Von Willebrand disease pathophysiology: Difference between revisions

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==Overview==
==Overview==
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]].


==Pathophysiology==
==Pathophysiology==
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'''Structure'''
'''Structure'''
* It is a [[glycoprotein]] present in blood and is involved in [[hemostasis]].
* It 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.
* Its [[synthesis]] takes place in the [[endothelium]] (in the Weibel-Palade bodies), [[Megakaryocyte|megakaryocytes]] (α-granules of [[platelets]]), and [[subendothelial]] [[connective tissue]].
* The fundamental vWF [[monomer]] is a 2050-[[Amino acid|amino acid protein]].
* The fundamental vWF [[monomer]] is a 2050-[[Amino acid|amino acid protein]].
These [[monomer]] contains a number of specific [[Protein domains|domains]] with a distinguishing function.
These [[monomer]] contains a number of specific [[Protein domains|domains]] with a distinguishing function.
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* Von Willebrand factor protects [[Factor VIII|FVIII]] from [[degradation]] and delivers it to the site of injury
* Von Willebrand factor protects [[Factor VIII|FVIII]] from [[degradation]] and delivers it to the site of injury
* [[Factor VIII]] degrades rapidly when not bound to vWF
* [[Factor VIII]] degrades rapidly when not bound to vWF
* [[Factor VIII]] is released from vWF by the action of thrombin.
* [[Factor VIII]] is released from vWF by the action of [[thrombin]].
* In the absence of vWF, [[factor VIII]] has a [[half-life]] of 1-2 hours
* In the absence of vWF, [[factor VIII]] has a [[half-life]] of 1-2 hours
* When it is carried by intact vWF, [[factor VIII]] [[half-life]] becomes 8-12 hour
* When it is carried by intact vWF, [[factor VIII]] [[half-life]] becomes 8-12 hour
* When vWF is exposed in [[endothelial cells]] due to damage occurring to the blood vessel, it binds to [[collagen]].
* When vWF is exposed in [[endothelial cells]] due to damage occurring to the blood vessel, it binds to [[collagen]].
* [[Endothelium]] also releases vWF which forms additional links between the [[Glycoprotein Ib|platelets' glycoprotein Ib]]/IX/V and the collagen fibrils
* [[Endothelium]] also releases vWF which forms additional links between the [[Glycoprotein Ib|platelets' glycoprotein Ib]]/IX/V and the [[Collagen|collagen fibrils]]
* Von Willebrand factor attaches to [[Platelet|platelets]] by its specific receptor to [[glycoprotein Ib]] on the [[platelet]] surface.
* Von Willebrand factor attaches to [[Platelet|platelets]] by its specific receptor to [[glycoprotein Ib]] on the [[platelet]] surface.
* It acts as an adhesive bridge between the [[Platelet|platelets]] and damaged [[subendothelium]] at the site o[[Vascular|f vascular]] injury
* It acts as an adhesive bridge between the [[Platelet|platelets]] and damaged [[subendothelium]] at the site o[[Vascular|f vascular]] injury
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====Heart-related conditions====
====Heart-related conditions====


*[[Mitral valve prolapse]]
*[[Mitral valve prolapse]]  
*Ventricular assist device
*Ventricular assist device  
*[[Ventricular septal defect]]
*[[Ventricular septal defect]]  
*[[Aortic stenosis]]
*[[Aortic stenosis]]


====Malignant diseases====
====Malignant diseases====
*[[Monoclonal gammopathy]] of undetermined significance
*[[Monoclonal gammopathy]] of undetermined significance
 
*[[chronic myeloid leukemia]] and [[chronic lymphocytic leukemia]]
*Leukemia example [[chronic myeloid leukemia]] and [[chronic lymphocytic leukemia]]
*[[Wilms tumor]]
*[[Wilms tumor]]
*[[Waldenström macroglobulinemia]]
*[[Waldenström macroglobulinemia]]

Latest revision as of 14:10, 5 October 2018

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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 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.

Pathophysiology

Physiology

Von Willebrand factor (vWF)

The normal physiology of von Willebrand’s factor can be understood as follows:[1]

Structure

These monomer contains a number of specific domains with a distinguishing function.

Function

Pathogenesis

von Willebrand disease is due to an abnormality, either quantitative or qualitative, of the von Willebrand factor[2]

Pathogenetic mechanisms of inherited VWD

VWD subtype Pathogenetic mechanisms
Type 1 VWD 65% have VWF mutations Partial quantitative deficiency of VWF
70% of VWF variants are missense substitutions affecting VWF trafficking, storage, secretion, and clearance
Transcription and splicing VWF mutations
Type 2A VWD Mutations in D1/D2/D′D3 assemblies, A2 and CTCK domains Loss of high-molecular-weight multimers (HMWMs)
Interference with HMW multimer formation, storage, and secretion
Increased ADAMTS13 proteolysis
Type 2B VWD Mutations in A1 domain The increase in binding of larger VWF multimers to platelet GP Ib results in sequestration of the platelets and VWF resulting in Thrombocytopenia
Excessive binding to GPIb glycoprotein Ib
Type 2M VWD Mutations in A1 and A3 domains Qualitative variants with decreased binding of VWF to GP Ib, resulting in decreased platelet adhesion
Diminished binding to GPIbα glycoprotein Ib (A1 domain) or collagen (A3 domain)
Type 2N VWD Missense variants in D′D3 assembly Qualitative variants with remarkably decreased affinity for FVIII
Reduced FVIII binding
Type 3 VWD VWF mutations found in 85%-90% of cases Produces null phenotype or the VWF that is not secreted.
VWF deletions, nonsense, splice site, and missense mutations

Pathogenetic mechanisms of acquired VWD

  • Acquired VWD is associated with other diseases resulting from different pathological processes. These pathological processes include:


Genetics

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. The diagram below illustrates autosomal dominant inheritance.

von Willebrand disease
von Willebrand disease types I and II are inherited in an autosomal dominant pattern.

Associated conditions

Acquired conditions associated with Von Willebrand disease include the following:[13][14][3][4][5][6][7]

Heart-related conditions

Malignant diseases

Drugs and other agents

Autoimmune disorders

Other disorders

References

  1. Peyvandi F, Garagiola I, Baronciani L (May 2011). "Role of von Willebrand factor in the haemostasis". Blood Transfus. 9 Suppl 2: s3–8. doi:10.2450/2011.002S. PMC 3159913. PMID 21839029.
  2. Lillicrap D (November 2013). "von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy". Blood. 122 (23): 3735–40. doi:10.1182/blood-2013-06-498303. PMC 3952678. PMID 24065240.
  3. 3.0 3.1 Franchini M, Lippi G (2007). "Acquired von Willebrand syndrome: an update". Am J Hematol. 82 (5): 368–75. doi:10.1002/ajh.20830. PMID 17133419.
  4. 4.0 4.1 Tiede A, Rand JH, Budde U, Ganser A, Federici AB (2011). "How I treat the acquired von Willebrand syndrome". Blood. 117 (25): 6777–85. doi:10.1182/blood-2010-11-297580. PMID 21540459.
  5. 5.0 5.1 Kumar S, Pruthi RK, Nichols WL (2002). "Acquired von Willebrand disease". Mayo Clin Proc. 77 (2): 181–7. doi:10.4065/77.2.181. PMID 11838652.
  6. 6.0 6.1 Veyradier A, Jenkins CS, Fressinaud E, Meyer D (2000). "Acquired von Willebrand syndrome: from pathophysiology to management". Thromb Haemost. 84 (2): 175–82. PMID 10959686.
  7. 7.0 7.1 Federici AB, Rand JH, Bucciarelli P, Budde U, van Genderen PJ, Mohri H; et al. (2000). "Acquired von Willebrand syndrome: data from an international registry". Thromb Haemost. 84 (2): 345–9. PMID 10959711.
  8. Ng et al. Diagnostic Approach to von Willebrand Disease. Blood 2015; 125(13): 2029-2037.
  9. Blomback et al. Von Willebrand Disease Biology Hemophilia 2012; 18: 141-147.
  10. Favarolo et al. Von Willebrand Disease and Platelet Disorders. Hemophilia 2014; 20: 59-64.
  11. van Genderen PJ, Vink T, Michiels JJ, van 't Veer MB, Sixma JJ, van Vliet HH (1994). "Acquired von Willebrand disease caused by an autoantibody selectively inhibiting the binding of von Willebrand factor to collagen". Blood. 84 (10): 3378–84. PMID 7949092.
  12. Handin RI, Martin V, Moloney WC (1976). "Antibody-induced von Willebrand's disease: a newly defined inhibitor syndrome". Blood. 48 (3): 393–405. PMID 1085186.
  13. Simone JV, Cornet JA, Abildgaard CF (1968). "Acquired von Willebrand's syndrome in systemic lupus erythematosus". Blood. 31 (6): 806–12. PMID 4172730.
  14. Wautier JL, Levy-Toledano S, Caen JP (1976). "Acquired von Willebrand's syndrome and thrombopathy in a patient with chronic lymphocytic leukaemia". Scand J Haematol. 16 (2): 128–34. PMID 1083062.

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