Von Willebrand Disease: Difference between revisions

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== Introduction: ==
== Introduction ==
Von Willebrand Disease (VWD) is considered to be the most common bleeding disorder in humans and in some animals such as dogs. VWD is named after the Finnish physician who described the disease in the 1920s. 1 in 100 to 10 000 individuals in estimated to have VWD.  Patients with mild VWD symptoms are rarely diagnosed resulting in the gap “100 to 10 000“<ref>Genetic Home of Reference. [https://ghr.nlm.nih.gov/condition/von-willebrand-disease Von Willebrand Disease.] U.S. National Library of Medicine. Published 2020. Accessed June 15, 2020.</ref>. It is estimated that it affects 1% of all US population<ref>Von Willebrand Disease. [https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Von-Willebrand-Disease. National Hemophilia Foundation].  Published 2020. Accessed June 15, 2020.</ref>.
Von Willebrand Disease (VWD) is considered to be the most common bleeding disorder in humans and in some animals such as dogs<ref>Brooks MB, Catalfamo JL. von Willebrand disease. Schalm's veterinary hematology. 2022 Apr 22:731-8.</ref>. '''VWD''' is named after the Finnish physician who described the disease in the 1920s. 1 in 100 to 10 000 individuals is estimated to have VWD.  Patients with mild VWD symptoms are rarely diagnosed resulting in the gap “100 to 10 000“<ref>Genetic Home of Reference. [https://ghr.nlm.nih.gov/condition/von-willebrand-disease Von Willebrand Disease.] U.S. National Library of Medicine. Published 2020. Accessed June 15, 2020.</ref>. It is estimated that it affects 1% of all US population<ref>Von Willebrand Disease. [https://www.hemophilia.org/Bleeding-Disorders/Types-of-Bleeding-Disorders/Von-Willebrand-Disease. National Hemophilia Foundation].  Published 2020. Accessed June 15, 2020.</ref>.


== History: ==
=== History ===
In 1926 the Finnish physician Erik Von Willebrand described a new bleeding disorder which he called “hereditary pseudo haemophilia.” He recognized that this new disease is different from haemophilia; but he couldn’t identify the responsible plasma factor. Later by many years; this factor was identified and name after him too and now it’s known as Von Willebrand Factor (VWF)<ref name=":0">Leebeek FWG, Eikenboom JCJ. [https://www.legeforeningen.no/contentassets/179859e1b3744d02903663b1dec0dd4f/von-willenbrands-sykdom-review-nejm.pdf Von Willebrand’s disease]. ''N Engl J Med''. 2016;375(21):2067-2080. doi:10.1056/NEJMra1601561</ref>.
In 1926 the Finnish physician Erik Von Willebrand described a new bleeding disorder which he called “hereditary pseudo haemophilia.” He recognized that this new disease is different from haemophilia, but he couldn’t identify the responsible plasma factor. Later by many years; this factor was identified and named after him too and now it’s known as Von Willebrand Factor (VWF)<ref name=":0">Leebeek FWG, Eikenboom JCJ. [https://www.legeforeningen.no/contentassets/179859e1b3744d02903663b1dec0dd4f/von-willenbrands-sykdom-review-nejm.pdf Von Willebrand’s disease]. ''N Engl J Med''. 2016;375(21):2067-2080.</ref>.


== Von Willebrand Factor: ==
==== Von Willebrand Factor ====
Von Willebrand Factor (VWF) is a multifunctional multimeric glycoprotein<ref name=":2">Rassoulzadegan M, Ala F, Jazebi M, et al. [https://link.springer.com/content/pdf/10.1007/s12185-019-02814-8.pdf Molecular and clinical profile of type 2 von Willebrand disease in Iran: a thirteen-year experience.] ''Int J Hematol''. 2020;111(4):535-543. doi:10.1007/s12185-019-02814-8</ref> which is synthesized in endothelial cells<ref name=":1">Randi AM, Laffan MA. [https://onlinelibrary.wiley.com/doi/pdf/10.1111/jth.13551 Von Willebrand factor and angiogenesis: basic and applied issues]. ''J Thromb Haemost''. 2017;15(1):13-20. doi:10.1111/jth.13551</ref>. The VWF consists of similar subunits that contain binding sites for glycoprotein receptors. The adhesive activity of VWF depends mainly on the size of its multimers<ref>Stockschlaeder M, Schneppenheim R, Budde U. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3969155/ Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis.] ''Blood Coagul Fibrinolysis''. 2014;25(3):206-216. doi:10.1097/MBC.0000000000000065</ref>. Von Willebrand Factor plays an important role in primary and secondary hemostasis, acts as a mediator for adhesion and a carrier for coagulation FVIII.<ref name=":1" /> It is also involved in angiogenesis and inflammatory processes.<ref>Lenting PJ, Casari C, Christophe OD, Denis C V. [https://onlinelibrary.wiley.com/doi/pdf/10.1111/jth.12008 von Willebrand factor: the old, the new and the unknown]. ''J Thromb Haemost''. 2012;10(12):2428-2437. doi:10.1111/jth.12008</ref>
Von Willebrand Factor (VWF) is a multifunctional multimeric glycoprotein<ref name=":2">Rassoulzadegan M, Ala F, Jazebi M, et al. [https://link.springer.com/content/pdf/10.1007/s12185-019-02814-8.pdf Molecular and clinical profile of type 2 von Willebrand disease in Iran: a thirteen-year experience.] ''Int J Hematol''. 2020;111(4):535-543.</ref> which is synthesized in endothelial cells<ref name=":1">Randi AM, Laffan MA. [https://onlinelibrary.wiley.com/doi/pdf/10.1111/jth.13551 Von Willebrand factor and angiogenesis: basic and applied issues]. ''J Thromb Haemost''. 2017;15(1):13-20.</ref>. The VWF consists of similar subunits that contain binding sites for glycoprotein receptors. The adhesive activity of VWF depends mainly on the size of its multimers<ref>Stockschlaeder M, Schneppenheim R, Budde U. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3969155/ Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis.] ''Blood Coagul Fibrinolysis''. 2014;25(3):206-216. </ref>. Von Willebrand Factor plays an important role in primary and secondary hemostasis, acts as a mediator for adhesion and a carrier for coagulation FVIII.<ref name=":1" /> It is also involved in angiogenesis and inflammatory processes.<ref>Lenting PJ, Casari C, Christophe OD, Denis C V. [https://onlinelibrary.wiley.com/doi/pdf/10.1111/jth.12008 von Willebrand factor: the old, the new and the unknown]. ''J Thromb Haemost''. 2012;10(12):2428-2437.</ref><ref>Kalot MA, Husainat N, El Alayli A, Abughanimeh O, Diab O, Tayiem S, Madoukh B, Dimassi AB, Qureini A, Ameer B, Eikenboom JC. [https://www.sciencedirect.com/science/article/pii/S2473952921006856/pdf?md5=538e9529289bae957c808959b5846d49&pid=1-s2.0-S2473952921006856-main.pdf von Willebrand factor levels in the diagnosis of von Willebrand disease: a systematic review and meta-analysis]. Blood advances. 2022 Jan 11;6(1):62-71.</ref>
 
==== Definition ====
{{#ev:youtube|R8JMfbYW2p4}}
Von Willebrand Disease can either be '''inherited or acquired'''.  
 
# As an autosomal inherited disease it results from a defect in the protein factor called VWF. Type 1 and 2 are autosomal dominant and type 3 is transmitted as autosomal recessive. It affects men and women equally as it is an autosomal linked disease<ref name=":0" /><ref>Sharma R, Haberichter SL. [http://ww.bloodadvances.org/hematology/article-pdf/2019/1/596/1546005/hem2019000064c.pdf New advances in the diagnosis of von Willebrand disease.] ''Hematology''. 2019;2019(1):596-600.</ref><ref>Echahdi H, El Hasbaoui B, El Khorassani M, Agadr A, Khattab M. [https://www.ajol.info/index.php/pamj/article/download/159926/149494 Von Willebrand’s disease: case report and review of the literature.] ''Pan Afr Med J''. 2017;27:147.</ref>.
== Definition: ==
# Acquired VWD is different from inherited VWD as the disease develops later in life and is not a result of genetic inheritance. Acquired VWD may be due to '''autoimmune reactions''' in people with cardiac defects; certain forms of [[Cancer pain|cancer]]<nowiki/>s; [[Diabetes|diabetes mellitus]]; [[Autoimmune Disorders|autoimmune disease]] or after usage of certain drugs such as valpronic acid.<ref name=":6">Nazzaro A-M, Philipp CS, Johnson RW, James AH. [https://rarediseases.org/rare-diseases/von-willebrand-disease/ Von Willebrand Disease]. National Organization of Rare Diseases... Published 2020. Accessed June 15, 2020.</ref>
Von Willebrand Disease can either be inherited or acquired. VWD is an autosomal inherited disease results from a defect in the protein factor called VWF. Type 1 and 2 are autosomal dominant and type 3 is transmitted as autosomal recessive. It affects men and women equally as it is an autosomal linked disease<ref name=":0" /><ref>Sharma R, Haberichter SL. [http://ww.bloodadvances.org/hematology/article-pdf/2019/1/596/1546005/hem2019000064c.pdf New advances in the diagnosis of von Willebrand disease.] ''Hematology''. 2019;2019(1):596-600. doi:10.1182/hematology.2019000064</ref><ref>Echahdi H, El Hasbaoui B, El Khorassani M, Agadr A, Khattab M. [https://www.ajol.info/index.php/pamj/article/download/159926/149494 Von Willebrand’s disease: case report and review of literature.] ''Pan Afr Med J''. 2017;27:147. doi:10.11604/pamj.2017.27.147.12248</ref>. Acquired VWD is different from inherited VWD as the disease develops later in life and is not as a result of genetic inheritance. Acquired VWD may be due to autoimmune reactions in people with cardiac defects; certain forms of cancers; diabetes mellitus; autoimmune disease or after usage of certain drugs such as valpronic acid.<ref name=":6">Nazzaro A-M, Philipp CS, Johnson RW, James AH. [https://rarediseases.org/rare-diseases/von-willebrand-disease/ Von Willebrand Disease]. National Organization of Rare Diseases.. Published 2020. Accessed June 15, 2020.</ref>{{#ev:youtube|I-uYvkTVwiM}}
{{#ev:youtube|I-uYvkTVwiM}}
== Classification of Inherited Von Willebrand Disease: ==
==== Classification of Inherited Von Willebrand Disease ====
There are several classifications of VWD (Figure below).  Inherited VWD is further categorized into type 1, 2 and 3 and acquired VWD. The international society of thrombosis and homeostasis further classifies VWD according to qualitative and quantitative VWF defects<ref>Bharati KP, Prashanth UR. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224412/ Von Willebrand disease: an overview.] ''Indian J Pharm Sci''. 2011;73(1):7-16. doi:10.4103/0250-474X.89751</ref>.
There are several classifications of VWD (Figure below).  Inherited VWD is further categorized into types 1, 2 and 3 and acquired VWD. The international society of thrombosis and homeostasis further classifies VWD according to qualitative and quantitative VWF defects<ref>Bharati KP, Prashanth UR. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3224412/ Von Willebrand disease: an overview.] ''Indian J Pharm Sci''. 2011;73(1):7-16.</ref>.


Type 1 and 2 are both autosomal dominant ([https://medlineplus.gov/images/PX00009C_PRESENTATION.jpeg image]): with this pattern of inheritance, the affected individual has 1 copy of a mutant gene and 1 normal gene on a pair of autosomal chromosomes. This means that people with autosomal dominant diseases have a 50/50 chance of passing the mutant gene and the disorder to each of their children. <ref>Schiel, WC.  [https://www.medicinenet.com/script/main/art.asp?articlekey=11974 Medical Definition of Autosomal Dominant.] MedicineNet. </ref>
Type 1 and 2 are both autosomal dominant ([https://medlineplus.gov/images/PX00009C_PRESENTATION.jpeg image]): with this pattern of inheritance, the affected individual has 1 copy of a mutant gene and 1 normal gene on a pair of autosomal chromosomes. This means that people with autosomal dominant diseases have a 50/50 chance of passing the mutant gene and the disorder to each of their children. <ref>Schiel, WC.  [https://www.medicinenet.com/script/main/art.asp?articlekey=11974 Medical Definition of Autosomal Dominant.] MedicineNet. </ref>
[[File:VWD Graphic.png|thumb|Classifications of Von Willebrand Disease|none|500x500px]]
[[File:VWD Graphic.png|thumb|Classifications of Von Willebrand Disease|none|500x500px]]


=== Type 1 Von Willebrand Disease: ===
==== Type 1 Von Willebrand Disease ====
Type 1 VWD is the most common. About 75% of people with VWD are type 1 <ref name=":3">Von Willebrand Disease. NHS. https://www.nhs.uk/conditions/von-willebrand-disease/. Published 2017. Accessed June 16, 2020.</ref><ref name=":4">Types of von Willebrand disease. Canadian Hemophilia Society. https://www.hemophilia.ca/types-of-von-willebrand-disease/. Published 2018. Accessed June 16, 2020.</ref>. It is considered to be the mildest type and it has a partial quantitative VWF defect<ref name=":3" />. Due to its mild presentation, it is the hardest to diagnose. Type 1 VWD is autosomal dominant. The most common manifestation of Type 1 VWD is tooth bleeding and bleeding post-operative or post injury. <ref name=":3" /><ref name=":5">Vanduine S, Ridley K, Bashutski J, Snyder M, Powell C, Taichman S. [https://content.sciendo.com/downloadpdf/journals/jhp/4/1/article-p49.pdf Gingival bleeding and oral hygiene in women with von Willebrand Disease (VWD): a pilot study.] ''J Haemoph Pract''. 2018;4(1):49-57. doi:10.17225/jhp00096</ref>
Type 1 VWD is the most common. About 75% of people with VWD are type 1 <ref name=":3">Von Willebrand Disease. NHS. https://www.nhs.uk/conditions/von-willebrand-disease/. Published 2017. Accessed June 16, 2020.</ref><ref name=":4">Types of von Willebrand disease. Canadian Hemophilia Society. https://www.hemophilia.ca/types-of-von-willebrand-disease/. Published 2018. Accessed June 16, 2020.</ref>. It is considered to be the mildest type and it has a partial quantitative VWF defect<ref name=":3" />. Due to its mild presentation, it is the hardest to diagnose. Type 1 VWD is autosomal dominant. The most common manifestation of Type 1 VWD is tooth bleeding and bleeding post-operative or post-injury. <ref name=":3" /><ref name=":5">Vanduine S, Ridley K, Bashutski J, Snyder M, Powell C, Taichman S. [https://content.sciendo.com/downloadpdf/journals/jhp/4/1/article-p49.pdf Gingival bleeding and oral hygiene in women with von Willebrand Disease (VWD): a pilot study.] ''J Haemoph Pract''. 2018;4(1):49-57.</ref>
[[File:Mouth bleeding.jpg|thumb|Dental bleeding in Von Willebrand Disease]]
[[File: Mouth bleeding.jpg|thumb|Dental bleeding in Von Willebrand Disease]]
 
==== Type 2 Von Willebrand Disease ====
20-25% of people with VWD have type 2, making it the second most common<ref name=":4" />. It is known for its qualitative VWF defect. With Type 2 there is enough VWF factor in the blood. But, the VWF factor does not work properly due to a mutation in the VWF multimer<ref name=":1" /><ref>Hemophilia of Georgia. [https://www.hog.org/handbook/article/1/7/types-of-von-willebrand-disease Types of von Willebrand Disease. The Hemophilia, von Willebrand Disease & Platelet Disorders Handbook]. Published 2007. Accessed June 16, 2020.</ref>. It is subdivided into four subtypes which are Type 2A, Type 2B, Type 2M and Type 2N<ref name=":2" />.


=== Type 2 Von Willebrand Disease: ===
* '''Type 2A'''
20-25% of people with VWD have type 2, making it the second most common<ref name=":4" />. It is known by its qualitative VWF defect. With Type 2 there is enough VWF factor in the blood. But, the VWF factor does not work properly due to a mutation in VWF multimer<ref name=":1" /><ref>Hemophilia of Georgia. [https://www.hog.org/handbook/article/1/7/types-of-von-willebrand-disease Types of von Willebrand Disease. The Hemophilia, von Willebrand Disease & Platelet Disorders Handbook]. Published 2007. Accessed June 16, 2020.</ref>. It is subdivided into four subtypes which are Type 2A, Type 2B, Type 2M and Type 2N<ref name=":2" />.


==== Type 2A: ====
Type 2A is the most common subtype in Type 2. The amount of VWF is normal but due to a mutational defect in VWF protein, the platelets can’t bind to each other properly. This causes a problem in the coagulation process<ref name=":0" />. Type 2A manifests by postoperative haemorrhage, menorrhagia and post-dental extraction haemorrhage.<ref name=":2" />
Type 2A is the most common subtype in Type 2. The amount of VWF is normal but due to a mutational defect in VWF protein, the platelets can’t bind to each other properly. This causes a problem in the coagulation process<ref name=":0" />. Type 2A manifests by postoperative haemorrhage, menorrhagia and post-dental extraction haemorrhage.<ref name=":2" />


==== Type 2B: ====
* '''Type 2B'''
Type 2B is the second most common subtype in Type 2. It has a different mutation in the VWF protein from Type 2A. This defect leads to the binding of the VWF to the platelets in the blood stream instead of binding at the injured site. The body then removes the abnormally bound platelets causing a decrease in the platelets amount<ref name=":4" />. Type 2B manifests by bruising easily, prolonged bleeding from minor wounds and nasal bleeding (epitaxis)<ref name=":1" />.
 
Type 2B is the second most common subtype in Type 2. It has a different mutation in the VWF protein from Type 2A. This defect leads to the binding of the VWF to the platelets in the bloodstream instead of binding at the injured site. The body then removes the abnormally bound platelets causing a decrease in the [[Platelet|platelets]] amount<ref name=":4" />. Type 2B manifests by bruising easily, prolonged bleeding from minor wounds and nasal bleeding (epistaxis)<ref name=":1" />.
 
* '''Type 2M'''


==== Type 2M: ====
M stands for Multimer. Type 2M is characterized by a mutation in the multimer of the VWF protein leading to decreased activity of VWF and its failure to bind with the platelets. Type 2 M manifests by prolonged bleeding from minor wounds similar to Type 2B<ref name=":6" />.
M stands for Multimer. Type 2M is characterized by a mutation in the multimer of the VWF protein leading to decreased activity of VWF and its failure to bind with the platelets. Type 2 M manifests by prolonged bleeding from minor wounds similar to Type 2B<ref name=":6" />.


==== Type 2N: ====
* '''Type 2N'''<ref>Seidizadeh O, Peyvandi F, Mannucci PM. [https://scholar.google.com/scholar?output=instlink&q=info:4njlsD6vLIsJ:scholar.google.com/&hl=en&as_sdt=0,44&as_ylo=2021&scillfp=15770476447702314716&oi=lle Von Willebrand disease type 2N: an update. Journal of Thrombosis and Haemostasis]. 2021 Apr;19(4):909-16.</ref>
 
“N “ refers to Normandy or in French Normaundie, a town in France where this subtype was first identified.<ref name=":4" />  It is characterized by a failure of Factor VIII transporting on VMF despite normal platelet binding with VWF. This results in low factor VIII levels. Type 2N is commonly mistaken for haemophilia A due to the low factor VIII levels.<ref name=":4" /> 
“N “ refers to Normandy or in French Normaundie, a town in France where this subtype was first identified.<ref name=":4" />  It is characterized by a failure of Factor VIII transporting on VMF despite normal platelet binding with VWF. This results in low factor VIII levels. Type 2N is commonly mistaken for haemophilia A due to the low factor VIII levels.<ref name=":4" /> 


=== Type 3 Von Willebrand Disease: ===
=== Type 3 Von Willebrand Disease ===
The most severe and rarest type of VMD is type 3 VWD. It is characterized by the complete absence of VWF in the blood plasma and blood platelets. In contrast to type 1 and type 2, type 3 is autosomal recessive. Type 3 VWD manifests as severe bleeding in soft tissues, joints, muscle, nose and gut<ref name=":3" />.
The most severe and rarest type of VMD is type 3 VWD. It is characterized by the complete absence of VWF in the blood plasma and blood platelets. In contrast to type 1 and type 2, type 3 is autosomal recessive. Type 3 VWD manifests as severe bleeding in soft tissues, joints, muscle, nose and gut<ref name=":3" />.


== Clinical Manifestations: ==
== Clinical Manifestations ==
The clinical manifestation of VWD is different according to the type of VWD<ref name=":3" />.
The clinical manifestation of VWD is different according to the type of VWD<ref name=":3" />.


The most common manifestations include:<ref>Pollak ES. Von Willebrand Disease Clinical Presentation. Medscape. https://emedicine.medscape.com/article/206996-clinical. Published 2019. Accessed June 16, 2020</ref>
The most common manifestations include:<ref>Pollak ES. Von Willebrand Disease Clinical Presentation. Medscape. https://emedicine.medscape.com/article/206996-clinical. Published 2019. Accessed June 16, 2020</ref><ref>Ichinose A, Osaki T, Souri M, Favaloro EJ. A review of autoimmune acquired von Willebrand factor deficiency in Japan. InSeminars in Thrombosis and Hemostasis 2022 Jul 8. Thieme Medical Publishers, Inc..</ref>
 
* Nasal haemorrhage
· Nasal haemorrhage
* Dental and oral cavity haemorrhage
* Prolonged [[Wound Healing|wound healing]]
* [[Menstruation and Menstrual Rehab|Menorrhagia]] which is excessive menstrual haemorrhage
* Gastrointestinal haemorrhage (with severe type)
Some common manifestations in the pediatric population include :<ref>Sanders Y V, Fijnvandraat K, Boender J, et al. [https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.24195 Bleeding spectrum in children with moderate or severe von Willebrand disease:  Relevance of pediatric-specific bleeding]. ''Am J Hematol''. 2015;90(12):1142-1148. </ref>
* Umbilical stump haemorrhage
* Cephalic haematoma
* Cheek haematoma
* Conjunctival haemorrhage
* After circumcision haemorrhage
* After venipuncture haemorrhage


· Dental and oral cavity haemorrhage
== Diagnostic Tools ==
Von Willebrand disease is the most common bleeding disorder, but it is also the hardest to diagnose.<ref>Castaman G, Linari S. [https://www.mdpi.com/2077-0383/6/4/45/pdf Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders]. ''J Clin Med''. 2017;6(4):45. </ref> Unfortunately, the usual blood clotting screening laboratory tests such as CBC, Activated Partial Thromboplastin Time (APTT) Test, Prothrombin Time (PT) Test and Fibrinogen test are all normal in patients with VWD especially those with mild and moderate types.<ref>National Center on Birth Defects and Developmental Disabilities. von Willebrand Disease (VWD) Diagnosis. Centres for Disease Control and Prevention. https://www.cdc.gov/ncbddd/vwd/diagnosis.html. Published 2019. Accessed June 17, 2020.</ref>


· Prolonged wound healing
To diagnose VWD there are screening and diagnostic laboratory tests that can be used.<ref>Roberts JC, Flood VH. [https://onlinelibrary.wiley.com/doi/pdf/10.1111/ijlh.12345 Laboratory diagnosis of von Willebrand disease.] ''Int J Lab Hematol''. 2015;37(1):139-148. </ref>


· Menorrhagia which is excessive menstrual haemorrhage
* '''VWD Screening Tests'''


· Gastrointestinal haemorrhage (with severe type)
* '''VWF antigen (VWF:Ag)'''


There are some common manifestations in the pediatric population that includes:<ref>Sanders Y V, Fijnvandraat K, Boender J, et al. [https://onlinelibrary.wiley.com/doi/pdf/10.1002/ajh.24195 Bleeding spectrum in children with moderate or severe von Willebrand disease:  Relevance of pediatric-specific bleeding]. ''Am J Hematol''. 2015;90(12):1142-1148. doi:10.1002/ajh.24195</ref>
VWF antigen is a quantitative reliable assessment tool of the plasma VWF protein level24. This method is efficient in detecting VWD quantitative defect types. The normal range of VWF: Ag is 50 to 200IU/dl. Anything lower than 50 may indicate the presence of VWD.<ref name=":7">Ng C, Motto DG, Paola J Di. [https://ashpublications.org/blood/article-abstract/125/13/2029/33953 Diagnostic approach to von Willebrand disease.] ''Blood''. 2015;125(13):2029-2037. doi:10.1182/blood-2014-08-528398</ref>


· Umbilical stump haemorrhage
* '''VWF ristocetin cofactor activity (VWF:RCo)'''


· Cephalic haematoma
The VWF: RCo is the most commonly used test to assess the ability of binding ability of VMF24. The normal ranges of VWF:RCo are between 50 and 200 IU/dL.<ref name=":7" />


· Cheek haematoma
* ''' Factor VIII activity (FVIII: C)'''


· Conjunctival haemorrhage
The measurement of FVIII: C is included in the screening laboratory tests of VWD. VWF is a carrier protein for FVIII. Normal ranges of FVIII:C/VWF: Ag ratio is approximately 1. In type 2N, this ratio is low, and in type 3 VWD, the FVIII:C is  less than10 IU/dL<ref name=":7" />.


· After circumcision haemorrhage
* '''VWF:RCo/VWF:Ag Ratio'''


· After venipuncture haemorrhage
The VWF: RCo/VWF: Ag ratio is used to diagnose the type of VWD. In Type 1 VWD the levels of both VWF: RCo and VWF: Ag decreases and as such the ratio between them remains around one. While in type 2 VWD the VWF: RCo decreases compared to the VWD: Ag level so the VWF: RCo/VWF: Ag is approximately 0.6.<ref name=":7" />


== Diagnostic Tools: ==
* '''VWD Confirmatory Tests'''
Von Willebrand disease is the most common bleeding disorder, but it is also the hardest to diagnose.<ref>Castaman G, Linari S. [https://www.mdpi.com/2077-0383/6/4/45/pdf Diagnosis and Treatment of von Willebrand Disease and Rare Bleeding Disorders]. ''J Clin Med''. 2017;6(4):45. doi:10.3390/jcm6040045</ref> Unfortunately, the usual blood clotting screening laboratory tests such as CBC, Activated Partial Thromboplastin Time (APTT) Test, Prothrombin Time (PT) Test and Fibrinogen test are all normal in patients with VWD especially those with mild and moderate types.<ref>National Center on Birth Defects and Developmental Disabilities. von Willebrand Disease (VWD) Diagnosis. Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/vwd/diagnosis.html. Published 2019. Accessed June 17, 2020.</ref>


To diagnose VWD there are screening and diagnostic laboratory tests that can be used.<ref>Roberts JC, Flood VH. [https://onlinelibrary.wiley.com/doi/pdf/10.1111/ijlh.12345 Laboratory diagnosis of von Willebrand disease.] ''Int J Lab Hematol''. 2015;37(1):139-148. doi:doi:10.1111/ijlh.12345</ref>
=== VWD Screening Tests ===
==== VWF antigen (VWF:Ag): ====
VWF antigen is a quantitative reliable assessment tool of the plasma VWF protein level24. This method is efficient in detecting VWD quantitative defect types. The normal range of VWF:Ag is 50 to 200IU/dl. Anything lower than 50 may indicate the presence of VWD.<ref name=":7">Ng C, Motto DG, Paola J Di. [https://ashpublications.org/blood/article-abstract/125/13/2029/33953 Diagnostic approach to von Willebrand disease.] ''Blood''. 2015;125(13):2029-2037. doi:10.1182/blood-2014-08-528398</ref>
==== VWF ristocetin cofactor activity (VWF:RCo): ====
The VWF:RCo is the most commonly used test to assess the ability of binding ability of VMF24. The normal ranges of VWF:RCo are between 50 and 200 IU/dL.<ref name=":7" />
==== Factor VIII activity (FVIII:C): ====
The measurement of FVIII:C is included in the screening laboratory tests of VWD. VWF is a carrier protein for FVIII. Normal ranges of FVIII:C/VWF:Ag ratio is approximately 1. In type 2N, this ratio is low, and in type 3 VWD, the FVIII:C is  less than10 IU/dL<ref name=":7" />.
==== VWF:RCo/VWF:Ag Ratio: ====
The VWF:RCo/VWF:Ag ratio is used to diagnose the type of VWD. In Type 1 VWD the levels of both VWF:RCo and VWF:Ag decreases and as such the ratio between them remains around one. While in type 2 VWD the VWF:RCo decreases compared to the VWD:Ag level so the VWF:RCo/VWF:Ag is approximately 0.6<ref name=":7" />
=== VWD Confirmatory Tests ===
Once VWD is diagnosed some confirmatory tests are run to indicate the type of VWD such as<ref name=":7" />:
Once VWD is diagnosed some confirmatory tests are run to indicate the type of VWD such as<ref name=":7" />:
* VWF multimer distribution which is found to be abnormal in type 2A and type 2B
* VWF: CB is abnormal in type 2A and types 2B, some type 2M.
* VWF: PB increases in type 2
* LD-RIPA increases in type 2B.
* VWF: FVIIIB decreases in type 2
* VWFpp/VWF: Ag ratio increases in type 1
* VWF gene sequencing is most helpful in differentiating type 2 variants


· VWF multimer distribution which is found to be abnormal in type 2A and type 2B
== Medical Management ==
Treatment of VWD is based on the severity of symptoms and the amount of haemorrhage. As most patients with VWD are type 1 (mild type); they don’t need regular treatment. The goals of treatment are to increase the circulating VWF activity and reduce haemorrhage.<ref name=":8">Chapin J. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124462/ Von Willebrand disease in the elderly: clinical perspectives]. ''Clin Interv Aging''. 2018;13:1531-1541.</ref>


· VWF:CB is abnormal in type 2A and type 2B, some type 2M.
Some medications are used in treating and decreasing the symptoms of VWD such as:


· VWF:PB increases in type 2
* '''Desmopressin'''


· LD-RIPA increases in type 2B.
Desmopressin can be administered by nasal spray, intravenous or subcutaneous injection. It that can be administered easily at home and is used for type 1 VWD. The recommended dosage is 0.3 mcg/kg intravenous or subcutaneous or 2 sprays intranasally (for patients above 50 kg) or 1 spray intranasal (for patients less than 50 kg).<ref name=":9">Sharma R, Flood VH. [https://ashpublications.org/blood/article-pdf/130/22/2386/1403377/blood782029.pdf Advances in the diagnosis and treatment of Von Willebrand disease]. Haematology. 2017 Dec 8;2017(1):379-84.</ref>


· VWF:FVIIIB decreases in type 2
* '''Plasma-derived VWF and FVIII Concentrates'''


· VWFpp/VWF:Ag ratio increases in type 1
Plasma-derived VWF and FVIII concentrate such as Humate P (VWF:RCo: FVIII ratio=  2.4:1), Wilate (VWF:RCo: FVIII ratio = 1:1) and Alphanate Plasma-derived VWF and FVIII concentrate (VWF:RCo: FVIII ratio 1:3) are intravenous medications that are used as an acute treatment in severe types of VWD. They can also act as prophylaxis against haemorrhage. The recommended dosage is 50-60 ristocetin cofactor activity units/kg for major surgery, depending on baseline VWF level and desired goal level.<ref name=":9" />


· VWF gene sequencing is most helpful in differentiating type 2 variants
* '''Antifibrinolytics'''


== Medical Management: ==
Antifibrinolytics such as Aminocaproic acid and Tranexamic acid inhibits fibrinolysis. They are used as active and prophylactic treatments, especially for mucosal surfaces. They are introduced orally or intravenously. The recommended dosage for Aminocaproic acid is 100 mg/kg then 50 mg/kg every 6 hours. The dosage for Tranexamic acid is  1500 mg 3 times daily for  5 days for menorrhagia cases.<ref name=":8" /><ref name=":9" />
Treatment of VWD is based on the severity of symptoms and the amount of haemorrhage. As most patients with VWD are type 1 (mild type); they don’t need regular treatment. The goals of treatment are to increase the circulating VWF activity and reduce haemorrhage.<ref name=":8">Chapin J. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124462/ Von Willebrand disease in the elderly: clinical perspectives]. ''Clin Interv Aging''. 2018;13:1531-1541. doi:10.2147/CIA.S136931</ref>


Some medications are used in treating and decreasing the symptoms of VWD such as:
* '''Hormonal therapy'''


=== Desmopressin: ===
Desmopressin can be administered by nasal spray, intravenous or subcutaneous injection. It that can be administered easily at home and is used for type 1 VWD. The recommended dosage 0.3 mcg/kg intravenous or subcutaneous or 2 sprays intranasally (for patients above 50 kg) or 1 spray intranasal (for patients less than 50 kg).<ref name=":9">Sharma R, Flood VH. [https://ashpublications.org/blood/article-pdf/130/22/2386/1403377/blood782029.pdf Advances in the diagnosis and treatment of Von Willebrand disease]. Hematology. 2017 Dec 8;2017(1):379-84.</ref>
=== Plasma-derived VWF and FVIII Concentrates: ===
Plasma-derived VWF and FVIII concentrate such as Humate P (VWF:RCo: FVIII ratio=  2.4:1), Wilate (VWF:RCo: FVIII ratio = 1:1) and Alphanate Plasma-derived VWF and FVIII concentrate (VWF:RCo: FVIII ratio 1:3) are intravenous medication that is used as acute treatment in severe types of VWD. They can also act as prophylaxis against haemorrhage. The recommended dosage is 50-60 ristocetin cofactor activity units/kg for major surgery, depending on baseline VWF level and desired goal level.<ref name=":9" />
=== Antifibrinolytics: ===
Antifibrinolytics such as Aminocaproic acid and Tranexamic acid inhibits fibrinolysis. They are used as active and prophylactic treatments, especially for mucosal surfaces. They are introduced orally or intravenously. The recommended dosage for Aminocaproic acid is 100 mg/kg then 50 mg/kg every 6 hours. The dosage for Tranexemic acid is  1500 mg 3 times daily  for  5 days for menorrhagia cases.<ref name=":8" /><ref name=":9" />
=== Hormonal therapy: ===
Hormonal therapy is also an option in treating menorrhagia.<ref>Green D. Diagnosis and Treatment of von Willebrand Disease. NEJM Jornal Watch. https://www.jwatch.org/na45666/2017/12/06/diagnosis-and-treatment-von-willebrand-disease. Published 2017. Accessed June 17, 2020.</ref>
Hormonal therapy is also an option in treating menorrhagia.<ref>Green D. Diagnosis and Treatment of von Willebrand Disease. NEJM Jornal Watch. https://www.jwatch.org/na45666/2017/12/06/diagnosis-and-treatment-von-willebrand-disease. Published 2017. Accessed June 17, 2020.</ref>


== Physical Therapy Management: ==
== Physical Therapy Management ==
Physical therapy has an important role in promoting functional skills in paediatrics and adults with VWD; that is why the National Haemophilia  Foundation formed a physical therapy working group to create the best physical therapy practice for bleeding disorders such as VWD<ref name=":10">Lowes LP, Alfano L, Orlin MN. [https://books.google.com/books?hl=en&lr=&id=kSFhAQAAQBAJ&oi=fnd&pg=PR4&dq=Meeting+the+Physical+Therapy+Needs+of+Children&ots=me7_sfi5t0&sig=Cka_f8Ki2B0lC0rRHqybBZ9J-8A Muscloskeltal System: Considerations and Interventions for Specific Pediatric Pathology. In: Effgen SK, ed. ''Meeting the Physical Therapy Needs of Children'']. 2nd ed. Philadelphia: F. A. Davis Company; 2013:226-227</ref>.
Physical therapy has an important role in promoting functional skills in paediatrics and adults with VWD; that is why the National Haemophilia  Foundation formed a physical therapy working group to create the best physical therapy practice for bleeding disorders such as VWD.<ref name=":10">Lowes LP, Alfano L, Orlin MN. [https://books.google.com/books?hl=en&lr=&id=kSFhAQAAQBAJ&oi=fnd&pg=PR4&dq=Meeting+the+Physical+Therapy+Needs+of+Children&ots=me7_sfi5t0&sig=Cka_f8Ki2B0lC0rRHqybBZ9J-8A Musculoskeletal System: Considerations and Interventions for Specific Pediatric Pathology. In: Effgen SK, ed. ''Meeting the Physical Therapy Needs of Children'']. 2nd ed. Philadelphia: F. A. Davis Company; 2013:226-227.</ref>


The Medical and Scientific Advisory Council (MASAC) developed guidelines and a framework for physical therapy management in bleeding disorders. MASAC stated that physical therapy is crucial in joint and muscles rehabilitation post soft tissue injuries and hemarthroses These clinical presentations mostly occur with the more severe types of VWD.
The Medical and Scientific Advisory Council (MASAC) developed guidelines and a framework for physical therapy management in bleeding disorders. MASAC stated that physical therapy is crucial in joint and muscles rehabilitation post soft tissue injuries and hemarthroses These clinical presentations mostly occur with the more severe types of VWD.


== Physical Therapy Evaluation ==
=== Physical Therapy Evaluation ===
According to the MASAC; the physical therapy evaluation is an important element of VWD management. The aim of evaluation is to detect musculoskeletal and other limitations caused by the bleeding disorder that affect functional activities and daily life activities(ADL)<ref name=":11">Medical and Scientific Advisory Counsil. Physical Therapy Evaulation Recommendations. ''Natl Hemoph Found''. 2018</ref>.
According to the MASAC; the physical therapy evaluation is an important element of VWD management. The evaluation aims to detect musculoskeletal and other limitations caused by the bleeding disorder that affect functional activities and daily life activities(ADL).<ref name=":11">Medical and Scientific Advisory Council. Physical Therapy Evaluation Recommendations. ''Natl Hemoph Found''. 2018.</ref>


=== History and Interview<ref name=":11" />: ===
==== History and Interview<ref name=":11" />====
It includes interviewing the patient or the caregiver and take the notes about:
It includes interviewing the patient or the caregiver and taking the notes about:
* Personal history
* Personal history
* Family history
* Family history
Line 143: Line 137:
Joints that have recurrent bleeding disorders are known as “Target Joints”. The most common target joints are knee, elbow, ankle, hip and shoulders.<ref name=":10" />
Joints that have recurrent bleeding disorders are known as “Target Joints”. The most common target joints are knee, elbow, ankle, hip and shoulders.<ref name=":10" />


=== Subjective Assessment: ===
==== Subjective Assessment ====
·      Palpation of joints at rest and during active range of motion to detect crepitus, synovitis, oedema or temperature
* Palpation of joints at rest and during active range of motion to detect crepitus, synovitis, oedema or temperature.
* [[Girth Measurement|Girth measurement]] (measuring circumference with a tape measure) to assess oedema/ muscle atrophy.
* Atypical Joint End feel detection via a passive range of motion.
* Manual Muscle Testing to assess muscular strength.
* Muscle Flexibility test.
* Sensation and proprioception.


·      [[Girth Measurement|Girth measurement]] (measuring circumference with a tape measure) to assess oedema/ muscle atrophy
==== Objective Assessment ====
* Balance and fall assessment
* Posture and alignment assessment
* Assessment of functional activities
* Gait analysis
* Neuromotor assessment
* Musculoskeletal Ultrasound


·      Atypical Joint End feel detection via passive range of motion
=== Physical Therapy Treatment ===
 
There is a recommended physical therapy program by the MASAC for muscles and joints bleeding in different recovery phases (Acute, Subacute and Chronic). All muscles follow the same guidelines, except for iliopsoas muscle, and all physical therapy suggested protocols are performed post factor replacement medication as follows :<ref>National Hemophilia Foundation. [https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendations-Regarding-Physical-Therapy-Guidelines-in-Patients-with-Bleeding-Disorders Physical Therapy Practice Guidelines for Persons with Bleeding Disorders: Muscle Bleed]. 2018;</ref>
·      Manual Muscle Testing to assess muscular strength
 
·      Muscle Flexibility test
 
·      Sensation and proprioception
 
=== Objective Assessment: ===
·      Balance and fall assessment
 
·      Posture and alignment assessment
 
·      Assessment of functional activities


·      Gait analysis
{|
 
!
·      Neuromotor assessment
!'''Acute Phase'''
 
!'''Subacute Phase'''
·      Musculoskeletal Ultrasound
!'''Chronic'''
 
!'''Other Treatment Considerations'''
== Physical Therapy Treatment: ==
!'''Precautions'''
There is a recommended physical therapy program by the MASAC for muscles and joints bleeding in different recovery phases (Acute, Subacute and Chronic). All muscles follow the same guidelines, except for iliopsoas muscle, and all physical therapy suggested protocols are performed post factor replacement medication as follows :<ref>National Hemophilia Foundation. [https://www.hemophilia.org/Researchers-Healthcare-Providers/Medical-and-Scientific-Advisory-Council-MASAC/MASAC-Recommendations/MASAC-Recommendations-Regarding-Physical-Therapy-Guidelines-in-Patients-with-Bleeding-Disorders Physical Therapy Practice Guidelines for Persons with Bleeding Disorders: Muscle Bleed]. 2018;</ref>
{| class="wikitable"
|
|'''Acute Phase'''
|'''Subacute Phase'''
|'''Chronic'''
|'''Other Treatment Considerations'''
|'''Precautions'''
|-
|-
| rowspan="2" |'''Muscles Bleeding except iliopsoas'''
| rowspan="2" |'''Muscles Bleeding except iliopsoas'''
Line 189: Line 174:


ADL limitation but without pain
ADL limitation but without pain
| rowspan="2" | - Electric stimulation
| rowspan="2" |Electric stimulation


- Work closely with hematologist
- Work closely with a haematologist


- Teach patient to avoid overstretching
- Teach patient to avoid overstretching
Line 202: Line 187:


- Ultrasound for blood absorption can be used with precautions.
- Ultrasound for blood absorption can be used with precautions.
| rowspan="2" | - Monitor for neurovascular compromise while Splinting
| rowspan="2" |Monitor for neurovascular compromise while Splinting


- Caution with use of compression on affected muscle.
- Caution with the use of compression on the affected muscle.


- Use of heat modalities including ultrasound  with precautions
- Use of heat modalities including ultrasound  with precautions
Line 212: Line 197:
- No compression in case of neuromuscular symptoms.
- No compression in case of neuromuscular symptoms.


- No active movement or weight bearing till bleeding stoppage.
- No active movement or weight-bearing till bleeding stoppage.


- Splinting.
- Splinting.
Line 223: Line 208:
- Splinting and assistive device to limit activity
- Splinting and assistive device to limit activity


- Toe touch Weight bearing
- Toe touch Weight-bearing


- Isometric contractions
- Isometric contractions
Line 256: Line 241:


ADL limitation but without pain
ADL limitation but without pain
| rowspan="2" | -   Electrical-stimulation to prevent femoral nerve palsy/atrophy.
| rowspan="2" |Electrical-stimulation to prevent femoral nerve palsy/atrophy.


-    Hip flexor stretching with caution.
-    Hip flexor stretching with caution.
Line 263: Line 248:


-   Treatment duration will vary based on individual
-   Treatment duration will vary based on individual
| rowspan="2" |Monitor for femoral nerve palsy
| rowspan="2" | - Monitor for femoral nerve palsy
|-
|-
|'''Physical Therapy''' '''Program :'''
|'''Physical Therapy''' '''Program :'''
Line 276: Line 261:
|'''Physical Therapy Program:'''
|'''Physical Therapy Program:'''


-   Toes touch weight bearing without increase in pain
-   Toes touch weight-bearing without an increase in pain


-   Isometric contractions
-   Isometric contractions


-   Active Range Of Motion exercises to involved Lower limb without increase in pain
-   Active Range Of Motion exercises to involve Lower limb without an increase in pain


-   Positioning with increasing hip extension Range Of Motion in supine and prone over pillows without increase in pain.
-   Positioning with increasing hip extension Range Of Motion in supine and prone over pillows without an increase in pain.


-   therapeutic exercises for non-involved limb
-   therapeutic exercises for non-involved limb
Line 289: Line 274:
-   Full Weight Bearing without  assistive devices
-   Full Weight Bearing without  assistive devices


-   positional stretches from prone position
-   positional stretches from a prone position


-   Active range of motion exercises
-   Active range of motion exercises
Line 295: Line 280:
-   Re-evaluation
-   Re-evaluation
|-
|-
| rowspan="2" |'''Joint Bleeding'''
| rowspan="2" | '''Joint Bleeding'''
|'''Main Problem:'''
|'''Main Problem:'''


Line 317: Line 302:
-   Myofascial release
-   Myofascial release


-   Work with haematologist.
-   Work with the haematologist.


-   Further MRI to determine the presence of chronic synovitis)
-   Further MRI to determine the presence of chronic synovitis)
Line 336: Line 321:
-    Splinting
-    Splinting


-    Non-Weight Bearing using  assistive device
-    Non-Weight Bearing using an assistive device
|'''Physical Therapy''' '''Program :'''
|'''Physical Therapy''' '''Program :'''


Line 343: Line 328:
-   Night resting splint for protection
-   Night resting splint for protection


-   Begin progressive weight bearing
-   Begin progressive weight-bearing


-   Activity modification to avoid pain
-   Activity modification to avoid pain
Line 375: Line 360:
<references />
<references />
[[Category:Course Pages]]
[[Category:Course Pages]]
[[Category:Plus Content]]
[[Category:Paediatrics]]
[[Category:Paediatrics]]
[[Category:Paediatrics - Conditions]]
[[Category:Paediatrics - Conditions]]
[[Category:Blood Disorders]]
[[Category:Blood Disorders]]
[[Category:Genetic Disorders]]

Latest revision as of 16:47, 28 March 2024

Introduction[edit | edit source]

Von Willebrand Disease (VWD) is considered to be the most common bleeding disorder in humans and in some animals such as dogs[1]. VWD is named after the Finnish physician who described the disease in the 1920s. 1 in 100 to 10 000 individuals is estimated to have VWD.  Patients with mild VWD symptoms are rarely diagnosed resulting in the gap “100 to 10 000“[2]. It is estimated that it affects 1% of all US population[3].

History[edit | edit source]

In 1926 the Finnish physician Erik Von Willebrand described a new bleeding disorder which he called “hereditary pseudo haemophilia.” He recognized that this new disease is different from haemophilia, but he couldn’t identify the responsible plasma factor. Later by many years; this factor was identified and named after him too and now it’s known as Von Willebrand Factor (VWF)[4].

Von Willebrand Factor[edit | edit source]

Von Willebrand Factor (VWF) is a multifunctional multimeric glycoprotein[5] which is synthesized in endothelial cells[6]. The VWF consists of similar subunits that contain binding sites for glycoprotein receptors. The adhesive activity of VWF depends mainly on the size of its multimers[7]. Von Willebrand Factor plays an important role in primary and secondary hemostasis, acts as a mediator for adhesion and a carrier for coagulation FVIII.[6] It is also involved in angiogenesis and inflammatory processes.[8][9]

Definition[edit | edit source]

Von Willebrand Disease can either be inherited or acquired.

  1. As an autosomal inherited disease it results from a defect in the protein factor called VWF. Type 1 and 2 are autosomal dominant and type 3 is transmitted as autosomal recessive. It affects men and women equally as it is an autosomal linked disease[4][10][11].
  2. Acquired VWD is different from inherited VWD as the disease develops later in life and is not a result of genetic inheritance. Acquired VWD may be due to autoimmune reactions in people with cardiac defects; certain forms of cancers; diabetes mellitus; autoimmune disease or after usage of certain drugs such as valpronic acid.[12]

Classification of Inherited Von Willebrand Disease[edit | edit source]

There are several classifications of VWD (Figure below).  Inherited VWD is further categorized into types 1, 2 and 3 and acquired VWD. The international society of thrombosis and homeostasis further classifies VWD according to qualitative and quantitative VWF defects[13].

Type 1 and 2 are both autosomal dominant (image): with this pattern of inheritance, the affected individual has 1 copy of a mutant gene and 1 normal gene on a pair of autosomal chromosomes. This means that people with autosomal dominant diseases have a 50/50 chance of passing the mutant gene and the disorder to each of their children. [14]

Classifications of Von Willebrand Disease

Type 1 Von Willebrand Disease[edit | edit source]

Type 1 VWD is the most common. About 75% of people with VWD are type 1 [15][16]. It is considered to be the mildest type and it has a partial quantitative VWF defect[15]. Due to its mild presentation, it is the hardest to diagnose. Type 1 VWD is autosomal dominant. The most common manifestation of Type 1 VWD is tooth bleeding and bleeding post-operative or post-injury. [15][17]

Dental bleeding in Von Willebrand Disease

Type 2 Von Willebrand Disease[edit | edit source]

20-25% of people with VWD have type 2, making it the second most common[16]. It is known for its qualitative VWF defect. With Type 2 there is enough VWF factor in the blood. But, the VWF factor does not work properly due to a mutation in the VWF multimer[6][18]. It is subdivided into four subtypes which are Type 2A, Type 2B, Type 2M and Type 2N[5].

  • Type 2A

Type 2A is the most common subtype in Type 2. The amount of VWF is normal but due to a mutational defect in VWF protein, the platelets can’t bind to each other properly. This causes a problem in the coagulation process[4]. Type 2A manifests by postoperative haemorrhage, menorrhagia and post-dental extraction haemorrhage.[5]

  • Type 2B

Type 2B is the second most common subtype in Type 2. It has a different mutation in the VWF protein from Type 2A. This defect leads to the binding of the VWF to the platelets in the bloodstream instead of binding at the injured site. The body then removes the abnormally bound platelets causing a decrease in the platelets amount[16]. Type 2B manifests by bruising easily, prolonged bleeding from minor wounds and nasal bleeding (epistaxis)[6].

  • Type 2M

M stands for Multimer. Type 2M is characterized by a mutation in the multimer of the VWF protein leading to decreased activity of VWF and its failure to bind with the platelets. Type 2 M manifests by prolonged bleeding from minor wounds similar to Type 2B[12].

“N “ refers to Normandy or in French Normaundie, a town in France where this subtype was first identified.[16]  It is characterized by a failure of Factor VIII transporting on VMF despite normal platelet binding with VWF. This results in low factor VIII levels. Type 2N is commonly mistaken for haemophilia A due to the low factor VIII levels.[16] 

Type 3 Von Willebrand Disease[edit | edit source]

The most severe and rarest type of VMD is type 3 VWD. It is characterized by the complete absence of VWF in the blood plasma and blood platelets. In contrast to type 1 and type 2, type 3 is autosomal recessive. Type 3 VWD manifests as severe bleeding in soft tissues, joints, muscle, nose and gut[15].

Clinical Manifestations[edit | edit source]

The clinical manifestation of VWD is different according to the type of VWD[15].

The most common manifestations include:[20][21]

  • Nasal haemorrhage
  • Dental and oral cavity haemorrhage
  • Prolonged wound healing
  • Menorrhagia which is excessive menstrual haemorrhage
  • Gastrointestinal haemorrhage (with severe type)

Some common manifestations in the pediatric population include :[22]

  • Umbilical stump haemorrhage
  • Cephalic haematoma
  • Cheek haematoma
  • Conjunctival haemorrhage
  • After circumcision haemorrhage
  • After venipuncture haemorrhage

Diagnostic Tools[edit | edit source]

Von Willebrand disease is the most common bleeding disorder, but it is also the hardest to diagnose.[23] Unfortunately, the usual blood clotting screening laboratory tests such as CBC, Activated Partial Thromboplastin Time (APTT) Test, Prothrombin Time (PT) Test and Fibrinogen test are all normal in patients with VWD especially those with mild and moderate types.[24]

To diagnose VWD there are screening and diagnostic laboratory tests that can be used.[25]

  • VWD Screening Tests
  • VWF antigen (VWF:Ag)

VWF antigen is a quantitative reliable assessment tool of the plasma VWF protein level24. This method is efficient in detecting VWD quantitative defect types. The normal range of VWF: Ag is 50 to 200IU/dl. Anything lower than 50 may indicate the presence of VWD.[26]

  • VWF ristocetin cofactor activity (VWF:RCo)

The VWF: RCo is the most commonly used test to assess the ability of binding ability of VMF24. The normal ranges of VWF:RCo are between 50 and 200 IU/dL.[26]

  • Factor VIII activity (FVIII: C)

The measurement of FVIII: C is included in the screening laboratory tests of VWD. VWF is a carrier protein for FVIII. Normal ranges of FVIII:C/VWF: Ag ratio is approximately 1. In type 2N, this ratio is low, and in type 3 VWD, the FVIII:C is  less than10 IU/dL[26].

  • VWF:RCo/VWF:Ag Ratio

The VWF: RCo/VWF: Ag ratio is used to diagnose the type of VWD. In Type 1 VWD the levels of both VWF: RCo and VWF: Ag decreases and as such the ratio between them remains around one. While in type 2 VWD the VWF: RCo decreases compared to the VWD: Ag level so the VWF: RCo/VWF: Ag is approximately 0.6.[26]

  • VWD Confirmatory Tests

Once VWD is diagnosed some confirmatory tests are run to indicate the type of VWD such as[26]:

  • VWF multimer distribution which is found to be abnormal in type 2A and type 2B
  • VWF: CB is abnormal in type 2A and types 2B, some type 2M.
  • VWF: PB increases in type 2
  • LD-RIPA increases in type 2B.
  • VWF: FVIIIB decreases in type 2
  • VWFpp/VWF: Ag ratio increases in type 1
  • VWF gene sequencing is most helpful in differentiating type 2 variants

Medical Management[edit | edit source]

Treatment of VWD is based on the severity of symptoms and the amount of haemorrhage. As most patients with VWD are type 1 (mild type); they don’t need regular treatment. The goals of treatment are to increase the circulating VWF activity and reduce haemorrhage.[27]

Some medications are used in treating and decreasing the symptoms of VWD such as:

  • Desmopressin

Desmopressin can be administered by nasal spray, intravenous or subcutaneous injection. It that can be administered easily at home and is used for type 1 VWD. The recommended dosage is 0.3 mcg/kg intravenous or subcutaneous or 2 sprays intranasally (for patients above 50 kg) or 1 spray intranasal (for patients less than 50 kg).[28]

  • Plasma-derived VWF and FVIII Concentrates

Plasma-derived VWF and FVIII concentrate such as Humate P (VWF:RCo: FVIII ratio=  2.4:1), Wilate (VWF:RCo: FVIII ratio = 1:1) and Alphanate Plasma-derived VWF and FVIII concentrate (VWF:RCo: FVIII ratio 1:3) are intravenous medications that are used as an acute treatment in severe types of VWD. They can also act as prophylaxis against haemorrhage. The recommended dosage is 50-60 ristocetin cofactor activity units/kg for major surgery, depending on baseline VWF level and desired goal level.[28]

  • Antifibrinolytics

Antifibrinolytics such as Aminocaproic acid and Tranexamic acid inhibits fibrinolysis. They are used as active and prophylactic treatments, especially for mucosal surfaces. They are introduced orally or intravenously. The recommended dosage for Aminocaproic acid is 100 mg/kg then 50 mg/kg every 6 hours. The dosage for Tranexamic acid is  1500 mg 3 times daily for  5 days for menorrhagia cases.[27][28]

  • Hormonal therapy

Hormonal therapy is also an option in treating menorrhagia.[29]

Physical Therapy Management[edit | edit source]

Physical therapy has an important role in promoting functional skills in paediatrics and adults with VWD; that is why the National Haemophilia  Foundation formed a physical therapy working group to create the best physical therapy practice for bleeding disorders such as VWD.[30]

The Medical and Scientific Advisory Council (MASAC) developed guidelines and a framework for physical therapy management in bleeding disorders. MASAC stated that physical therapy is crucial in joint and muscles rehabilitation post soft tissue injuries and hemarthroses These clinical presentations mostly occur with the more severe types of VWD.

Physical Therapy Evaluation[edit | edit source]

According to the MASAC; the physical therapy evaluation is an important element of VWD management. The evaluation aims to detect musculoskeletal and other limitations caused by the bleeding disorder that affect functional activities and daily life activities(ADL).[31]

History and Interview[31][edit | edit source]

It includes interviewing the patient or the caregiver and taking the notes about:

  • Personal history
  • Family history
  • Bleeding history
  • Medical and surgical history
  • Pain history
  • ADL concerns   
  • Occupational concerns

Joints that have recurrent bleeding disorders are known as “Target Joints”. The most common target joints are knee, elbow, ankle, hip and shoulders.[30]

Subjective Assessment[edit | edit source]

  • Palpation of joints at rest and during active range of motion to detect crepitus, synovitis, oedema or temperature.
  • Girth measurement (measuring circumference with a tape measure) to assess oedema/ muscle atrophy.
  • Atypical Joint End feel detection via a passive range of motion.
  • Manual Muscle Testing to assess muscular strength.
  • Muscle Flexibility test.
  • Sensation and proprioception.

Objective Assessment[edit | edit source]

  • Balance and fall assessment
  • Posture and alignment assessment
  • Assessment of functional activities
  • Gait analysis
  • Neuromotor assessment
  • Musculoskeletal Ultrasound

Physical Therapy Treatment[edit | edit source]

There is a recommended physical therapy program by the MASAC for muscles and joints bleeding in different recovery phases (Acute, Subacute and Chronic). All muscles follow the same guidelines, except for iliopsoas muscle, and all physical therapy suggested protocols are performed post factor replacement medication as follows :[32]

Acute Phase Subacute Phase Chronic Other Treatment Considerations Precautions
Muscles Bleeding except iliopsoas Main Problem:

Present pain at rest and with movement

Main Problem :

Limitations in ADL without increasing pain from baseline

Main Problem :

ADL limitation but without pain

Electric stimulation

- Work closely with a haematologist

- Teach patient to avoid overstretching

- Education on activity modification

- Kinesiotape®

- Treatment duration will vary based on individual needs

- Ultrasound for blood absorption can be used with precautions.

Monitor for neurovascular compromise while Splinting

- Caution with the use of compression on the affected muscle.

- Use of heat modalities including ultrasound  with precautions

Physical Therapy Program:

- No compression in case of neuromuscular symptoms.

- No active movement or weight-bearing till bleeding stoppage.

- Splinting.

- RICE: Rest, Ice, Compression & Elevation

- TENS

Physical Therapy Program:

- Splinting and assistive device to limit activity

- Toe touch Weight-bearing

- Isometric contractions

- Active range of motion

- Positioning 

- AAROM without pain

- TENS

Physical Therapy Program:

- Full Weight Bearing without assistive devices

- Positional stretching

-  Active Range of Motion exercises

- unrestricted lifting

- Re-evaluation.

Iliopsoas Muscle Bleeding Main Problem:

pain presented at rest and with movement

Main Problem :

ADL limitation without increase pain from baseline

Main Problem :

ADL limitation but without pain

Electrical-stimulation to prevent femoral nerve palsy/atrophy.

-    Hip flexor stretching with caution.

-   Teach patient to avoid overstretching

-   Treatment duration will vary based on individual

- Monitor for femoral nerve palsy
Physical Therapy Program :

-   Bedrest

-   Toe Touch Weight Bearing for household mobility

-   Rest

-   Opposite limb ROM Ankle pumps involved lower limb with pain avoidance

Physical Therapy Program:

-   Toes touch weight-bearing without an increase in pain

-   Isometric contractions

-   Active Range Of Motion exercises to involve Lower limb without an increase in pain

-   Positioning with increasing hip extension Range Of Motion in supine and prone over pillows without an increase in pain.

-   therapeutic exercises for non-involved limb

Physical Therapy Program:

-   Full Weight Bearing without  assistive devices

-   positional stretches from a prone position

-   Active range of motion exercises

-   Re-evaluation

Joint Bleeding Main Problem:

pain presented at rest and with movement

Main Problem :

ADL limitation without increase pain from baseline

Main Problem :

ADL limitation but without pain

-   TENS

-   Relaxation Techniques

-    Kinesiology tape

-   Cryotherapy

-   Elastic stockinette

-   Myofascial release

-   Work with the haematologist.

-   Further MRI to determine the presence of chronic synovitis)

-   Treatment duration will vary based on individual needs.

-   Avoid aggressive exercise too early

-   Monitor for nerve compression

-   Use of heat modalities including ultrasound with precautions

-    No return to sports or activity until pain-free full ROM and strength

Physical Therapy Program:

-   RICE (ice for 10-20 minutes every 1-2 hours)

-    Splinting

-    Non-Weight Bearing using an assistive device

Physical Therapy Program :

-    Continue RICE for pain and after exertion Splinting

-   Night resting splint for protection

-   Begin progressive weight-bearing

-   Activity modification to avoid pain

-   Pain-free gentle active Range of motion 

-   Pain-free progressive strengthening

Physical Therapy Program :

-   Dynamic splinting to increase ROM

-   Active range of motion Progressive

-   Strengthening as Open chain, closed chain and resistive band

-   proprioceptive training

-   Gentle joint mobilizations

-   Modified functional activities

-   Orthotics

-   Reevaluations

Additional Resources[edit | edit source]

References[edit | edit source]

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