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von Willebrand disease type 1(VWD1)

MedGen UID:
220393
Concept ID:
C1264039
Disease or Syndrome
Synonyms: VON WILLEBRAND DISEASE, TYPE I; VWD, TYPE 1; VWD1
SNOMED CT: von Willebrand disease type 1 (128106003); Hereditary von Willebrand disease type 1 (128106003)
Modes of inheritance:
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): VWF (12p13.31)
 
Monarch Initiative: MONDO:0008668
OMIM®: 193400
Orphanet: ORPHA166078

Disease characteristics

Excerpted from the GeneReview: von Willebrand Disease
Von Willebrand disease (VWD), a congenital bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF), may only become apparent on hemostatic challenge, and bleeding history may become more apparent with increasing age. Recent guidelines on VWD have recommended taking a VWF level of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type. Type 1 VWD (~30% of VWD) typically manifests as mild mucocutaneous bleeding. Type 2 VWD accounts for approximately 60% of VWD. Type 2 subtypes include: Type 2A, which usually manifests as mild-to-moderate mucocutaneous bleeding; Type 2B, which typically manifests as mild-to-moderate mucocutaneous bleeding that can include thrombocytopenia that worsens in certain circumstances; Type 2M, which typically manifests as mild-moderate mucocutaneous bleeding; Type 2N, which can manifest as excessive bleeding with surgery and mimics mild hemophilia A. Type 3 VWD (<10% of VWD) manifests with severe mucocutaneous and musculoskeletal bleeding. [from GeneReviews]
Authors:
Anne Goodeve  |  Paula James   view full author information

Additional description

From OMIM
Von Willebrand disease is the most common inherited bleeding disorder. It is characterized clinically by mucocutaneous bleeding, such as epistaxis and menorrhagia, and prolonged bleeding after surgery or trauma. The disorder results from a defect in platelet aggregation due to defects in the von Willebrand factor protein. Von Willebrand factor is a large, multimeric protein that plays a role in platelet adhesion and also serves as a carrier for the thrombotic protein factor VIII (F8; 300841). F8 is mutated in hemophilia A (summary by Goodeve, 2010). For a review of the various forms of von Willebrand disease, see Leebeek and Eikenboom (2016). Classification of von Willebrand Disease The classification of von Willebrand disease has a long and complex history. The current classification is based on that described by Sadler (1994) and updated by Sadler et al. (2006), which delineates 3 main subtypes according to the mutant protein phenotype. An earlier classification developed by a working party of the European Thrombosis Research Organization was provided by Zimmerman and Ruggeri (1983). Von Willebrand Disease Type 1 VWD type 1 is a quantitative partial deficiency of circulating VWF. In this type of VWD, there is a normal ratio of functional VWF activity (VWF:RCo, ristocetin cofactor activity) relative to VWF antigen level (VWF:Ag) (Sadler et al., 2006, Goodeve, 2010). Mannucci (2004) stated that type 1 VWD accounts for 60 to 80% of all VWD cases and is characterized by mild to moderate quantitative deficiencies of VWF and factor VIII, which are coordinately reduced to 5 to 30% of normal plasma levels (pathogenic levels of 5 to 30 IU/dL). In an updated consensus statement, Sadler et al. (2006) noted that (1) some cases of VWF type 1 may have subtle abnormal VWF multimer patterns, but still retain normal functional activity, and (2) that loci other than VWF may be responsible for some cases of VWD. In reviews, James and Lillicrap (2008) and Lillicrap (2009) stated that the knowledge of the pathogenesis and molecular basis of type 1 VWD is still in its infancy and still evolving. Population studies have indicated that type 1 VWD is a complex genetic trait associated with a variety of genetic and environmental factors, and that additional loci in addition to VWF are likely involved. There is still uncertainty about the pathogenicity of many identified putative VWF variants, and the incomplete penetrance and variable expressivity of type 1 disease contributes to complexity in diagnosis and understanding of disease pathogenesis. Von Willebrand Disease Type 2 VWD type 2 (613554), which accounts for 10 to 30% of cases, is characterized by qualitative abnormalities of VWF; it is further divided into subtypes 2A, 2B, 2M, and 2N. The mutant VWF protein in types 2A, 2B, and 2M are defective in their platelet-dependent function, whereas the mutant protein in type 2N is defective in its ability to bind F8 (Mannucci, 2004; Sadler et al., 2006; Goodeve, 2010). Von Willebrand Disease Type 3 VWD type 3 (277480), which accounts for 1 to 5% of cases, is characterized by a severe quantitative defect of VWF in plasma (less than 1% of normal plasma levels), with low but usually detectable levels of factor VIII (1 to 10% of normal plasma levels). In the rare type 3 disease (1 in 1 million people), symptoms are more frequent and severe (Mannucci, 2004, Sadler et al., 2006).  http://www.omim.org/entry/193400

Clinical features

From HPO
Aortic valve stenosis
MedGen UID:
1621
Concept ID:
C0003507
Pathologic Function
The presence of a stenosis (narrowing) of the aortic valve.
Joint hemorrhage
MedGen UID:
5479
Concept ID:
C0018924
Pathologic Function
Hemorrhage occurring within a joint.
Mitral valve prolapse
MedGen UID:
7671
Concept ID:
C0026267
Disease or Syndrome
One or both of the leaflets (cusps) of the mitral valve bulges back into the left atrium upon contraction of the left ventricle.
Gastrointestinal angiodysplasia
MedGen UID:
163130
Concept ID:
C0854242
Disease or Syndrome
Dysplasia affecting the vasculature of the gastrointestinal tract.
Gastrointestinal hemorrhage
MedGen UID:
8971
Concept ID:
C0017181
Pathologic Function
Hemorrhage affecting the gastrointestinal tract.
Epistaxis
MedGen UID:
4996
Concept ID:
C0014591
Pathologic Function
Epistaxis, or nosebleed, refers to a hemorrhage localized in the nose.
Menorrhagia
MedGen UID:
44358
Concept ID:
C0025323
Pathologic Function
Prolonged and excessive menses at regular intervals in excess of 80 mL or lasting longer than 7 days.
Prolonged bleeding time
MedGen UID:
56231
Concept ID:
C0151529
Finding
Prolongation of the time taken for a standardized skin cut of fixed depth and length to stop bleeding.
Prolonged whole-blood clotting time
MedGen UID:
488780
Concept ID:
C0151563
Finding
An abnormal prolongation (delay) in the time required by whole blood to produce a visible clot.
Persistent bleeding after trauma
MedGen UID:
375403
Concept ID:
C1844374
Finding
Impaired platelet aggregation
MedGen UID:
383786
Concept ID:
C1855853
Finding
An impairment in the rate and degree to which platelets aggregate after the addition of an agonist that stimulates platelet clumping. Platelet aggregation is measured using aggregometer to measure the optical density of platelet-rich plasma, whereby platelet aggregation causes the plasma to become more transparent.
Prolonged bleeding after dental extraction
MedGen UID:
369536
Concept ID:
C1969572
Pathologic Function
Prolonged bleeding post dental extraction sufficient to require medical intervention.
Prolonged bleeding after surgery
MedGen UID:
867284
Concept ID:
C4021646
Pathologic Function
Bleeding that persists longer than the normal time following a surgical procedure.
Reduced quantity of Von Willebrand factor
MedGen UID:
893065
Concept ID:
C4023022
Finding
Decreased quantity of von Willebrand factor.
Reduced factor VIII activity
MedGen UID:
892907
Concept ID:
C4025649
Finding
Reduced activity of coagulation factor VIII. Factor VIII (fVIII) is a cofactor in the intrinsic clotting cascade that is activated to fVIIIa in the presence of minute quantities of thrombin. fVIIIa acts as a receptor, for factors IXa and X.
Bruising susceptibility
MedGen UID:
140849
Concept ID:
C0423798
Finding
An ecchymosis (bruise) refers to the skin discoloration caused by the escape of blood into the tissues from ruptured blood vessels. This term refers to an abnormally increased susceptibility to bruising. The corresponding phenotypic abnormality is generally elicited on medical history as a report of frequent ecchymoses or bruising without adequate trauma.

Professional guidelines

PubMed

Dorgalaleh A, Farshi Y, Haeri K, Ghanbari OB, Ahmadi A
Semin Thromb Hemost 2022 Apr;48(3):344-355. Epub 2022 Jan 6 doi: 10.1055/s-0041-1740566. PMID: 34991167
Castaman G, Goodeve A, Eikenboom J; European Group on von Willebrand Disease
Haematologica 2013 May;98(5):667-74. doi: 10.3324/haematol.2012.077263. PMID: 23633542Free PMC Article
Castaman G, Rodeghiero F
Expert Rev Hematol 2011 Feb;4(1):95-106. doi: 10.1586/ehm.11.1. PMID: 21322782

Curated

Cumming AM, Keeney S, Jenkins PV, Nash MJ, O'Donnell JS
Eur J Hum Genet 2011 May;19(5) Epub 2011 Jan 5 doi: 10.1038/ejhg.2010.222. PMID: 21206511Free PMC Article

Recent clinical studies

Etiology

Sadler B, Christopherson PA, Haller G, Montgomery RR, Di Paola J
Blood 2021 Jun 10;137(23):3277-3283. doi: 10.1182/blood.2020009999. PMID: 33556167Free PMC Article
Castaman G
Thromb Res 2020 Dec;196:618-625. Epub 2020 Aug 3 doi: 10.1016/j.thromres.2020.07.051. PMID: 32819724
Bowman ML, James PD
Int J Lab Hematol 2017 May;39 Suppl 1:61-68. doi: 10.1111/ijlh.12653. PMID: 28447419
Sadler JE
Hematology Am Soc Hematol Educ Program 2009:106-12. doi: 10.1182/asheducation-2009.1.106. PMID: 20008188
Sadler JE
Blood 2003 Mar 15;101(6):2089-93. Epub 2002 Oct 31 doi: 10.1182/blood-2002-09-2892. PMID: 12411289

Diagnosis

Flood VH, Garcia J, Haberichter SL
Curr Opin Hematol 2019 Sep;26(5):331-335. doi: 10.1097/MOH.0000000000000524. PMID: 31261173Free PMC Article
Sharma R, Flood VH
Hematology Am Soc Hematol Educ Program 2017 Dec 8;2017(1):379-384. doi: 10.1182/asheducation-2017.1.379. PMID: 29222282Free PMC Article
Bowman ML, James PD
Int J Lab Hematol 2017 May;39 Suppl 1:61-68. doi: 10.1111/ijlh.12653. PMID: 28447419
Castaman G, Rodeghiero F
Expert Rev Hematol 2011 Feb;4(1):95-106. doi: 10.1586/ehm.11.1. PMID: 21322782
Michiels JJ, Berneman Z, Gadisseur A, van der Planken M, Schroyens W, van Vliet HH
Acta Haematol 2009;121(2-3):85-97. Epub 2009 Jun 8 doi: 10.1159/000214847. PMID: 19506353

Therapy

Sadler B, Christopherson PA, Haller G, Montgomery RR, Di Paola J
Blood 2021 Jun 10;137(23):3277-3283. doi: 10.1182/blood.2020009999. PMID: 33556167Free PMC Article
Castaman G
Thromb Res 2020 Dec;196:618-625. Epub 2020 Aug 3 doi: 10.1016/j.thromres.2020.07.051. PMID: 32819724
Sharma R, Flood VH
Hematology Am Soc Hematol Educ Program 2017 Dec 8;2017(1):379-384. doi: 10.1182/asheducation-2017.1.379. PMID: 29222282Free PMC Article
Castaman G, Rodeghiero F
Expert Rev Hematol 2011 Feb;4(1):95-106. doi: 10.1586/ehm.11.1. PMID: 21322782
Sadler JE
Blood 2003 Mar 15;101(6):2089-93. Epub 2002 Oct 31 doi: 10.1182/blood-2002-09-2892. PMID: 12411289

Prognosis

Lavin M, Christopherson P, Grabell J, Abshire T, Flood V, Haberichter SL, Lillicrap D, O'Donnell JS, Montgomery RR, James PD
J Thromb Haemost 2022 Oct;20(10):2246-2254. Epub 2022 Jul 26 doi: 10.1111/jth.15807. PMID: 35780487Free PMC Article
Sadler B, Christopherson PA, Haller G, Montgomery RR, Di Paola J
Blood 2021 Jun 10;137(23):3277-3283. doi: 10.1182/blood.2020009999. PMID: 33556167Free PMC Article
Atiq F, Wuijster E, de Maat MPM, Kruip MJHA, Cnossen MH, Leebeek FWG
J Thromb Haemost 2021 Mar;19(3):719-731. Epub 2021 Jan 24 doi: 10.1111/jth.15227. PMID: 33370487Free PMC Article
Miki K, Arimura K, Nishimura A, Yoshimoto K, Sayama T, Iihara K
World Neurosurg 2017 Dec;108:991.e17-991.e21. Epub 2017 Sep 1 doi: 10.1016/j.wneu.2017.08.141. PMID: 28866059
Castaman G, Rodeghiero F
Expert Rev Hematol 2011 Feb;4(1):95-106. doi: 10.1586/ehm.11.1. PMID: 21322782

Clinical prediction guides

Seidizadeh O, Baronciani L, Pagliari MT, Cozzi G, Colpani P, Cairo A, Siboni SM, Biguzzi E, Peyvandi F
J Thromb Haemost 2023 May;21(5):1112-1122. Epub 2023 Jan 20 doi: 10.1016/j.jtha.2023.01.012. PMID: 36754679
Lavin M, Christopherson P, Grabell J, Abshire T, Flood V, Haberichter SL, Lillicrap D, O'Donnell JS, Montgomery RR, James PD
J Thromb Haemost 2022 Oct;20(10):2246-2254. Epub 2022 Jul 26 doi: 10.1111/jth.15807. PMID: 35780487Free PMC Article
Sadler B, Christopherson PA, Haller G, Montgomery RR, Di Paola J
Blood 2021 Jun 10;137(23):3277-3283. doi: 10.1182/blood.2020009999. PMID: 33556167Free PMC Article
Bykowska K, Ceglarek B
Pol Arch Intern Med 2020 Mar 27;130(3):225-231. Epub 2020 Jan 28 doi: 10.20452/pamw.15162. PMID: 31990275
Castaman G, Rodeghiero F
Expert Rev Hematol 2011 Feb;4(1):95-106. doi: 10.1586/ehm.11.1. PMID: 21322782

Recent systematic reviews

Pierce-Williams RAM, Makhamreh MM, Blakey-Cheung S, Gao Z, Al-Kouatly HB
Semin Thromb Hemost 2022 Mar;48(2):219-228. Epub 2021 Nov 8 doi: 10.1055/s-0041-1736572. PMID: 34749402
Kalot MA, Husainat N, El Alayli A, Abughanimeh O, Diab O, Tayiem S, Madoukh B, Dimassi AB, Qureini A, Ameer B, Eikenboom JCJ, Giraud N, McLintock C, McRae S, Montgomery RR, O'Donnell JS, Scappe N, Sidonio RF, Brignardello-Petersen R, Flood VH, Connell NT, James PD, Mustafa RA
Blood Adv 2022 Jan 11;6(1):62-71. doi: 10.1182/bloodadvances.2021005430. PMID: 34610118Free PMC Article

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