View source for Von Willebrand disease

'''For patient information click [[Von Willebrand disease (patient information)|here]]'''

{{Infobox Disease
|Name           = Von Willebrand disease
|Image          = 
|Caption        = 
|DiseasesDB     = 14007 
|ICD10          = {{ICD10|D|68|0|d|65}}
|ICD9           = {{ICD9|286.4}}
|ICDO           = 
|OMIM           = 193400
|MedlinePlus    = 000544 
|MeshID         = D014842
}}
{{SI}}
{{CMG}}

{{EH}}

==Overview==
'''Von Willebrand disease''' (vWD) is the most common hereditary [[coagulation]] abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of [[von Willebrand factor]] (vWF), a [[Protein subunit|multimeric]] protein that is required for [[platelet]] adhesion. It is known to affect humans and dogs. There are four types of [[hereditary]] vWD. Other factors including ABO blood groups may also play a part in the severity of the condition.

==Signs and symptoms==
The various types of vWD present with varying degrees of [[bleeding tendency]], usually in the form of easy bruising, [[epistaxis|nosebleeds]] and bleeding gums. Women may experience [[menorrhagia|heavy menstrual periods]] and blood loss during [[childbirth]].

Severe [[internal bleeding|internal]] or [[hemarthrosis|joint bleeding]] is rare (which only occurs in type 3 vWD).

==Diagnosis==
When suspected, [[blood plasma]] of a patient needs to be investigated for quantitative and qualitative deficiencies of vWF.  This is achieved by measuring the amount of vWF in a vWF antigen assay and the functionality of vWF with a [[glycoprotein]] (GP)Ib binding assay, a [[collagen]] binding assay or, a ''[[ristocetin]] cofactor'' activity (RiCof) or ''[[ristocetin induced platelet agglutination]]'' (RIPA) assays. [[Factor VIII]] levels are also performed as factor VIII is bound to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of vWF can therefore lead to a reduction in factor VIII levels. Normal levels do not exclude all forms of vWD: particularly type 2 which may only be revealed by investigating platelet interaction with subendothelium under flow (PAF), a highly specialized coagulation study not routinely performed in most [[medical laboratory|medical laboratories]]. A platelet aggregation assay will show an abnormal response to ristocetin with normal responses to the other agonists used. A [[PFA-100|platelet function assay]] (PFA) will give an abnormal collagen/[[adrenaline]] closure time and in most cases (but not all) a normal collagen/[[adenosine diphosphate|ADP]] time. Type 2N can only be diagnosed by performing a "factor VIII binding" assay. Detection of vWD is complicated by vWF being an [[acute phase reactant]] with levels rising in [[infection]], [[pregnancy]] and [[stress (medicine)|stress]].

Other tests performed in any patient with bleeding problems are a [[complete blood count]] (especially [[platelet]] counts), [[APTT]] (activated partial thromboplastin time), [[prothrombin time]], [[thrombin]] time and [[fibrinogen]] level. Testing for [[factor IX]] may also be performed if [[hemophilia B]] is suspected. Other [[coagulation factor]] assays may be performed depending on the results of a coagulation screen.  Patients with Von Willebrand disease will typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.

==Classification and types==
===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 Haemostasis'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>

===Type 1===
Type 1 vWD (60-80% of all vWD cases) is a quantitative defect (heterozygous for the defective gene) 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).

===Type 2===
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, no detectable [[vWF antigen]], 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]]).  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.

==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.

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.

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

==Pathophysiology==
{{For|the normal function of the coagulation factor|von Willebrand factor}}

vWF is mainly active in conditions of high blood flow and [[shear stress]]. Deficiency of vWF therefore shows primarily in organs with extensive small vessels, such as the skin, the [[gastrointestinal tract]] and the [[uterus]]. In [[angiodysplasia]], a form of [[telangiectasia]] of the [[colon (anatomy)|colon]], shear stress is much higher than in average [[capillary|capillaries]], and the risk of bleeding is increased concomitantly.

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>

==Genetics==
[[Image:autodominant.jpg|thumb|left|von Willebrand disease types I and II are inherited in an [[autosomal dominant]] pattern.]]
[[Image:autorecessive.svg|thumb|left|von Willebrand disease type III (and sometimes II) is inherited in an [[autosomal recessive]] pattern.]]
The vWF gene is located on [[Chromosome 12 (human)|chromosome twelve]] (12p13.2). It has 52 exons spanning 178kbp. Types 1 and 2 are inherited as [[autosomal dominant]] traits and type 3 is inherited as [[autosomal recessive]]. Occasionally type 2 also inherits recessively.

==Epidemiology==
In humans, the incidence of vWD is roughly about 1 in 100 individuals. Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during [[menstruation]]. The actual abnormality (which does not necessarily lead to disease) occurs in 0.9-3% of the population. It may be more severe or apparent in people with [[blood type]] O.

==Therapy==
Patients with vWD normally require no regular treatment, although they are always at increased risk for bleeding. For women with heavy menstrual bleeding, the [[combined oral contraceptive pill]] may be effective in reducing bleeding or in reducing the length or frequency of periods. Prophylactic treatment is sometimes given for patients with vWD who are scheduled for surgery. They can be treated with human derived medium purity [[factor VIII]] concentrates complexed to vWF(antihemophilic factor, more commonly known as [http://www.cslbehring-us.com/s1/cs/enus/1151517250474/page/1151517250857/ProductsList.htm Humate-P]) Mild cases of vWD can be trialled on [[desmopressin]] (1-desamino-8-D-arginine vasopressin, DDAVP) (desmopressin acetate, [http://www.cslbehring-us.com/s1/cs/enus/1151517250474/page/1151517250857/ProductsList.htm Stimate]), which works by raising the patient's own plasma levels of vWF by inducing release of vWF stored in the [[Weibel-Palade body|Weibel-Palade bodies]] in the endothelial cells.

==History==
vWD is [[eponym|named]] after [[Erik Adolf von Willebrand]], a Finnish [[paediatrics|paediatrician]] (1870–1949).<ref>{{WhoNamedIt|doctor|2690}}</ref> He first described the disease in 1926.


== References ==
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==See also==
* [[Blood diseases]]
* [[Bernard-Soulier syndrome]], caused by a deficiency in the vWF receptor, GPIb

==External links==
* [http://www.nhlbi.nih.gov/guidelines/vwd/index.htm Clinical Practice Guidelines]

{{Hematology}}
{{SIB}}
[[ar:مرض فون ويليبراند]]
[[de:Willebrand-Jürgens-Syndrom]]
[[es:Enfermedad de Von Willebrand]]
[[fr:Maladie de Willebrand]]
[[it:Malattia di von Willebrand]]
[[no:Von Willebrands sykdom]]
[[pl:Choroba von Willebranda]]
[[pt:Doença de von Willebrand]]
[[fi:Von Willebrandin tauti]]
[[sv:Von Willebrands sjukdom]]

{{WH}}
{{WS}}

[[Category:Disease]]
[[Category:Pediatrics]]
[[Category:Blood disorders]]
[[Category:Genetic disorders]]
[[Category:Hematology]]
[[Category:Mature chapter]]