Von Willebrand disease pathophysiology: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
No edit summary
Line 2: Line 2:
{{Von Willebrand disease}}
{{Von Willebrand disease}}


{{CMG}}    {{AE}} {{PTD}}  
{{CMG}}    {{AE}} {{PTD}}  


==Overview==
==Overview==


In healthy individuals, VWF circulates as high-molecular-weight multimers carrying factor VIII. Some persons have mildly reduced [[VWF]] levels, which may contribute to a bleeding phenotype but are not necessarily caused by defects in the VWF gene. Persons with low VWF levels and a bleeding tendency are classified as having low VWF, rather than [[von Willebrand’s disease]] (VWD). There is a partial deficiency of functionally normal [[VWF]] in type 1 [[VWD]] and a complete deficiency in type 3 disease. This deficiency can result from a reduction in protein synthesis, which is often caused by null alleles (large gene deletions, stop codons, [[frame-shift mutations]], or [[splice-site mutations]]) but may also be due to [[mutations]] in the [[promotor]] regions. Homozygosity or compound heterozygosity for these defects results in type 3 VWD. Some heterozygous carriers have mild symptoms and receive a diagnosis of type 1 disease. However, most cases of type 1 [[VWD]] are caused by heterozygous [[missense]] mutations that exert a dominant-negative effect because the mutant subunits are incorporated into the multimer together with the normal subunits, resulting in a abnormality of the entire multimer. Almost all cases of type 2 [[VWD]] are caused by [[missense]] [[mutations]], which are usually restricted to specific functional domains. Inheritance of subtypes of type 2 disease is [[autosomal dominant]], with the exception of type 2N,<ref name="pmid22102189">{{cite journal| author=Hampshire DJ, Goodeve AC| title=The international society on thrombosis and haematosis von Willebrand disease database: an update. | journal=Semin Thromb Hemost | year= 2011 | volume= 37 | issue= 5 | pages= 470-9 | pmid=22102189 | doi=10.1055/s-0031-1281031 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102189  }} </ref> which has a recessive pattern of inheritance. Patients may be either homozygous for two type 2N mutations or compound heterozygous for a type 1 defect and a type 2N defect.
==Pathophysiology==
Type 2 [[vWD]] (20-30%) is a qualitative defect and the bleeding tendency can vary between individuals. There are normal levels of vWF, but the multimers are structurally abnormal, or subgroups of large or small multimers are absent.
 
Deficiency of [[vWF]] shows primarily in organs with extensive small vessels, such as the skin, the [[gastrointestinal tract]] and the [[uterus]].
=== Physiology ===
In more severe cases of type 1 [[vWD]], genetic changes are common within the [[vWF]] gene and are highly [[Penetrance|penetrant]]. In milder cases of type 1 [[vWD]] there may be a complex spectrum of molecular [[pathology]] in addition to [[Polymorphism (biology)|polymorphism]]s of the vWF gene alone.<ref>{{cite journal | author = James P, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S, Brown C, Andrews C, Labelle A, Chirinian Y, O'Brien L, Othman M, Rivard G, Rapson D, Hough C, Lillicrap D | title = The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study | journal = Blood | volume = 109 | issue = 1 | pages = 145–54 | year = 2007 | pmid = 17190853 | doi = 10.1182/blood-2006-05-021105}}</ref> The individual's [[ABO blood group system|ABO blood group]] can influence presentation and pathology of vWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group–specific vWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I vWD, and some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood group.<ref>{{cite journal | last = Gill | first = JC | coauthors = Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR | title = The effect of ABO blood group on the diagnosis of von Willebrand disease | journal = Blood | volume = 69 | issue = 6 | pages = 1691–5 | publisher = | date = 1987 | url = http://www.bloodjournal.org/cgi/content/abstract/69/6/1691 | doi = | pmid = 3495304 | accessdate =  }}</ref>
 
==== '''Von Willebrand factor''' ('''vWF''') ====
The normal [[physiology]] of [[von Willebrand’s disease|von Willebrand’s factor]] can be understood as follows:<ref name="pmid21839029">{{cite journal |vauthors=Peyvandi F, Garagiola I, Baronciani L |title=Role of von Willebrand factor in the haemostasis |journal=Blood Transfus |volume=9 Suppl 2 |issue= |pages=s3–8 |date=May 2011 |pmid=21839029 |pmc=3159913 |doi=10.2450/2011.002S |url=}}</ref>
 
'''Structure'''
* It is a [[glycoprotein]] present in blood and is involved in [[hemostasis]].
* Its [[synthesis]] takes place in the [[endothelium]] (in the Weibel-Palade bodies), [[Megakaryocyte|megakaryocytes]] (α-granules of platelets), and subendothelial connective tissue.
* The fundamental vWF [[monomer]] is a 2050-[[Amino acid|amino acid protein]].
These [[monomer]] contains a number of specific [[Protein domains|domains]] with a distinguishing function.
* D'/D3 [[Protein domains|domain]], binds to factor VIII
* A1 [[Protein domains|domain]], which binds to:
** Platelet GPIb-receptor
** [[Heparin]]
** [[Collagen]]
* the A2 [[Domain (biology)|domain]] unfolds and then attach to ADAMTS13 protease that inactivates vWF by making smaller [[Multimeric protein|multimers]].
* The partial unfolding is affected by shear flow in the blood, by [[calcium]] binding, and by the "vicinal disulfide" at the A2-domain C-terminus.
* the A3 [[Protein domains|domain]] binds to [[collagen]] (Von Willebrand factor type A domain)
* the C1 [[Protein domains|domain]], in which the RGD motif binds to [[platelet]] integrin α<sub>IIb</sub>β<sub>3</sub> when this is activated (Von Willebrand factor type C domain)
* Platelet integrin are the [[Transmembrane receptor|transmembrane receptors]] which facilitate [[extracellular matrix]] adhesion.
* The "cystine knot" [[Domain (biology)|domain]] (at the C-terminal end of the protein), which vWF shares with [[platelet-derived growth factor]](PDGF), [[Transforming growth factor-β|transforming growth factor]]-β (TGFβ) and [[Human chorionic gonadotropin|β-human chorionic gonadotropin]] (βHCG, of pregnancy test fame). (Von Willebrand factor type C domain)
 
* [[Monomer|Monomers]] are subsequently N-glycosylated, arranged into [[Dimer|dimers]] in the [[endoplasmic reticulum]] and into [[Multimeric protein|multimers]] in the [[Golgi apparatus]].
* [[Multimeric protein|Multimers]] of vWF are usually very large, >20,000 kDa, and consist of almost 80 subunits.
* Only the large [[Multimeric protein|multimers]] are functional.  
* Some cleavage products from vWF production that are also secreted but serve no function.
'''Function'''
* Von Willebrand factor's main function is binding to other [[Protein|proteins]], specially [[factor VIII]].
* It plays an important role in [[platelet]] adhesion to wound sites.  
* Von Willebrand factor binds to [[factor VIII]] while it is inactive in circulation
* Von Willebrand factor protects [[Factor VIII|FVIII]] from [[degradation]] and delivers it to the site of injury
* [[Factor VIII]] degrades rapidly when not bound to vWF
* [[Factor VIII]] is released from vWF by the action of thrombin.
* In the absence of vWF, [[factor VIII]] has a [[half-life]] of 1-2 hours
* When it is carried by intact vWF, [[factor VIII]] [[half-life]] becomes 8-12 hour
* When vWF is exposed in [[endothelial cells]] due to damage occurring to the blood vessel, it binds to [[collagen]].
* [[Endothelium]] also releases vWF which forms additional links between the [[Glycoprotein Ib|platelets' glycoprotein Ib]]/IX/V and the collagen fibrils
* Von Willebrand factor attaches to [[Platelet|platelets]] by its specific receptor to [[glycoprotein Ib]] on the [[platelet]] surface.
* It acts as an adhesive bridge between the [[Platelet|platelets]] and damaged [[subendothelium]] at the site o[[Vascular|f vascular]] injury
* VWF binds to [[Platelet gp 1 b|platelet]] [[glycoprotein Ib]] when it forms a complex with gpIX and gpV
* This binding is most efficient under high shear stress
* When [[coagulation]] has been stimulated vWF binds to other [[platelet]] receptors that are activated by [[thrombin]].


Von Willebrand's Disease is usually inherited in an [[autosomal dominant]] manner, although there are recessive forms as well, and it can also be acquired secondary to another disease.<ref name="pmid17133419">{{cite journal| author=Franchini M, Lippi G| title=Acquired von Willebrand syndrome: an update. | journal=Am J Hematol | year= 2007 | volume= 82 | issue= 5 | pages= 368-75 | pmid=17133419 | doi=10.1002/ajh.20830 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17133419  }} </ref><ref name="pmid21540459">{{cite journal| author=Tiede A, Rand JH, Budde U, Ganser A, Federici AB| title=How I treat the acquired von Willebrand syndrome. | journal=Blood | year= 2011 | volume= 117 | issue= 25 | pages= 6777-85 | pmid=21540459 | doi=10.1182/blood-2010-11-297580 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21540459  }} </ref><ref name="pmid11838652">{{cite journal| author=Kumar S, Pruthi RK, Nichols WL| title=Acquired von Willebrand disease. | journal=Mayo Clin Proc | year= 2002 | volume= 77 | issue= 2 | pages= 181-7 | pmid=11838652 | doi=10.4065/77.2.181 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11838652  }} </ref><ref name="pmid10959686">{{cite journal| author=Veyradier A, Jenkins CS, Fressinaud E, Meyer D| title=Acquired von Willebrand syndrome: from pathophysiology to management. | journal=Thromb Haemost | year= 2000 | volume= 84 | issue= 2 | pages= 175-82 | pmid=10959686 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10959686  }} </ref><ref name="pmid10959711">{{cite journal| author=Federici AB, Rand JH, Bucciarelli P, Budde U, van Genderen PJ, Mohri H et al.| title=Acquired von Willebrand syndrome: data from an international registry. | journal=Thromb Haemost | year= 2000 | volume= 84 | issue= 2 | pages= 345-9 | pmid=10959711 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10959711  }} </ref><ref>Ng et al. Diagnostic Approach to von Willebrand Disease.  Blood 2015; 125(13): 2029-2037.</ref><ref>Blomback et al. Von Willebrand Disease Biology Hemophilia 2012; 18: 141-147.</ref><ref>Favarolo et al. Von Willebrand Disease and Platelet Disorders.  Hemophilia 2014; 20: 59-64.</ref> Acquired [[VWD]] is associated with other diseases resulting from different pathological processes example, impaired vWF function, enhanced [[proteolysis]], decreased synthesis and antibody formation resulting in increased clearance of [[VWF]].<ref name="pmid7949092">{{cite journal| author=van Genderen PJ, Vink T, Michiels JJ, van 't Veer MB, Sixma JJ, van Vliet HH| title=Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen. | journal=Blood | year= 1994 | volume= 84 | issue= 10 | pages= 3378-84 | pmid=7949092 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7949092  }} </ref><ref name="pmid1085186">{{cite journal| author=Handin RI, Martin V, Moloney WC| title=Antibody-induced von Willebrand's disease: a newly defined inhibitor syndrome. | journal=Blood | year= 1976 | volume= 48 | issue= 3 | pages= 393-405 | pmid=1085186 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1085186  }} </ref>
=== Pathogenesis ===
von Willebrand disease is due to an abnormality, either [[quantitative]] or [[qualitative]], of the von Willebrand factor<ref name="pmid24065240">{{cite journal |vauthors=Lillicrap D |title=von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy |journal=Blood |volume=122 |issue=23 |pages=3735–40 |date=November 2013 |pmid=24065240 |pmc=3952678 |doi=10.1182/blood-2013-06-498303 |url=}}</ref>


==Pathophysiology==
'''Pathogenetic mechanisms of  inherited VWD'''
{| class="wikitable"
! colspan="1" rowspan="1" |VWD subtype
! colspan="1" rowspan="1" |Pathogenetic mechanisms
!
|-
| colspan="1" rowspan="1" |Type 1 VWD
| colspan="1" rowspan="1" |65% have ''VWF'' [[Mutation|mutations]]
| rowspan="3" |Partial [[Quantitative|quantitative deficiency]] of VWF
|-
| colspan="1" rowspan="1" |
| colspan="1" rowspan="1" |70% of ''VWF'' variants are [[Missense mutation|missense]] substitutions affecting VWF trafficking, storage, [[secretion]], and clearance
|-
| colspan="1" rowspan="1" |
| colspan="1" rowspan="1" |[[Transcription (genetics)|Transcription]] and [[Splicing (genetics)|splicing]] ''VWF'' [[Mutation|mutations]]
|-
| colspan="1" rowspan="1" |Type 2A VWD
| colspan="1" rowspan="1" |[[Mutation|Mutations]] in D1/D2/D′D3 assemblies, A2 and CTCK [[Protein domains|domains]]
| rowspan="3" |Loss of high-molecular-weight multimers (HMWMs)
|-
| colspan="1" rowspan="1" |
| colspan="1" rowspan="1" |Interference with [[Multimeric protein|HMW multimer]] formation, storage, and [[secretion]]
|-
| colspan="1" rowspan="1" |
| colspan="1" rowspan="1" |Increased ADAMTS13 [[proteolysis]]
|-
| colspan="1" rowspan="1" |Type 2B VWD
| colspan="1" rowspan="1" |[[Mutation|Mutations]] in A1 [[Protein domains|domain]]
| rowspan="2" |The increase in binding of larger VWF multimers to [[platelet]] GP Ib results in sequestration of the [[platelets]] and VWF resulting in [[Thrombocytopenia]]
|-
| colspan="1" rowspan="1" |
| colspan="1" rowspan="1" |Excessive binding to GPIb [[Glycoprotein Ib|''glycoprotein Ib'']]
|-
| colspan="1" rowspan="1" |Type 2M VWD
| colspan="1" rowspan="1" |[[Mutation|Mutations]] in A1 and A3 [[Protein domains|domains]]
| rowspan="2" |[[Qualitative]] variants with decreased binding of VWF to GP Ib, resulting in decreased platelet adhesion
|-
| colspan="1" rowspan="1" |
| colspan="1" rowspan="1" |Diminished binding to GPIb''α [[glycoprotein Ib]]''  (A1 domain) or [[collagen]] (A3 domain)
|-
| colspan="1" rowspan="1" |Type 2N VWD
| colspan="1" rowspan="1" |Missense variants in D′D3 assembly
| rowspan="2" |[[Qualitative]] variants with remarkably decreased [[affinity]] for [[Factor VIII|FVIII]]
|-
| colspan="1" rowspan="1" |
| colspan="1" rowspan="1" |Reduced [[Factor VIII|FVIII]] binding
|-
| colspan="1" rowspan="1" |Type 3 VWD
| colspan="1" rowspan="1" |''VWF'' [[Mutation|mutations]] found in 85%-90%  of cases
| rowspan="2" |Produces  [[Phenotype|null phenotype]] or the VWF that is not secreted.
|-
| colspan="1" rowspan="1" |
| colspan="1" rowspan="1" |''VWF'' [[Deletion (genetics)|deletions]], nonsense, [[Splice site|splice site,]] and [[Missense mutation|missense mutations]]
|}
 
'''Pathogenetic mechanisms of acquired VWD'''
 
* Von Willebrand's Disease can also be acquired secondary to another disease.<ref name="pmid17133419">{{cite journal| author=Franchini M, Lippi G| title=Acquired von Willebrand syndrome: an update. | journal=Am J Hematol | year= 2007 | volume= 82 | issue= 5 | pages= 368-75 | pmid=17133419 | doi=10.1002/ajh.20830 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17133419  }} </ref><ref name="pmid21540459">{{cite journal| author=Tiede A, Rand JH, Budde U, Ganser A, Federici AB| title=How I treat the acquired von Willebrand syndrome. | journal=Blood | year= 2011 | volume= 117 | issue= 25 | pages= 6777-85 | pmid=21540459 | doi=10.1182/blood-2010-11-297580 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21540459  }} </ref><ref name="pmid11838652">{{cite journal| author=Kumar S, Pruthi RK, Nichols WL| title=Acquired von Willebrand disease. | journal=Mayo Clin Proc | year= 2002 | volume= 77 | issue= 2 | pages= 181-7 | pmid=11838652 | doi=10.4065/77.2.181 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11838652  }} </ref><ref name="pmid10959686">{{cite journal| author=Veyradier A, Jenkins CS, Fressinaud E, Meyer D| title=Acquired von Willebrand syndrome: from pathophysiology to management. | journal=Thromb Haemost | year= 2000 | volume= 84 | issue= 2 | pages= 175-82 | pmid=10959686 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10959686  }} </ref><ref name="pmid10959711">{{cite journal| author=Federici AB, Rand JH, Bucciarelli P, Budde U, van Genderen PJ, Mohri H et al.| title=Acquired von Willebrand syndrome: data from an international registry. | journal=Thromb Haemost | year= 2000 | volume= 84 | issue= 2 | pages= 345-9 | pmid=10959711 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10959711  }} </ref><ref>Ng et al. Diagnostic Approach to von Willebrand Disease.  Blood 2015; 125(13): 2029-2037.</ref><ref>Blomback et al. Von Willebrand Disease Biology Hemophilia 2012; 18: 141-147.</ref><ref>Favarolo et al. Von Willebrand Disease and Platelet Disorders.  Hemophilia 2014; 20: 59-64.</ref>


In healthy individuals, VWF circulates as high-molecular-weight multimers carrying factor VIII. Some persons have mildly reduced [[VWF]] levels, which may contribute to a bleeding phenotype but are not necessarily caused by defects in the VWF gene. Persons with low VWF levels and a bleeding tendency are classified as having low VWF, rather than [[von Willebrand’s disease]] (VWD). There is a partial deficiency of functionally normal [[VWF]] in type 1 [[VWD]] and a complete deficiency in type 3 disease. This deficiency can result from a reduction in protein synthesis, which is often caused by null alleles (large gene deletions, stop codons, [[frame-shift mutations]], or [[splice-site mutations]]) but may also be due to [[mutations]] in the [[promotor]] regions. Homozygosity or compound heterozygosity for these defects results in type 3 VWD. Some heterozygous carriers have mild symptoms and receive a diagnosis of type 1 disease. However, most cases of type 1 [[VWD]] are caused by heterozygous [[missense]] mutations that exert a dominant-negative effect because the mutant subunits are incorporated into the multimer together with the normal subunits, resulting in a abnormality of the entire multimer. Almost all cases of type 2 [[VWD]] are caused by [[missense]] [[mutations]], which are usually restricted to specific functional domains. Inheritance of subtypes of type 2 disease is [[autosomal dominant]], with the exception of type 2N,<ref name="pmid22102189">{{cite journal| author=Hampshire DJ, Goodeve AC| title=The international society on thrombosis and haematosis von Willebrand disease database: an update. | journal=Semin Thromb Hemost | year= 2011 | volume= 37 | issue= 5 | pages= 470-9 | pmid=22102189 | doi=10.1055/s-0031-1281031 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102189  }} </ref> which has a recessive pattern of inheritance. Patients may be either homozygous for two type 2N mutations or compound heterozygous for a type 1 defect and a type 2N defect.
* [[Acquired disorder|Acquired]] [[VWD]] is associated with other diseases resulting from different pathological processes. These pathological processes include:  
Type 2 [[vWD]] (20-30%) is a qualitative defect and the bleeding tendency can vary between individuals. There are normal levels of vWF, but the multimers are structurally abnormal, or subgroups of large or small multimers are absent.
Deficiency of [[vWF]] shows primarily in organs with extensive small vessels, such as the skin, the [[gastrointestinal tract]] and the [[uterus]].
In more severe cases of type 1 [[vWD]], genetic changes are common within the [[vWF]] gene and are highly [[Penetrance|penetrant]]. In milder cases of type 1 [[vWD]] there may be a complex spectrum of molecular [[pathology]] in addition to [[Polymorphism (biology)|polymorphism]]s of the vWF gene alone.<ref>{{cite journal | author = James P, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S, Brown C, Andrews C, Labelle A, Chirinian Y, O'Brien L, Othman M, Rivard G, Rapson D, Hough C, Lillicrap D | title = The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study | journal = Blood | volume = 109 | issue = 1 | pages = 145–54 | year = 2007 | pmid = 17190853 | doi = 10.1182/blood-2006-05-021105}}</ref> The individual's [[ABO blood group system|ABO blood group]] can influence presentation and pathology of vWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group–specific vWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I vWD, and some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood group.<ref>{{cite journal | last = Gill | first = JC | coauthors = Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR | title = The effect of ABO blood group on the diagnosis of von Willebrand disease | journal = Blood | volume = 69 | issue = 6 | pages = 1691–5 | publisher = | date = 1987 | url = http://www.bloodjournal.org/cgi/content/abstract/69/6/1691 | doi = | pmid = 3495304 | accessdate =  }}</ref>


Von Willebrand's Disease is usually inherited in an [[autosomal dominant]] manner, although there are recessive forms as well, and it can also be acquired secondary to another disease.<ref name="pmid17133419">{{cite journal| author=Franchini M, Lippi G| title=Acquired von Willebrand syndrome: an update. | journal=Am J Hematol | year= 2007 | volume= 82 | issue= 5 | pages= 368-75 | pmid=17133419 | doi=10.1002/ajh.20830 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17133419  }} </ref><ref name="pmid21540459">{{cite journal| author=Tiede A, Rand JH, Budde U, Ganser A, Federici AB| title=How I treat the acquired von Willebrand syndrome. | journal=Blood | year= 2011 | volume= 117 | issue= 25 | pages= 6777-85 | pmid=21540459 | doi=10.1182/blood-2010-11-297580 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21540459  }} </ref><ref name="pmid11838652">{{cite journal| author=Kumar S, Pruthi RK, Nichols WL| title=Acquired von Willebrand disease. | journal=Mayo Clin Proc | year= 2002 | volume= 77 | issue= 2 | pages= 181-7 | pmid=11838652 | doi=10.4065/77.2.181 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11838652  }} </ref><ref name="pmid10959686">{{cite journal| author=Veyradier A, Jenkins CS, Fressinaud E, Meyer D| title=Acquired von Willebrand syndrome: from pathophysiology to management. | journal=Thromb Haemost | year= 2000 | volume= 84 | issue= 2 | pages= 175-82 | pmid=10959686 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10959686  }} </ref><ref name="pmid10959711">{{cite journal| author=Federici AB, Rand JH, Bucciarelli P, Budde U, van Genderen PJ, Mohri H et al.| title=Acquired von Willebrand syndrome: data from an international registry. | journal=Thromb Haemost | year= 2000 | volume= 84 | issue= 2 | pages= 345-9 | pmid=10959711 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10959711  }} </ref><ref>Ng et al. Diagnostic Approach to von Willebrand Disease.  Blood 2015; 125(13): 2029-2037.</ref><ref>Blomback et al. Von Willebrand Disease Biology Hemophilia 2012; 18: 141-147.</ref><ref>Favarolo et al. Von Willebrand Disease and Platelet Disorders.  Hemophilia 2014; 20: 59-64.</ref> Acquired [[VWD]] is associated with other diseases resulting from different pathological processes.
*[[Antibody]] formation resulting in:<ref name="pmid7949092">{{cite journal| author=van Genderen PJ, Vink T, Michiels JJ, van 't Veer MB, Sixma JJ, van Vliet HH| title=Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen. | journal=Blood | year= 1994 | volume= 84 | issue= 10 | pages= 3378-84 | pmid=7949092 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7949092  }} </ref><ref name="pmid1085186">{{cite journal| author=Handin RI, Martin V, Moloney WC| title=Antibody-induced von Willebrand's disease: a newly defined inhibitor syndrome. | journal=Blood | year= 1976 | volume= 48 | issue= 3 | pages= 393-405 | pmid=1085186 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1085186  }} </ref>
These pathological processes include:
*Antibody formation resulting in:<ref name="pmid7949092">{{cite journal| author=van Genderen PJ, Vink T, Michiels JJ, van 't Veer MB, Sixma JJ, van Vliet HH| title=Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen. | journal=Blood | year= 1994 | volume= 84 | issue= 10 | pages= 3378-84 | pmid=7949092 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7949092  }} </ref><ref name="pmid1085186">{{cite journal| author=Handin RI, Martin V, Moloney WC| title=Antibody-induced von Willebrand's disease: a newly defined inhibitor syndrome. | journal=Blood | year= 1976 | volume= 48 | issue= 3 | pages= 393-405 | pmid=1085186 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1085186  }} </ref>
**Impaired vWF function  
**Impaired vWF function  
**Increased clearance of [[VWF]]
**Increased clearance of [[VWF]]
*Enhanced [[proteolysis]]
*Enhanced [[proteolysis]]
*Decreased synthesis
*Decreased [[synthesis]]




Line 37: Line 130:
|+ '''von Willebrand disease'''
|+ '''von Willebrand disease'''
!
!
|-valign="top"
|- valign="top"
|[[Image:autodominant.jpg|thumb|von Willebrand disease types I and II are inherited in an [[autosomal dominant]] pattern.]]
|[[Image:autodominant.jpg|thumb|von Willebrand disease types I and II are inherited in an [[autosomal dominant]] pattern.]]
|}
|}
Line 56: Line 149:


====Malignant diseases====
====Malignant diseases====
*Monoclonal gammopathy of undetermined significance
*[[Monoclonal gammopathy]] of undetermined significance


*Leukemia example [[chronic myeloid leukemia]] and [[chronic lymphocytic leukemia]]
*Leukemia example [[chronic myeloid leukemia]] and [[chronic lymphocytic leukemia]]

Revision as of 16:26, 29 August 2018

Von Willebrand disease Microchapters

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Von Willebrand disease 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

Chest X Ray

CT

MRI

Ultrasound

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

Von Willebrand disease pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Von Willebrand disease pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Von Willebrand disease pathophysiology

on Von Willebrand disease pathophysiology

Von Willebrand disease pathophysiology in the news

Blogs on Von Willebrand disease pathophysiology

Directions to Hospitals Treating Von Willebrand disease

Risk calculators and risk factors for Von Willebrand disease pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

Overview

Pathophysiology

Physiology

Von Willebrand factor (vWF)

The normal physiology of von Willebrand’s factor can be understood as follows:[1]

Structure

These monomer contains a number of specific domains with a distinguishing function.

Function

Pathogenesis

von Willebrand disease is due to an abnormality, either quantitative or qualitative, of the von Willebrand factor[2]

Pathogenetic mechanisms of inherited VWD

VWD subtype Pathogenetic mechanisms
Type 1 VWD 65% have VWF mutations Partial quantitative deficiency of VWF
70% of VWF variants are missense substitutions affecting VWF trafficking, storage, secretion, and clearance
Transcription and splicing VWF mutations
Type 2A VWD Mutations in D1/D2/D′D3 assemblies, A2 and CTCK domains Loss of high-molecular-weight multimers (HMWMs)
Interference with HMW multimer formation, storage, and secretion
Increased ADAMTS13 proteolysis
Type 2B VWD Mutations in A1 domain The increase in binding of larger VWF multimers to platelet GP Ib results in sequestration of the platelets and VWF resulting in Thrombocytopenia
Excessive binding to GPIb glycoprotein Ib
Type 2M VWD Mutations in A1 and A3 domains Qualitative variants with decreased binding of VWF to GP Ib, resulting in decreased platelet adhesion
Diminished binding to GPIbα glycoprotein Ib (A1 domain) or collagen (A3 domain)
Type 2N VWD Missense variants in D′D3 assembly Qualitative variants with remarkably decreased affinity for FVIII
Reduced FVIII binding
Type 3 VWD VWF mutations found in 85%-90% of cases Produces null phenotype or the VWF that is not secreted.
VWF deletions, nonsense, splice site, and missense mutations

Pathogenetic mechanisms of acquired VWD

  • Acquired VWD is associated with other diseases resulting from different pathological processes. These pathological processes include:


Genetics

Von Willebrand disease types 1 and 2 (except type 2N which is inherited recessively) are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. The diagram below illustrates autosomal dominant inheritance.

von Willebrand disease
von Willebrand disease types I and II are inherited in an autosomal dominant pattern.

Associated conditions

Acquired conditions associated with Von Willebrand disease include the following:[13][14][3][4][5][6][7]

Heart-related conditions

Malignant diseases

Drugs and other agents

Autoimmune disorders

Other disorders

References

  1. ↑ Peyvandi F, Garagiola I, Baronciani L (May 2011). "Role of von Willebrand factor in the haemostasis". Blood Transfus. 9 Suppl 2: s3–8. doi:10.2450/2011.002S. PMC 3159913. PMID 21839029.
  2. ↑ Lillicrap D (November 2013). "von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy". Blood. 122 (23): 3735–40. doi:10.1182/blood-2013-06-498303. PMC 3952678. PMID 24065240.
  3. ↑ 3.0 3.1 Franchini M, Lippi G (2007). "Acquired von Willebrand syndrome: an update". Am J Hematol. 82 (5): 368–75. doi:10.1002/ajh.20830. PMID 17133419.
  4. ↑ 4.0 4.1 Tiede A, Rand JH, Budde U, Ganser A, Federici AB (2011). "How I treat the acquired von Willebrand syndrome". Blood. 117 (25): 6777–85. doi:10.1182/blood-2010-11-297580. PMID 21540459.
  5. ↑ 5.0 5.1 Kumar S, Pruthi RK, Nichols WL (2002). "Acquired von Willebrand disease". Mayo Clin Proc. 77 (2): 181–7. doi:10.4065/77.2.181. PMID 11838652.
  6. ↑ 6.0 6.1 Veyradier A, Jenkins CS, Fressinaud E, Meyer D (2000). "Acquired von Willebrand syndrome: from pathophysiology to management". Thromb Haemost. 84 (2): 175–82. PMID 10959686.
  7. ↑ 7.0 7.1 Federici AB, Rand JH, Bucciarelli P, Budde U, van Genderen PJ, Mohri H; et al. (2000). "Acquired von Willebrand syndrome: data from an international registry". Thromb Haemost. 84 (2): 345–9. PMID 10959711.
  8. ↑ Ng et al. Diagnostic Approach to von Willebrand Disease. Blood 2015; 125(13): 2029-2037.
  9. ↑ Blomback et al. Von Willebrand Disease Biology Hemophilia 2012; 18: 141-147.
  10. ↑ Favarolo et al. Von Willebrand Disease and Platelet Disorders. Hemophilia 2014; 20: 59-64.
  11. ↑ van Genderen PJ, Vink T, Michiels JJ, van 't Veer MB, Sixma JJ, van Vliet HH (1994). "Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen". Blood. 84 (10): 3378–84. PMID 7949092.
  12. ↑ Handin RI, Martin V, Moloney WC (1976). "Antibody-induced von Willebrand's disease: a newly defined inhibitor syndrome". Blood. 48 (3): 393–405. PMID 1085186.
  13. ↑ Simone JV, Cornet JA, Abildgaard CF (1968). "Acquired von Willebrand's syndrome in systemic lupus erythematosus". Blood. 31 (6): 806–12. PMID 4172730.
  14. ↑ Wautier JL, Levy-Toledano S, Caen JP (1976). "Acquired von Willebrand's syndrome and thrombopathy in a patient with chronic lymphocytic leukaemia". Scand J Haematol. 16 (2): 128–34. PMID 1083062.

Template:WH Template:WS

Retrieved from "https://www.wikidoc.org/index.php?title=Von_Willebrand_disease_pathophysiology&oldid=1492443"