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Latest revision as of 17:27, 4 September 2018

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

Overview

Von Willebrand’s disease is an genetic coagulation disorder with resultant abnormality in platelet adhesion and aggregation. Von Willebrand disease (vWD) is the most common genetic coagulation disorder described in humans. It affects up to 1% of the population, although most cases are mild. Symptomatic vWD is much rare, ~1 in 10000. Von Willebrand disease arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a large glycoprotein protein that is required for platelets to bind to collagen. vWF is therefore important in primary hemostasis. When the disease comes to medical attention, it usually presents in the typical manner for platelet disorders mucosal bleeding and easy bruising. The 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.

Historical Perspective

Von Willebrand's disease was first described by Erik Adolf von Willebrand, a Finnish pediatrician in 1926. Dr. Erik Adolf von Willebrand was also the first to differentiate Von Willebrand's disease from hemophilia. Von Willebrand's disease was initially named hereditary pseudo hemophilia. In the mid 1950s it was recognized that Von Willebrand's disease was usually accompanied by decreased level of coagulation factor VIII (FVIII) activity. In the early 1970s the immunologic distinction between FVIII and von Willebrand factor was established. In the 1980s, Cloning of the VWF gene was investigated which has facilitated investigation into the genetic basis of VWD.

Classification

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.

Pathophysiology

Von Willebrand factor is a glycoprotein present in blood and is involved in hemostasis. Its synthesis takes place in the endothelium (in the Weibel-Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue and are stored there too. The vWF monomer contains a number of specific domains which binds to factor VIII, platelet GPIb-receptor, Heparin, Collagen. Von Willebrand disease is due to an abnormality, either quantitative or qualitative, of the von Willebrand factor. Von Willebrand factor gene mutations results in problems with subunit or multimer formation, storage, secretion, proteolysis, and increased clearance. Von Willebrand's Disease can also be acquired secondary to another diseases. Acquired VWD is associated with other diseases resulting from different pathological processes. These pathological processes includes Antibody formation resulting in Impaired vWF function and Increased clearance of VWF. Other mechanisms are enhanced proteolysis and decreased synthesis of von Willebrand factor (vWF). 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.

Causes

VWD is caused by a quantitative or qualitative defect in vWF. Most cases of vWD are due to inherited mutations that affect production of vWF. There are also acquired forms of vWD where vWF is impaired due to other pathological processes. Acquired defects in vWF can be caused by a number of conditions,for example mitral valve prolapse, ventricular assist device, ventricular septal defect, aortic stenosis, monoclonal gammopathy of undetermined significance, chronic myeloid leukemia and chronic lymphocytic leukemia, wilms tumor, waldenström macroglobulinemia, essential thrombocythemia, multiple myeloma, non-Hodgkin lymphoma, polycythemia vera, valproic acid, ciprofloxacin, griseofulvin, systemic lupus erythematosus,hypothyroidism, uremia, hemoglobinopathies and angiodysplasia.

Differentiating Von Willebrand disease from other diseases

vWD must be differentiated from platelet disorders, thrombophilias, and hemophilias based on genetic disoder, clinical presentation, laboratory findings and treatment.

Epidemiology and Demographics

The prevalence of von Willebrand’s disease is 0.6 to 1.3%. It is estimated that the referral prevalence of von Willebrand’s disease is approximately 1 case per 10,000 persons. The actual abnormality (which does not necessarily lead to disease) occurs in 0.9-3% of the population. The symptoms of VWD is disproportionately more common in women of child-bearing age. Although autosomal inheritance pattern of disease lead to an equal distribution of male patients and female patients, the disease has female predominance whose bleeding tendency shows during menstruation. There is no racial predilection to vWD however, it may be more severe or apparent in people with blood type O.

Risk Factors

Common risk factors in the development of Von Willebrand disease include positive family history and consanguineous relationships. Less common risk factors in the development of Von Willebrand disease include lymphoproliferative disorders and aortic stenosis.

Screening

The ISTH-Bleeding Assessment Tool is a validated instrument that is used to screen patients referred for bleeding symptoms for further laboratory testing. The three main screening tests used in the diagnosis of VWD include vonWillebrand Factor (VWF) antigen, platelet-dependent VWF activity, and factor VIII activity

Natural History, Complications, and Prognosis

Patients with VWD can become symptomatic at any age. A typical history in a patient with mild to moderate disease includes epistaxis lasting longer than 10 minutes in childhood lifelong easy bruising, bleeding following dental extractions, other invasive dental procedures, or other forms of surgery. Women with VWD usually have a history of heavy menstrual bleeding and may have bleeding during the peripartum period, often at or within hours of delivery and at 5 to 10 days after delivery. Menorrhagia is a major complication. Angiodysplasia is serious, and possibly life-threatening complication. Intraarticular bleeding may be a presenting symptom in those with type 2N or type 3 disease. For some patients, vWD is a mild bleeding disorder and can be managed easily. Patients with mild disease may experience clinically severe hemorrhage following trauma or invasive procedures. Variability of symptoms exists among family members. People with vWD types II and III face severe and potentially life threatening bleeding episodes. Type III disease patients have low FVIII levels and present with arthropathies. Levels of vWF normally increase with age in patients with type I vWD, In patients with type II vWD, vWF levels does not increase with aging.

Diagnosis

Diagnostic Study of Choice

There is no single diagnostic study of choice for the diagnosis of von Willebrand disease, but von Willebrand disease can be diagnosed based on screening tests followed by confirmatory tests. The screening tests for VWD that are selected by the National Heart, Lung, and Blood Institute include testing for vWF antigen, VWF ristocetin cofactor activityand factor VIII clotting activity. When one of the VWD screening test is abnormal, further confirmatory tests are performed to establish the correct diagnosis and determine the type of VWD. Genotyping is most beneficial for type 1 patients with vWF ≤30 IU/dL and those with type 2 or 3. Genotyping also detects a benign type of vWD the D1472H, It affects ristocetin binding but not vWF function.

History and Symptoms

Patients with von Willebrand’s disease present with history of mucosal bleeding, recurrent nose bleeds, oral cavity bleeding, and positive family history of similer symptoms among other family members. Adults patients with vWD mainly present with bleeding after dental extraction/ or other surgery. Heavy menstrual periods and postpartum hemorrhage are common among affected females with von Willebrand’s disease. Severe internal or joint bleeding can occur but is usually rare.

Physical Examination

Patients with vWD commonly have negative physical examination findings however the findings may include ecchymoses, hematomas with varying sizes and location and evidence of current or recent mucosal bleeding.

Laboratory Findings

The diagnosis of von Willebrand’s disease (VWD) begins with a relevant personal or family history of mucocutaneous bleeding. When VWD is suspected, several levels of testing are needed in order to make diagnosis. Initail tests involve measurement of VWF antigen (VWF:Ag) level, Factor VIII activity (FVIII:C) and VWF–ristocetin cofactor activity [VWF:RCo]. When the results of all first-level tests are normal, VWD is ruled out; because of biologic variability, however, the tests should be repeated if values are at the low end of the normal range or if VWD is strongly suspected. Persons with a bleeding tendency who have VWF levels between 30 and 50 IU per deciliter are classified as having “low VWF” or “possible type 1 disease” but are not classified as having definitive VWD. When von Willebrand factor antigen is undetectable (or the level is <5 IU per deciliter, according to the latest disease classification), type 3 von Willebrand’s disease is diagnosed. If these first-level tests reveal definitive abnormalities, a diagnosis of VWD can be made; if the results are not conclusive, second-level tests are required. Second level testing involves repeating the initial tests and then measurement of VWF multimer distribution using gel electrophoresis and ristocetin-induced platelet aggregation (RIPA). Other tests performed in any patient with bleeding problems include: complete blood count (especially platelet counts), APTT (activated partial thromboplastin time), prothrombin time, thrombin time, fibrinogen level, testing for factor IX if hemophilia B is suspected and 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.

Imaging Findings

There are no imaging findings associated with Von Willebrand disease.

Other Diagnostic Studies

There are no other diagnostic findings associated with Von Willebrand disease.

Treatment

Medical Therapy

The mainstay of management of VWD is medical therapy. Medical therapy of von Willebrand's disease ( vWD) involves normalizing the von Willebrand factor and factor VIIIlevels. Endogenous factor levels can be increased by the use of desmopressin or by infusing exogenous coagulation factors example high-purity or low-purity von Willebrand factor concentrate. Medical therapy depends on the type of von Willebrand's disease. Desmopressin is used for type 1 and 2 von Willebrand's disease. von Willebrand factor-factor VIII or von Willebrand factor concentrate is used in some of type 2 von Willebrand's disease and all of type 3 von Willebrand's disease. Alternate or additional therapy involves the use of tranexamic acid or aminocaproic acid.

Prevention

There are no known preventive measures for von Willebrand disease. In families with type 3 disease, genetic analysis may be useful for counseling.

References

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 {{Von Willebrand disease}}
-{{CMG}} {{AE}}  {{PTD}}
+{{CMG}} {{AE}}  {{PTD}}  {{N.F}}
 ==Overview==
-Von Willebrand’s disease is an genetic coagulation disorder with resultant abnormality in platelet adhesion and aggregation.
+Von Willebrand’s disease is an genetic [[coagulation disorder]] with resultant abnormality in platelet adhesion and aggregation. [[Von Willebrand disease]] ([[vWD]]) is the most common genetic coagulation disorder described in humans.  It affects up to 1% of the population, although most cases are mild. Symptomatic [[vWD]] is much rare, ~1 in 10000.  Von Willebrand disease arises from a [[qualitative]] or [[quantitative]] deficiency of [[von Willebrand factor]] ([[vWF]]), a large [[glycoprotein]] protein that is required for [[platelet]]<nowiki/>s to bind to collagen.  [[vWF]] is therefore important in primary [[hemostasis]].  When the disease comes to medical attention, it usually presents in the typical manner for platelet disorders mucosal bleeding and easy bruising. The 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.
-[[Von Willebrand disease]] ([[vWD]]) is the most common genetic coagulation disorder described in humans.<ref name="pmid3492222">{{cite journal| author=Rodeghiero F, Castaman G, Dini E| title=Epidemiological investigation of the prevalence of von Willebrand's disease. | journal=Blood | year= 1987 | volume= 69 | issue= 2 | pages= 454-9 | pmid=3492222 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3492222  }} </ref>  It affects up to 1% of the population, although most cases are mild.  Symptomatic [[vWD]] is much rare, ~1 in 10000.  Von Willebrand disease arises from a qualitative or quantitative deficiency of [[von Willebrand factor]] ([[vWF]]), a large glycoprotein protein that is required for [[platelet]]<nowiki/>s to bind to collagen.  [[vWF]] is therefore important in primary hemostasis.  When the disease comes to medical attention, it usually presents in the typical manner for platelet disorders: mucosal bleeding and easy bruising.  The 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>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>
 ==Historical Perspective==
-*[[Von Willebrand's disease]] was first described by [[Erik Adolf von Willebrand]], a Finnish [[paediatrics|paediatrician]] in 1926.<ref>{{WhoNamedIt|doctor|2690}}</ref><ref name="pmid23020315">{{cite journal| author=Lenting PJ, Casari C, Christophe OD, Denis CV| title=von Willebrand factor: the old, the new and the unknown. | journal=J Thromb Haemost | year= 2012 | volume= 10 | issue= 12 | pages= 2428-37 | pmid=23020315 | doi=10.1111/jth.12008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23020315  }} </ref>
+[[Von Willebrand's disease]] was first described by [[Erik Adolf von Willebrand]], a Finnish [[Paediatrics|pediatrician]] in 1926. Dr. [[Erik Adolf von Willebrand]] was also the first to differentiate [[Von Willebrand's disease]] from [[hemophilia]]. [[Von Willebrand's disease]] was initially named hereditary [[pseudo hemophilia]]. In the mid 1950s it was recognized that [[Von Willebrand's disease]] was usually accompanied by decreased level of coagulation [[factor VIII]] (FVIII) activity. In the early 1970s the immunologic distinction between [[FVIII]] and [[von Willebrand factor]] was established. In the 1980s, Cloning of the VWF gene was investigated which has facilitated investigation into the genetic basis of VWD.
-*Dr. [[Erik Adolf von Willebrand]] was also the first to differeentiate [[Von Willebrand's disease]] from hemophilia.<ref name="pmid23020315">{{cite journal| author=Lenting PJ, Casari C, Christophe OD, Denis CV| title=von Willebrand factor: the old, the new and the unknown. | journal=J Thromb Haemost | year= 2012 | volume= 10 | issue= 12 | pages= 2428-37 | pmid=23020315 | doi=10.1111/jth.12008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23020315  }} </ref>
-*[[Von Willebrand's disease]] was initially named hereditary pseudohemophilia.<ref name="pmid23020315">{{cite journal| author=Lenting PJ, Casari C, Christophe OD, Denis CV| title=von Willebrand factor: the old, the new and the unknown. | journal=J Thromb Haemost | year= 2012 | volume= 10 | issue= 12 | pages= 2428-37 | pmid=23020315 | doi=10.1111/jth.12008 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23020315  }} </ref>
-*In the mid 1950s it was recognized that [[Von Willebrand's disease]] was usually accompanied by the following:<ref name="pmid21289515">{{cite journal| author=James PD, Goodeve AC| title=von Willebrand disease. | journal=Genet Med | year= 2011 | volume= 13 | issue= 5 | pages= 365-76 | pmid=21289515 | doi=10.1097/GIM.0b013e3182035931 | pmc=3832952 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21289515  }} </ref>
+==Classification==
-**A decreased level of coagulation [[factor VIII]] (FVIII) activity
+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.
-**Bleeding phenotype could be corrected by the infusion of normal plasma.
-*In the early 1970s the immunologic distinction between [[FVIII]] and [[von Willebrand factor]] was made.<ref name="pmid21289515">{{cite journal| author=James PD, Goodeve AC| title=von Willebrand disease. | journal=Genet Med | year= 2011 | volume= 13 | issue= 5 | pages= 365-76 | pmid=21289515 | doi=10.1097/GIM.0b013e3182035931 | pmc=3832952 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21289515  }} </ref>
-*In the 1980s, cloning of the VWF gene was investigated which has facilitated investigation into the genetic basis of VWD.<ref name="pmid21289515">{{cite journal| author=James PD, Goodeve AC| title=von Willebrand disease. | journal=Genet Med | year= 2011 | volume= 13 | issue= 5 | pages= 365-76 | pmid=21289515 | doi=10.1097/GIM.0b013e3182035931 | pmc=3832952 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21289515  }} </ref><ref name="pmid3873280">{{cite journal| author=Lynch DC, Zimmerman TS, Collins CJ, Brown M, Morin MJ, Ling EH et al.| title=Molecular cloning of cDNA for human von Willebrand factor: authentication by a new method. | journal=Cell | year= 1985 | volume= 41 | issue= 1 | pages= 49-56 | pmid=3873280 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3873280  }} </ref><ref name="pmid2864688">{{cite journal| author=Sadler JE, Shelton-Inloes BB, Sorace JM, Harlan JM, Titani K, Davie EW| title=Cloning and characterization of two cDNAs coding for human von Willebrand factor. | journal=Proc Natl Acad Sci U S A | year= 1985 | volume= 82 | issue= 19 | pages= 6394-8 | pmid=2864688 | doi= | pmc=390722 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2864688  }} </ref><ref name="pmid3874428">{{cite journal| author=Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GA, Latt SA et al.| title=Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. | journal=Science | year= 1985 | volume= 228 | issue= 4706 | pages= 1401-6 | pmid=3874428 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3874428  }} </ref><ref name="pmid3019665">{{cite journal| author=Verweij CL, Diergaarde PJ, Hart M, Pannekoek H| title=Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit. | journal=EMBO J | year= 1986 | volume= 5 | issue= 8 | pages= 1839-47 | pmid=3019665 | doi= | pmc=1167049 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3019665  }} </ref>
-==Classification==
-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> 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> 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>
 ==Pathophysiology==
-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.
+Von Willebrand factor 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 and are stored there too. The vWF [[monomer]] contains a number of specific [[Protein domains|domains]] which binds to [[factor VIII]], platelet GPIb-receptor, [[Heparin]], [[Collagen]]. Von Willebrand disease is due to an abnormality, either [[quantitative]] or [[qualitative]], of the von Willebrand factor. Von Willebrand factor gene [[Mutation|mutations]] results in problems with subunit or multimer formation, storage, secretion, [[proteolysis]], and increased clearance. Von Willebrand's Disease can also be [[Acquired disorder|acquired]] secondary to another diseases. [[Acquired disorder|Acquired]] [[VWD]] is associated with other diseases resulting from different pathological processes. These pathological processes includes [[Antibody]] formation resulting in Impaired vWF function and Increased clearance of [[VWF]]. Other mechanisms are enhanced [[proteolysis]] and decreased [[synthesis]] of von Willebrand factor (vWF). [[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]].
-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 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>
+==Causes==
+[[VWD]] is caused by a quantitative or qualitative defect in [[vWF]]. Most cases of vWD are due to inherited mutations that affect production of vWF. There are also acquired forms of vWD where vWF is impaired due to other pathological processes. Acquired defects in [[vWF]] can be caused by a number of conditions,for example [[mitral valve prolapse]], ventricular assist device, [[ventricular septal defect]], [[aortic stenosis]], [[monoclonal gammopathy]] of undetermined significance, [[chronic myeloid leukemia]] and [[chronic lymphocytic leukemia]], [[wilms tumor]], [[waldenström macroglobulinemia]], [[essential thrombocythemia]], [[multiple myeloma]], [[non-Hodgkin lymphoma]], [[polycythemia vera]], [[valproic acid]], [[ciprofloxacin]], [[griseofulvin]], [[systemic lupus erythematosus]],[[hypothyroidism]], [[uremia]], [[hemoglobinopathies]] and [[angiodysplasia]].
-==Causes==
+==Differentiating Von Willebrand disease from other diseases==
-[[VWD]] is caused by a quantitative or qualitative defect in [[vWF]].  [[Von Willebrand Factor]] binds [[platelets]] to [[collagen]] and is important in primary [[hemostasis]].  It also serves as a carrier for [[Factor VIII]] and prevents it form being degraded.  Most cases of vWD are due to inherited mutations that affect production of vWF.  There are also acquired forms of vWD where vWF is impaired due to other pathological processes. Acquired defects in [[vWF]] can be caused by a number of conditions example [[mitral valve prolapse]], ventricular assist device, [[ventricular septal defect]], [[aortic stenosis]], monoclonal gammopathy of undetermined significance,  leukemia example [[chronic myeloid leukemia]] and [[chronic lymphocytic leukemia]], [[wilms tumor]], [[waldenström macroglobulinemia]],[[essential thrombocythemia]], [[multiple myeloma]], [[non-Hodgkin lymphoma]], [[polycythemia vera]], [[valproic acid]], [[ciprofloxacin]], [[griseofulvin]], [[systemic lupus erythematosus]],[[hypothyroidism]], [[uremia]], [[hemoglobinopathies]] and [[angiodysplasia]].<ref name="pmid4172730">{{cite journal| author=Simone JV, Cornet JA, Abildgaard CF| title=Acquired von Willebrand's syndrome in systemic lupus erythematosus. | journal=Blood | year= 1968 | volume= 31 | issue= 6 | pages= 806-12 | pmid=4172730 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4172730  }} </ref><ref name="pmid1083062">{{cite journal| author=Wautier JL, Levy-Toledano S, Caen JP| title=Acquired von Willebrand's syndrome and thrombopathy in a patient with chronic lymphocytic leukaemia. | journal=Scand J Haematol | year= 1976 | volume= 16 | issue= 2 | pages= 128-34 | pmid=1083062 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=1083062  }} </ref><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>
+[[vWD]] must be differentiated from platelet disorders, thrombophilias, and hemophilias based on genetic disoder, clinical presentation, laboratory findings and treatment.
 ==Epidemiology and Demographics==
-The prevalence of von Willebrand’s disease is 0.6 to 1.3%.<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><ref name="pmid3492222">{{cite journal| author=Rodeghiero F, Castaman G, Dini E| title=Epidemiological investigation of the prevalence of von Willebrand's disease. | journal=Blood | year= 1987 | volume= 69 | issue= 2 | pages= 454-9 | pmid=3492222 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3492222  }} </ref>
+The prevalence of von Willebrand’s disease is 0.6 to 1.3%. It is estimated that the referral prevalence of von Willebrand’s disease is approximately 1 case per 10,000 persons. The actual abnormality (which does not necessarily lead to disease) occurs in 0.9-3% of the population. The symptoms of VWD is disproportionately more common in women of child-bearing age. Although autosomal inheritance pattern of disease lead to an equal distribution of male patients and female patients, the disease has female predominance whose bleeding tendency shows during [[menstruation]]. There is no racial predilection to [[vWD]] however, it may be more severe or apparent in people with [[blood type]] O.
-It is estimated that the referral prevalence of von Willebrand’s disease is approximately 1 case per 10,000 persons.<ref name="pmid10959685">{{cite journal| author=Sadler JE, Mannucci PM, Berntorp E, Bochkov N, Boulyjenkov V, Ginsburg D et al.| title=Impact, diagnosis and treatment of von Willebrand disease. | journal=Thromb Haemost | year= 2000 | volume= 84 | issue= 2 | pages= 160-74 | pmid=10959685 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10959685  }} </ref> The actual abnormality (which does not necessarily lead to disease) occurs in 0.9-3% of the population. The symptoms of VWD is disproportionately more common in women of child-bearing age.<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> Although autosomal inheritance pattern of disease lead to an equal distribution of male patients and female patients, the disease has female predominance whose bleeding tendency shows during [[menstruation]].<ref name="pmid10513768">{{cite journal| author=Lee CA| title=Women and inherited bleeding disorders: menstrual issues. | journal=Semin Hematol | year= 1999 | volume= 36 | issue= 3 Suppl 4 | pages= 21-7 | pmid=10513768 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10513768  }} </ref><ref name="pmid21040234">{{cite journal| author=Miller CH, Philipp CS, Stein SF, Kouides PA, Lukes AS, Heit JA et al.| title=The spectrum of haemostatic characteristics of women with unexplained menorrhagia. | journal=Haemophilia | year= 2011 | volume= 17 | issue= 1 | pages= e223-9 | pmid=21040234 | doi=10.1111/j.1365-2516.2010.02382.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21040234  }} </ref> There is no racial predilection to [[vWD]] however, it may be more severe or apparent in people with [[blood type]] O.<ref name="pmid3495304">{{cite journal| author=Gill JC, 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 | year= 1987 | volume= 69 | issue= 6 | pages= 1691-5 | pmid=3495304 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3495304  }} </ref>
 ==Risk Factors==
-There are no established risk factors for Von Willebrand disease however, 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.<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>
+Common risk factors in the development of Von Willebrand disease include positive family history and consanguineous relationships. Less common risk factors in the development of Von Willebrand disease include lymphoproliferative disorders and aortic stenosis.
-Interestingly the risks of cardiovascular disease and ischemic stroke are reduced among patients with von Willebrand’s disease.<ref name="pmid23506463">{{cite journal| author=Sanders YV, Eikenboom J, de Wee EM, van der Bom JG, Cnossen MH, Degenaar-Dujardin ME et al.| title=Reduced prevalence of arterial thrombosis in von Willebrand disease. | journal=J Thromb Haemost | year= 2013 | volume= 11 | issue= 5 | pages= 845-54 | pmid=23506463 | doi=10.1111/jth.12194 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23506463  }} </ref><ref name="pmid26368360">{{cite journal| author=Seaman CD, Yabes J, Comer DM, Ragni MV| title=Does deficiency of von Willebrand factor protect against cardiovascular disease? Analysis of a national discharge register. | journal=J Thromb Haemost | year= 2015 | volume= 13 | issue= 11 | pages= 1999-2003 | pmid=26368360 | doi=10.1111/jth.13142 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26368360  }} </ref>
 ==Screening==
-There is no established screening modality for Von Willebrand disease. However, several questionnaires and laboratory investigations have been developed to help in the screening process. Von Willebrand factor antigen and activity have been tried in the screening for von Willebrand disease.<ref name="pmid23551532">{{cite journal |vauthors=Verfaillie CJ, De Witte E, Devreese KM |title=Validation of a new panel of automated chemiluminescence assays for von Willebrand factor antigen and activity in the screening for von Willebrand disease |journal=Int J Lab Hematol |volume=35 |issue=5 |pages=555–65 |year=2013 |pmid=23551532 |doi=10.1111/ijlh.12087 |url=}}</ref> The use of platelet function analyzer as a screening tool for the diagnosis of von Willebrand disease in adolescents with menorrhagia is not sufficiently sensitive to detect Von Willebrand Ristocetin cofactor activity (RCoF) values <50 IU/dl with normal multimer patterns.<ref name="pmid23335259">{{cite journal |vauthors=Naik S, Teruya J, Dietrich JE, Jariwala P, Soundar E, Venkateswaran L |title=Utility of platelet function analyzer as a screening tool for the diagnosis of von Willebrand disease in adolescents with menorrhagia |journal=Pediatr Blood Cancer |volume=60 |issue=7 |pages=1184–7 |year=2013 |pmid=23335259 |doi=10.1002/pbc.24456 |url=}}</ref>
+The ISTH-Bleeding Assessment Tool is a validated instrument that is used to screen patients referred for bleeding symptoms for further laboratory testing. The three main screening tests used in the diagnosis of VWD include vonWillebrand Factor (VWF) antigen, platelet-dependent VWF activity, and factor VIII activity
 ==Natural History, Complications, and Prognosis==
-*Patients with von willebrand disease have a lower health-related quality of life compared to the general population especially with the bleeding phenotype.<ref name="pmid20345712">{{cite journal |vauthors=de Wee EM, Mauser-Bunschoten EP, Van Der Bom JG, Degenaar-Dujardin ME, Eikenboom HC, Fijnvandraat K, de Goede-Bolder A, Laros-van Gorkom BA, Meijer K, Raat H, Leebeek FW |title=Health-related quality of life among adult patients with moderate and severe von Willebrand disease |journal=J. Thromb. Haemost. |volume=8 |issue=7 |pages=1492–9 |year=2010 |pmid=20345712 |doi=10.1111/j.1538-7836.2010.03864.x |url=}}</ref>
+Patients with VWD can become symptomatic at any age. A typical history in a patient with mild to moderate disease includes [[epistaxis]] lasting longer than 10 minutes in childhood lifelong easy bruising, bleeding following dental extractions, other [[invasive]] dental procedures, or other forms of surgery. Women with VWD usually have a history of heavy menstrual bleeding and may have bleeding during the peripartum period, often at or within hours of delivery and at 5 to 10 days after delivery. [[Menorrhagia]] is a major complication. [[Angiodysplasia]] is serious, and possibly life-threatening complication. [[Intraarticular]] bleeding may be a presenting symptom in those with type 2N or type 3 disease. For some patients, vWD is a mild bleeding disorder and can be managed easily. Patients with mild disease may experience clinically severe [[hemorrhage]] following trauma or invasive procedures. Variability of symptoms exists among family members. People with vWD types II and III face severe and potentially life threatening bleeding episodes. Type III disease patients have low FVIII levels and present with [[arthropathies]]. Levels of vWF normally increase with age in patients with type I vWD, In patients with type II vWD, vWF levels does not increase with aging.
-*There is physiologic rise in von Willebrand factor levels throughout life. As a result of this, patients with type 1 von Willebrand’s disease may have normal levels of vWF at older age.<ref name="pmid25756206">{{cite journal |vauthors=Rydz N, Grabell J, Lillicrap D, James PD |title=Changes in von Willebrand factor level and von Willebrand activity with age in type 1 von Willebrand disease |journal=Haemophilia |volume=21 |issue=5 |pages=636–41 |year=2015 |pmid=25756206 |pmc=4678413 |doi=10.1111/hae.12664 |url=}}</ref> However, bleeding symptoms occur at similar frequency in patients older than 65 years as well as in those who are 18 to 65 years of age<ref name="pmid24750783">{{cite journal |vauthors=Sanders YV, Giezenaar MA, Laros-van Gorkom BA, Meijer K, van der Bom JG, Cnossen MH, Nijziel MR, Ypma PF, Fijnvandraat K, Eikenboom J, Mauser-Bunschoten EP, Leebeek FW |title=von Willebrand disease and aging: an evolving phenotype |journal=J. Thromb. Haemost. |volume=12 |issue=7 |pages=1066–75 |year=2014 |pmid=24750783 |doi=10.1111/jth.12586 |url=}}</ref>
-*Menorrhagia is a major complication, which also impairs the quality of life.<ref name="pmid20584085">{{cite journal |vauthors=Kadir RA, Edlund M, Von Mackensen S |title=The impact of menstrual disorders on quality of life in women with inherited bleeding disorders |journal=Haemophilia |volume=16 |issue=5 |pages=832–9 |year=2010 |pmid=20584085 |doi=10.1111/j.1365-2516.2010.02269.x |url=}}</ref>
-*Angiodysplasia is serious, and possibly life-threatening complication.<ref name="pmid25381842">{{cite journal |vauthors=Makris M, Federici AB, Mannucci PM, Bolton-Maggs PH, Yee TT, Abshire T, Berntorp E |title=The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand disease |journal=Haemophilia |volume=21 |issue=3 |pages=338–42 |year=2015 |pmid=25381842 |doi=10.1111/hae.12571 |url=}}</ref>
-*Intraarticular bleeding (although rare) may be a presenting symptom in those with type 2N or type 3 disease.<ref name="pmid23010260">{{cite journal |vauthors=van Galen KP, Mauser-Bunschoten EP, Leebeek FW |title=Hemophilic arthropathy in patients with von Willebrand disease |journal=Blood Rev. |volume=26 |issue=6 |pages=261–6 |year=2012 |pmid=23010260 |doi=10.1016/j.blre.2012.09.002 |url=}}</ref>
-*Primary and secondary postpartum bleeding is a commmon complication.<ref name="pmid26164463">{{cite journal |vauthors=Kouides PA |title=An update on the management of bleeding disorders during pregnancy |journal=Curr. Opin. Hematol. |volume=22 |issue=5 |pages=397–405 |year=2015 |pmid=26164463 |doi=10.1097/MOH.0000000000000167 |url=}}</ref><ref name="pmid21947221">{{cite journal |vauthors=De Wee EM, Knol HM, Mauser-Bunschoten EP, van der Bom JG, Eikenboom JC, Fijnvandraat K, De Goede-Bolder A, Laros-van Gorkom B, Ypma PF, Zweegman S, Meijer K, Leebeek FW |title=Gynaecological and obstetric bleeding in moderate and severe von Willebrand disease |journal=Thromb. Haemost. |volume=106 |issue=5 |pages=885–92 |year=2011 |pmid=21947221 |doi=10.1160/TH11-03-0180 |url=}}</ref><ref name="pmid25688733">{{cite journal |vauthors=Stoof SC, van Steenbergen HW, Zwagemaker A, Sanders YV, Cannegieter SC, Duvekot JJ, Leebeek FW, Peters M, Kruip MJ, Eikenboom J |title=Primary postpartum haemorrhage in women with von Willebrand disease or carriership of haemophilia despite specialised care: a retrospective survey |journal=Haemophilia |volume=21 |issue=4 |pages=505–12 |year=2015 |pmid=25688733 |doi=10.1111/hae.12635 |url=}}</ref>
 ==Diagnosis==
+=== Diagnostic Study of Choice ===
+There is no single diagnostic study of choice for the diagnosis of von Willebrand disease, but von Willebrand disease can be diagnosed based on [[Screening test|screening tests]] followed by confirmatory tests. The [[Screening test|screening tests]] for VWD that are selected by the National Heart, Lung, and Blood Institute include testing for vWF antigen, VWF [[Ristocetin|ristocetin cofactor activity]]<nowiki/>and [[factor VIII]] clotting activity. When one of the VWD [[screening test]] is abnormal, further confirmatory tests are performed to establish the correct diagnosis and determine the type of VWD. Genotyping is most beneficial for type 1 patients with vWF ≤30 IU/dL and those with type 2 or 3. Genotyping also detects a benign type of vWD the D1472H, It affects ristocetin binding but not vWF function.
 ===History and Symptoms===
-The symptoms of von Willebrand’s disease vary among patients, depending on the level of residual von Willebrand factor activity, the disease subtype, and to some extent, age and sex.<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> Children with von Willebrand’s disease most frequently present with symptoms of bruising and epistaxis.<ref name="pmid26375306">{{cite journal| author=Sanders YV, Fijnvandraat K, Boender J, Mauser-Bunschoten EP, van der Bom JG, de Meris J et al.| title=Bleeding spectrum in children with moderate or severe von Willebrand disease: Relevance of pediatric-specific bleeding. | journal=Am J Hematol | year= 2015 | volume= 90 | issue= 12 | pages= 1142-8 | pmid=26375306 | doi=10.1002/ajh.24195 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26375306  }} </ref>
+Patients with von Willebrand’s disease present with history of [[Mucosal bleeding|mucosal bleeding,]] recurrent nose bleeds, [[Oral cavity|oral cavity bleeding]], and positive family history of similer symptoms among other family members. Adults patients with vWD mainly present with bleeding after [[Extraction (dental)|dental extraction]]/ or other surgery. [[Menorrhagia|Heavy menstrual periods]] and [[postpartum hemorrhage]] are common among affected females with von Willebrand’s disease. Severe [[Internal bleeding|internal]] or [[Hemarthrosis|joint bleeding]] can occur but is usually rare.
-Adults patients with vWD mainly present with bleeding after surgery (example bleeding after dental extraction/surgery), mucosa-associated bleeding, [[menorrhagia|Heavy menstrual periods]] and [[postpartum hemorrhage|postpartum hemorrhage]]. Severe [[internal bleeding|internal]] or [[hemarthrosis|joint bleeding]] is rare (which only occurs in type 3 vWD). <ref name="pmid22918553">{{cite journal| author=de Wee EM, Sanders YV, Mauser-Bunschoten EP, van der Bom JG, Degenaar-Dujardin ME, Eikenboom J et al.| title=Determinants of bleeding phenotype in adult patients with moderate or severe von Willebrand disease. | journal=Thromb Haemost | year= 2012 | volume= 108 | issue= 4 | pages= 683-92 | pmid=22918553 | doi=10.1160/TH12-04-0244 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22918553  }} </ref>
 ===Physical Examination===
+Patients with vWD commonly have negative physical examination findings however the findings may include [[ecchymoses]], [[Hematoma|hematomas]] with varying sizes and location and evidence of current or recent [[Mucosal bleeding|mucosal bleeding.]]
 ===Laboratory Findings===
+The diagnosis of [[von Willebrand’s disease]] (VWD) begins with a relevant personal or family history of mucocutaneous bleeding. When [[VWD]] is suspected, several levels of testing are needed in order to make diagnosis. Initail tests involve measurement of [[VWF]] antigen (VWF:Ag) level, [[Factor VIII]] activity (FVIII:C) and VWF–ristocetin cofactor activity [VWF:RCo]. When the results of all first-level tests are normal, VWD is ruled out; because of biologic variability, however, the tests should be repeated if values are at the low end of the normal range or if VWD is strongly suspected. Persons with a bleeding tendency who have VWF levels between 30 and 50 IU per deciliter are classified as having “low VWF” or “possible type 1 disease” but are not classified as having definitive VWD. When von Willebrand factor antigen is undetectable (or the level is <5 IU per deciliter, according to the latest disease classification), type 3 von Willebrand’s disease is diagnosed. If these first-level tests reveal definitive abnormalities, a diagnosis of [[VWD]] can be made; if the results are not conclusive, second-level tests are required. Second level testing involves repeating the initial tests and then measurement of VWF multimer distribution using gel electrophoresis and ristocetin-induced platelet aggregation (RIPA). Other tests performed in any patient with bleeding problems include: [[complete blood count]] (especially [[platelet]] counts), [[APTT]] (activated partial thromboplastin time), [[prothrombin time]], [[thrombin]] time, [[fibrinogen]] level, testing for [[factor IX]] if [[hemophilia B]] is suspected and 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.
 ===Imaging Findings===
@@ Line 70: / Line 58: @@
 ===Medical Therapy===
+The mainstay of management of VWD is medical therapy. Medical therapy of [[von Willebrand's disease]] ( [[vWD]]) involves normalizing the [[von Willebrand factor]] and [[factor VIII]]<nowiki/>levels. Endogenous factor levels can be increased by the use of [[desmopressin]] or by infusing exogenous coagulation factors example high-purity or low-purity [[von Willebrand factor]] concentrate. Medical therapy depends on the type of [[von Willebrand's disease]]. [[Desmopressin]] is used for type 1 and 2 [[von Willebrand's disease]]. [[von Willebrand factor]]-[[factor VIII]] or [[von Willebrand factor]] concentrate is used in some of type 2 [[von Willebrand's disease]] and all of type 3 [[von Willebrand's disease]]. Alternate or additional therapy involves the use of tranexamic acid or [[aminocaproic acid]].
 ===Prevention===
+There are no known preventive measures for von Willebrand disease. In families with type 3 disease, genetic analysis may be useful for counseling.
-*There are no known preventive measures for von Willebrand disease.
-*In families with type 3 disease, genetic analysis may be useful for counseling.<ref name="pmid26245874">{{cite journal |vauthors=Batlle J, Pérez-Rodríguez A, Corrales I, López-Fernández MF, Rodríguez-Trillo Á, Lourés E, Cid AR, Bonanad S, Cabrera N, Moret A, Parra R, Mingot-Castellano ME, Balda I, Altisent C, Pérez-Montes R, Fisac RM, Iruín G, Herrero S, Soto I, de Rueda B, Jiménez-Yuste V, Alonso N, Vilariño D, Arija O, Campos R, Paloma MJ, Bermejo N, Toll T, Mateo J, Arribalzaga K, Marco P, Palomo Á, Sarmiento L, Iñigo B, Nieto Mdel M, Vidal R, Martínez MP, Aguinaco R, César JM, Ferreiro M, García-Frade J, Rodríguez-Huerta AM, Cuesta J, Rodríguez-González R, García-Candel F, Cornudella R, Aguilar C, Borràs N, Vidal F |title=Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): Proposal for a new diagnostic paradigm |journal=Thromb. Haemost. |volume=115 |issue=1 |pages=40–50 |year=2016 |pmid=26245874 |doi=10.1160/TH15-04-0282 |url=}}</ref>
 ==References==