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von Willebrand disease type 3(VWD3)

MedGen UID:
266075
Concept ID:
C1264041
Disease or Syndrome
Synonyms: Type 3 Von Willebrand's disease; Type 3 VWD; V WD3; Von Willebrand disease, recessive form; Von Willebrand disease, severe form; VON WILLEBRAND DISEASE, TYPE III; VWD3
SNOMED CT: von Willebrand disease type 3 (128108002); Hereditary von Willebrand disease type 3 (128108002); von Willebrand disease type III (128108002)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
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 individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
 
Gene (location): VWF (12p13.31)
 
Monarch Initiative: MONDO:0010191
OMIM®: 277480
Orphanet: ORPHA166096

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

Clinical features

From HPO
Joint hemorrhage
MedGen UID:
5479
Concept ID:
C0018924
Pathologic Function
Hemorrhage occurring within a joint.
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.
Thrombocytopenia
MedGen UID:
52737
Concept ID:
C0040034
Disease or Syndrome
A reduction in the number of circulating thrombocytes.
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.
Abnormal bleeding
MedGen UID:
264316
Concept ID:
C1458140
Pathologic Function
An abnormal susceptibility to bleeding, often referred to as a bleeding diathesis. A bleeding diathesis may be related to vascular, platelet and coagulation defects.
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 surgery
MedGen UID:
867284
Concept ID:
C4021646
Pathologic Function
Bleeding that persists longer than the normal time following a surgical procedure.
Reduced von Willebrand factor activity
MedGen UID:
870263
Concept ID:
C4024701
Finding
Decreased activity of von Willebrand factor. Von Willebrand factor mediates the adhesion of platelets to the collagen exposed on endothelial cell surfaces.
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
Federici AB, James P
Acta Haematol 2012;128(2):88-99. Epub 2012 Jun 19 doi: 10.1159/000338208. PMID: 22722677
Lusher JM
Am J Obstet Gynecol 1996 Sep;175(3 Pt 2):778-83. doi: 10.1016/s0002-9378(96)80084-6. PMID: 8828561

Recent clinical studies

Etiology

Noone S, Schubert R, Fichtlscherer S, Hilberg T, Alesci S, Miesbach W
Clin Appl Thromb Hemost 2021 Jan-Dec;27:1076029620984546. doi: 10.1177/1076029620984546. PMID: 33448867Free PMC Article
Makhamreh MM, Kass SL, Russo ML, Ahmadzia H, Al-Kouatly HB
Am J Perinatol 2021 Apr;38(5):436-448. Epub 2019 Nov 22 doi: 10.1055/s-0039-1700541. PMID: 31756759
Elayaperumal S, Fouzia NA, Biswas A, Nair SC, Viswabandya A, George B, Abraham A, Oldenburg J, Edison ES, Srivastava A
Haemophilia 2018 Nov;24(6):930-940. Epub 2018 Jul 8 doi: 10.1111/hae.13542. PMID: 29984440
Goodeve A
Hematology Am Soc Hematol Educ Program 2016 Dec 2;2016(1):678-682. doi: 10.1182/asheducation-2016.1.678. PMID: 27913546Free PMC Article
Eikenboom JC
Best Pract Res Clin Haematol 2001 Jun;14(2):365-79. doi: 10.1053/beha.2001.0139. PMID: 11686105

Diagnosis

James P, Leebeek F, Casari C, Lillicrap D
Haemophilia 2024 Apr;30 Suppl 3:103-111. Epub 2024 Mar 13 doi: 10.1111/hae.14970. PMID: 38481079
Stonebraker JS, Iorio A, Lavin M, Rezende SM, Srivastava A, Pierce GF, Coffin D, Tootoonchian E, Makris M
Haemophilia 2023 Jul;29(4):975-986. Epub 2023 Jun 5 doi: 10.1111/hae.14810. PMID: 37276350
O'Sullivan JM, Tootoonchian E, Ziemele B, Makris M, Federici AB, Khayat Djambas C, El Ekiaby M, Rotellini D, Sidonio RF, Iorio A, Coffin D, Pierce GF, Stonebraker J, James PD, Lavin M
Haemophilia 2023 Jul;29(4):1104-1112. Epub 2023 May 22 doi: 10.1111/hae.14804. PMID: 37216656
Goodeve A
Hematology Am Soc Hematol Educ Program 2016 Dec 2;2016(1):678-682. doi: 10.1182/asheducation-2016.1.678. PMID: 27913546Free PMC Article
Lillicrap D
Hematology Am Soc Hematol Educ Program 2013;2013:254-60. doi: 10.1182/asheducation-2013.1.254. PMID: 24319188

Therapy

James P, Leebeek F, Casari C, Lillicrap D
Haemophilia 2024 Apr;30 Suppl 3:103-111. Epub 2024 Mar 13 doi: 10.1111/hae.14970. PMID: 38481079
Roullet S, Luc N, Rayes J, Solarz J, Disharoon D, Ditto A, Gahagan E, Pawlowski C, Sefiane T, Adam F, Casari C, Christophe OD, Bruckman M, Lenting PJ, Sen Gupta A, Denis CV
Blood 2023 Jun 8;141(23):2891-2900. doi: 10.1182/blood.2022018956. PMID: 36928925Free PMC Article
Berntorp E, Trakymienė SS, Federici AB, Holstein K, Corrales-Medina FF, Pierce GF, Srivastava A, Prondzinski MVD, Johnsen JM, Zupan IP, Halimeh S, Nummi V, Roberts JC
Haemophilia 2022 Jul;28 Suppl 5(Suppl 5):3-15. doi: 10.1111/hae.14495. PMID: 35861919Free PMC Article
Saccullo G, Makris M
Semin Thromb Hemost 2016 Jul;42(5):498-506. Epub 2016 Jun 2 doi: 10.1055/s-0036-1581106. PMID: 27253087
Lillicrap D
Hematology Am Soc Hematol Educ Program 2013;2013:254-60. doi: 10.1182/asheducation-2013.1.254. PMID: 24319188

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
Christopherson PA, Haberichter SL, Flood VH, Perry CL, Sadler BE, Bellissimo DB, Di Paola J, Montgomery RR; Zimmerman Program Investigators
J Thromb Haemost 2022 Jul;20(7):1576-1588. Epub 2022 Apr 6 doi: 10.1111/jth.15713. PMID: 35343054
Baronciani L, Peake I, Schneppenheim R, Goodeve A, Ahmadinejad M, Badiee Z, Baghaipour MR, Benitez O, Bodó I, Budde U, Cairo A, Castaman G, Eshghi P, Goudemand J, Hassenpflug W, Hoorfar H, Karimi M, Keikhaei B, Lassila R, Leebeek FWG, Lopez Fernandez MF, Mannucci PM, Marino R, Nikšić N, Oyen F, Santoro C, Tiede A, Toogeh G, Tosetto A, Trossaert M, Zetterberg EMK, Eikenboom J, Federici AB, Peyvandi F
Blood Adv 2021 Aug 10;5(15):2987-3001. doi: 10.1182/bloodadvances.2020003397. PMID: 34351388Free PMC Article
McNicholas A, Sharma N, Rowe EL, Benotti SA, Braverman BR, Normandin PA
J Emerg Nurs 2021 Jul;47(4):661-668. doi: 10.1016/j.jen.2021.04.008. PMID: 34275529
Chornenki NLJ, Shanjer M, James PD
J Thromb Haemost 2021 Sep;19(9):2151-2160. Epub 2021 Jul 9 doi: 10.1111/jth.15410. PMID: 34060212

Clinical prediction guides

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
Christopherson PA, Haberichter SL, Flood VH, Perry CL, Sadler BE, Bellissimo DB, Di Paola J, Montgomery RR; Zimmerman Program Investigators
J Thromb Haemost 2022 Jul;20(7):1576-1588. Epub 2022 Apr 6 doi: 10.1111/jth.15713. PMID: 35343054
Kempers EK, van Kwawegen CB, de Meris J, Schols SEM, van Galen KPM, Meijer K, Cnossen MH, van der Bom JG, Fijnvandraat K, Eikenboom J, Atiq F, Leebeek FWG; WiN study group
Haemophilia 2022 Mar;28(2):278-285. Epub 2021 Dec 29 doi: 10.1111/hae.14475. PMID: 34964530Free PMC Article
Baronciani L, Peake I, Schneppenheim R, Goodeve A, Ahmadinejad M, Badiee Z, Baghaipour MR, Benitez O, Bodó I, Budde U, Cairo A, Castaman G, Eshghi P, Goudemand J, Hassenpflug W, Hoorfar H, Karimi M, Keikhaei B, Lassila R, Leebeek FWG, Lopez Fernandez MF, Mannucci PM, Marino R, Nikšić N, Oyen F, Santoro C, Tiede A, Toogeh G, Tosetto A, Trossaert M, Zetterberg EMK, Eikenboom J, Federici AB, Peyvandi F
Blood Adv 2021 Aug 10;5(15):2987-3001. doi: 10.1182/bloodadvances.2020003397. PMID: 34351388Free PMC Article
Elayaperumal S, Fouzia NA, Biswas A, Nair SC, Viswabandya A, George B, Abraham A, Oldenburg J, Edison ES, Srivastava A
Haemophilia 2018 Nov;24(6):930-940. Epub 2018 Jul 8 doi: 10.1111/hae.13542. PMID: 29984440

Recent systematic reviews

Makhamreh MM, Kass SL, Russo ML, Ahmadzia H, Al-Kouatly HB
Am J Perinatol 2021 Apr;38(5):436-448. Epub 2019 Nov 22 doi: 10.1055/s-0039-1700541. PMID: 31756759

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