which does not come from human plasma. The concentrate is genetically engineered using [[DNA]] technology. Commercially prepared factor concentrates are treated to remove or inactivate blood borne viruses. In addition, recombinant [[factor VIII]] (8) and [[factor IX]] (9) are available that do not contain any plasma or [[albumin]] and, therefore, cannot transmit any blood borne viruses.
'''2. Recombinant factor concentrates'''
The products can be used as needed when a person is bleeding or they can be used on a regular basis to prevent bleeds from occurring. Today, people with hemophilia and their families can learn how to give their own clotting factor at home. Giving factor at home means that bleeds can be treated quicker, resulting in less serious bleeding and fewer side effects.
*These concentrates are [[Genetic engineering|genetically engineered]] with the use of [[DNA]] technology.<ref>https://www.cdc.gov/ncbddd/hemophilia/treatment.html</ref>
*Other treatment products:
*The absence of [[Blood plasma|plasma]] and [[albumin]] has paved the way for negative [[Transmission (medicine)|transmission]] of [[Blood-borne disease|bloodborne]] [[Virus|viruses]].<ref>https://www.cdc.gov/ncbddd/hemophilia/treatment.html</ref>
**'''DDAVP® (Desmopressin Acetate)'''-[[DDAVP]]® is a chemical that is similar to a hormone that occurs naturally in the body. It releases [[factor VIII]] (8) from where it is stored in the body tissues. For people with mild, and some cases of moderate hemophilia, this can work to increase their own [[factor VIII]] (8) levels so that they do not have to use [[clotting factor]]. This medicine can be given through a vein (DDAVP®) or through nasal spray (Stimate®).
===Complications Clotting Factor Replacement===
**'''Amicar® (Epsilon Aminocaproic Acid)'''-Amicar® is a chemical that can be given in a vein or by mouth (as a pill or a liquid). It prevents clots from breaking down, resulting in a firmer clot. It is often used for bleeding in the mouth or after a tooth has been removed because it blocks an enzyme in the saliva that breaks down clots.
*Development of inhibitors ([[antibodies]] directed against the [[clotting]] factor concentrates)<ref>https://www.nhlbi.nih.gov/health-topics/hemophilia#Treatment</ref>
**'''Cryoprecipitate'''-Cryoprecipitate is a substance that comes from thawing [[fresh frozen plasma]]. It is rich in [[factor VIII]] (8) and was commonly used to control serious bleeding in the past. However, because there is no method to kill viruses, such as [[HIV]] and[[ hepatitis]], in [[cryoprecipitate]] it is no longer used as the current standard of treatment in the U.S. It is, however, still used in most developing countries.<ref>{{Cite web | title = CDC Hemophilia Treatment| url =http://www.cdc.gov/ncbddd/hemophilia/treatment.html}}</ref>
*[[Transmission (medicine)|Transmission]] of [[Blood-borne disease|bloodborne]] [[Pathogen|pathogens]]<ref>https://www.nhlbi.nih.gov/health-topics/hemophilia#Treatment</ref>
 
===Other Products===
==Gene Therapy==
*The other products used as a part of [[Medicine|medical]] [[therapy]] of hemophilia include:
*Researchers are trying to find ways to correct the faulty genes that cause hemophilia. [[Gene ]]therapy hasn't yet developed to the point that it's an accepted treatment for hemophilia. However, researchers continue to test gene therapy in clinical trials.For more information, go to the "Clinical Trials" section of this article. On 10 December 2011, a team of British and American investigators reported the successful treatment of hemophilia B using [[gene]] therapy. The investigators inserted the ''F9'' [[gene]] into an adeno-associated virus-8 vector, which has a propensity for the [[liver]], where [[factor IX]] is produced, and remains outside the chromosomes so as not to disrupt other [[ genes]]. The transduced virus was infused intravenously. To prevent rejection, the people were primed with steroids to suppress their immune response.  
'''1. Antifibrinolytics'''  
*In October 2013, the Royal Free London NHS Foundation Trust in London reported that after treating six people with hemophilia in early 2011 with the genetically modified [[adeno-associated virus]], over two years later all were still producing blood plasma clotting factor.<ref>{{Cite web | title = Wikipedia Hemophilia Treatment| url =https://en.wikipedia.org/wiki/Haemophilia}}</ref>
*[[Tranexamic acid]] and epsilon amino caproic acid can be used in the [[Medicine|medical]] [[therapy]] of hemophilia<ref name="pmid28338025">{{cite journal |vauthors=Watterson C, Beacher N |title=Preventing perioperative bleeding in patients with inherited bleeding disorders |journal=Evid Based Dent |volume=18 |issue=1 |pages=28–29 |date=March 2017 |pmid=28338025 |doi=10.1038/sj.ebd.6401226 |url=}}</ref><ref name="pmid28338025">{{cite journal |vauthors=Watterson C, Beacher N |title=Preventing perioperative bleeding in patients with inherited bleeding disorders |journal=Evid Based Dent |volume=18 |issue=1 |pages=28–29 |date=March 2017 |pmid=28338025 |doi=10.1038/sj.ebd.6401226 |url=}}</ref>
===Complications of replacement therapy include===
*Especially beneficial in [[Prevention (medical)|preventing]] [[Mouth|oral]] [[bleeding]]<ref name="pmid26704192">{{cite journal |vauthors=van Galen KP, Engelen ET, Mauser-Bunschoten EP, van Es RJ, Schutgens RE |title=Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions |journal=Cochrane Database Syst Rev |volume= |issue=12 |pages=CD011385 |date=December 2015 |pmid=26704192 |doi=10.1002/14651858.CD011385.pub2 |url=}}</ref><ref name="pmid28338025">{{cite journal |vauthors=Watterson C, Beacher N |title=Preventing perioperative bleeding in patients with inherited bleeding disorders |journal=Evid Based Dent |volume=18 |issue=1 |pages=28–29 |date=March 2017 |pmid=28338025 |doi=10.1038/sj.ebd.6401226 |url=}}</ref><ref name="pmid28338025">{{cite journal |vauthors=Watterson C, Beacher N |title=Preventing perioperative bleeding in patients with inherited bleeding disorders |journal=Evid Based Dent |volume=18 |issue=1 |pages=28–29 |date=March 2017 |pmid=28338025 |doi=10.1038/sj.ebd.6401226 |url=}}</ref>
*Developing [[antibodies]] (proteins) that attack the clotting factor
'''2. Desmopressin acetate'''
*Developing viral infections from human clotting factors
*[[Desmopressin acetate (patient information)|Desmopressin acetate]] can be used to [[Prevention (medical)|prevent]] or treat [[bleeding]] episodes in [[Patient|patients]] with hemophilia<ref name="pmid23815950">{{cite journal |vauthors=Franchini M, Mannucci PM |title=Hemophilia A in the third millennium |journal=Blood Rev. |volume=27 |issue=4 |pages=179–84 |date=July 2013 |pmid=23815950 |doi=10.1016/j.blre.2013.06.002 |url=}}</ref><ref name="pmid30004154">{{cite journal |vauthors=Hews-Girard J, Rydz N, Lee A, Goodyear MD, Poon MC |title=Desmopressin in non-severe haemophilia A: Test-response and clinical outcomes in a single Canadian centre review |journal=Haemophilia |volume=24 |issue=5 |pages=720–725 |date=September 2018 |pmid=30004154 |doi=10.1111/hae.13586 |url=}}</ref>
*Damage to joints, muscles, or other parts of the body resulting from delays in treatment
'''3. Cryoprecipitate'''
 
*Effective for mild to moderate [[bleeding]]<ref name="pmid24745720">{{cite journal |vauthors=Lenk H |title=Treatment of haemophilia patients in East Germany prior to and after reunification in 1990 |journal=Thromb. Res. |volume=134 Suppl 1 |issue= |pages=S57–60 |date=November 2014 |pmid=24745720 |doi=10.1016/j.thromres.2013.10.018 |url=}}</ref><ref name="pmid30392819">{{cite journal |vauthors=Jain S, Acharya SS |title=Management of rare coagulation disorders in 2018 |journal=Transfus. Apher. Sci. |volume=57 |issue=6 |pages=705–712 |date=December 2018 |pmid=30392819 |doi=10.1016/j.transci.2018.10.009 |url=}}</ref>
*Can have a [[Prevention (medical)|preventive]] as well as [[Therapy|therapeutic]] action<ref name="pmid24745720">{{cite journal |vauthors=Lenk H |title=Treatment of haemophilia patients in East Germany prior to and after reunification in 1990 |journal=Thromb. Res. |volume=134 Suppl 1 |issue= |pages=S57–60 |date=November 2014 |pmid=24745720 |doi=10.1016/j.thromres.2013.10.018 |url=}}</ref><ref name="pmid24972790">{{cite journal |vauthors=Nascimento B, Goodnough LT, Levy JH |title=Cryoprecipitate therapy |journal=Br J Anaesth |volume=113 |issue=6 |pages=922–34 |date=December 2014 |pmid=24972790 |pmc=4627369 |doi=10.1093/bja/aeu158 |url=}}</ref><ref name="pmid30392819">{{cite journal |vauthors=Jain S, Acharya SS |title=Management of rare coagulation disorders in 2018 |journal=Transfus. Apher. Sci. |volume=57 |issue=6 |pages=705–712 |date=December 2018 |pmid=30392819 |doi=10.1016/j.transci.2018.10.009 |url=}}</ref>
===Immune Tolerance Induction===
*[[Immune tolerance]] can be [[Induction (biology)|induced]] (by daily [[Injection (medicine)|injection]] of large amounts of [[factor VIII]] concentrate) to eradicate [[factor VIII]] inhibitors.<ref name="pmid30545924">{{cite journal |vauthors=Delignat S, Russick J, Gangadharan B, Rayes J, Ing M, Voorberg J, Kaveri SV, Lacroix-Desmazes S |title=Prevention of the anti-factor VIII memory B-cell response by inhibition of the Bruton's tyrosine kinase in experimental hemophilia A |journal=Haematologica |volume= |issue= |pages= |date=December 2018 |pmid=30545924 |doi=10.3324/haematol.2018.200279 |url=}}</ref>
===Gene Therapy===
*[[Gene therapy]] is the transfer of a functional [[gene]] to replace the [[Hemophilia|hemophilic]] defective [[gene]].<ref name="pmid28895852">{{cite journal |vauthors=Nathwani AC, Davidoff AM, Tuddenham EGD |title=Gene Therapy for Hemophilia |journal=Hematol. Oncol. Clin. North Am. |volume=31 |issue=5 |pages=853–868 |date=October 2017 |pmid=28895852 |doi=10.1016/j.hoc.2017.06.011 |url=}}</ref><ref name="pmid29222308">{{cite journal |vauthors=George LA |title=Hemophilia gene therapy comes of age |journal=Hematology Am Soc Hematol Educ Program |volume=2017 |issue=1 |pages=587–594 |date=December 2017 |pmid=29222308 |pmc=6142599 |doi=10.1182/asheducation-2017.1.587 |url=}}</ref>
*This [[therapy]] induces continuous [[Endogeny|endogenous]] expression of [[factor VIII]] or [[Factor IX|IX]].<ref name="pmid28895852">{{cite journal |vauthors=Nathwani AC, Davidoff AM, Tuddenham EGD |title=Gene Therapy for Hemophilia |journal=Hematol. Oncol. Clin. North Am. |volume=31 |issue=5 |pages=853–868 |date=October 2017 |pmid=28895852 |doi=10.1016/j.hoc.2017.06.011 |url=}}</ref><ref name="pmid29222308">{{cite journal |vauthors=George LA |title=Hemophilia gene therapy comes of age |journal=Hematology Am Soc Hematol Educ Program |volume=2017 |issue=1 |pages=587–594 |date=December 2017 |pmid=29222308 |pmc=6142599 |doi=10.1182/asheducation-2017.1.587 |url=}}</ref>


==References==
==References==

Latest revision as of 19:11, 31 May 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Sabawoon Mirwais, M.B.B.S, M.D.[2]

Overview

Clotting factor replacement is the mainstay of hemophilia treatment. Plasma-derived factor concentrates and recombinant factor concentrates are the two types used in the replacement therapy. Other products used as therapy include desmopressin acetate, antifibrinolytics, and cryoprecipitate. Gene therapy has the potential to change the course of hemophilia therapy and care.

Medical Therapy

Clotting Factor Replacement

  • Clotting factor replacement is the mainstay of hemophilia treatment
  • The two types of clotting factor concentrates used as replacement are:

1. Plasma-derived factor concentrates

2. Recombinant factor concentrates

Complications Clotting Factor Replacement

Other Products

  • The other products used as a part of medical therapy of hemophilia include:

1. Antifibrinolytics

2. Desmopressin acetate

3. Cryoprecipitate

Immune Tolerance Induction

Gene Therapy

References

  1. ↑ 1.0 1.1 Kevane B, O'Connell N (August 2018). "The current and future role of plasma-derived clotting factor concentrate in the treatment of haemophilia A". Transfus. Apher. Sci. 57 (4): 502–506. doi:10.1016/j.transci.2018.07.012. PMID 30107983.
  2. ↑ Stonebraker, J. S.; Brooker, M.; Amand, R. E.; Farrugia, A.; Srivastava, A. (2010). "A study of reported factor VIII use around the world". Haemophilia. 16 (1): 33–46. doi:10.1111/j.1365-2516.2009.02131.x. ISSN 1351-8216.
  3. ↑ Peyvandi, Flora; Mannucci, Pier M.; Garagiola, Isabella; El-Beshlawy, Amal; Elalfy, Mohsen; Ramanan, Vijay; Eshghi, Peyman; Hanagavadi, Suresh; Varadarajan, Ramabadran; Karimi, Mehran; Manglani, Mamta V.; Ross, Cecil; Young, Guy; Seth, Tulika; Apte, Shashikant; Nayak, Dinesh M.; Santagostino, Elena; Mancuso, Maria Elisa; Sandoval Gonzalez, Adriana C.; Mahlangu, Johnny N.; Bonanad Boix, Santiago; Cerqueira, Monica; Ewing, Nadia P.; Male, Christoph; Owaidah, Tarek; Soto Arellano, Veronica; Kobrinsky, Nathan L.; Majumdar, Suvankar; Perez Garrido, Rosario; Sachdeva, Anupam; Simpson, Mindy; Thomas, Mathew; Zanon, Ezio; Antmen, Bulent; Kavakli, Kaan; Manco-Johnson, Marilyn J.; Martinez, Monica; Marzouka, Esperanza; Mazzucconi, Maria G.; Neme, Daniela; Palomo Bravo, Angeles; Paredes Aguilera, Rogelio; Prezotti, Alessandra; Schmitt, Klaus; Wicklund, Brian M.; Zulfikar, Bulent; Rosendaal, Frits R. (2016). "A Randomized Trial of Factor VIII and Neutralizing Antibodies in Hemophilia A". New England Journal of Medicine. 374 (21): 2054–2064. doi:10.1056/NEJMoa1516437. ISSN 0028-4793.
  4. ↑ Makris, M.; Kessler, C. M. (2017). "SIPPET trial: the answers". Haemophilia. 23 (3): 344–345. doi:10.1111/hae.13239. ISSN 1351-8216.
  5. ↑ Fallon, P. G.; Lavin, M.; O'Donnell, J. S. (2018). "SIPPET: insights into factor VIII immunogenicity". Journal of Thrombosis and Haemostasis. 16 (1): 36–38. doi:10.1111/jth.13886. ISSN 1538-7933.
  6. ↑ https://www.cdc.gov/ncbddd/hemophilia/treatment.html
  7. ↑ https://www.cdc.gov/ncbddd/hemophilia/treatment.html
  8. ↑ https://www.nhlbi.nih.gov/health-topics/hemophilia#Treatment
  9. ↑ https://www.nhlbi.nih.gov/health-topics/hemophilia#Treatment
  10. ↑ 10.0 10.1 10.2 10.3 Watterson C, Beacher N (March 2017). "Preventing perioperative bleeding in patients with inherited bleeding disorders". Evid Based Dent. 18 (1): 28–29. doi:10.1038/sj.ebd.6401226. PMID 28338025.
  11. ↑ van Galen KP, Engelen ET, Mauser-Bunschoten EP, van Es RJ, Schutgens RE (December 2015). "Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions". Cochrane Database Syst Rev (12): CD011385. doi:10.1002/14651858.CD011385.pub2. PMID 26704192.
  12. ↑ Franchini M, Mannucci PM (July 2013). "Hemophilia A in the third millennium". Blood Rev. 27 (4): 179–84. doi:10.1016/j.blre.2013.06.002. PMID 23815950.
  13. ↑ Hews-Girard J, Rydz N, Lee A, Goodyear MD, Poon MC (September 2018). "Desmopressin in non-severe haemophilia A: Test-response and clinical outcomes in a single Canadian centre review". Haemophilia. 24 (5): 720–725. doi:10.1111/hae.13586. PMID 30004154.
  14. ↑ 14.0 14.1 Lenk H (November 2014). "Treatment of haemophilia patients in East Germany prior to and after reunification in 1990". Thromb. Res. 134 Suppl 1: S57–60. doi:10.1016/j.thromres.2013.10.018. PMID 24745720.
  15. ↑ 15.0 15.1 Jain S, Acharya SS (December 2018). "Management of rare coagulation disorders in 2018". Transfus. Apher. Sci. 57 (6): 705–712. doi:10.1016/j.transci.2018.10.009. PMID 30392819.
  16. ↑ Nascimento B, Goodnough LT, Levy JH (December 2014). "Cryoprecipitate therapy". Br J Anaesth. 113 (6): 922–34. doi:10.1093/bja/aeu158. PMC 4627369. PMID 24972790.
  17. ↑ Delignat S, Russick J, Gangadharan B, Rayes J, Ing M, Voorberg J, Kaveri SV, Lacroix-Desmazes S (December 2018). "Prevention of the anti-factor VIII memory B-cell response by inhibition of the Bruton's tyrosine kinase in experimental hemophilia A". Haematologica. doi:10.3324/haematol.2018.200279. PMID 30545924.
  18. ↑ 18.0 18.1 Nathwani AC, Davidoff AM, Tuddenham E (October 2017). "Gene Therapy for Hemophilia". Hematol. Oncol. Clin. North Am. 31 (5): 853–868. doi:10.1016/j.hoc.2017.06.011. PMID 28895852. Vancouver style error: initials (help)
  19. ↑ 19.0 19.1 George LA (December 2017). "Hemophilia gene therapy comes of age". Hematology Am Soc Hematol Educ Program. 2017 (1): 587–594. doi:10.1182/asheducation-2017.1.587. PMC 6142599. PMID 29222308.

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