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| ==Overview== | | ==Overview== |
| Von Willebrand disease may be classified as acquired or inherited. There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type.<ref name="pmid16889557">{{cite journal| author=Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L et al.| title=Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. | journal=J Thromb Haemost | year= 2006 | volume= 4 | issue= 10 | pages= 2103-14 | pmid=16889557 | doi=10.1111/j.1538-7836.2006.02146.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16889557 }} </ref> Most cases are hereditary, but ''acquired'' forms of vWD have been described. The International Society on Thrombosis and Hemostasis's (ISTH) classification depends on the definition of qualitative and quantitative defects.<ref>{{cite journal |author=Sadler JE |title=A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis |journal=Thromb. Haemost. |volume=71 |issue=4 |pages=520–5 |year=1994 |pmid=8052974 |doi= |url=}}</ref><ref name="pmid16889557">{{cite journal| author=Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L et al.| title=Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. | journal=J Thromb Haemost | year= 2006 | volume= 4 | issue= 10 | pages= 2103-14 | pmid=16889557 | doi=10.1111/j.1538-7836.2006.02146.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16889557 }} </ref> The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD.<ref name="pmid18315614">{{cite journal| author=Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL et al.| title=von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). | journal=Haemophilia | year= 2008 | volume= 14 | issue= 2 | pages= 171-232 | pmid=18315614 | doi=10.1111/j.1365-2516.2007.01643.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18315614 }} </ref>
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| ==Classification== | | ==Classification== |
| Von Willebrand disease may be classified as acquired or inherited. There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type.<ref name="pmid16889557">{{cite journal| author=Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L et al.| title=Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. | journal=J Thromb Haemost | year= 2006 | volume= 4 | issue= 10 | pages= 2103-14 | pmid=16889557 | doi=10.1111/j.1538-7836.2006.02146.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16889557 }} </ref> Most cases are hereditary, but ''acquired'' forms of vWD have been described. The International Society on Thrombosis and Hemostasis's (ISTH) classification depends on the definition of qualitative and quantitative defects.<ref>{{cite journal |author=Sadler JE |title=A revised classification of von Willebrand disease. For the Subcommittee on von Willebrand Factor of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis |journal=Thromb. Haemost. |volume=71 |issue=4 |pages=520–5 |year=1994 |pmid=8052974 |doi= |url=}}</ref><ref name="pmid16889557">{{cite journal| author=Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L et al.| title=Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. | journal=J Thromb Haemost | year= 2006 | volume= 4 | issue= 10 | pages= 2103-14 | pmid=16889557 | doi=10.1111/j.1538-7836.2006.02146.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16889557 }} </ref> The pathophysiology, classification, diagnosis and management of VWD are relatively complex, but understanding them is important for proper diagnosis and management of patients with VWD.<ref name="pmid18315614">{{cite journal| author=Nichols WL, Hultin MB, James AH, Manco-Johnson MJ, Montgomery RR, Ortel TL et al.| title=von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). | journal=Haemophilia | year= 2008 | volume= 14 | issue= 2 | pages= 171-232 | pmid=18315614 | doi=10.1111/j.1365-2516.2007.01643.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18315614 }} </ref>
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| ===Type 1===
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| Type 1 vWD (60-80% of all vWD cases) is a partial deficiency of functionally normal VWF but may not have clearly impaired [[coagulation|clotting]], most patients usually end up leading a nearly normal life. Trouble may arise in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or [[menorrhagia]] (heavy [[menstruation|periods]]). Decreased levels of vWF are detected (10-45% of normal, i.e. 10-45 IU).
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| Most cases of type 1 VWD are caused by heterozygous missense mutations that exert a dominant-negative effect.<ref name="pmid17190853">{{cite journal| author=James PD, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S et al.| title=The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study. | journal=Blood | year= 2007 | volume= 109 | issue= 1 | pages= 145-54 | pmid=17190853 | doi=10.1182/blood-2006-05-021105 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17190853 }} </ref><ref name="pmid16985174">{{cite journal| author=Goodeve A, Eikenboom J, Castaman G, Rodeghiero F, Federici AB, Batlle J et al.| title=Phenotype and genotype of a cohort of families historically diagnosed with type 1 von Willebrand disease in the European study, Molecular and Clinical Markers for the Diagnosis and Management of Type 1 von Willebrand Disease (MCMDM-1VWD). | journal=Blood | year= 2007 | volume= 109 | issue= 1 | pages= 112-21 | pmid=16985174 | doi=10.1182/blood-2006-05-020784 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16985174 }} </ref><ref name="pmid26245874">{{cite journal| author=Batlle J, Pérez-Rodríguez A, Corrales I, López-Fernández MF, Rodríguez-Trillo Á, Lourés E et al.| title=Molecular and clinical profile of von Willebrand disease in Spain (PCM-EVW-ES): Proposal for a new diagnostic paradigm. | journal=Thromb Haemost | year= 2016 | volume= 115 | issue= 1 | pages= 40-50 | pmid=26245874 | doi=10.1160/TH15-04-0282 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26245874 }} </ref><ref name="pmid26986123">{{cite journal| author=Veyradier A, Boisseau P, Fressinaud E, Caron C, Ternisien C, Giraud M et al.| title=A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. | journal=Medicine (Baltimore) | year= 2016 | volume= 95 | issue= 11 | pages= e3038 | pmid=26986123 | doi=10.1097/MD.0000000000003038 | pmc=4839904 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26986123 }} </ref> The mutant subunits are incorporated into the multimer together with the normal subunits, resulting in a disturbance of the entire multimer.
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| ===Type 2===
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| Almost all cases of type 2 VWD are caused by missense mutations, which are usually restricted to specific functional domains. Inheritance of subtypes of type 2 disease is autosomal dominant, with the exception of type 2N,<ref name="pmid22102189">{{cite journal| author=Hampshire DJ, Goodeve AC| title=The international society on thrombosis and haematosis von Willebrand disease database: an update. | journal=Semin Thromb Hemost | year= 2011 | volume= 37 | issue= 5 | pages= 470-9 | pmid=22102189 | doi=10.1055/s-0031-1281031 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102189 }} </ref> which has a recessive pattern of inheritance. Patients may be either homozygous for two type 2N mutations or compound heterozygous for a type 1 defect and a type 2N defect.
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| Type 2 vWD (20-30%) is a qualitative defect and the bleeding tendency can vary between individuals. There are normal levels of vWF, but the multimers are structurally abnormal, or subgroups of large or small multimers are absent. Four subtypes exist: 2A, 2B, 2M and 2N.
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| ====Type 2A====
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| This is an abnormality of the synthesis or proteolysis of the vWF multimers resulting in the presence of small multimer units in circulation. Factor VIII binding is normal. It has a disproportionately low ristocetin co-factor activity compared to the von Willebrand's antigen.
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| ====Type 2B====
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| This is a "gain of function" defect leading to spontaneous binding to platelets and subsequent rapid clearance of the platelets and the large vWF multimers. A mild [[thrombocytopenia]] may occur. The large vWF multimers are absent in the circulation and the factor VIII binding is normal. Like type 2A, the RiCof:vWF antigen assay is low when the patient's platelet-poor plasma is assayed against formalin-fixed, normal donor platelets. However, when the assay is performed with the patient's own platelets ("platelet-rich plasma"), a lower-than-normal amount of ristocetin causes aggregation to occur. This is due to the large vWF multimers remaining bound to the patient's platelets. Patients with this sub-type are unable to use desmopressin as a treatment for bleeding, because it can lead to unwanted platelet aggregation.
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| ====Type 2M====
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| This is caused by decreased or absent binding to GPIb on the platelets. Factor VIII binding is normal.
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| ====Type 2N (Normandy)====
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| This is a deficiency of the binding of vWF to factor VIII. This type gives a normal vWF antigen level and normal functional test results but has a low factor VIII. This has probably led to some 2N patients being misdiagnosed in the past as having hemophilia A, and should be suspected if the patient has the clinical findings of [[haemophilia A|hemophilia A]] but a pedigree suggesting autosomal, rather than X-linked, inheritance.
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| ===Type 3===
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| Type 3 is the most severe form of vWD (homozygous for the defective gene) and may have severe mucosal bleeding. In 80% of patients with type 3 von Willebrand’s disease, the genetic defects in the [[VWF]] gene are null alleles, explaining the complete absence of von Willebrand factor with no detectable [[vWF antigen]]<ref name="pmid26986123">{{cite journal| author=Veyradier A, Boisseau P, Fressinaud E, Caron C, Ternisien C, Giraud M et al.| title=A Laboratory Phenotype/Genotype Correlation of 1167 French Patients From 670 Families With von Willebrand Disease: A New Epidemiologic Picture. | journal=Medicine (Baltimore) | year= 2016 | volume= 95 | issue= 11 | pages= e3038 | pmid=26986123 | doi=10.1097/MD.0000000000003038 | pmc=4839904 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26986123 }} </ref><ref name="pmid22102189">{{cite journal| author=Hampshire DJ, Goodeve AC| title=The international society on thrombosis and haematosis von Willebrand disease database: an update. | journal=Semin Thromb Hemost | year= 2011 | volume= 37 | issue= 5 | pages= 470-9 | pmid=22102189 | doi=10.1055/s-0031-1281031 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102189 }} </ref>, and may have sufficiently low [[factor VIII]] that they have occasional [[hemarthrosis|hemarthroses]] (joint bleeding), as in cases of mild [[hemophilia]].
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| ===Platelet-type===
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| Platelet-type vWD is an autosomal dominant type of vWD caused by gain of function mutations of the vWF receptor on platelets; specifically, the alpha chain of the glycoprotein Ib receptor ([[GPIb]]).<ref name="pmid22102189">{{cite journal| author=Hampshire DJ, Goodeve AC| title=The international society on thrombosis and haematosis von Willebrand disease database: an update. | journal=Semin Thromb Hemost | year= 2011 | volume= 37 | issue= 5 | pages= 470-9 | pmid=22102189 | doi=10.1055/s-0031-1281031 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22102189 }} </ref><ref name="GP1BA glycoprotein Ib platelet alpha subunit">https://www.ncbi.nlm.nih.gov/gene/2811</ref> This protein is part of the larger complex (GPIb/V/IX) which forms the full vWF receptor on platelets. The ristocetin activity and loss of large vWF multimers is similar to type 2B, but genetic testing of VWF will reveal no mutations.
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| ==Acquired von Willebrand disease==
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| Acquired vWD can occur in patients with [[autoantibody|autoantibodies]]. In this case the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the circulation.
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| A form of vWD occurs in patients with [[aortic valve stenosis]], leading to [[gastrointestinal bleeding]] ([[Heyde's syndrome]]). This form of acquired vWD may be more prevalent than is presently thought.
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| Acquired vWF has also been described in the following disorders: [[Wilms' tumor|Wilms' tumour]], [[hypothyroidism]] and mesenchymal dysplasias.
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