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Encyclopedia > Von Willebrand disease
Von Willebrand disease
Classification & external resources
ICD-10 D68.0
ICD-9 286.4
OMIM 193400
DiseasesDB 14007
eMedicine ped/2419 
MeSH D014842

Von Willebrand disease (vWD) is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion. It is known to affect humans and in veterinary medicine, dogs. There are three types of hereditary vWD. Other factors including ABO blood groups may also play a part in the severity of the condition. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The International Statistical Classification of Diseases and Related Health Problems 10th Revision (ICD-10) is a coding of diseases and signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or diseases, as classified by the World Health Organization (WHO). ... // C00-D48 - Neoplasms (C00-C14) Malignant neoplasms, lip, oral cavity and pharynx (C00) Malignant neoplasm of lip (C01) Malignant neoplasm of base of tongue (C02) Malignant neoplasm of other and unspecified parts of tongue (C03) Malignant neoplasm of gum (C04) Malignant neoplasm of floor of mouth (C05) Malignant neoplasm of... The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify diseases and a wide variety of signs, symptoms, abnormal findings, complaints, social circumstances and external causes of injury or disease. ... The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The Disease Bold textDatabase is a free website that provides information about the relationships between medical conditions, symptoms, and medications. ... eMedicine is an online clinical medical knowledge base that was founded in 1996. ... Medical Subject Headings (MeSH) is a huge controlled vocabulary (or metadata system) for the purpose of indexing journal articles and books in the life sciences. ... Coagulation is a complex process by which blood forms solid clots. ... Von Willebrand factor is a blood glycoprotein of the coagulation system. ... In structural biology, a protein subunit or subunit protein is a double protein molecule that assembles (or coassembles) with other protein molecules to form a multimeric or oligomeric protein. ... A 250 ml bag of newly collected platelets. ... Veterinary medicine is the application of medical, diagnostic, and therapeutic principles to companion, domestic, exotic, wildlife, and production animals. ... For the scientific journal Heredity see Heredity (journal) Heredity (the adjective is hereditary) is the transfer of characters from parent to offspring, either through their genes or through the social institution called inheritance (for example, a title of nobility is passed from individual to individual according to relevant customs and...

Contents

Symptoms

The various types of vWD present with varying degrees of bleeding tendency. Severe internal or joint bleeding is rare (only in type 3 vWD); bruising, nosebleeds, heavy menstrual periods (in women) and blood loss during childbirth (rare) may occur. Death may occur. In medicine (hematology), a bleeding diathesis is a propensity to bleeding (hemorrhage) due to a defect in the system of coagulation. ... This article or section does not adequately cite its references or sources. ... Hemarthrosis (or haemarthrosis, plural h(a)emarthroses) is a bleeding into joint spaces. ... A bruise or contusion or ecchymoses is a kind of injury, usually caused by blunt impact, in which the capillaries are damaged, allowing blood to seep into the surrounding tissue. ... Nosebleed as a result of fracture through a rugby impact. ... Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. ... Parturition redirects here. ...


Diagnosis

When suspected, blood plasma of a patient needs to be investigated for quantitative and qualitative deficiencies of vWF. This is achieved by measuring the amount of vWF in a vWF antigen assay and the functionallity of vWF with a glycoprotein (GP)Ib binding assay, a collagen binding assay or, a ristocetin cofactor activity (RiCof) or ristocetin induced platelet agglutination (RIPA) assays. Factor VIII levels are also performed as factor VIII is bound to vWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of vWF can therefore lead to a reduction in factor VIII levels. Normal levels do not exclude all forms of vWD: particularly type 2 which may only be revealed by investigating platelet interaction with subendothelium under flow (PAF), a highly specialized coagulation study not routinely performed in most medical laboratories. A platelet aggregation assay will show an abnormal response to ristocetin with normal responses to the other agonists used. A platelet function assay (PFA) will give an abnormal collagen/adrenaline closure time but a normal collagen/ADP time. Type 2N can only be diagnosed by performing a "factor VIII binding" assay. Detection of vWD is complicated by vWF being an acute phase reactant with levels rising in infection, pregnancy and stress. Blood plasma is the liquid component of blood, in which the blood cells are suspended. ... A glycoprotein is a macromolecule composed of a protein and a carbohydrate (an oligosaccharide). ... Tropocollagen triple helix. ... Ristocetin is an antibiotic, obtained from Amycolatopsis lurida, previously used to treat staphylococcal infections. ... The ristocetin induced platelet aggregation (RIPA) is an in vitro assay for von Willebrand factor activity used to diagnose von Willebrand disease. ... Factor VIII (FVIII) is an essential clotting factor. ... A medical laboratory or clinical laboratory is a laboratory where tests are done on biological specimens in order to get information about the health of a patient. ... Epinephrine (INN) or adrenaline (BAN) is a hormone and a neurotransmitter. ... Adenosine diphosphate, abbreviated ADP, is a nucleotide. ... An infection is the detrimental colonization of a host organism by a foreign species. ... A pregnant woman near the end of her term Pregnancy is the carrying of one or more offspring in an embryonal or fetal stage of development by female mammals, including humans, inside their bodies, between the stages of conception and birth. ... In medical terms, stress is the disruption of homeostasis through physical or psychological stimuli. ...


Other tests performed in any patient with bleeding problems are a full blood count (especially platelet counts), APTT (activated partial thromboplastin time), prothrombin time, thrombin time and fibrinogen level. Testing for factor IX may also be performed if hemophilia B is suspected. Other coagulation factor assays may be performed depending on the results of a coagulation screen. A full blood count (FBC) or complete blood count (CBC) is a test requested by a doctor or other medical professional that gives information about the cells in a patients blood. ... A 250 ml bag of newly collected platelets. ... The partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) is a commonly performed test for the system of coagulation, especially its intrinsic pathway. ... The prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) are measures of the extrinsic pathway of coagulation. ... Thrombin (activated Factor II) is a coagulation protein that has many effects in the coagulation cascade. ... Fibrin is a protein involved in the clotting of blood. ... Factor IX (or Christmas factor or Christmas-Eve factor) is one of the serine proteases (EC 3. ... Haemophilia B (also spelled Hemophilia B or Hæmophilia B) is a blood clotting disorder caused by a mutation of the Factor IX gene. ... Coagulation is the thickening or congealing of any liquid into solid clots. ...


Classification and types

Classification

There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type. There are inherited and acquired forms of vWD. Most cases are hereditary, but acquired forms of vWD have been described. The International Society on Thrombosis and Haemostasis's (ISTH) classification depends on the definition of qualitative and quantitative defects.[1]


Type 1

Type 1 vWD (60-80% of all vWD cases) is a quantitative defect (heterozygous for the defective gene) but may not have clearly impaired 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 periods). Decreased levels of vWF are detected (10-45% of normal, i.e. 10-45 IU). Coagulation is a complex process by which blood forms solid clots. ... Menorrhagia is an abnormally heavy and prolonged menstrual period at regular intervals. ... Menstrual cycle. ...


Type 2

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.


Type 2A

This is an abnormality of the synthesis or protelysis 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.


Type 2B

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 thrombocytopaenia 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. Thrombocytopenia (or -paenia, or thrombopenia in short) is the presence of relatively few platelets in blood. ...


Type 2M

This is caused by decreased or absent binding to GPIb on the platelets. Factor VIII binding is normal.


Type 2N (Normandy)

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 hemophilia A but a pedigree suggesting autosomal, rather than X-linked, inheritance.


Type 3

Type 3 is the most severe form of vWD (homozygous for the defective gene) and may have severe mucosal bleeding, no detectable vWF antigen, and may have sufficiently low factor VIII that they have occasional hemarthoses (joint bleeding), as in cases of mild hemophilia. Von Willebrand factor (vWF, also called Factor VIII-related antigen) is a blood protein of the coagulation system. ... Factor VIII (FVIII) is an essential clotting factor. ... Hemarthrosis (or haemarthrosis, plural h(a)emarthroses) is a bleeding into joint spaces. ... Haemophilia or hemophilia is the name of any of several hereditary genetic illnesses that impair the bodys ability to control bleeding. ...


Platelet-type

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). 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. The Hewlett-Packard Instrument Bus (HP-IB), is a short-range digital communications cable standard developed by Hewlett-Packard (HP) in the 1970s for connecting electronic test and measurement devices (e. ...


Acquired von Willebrand disease

Acquired vWD can occur in patients with autoantibodies. In this case the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the circulation. An autoantibody is an antibody (a type of protein) manufactured by the immune system that is directed against one or more of the individuals own proteins. ...


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. Aortic valve stenosis (AS) is a heart condition caused by the incomplete opening of the aortic valve. ... Gastrointestinal bleeding describes every form of hemorrhage (blood loss) in the gastrointestinal tract, from the pharynx to the rectum. ... Heydes syndrome is a syndrome of aortic valve stenosis associated with gastrointestinal bleeding from colonic angiodysplasia. ...


Acquired vWF has also been described in the following disorders: Wilms' tumour, hypothyroidism and mesenchymal dysplasias. Wilms tumor is a neoplasm of the kidneys that typically occurs in children. ... This article or section does not cite its references or sources. ...


Pathophysiology

vWF is mainly active in conditions of high blood flow and shear stress. Deficiency of vWF therefore shows primarily in organs with extensive small vessels, such as the skin, the gastrointestinal tract and the uterus. In angiodysplasia, a form of telangiectasia of the colon, shear stress is much higher than in average capillaries, and the risk of bleeding is increased concomitantly. Von Willebrand factor is a blood glycoprotein of the coagulation system. ... Shear stress is a stress state where the stress is parallel or tangential to a face of the material, as opposed to normal stress when the stress is perpendicular to the face. ... Upper and Lower gastrointestinal tract The gastrointestinal tract (GI tract), also called the digestive tract, or the alimentary canal, is the system of organs within multicellular animals that takes in food, digests it to extract energy and nutrients, and expels the remaining waste. ... The uterus or womb is the major female reproductive organ of most mammals, including humans. ... An angiodysplasia in the colon being treated with argon plasma coagulation administered via probe through the colonoscope. ... Telangiectasias, or spider veins, are small dilated blood vessels near the surface of the skin; usually they measure only a few millimeters. ... It has been suggested that this article or section be merged with Large intestine. ... This article does not cite any references or sources. ...


In more severe cases of type 1 vWD, genetic changes are common within the VWF gene and are highly penetrant. In milder cases of type 1 vWD there may be a complex spectrum of molecular pathology in addition to polymorphisms of the vWF gene alone.[2] The individual's ABO blood group can influence presentation and pathology of vWD. Those individuals with blood group O have a lower mean level than individuals with other blood groups. Unless ABO group–specific vWF:antigen reference ranges are used, normal group O individuals can be diagnosed as type I vWD, and some individuals of blood group AB with a genetic defect of vWF may have the diagnosis overlooked because vWF levels are elevated due to blood group.[3] Penetrance is a term used in genetics that describes the extent to which the properties controlled by a gene, its phenotype, will be expressed. ... Pathology (from Greek pathos, feeling, pain, suffering; and logos, study of; see also -ology) is the study of the processes underlying disease and other forms of illness, harmful abnormality, or dysfunction. ... In biology, polymorphism can be defined as the occurrence in the same habitat of two or more forms of a trait in such frequencies that the rarer cannot be maintained by recurrent mutation alone. ... ABO blood group antigens present on red blood cells and IgM antibodies present in the serum The ABO blood group system is the most important blood type system (or blood group system) in human blood transfusion. ...


Genetics

von Willebrand disease types I and II are inherited in an autosomal dominant pattern.
von Willebrand disease types I and II are inherited in an autosomal dominant pattern.
von Willebrand disease type III (and sometimes II) is inherited in an autosomal recessive pattern.
von Willebrand disease type III (and sometimes II) is inherited in an autosomal recessive pattern.

The vWF gene is located on chromosome twelve (12p13.2). It has 52 exons spanning 178kbp. Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. Occasionally type 2 also inherits recessively. Image File history File links Autodominant. ... Image File history File links Autodominant. ... It has been suggested that this article or section be merged into Dominance relationship. ... Wikipedia does not yet have an article with this exact name. ... Wikipedia does not yet have an article with this exact name. ... In genetics, the term recessive gene refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele). ... Chromosome 12 is one of the 23 pairs of chromosomes in humans. ... It has been suggested that this article or section be merged into Dominance relationship. ... In genetics, the term recessive gene refers to an allele that causes a phenotype (visible or detectable characteristic) that is only seen in a homozygous genotype (an organism that has two copies of the same allele). ...


Epidemiology

In humans, the incidence of vWD is roughly about 1 in 100 individuals. Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation. The actual abnormality (which does not necessarily lead to disease) occurs in 0.9-3% of the population. It may be more severe or apparent in people with blood type O. Menstrual cycle. ... Blood type (or blood group) is determined, in part, by the ABO blood group antigens present on red blood cells. ...


Therapy

Patients with vWD normally require no regular treatment, although they are always at increased risk for bleeding. Prophylactic treatment is sometimes given for patients with vWD who are scheduled for surgery. They can be treated with human derived medium purity factor VIII concentrates complexed to vWF(antihemophilic factor, more commonly known as Humate-P®) Mild cases of vWD can be trialled on desmopressin (1-desamino-8-D-arginine vasopressin, DDAVP) (desmopressin acetate, Stimate®), which works by raising the patient's own plasma levels of vWF by inducing release of vWF stored in the Weibel-Palade bodies in the endothelial cells. Factor VIII (FVIII) is an essential clotting factor. ... Desmopressin (DDAVP®, Stimate®, Minirin®) is a synthetic drug that mimics the action of antidiuretic hormone, also known as arginine vasopressin. ... In physiology, Weibel-Palade bodies are organelles in the endothelium, the cells lining all blood vessels. ...


History

vWD is named after Erik Adolf von Willebrand, a Finnish paediatrician (1870–1949).[4] He first described the disease in 1926. An eponym is the name of a person, whether real or fictitious, who has (or is thought to have) given rise to the name of a particular place, tribe, discovery, or other item. ... jhjutuihjiorjknmhrkgsnmjkhsugtu89576894-723698902368968590udghiojkgjbjkgjibugfjuhiuhry89u9ety8 message 7. ... Pediatrics (also spelled paediatrics or pædiatrics) is the branch of medicine that deals with the medical care of infants and children. ...


Sources

  • Harrison's textbook of Internal Medicine, Chapter 177.
  • Sadler, J. E. "Biochemistry and Genetics of von Willebrand factor." Annu Rev Biochem 1998; 67:395-424. (fulltext)
  • Mannucci PM. Treatment of von Willebrands disease. N Engl J Med 2004;351:683-94. PMID 15306670
  • Laffan m. Brown S. etal. The diagnosis of von Willebrand disease: a guideline from the UK Haemophilia Centre Doctors Organisation. Haemophilia; 2004, 10, 199-217

The New England Journal of Medicine (NEJM) is a peer-reviewed medical journal published by the Massachusetts Medical Society. ...

References

  1. ^ Sadler JE. A revised classification of von Willebrand disease. Thromb Haemost 1994;71:520-5. PMID 8052974.
  2. ^ James P, Notley C, Hegadorn C, Leggo J, Tuttle A, Tinlin S, Brown C, Andrews C, Labelle A, Chirinian Y, O'Brien L, Othman M, Rivard G, Rapson D, Hough C, Lillicrap D (2007). "The mutational spectrum of type 1 von Willebrand disease: Results from a Canadian cohort study". Blood 109 (1): 145-54. PMID 17190853. 
  3. ^ Gill, JC; Endres-Brooks J, Bauer PJ, Marks WJ, Montgomery RR (1987 Jun). "The effect of ABO blood group on the diagnosis of von Willebrand disease". Blood 69 (6): 1691-5. PMID 3495304. 
  4. ^ doctor/2690 at Who Named It

Who Named It is a Norwegian database of several thousand eponymous medical signs and the doctors associated with their identification. ...

See also

  • Blood diseases
  • Bernard-Soulier syndrome, caused by a deficiency in the vWF receptor, GPIb

Blood diseases affect the production of blood and its components, such as blood cells, hemoglobin, blood proteins, the mechanism of coagulation, etc. ... Bernard-Soulier syndrome (BSS, named after Jean Bernard and Jean Pierre Soulier) is a rare congenital bleeding disorder characterized by thrombocytopenia and large platelets and was first described in 1948. ...

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