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.<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> 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> The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD.<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>
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==
Von Willebrand disease may be classified as acquired or inherited.
=== 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.
Classification of von Willebrand disease,
Classification of von Willebrand disease,
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=== Inherited ===
Von Willebrand disease may be classified as nherited 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>
* 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.
* Type 1 VWD
== Inherited ==
** efers to partial quantitative deficiency of VWF.
* 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 2 VWD refers to qualitative deficiency of VWF.
* '''Type 1 VWD'''
** Refers to partial quantitative deficiency of VWF.
* '''Type 2 VWD'''
** Refers to qualitative deficiency of VWF.
** '''Type 2A'''
** '''Type 2A'''
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** Patient has the clinical findings of [[haemophilia A|hemophilia A]] but a pedigree suggesting autosomal, rather than X-linked, inheritance.
** Patient has the clinical findings of [[haemophilia A|hemophilia A]] but a pedigree suggesting autosomal, rather than X-linked, inheritance.
* Type 3 VWD refers to virtually complete deficiency of VWF. platelet-dependent function that is associated with the absence of high-molecular-weight VWF multimers. 4. Type 28 VWD refers to qualitative variants with increased affinity for platelet glycoprotein lb. platelet-dependent function that is not caused by the absence of high-molecular-weight VWF multimers. 6. Type 2N VWD refers to qualitative variants with markedly decreased affinity for factor VIII. 7. When recognized, a mixed phenotype caused by compound heterozygosity is indicated by separate classification of each allele separated by a slash (h. suggested for amino acids and nucleotides. 3. Type 2A VWD refers to qualitative variants with decreased 5. Type 2M VWD refers to qualitative variants with decreased 8. For the description of mutations, numbering sy
* '''Type 3 VWD'''
** 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>
===Type 1===
** Most severe form of vWD
** Patients have severe mucosal bleeding.
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).
** Low levels of [[factor VIII]]
Most cases of type 1 VWD are caused by heterozygous missense mutations that exert a dominant-negative effect.<ref name="pmid17190853">{{cite journal| author=James PD, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S et al.| title=The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. | journal=Blood | year= 2007 | volume= 109 | issue= 1 | pages= 145-54 | pmid=17190853 | doi=10.1182/blood-2006-05-021105 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17190853 }} </ref><ref name="pmid16985174">{{cite journal| author=Goodeve A, Eikenboom J, Castaman G, Rodeghiero F, Federici AB, Batlle J et al.| title=Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). | journal=Blood | year= 2007 | volume= 109 | issue= 1 | pages= 112-21 | pmid=16985174 | doi=10.1182/blood-2006-05-020784 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16985174 }} </ref><ref name="pmid26245874">{{cite journal| author=Batlle J, Pérez-Rodríguez A, Corrales I, López-Fernández MF, Rodríguez-Trillo Á, Lourés E et al.| title=Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): Proposal for a new diagnostic paradigm. | journal=Thromb Haemost | year= 2016 | volume= 115 | issue= 1 | pages= 40-50 | pmid=26245874 | doi=10.1160/TH15-04-0282 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26245874 }} </ref><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> The mutant subunits are incorporated into the multimer together with the normal subunits, resulting in a disturbance of the entire multimer.
===Type 2===
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.
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====
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.
====Type 2B====
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.
====Type 2M====
This is caused by decreased or absent binding 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 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.
===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><ref name="GP1BA glycoprotein Ib platelet alpha subunit">https://www.ncbi.nlm.nih.gov/gene/2811</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.
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
Type 1
Partial quantitative deficiency of VWF
Accounts for 60%-70% of patients with VWD
Bleeding severity mild to severe
AD inheritance
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 nherited 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
Refers to partial quantitative deficiency of VWF.
Type 2 VWD
Refers to qualitative deficiency of VWF.
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.
Acquired vWD can occur in patients with autoantibodies. In this case the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the circulation.
↑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. PMID8052974.