Hemophilia pathophysiology: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
No edit summary
 
(76 intermediate revisions by 6 users not shown)
Line 1: Line 1:


__NOTOC__
__NOTOC__
<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=nkC1vZaUpxs|350}}
|-
|}
{{Hemophilia}}
{{Hemophilia}}
{{CMG}}
{{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]], '' 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==
===Factor VIII production, processing and structure===
===Physiology===
FVIII is a glycoprotein procofactor. Although the primary site of release in humans is ambiguous, it is synthesized and released into the bloodstream by the vascular, glomerular, and tubular endothelium, and the sinusoidal cells of the liver. Hemophilia A has been corrected by liver transplantation. Transplanting hepatocytes was ineffective, but liver endothelial cells were effective.In the blood, it mainly circulates in a stable noncovalent complex with von Willebrand factor. Upon activation by thrombin, (factor IIa), it dissociates from the complex to interact with factor IXa in the coagulation cascade. It is a cofactor to factor IXa in the activation of factor X, which, in turn, with its cofactor factor Va, activates more thrombin. Thrombin cleaves fibrinogen into fibrin which polymerizes and crosslinks (using factor XIII) into a blood clot. No longer protected by vWF, activated FVIII is proteolytically inactivated in the process (most prominently by activated protein C and factor IXa) and quickly cleared from the blood stream.
The normal [[physiology]] of [[hemostasis]] can be summarized as follows:
 
*[[Hemostasis]] is a tightly regulated process whereby the [[Human body|body]] maintains a [[Homeostasis|homeostatic]] balance to permit normal [[blood flow]], without [[thrombosis]] or [[bleeding]].<ref name="pmid19308889">{{cite journal |vauthors=Lippi G, Favaloro EJ, Franchini M, Guidi GC |title=Milestones and perspectives in coagulation and hemostasis |journal=Semin. Thromb. Hemost. |volume=35 |issue=1 |pages=9–22 |date=February 2009 |pmid=19308889 |doi=10.1055/s-0029-1214144 |url=}}</ref>
Factor VIII is not affected by liver disease. In fact, levels usually are elevated in such instances.
*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.
===Von Willebrand Factor[vWF] synthesis, structure and function===
*[[Hemostasis]] can be divided into three phases
vWF is a large multimeric glycoprotein present in blood plasma and produced constitutively as ultra-large vWF in endothelium (in the Weibel-Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue.The basic vWF monomer is a 2050-amino acid protein. Every monomer contains a number of specific domains with a specific function. Von Willebrand factor primary function is binding to other proteins, in particular factor VIII, and it is important in platelet adhesion to wound sites. It is not an enzyme and, thus, has no catalytic activity. vWF binds to a number of cells and molecules. The most important ones are:
**Each phase is explained as follows:
*Factor VIII is bound to vWF while inactive in circulation; factor VIII degrades rapidly when not bound to vWF. Factor VIII is released from vWF by the action of thrombin.
'''1. Primary hemostasis'''
*vWF binds to collagen, e.g., when it is exposed in endothelial cells due to damage occurring to the blood vessel.
*[[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>
*vWF binds to platelet gpIb when it forms a complex with gpIX and gpV; this binding occurs under all circumstances, but is most efficient under high shear stress (i.e., rapid blood flow in narrow blood vessels, see below).
*It involves [[platelet]] [[adhesion]], activation and [[aggregation]], to form a [[platelet]] plug at the [[injury]] site.
*vWF binds to other platelet receptors when they are activated, e.g., by thrombin (i.e., when coagulation has been stimulated).
*Circulating [[Platelet|platelets]] and [[Endothelial|endothelial cells]], both provide the source of [[Von Willebrand factor|von Willebrand factor (VWF)]].
vWF plays a major role in blood coagulation. Therefore, vWF deficiency or dysfunction (von Willebrand disease) leads to a bleeding tendency, which is most apparent in tissues having high blood flow shear in narrow vessels. From studies it appears that vWF uncoils under these circumstances, decelerating passing platelets. Calcium enhances the refolding rate of vWF A2 domain, allowing the protein to act as a shear force sensor.
*[[Von Willebrand factor|Von Willebrand factor (VWF)]] has two main functions. First, it acts as a [[mediator]] in binding of [[Platelet|platelets]] to the sub-[[endothelium]]. Then it protects the circulating [[factor VIII]] from [[Proteolysis|proteolytic]] [[degradation]].<ref name="pmid16889557">{{cite journal |vauthors=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 |title=Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor |journal=J. Thromb. Haemost. |volume=4 |issue=10 |pages=2103–14 |date=October 2006 |pmid=16889557 |doi=10.1111/j.1538-7836.2006.02146.x |url=}}</ref><ref name="pmid24338608">{{cite journal |vauthors=Yee A, Kretz CA |title=Von Willebrand factor: form for function |journal=Semin. Thromb. Hemost. |volume=40 |issue=1 |pages=17–27 |date=February 2014 |pmid=24338608 |doi=10.1055/s-0033-1363155 |url=}}</ref>
===Factor IX synthesis, structure and function===
*The [[Endothelium|endothelial]] [[Cell (biology)|cells]], which normally promote [[Anticoagulant|anticoagulation]], switch from [[anticoagulant]] to [[Coagulation|procoagulant]] upon [[vascular injury]]. They promote [[platelet]] [[aggregation]] by releasing the contents of their [[Weibel-Palade body|Weibel-Palade bodies]] and hence leading to enhanced local concentrations of [[Von Willebrand factor|von Willebrand factor (VWF)]] and [[Tissue factor|tissue factor (TF)]].<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>
*Factor IX (or Christmas factor) is one of the serine proteases of the coagulation system; it belongs to peptidase family S1. Deficiency of this protein causes hemophilia B. Factors VII, IX, and X all play key roles in blood coagulation and also share a common domain architecture. The factor IX protein is composed of four protein domains: the Gla domain, two tandem copies of the EGF domain and a C-terminal trypsin-like peptidase domain which carries out the catalytic cleavage.The N-terminal EGF domain has been shown to at least in part be responsible for binding tissue factor. Wilkinson et al. conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the factor X activating complex. The structures of all four domains have been solved. A structure of the two EGF domains and the trypsin-like domain was determined for the pig protein. The structure of the Gla domain, which is responsible for Ca(II)-dependent phospholipid binding, was also determined by NMR. Several structures of 'super active' mutants have been solved, which reveal the nature of factor IX activation by other proteins in the clotting cascade.
*The released [[Von Willebrand factor|von Willebrand factor (VWF)]] binds to the [[collagen]] on the exposed sub-[[Endothelium|endothelial]] surface, and is then utilized for [[platelet]] binding via the [[Glycoprotein Ib|glycoprotein Ib (GPIb) complex]].
* Factor IX is produced as a zymogen, an inactive precursor. It is processed to remove the signal peptide, glycosylated and then cleaved by factor XIa (of the contact pathway) or factor VIIa (of the tissue factor pathway) to produce a two-chain form where the chains are linked by a disulfide bridge. When activated into factor IXa, in the presence of Ca2+, membrane phospholipids, and a Factor VIII cofactor, it hydrolyses one arginine-isoleucine bond in factor X to form factor Xa. Factor IX is inhibited by antithrombin. Factor IX expression increases with age in humans and mice. In mouse models mutations within the promoter region of factor IX have an age-dependent phenotype.
*The [[Platelet|platelets]] release their [[Granule (cell biology)|granules]] after undergoing a shape change. This event marks the formation of a [[platelet]] plug.
==Clotting cascade==
'''2. Secondary hemostasis'''
 
*The main goal of [[secondary]] [[hemostasis]] is to stabilize the [[platelet]] plug.<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>
 
*It involves the activation of [[Coagulation|coagulation system]] and [[Coagulation|coagulation factors]] to eventually produce cross-linked [[fibrinogen]] [[Fibrin|(“fibrin”)]].
[[File:Classical_blood_coagulation_pathway.png|left|thumb|classical_blood_coagulation_pathway]]
*The process of [[platelet]] plug stabilization has been always referred to as the “[[Coagulation|Coagulation cascade]]” which can be separated into the [[Coagulation|intrinsic]], [[Coagulation|extrinsic]], and [[Coagulation|common pathways]].
The coagulation cascade of secondary hemostasis has two initial pathways which lead to fibrin formation. These are the contact activation pathway (also known as the intrinsic pathway), and the tissue factor pathway (also known as the extrinsic pathway) which both lead to the same fundamental reactions that produce fibrin. It was previously thought that the two pathways of coagulation cascade were of equal importance, but it is now known that the primary pathway for the initiation of blood coagulation is the tissue factor pathway. The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a serine protease and its glycoprotein co-factor are activated to become active components that then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin. Coagulation factors are generally indicated by Roman numerals, with a lowercase a appended to indicate an active form.
'''3. Fibrinolysis'''
The coagulation factors are generally serine proteases (enzymes), which act by cleaving downstream proteins. There are some exceptions. For example, FVIII and FV are glycoproteins, and Factor XIII is a transglutaminase. The coagulation factors circulate as inactive zymogens. The coagulation cascade is therefore classically divided into three pathways. The tissue factor and contact activation pathways both activate the "final common pathway" of factor X, thrombin and fibrin.
*[[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====
===Tissue factor pathway (extrinsic)===
*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]].
*The model proposes three overlapping phases of [[hemostasis]] which are explained as follows:
'''a. Initiation'''
*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>
*[[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]].  
*Effective initiation means bringing [[Factor VII|FVIIa]]/[[Tissue factor|TF]] activity into close proximity to the activated [[platelet]] surfaces.
'''b. Amplification'''
*It occurs on the surface of the [[Platelet|platelets]] as they get activated.<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>
*[[Platelet|Platelets]] adhere at the site of [[Endothelium|endothelial]] [[injury]] and get activated by [[thrombin]].
*[[Platelet]] activation is marked by the execution of the following processes:
:*The release of [[Platelet alpha-granule|alpha granules]] which contain [[Factor V]] and [[Von Willebrand factor|von Willebrand factor (VWF)]]
:*Binding to [[Blood proteins|plasma proteins]] including [[Von Willebrand factor|von Willebrand factor (VWF)]]
:*Promoting the assemblage of [[Coagulation|procoagulant]] complexes
:*Ensuring prompt [[thrombin]] generation.
'''c. Propagation'''
*Propagation occurs on the surface of activated [[Platelet|platelets]].<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>
*It involves the assembly of [[Tenase|“tenase”]] ([[Factor VII|FVIIa]] and [[Factor IX|FIXa]]/[[Factor VIII|FVIIIa]]) and [[Prothrombinase|“prothrombinase”]] ([[Factor X|FXa]]/[[Factor V|FVa]]) complexes on the [[platelet]] surface, thus allowing [[thrombin]] generation to take place on a large scale which is necessary to form a [[hemostatic]] [[fibrin]] clot.<ref name="pmid28804815">{{cite journal |vauthors=Bonar RA, Lippi G, Favaloro EJ |title=Overview of Hemostasis and Thrombosis and Contribution of Laboratory Testing to Diagnosis and Management of Hemostasis and Thrombosis Disorders |journal=Methods Mol. Biol. |volume=1646 |issue= |pages=3–27 |date=2017 |pmid=28804815 |doi=10.1007/978-1-4939-7196-1_1 |url=}}</ref>


The main role of the tissue factor pathway is to generate a "thrombin burst", a process by which thrombin, the most important constituent of the coagulation cascade in terms of its feedback activation roles, is released very rapidly. FVIIa circulates in a higher amount than any other activated coagulation factor. The process includes the following steps:
===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:


*Following damage to the blood vessel, FVII leaves the circulation and comes into contact with tissue factor (TF) expressed on tissue-factor-bearing cells (stromal fibroblasts and leukocytes), forming an activated complex (TF-FVIIa).
====Hemophilia A====
*TF-FVIIa activates FIX and FX.
*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>
*FVII is itself activated by thrombin, FXIa, FXII and FXa.
*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>
*The activation of FX (to form FXa) by TF-FVIIa is almost immediately inhibited by tissue factor pathway inhibitor (TFPI).
*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>
*FXa and its co-factor FVa form the prothrombinase complex, which activates prothrombin to thrombin.
*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>
*Thrombin then activates other components of the coagulation cascade, including FV and FVIII (which activates FXI, which, in turn, activates FIX), and activates and releases FVIII from being bound to vWF.
*The [[Molecule|molecular]] causes of [[Factor VIII|FVIII]] [[deficiency]] can be divided into 3 main categories:
*FVIIa is the co-factor of FIXa, and together they form the "tenase" complex, which activates FX; and so the cycle continues. ("Tenase" is a contraction of "ten" and the suffix "-ase" used for enzymes.)
#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>


===Contact activation pathway (intrinsic)===
====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>


The contact activation pathway begins with formation of the primary complex on collagen by high-molecular-weight kininogen (HMWK),prekallikrein, and FXII (Hageman factor). Prekallikrein is converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates FIX, which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The minor role that the contact activation pathway has in initiating clot formation can be illustrated by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a bleeding disorder. Instead, contact activation system seems to be more involved in inflammation.[7]
==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>


===Final common pathway===
====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>


The division of coagulation in two pathways is mainly artificial, it originates from laboratory tests in which clotting times were measured after the clotting was initiated by glass (intrinsic pathway) or by thromboplastin (a mix of tissue factor and phospholipids). In fact thrombin is present from the very beginning, already when platelets are making the plug.Thrombin has a large array of functions, not only the conversion of fibrinogen to fibrin, the building block of a hemostatic plug. In addition, it is the most important platelet activator and on top of that it activates Factors VIII and V and their inhibitor protein C (in the presence of thrombomodulin), and it activates Factor XIII, which forms covalent bonds that crosslink the fibrin polymers that form from activated monomers.
==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>


Following activation by the contact factor or tissue factor pathways, the coagulation cascade is maintained in a prothrombotic state by the continued activation of FVIII and FIX to form the tenase complex, until it is down-regulated by the anticoagulant pathways
==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>


==References==
==References==

Latest revision as of 14:27, 2 August 2019


https://https://www.youtube.com/watch?v=nkC1vZaUpxs%7C350}}

Hemophilia Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Hemophilia from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic Study of Choice

History and Symptoms

Physical Examination

Laboratory Findings

Electrocardiogram

X-ray

Echocardiography and Ultrasound

CT scan

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Hemophilia pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Hemophilia pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Hemophilia pathophysiology

CDC on Hemophilia pathophysiology

Hemophilia pathophysiology in the news

Blogs on Hemophilia pathophysiology

Directions to Hospitals Treating Hemophilia

Risk calculators and risk factors for Hemophilia pathophysiology

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

Template:WH Template:WS

Retrieved from "https://www.wikidoc.org/index.php?title=Hemophilia_pathophysiology&oldid=1578160"