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==Overview==
==Overview==
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 factor===
===Clotting Factor Replacement===
Though there is no cure for haemophilia, it can be controlled with '''regular infusions''' of the deficient clotting factor, i.e. [[factor VIII]] in haemophilia A or [[factor IX]] in haemophilia B. Some haemophiliacs develop antibodies (inhibitors) against the replacement factors given to them, so the amount of the factor has to be increased or non-human replacement products must be given, such as [[porcine]] factor VIII Troy.
*[[Clotting]] factor replacement is the mainstay of hemophilia treatment
 
*The two types of [[clotting]] factor concentrates used as replacement are:
If a patient becomes refractory to replacement coagulation factor as a result of circulating inhibitors, this may be overcome with recombinant human [[factor VII]] (NovoSeven®), which is registered for this indication in many countries.
'''1. Plasma-derived factor concentrates'''
 
*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>
*The two main types of clotting factor concentrates available are:
*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>
**Plasma-Derived Factor Concentrates
'''2. Recombinant factor concentrates'''
 
*These concentrates are [[Genetic engineering|genetically engineered]] with the use of [[DNA]] technology.<ref>https://www.cdc.gov/ncbddd/hemophilia/treatment.html</ref>
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.
*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>
**Recombinant Factor Concentrates
===Complications Clotting Factor Replacement===
 
*Development of inhibitors ([[antibodies]] directed against the [[clotting]] factor concentrates)<ref>https://www.nhlbi.nih.gov/health-topics/hemophilia#Treatment</ref>
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 bloodborne viruses. In addition, recombinant factors VIII (8) and IX (9) are available that do not contain any plasma or albumin and, therefore, cannot transmit any bloodborne viruses.
*[[Transmission (medicine)|Transmission]] of [[Blood-borne disease|bloodborne]] [[Pathogen|pathogens]]<ref>https://www.nhlbi.nih.gov/health-topics/hemophilia#Treatment</ref>
 
===Other Products===
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.
*The other products used as a part of [[Medicine|medical]] [[therapy]] of hemophilia include:
 
'''1. Antifibrinolytics'''
Other treatment products:
*[[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>
**DDAVP® (Desmopressin Acetate)
*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>
 
'''2. 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®).
*[[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>
**Amicar® (Epsilon Amino Caproic Acid)
'''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>
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.
*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>
**Cryoprecipitate
===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>
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.
===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>
In western countries, common standards of care fall into one of two categories: prophylaxis or on-demand. Prophylaxis involves the infusion of clotting factor on a regular schedule in order to keep clotting levels sufficiently high to prevent spontaneous bleeding episodes. On-demand treatment involves treating bleeding episodes once they arise. In 2007, a clinical trial was published in the New England Journal of Medicine comparing on-demand treatment of boys (< 30 months) with Haemophilia A with prophylactic treatment (infusions of 25 IU/kg body weight of [[Factor VIII]] every other day) in respect to its effect on the prevention of joint-diseases. When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group had a normal index joint-structure on [[MRI]]. <ref> Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, Ingram JD, Manco-Johnson ML, Funk S, Jacobson L, Valentino LA, Hoots WK, Buchanan GR, DiMichele D, Recht M, Brown D, Leissinger C, Bleak S, Cohen A, Mathew P, Matsunaga A, Medeiros D, Nugent D, Thomas GA, Thompson AA, McRedmond K, Soucie JM, Austin H, Evatt BL. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe haemophilia. N Engl J Med. 2007 Aug 9;357(6):535-44. PMID 17687129 </ref> Prophylactic treatment, however, resulted in average costs of $300,000 per year. The author of an editorial published in the same issue of the New England Journal of Medicine demands more clinical studies addressing the cost-effectiveness of prophylactic treatment. <ref> Roosendaal G, Lafeber F. Prophylactic treatment for prevention of joint disease in haemophilia--cost versus benefit. N Engl J Med. 2007 Aug 9;357(6):603-5. PMID 17687136  </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>
 
As a direct result of the contamination of the blood supply in the late 1970s and early/mid 1980s with viruses such as [[Hepatitis]] and [[HIV]], new methods were developed in the production of clotting factor products. The initial response was to heat-treat ([[pasteurize]]) plasma-derived factor concentrate, followed by the development of monoclonal factor concentrates, which use a combination of heat treatment and affinity chromatography to inactivate any viral agents in the pooled plasma from which the factor concentrate is derived. The [[Lindsay Tribunal]] in Ireland investigated, among other things, the slow adoption of the new methods.
 
Since 1993 (Dr. Mary Nugent), recombinant factor products (which are typically cultured in Chinese hamster ovary ([[Chinese Hamster Ovary cell|CHO]]) tissue culture cells and involve little, if any human plasma products) have become available and are widely used in wealthier western countries. While recombinant clotting factor products offer higher purity and safety, they are, like concentrate, extremely expensive, and not generally available in the developing world. In many cases, factor products of any sort are difficult to obtain in developing countries.
 
It was claimed that Rasputin was successful at treating the Tsarevich Alexei of Russia's haemophilia: however, to this day it is unclear how he accomplished this.


==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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