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Von Willebrand disease (VWD) is the most common
hereditary Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic info ...
blood-clotting disorder in humans. An acquired form can sometimes result from other medical conditions. It arises from a deficiency in the quality or quantity of
von Willebrand factor Von Willebrand factor (VWF) () is a blood glycoprotein involved in hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytope ...
(VWF), a multimeric protein that is required for
platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby in ...
adhesion Adhesion is the tendency of dissimilar particles or surfaces to cling to one another ( cohesion refers to the tendency of similar or identical particles/surfaces to cling to one another). The forces that cause adhesion and cohesion can b ...
. It is known to affect several breeds of dogs as well as humans. The three forms of VWD are hereditary, acquired, and pseudo or platelet type. The three types of hereditary VWD are VWD type 1, VWD type 2, and VWD type 3. Type 2 contains various subtypes. Platelet type VWD is also an inherited condition. In 2008 a new diagnostic category of "Low VWF" was proposed to include those individuals whose von Willebrand factor levels were below the normal reference range but not low enough to be von Willebrand disease (levels in the 30-50 IU/dL range). Patients with low VWF can experience bleeding, despite mild reductions in VWF levels. VWD type 1 is the most common type of the disorder, with mild bleeding symptoms such as
nosebleeds A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significant that low b ...
, though occasionally more severe symptoms can occur.
Blood type A blood type (also known as a blood group) is a classification of blood, based on the presence and absence of antibodies and inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrates ...
can affect the presentation and severity of symptoms of VWD. VWD type 2 is the second most common type of the disorder and has mild to moderate symptoms. The factor is named after the Finnish physician Erik Adolf von Willebrand who first described the condition in 1926. Guidelines for the diagnosis and management of VWD were updated in 2021.


Signs and symptoms

The various types of VWD present with varying degrees of bleeding tendency, usually in the form of easy
bruising A bruise, also known as a contusion, is a type of hematoma of tissue, the most common cause being capillaries damaged by trauma, causing localized bleeding that extravasates into the surrounding interstitial tissues. Most bruises occur clos ...
,
nosebleed A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significant that low ...
s, and bleeding gums. People may experience heavy menstrual periods and
blood loss Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, vagi ...
during childbirth. Severe
internal bleeding Internal bleeding (also called internal hemorrhage) is a loss of blood from a blood vessel that collects inside the body. Internal bleeding is usually not visible from the outside. It is a serious medical emergency but the extent of severity dep ...
and bleeding into joints are uncommon in all but the most severe type, VWD type 3.


Genetics

The VWF gene is located on the short arm ''p'' of
chromosome 12 Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the ...
(12p13.2). It has 52
exons An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequenc ...
spanning 178 kbp. Types 1 and 2 are inherited as
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and ...
traits. Occasionally, type 2 also inherits recessively. Type 3 is inherited as
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant an ...
. However, some individuals heterozygous for type 3 may be diagnosed with VWD type 1, indicating an intermediate inheritance in that cases. VWD occurs in approximately 1% of the population and affects men and women equally. Genetic testing is typically not part of the initial workup for von Willebrand disease, and is not needed for people diagnosed with type 1 VWD based on clinical history and laboratory tests. It is mainly useful for: * Evaluating family members of individuals who have known variants. * Differentiating between type 2B and platelet-type VWD, as well as between type 2N VWD and
hemophilia A Haemophilia A (or hemophilia A) is a genetic deficiency in clotting factor VIII, which causes increased bleeding and usually affects males. In the majority of cases it is inherited as an X-linked recessive trait, though there are cases which arise ...
.


Pathophysiology

Von Willebrand factor Von Willebrand factor (VWF) () is a blood glycoprotein involved in hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytope ...
is mainly active in conditions of high blood flow and
shear stress Shear stress, often denoted by (Greek: tau), is the component of stress coplanar with a material cross section. It arises from the shear force, the component of force vector parallel to the material cross section. ''Normal stress'', on th ...
. Deficiency of VWF, therefore, shows primarily in organs with extensive small vessels, such as
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other animal coverings, such as the arthropod exoskeleton, have different d ...
,
gastrointestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans a ...
, and
uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. Th ...
. In angiodysplasia, a form of
telangiectasia Telangiectasias, also known as spider veins, are small dilated blood vessels that can occur near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter. These dilated blood vessels can develop anywhere on ...
of the colon, shear stress is much higher than in average
capillaries A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
, and the risk of bleeding is increased concomitantly. 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, a complex spectrum of molecular
pathology Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used i ...
may exist in addition to polymorphisms of the VWF gene alone. 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.


Diagnosis

Basic tests performed in any patient with bleeding problems are a
complete blood count A complete blood count (CBC), also known as a full blood count (FBC), is a set of medical laboratory tests that provide information about the cells in a person's blood. The CBC indicates the counts of white blood cells, red blood cells and p ...
-CBC (especially
platelet Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby in ...
counts), activated partial thromboplastin time-APTT,
prothrombin time The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the ''extrinsic'' pathway and common pathway of coagulation. This blood test is al ...
with International Normalized Ratio-PTINR,
thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
time-TT, and
fibrinogen Fibrinogen (factor I) is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood c ...
level. Patients with abnormal tests typically undergo further testing for hemophilias. Other
coagulation factor Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanis ...
assays may be performed depending on the results of a coagulation screen. Patients with von Willebrand disease typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time. When VWD is suspected,
blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the int ...
of a patient must 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 functionality of VWF with a
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
(GP)Ib binding assay, a
collagen Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whol ...
binding assay, or a ristocetin cofactor activity (RiCof) or ristocetin-induced platelet agglutination (RIPA) assays.
Factor VIII Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the ''F8'' gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disord ...
levels are also performed because factor VIII is bound to VWF which protects the factor VIII from rapid breakdown within the blood. Deficiency of VWF can then lead to a reduction in factor VIII levels, which explains the elevation in PTT. 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, 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 may give an abnormal collagen/
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands an ...
closure time, and in most cases, a normal collagen/ ADP time. Type 2N may be considered if factor VIII levels are disproportionately low, but confirmation requires a "factor VIII binding" assay. Additional laboratory tests that help classify sub-types of VWD include von Willebrand multimer analysis, modified ristocetin induced platelet aggregation assay and VWF propeptide to VWF propeptide antigen ratio. In cases of suspected acquired von Willebrand syndrome, a mixing study (analysis of patient plasma along with pooled normal plasma/PNP and a mixture of the two tested immediately, at one hour, and at two hours) should be performed. Detection of VWD is complicated by VWF being an acute-phase reactant with levels rising in infection, pregnancy, and stress. The testing for VWD can be influenced by laboratory procedures. Numerous variables exist in the testing procedure that may affect the validity of the test results and may result in a missed or erroneous diagnosis. The chance of procedural errors are typically greatest during the preanalytical phase (during collecting storage and transportation of the specimen) especially when the testing is contracted to an outside facility and the specimen is frozen and transported long distances. Diagnostic errors are not uncommon, and the rate of testing proficiency varies amongst laboratories, with error rates ranging from 7 to 22% in some studies to as high as 60% in cases of misclassification of VWD subtype. To increase the probability of a proper diagnosis, testing should be done at a facility with immediate on-site processing in a specialized coagulation laboratory.


Types

The four hereditary types of VWD described are type 1, type 2, type 3, and pseudo- or platelet-type. Most cases are hereditary, but acquired forms of VWD have been described. The International Society on Thrombosis and Haemostasis's classification depends on the definition of qualitative and quantitative defects.


Type 1

Type 1 VWD (40-80% of all VWD cases) is a quantitative defect which is
heterozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...
for the defective gene. It can arise from failure to secrete VWF into the circulation or from VWF being cleared more quickly than normal. Decreased levels of VWF are detected at 20-50% of normal, i.e. 20-50 IU. Many patients are asymptomatic or may have mild symptoms and not have clearly impaired
clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism ...
, which might suggest a bleeding disorder. Often, the discovery of VWD occurs incidentally to other medical procedures requiring a blood work-up. Most cases of type 1 VWD are never diagnosed due to the asymptomatic or mild presentation of type I and most people usually end up leading a normal life free of complications, with many being unaware that they have the disorder. Trouble may, however, arise in some patients in the form of bleeding following surgery (including dental procedures), noticeable easy bruising, or
menorrhagia Heavy menstrual bleeding (HMB), previously known as menorrhagia or hypermenorrhea, is a menstrual period with excessively heavy flow. It is a type of abnormal uterine bleeding (AUB). Abnormal uterine bleeding can be caused by structural abnor ...
(heavy menstrual periods). The minority of cases of type 1 may present with severe hemorrhagic symptoms.


Type 2

Type 2 VWD (15-50% of cases) is a qualitative defect and the bleeding tendency can vary between individuals. Four subtypes exist: 2A, 2B, 2M, and 2N. These subtypes depend on the presence and behavior of the underlying multimers.


=Type 2A

= The ability of the qualitatively defective von Willebrand factors to coalesce and form large VWF multimers is impaired, resulting in decreased quantity of large VWF multimers and low RCoF activity. Only small multimer units are detected in the circulation. von Willebrand factor antigen (VWF:Ag) assay is low or normal.


=Type 2B

= This is a "
gain of function Gain-of-function research (GoF research or GoFR) is medical research that genetically alters an organism in a way that may enhance the biological functions of gene products. This may include an altered pathogenesis, transmissibility, or host ra ...
" defect. The ability of the qualitatively defective VWF to bind to glycoprotein Ib (GPIb) receptor on the platelet membrane is abnormally enhanced, leading to its spontaneous binding to platelets and subsequent rapid clearance of the bound platelets and of the large VWF multimers. Thrombocytopenia may occur. Large VWF multimers are reduced or absent from the circulation. The ristocetin cofactor activity 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 subtype are unable to use desmopressin as a treatment for bleeding, because it can lead to unwanted platelet aggregation and aggravation of thrombocytopenia.


=Type 2M

= Type 2M VWD is a qualitative defect of VWF characterized by its decreased ability to bind to GPIb receptor on the platelet membrane and normal capability at multimerization. The VWF antigen levels are normal. The ristocetin cofactor activity is decreased and high molecular weight large VWF multimers are present in the circulation.


=Type 2N (Normandy)

= This is a deficiency of the binding of VWF to coagulation factor VIII. The VWF antigen test is normal, indicating normal quantity of VWF. The ristocetin cofactor assay is normal. Assay for coagulation factor VIII will show marked quantitative decrease, equivalent to levels seen in hemophilia A. This has led to some VWD type 2N patients being misdiagnosed as having hemophilia A.


Type 3

Type 3 is the most severe form of VWD (homozygous for the defective gene) and is characterized by complete absence of production of VWF. The von Willebrand factor is undetectable in the VWF antigen assay. Since the VWF protects coagulation factor VIII from proteolytic degradation, total absence of VWF leads to extremely low factor VIII level, equivalent to that seen in severe hemophilia A with its clinical manifestations of life-threatening external and internal hemorrhages. The inheritance pattern of VWD type 3 is autosomal recessive, while the inheritance pattern of hemophilia A is
X-linked recessive X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one ...
.


Comparison


Platelet-type

Platelet-type VWD (also known as pseudo-VWD) is an autosomal dominant genetic defect of the platelets. The VWF is qualitatively normal and genetic testing of the von Willebrand gene and VWF protein reveals no mutational alteration. The defect lies in the qualitatively altered GPIb receptor on the platelet membrane which increases its affinity to bind to the VWF. Large platelet aggregates and high molecular weight VWF multimers are removed from the circulation resulting in thrombocytopenia and diminished or absent large VWF multimers. The ristocetin cofactor activity and loss of large VWF multimers are similar to VWD type 2B.


Acquired

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. A form of VWD occurs in patients with
aortic valve stenosis Aortic stenosis (AS or AoS) is the narrowing of the exit of the left ventricle of the heart (where the aorta begins), such that problems result. It may occur at the aortic valve as well as above and below this level. It typically gets worse ove ...
, leading to
gastrointestinal bleeding Gastrointestinal bleeding (GI bleed), also called gastrointestinal hemorrhage (GIB), is all forms of bleeding in the gastrointestinal tract, from the mouth to the rectum. When there is significant blood loss over a short time, symptoms may include ...
( Heyde's syndrome). This form of acquired VWD may be more prevalent than is presently thought. In 2003, Vincentelli ''et al.'' noted that patients with acquired VWD and aortic stenosis who underwent valve replacement experienced a correction of their hemostatic abnormalities, but that the hemostatic abnormalities can recur after 6 months when the prosthetic valve is a poor match with the patient. Similarly, acquired VWD contributes to the bleeding tendency in people with an implant of a left ventricular assist device (a pump that pumps blood from the left ventricle of the heart into the aorta).


Treatment

For patients with VWD type 1 and VWD type 2A,
desmopressin Desmopressin, sold under the trade name DDAVP among others, is a medication used to treat diabetes insipidus, bedwetting, hemophilia A, von Willebrand disease, and high blood urea levels. In hemophilia A and von Willebrand disease, it should o ...
is available as different preparations, recommended for use in cases of minor trauma, or in preparation for dental or minor surgical procedures. Desmopressin stimulates the release of VWF from the Weibel–Palade bodies of
endothelial cells The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the ve ...
, thereby increasing the levels of VWF (as well as coagulant
factor VIII Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the ''F8'' gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disord ...
) three- to five-fold. Desmopressin is also available as a preparation for intranasal administration (Stimate) and as a preparation for intravenous administration. Desmopressin is contraindicated in VWD type 2b because of the risk of aggravated thrombocytopenia and thrombotic complications. Desmopressin is probably not effective in VWD type 2M and is rarely effective in VWD type 2N. It is totally ineffective in VWD type 3. For women with heavy menstrual bleeding, estrogen-containing oral contraceptive medications are effective in reducing the frequency and duration of the menstrual periods. Estrogen and progesterone compounds available for use in the correction of menorrhagia are
ethinylestradiol Ethinylestradiol (EE) is an estrogen medication which is used widely in birth control pills in combination with progestins. In the past, EE was widely used for various indications such as the treatment of menopausal symptoms, gynecological dis ...
and
levonorgestrel Levonorgestrel is a hormonal medication which is used in a number of birth control methods. It is combined with an estrogen to make combination birth control pills. As an emergency birth control, sold under the brand name Plan B One-Step amo ...
(Levona, Nordette, Lutera, Trivora). Administration of ethinylestradiol diminishes the secretion of luteinizing hormone and follicle-stimulating hormone from the pituitary, leading to stabilization of the endometrial surface of the uterus. Desmopressin is a synthetic analog of the natural antidiuretic hormone
vasopressin Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then ...
. Its overuse can lead to water retention and dilutional hyponatremia with consequent convulsion. For patients with VWD scheduled for surgery and cases of VWD disease complicated by clinically significant hemorrhage, human-derived medium purity factor VIII concentrates, which also contain von Willebrand factors, are available for prophylaxis and treatment. Humate P, Alphanate, Wilate and Koate HP are commercially available for prophylaxis and treatment of VWD. Monoclonally purified factor VIII concentrates and recombinant factor VIII concentrates contain insignificant quantity of VWF, so are not clinically useful. Development of alloantibodies occurs in 10-15% of patients receiving human-derived medium-purity factor VIII concentrates and the risk of allergic reactions including anaphylaxis must be considered when administering these preparations. Administration of the latter is also associated with increased risk of venous thromboembolic complications. Blood transfusions are given as needed to correct anemia and hypotension secondary to hypovolemia. Infusion of platelet concentrates is recommended for correction of hemorrhage associated with platelet-type VWD. Vonicog alfa is a recombinant
von Willebrand factor Von Willebrand factor (VWF) () is a blood glycoprotein involved in hemostasis, specifically, platelet adhesion. It is deficient and/or defective in von Willebrand disease and is involved in many other diseases, including thrombotic thrombocytope ...
that was approved for use in the United States in December 2015, and for use in the European Union in August 2018.


Epidemiology

The
prevalence In epidemiology, prevalence is the proportion of a particular population found to be affected by a medical condition (typically a disease or a risk factor such as smoking or seatbelt use) at a specific time. It is derived by comparing the number ...
of VWD is about one in 100 individuals. However, the majority of these people do not have symptoms. The prevalence of clinically significant cases is one per 10,000. Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during
menstruation Menstruation (also known as a period, among other colloquial terms) is the regular discharge of blood and mucosal tissue from the inner lining of the uterus through the vagina. The menstrual cycle is characterized by the rise and fall of ...
. It may be more severe or apparent in people with
blood type A blood type (also known as a blood group) is a classification of blood, based on the presence and absence of antibodies and inherited antigenic substances on the surface of red blood cells (RBCs). These antigens may be proteins, carbohydrates ...
O.


History

In 1924, a 5-year-old girl from
Föglö Föglö is a group of islands and municipality in Åland, an autonomous territory of Finland. The municipality has a population of () and covers an area of of which is water. The population density is . The municipality is unilingually Swedish ...
,
Åland Åland ( fi, Ahvenanmaa: ; ; ) is an autonomous and demilitarised region of Finland since 1920 by a decision of the League of Nations. It is the smallest region of Finland by area and population, with a size of 1,580 km2, and a popul ...
, Finland, was brought to the Deaconess Hospital in Helsinki, where she was seen by Finnish physician Erik Adolf von Willebrand. He ultimately assessed 66 members of her family and reported in a 1926 Swedish-language article that this was a previously undescribed bleeding disorder that differed from hemophilia. He published another article on the disorder in 1931, in the German language, which attracted international attention in the disease. The eponymous name was assigned to the disease between the late 1930s and the early 1940s, in recognition of von Willebrand's extensive research. In the 1950s, it became clear that a "plasma factor",
factor VIII Factor VIII (FVIII) is an essential blood-clotting protein, also known as anti-hemophilic factor (AHF). In humans, factor VIII is encoded by the ''F8'' gene. Defects in this gene result in hemophilia A, a recessive X-linked coagulation disord ...
, was decreased in these persons and that Cohn fraction I-0 could correct both the plasma deficiency of FVIII and the prolonged bleeding time. Since this time, the factor causing the long bleeding time was called the "von Willebrand factor" in honor of Erik Adolf von Willebrand. Variant forms of VWF were recognized in the 1970s, and these variations are now recognized as the result of synthesis of an abnormal protein. During the 1980s, molecular and cellular studies distinguished hemophilia A and VWD more precisely. Persons who had VWD had a normal FVIII gene on the X chromosome, and some had an abnormal VWF gene on chromosome 12. Gene sequencing identified many of these persons as having a VWF gene mutation. The genetic causes of milder forms of low VWF are still under investigation, and these forms may not always be caused by an abnormal VWF gene.


Other animals

VWD can also affect dogs, pigs, and mice. Furthermore, cases have been reported in cats, horses, cattle, and rabbits. The causal mutation for VWD type 1 was identified in dogs of the breeds Doberman Pinscher, German Pinscher,
Bernese Mountain Dog The Bernese Mountain Dog (german: Berner Sennenhund) is a large dog breed, one of the four breeds of Sennenhund- type dogs from Bern, Switzerland and the Swiss Alps. These dogs have roots in the Roman mastiffs. The name ''Sennenhund'' is derived ...
,
Manchester Terrier The Manchester Terrier is a breed of dog of the smooth-haired terrier type. It was first bred in the 19th century to control vermin, notably rats, at which it excelled. So efficient at the task was it that it often appeared in rat-baiting pits ...
,
Kerry Blue Terrier The Kerry Blue Terrier (also known as the Irish Blue Terrier) ( gle, An Brocaire Gorm) is a breed of dog. Originally bred to control vermin including rats, rabbits, badgers, foxes, otters and hares, over time the Kerry became a general working d ...
, Cardigan Welsh Corgi,
Poodle The Poodle, called the Pudel in German and the Caniche in French, is a breed of water dog. The breed is divided into four varieties based on size, the Standard Poodle, Medium Poodle, Miniature Poodle and Toy Poodle, although the Medium Poodle var ...
,
Coton de Tulear The Coton de Tuléar is a breed of small dog named for the city of Tuléar (also known as Toliara) in Madagascar. This breed is thought to have originated from a group of small white dogs that swam across the Malagasy channel following a shipwreck ...
, Drentse Patrijshond, Papillon, and Stabyhoun. Causal mutations for type 2 were identified in dogs of the breeds German Wirehaired Pointer, German Shorthaired Pointer, and Chinese Crested; and for type 3 in dogs of the breeds
Kooikerhondje The Kooikerhondje (Dutch for "Duck catcher's small dog") is a small spaniel-type breed of dog of Dutch ancestry that was originally used as a working dog, particularly in an ''eendenkooi'' ( duck decoy) to lure ducks. Kooikers were popular in th ...
,
Scottish Terrier The Scottish Terrier ( gd, Abhag Albannach; also known as the Aberdeen Terrier), popularly called the Scottie, is a breed of dog. Initially one of the highland breeds of terrier that were grouped under the name of ''Skye Terrier'', it is one o ...
and
Shetland Sheepdog The Shetland Sheepdog, often known as the Sheltie, is a breed of herding dog that originated in the Shetland Islands of Scotland. The original name was ''Shetland Collie,'' but this caused controversy amongst Rough Collie breeders of the time, ...
. In dogs affected by type 1 VWD, the causal mutation was the same across all breeds and the same mutation was also detected in some human VWD type 1 patients. In contrast, the mutations causing VWD type 3 in dogs are specific to each breed. Genetic screening is offered for known breeds. In pigs, the causal mutation for VWD type 3 has also been identified. It is a large duplication within the VWF gene and causes serious damage to the gene function, so that virtually no VWF protein is produced. The clinical picture in pigs is most similar to that in humans with VWD type 3. Therefore, those pigs are valuable models for clinical and pharmacological research. Mice affected by VWD type 3 were produced by genetic engineering to obtain a small sized model for the human disease. In these strains, the VWF gene has been knocked out. In animals of other species affected by VWD, the causal mutations have not yet been identified.


Oral manifestations

In the case of severe deficiency, there may be spontaneous gingival bleeding,
ecchymosis A bruise, also known as a contusion, is a type of hematoma of tissue, the most common cause being capillaries damaged by trauma, causing localized bleeding that extravasates into the surrounding interstitial tissues. Most bruises occur close ...
, and
epistaxis A nosebleed, also known as epistaxis, is bleeding from the nose. Blood can flow down into the stomach, and cause nausea and vomiting. In more severe cases, blood may come out of both nostrils. Rarely, bleeding may be so significant that low bl ...
. Symptoms of VWD include postoperative bleeding, bleeding after dental extraction, gingival bleeding, epistaxis and easy bruising. The intake of oral contraceptives as the first-line treatment for
menorrhagia Heavy menstrual bleeding (HMB), previously known as menorrhagia or hypermenorrhea, is a menstrual period with excessively heavy flow. It is a type of abnormal uterine bleeding (AUB). Abnormal uterine bleeding can be caused by structural abnor ...
may lead to gingival enlargement and bleeding in women.''"Hemophilia A" (PDF). College of Dental Hygienists of Ontario. September 2, 2015.'' Platelet or coagulation disorders with severely altered hemostasis can cause spontaneous gingival bleeding, as seen in conjunction with hyperplastic hyperemic gingival enlargements in leukemic patients. Deposition of hemosiderin and other blood degradation products on the tooth surfaces turning them brown can occur with continuous oral bleeding over long periods.''Glick, Michael (2015). Burket's Oral Medicine. USA: People's Medical Publishing House. pp. 473, 475, 481, 482. .'' The location of oral bleeds was as follows: labial frenum, 60%; tongue, 23%; buccal mucosa, 17% and gingiva and palate, 0.5%. Severe hemophilia will have most frequent bleeding occurrences, followed by moderate and then mild hemophilia. They mostly come from traumatic injuries. Bleeding will also be induced by iatrogenic factors and poor oral hygiene practices. The frequency of oral hemorrhage by location in people with deficiency of F VIII and F IX is: gingiva, 64%; dental pulp, 13%; tongue, 7.5%; lip, 7%; palate, 2% and buccal mucosa, 1%.


Dental considerations

The protocols suggest the use of factor concentrate along with the use of local hemostatic techniques, such as suturing, and local measures, such as the use of oxidized cellulose, for example, Surgicel or fibrin glue in conjunction with post-operatively administered antifibrinolytic agents where appropriate.''Andrew Brewer, Maria Elvira Correa (May 2006). "Guildelines for Dental Treatment of Patients with Inherited Bleeding Disorders" (PDF). Treatment of Hemophilia. 40: 9 – via World Federation of Hemophilia (WFH).'' The use of any non-steroidal anti-inflammatory drug (NSAID) must be discussed beforehand with the patient's hematologist because of their effect on platelet aggregation. There are no restrictions regarding the type of local anaesthetic agent used although those with vasoconstrictors may provide additional local hemostasis.


See also

*
Bernard–Soulier syndrome Bernard–Soulier syndrome (BSS) is a rare autosomal recessive bleeding disorder that is caused by a deficiency of the '' glycoprotein Ib-IX-V complex'' (GPIb-IX-V), the receptor for von Willebrand factor. The incidence of BSS is estimated to be ...
, caused by a deficiency in the VWF receptor,
GPIb Glycoprotein Ib (GPIb), also known as CD42, is a component of the GPIb-V-IX complex on platelets. The GPIb-V-IX complex binds von Willebrand factor, allowing platelet adhesion and platelet plug formation at sites of vascular injury. It is defici ...
*
List of hematologic conditions :''This is an incomplete list, which may never be able to satisfy certain standards for completion.'' There are many conditions of or affecting the human hematologic system—the biological system that includes plasma, platelets, leukocytes, ...
*
Purpura Purpura () is a condition of red or purple discolored spots on the skin that do not blanch on applying pressure. The spots are caused by bleeding underneath the skin secondary to platelet disorders, vascular disorders, coagulation disorders, ...


References


Further reading

* ''Harrison's textbook of Internal Medicine'', Chapter 177. * * * * Williams Hematology, 7th edition, Grune and Stratton, chapters 112 (p. 1806) and 118 (p. 1937)


External links


GeneReviews/NCBI/NIH/UW entry on von Willebrand Disease
* {{DEFAULTSORT:Von Willebrand Disease Autosomal dominant disorders Coagulopathies Rare syndromes