Hemophilia pathophysiology: Difference between revisions

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{{Hemophilia}}
{{Hemophilia}}
{{CMG}};{{AE}} {{Simrat}}
{{CMG}};{{AE}} {{Sab}}{{FNY}}


==Overview==
==Overview==
Hemophilia is a [[Genetic disorder|genetic bleeding disorder]] resulting from the insufficient levels of [[Coagulation|clotting factors]] in the [[Human body|body]]. The [[Coagulation|clotting factors]] irregularity causes a lack of [[Coagulation|clumping of blood]] required to form a [[Thrombus|clot]] to plug a site of a [[wound]]. The [[genes]] involved in the [[pathogenesis]] of hemophilia include the'' F8 ''[[gene]] in [[hemophilia A]] and'' F9'' [[gene]] in [[hemophilia B]] and [[Hemophilia C|C]]. Hemophilia predominantly affects the male population but the sub-type [[hemophilia C]], with an [[Autosome|autosomal]] [[Heredity|inheritance]] pattern, can affect the males as well as females.
Hemophilia is a [[Genetic disorder|genetic bleeding disorder]] resulting from the insufficient levels of [[Coagulation|clotting factors]] in the [[Human body|body]]. The [[Coagulation|clotting factors]] irregularity causes a lack of [[Coagulation|clumping of blood]] required to form a [[Thrombus|clot]] to plug a site of a [[wound]]. The [[genes]] involved in the [[pathogenesis]] of hemophilia include the'' F8 ''[[gene]] in [[hemophilia A]], '' F9'' [[gene]] in [[hemophilia B]], and ''F11'' [[gene]] in [[Hemophilia C|C]]. Hemophilia predominantly affects the male population but the sub-type [[hemophilia C]], with an [[Autosome|autosomal]] [[Heredity|inheritance]] pattern, can affect the males as well as females.


==Pathophysiology==
==Pathophysiology==
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*The process of [[hemostasis]] involves a fine balance between the [[Coagulation|procoagulant]] and [[anticoagulant]] factors. It attempts to maintain [[blood flow]] within the [[vascular]] compartment and promotes the formation of [[Thrombus|blood clots]] following [[vascular injury]].<ref name="pmid17243907">{{cite journal |vauthors=Lippi G, Franchini M, Guidi GC |title=Diagnostic approach to inherited bleeding disorders |journal=Clin. Chem. Lab. Med. |volume=45 |issue=1 |pages=2–12 |date=2007 |pmid=17243907 |doi=10.1515/CCLM.2007.006 |url=}}</ref>
*The process of [[hemostasis]] involves a fine balance between the [[Coagulation|procoagulant]] and [[anticoagulant]] factors. It attempts to maintain [[blood flow]] within the [[vascular]] compartment and promotes the formation of [[Thrombus|blood clots]] following [[vascular injury]].<ref name="pmid17243907">{{cite journal |vauthors=Lippi G, Franchini M, Guidi GC |title=Diagnostic approach to inherited bleeding disorders |journal=Clin. Chem. Lab. Med. |volume=45 |issue=1 |pages=2–12 |date=2007 |pmid=17243907 |doi=10.1515/CCLM.2007.006 |url=}}</ref>
*It also enables repair after [[vascular injury]], promotes [[Blood vessel|vessel]] healing, and maintains [[Blood vessel|vessel]] integrity.
*It also enables repair after [[vascular injury]], promotes [[Blood vessel|vessel]] healing, and maintains [[Blood vessel|vessel]] integrity.
*[[Hemostasis]] can be divided into three phases. Each phase is explained as follows:
*[[Hemostasis]] can be divided into three phases
**Each phase is explained as follows:
'''1. Primary hemostasis'''
'''1. Primary hemostasis'''
*[[Endothelium|Endothelial]] damage marks the beginning of this phase.<ref>{{cite book | last = Favaloro | first = Emmanuel | title = Hemostasis and thrombosis : methods and protocols | publisher = Humana Press Springer | location = New York | year = 2017 | isbn = 9781493971961 }}</ref>
*[[Endothelium|Endothelial]] damage marks the beginning of this phase.<ref>{{cite book | last = Favaloro | first = Emmanuel | title = Hemostasis and thrombosis : methods and protocols | publisher = Humana Press Springer | location = New York | year = 2017 | isbn = 9781493971961 }}</ref>
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'''3. Fibrinolysis'''
'''3. Fibrinolysis'''
*[[Fibrinolysis]] involves the process of [[Physiology|physiological]] [[lysis]] of the [[Thrombus|clot]], generated by the actions of primary and secondary hemostasis, to permit [[Tissue (biology)|tissue]] repair under the supervision and help of multiple [[Protein|proteins]].<ref name="pmid28253534">{{cite journal |vauthors=Kwaan H, Lisman T, Medcalf RL |title=Fibrinolysis: Biochemistry, Clinical Aspects, and Therapeutic Potential |journal=Semin. Thromb. Hemost. |volume=43 |issue=2 |pages=113–114 |date=March 2017 |pmid=28253534 |doi=10.1055/s-0036-1598000 |url=}}</ref>
*[[Fibrinolysis]] involves the process of [[Physiology|physiological]] [[lysis]] of the [[Thrombus|clot]], generated by the actions of primary and secondary hemostasis, to permit [[Tissue (biology)|tissue]] repair under the supervision and help of multiple [[Protein|proteins]].<ref name="pmid28253534">{{cite journal |vauthors=Kwaan H, Lisman T, Medcalf RL |title=Fibrinolysis: Biochemistry, Clinical Aspects, and Therapeutic Potential |journal=Semin. Thromb. Hemost. |volume=43 |issue=2 |pages=113–114 |date=March 2017 |pmid=28253534 |doi=10.1055/s-0036-1598000 |url=}}</ref>
===Cell-Based Model of Coagulation===
====Cell-Based Model of Coagulation====
*The [[Cell (biology)|cell]]-based model of [[hemostasis]] basically says that [[blood]] has to be exposed to [[Cell (biology)|cells]] containing the [[Tissue factor|tissue factor (TF)]] for the initiation of the [[Coagulation|clotting process]].<ref name="Hoffman2003">{{cite journal|last1=Hoffman|first1=Maureane|title=A cell-based model of coagulation and the role of factor VIIa|journal=Blood Reviews|volume=17|year=2003|pages=S1–S5|issn=0268960X|doi=10.1016/S0268-960X(03)90000-2}}</ref>
*The [[Cell (biology)|cell]]-based model of [[hemostasis]] basically says that [[blood]] has to be exposed to [[Cell (biology)|cells]] containing the [[Tissue factor|tissue factor (TF)]] for the initiation of the [[Coagulation|clotting process]].<ref name="Hoffman2003">{{cite journal|last1=Hoffman|first1=Maureane|title=A cell-based model of coagulation and the role of factor VIIa|journal=Blood Reviews|volume=17|year=2003|pages=S1–S5|issn=0268960X|doi=10.1016/S0268-960X(03)90000-2}}</ref>
*It better reflects true [[in vivo]] [[hemostasis]].
*It better reflects true [[in vivo]] [[hemostasis]].
*The model proposes three overlapping phases of [[hemostasis]] which are explained as follows:
*The model proposes three overlapping phases of [[hemostasis]] which are explained as follows:
'''a. Initiation'''
'''a. Initiation'''
*It occurs on the surface of the [[tissue factor]]-bearing cell.
*It occurs on the surface of the [[tissue factor]]-bearing [[Cell (biology)|cell]].
*[[Tissue factor]]-bearing cells such as the [[Fibroblast|fibroblasts]] bind to the surface of [[Platelet|platelets]] in an evolving [[thrombus]].<ref name="Hoffman2003">{{cite journal|last1=Hoffman|first1=Maureane|title=A cell-based model of coagulation and the role of factor VIIa|journal=Blood Reviews|volume=17|year=2003|pages=S1–S5|issn=0268960X|doi=10.1016/S0268-960X(03)90000-2}}</ref>
*[[Tissue factor]]-bearing cells such as the [[Fibroblast|fibroblasts]] bind to the surface of [[Platelet|platelets]] in an evolving [[thrombus]].<ref name="Hoffman2003">{{cite journal|last1=Hoffman|first1=Maureane|title=A cell-based model of coagulation and the role of factor VIIa|journal=Blood Reviews|volume=17|year=2003|pages=S1–S5|issn=0268960X|doi=10.1016/S0268-960X(03)90000-2}}</ref>
*[[Factor VII]] comes into direct contact with the [[tissue factor]]-bearing [[Vascular|extravascular]] [[Cell (biology)|cells]] during [[vascular injury]], and rapidly undergoes activation via the [[Coagulation|extrinsic pathway]].  
*[[Factor VII]] comes into direct contact with the [[tissue factor]]-bearing [[Vascular|extravascular]] [[Cell (biology)|cells]] during [[vascular injury]], and rapidly undergoes activation via the [[Coagulation|extrinsic pathway]].  
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===Pathogenesis===
===Pathogenesis===
*
*Hemophilia is an [[Sex linkage|X-linked]] [[bleeding]] disorder caused by a [[deficiency]] or complete absence of [[Factor VIII|coagulation factor VIII]] (hemophilia A) or [[factor IX]] (hemophilia B).<ref name="pmid11396445">{{cite journal |vauthors=Mannucci PM, Tuddenham EG |title=The hemophilias--from royal genes to gene therapy |journal=N. Engl. J. Med. |volume=344 |issue=23 |pages=1773–9 |date=June 2001 |pmid=11396445 |doi=10.1056/NEJM200106073442307 |url=}}</ref>
*[[Bleeding]] in hemophilia occurs due to the failure of [[Coagulation|secondary hemostasis]].<ref name="Bolton-MaggsPasi2003">{{cite journal|last1=Bolton-Maggs|first1=Paula HB|last2=Pasi|first2=K John|title=Haemophilias A and B|journal=The Lancet|volume=361|issue=9371|year=2003|pages=1801–1809|issn=01406736|doi=10.1016/S0140-6736(03)13405-8}}</ref>
*[[Coagulation|Primary hemostasis]] and the formation of [[platelet]] plug occurs normally but stabilization of the plug by [[fibrin]] is [[Defect|defective]] because of the [[generation]] of inadequate amounts of [[thrombin]].<ref name="Bolton-MaggsPasi2003">{{cite journal|last1=Bolton-Maggs|first1=Paula HB|last2=Pasi|first2=K John|title=Haemophilias A and B|journal=The Lancet|volume=361|issue=9371|year=2003|pages=1801–1809|issn=01406736|doi=10.1016/S0140-6736(03)13405-8}}</ref>
*[[Clinical]] expression of hemophilia usually correlates with the activity of the [[coagulation]] factor and the [[disease]] can be classified as:
:*Mild (factor level > 0.05–0.40 IU/mL)
:*Moderate (factor level = 0.01–0.05 IU/mL)
:*Severe (factor level < 0.01 IU/mL)
*Excessive [[bleeding]] in mild hemophilia [[Patient|patients]] occurs only after major injuries, [[surgery]], or other [[Invasive (medical)|invasive]] [[Surgery|procedures]].<ref name="pmid11396445">{{cite journal |vauthors=Mannucci PM, Tuddenham EG |title=The hemophilias--from royal genes to gene therapy |journal=N. Engl. J. Med. |volume=344 |issue=23 |pages=1773–9 |date=June 2001 |pmid=11396445 |doi=10.1056/NEJM200106073442307 |url=}}</ref>
*In [[Patient|patients]] with moderate hemophilia, [[Hemarthrosis|hemarthroses]] and muscle [[Hematoma|hematomas]] may occur after relatively minor [[Injury|injuries]].<ref name="pmid11396445">{{cite journal |vauthors=Mannucci PM, Tuddenham EG |title=The hemophilias--from royal genes to gene therapy |journal=N. Engl. J. Med. |volume=344 |issue=23 |pages=1773–9 |date=June 2001 |pmid=11396445 |doi=10.1056/NEJM200106073442307 |url=}}</ref>
*[[Bleeding]] occurs frequently and spontaneously in [[Patient|patients]] with severe hemophilia and this group can rarely also experience life-threatening episodes such as [[Retroperitoneum|retroperitoneal]] and [[Intracranial hemorrhage|intracranial bleeds]].<ref name="pmid11396445">{{cite journal |vauthors=Mannucci PM, Tuddenham EG |title=The hemophilias--from royal genes to gene therapy |journal=N. Engl. J. Med. |volume=344 |issue=23 |pages=1773–9 |date=June 2001 |pmid=11396445 |doi=10.1056/NEJM200106073442307 |url=}}</ref><ref name="pmid22456059">{{cite journal |vauthors=Berntorp E, Shapiro AD |title=Modern haemophilia care |journal=Lancet |volume=379 |issue=9824 |pages=1447–56 |date=April 2012 |pmid=22456059 |doi=10.1016/S0140-6736(11)61139-2 |url=}}</ref>
*Peculiar [[pathology]] of the types of hemophilia is discussed below:


==Genes affected in Hemophilia==
====Hemophilia A====
*Changes in the ''F8'' [[gene]] are responsible for hemophilia A, while mutations in the ''F9'' gene cause hemophilia B. The ''F8'' gene provides instructions for making a protein called coagulation [[factor VIII]]. A related protein, coagulation [[factor IX]], is produced from the ''F9'' gene. Coagulation factors are proteins that work together in the blood clotting process. After an injury, blood clots protect the body by sealing off damaged blood vessels and preventing excessive blood loss.
*Hemophilia A is caused by an absence or deficiency of [[Factor VIII|factor VIII (FVIII) protein]] activity.<ref name="OldenburgEl-Maarri2006">{{cite journal|last1=Oldenburg|first1=Johannes|last2=El-Maarri|first2=Osman|title=New Insight into the Molecular Basis of Hemophilia A|journal=International Journal of Hematology|volume=83|issue=2|year=2006|pages=96–102|issn=0925-5710|doi=10.1532/IJH97.06012}}</ref>
*It is a lifetime [[disease]] that is [[Transmittance|transmitted]] from usually asymptomatic carrier females to their male offspring.<ref name="OldenburgEl-Maarri2006">{{cite journal|last1=Oldenburg|first1=Johannes|last2=El-Maarri|first2=Osman|title=New Insight into the Molecular Basis of Hemophilia A|journal=International Journal of Hematology|volume=83|issue=2|year=2006|pages=96–102|issn=0925-5710|doi=10.1532/IJH97.06012}}</ref>
*Hemophilia A is characterized by recurrent [[bleeding]], in particular into [[Joint|joints]].<ref name="Bolton-MaggsPasi2003">{{cite journal|last1=Bolton-Maggs|first1=Paula HB|last2=Pasi|first2=K John|title=Haemophilias A and B|journal=The Lancet|volume=361|issue=9371|year=2003|pages=1801–1809|issn=01406736|doi=10.1016/S0140-6736(03)13405-8}}</ref>
*The recurrent [[bleeding]] in [[Joint|joints]] leads almost inevitably to severe [[arthropathy]].<ref name="pmid16684006">{{cite journal |vauthors=Roosendaal G, Lafeber FP |title=Pathogenesis of haemophilic arthropathy |journal=Haemophilia |volume=12 Suppl 3 |issue= |pages=117–21 |date=July 2006 |pmid=16684006 |doi=10.1111/j.1365-2516.2006.01268.x |url=}}</ref>
*The [[Molecule|molecular]] causes of [[Factor VIII|FVIII]] [[deficiency]] can be divided into 3 main categories:
#Classic [[Mutation|mutations]] in the ''F8'' [[gene]] that cause structural changes in the [[Factor VIII|FVIII]] [[molecule]] or even produce a truncated [[protein]] lacking essential functional [[Protein domains|domains]].<ref name="pmid9020152">{{cite journal |vauthors=Morris JA, Dorner AJ, Edwards CA, Hendershot LM, Kaufman RJ |title=Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins |journal=J. Biol. Chem. |volume=272 |issue=7 |pages=4327–34 |date=February 1997 |pmid=9020152 |doi= |url=}}</ref><ref name="pmid9525969">{{cite journal |vauthors=Pipe SW, Morris JA, Shah J, Kaufman RJ |title=Differential interaction of coagulation factor VIII and factor V with protein chaperones calnexin and calreticulin |journal=J. Biol. Chem. |volume=273 |issue=14 |pages=8537–44 |date=April 1998 |pmid=9525969 |doi= |url=}}</ref>
#[[Mutation|Mutations]] in [[Protein|proteins]] that interact [[Intracellular|intracellularly]] in the correct [[Protein folding|folding]] and trafficking of the [[Factor VIII|FVIII]] protein or [[Mutation|mutations]] in [[extracellular]] [[Blood plasma|plasma]] proteins such as [[Von Willebrand factor|von Willebrand factor (VWF)]].<ref name="pmid9546392">{{cite journal |vauthors=Nichols WC, Seligsohn U, Zivelin A, Terry VH, Hertel CE, Wheatley MA, Moussalli MJ, Hauri HP, Ciavarella N, Kaufman RJ, Ginsburg D |title=Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII |journal=Cell |volume=93 |issue=1 |pages=61–70 |date=April 1998 |pmid=9546392 |doi= |url=}}</ref><ref name="pmid12717434">{{cite journal |vauthors=Zhang B, Cunningham MA, Nichols WC, Bernat JA, Seligsohn U, Pipe SW, McVey JH, Schulte-Overberg U, de Bosch NB, Ruiz-Saez A, White GC, Tuddenham EG, Kaufman RJ, Ginsburg D |title=Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex |journal=Nat. Genet. |volume=34 |issue=2 |pages=220–5 |date=June 2003 |pmid=12717434 |doi=10.1038/ng1153 |url=}}</ref><ref name="pmid2506947">{{cite journal |vauthors=Nishino M, Girma JP, Rothschild C, Fressinaud E, Meyer D |title=New variant of von Willebrand disease with defective binding to factor VIII |journal=Blood |volume=74 |issue=5 |pages=1591–9 |date=October 1989 |pmid=2506947 |doi= |url=}}</ref><ref name="pmid1832934">{{cite journal |vauthors=Gaucher C, Mercier B, Jorieux S, Oufkir D, Mazurier C |title=Identification of two point mutations in the von Willebrand factor gene of three families with the 'Normandy' variant of von Willebrand disease |journal=Br. J. Haematol. |volume=78 |issue=4 |pages=506–14 |date=August 1991 |pmid=1832934 |doi= |url=}}</ref>
#The third category encompasses [[Patient|patients]] who have the clinical [[disease]] but have no [[Mutation|mutations]] in the ''F8'' [[gene]] or in any of the known interacting partners.<ref name="OldenburgEl-Maarri2006">{{cite journal|last1=Oldenburg|first1=Johannes|last2=El-Maarri|first2=Osman|title=New Insight into the Molecular Basis of Hemophilia A|journal=International Journal of Hematology|volume=83|issue=2|year=2006|pages=96–102|issn=0925-5710|doi=10.1532/IJH97.06012}}</ref>
*Less than 1/3 of the [[Patient|patients]] (mostly [[Old age|elderly]] with [[Comorbidity|comorbidities]]) of hemophilia develop [[Autoantibody|autoantibodies]] (inhibitors) against [[Factor VIII|factor VIII (FVIII)]] that can lead to spontaneous and severe [[bleeding]].<ref name="pmid28470674">{{cite journal |vauthors=Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, Tiede A, Kessler CM |title=Acquired hemophilia A: Updated review of evidence and treatment guidance |journal=Am. J. Hematol. |volume=92 |issue=7 |pages=695–705 |date=July 2017 |pmid=28470674 |doi=10.1002/ajh.24777 |url=}}</ref><ref name="pmid30562791">{{cite journal |vauthors=Yang F, Zhou YS, Jia Y |title=[Systemic lupus erythematosus with acquired hemophilia A: a case report] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=50 |issue=6 |pages=1108–1111 |date=December 2018 |pmid=30562791 |doi= |url=}}</ref>


*Mutations in the ''F8'' or ''F9'' gene lead to the production of an abnormal version of coagulation factor VIII or coagulation factor IX, or reduce the amount of one of these proteins. The altered or missing protein cannot participate effectively in the blood clotting process. As a result, blood clots cannot form properly in response to injury. These problems with blood clotting lead to continuous bleeding that can be difficult to control. The mutations that cause severe hemophilia almost completely eliminate the activity of coagulation factor VIII or coagulation factor IX. The mutations responsible for mild and moderate hemophilia reduce but do not eliminate the activity of one of these proteins.
====Hemophilia B====
*Hemophilia B is an [[Sex linkage|X-linked]] bleeding disorder caused by the [[deficiency]] of [[Factor IX|factor IX (FIX)]].<ref name="CastamanBonetti2013">{{cite journal|last1=Castaman|first1=G.|last2=Bonetti|first2=E.|last3=Messina|first3=M.|last4=Morfini|first4=M.|last5=Rocino|first5=A.|last6=Scaraggi|first6=F. A.|last7=Tagariello|first7=G.|title=Inhibitors in haemophilia B: the Italian experience|journal=Haemophilia|volume=19|issue=5|year=2013|pages=686–690|issn=13518216|doi=10.1111/hae.12158}}</ref>
*[[Factor IX]] is a [[vitamin K]]–dependent [[Blood plasma|plasma]] [[protease]] that plays a role in the [[Coagulation|intrinsic pathway]] of [[hemostasis]] and whose function is to cleave and activate [[Factor X]].<ref name="pmid25851415">{{cite journal |vauthors=Goodeve AC |title=Hemophilia B: molecular pathogenesis and mutation analysis |journal=J. Thromb. Haemost. |volume=13 |issue=7 |pages=1184–95 |date=July 2015 |pmid=25851415 |pmc=4496316 |doi=10.1111/jth.12958 |url=}}</ref>
*[[Bleeding]] tendency in hemophilia B is in good accordance with the severity of factor [[deficiency]].<ref name="pmid19515028">{{cite journal |vauthors=Chitlur M, Warrier I, Rajpurkar M, Lusher JM |title=Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997-2006) |journal=Haemophilia |volume=15 |issue=5 |pages=1027–31 |date=September 2009 |pmid=19515028 |doi=10.1111/j.1365-2516.2009.02039.x |url=}}</ref>
*[[Patient|Patients]] with the severe form ([[Factor IX]] <1%), a significant proportion of 30 to 45% of all affected by hemophilia B, usually suffer from recurrent [[joint]], [[Soft tissue|soft-tissue]], and [[muscle]] [[Bleeding|bleeds]].<ref name="pmid19515028">{{cite journal |vauthors=Chitlur M, Warrier I, Rajpurkar M, Lusher JM |title=Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997-2006) |journal=Haemophilia |volume=15 |issue=5 |pages=1027–31 |date=September 2009 |pmid=19515028 |doi=10.1111/j.1365-2516.2009.02039.x |url=}}</ref>
====Hemophilia C====
*Hemophilia C is an [[autosomal]] [[genetic disorder]] involving a lack of functional [[factor XI|clotting factor XI]].<ref name="pmid23610841">{{cite journal |vauthors=Shearin-Patterson T, Davidson E |title=Hemophilia C |journal=JAAPA |volume=26 |issue=4 |pages=50 |date=April 2013 |pmid=23610841 |doi= |url=}}</ref>
*This condition is not completely [[recessive]], as [[heterozygous]] individuals also show increased [[bleeding]].<ref name="pmid23610841">{{cite journal |vauthors=Shearin-Patterson T, Davidson E |title=Hemophilia C |journal=JAAPA |volume=26 |issue=4 |pages=50 |date=April 2013 |pmid=23610841 |doi= |url=}}</ref>
*The [[bleeding]] diathesis in hemophilia C is considerably milder than in hemophilia A or B.<ref name="pmid23929304">{{cite journal |vauthors=Duga S, Salomon O |title=Congenital factor XI deficiency: an update |journal=Semin. Thromb. Hemost. |volume=39 |issue=6 |pages=621–31 |date=September 2013 |pmid=23929304 |doi=10.1055/s-0033-1353420 |url=}}</ref><ref name="pmid20008187">{{cite journal |vauthors=Bolton-Maggs PH |title=Factor XI deficiency--resolving the enigma? |journal=Hematology Am Soc Hematol Educ Program |volume= |issue= |pages=97–105 |date=2009 |pmid=20008187 |doi=10.1182/asheducation-2009.1.97 |url=}}</ref>
*The spontaneous [[soft tissue]] [[Bleeding|bleeds]] and [[Hemarthrosis|hemarthroses]] characteristic of hemophilia A and B are not features of hemophilia C.<ref name="pmid27216469">{{cite journal |vauthors=Wheeler AP, Gailani D |title=Why factor XI deficiency is a clinical concern |journal=Expert Rev Hematol |volume=9 |issue=7 |pages=629–37 |date=July 2016 |pmid=27216469 |doi=10.1080/17474086.2016.1191944 |url=}}</ref>
*[[Menorrhagia]] and [[epistaxis]] are the most common [[bleeding]] episodes encountered in hemophilia C.<ref name="pmid9883805">{{cite journal |vauthors=Kadir RA, Economides DL, Lee CA |title=Factor XI deficiency in women |journal=Am. J. Hematol. |volume=60 |issue=1 |pages=48–54 |date=January 1999 |pmid=9883805 |doi= |url=}}</ref>
*[[Factor XI]] [[deficiency]] can especially be a problem when [[Physical trauma|trauma]] involves the [[Mouth|oral]] and [[Nasal cavity|nasal cavities]] or the [[Urinary system|urinary tract]].<ref name="pmid23929304">{{cite journal |vauthors=Duga S, Salomon O |title=Congenital factor XI deficiency: an update |journal=Semin. Thromb. Hemost. |volume=39 |issue=6 |pages=621–31 |date=September 2013 |pmid=23929304 |doi=10.1055/s-0033-1353420 |url=}}</ref><ref name="pmid2052060">{{cite journal |vauthors=Asakai R, Chung DW, Davie EW, Seligsohn U |title=Factor XI deficiency in Ashkenazi Jews in Israel |journal=N. Engl. J. Med. |volume=325 |issue=3 |pages=153–8 |date=July 1991 |pmid=2052060 |doi=10.1056/NEJM199107183250303 |url=}}</ref>
*[[Symptom|Symptoms]] in hemophilia C [[Patient|patients]] correlate poorly with [[factor XI]] activity measured by [[Partial thromboplastin time|aPTT]]-based [[Assay|assays]].<ref name="pmid20008187">{{cite journal |vauthors=Bolton-Maggs PH |title=Factor XI deficiency--resolving the enigma? |journal=Hematology Am Soc Hematol Educ Program |volume= |issue= |pages=97–105 |date=2009 |pmid=20008187 |doi=10.1182/asheducation-2009.1.97 |url=}}</ref><ref name="pmid25623511">{{cite journal |vauthors=Santoro C, Di Mauro R, Baldacci E, De Angelis F, Abbruzzese R, Barone F, Bochicchio RA, Ferrara G, Guarini A, Foà R, Mazzucconi MG |title=Bleeding phenotype and correlation with factor XI (FXI) activity in congenital FXI deficiency: results of a retrospective study from a single centre |journal=Haemophilia |volume=21 |issue=4 |pages=496–501 |date=July 2015 |pmid=25623511 |doi=10.1111/hae.12628 |url=}}</ref><ref name="pmid3871646">{{cite journal |vauthors=Ragni MV, Sinha D, Seaman F, Lewis JH, Spero JA, Walsh PN |title=Comparison of bleeding tendency, factor XI coagulant activity, and factor XI antigen in 25 factor XI-deficient kindreds |journal=Blood |volume=65 |issue=3 |pages=719–24 |date=March 1985 |pmid=3871646 |doi= |url=}}</ref><ref name="pmid7792729">{{cite journal |vauthors=Bolton-Maggs PH, Patterson DA, Wensley RT, Tuddenham EG |title=Definition of the bleeding tendency in factor XI-deficient kindreds--a clinical and laboratory study |journal=Thromb. Haemost. |volume=73 |issue=2 |pages=194–202 |date=February 1995 |pmid=7792729 |doi= |url=}}</ref>
 
==Genetics==
====Hemophilia A====
*Hemophilia A can be characterized by the detection of inversions of [[intron]] 22 (reported in 40–45% of severe [[Patient|patients]]) and [[intron]] 1 (reported in 1–6% of severe [[Patient|patients]]) of ''F8'' [[gene]] (which encodes [[factor VIII]]).<ref name="LakichKazazian1993">{{cite journal|last1=Lakich|first1=Delia|last2=Kazazian|first2=Haig H.|last3=Antonarakis|first3=Stylianos E.|last4=Gitschier|first4=Jane|title=Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A|journal=Nature Genetics|volume=5|issue=3|year=1993|pages=236–241|issn=1061-4036|doi=10.1038/ng1193-236}}</ref><ref name="Bagnall2002">{{cite journal|last1=Bagnall|first1=R. D.|title=Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A|journal=Blood|volume=99|issue=1|year=2002|pages=168–174|issn=00064971|doi=10.1182/blood.V99.1.168}}</ref>
*The ''F8'' [[gene]] is located on the X [[Chromosome (genetic algorithm)|chromosome]].<ref name="pmid6438525">{{cite journal |vauthors=Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM |title=Characterization of the human factor VIII gene |journal=Nature |volume=312 |issue=5992 |pages=326–30 |date=1984 |pmid=6438525 |doi= |url=}}</ref>
*[[Point mutation|Point mutations]] ([[Missense mutation|missense]], [[Nonsense mutation|nonsense]], and [[Splice site mutation|splice site mutations]]) account for 67% of [[Molecule|molecular]] [[Defect|defects]] described.
*Small insertions and deletions represent 25% of such [[Defect|defects]].<ref name="LannoyAbinet2009">{{cite journal|last1=Lannoy|first1=N.|last2=Abinet|first2=I.|last3=Dahan|first3=K.|last4=Hermans|first4=C.|title=Identification ofde novodeletion in the factor VIII gene by MLPA technique in two girls with isolated factor VIII deficiency|journal=Haemophilia|volume=15|issue=3|year=2009|pages=797–801|issn=13518216|doi=10.1111/j.1365-2516.2008.01974.x}}</ref>
*Roughly 6% of all [[Mutation|mutations]] are large deletions.<ref name="LannoyAbinet2009">{{cite journal|last1=Lannoy|first1=N.|last2=Abinet|first2=I.|last3=Dahan|first3=K.|last4=Hermans|first4=C.|title=Identification ofde novodeletion in the factor VIII gene by MLPA technique in two girls with isolated factor VIII deficiency|journal=Haemophilia|volume=15|issue=3|year=2009|pages=797–801|issn=13518216|doi=10.1111/j.1365-2516.2008.01974.x}}</ref>
====Hemophilia B====
*[[Missense mutation|Missense]], [[Nonsense mutation|nonsense]], and [[Splice site mutation|splice site mutations]] in the ''F9'' [[gene]] (which is located on the X chromosome and encodes [[factor XI]]) are the most common, accounting for around 70% of [[Mutation|mutations]].<ref name="PeyvandiGaragiola2016">{{cite journal|last1=Peyvandi|first1=Flora|last2=Garagiola|first2=Isabella|last3=Young|first3=Guy|title=The past and future of haemophilia: diagnosis, treatments, and its complications|journal=The Lancet|volume=388|issue=10040|year=2016|pages=187–197|issn=01406736|doi=10.1016/S0140-6736(15)01123-X}}</ref><ref name="pmid237463">{{cite journal |vauthors=Davie EW, Fujikawa K |title=Basic mechanisms in blood coagulation |journal=Annu. Rev. Biochem. |volume=44 |issue= |pages=799–829 |date=1975 |pmid=237463 |doi=10.1146/annurev.bi.44.070175.004055 |url=}}</ref><ref name="pmid2994716">{{cite journal |vauthors=Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi K |title=Nucleotide sequence of the gene for human factor IX (antihemophilic factor B) |journal=Biochemistry |volume=24 |issue=14 |pages=3736–50 |date=July 1985 |pmid=2994716 |doi= |url=}}</ref>
*[[Frameshift mutation|Frameshift mutations]] in the F9 [[gene]] account for approximately 17%.<ref name="PeyvandiGaragiola2016">{{cite journal|last1=Peyvandi|first1=Flora|last2=Garagiola|first2=Isabella|last3=Young|first3=Guy|title=The past and future of haemophilia: diagnosis, treatments, and its complications|journal=The Lancet|volume=388|issue=10040|year=2016|pages=187–197|issn=01406736|doi=10.1016/S0140-6736(15)01123-X}}</ref>
*Large [[Deletion (genetics)|deletions]] and [[promoter region]] [[Mutation|mutations]] are relatively rare, accounting for 3% and 2% respectively.<ref name="PeyvandiGaragiola2016">{{cite journal|last1=Peyvandi|first1=Flora|last2=Garagiola|first2=Isabella|last3=Young|first3=Guy|title=The past and future of haemophilia: diagnosis, treatments, and its complications|journal=The Lancet|volume=388|issue=10040|year=2016|pages=187–197|issn=01406736|doi=10.1016/S0140-6736(15)01123-X}}</ref>
 
====Hemophilia C====
*Hemophilia C, characterized by a [[deficiency]] of [[factor XI]], results from [[Mutation|mutations]] ([[Splice site mutation|splice site]], [[Nonsense mutation|nonsense]], or [[missense mutation]]) in the F11 [[gene]].<ref name="pmid2813350">{{cite journal |vauthors=Asakai R, Chung DW, Ratnoff OD, Davie EW |title=Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=86 |issue=20 |pages=7667–71 |date=October 1989 |pmid=2813350 |pmc=298131 |doi= |url=}}</ref>
*[[Zygosity|Homozygous]] or [[Zygosity|compound heterozygous]] [[deficiency]] of [[factor XI]] results in a variable [[bleeding]] [[phenotype]] but the clinical presentation in [[Zygosity|heterozygotes]] is less predictable.<ref name="pmid25817556">{{cite journal |vauthors=Bauduer F, de Raucourt E, Boyer-Neumann C, Trossaert M, Beurrier P, Faradji A, Peynet J, Borg JY, Chamouni P, Chatelanaz C, Henriet C, Bridey F, Goudemand J |title=Factor XI replacement for inherited factor XI deficiency in routine clinical practice: results of the HEMOLEVEN prospective 3-year postmarketing study |journal=Haemophilia |volume=21 |issue=4 |pages=481–9 |date=July 2015 |pmid=25817556 |pmc=4657494 |doi=10.1111/hae.12655 |url=}}</ref>
 
==Associated Conditions==
*Hemophilia can be associated with the following conditions:
:*[[End stage liver failure|End-stage liver disease]]<ref name="pmid12176875">{{cite journal |vauthors=Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC, Angiolillo AL, Luban NL, Sherman KE, Manco-Johnson M, Preiss L, Leissinger C, Kessler CM, Cohen AR, DiMichele D, Hilgartner MW, Aledort LM, Kroner BL, Rosenberg PS, Hatzakis A |title=End-stage liver disease in persons with hemophilia and transfusion-associated infections |journal=Blood |volume=100 |issue=5 |pages=1584–9 |date=September 2002 |pmid=12176875 |doi= |url=}}</ref><ref name="pmid30278553">{{cite journal |vauthors=Qvigstad C, Tait RC, Rauchensteiner S, Berntorp E, de Moerloose P, Schutgens RE, Holme PA |title=The elevated prevalence of risk factors for chronic liver disease among ageing people with hemophilia and implications for treatment |journal=Medicine (Baltimore) |volume=97 |issue=39 |pages=e12551 |date=September 2018 |pmid=30278553 |pmc=6181599 |doi=10.1097/MD.0000000000012551 |url=}}</ref>
:*[[Autoimmunity|Autoimmune]] [[thyroiditis]]<ref name="pmid25547669">{{cite journal |vauthors=Pathirana UG, Gunawardena N, Abeysinghe H, Copley HC, Somarathne MG |title=Acquired haemophilia A associated with autoimmune thyroiditis: a case report |journal=J Med Case Rep |volume=8 |issue= |pages=469 |date=December 2014 |pmid=25547669 |pmc=4320580 |doi=10.1186/1752-1947-8-469 |url=}}</ref>
:*[[Autoimmune pancreatitis]]<ref name="pmid29582334">{{cite journal |vauthors=Narazaki T, Haji S, Nakashima Y, Tsukamoto Y, Tsuda M, Takamatsu A, Ohno H, Matsushima T, Matsumoto T, Nogami K, Shima M, Shiratsuchi M, Ogawa Y |title=Acquired hemophilia A associated with autoimmune pancreatitis with serum IgG4 elevation |journal=Int. J. Hematol. |volume=108 |issue=3 |pages=335–338 |date=September 2018 |pmid=29582334 |doi=10.1007/s12185-018-2441-3 |url=}}</ref>
:*[[Hematology|Hematologic]] [[Cancer|malignancies]]<ref name="pmid24750687">{{cite journal |vauthors=Mulliez SM, Vantilborgh A, Devreese KM |title=Acquired hemophilia: a case report and review of the literature |journal=Int J Lab Hematol |volume=36 |issue=3 |pages=398–407 |date=June 2014 |pmid=24750687 |doi=10.1111/ijlh.12210 |url=}}</ref>
:*[[Hepatocellular carcinoma|Hepatocellular carcinoma (HCC)]]<ref name="pmid26754251">{{cite journal |vauthors=Shetty S, Sharma N, Ghosh K |title=Epidemiology of hepatocellular carcinoma (HCC) in hemophilia |journal=Crit. Rev. Oncol. Hematol. |volume=99 |issue= |pages=129–33 |date=March 2016 |pmid=26754251 |doi=10.1016/j.critrevonc.2015.12.009 |url=}}</ref>
:*[[Pregnancy]]<ref name="pmid28262242">{{cite journal |vauthors=Barg AA, Livnat T, Kenet G |title=An extra X does not prevent acquired hemophilia - Pregnancy-associated acquired hemophilia A |journal=Thromb. Res. |volume=151 Suppl 1 |issue= |pages=S82–S85 |date=March 2017 |pmid=28262242 |doi=10.1016/S0049-3848(17)30074-9 |url=}}</ref>
:*[[Polymyositis and dermatomyositis|Polymyositis]]<ref name="pmid30562791">{{cite journal |vauthors=Yang F, Zhou YS, Jia Y |title=[Systemic lupus erythematosus with acquired hemophilia A: a case report] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=50 |issue=6 |pages=1108–1111 |date=December 2018 |pmid=30562791 |doi= |url=}}</ref>
:*[[Autoimmune hemolytic anemia]]<ref name="pmid30562791">{{cite journal |vauthors=Yang F, Zhou YS, Jia Y |title=[Systemic lupus erythematosus with acquired hemophilia A: a case report] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=50 |issue=6 |pages=1108–1111 |date=December 2018 |pmid=30562791 |doi= |url=}}</ref>
:*[[Hepatitis A]], [[Hepatitis B|B]], and [[Hepatitis C|C]]<ref name="pmid28300362">{{cite journal |vauthors=Makris M, Konkle BA |title=Hepatitis C in haemophilia: time for treatment for all |journal=Haemophilia |volume=23 |issue=2 |pages=180–181 |date=March 2017 |pmid=28300362 |doi=10.1111/hae.13183 |url=}}</ref><ref name="pmid15009473">{{cite journal |vauthors=Kasper CK |title=AIDS, hepatitis and hemophilia |journal=J. Thromb. Haemost. |volume=2 |issue=3 |pages=516–8 |date=March 2004 |pmid=15009473 |doi= |url=}}</ref><ref>{{cite book | last = Goodman | first = Catherine | title = Pathology : implications for the physical therapist | publisher = Elsevier Saunders | location = St. Louis, Missouri | year = 2015 | isbn = 9781455745913 }}</ref><ref name="pmid28752601">{{cite journal |vauthors=Murphy N, O'Mahony B, Flanagan P, Noone D, White B, Bergin C, Norris S, Thornton L |title=Progression of hepatitis C in the haemophiliac population in Ireland, after 30 years of infection in the pre-DAA treatment era |journal=Haemophilia |volume=23 |issue=5 |pages=712–720 |date=September 2017 |pmid=28752601 |doi=10.1111/hae.13244 |url=}}</ref>
:*[[Osteoporosis]]<ref name="pmid26825623">{{cite journal |vauthors=Eldash HH, Atwa ZT, Saad MA |title=Vitamin D deficiency and osteoporosis in hemophilic children: an intermingled comorbidity |journal=Blood Coagul. Fibrinolysis |volume=28 |issue=1 |pages=14–18 |date=January 2017 |pmid=26825623 |doi=10.1097/MBC.0000000000000519 |url=}}</ref><ref name="pmid25485786">{{cite journal |vauthors=Albayrak C, Albayrak D |title=Vitamin D levels in children with severe hemophilia A: an underappreciated deficiency |journal=Blood Coagul. Fibrinolysis |volume=26 |issue=3 |pages=285–9 |date=April 2015 |pmid=25485786 |doi=10.1097/MBC.0000000000000237 |url=}}</ref>
:*[[Rheumatoid arthritis]]<ref name="pmid30562791">{{cite journal |vauthors=Yang F, Zhou YS, Jia Y |title=[Systemic lupus erythematosus with acquired hemophilia A: a case report] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=50 |issue=6 |pages=1108–1111 |date=December 2018 |pmid=30562791 |doi= |url=}}</ref>
:*[[Myasthenia gravis|Myasthenia Gravis]]<ref name="pmid23395131">{{cite journal |vauthors=Cano LM, Quesada H, García-Alhama J, Cardona P |title=[Acquired haemophilia associated to myasthenia gravis] |language=Spanish; Castilian |journal=Med Clin (Barc) |volume=141 |issue=4 |pages=185–6 |date=August 2013 |pmid=23395131 |doi=10.1016/j.medcli.2012.12.005 |url=}}</ref>
:*[[Systemic lupus erythematosus|Systemic lupus erythematosus (SLE)]]<ref name="pmid30562791">{{cite journal |vauthors=Yang F, Zhou YS, Jia Y |title=[Systemic lupus erythematosus with acquired hemophilia A: a case report] |language=Chinese |journal=Beijing Da Xue Xue Bao |volume=50 |issue=6 |pages=1108–1111 |date=December 2018 |pmid=30562791 |doi= |url=}}</ref>
:*[[Moyamoya disease|Moyamoya syndrome]]<ref name="pmid27638653">{{cite journal |vauthors=Saini AG, Goswami JN, Suthar R, Sankhyan N, Vyas S, Singhi P |title=Probable Moyamoya Syndrome in Association with Hemophilia A in an Infant |journal=Indian J Pediatr |volume=84 |issue=2 |pages=164–165 |date=February 2017 |pmid=27638653 |doi=10.1007/s12098-016-2229-5 |url=}}</ref>
 
==Gross Pathology==
On [[gross pathology]], hemophilia is characterized by the following findings:
*[[Hemarthrosis|Hemarthroses]]<ref name="pmid11396445">{{cite journal |vauthors=Mannucci PM, Tuddenham EG |title=The hemophilias--from royal genes to gene therapy |journal=N. Engl. J. Med. |volume=344 |issue=23 |pages=1773–9 |date=June 2001 |pmid=11396445 |doi=10.1056/NEJM200106073442307 |url=}}</ref>
*[[Muscle]] [[Hematoma|hematomas]]<ref name="pmid11396445">{{cite journal |vauthors=Mannucci PM, Tuddenham EG |title=The hemophilias--from royal genes to gene therapy |journal=N. Engl. J. Med. |volume=344 |issue=23 |pages=1773–9 |date=June 2001 |pmid=11396445 |doi=10.1056/NEJM200106073442307 |url=}}</ref>
*[[Subcutaneous tissue|Subcutaneous]] [[bleeding]]<ref name="pmid23719140">{{cite journal |vauthors=Kimura H, Uegaki M, Aoyama T, Miyoshi T, Nagai K, Hashimura T |title=[Acquired hemophilia presenting as gross hematuria and perineal subcutaneous hemorrhage after prostate biopsy: a case report] |language=Japanese |journal=Hinyokika Kiyo |volume=59 |issue=5 |pages=305–8 |date=May 2013 |pmid=23719140 |doi= |url=}}</ref>
*[[Gross examination|Gross]] [[hematuria]]<ref name="pmid23719140">{{cite journal |vauthors=Kimura H, Uegaki M, Aoyama T, Miyoshi T, Nagai K, Hashimura T |title=[Acquired hemophilia presenting as gross hematuria and perineal subcutaneous hemorrhage after prostate biopsy: a case report] |language=Japanese |journal=Hinyokika Kiyo |volume=59 |issue=5 |pages=305–8 |date=May 2013 |pmid=23719140 |doi= |url=}}</ref>
*[[Limb (anatomy)|Extremity]] [[Edema|swelling]]<ref name="MaesakoShimomura2013">{{cite journal|last1=Maesako|first1=Yoshitomo|last2=Shimomura|first2=Daiki|last3=Ohno|first3=Hitoshi|title=Acquired hemophilia A|journal=Tenri Medical Bulletin|volume=16|issue=2|year=2013|pages=133–135|issn=1344-1817|doi=10.12936/tenrikiyo.16-015}}</ref>
*[[Epistaxis]]<ref name="pmid9883805">{{cite journal |vauthors=Kadir RA, Economides DL, Lee CA |title=Factor XI deficiency in women |journal=Am. J. Hematol. |volume=60 |issue=1 |pages=48–54 |date=January 1999 |pmid=9883805 |doi= |url=}}</ref>
*[[Menorrhagia]]<ref name="pmid9883805">{{cite journal |vauthors=Kadir RA, Economides DL, Lee CA |title=Factor XI deficiency in women |journal=Am. J. Hematol. |volume=60 |issue=1 |pages=48–54 |date=January 1999 |pmid=9883805 |doi= |url=}}</ref>
*Excessive uncontrollable [[bleeding]] after major/minor [[Injury|injuries]]<ref name="pmid11396445">{{cite journal |vauthors=Mannucci PM, Tuddenham EG |title=The hemophilias--from royal genes to gene therapy |journal=N. Engl. J. Med. |volume=344 |issue=23 |pages=1773–9 |date=June 2001 |pmid=11396445 |doi=10.1056/NEJM200106073442307 |url=}}</ref><ref name="pmid22456059">{{cite journal |vauthors=Berntorp E, Shapiro AD |title=Modern haemophilia care |journal=Lancet |volume=379 |issue=9824 |pages=1447–56 |date=April 2012 |pmid=22456059 |doi=10.1016/S0140-6736(11)61139-2 |url=}}</ref>
==Microscopic Pathology==
On [[microscopic]] [[Histopathology|histopathological]] [[analysis]], hemophilia can be characterized by the following findings:
*Reduced [[Red blood cell|red blood cell (RBC)]] count<ref>Centers for Disease Control and Prevention. Hemophilia Diagnosis. http://www.cdc.gov/ncbddd/hemophilia/diagnosis.html</ref>


*Another form of the disorder, known as [[acquired]] hemophilia, is not caused by inherited gene mutation. This rare condition is characterized by abnormal bleeding into the skin, muscles, or other soft tissues, usually beginning in adulthood. Acquired hemophilia results when the body makes specialized proteins called auto antibodies that attack and disable coagulation factor VIII. The production of auto antibodies is sometimes associated with pregnancy, immune system disorders, cancer, or allergic reactions to certain drugs. In about half of cases, the cause of acquired hemophilia is unknown.<ref>{{Cite web | title = NIH Hemophilia Pathophysiology| url =http://ghr.nlm.nih.gov/condition/hemophilia }}</ref>
==References==
==References==
{{reflist|2}}
{{reflist|2}}

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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]Fahd Yunus, M.D. [3]

Overview

Hemophilia is a genetic bleeding disorder resulting from the insufficient levels of clotting factors in the body. The clotting factors irregularity causes a lack of clumping of blood required to form a clot to plug a site of a wound. The genes involved in the pathogenesis of hemophilia include the F8 gene in hemophilia A, F9 gene in hemophilia B, and F11 gene in C. Hemophilia predominantly affects the male population but the sub-type hemophilia C, with an autosomal inheritance pattern, can affect the males as well as females.

Pathophysiology

Physiology

The normal physiology of hemostasis can be summarized as follows:

1. Primary hemostasis

2. Secondary hemostasis

3. Fibrinolysis

Cell-Based Model of Coagulation

a. Initiation

b. Amplification

c. Propagation

Pathogenesis

  • Mild (factor level > 0.05–0.40 IU/mL)
  • Moderate (factor level = 0.01–0.05 IU/mL)
  • Severe (factor level < 0.01 IU/mL)

Hemophilia A

  1. Classic mutations in the F8 gene that cause structural changes in the FVIII molecule or even produce a truncated protein lacking essential functional domains.[18][19]
  2. Mutations in proteins that interact intracellularly in the correct folding and trafficking of the FVIII protein or mutations in extracellular plasma proteins such as von Willebrand factor (VWF).[20][21][22][23]
  3. The third category encompasses patients who have the clinical disease but have no mutations in the F8 gene or in any of the known interacting partners.[16]

Hemophilia B

Hemophilia C

Genetics

Hemophilia A

Hemophilia B

Hemophilia C

Associated Conditions

  • Hemophilia can be associated with the following conditions:

Gross Pathology

On gross pathology, hemophilia is characterized by the following findings:

Microscopic Pathology

On microscopic histopathological analysis, hemophilia can be characterized by the following findings:

References

  1. ↑ Lippi G, Favaloro EJ, Franchini M, Guidi GC (February 2009). "Milestones and perspectives in coagulation and hemostasis". Semin. Thromb. Hemost. 35 (1): 9–22. doi:10.1055/s-0029-1214144. PMID 19308889.
  2. ↑ Lippi G, Franchini M, Guidi GC (2007). "Diagnostic approach to inherited bleeding disorders". Clin. Chem. Lab. Med. 45 (1): 2–12. doi:10.1515/CCLM.2007.006. PMID 17243907.
  3. ↑ Favaloro, Emmanuel (2017). Hemostasis and thrombosis : methods and protocols. New York: Humana Press Springer. ISBN 9781493971961.
  4. ↑ Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, Ingerslev J, Lee CA, Lillicrap D, Mannucci PM, Mazurier C, Meyer D, Nichols WL, Nishino M, Peake IR, Rodeghiero F, Schneppenheim R, Ruggeri ZM, Srivastava A, Montgomery RR, Federici AB (October 2006). "Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor". J. Thromb. Haemost. 4 (10): 2103–14. doi:10.1111/j.1538-7836.2006.02146.x. PMID 16889557.
  5. ↑ Yee A, Kretz CA (February 2014). "Von Willebrand factor: form for function". Semin. Thromb. Hemost. 40 (1): 17–27. doi:10.1055/s-0033-1363155. PMID 24338608.
  6. ↑ Favaloro, Emmanuel (2017). Hemostasis and thrombosis : methods and protocols. New York: Humana Press Springer. ISBN 9781493971961.
  7. ↑ Favaloro, Emmanuel (2017). Hemostasis and thrombosis : methods and protocols. New York: Humana Press Springer. ISBN 9781493971961.
  8. ↑ Kwaan H, Lisman T, Medcalf RL (March 2017). "Fibrinolysis: Biochemistry, Clinical Aspects, and Therapeutic Potential". Semin. Thromb. Hemost. 43 (2): 113–114. doi:10.1055/s-0036-1598000. PMID 28253534.
  9. ↑ 9.0 9.1 Hoffman, Maureane (2003). "A cell-based model of coagulation and the role of factor VIIa". Blood Reviews. 17: S1–S5. doi:10.1016/S0268-960X(03)90000-2. ISSN 0268-960X.
  10. ↑ Favaloro, Emmanuel (2017). Hemostasis and thrombosis : methods and protocols. New York: Humana Press Springer. ISBN 9781493971961.
  11. ↑ Favaloro, Emmanuel (2017). Hemostasis and thrombosis : methods and protocols. New York: Humana Press Springer. ISBN 9781493971961.
  12. ↑ Bonar RA, Lippi G, Favaloro EJ (2017). "Overview of Hemostasis and Thrombosis and Contribution of Laboratory Testing to Diagnosis and Management of Hemostasis and Thrombosis Disorders". Methods Mol. Biol. 1646: 3–27. doi:10.1007/978-1-4939-7196-1_1. PMID 28804815.
  13. ↑ 13.0 13.1 13.2 13.3 13.4 13.5 13.6 Mannucci PM, Tuddenham EG (June 2001). "The hemophilias--from royal genes to gene therapy". N. Engl. J. Med. 344 (23): 1773–9. doi:10.1056/NEJM200106073442307. PMID 11396445.
  14. ↑ 14.0 14.1 14.2 Bolton-Maggs, Paula HB; Pasi, K John (2003). "Haemophilias A and B". The Lancet. 361 (9371): 1801–1809. doi:10.1016/S0140-6736(03)13405-8. ISSN 0140-6736.
  15. ↑ 15.0 15.1 Berntorp E, Shapiro AD (April 2012). "Modern haemophilia care". Lancet. 379 (9824): 1447–56. doi:10.1016/S0140-6736(11)61139-2. PMID 22456059.
  16. ↑ 16.0 16.1 16.2 Oldenburg, Johannes; El-Maarri, Osman (2006). "New Insight into the Molecular Basis of Hemophilia A". International Journal of Hematology. 83 (2): 96–102. doi:10.1532/IJH97.06012. ISSN 0925-5710.
  17. ↑ Roosendaal G, Lafeber FP (July 2006). "Pathogenesis of haemophilic arthropathy". Haemophilia. 12 Suppl 3: 117–21. doi:10.1111/j.1365-2516.2006.01268.x. PMID 16684006.
  18. ↑ Morris JA, Dorner AJ, Edwards CA, Hendershot LM, Kaufman RJ (February 1997). "Immunoglobulin binding protein (BiP) function is required to protect cells from endoplasmic reticulum stress but is not required for the secretion of selective proteins". J. Biol. Chem. 272 (7): 4327–34. PMID 9020152.
  19. ↑ Pipe SW, Morris JA, Shah J, Kaufman RJ (April 1998). "Differential interaction of coagulation factor VIII and factor V with protein chaperones calnexin and calreticulin". J. Biol. Chem. 273 (14): 8537–44. PMID 9525969.
  20. ↑ Nichols WC, Seligsohn U, Zivelin A, Terry VH, Hertel CE, Wheatley MA, Moussalli MJ, Hauri HP, Ciavarella N, Kaufman RJ, Ginsburg D (April 1998). "Mutations in the ER-Golgi intermediate compartment protein ERGIC-53 cause combined deficiency of coagulation factors V and VIII". Cell. 93 (1): 61–70. PMID 9546392.
  21. ↑ Zhang B, Cunningham MA, Nichols WC, Bernat JA, Seligsohn U, Pipe SW, McVey JH, Schulte-Overberg U, de Bosch NB, Ruiz-Saez A, White GC, Tuddenham EG, Kaufman RJ, Ginsburg D (June 2003). "Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex". Nat. Genet. 34 (2): 220–5. doi:10.1038/ng1153. PMID 12717434.
  22. ↑ Nishino M, Girma JP, Rothschild C, Fressinaud E, Meyer D (October 1989). "New variant of von Willebrand disease with defective binding to factor VIII". Blood. 74 (5): 1591–9. PMID 2506947.
  23. ↑ Gaucher C, Mercier B, Jorieux S, Oufkir D, Mazurier C (August 1991). "Identification of two point mutations in the von Willebrand factor gene of three families with the 'Normandy' variant of von Willebrand disease". Br. J. Haematol. 78 (4): 506–14. PMID 1832934.
  24. ↑ Kruse-Jarres R, Kempton CL, Baudo F, Collins PW, Knoebl P, Leissinger CA, Tiede A, Kessler CM (July 2017). "Acquired hemophilia A: Updated review of evidence and treatment guidance". Am. J. Hematol. 92 (7): 695–705. doi:10.1002/ajh.24777. PMID 28470674.
  25. ↑ 25.0 25.1 25.2 25.3 25.4 Yang F, Zhou YS, Jia Y (December 2018). "[Systemic lupus erythematosus with acquired hemophilia A: a case report]". Beijing Da Xue Xue Bao (in Chinese). 50 (6): 1108–1111. PMID 30562791.
  26. ↑ Castaman, G.; Bonetti, E.; Messina, M.; Morfini, M.; Rocino, A.; Scaraggi, F. A.; Tagariello, G. (2013). "Inhibitors in haemophilia B: the Italian experience". Haemophilia. 19 (5): 686–690. doi:10.1111/hae.12158. ISSN 1351-8216.
  27. ↑ Goodeve AC (July 2015). "Hemophilia B: molecular pathogenesis and mutation analysis". J. Thromb. Haemost. 13 (7): 1184–95. doi:10.1111/jth.12958. PMC 4496316. PMID 25851415.
  28. ↑ 28.0 28.1 Chitlur M, Warrier I, Rajpurkar M, Lusher JM (September 2009). "Inhibitors in factor IX deficiency a report of the ISTH-SSC international FIX inhibitor registry (1997-2006)". Haemophilia. 15 (5): 1027–31. doi:10.1111/j.1365-2516.2009.02039.x. PMID 19515028.
  29. ↑ 29.0 29.1 Shearin-Patterson T, Davidson E (April 2013). "Hemophilia C". JAAPA. 26 (4): 50. PMID 23610841.
  30. ↑ 30.0 30.1 Duga S, Salomon O (September 2013). "Congenital factor XI deficiency: an update". Semin. Thromb. Hemost. 39 (6): 621–31. doi:10.1055/s-0033-1353420. PMID 23929304.
  31. ↑ 31.0 31.1 Bolton-Maggs PH (2009). "Factor XI deficiency--resolving the enigma?". Hematology Am Soc Hematol Educ Program: 97–105. doi:10.1182/asheducation-2009.1.97. PMID 20008187.
  32. ↑ Wheeler AP, Gailani D (July 2016). "Why factor XI deficiency is a clinical concern". Expert Rev Hematol. 9 (7): 629–37. doi:10.1080/17474086.2016.1191944. PMID 27216469.
  33. ↑ 33.0 33.1 33.2 Kadir RA, Economides DL, Lee CA (January 1999). "Factor XI deficiency in women". Am. J. Hematol. 60 (1): 48–54. PMID 9883805.
  34. ↑ Asakai R, Chung DW, Davie EW, Seligsohn U (July 1991). "Factor XI deficiency in Ashkenazi Jews in Israel". N. Engl. J. Med. 325 (3): 153–8. doi:10.1056/NEJM199107183250303. PMID 2052060.
  35. ↑ Santoro C, Di Mauro R, Baldacci E, De Angelis F, Abbruzzese R, Barone F, Bochicchio RA, Ferrara G, Guarini A, Foà R, Mazzucconi MG (July 2015). "Bleeding phenotype and correlation with factor XI (FXI) activity in congenital FXI deficiency: results of a retrospective study from a single centre". Haemophilia. 21 (4): 496–501. doi:10.1111/hae.12628. PMID 25623511.
  36. ↑ Ragni MV, Sinha D, Seaman F, Lewis JH, Spero JA, Walsh PN (March 1985). "Comparison of bleeding tendency, factor XI coagulant activity, and factor XI antigen in 25 factor XI-deficient kindreds". Blood. 65 (3): 719–24. PMID 3871646.
  37. ↑ Bolton-Maggs PH, Patterson DA, Wensley RT, Tuddenham EG (February 1995). "Definition of the bleeding tendency in factor XI-deficient kindreds--a clinical and laboratory study". Thromb. Haemost. 73 (2): 194–202. PMID 7792729.
  38. ↑ Lakich, Delia; Kazazian, Haig H.; Antonarakis, Stylianos E.; Gitschier, Jane (1993). "Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A". Nature Genetics. 5 (3): 236–241. doi:10.1038/ng1193-236. ISSN 1061-4036.
  39. ↑ Bagnall, R. D. (2002). "Recurrent inversion breaking intron 1 of the factor VIII gene is a frequent cause of severe hemophilia A". Blood. 99 (1): 168–174. doi:10.1182/blood.V99.1.168. ISSN 0006-4971.
  40. ↑ Gitschier J, Wood WI, Goralka TM, Wion KL, Chen EY, Eaton DH, Vehar GA, Capon DJ, Lawn RM (1984). "Characterization of the human factor VIII gene". Nature. 312 (5992): 326–30. PMID 6438525.
  41. ↑ 41.0 41.1 Lannoy, N.; Abinet, I.; Dahan, K.; Hermans, C. (2009). "Identification ofde novodeletion in the factor VIII gene by MLPA technique in two girls with isolated factor VIII deficiency". Haemophilia. 15 (3): 797–801. doi:10.1111/j.1365-2516.2008.01974.x. ISSN 1351-8216.
  42. ↑ 42.0 42.1 42.2 Peyvandi, Flora; Garagiola, Isabella; Young, Guy (2016). "The past and future of haemophilia: diagnosis, treatments, and its complications". The Lancet. 388 (10040): 187–197. doi:10.1016/S0140-6736(15)01123-X. ISSN 0140-6736.
  43. ↑ Davie EW, Fujikawa K (1975). "Basic mechanisms in blood coagulation". Annu. Rev. Biochem. 44: 799–829. doi:10.1146/annurev.bi.44.070175.004055. PMID 237463.
  44. ↑ Yoshitake S, Schach BG, Foster DC, Davie EW, Kurachi K (July 1985). "Nucleotide sequence of the gene for human factor IX (antihemophilic factor B)". Biochemistry. 24 (14): 3736–50. PMID 2994716.
  45. ↑ Asakai R, Chung DW, Ratnoff OD, Davie EW (October 1989). "Factor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations". Proc. Natl. Acad. Sci. U.S.A. 86 (20): 7667–71. PMC 298131. PMID 2813350.
  46. ↑ Bauduer F, de Raucourt E, Boyer-Neumann C, Trossaert M, Beurrier P, Faradji A, Peynet J, Borg JY, Chamouni P, Chatelanaz C, Henriet C, Bridey F, Goudemand J (July 2015). "Factor XI replacement for inherited factor XI deficiency in routine clinical practice: results of the HEMOLEVEN prospective 3-year postmarketing study". Haemophilia. 21 (4): 481–9. doi:10.1111/hae.12655. PMC 4657494. PMID 25817556.
  47. ↑ Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC, Angiolillo AL, Luban NL, Sherman KE, Manco-Johnson M, Preiss L, Leissinger C, Kessler CM, Cohen AR, DiMichele D, Hilgartner MW, Aledort LM, Kroner BL, Rosenberg PS, Hatzakis A (September 2002). "End-stage liver disease in persons with hemophilia and transfusion-associated infections". Blood. 100 (5): 1584–9. PMID 12176875.
  48. ↑ Qvigstad C, Tait RC, Rauchensteiner S, Berntorp E, de Moerloose P, Schutgens RE, Holme PA (September 2018). "The elevated prevalence of risk factors for chronic liver disease among ageing people with hemophilia and implications for treatment". Medicine (Baltimore). 97 (39): e12551. doi:10.1097/MD.0000000000012551. PMC 6181599. PMID 30278553.
  49. ↑ Pathirana UG, Gunawardena N, Abeysinghe H, Copley HC, Somarathne MG (December 2014). "Acquired haemophilia A associated with autoimmune thyroiditis: a case report". J Med Case Rep. 8: 469. doi:10.1186/1752-1947-8-469. PMC 4320580. PMID 25547669.
  50. ↑ Narazaki T, Haji S, Nakashima Y, Tsukamoto Y, Tsuda M, Takamatsu A, Ohno H, Matsushima T, Matsumoto T, Nogami K, Shima M, Shiratsuchi M, Ogawa Y (September 2018). "Acquired hemophilia A associated with autoimmune pancreatitis with serum IgG4 elevation". Int. J. Hematol. 108 (3): 335–338. doi:10.1007/s12185-018-2441-3. PMID 29582334.
  51. ↑ Mulliez SM, Vantilborgh A, Devreese KM (June 2014). "Acquired hemophilia: a case report and review of the literature". Int J Lab Hematol. 36 (3): 398–407. doi:10.1111/ijlh.12210. PMID 24750687.
  52. ↑ Shetty S, Sharma N, Ghosh K (March 2016). "Epidemiology of hepatocellular carcinoma (HCC) in hemophilia". Crit. Rev. Oncol. Hematol. 99: 129–33. doi:10.1016/j.critrevonc.2015.12.009. PMID 26754251.
  53. ↑ Barg AA, Livnat T, Kenet G (March 2017). "An extra X does not prevent acquired hemophilia - Pregnancy-associated acquired hemophilia A". Thromb. Res. 151 Suppl 1: S82–S85. doi:10.1016/S0049-3848(17)30074-9. PMID 28262242.
  54. ↑ Makris M, Konkle BA (March 2017). "Hepatitis C in haemophilia: time for treatment for all". Haemophilia. 23 (2): 180–181. doi:10.1111/hae.13183. PMID 28300362.
  55. ↑ Kasper CK (March 2004). "AIDS, hepatitis and hemophilia". J. Thromb. Haemost. 2 (3): 516–8. PMID 15009473.
  56. ↑ Goodman, Catherine (2015). Pathology : implications for the physical therapist. St. Louis, Missouri: Elsevier Saunders. ISBN 9781455745913.
  57. ↑ Murphy N, O'Mahony B, Flanagan P, Noone D, White B, Bergin C, Norris S, Thornton L (September 2017). "Progression of hepatitis C in the haemophiliac population in Ireland, after 30 years of infection in the pre-DAA treatment era". Haemophilia. 23 (5): 712–720. doi:10.1111/hae.13244. PMID 28752601.
  58. ↑ Eldash HH, Atwa ZT, Saad MA (January 2017). "Vitamin D deficiency and osteoporosis in hemophilic children: an intermingled comorbidity". Blood Coagul. Fibrinolysis. 28 (1): 14–18. doi:10.1097/MBC.0000000000000519. PMID 26825623.
  59. ↑ Albayrak C, Albayrak D (April 2015). "Vitamin D levels in children with severe hemophilia A: an underappreciated deficiency". Blood Coagul. Fibrinolysis. 26 (3): 285–9. doi:10.1097/MBC.0000000000000237. PMID 25485786.
  60. ↑ Cano LM, Quesada H, García-Alhama J, Cardona P (August 2013). "[Acquired haemophilia associated to myasthenia gravis]". Med Clin (Barc) (in Spanish; Castilian). 141 (4): 185–6. doi:10.1016/j.medcli.2012.12.005. PMID 23395131.
  61. ↑ Saini AG, Goswami JN, Suthar R, Sankhyan N, Vyas S, Singhi P (February 2017). "Probable Moyamoya Syndrome in Association with Hemophilia A in an Infant". Indian J Pediatr. 84 (2): 164–165. doi:10.1007/s12098-016-2229-5. PMID 27638653.
  62. ↑ 62.0 62.1 Kimura H, Uegaki M, Aoyama T, Miyoshi T, Nagai K, Hashimura T (May 2013). "[Acquired hemophilia presenting as gross hematuria and perineal subcutaneous hemorrhage after prostate biopsy: a case report]". Hinyokika Kiyo (in Japanese). 59 (5): 305–8. PMID 23719140.
  63. ↑ Maesako, Yoshitomo; Shimomura, Daiki; Ohno, Hitoshi (2013). "Acquired hemophilia A". Tenri Medical Bulletin. 16 (2): 133–135. doi:10.12936/tenrikiyo.16-015. ISSN 1344-1817.
  64. ↑ Centers for Disease Control and Prevention. Hemophilia Diagnosis. http://www.cdc.gov/ncbddd/hemophilia/diagnosis.html

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