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{{Von Willebrand disease}}
{{Von Willebrand disease}}


{{CMG}}
{{CMG}}  {{AE}} {{N.F}}


==Overview==
==Overview==
Von Willebrand disease may be classified as [[Acquired disorder|acquired]] or [[inherited]]. There are four [[hereditary]] types of vWD described - type 1, type 2, type 3, and platelet-type. Most cases are [[hereditary]], but ''[[Acquired disorder|acquired]]'' forms of vWD have been described. The International Society on [[Thrombosis]] and [[Hemostasis|Hemostasis's]] (ISTH) classification depends on the definition of [[qualitative]] and [[quantitative]] defects in Von Willebrand factor.


==Classification==
==Classification==  
There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type. There are inherited and acquired forms of  vWD. Most cases are hereditary, but ''acquired'' forms of vWD have been described. The International Society on Thrombosis and Hemostasis's (ISTH) classification depends on the definition of qualitative and quantitative defects.<ref>{{cite journal |author=Sadler JE |title=A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis |journal=Thromb. Haemost. |volume=71 |issue=4 |pages=520–5 |year=1994 |pmid=8052974 |doi= |url=}}</ref><ref name="pmid16889557">{{cite journal| author=Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L et al.| title=Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. | journal=J Thromb Haemost | year= 2006 | volume= 4 | issue= 10 | pages= 2103-14 | pmid=16889557 | doi=10.1111/j.1538-7836.2006.02146.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16889557  }} </ref>


===Type 1===
Classification of von Willebrand disease,
{| class="wikitable"
Type 1 vWD (60-80% of all vWD cases) is a partial deficiency of functionally normal VWF but may not have clearly impaired [[coagulation|clotting]], most patients usually end up leading a nearly normal life. Trouble may arise in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or [[menorrhagia]] (heavy [[menstruation|periods]]). Decreased levels of vWF are detected (10-45% of normal, i.e. 10-45 IU).
| colspan="1" rowspan="1" |'''Types'''
Most cases of type 1 VWD are caused by heterozygous missense mutations that exert a dominant-negative effect. The mutant subunits are incorporated into the multimer together with the normal subunits, resulting in a disturbance of the entire multimer.
| colspan="1" rowspan="1" |'''Quantitative Deficiency of VWF'''
|Comments
|-
| colspan="1" rowspan="1" |'''Type 1'''
| colspan="1" rowspan="1" |Partial quantitative deficiency of VWF
|
* Accounts for 60%-70% of patients with VWD
* Bleeding severity  mild to severe
* AD inheritance
* Factor VIII levels low,
|-
| colspan="1" rowspan="1" |'''Type 3'''
| colspan="1" rowspan="1" |Complete deficiency of VWF  
|
* Rare, 1%–2% of all cases
* Clinically similar to [[hemophilia A]] with joint and soft tissue bleeding
* Severe [[mucosal bleeding]]
* AR inheritance
* VWF activity and RIPA absent or decreased
* Factor VIII levels low, 1-10%
|-
| colspan="1" rowspan="1" |
| colspan="2" rowspan="1" |'''Qualitative Deficiency of VWF'''
|-
| colspan="1" rowspan="1" |'''Type 2'''
| colspan="1" rowspan="1" |Qualitative deficiency of VWF
|25%–30% of cases
|-
| colspan="1" rowspan="1" |'''Type 2A'''
| colspan="1" rowspan="1" |Qualitative variants with the absence of high and intermediate-molecular-weight VWF multimers
|
* Accounts for approximately one-tenth to one-fifth of patients with VWD
* Moderate to severe bleeding
* AD or AR inheritance
* VWF activity and RIPA decreased
* Factor VIII levels may be normal or reduced
|-
| colspan="1" rowspan="1" |'''Type 2B'''
| colspan="1" rowspan="1" |Qualitative variants with increased affinity for platelet GpIb
|
* Accounts for approximately 5% of patients with VWD
* The increase in binding of larger VWF multimers to [[platelet]] GP Ib results in sequestration of the [[platelets]] and VWF
* [[Thrombocytopenia]]
* Moderate to severe bleeding
* AD inheritance
* VWF activity decreased
* RIPA increased
* [[Factor VIII]] levels may be normal or reduced
|-
| colspan="1" rowspan="1" |'''Type 2M'''
| colspan="1" rowspan="1" |[[Qualitative]] variants with decreased binding of VWF to GP Ib, resulting in decreased platelet adhesion
|
* Uncommon
* Moderate to severe bleeding
* AD or AR inheritance
* VWF activity and RIPA decreased
* Factor VIII levels may be normal or decreased
|-
| colspan="1" rowspan="1" |'''Type 2N'''
| colspan="1" rowspan="1" |Qualitative variants with remarkably decreased [[affinity]] for [[Factor VIII|FVIII]]
|
* Uncommon
* Clinically similar to [[hemophilia A]] with joint, soft tissue, urinary bleeding
* AR inheritance
* VWF activity and RIPA normal
* [[Factor VIII]] levels low (5 to 15%)
|}


===Type 2===
Von Willebrand disease may be classified as inherited and acquired<ref name="pmid16889557">{{cite journal| author=Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L et al.| title=Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. | journal=J Thromb Haemost | year= 2006 | volume= 4 | issue= 10 | pages= 2103-14 | pmid=16889557 | doi=10.1111/j.1538-7836.2006.02146.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16889557  }} </ref><ref>{{cite journal |author=Sadler JE |title=A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis |journal=Thromb. Haemost. |volume=71 |issue=4 |pages=520–5 |year=1994 |pmid=8052974 |doi= |url=}}</ref><ref name="pmid18315614">{{cite journal| author=Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL et al.| title=von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). | journal=Haemophilia | year= 2008 | volume= 14 | issue= 2 | pages= 171-232 | pmid=18315614 | doi=10.1111/j.1365-2516.2007.01643.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18315614  }} </ref>
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, 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.
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. Four subtypes exist: 2A, 2B, 2M and 2N.


====Type 2A====
== Inherited ==
This is an abnormality of the synthesis or proteolysis of the vWF multimers resulting in the presence of small multimer units in circulation. Factor VIII binding is normal. It has a disproportionately low ristocetin co-factor activity compared to the von Willebrand's antigen.
* VWD is caused by [[mutations]] at the VWF locus and is usually classified into three main types according to quantitative (Types 1 and 3) or qualitative (Types 2A, 2B, 2M, 2N) abnormalities.<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>
* '''Type 1 VWD'''
** Refers to partial [[quantitative]] deficiency of VWF.
* '''Type 2 VWD'''  
** Refers to [[qualitative]] deficiency of VWF.


====Type 2B====
** '''Type 2A'''
This is a "gain of function" defect leading to spontaneous binding to platelets and subsequent rapid clearance of the platelets and the large vWF multimers. A mild [[thrombocytopenia]] may occur. The large vWF multimers are absent in the circulation and the factor VIII binding is normal. Like type 2A, the RiCof:vWF antigen assay is low when the patient's platelet-poor plasma is assayed against formalin-fixed, normal donor platelets.  However, when the assay is performed with the patient's own platelets ("platelet-rich plasma"), a lower-than-normal amount of ristocetin causes aggregation to occur.  This is due to the large vWF multimers remaining bound to the patient's platelets. Patients with this sub-type are unable to use desmopressin as a treatment for bleeding, because it can lead to unwanted platelet aggregation.
*** This is an abnormality of the [[synthesis]] or [[proteolysis]] of the vWF multimers.
*** This results in the presence of small multimer units in circulation.
***  [[Factor VIII]] binding is normal.
***  [[Ristocetin]] co-factor activity is low.
** '''Type 2B'''
***  There is a increase binding of vWF to [[platelets]]
***  There is rapid clearance of the [[platelets]] and the large vWF multimers.  
***  A mild [[thrombocytopenia]] may occur.  
***  The large vWF multimers are absent in the circulation
***  [[Factor VIII]] binding is normal.  
***  The RiCof:vWF antigen assay is low.
** '''Type 2M'''
***  This is caused by decreased or absent binding of vWF to [[Glycoprotein Ib|GPIb]] on the [[Platelets|platelets.]]
*** [[Factor VIII]] binding is normal.
***  '''Type 2N (Normandy)'''
***  This is a deficiency of the binding of vWF to [[factor VIII]].  
*** This type has a normal vWF antigen level and normal functional test results.
***  [[Factor VIII]] is low.
***  Patient has the clinical findings of [[haemophilia A|hemophilia A]] but a [[Pedigrees|pedigree]] suggesting [[Autosomal|autosomal,]] rather than X-linked, inheritance.


====Type 2M====
* '''Type 3 VWD'''
This is caused by decreased or absent binding to GPIb on the platelets. Factor VIII binding is normal.
** Virtually complete deficiency of VWF.<ref name="pmid26986123">{{cite journal| author=Veyradier A, Boisseau P, Fressinaud E, Caron C, Ternisien C, Giraud M et al.| title=A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. | journal=Medicine (Baltimore) | year= 2016 | volume= 95 | issue= 11 | pages= e3038 | pmid=26986123 | doi=10.1097/MD.0000000000003038 | pmc=4839904 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26986123  }} </ref>
 
** Most severe form of vWD
====Type 2N (Normandy)====
** Patients have severe [[Mucosal bleeding|mucosal bleeding.]]
This is a deficiency of the binding of vWF to factor VIII. This type gives a normal vWF antigen level and normal functional test results but has a low factor VIII. This has probably led to some 2N patients being misdiagnosed in the past as having hemophilia A, and should be suspected if the patient has the clinical findings of [[haemophilia A|hemophilia A]] but a pedigree suggesting autosomal, rather than X-linked, inheritance.
** Low levels of [[factor VIII]]
 
===Type 3===
Type 3 is the most severe form of vWD (homozygous for the defective gene) and may have severe mucosal bleeding. In 80% of patients with type 3 von Willebrand’s disease, the genetic defects in the [[VWF]] gene are null alleles, explaining the complete absence of von Willebrand factor with no detectable [[vWF antigen]]<ref name="pmid26986123">{{cite journal| author=Veyradier A, Boisseau P, Fressinaud E, Caron C, Ternisien C, Giraud M et al.| title=A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. | journal=Medicine (Baltimore) | year= 2016 | volume= 95 | issue= 11 | pages= e3038 | pmid=26986123 | doi=10.1097/MD.0000000000003038 | pmc=4839904 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26986123  }} </ref><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>, and may have sufficiently low [[factor VIII]] that they have occasional [[hemarthrosis|hemarthroses]] (joint bleeding), as in cases of mild [[hemophilia]].
 
===Platelet-type===
Platelet-type vWD is an autosomal dominant type of vWD caused by gain of function mutations of the vWF receptor on platelets; specifically, the alpha chain of the glycoprotein Ib receptor ([[GPIb]])<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>.  This protein is part of the larger complex (GPIb/V/IX) which forms the full vWF receptor on platelets.  The ristocetin activity and loss of large vWF multimers is similar to type 2B, but genetic testing of VWF will reveal no mutations. <ref name="GP1BA glycoprotein Ib platelet alpha subunit">https://www.ncbi.nlm.nih.gov/gene/2811</ref>


==Acquired von Willebrand disease==
==Acquired von Willebrand disease==
Acquired vWD can occur in patients with [[autoantibody|autoantibodies]]. In this case the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the circulation.
* [[Acquired disorder|Acquired]] vWD can occur in patients with [[autoantibody|autoantibodies]].
 
* In such cases the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the [[circulation]].
A form of vWD occurs in patients with [[aortic valve stenosis]], leading to [[gastrointestinal bleeding]] ([[Heyde's syndrome]]). This form of acquired vWD may be more prevalent than is presently thought.
* This form of vWD occurs in patients with [[aortic valve stenosis]], leading to [[gastrointestinal bleeding]] ([[Heyde's syndrome]]).  
 
Acquired vWF has also been described in the following disorders: [[Wilms' tumor|Wilms' tumour]], [[hypothyroidism]] and mesenchymal dysplasias.


* [[Acquired]] vWF has also been described in [[Wilms' tumor|Wilms' tumour]], [[hypothyroidism]] and mesenchymal dysplasias.


==References==
==References==

Latest revision as of 14:42, 13 September 2018

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nazia Fuad M.D.

Overview

Von Willebrand disease may be classified as acquired or inherited. There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type. Most cases are hereditary, but acquired forms of vWD have been described. The International Society on Thrombosis and Hemostasis's (ISTH) classification depends on the definition of qualitative and quantitative defects in Von Willebrand factor.

Classification

Classification of von Willebrand disease,

Types Quantitative Deficiency of VWF Comments
Type 1 Partial quantitative deficiency of VWF
  • Accounts for 60%-70% of patients with VWD
  • Bleeding severity mild to severe
  • AD inheritance
  • Factor VIII levels low,
Type 3 Complete deficiency of VWF
  • Rare, 1%–2% of all cases
  • Clinically similar to hemophilia A with joint and soft tissue bleeding
  • Severe mucosal bleeding
  • AR inheritance
  • VWF activity and RIPA absent or decreased
  • Factor VIII levels low, 1-10%
Qualitative Deficiency of VWF
Type 2 Qualitative deficiency of VWF 25%–30% of cases
Type 2A Qualitative variants with the absence of high and intermediate-molecular-weight VWF multimers
  • Accounts for approximately one-tenth to one-fifth of patients with VWD
  • Moderate to severe bleeding
  • AD or AR inheritance
  • VWF activity and RIPA decreased
  • Factor VIII levels may be normal or reduced
Type 2B Qualitative variants with increased affinity for platelet GpIb
  • Accounts for approximately 5% of patients with VWD
  • The increase in binding of larger VWF multimers to platelet GP Ib results in sequestration of the platelets and VWF
  • Thrombocytopenia
  • Moderate to severe bleeding
  • AD inheritance
  • VWF activity decreased
  • RIPA increased
  • Factor VIII levels may be normal or reduced
Type 2M Qualitative variants with decreased binding of VWF to GP Ib, resulting in decreased platelet adhesion
  • Uncommon
  • Moderate to severe bleeding
  • AD or AR inheritance
  • VWF activity and RIPA decreased
  • Factor VIII levels may be normal or decreased
Type 2N Qualitative variants with remarkably decreased affinity for FVIII
  • Uncommon
  • Clinically similar to hemophilia A with joint, soft tissue, urinary bleeding
  • AR inheritance
  • VWF activity and RIPA normal
  • Factor VIII levels low (5 to 15%)

Von Willebrand disease may be classified as inherited and acquired[1][2][3]

Inherited

  • VWD is caused by mutations at the VWF locus and is usually classified into three main types according to quantitative (Types 1 and 3) or qualitative (Types 2A, 2B, 2M, 2N) abnormalities.[4]
  • Type 1 VWD
  • Type 2 VWD
    • Type 2A
      • This is an abnormality of the synthesis or proteolysis of the vWF multimers.
      • This results in the presence of small multimer units in circulation.
      • Factor VIII binding is normal.
      • Ristocetin co-factor activity is low.
    • Type 2B
      • There is a increase binding of vWF to platelets
      • There is rapid clearance of the platelets and the large vWF multimers.
      • A mild thrombocytopenia may occur.
      • The large vWF multimers are absent in the circulation
      • Factor VIII binding is normal.
      • The RiCof:vWF antigen assay is low.
    • Type 2M
      • This is caused by decreased or absent binding of vWF to GPIb on the platelets.
      • Factor VIII binding is normal.
      • Type 2N (Normandy)
      • This is a deficiency of the binding of vWF to factor VIII.
      • This type has a normal vWF antigen level and normal functional test results.
      • Factor VIII is low.
      • Patient has the clinical findings of hemophilia A but a pedigree suggesting autosomal, rather than X-linked, inheritance.

Acquired von Willebrand disease

References

  1. ↑ Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L; et al. (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.
  2. ↑ Sadler JE (1994). "A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis". Thromb. Haemost. 71 (4): 520–5. PMID 8052974.
  3. ↑ Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL; et al. (2008). "von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)". Haemophilia. 14 (2): 171–232. doi:10.1111/j.1365-2516.2007.01643.x. PMID 18315614.
  4. ↑ Hampshire DJ, Goodeve AC (2011). "The international society on thrombosis and haematosis von Willebrand disease database: an update". Semin Thromb Hemost. 37 (5): 470–9. doi:10.1055/s-0031-1281031. PMID 22102189.
  5. ↑ Veyradier A, Boisseau P, Fressinaud E, Caron C, Ternisien C, Giraud M; et al. (2016). "A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture". Medicine (Baltimore). 95 (11): e3038. doi:10.1097/MD.0000000000003038. PMC 4839904. PMID 26986123.

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