Von Willebrand Disease

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Definition

Von Willebrand disease is caused by a deficiency or an abnormality in a protein called von Willebrand factor and is characterized by prolonged bleeding.

Description

The Finnish physician Erik von Willebrand was the first to describe von Willebrand disease (VWD). In 1926 Dr. von Willebrand noticed that many male and female members of a large family from the Aland Islands had increased bruising (bleeding into the skin) and prolonged episodes of bleeding. The severity of the bleeding varied between family members and ranged from mild to severe and typically involved the mouth, nose, genital and urinary tracts, and occasionally the intestinal tract. Excessive bleeding during the menstrual period was also experience by some of the women in this family. What differentiated this bleeding disorder from classical hemophilia was that it appeared not to be associated with muscle and joint bleeding and affected women and men rather than just men. Dr. von Willebrand named this disorder hereditary pseudohemophilia.

Pseudohemophilia, or von Willebrand disease (VWD) as it is now called, is caused when the body does not produce enough of a protein called von Willebrand factor(vWF) or produces abnormal vWF. vWF is involved in the process of blood clotting (coagulation). Blood clotting is necessary to heal an injury to a blood vessel. When a blood vessel is injured, vWF enables blood cells called platelets to bind to the injured area and form a temporary plug to seal the hole and stop the bleeding. vWF is secreted by platelets and by the cells that line the inner wall of the blood vessels (endothelial cells). The platelets release other chemicals, called factors, in response to a blood vessel injury, which are involved in forming a strong permanent clot. vWF binds to and stabilizes factor VIII, one of the factors involved in forming the permanent clot.

A deficiency or abnormality in vWF can interfere with the formation of the temporary platelet plug and also affect the normal survival of factor VIII, which can indirectly interfere with the production of the permanent clot. Individuals with VWD, therefore, have difficulty in forming blood clots and as a result they may bleed for longer periods of time. In most cases the bleeding is due to an obvious injury, although it can sometimes occur spontaneously.

VWD is classified into three basic types: type 1, 2, and 3 based on the amount and type of vWF that is produced. Type 1 is the most common and mildest form and results when the body produces slightly decreased amounts of typically normal vWF. Type 2 can be classified into five subtypes (A,B,M,N) and results when the body produces an abnormal type of vWF. Type 3 is the rarest and most severe form and results when the body does not produce any detectable vWF.

Approximately one out of 100 people are affected with VWD, making it the most common inherited bleeding disorder (hemophilia). VWD affects people of all ethnic backgrounds. Approximately 70–80% of people with VWD have type 1 and close to 20–30% have type 2. Type 3 is very rare and occurs in less than one percent of people with VWD.

— Lisa Maria Andres, MS, CGC

Dictionary: von Wil·le·brand's disease  (vŏn wĭl'ə-brăndz', fôn vĭl'ə-bränts')

A hereditary disease characterized by a tendency to hemorrhage, caused by a deficiency or abnormality of the blood proteins that control platelet activity.

[After Erik Adolf von Willebrand (1870–1949), Finnish physician.]

An inherited blood coagulation disorder attributed to a deficiency or malfunction of factor VIII. It may cause prolonged or excessive gingival bleeding.

Definition

Von Willebrand disease is caused by a deficiency or an abnormality in a protein called von Willebrand factor and is characterized by prolonged bleeding.

Description

The Finnish physician Erik von Willebrand was the first to describe von Willebrand disease (VWD). In 1926, von Willebrand noticed that many male and female members of a large family from the Aland Islands had increased bruising (bleeding into the skin) and prolonged episodes of bleeding. The severity of the bleeding varied among family members and ranged from mild to severe and typically involved the mouth, nose, genital and urinary tracts, and occasionally the intestinal tract. Some women in the family also experienced excessive menstrual bleeding. What differentiated this bleeding disorder from classical hemophilia was that it appeared not to be associated with muscle and joint bleeding and affected women and men rather than just men. Dr. von Willebrand named this disorder hereditary pseudohemophilia.

Pseudohemophilia, or von Willebrand disease (VWD) as it is called in the twenty-first century, occurs when the body does not produce enough of a protein, called von Willebrand factor(vWF), or produces abnormal vWF. vWF is involved in the process of blood clotting (coagulation). Blood clotting is necessary to heal an injury to a blood vessel. When a blood vessel is injured, vWF enables blood cells called platelets to bind to the injured area and form a temporary plug to seal the hole and stop the bleeding. vWF is secreted by platelets and by the cells that line the inner wall of the blood vessels (endothelial cells). The platelets stimulate the release other chemicals, called factors, which help form a strong permanent clot. vWF binds to and stabilizes factor VIII, one of the factors involved in forming the permanent clot.

A deficiency or abnormality in vWF can interfere with the formation of the temporary platelet plug and affect the normal survival of factor VIII. This indirectly interferes with the production of the permanent clot. Individuals with VWD, therefore, have difficulty in forming blood clots, and as a result, they may bleed for a longer time. In most cases the bleeding is due to an obvious injury, although it sometimes occurs spontaneously.

VWD is classified into three basic types: type 1, 2, and 3 based on the amount and type of vWF that is produced. Type 1 is the most common and mildest form and results when the body produces slightly decreased amounts of normal vWF. Type 2 can be classified into four subtypes (A, B, M, N) and results when the body produces an abnormal type of vWF. Type 3 is the rarest and most severe form and results when the body does not produce any detectable vWF.

Demographics

Approximately one out of 100 people are affected with VWD, making it the most common inherited bleeding disorder. VWD affects people of all ethnic backgrounds. Approximately 70 to 80 percent of people with VWD have type 1, and close to 20 to 30 percent have type 2. Type 3 is very rare and occurs in less than 1 percent of people with VWD. Type 3 occurs in about one out of every million people.

Causes and Symptoms

The complex genetics of VWD involve a gene found on chromosome 12. Different types of changes in the vWF gene can affect the production of vWF. Some changes cause the vWF gene to produce decreased amounts of normal vWF, while other changes cause the gene to produce abnormal vWF. Each individual inherits two copies of each gene, one from the mother and one from the father. Most of the vWF gene changes are significant enough that a change in only one vWF gene is sufficient to cause VWD. However, some types of gene changes only cause VWD if both genes are changed, which often leads to more severe symptoms.

Type 1 VWD is called an autosomal dominant condition since it is caused by a change in only one vWF gene. Since type 1 VWD results in only a slight decrease in the amount of vWF produced, the symptoms are often mild and not apparent in some individuals. Most cases of type 2 VWD are autosomal dominant since a change in only one vWF gene results in the production of an abnormal form of vWF. An autosomal dominant form of VWD can be inherited from either parent or can occur as a spontaneous gene mutation (change) in the embryo that is formed when the egg and sperm cells come together during fertilization.

Some cases of type 2 VWD and all cases of type 3 VWD are autosomal recessive, since they are caused only by changes in both vWF genes. A person with an autosomal recessive form of VWD has inherited both a changed gene from the mother and a changed gene from the father. Parents who have a child with an autosomal recessive form of VWD are called carriers, since they each possess at least one changed vWF gene. Many carriers for the autosomal recessive forms of type 2 VWD and type 3 VWD do not have any symptoms. Each child born to parents who both have one changed gene has a 25 percent chance of having VWD, a 50 percent chance of being a carrier, and a 25 percent chance of not being and not having VWD disease. A person with an autosomal dominant form of VWD has a 50 percent chance of passing the changed gene on to his or her children who may or may not have symptoms.

VWD is usually a relatively mild disorder characterized by easy bruising, recurrent nosebleeds, heavy menstrual periods, and extended bleeding after surgeries and invasive dental work. There is a great deal of variability in the severity of symptoms, which can range from clinically insignificant to life threatening. Even children within the same family who are affected with the same type of VWD may exhibit different symptoms. A child with VWD may exhibit a range of symptoms over the course of his or her lifetime and may experience an improvement in symptoms with age. The severity of the disease is partially related to the amount and type of vWF that the body produces, but it is also influenced by other genetic and non-genetic factors.

Type 1

Type 1, the mildest form of VWD, is usually associated with easy bruising, recurrent nosebleeds, heavy menstrual periods, and prolonged bleeding after surgeries and invasive work. Many people with type 1 VWD do not have any noticeable symptoms or only have prolonged bleeding after surgery or significant trauma. The amount of vWF produced by the body increases during pregnancy, so prolonged bleeding during delivery is uncommon in people with type 1 VWD.

Type 2

Children with type 2 VWD usually have symptoms from early childhood. Symptoms may even be present at birth. These children usually experience prolonged bleeding from cuts, easy bruising, nosebleeds, skin hematomas, and prolonged bleeding from the gums following tooth extraction and minor trauma. Gastrointestinal bleeding is rare but can be life-threatening. More than 50 percent of women with type 2 VWD experience heavy menstrual periods that may require a blood transfusion. Some women with type 2 VWD exhibit prolonged bleeding during delivery.

Type 3

Type 3 VWD can be quite severe and is associated with bruising and bleeding from the mouth, nose, and from the intestinal, genital, and urinary tracts. Type 3 is also associated with spontaneous bleeding into the muscles and joints, which can result in joint deformities. Some women with type 3 VWD experience prolonged bleeding during delivery.

When to Call the Doctor

If a child frequently experiences significant bleeding, takes longer than normal to stop bleeding, or experiences easy bruising, then the doctor should be consulted.

Diagnosis

Many children with VWD have mild symptoms or symptoms that can be confused with other bleeding disorders, making it difficult for a doctor to diagnose VWD based on clinical symptoms. VWD should be suspected in any child with a normal number of platelets in the blood and bleeding from the mucous membranes such as the nose, gums, and gastrointestinal tract. Testing for a child with suspected VWD often includes the measurement of the following:

• how long it takes for the bleeding to stop after a tiny cut is made in the skin (bleeding time)
• the amount of vWF (vWF antigen measurement)
• the activity of vWF (ristocetin co-factor activity)
• the amount of factor VIII (factor VIII antigen measurement)
• activity of factor VIII

Children with type 1 VWD usually have an increased bleeding time, but they may have an intermittently normal time. They also have a decreased amount of vWF and decreased vWF activity and usually have slightly decreased factor VIII levels and activity. Children with type 2 VWD have a prolonged bleeding time and decreased activity of vWF; they may also have decreased amounts of vWF and factor VIII and decreased factor VIII activity. Type 3 children have undetectable amounts of vWF, negligible vWF activity, factor VIII levels of less than 5 to 10 percent, and significantly reduced factor VIII activity. The activity of vWF is reduced for all types of VWD, making it the most sensitive means of identifying all three types. Individuals with borderline results should be tested two to three times over a three-month period.

Once a person is diagnosed with VWD, further testing such as vWF multimer analysis and ristocetin-induced platelet aggregation (RIPA) should be performed to determine the subtype. Multimer analysis evaluates the structure of the vWF, and RIPA measures how much ristocetin is required to cause the clumping of platelets in a blood sample. The vWF multimer analysis is able to differentiate children with a structurally normal vWF (Type 1) from children with a structurally abnormal vWF (Type 2) and is often able to identify the subtype of patients with Type 2 VWD. Children with type 1 VWD usually have normal to decreased RIPA concentrations. Depending on the subtype, patients with type 2 VWD either have increased or decreased RIPA. RIPA is usually absent and the multimer analysis shows undetectable vWF in children with type 3 VWD.

In some cases, DNA testing can be a valuable adjunct to biochemical testing. The detection of gene alteration(s) can confirm a diagnosis and can determine the type and subtype of VWD. It can also help to facilitate prenatal testing and testing of other family members. Unfortunately many people with VWD possess DNA changes that are not detectable through DNA testing. A child who has a mother, father, or sibling diagnosed with VWD should undergo biochemical testing for VWD. If the relative with VWD possesses a detectable gene change, then DNA testing should be considered.

Prenatal Testing

If one parent has been diagnosed with an autosomal dominant form of VWD or both parents are carriers for an autosomal recessive form of VWD, then prenatal testing should be considered. DNA testing can be performed through amniocentesis or chorionic villus sampling. If the DNA change in the parent(s) is unknown, then prenatal testing can sometimes be performed through biochemical testing of blood obtained from the umbilical cord. However this procedure is less accurate and is associated with a higher risk of pregnancy loss.

Treatment

VWD is most commonly treated by replacement of vWF through the administration of blood products that contain vWF or through treatment with desmopressin (DDAVP, 1-deamino-8-D-arginine vasopressin). DDAVP functions by increasing the amount of factor VIII and vWF in the circulating blood. Treatment with blood products or DDAVP may be started in response to uncontrollable bleeding or may be administered before procedures such as surgeries or dental work. The type of treatment chosen depends on the type of VWD and a patient's response to a preliminary treatment trial.

Treatment With Desmopressin (Ddavp)

DDAVP is the most common treatment for people with type 1 VWD. About 80 percent of people with type 1 VWD respond to DDAVP therapy. Treatment with DDAVP can also be used to treat some people with type 2 VWD. Patients with type 2B VWD should not be treated with this medication, since DDAVP can induce dangerous platelet clumping. Type 3 VWD should not be treated with DDAVP, since this medication does not increase the level of vWF in type 3 patients. DDAVP should only be used in people who have been shown to be responsive through a pre-treatment trial transfusion with this medication.

DDAVP can be administered intravenously or through a nasal inhaler. DDAVP has relatively few side effects although some people may experience facial flushing, tingling sensations, and headaches after treatment with this medication. Often treatment with this medication is only required prior to invasive surgeries or dental procedures.

Treatment With Blood Products

Patients who are unable to tolerate or are unresponsive to drug-based treatments are treated with concentrated factor VIII obtained from blood products. Not all factor VIII concentrates can be used, since some do not contain enough vWF. The concentrate is treated to kill most viruses, although caution should be used since not all types of viruses are destroyed. If the factor VIII concentrates are unable to manage a severe bleeding episode, then blood products called cryoprecipitates, which contain concentrated amounts of vWF, or platelet concentrates should be considered. Caution should be used when treating with these blood products since they are not treated to kill viruses.

Other Treatments and Precautions

Medications called fibrinolytic inhibitors can be helpful in controlling intestinal, mouth, and nose bleeding. Estrogens, such as are found in oral contraceptives, increase the synthesis of vWF and can sometimes be used in the long-term treatment of women with mild to moderate VWD. Estrogens are also sometimes used before surgery in women with type 1 VWD. Some topical agents are available to treat nose and mouth bleeds. Patients with VWD should avoid taking aspirin, which can increase their susceptibility to bleeding. Children with severe forms of VWD should avoid activities that increase their risk of injury such as contact sports.

Prognosis

The prognosis for VWD is generally good, and most individuals have a normal lifespan. The prognosis can depend, however, on accurate diagnosis and appropriate medical treatment.

Prevention

There is no known way to prevent VWD. If an individual planning to become a parent believes he or she may be a carrier of VWD, genetic counseling is suggested so that options may be explored.

Parental Concerns

VWD is usually very mild and does not cause unusual bleeding except after trauma or surgery. Children with moderate or severe VWD may need to be discouraged from playing contact sports or participating in other activities where injury is likely. Special care should be taken before surgical or dental procedures to ensure that severe bleeding does not occur.

Resources

Books

Berntorp, Erik, et al. Textbook on Hemophilia. Oxford, UK: Blackwell Publishing, 2005.

Cannon, Christopher P., et al. Platelet Function: Assessment, Diagnosis, Treatment. Totowa, NJ: Humana Press, 2004.

Periodicals

Renee Paper. "Can You Recognize and Respond to von Willebrand Disease?" Nursing 33 (July 2003): 54–6.

Society for the Advancement of Education. "Diagnosis Key to Treating von Willebrand Disease." USA Today 131 (February 2003): 546–9.

Organizations

National Hemophilia Foundation. 116 West 32nd Street, 11th Floor, New York, NY 10001. Web site: www.hemophilia.org.

[Article by: Tish Davidson, A.M. Lisa Maria Andres, MS, CGC]

A congenital hemorrhagic diathesis, inherited as an autosomal dominant trait in dogs, pigs and rabbits; abbreviated VWD. It is characterized by a prolonged bleeding time, deficiency of coagulation factor VIII and factor VIII-related antigen, and often impairment of platelet adhesion and usually associated with mild bleeding tendencies. Called also angiohemophilia, pseudohemophilia and vascular hemophilia.

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 four types of hereditary vWD. Other factors including ABO blood groups may also play a part in the severity of the condition.

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.

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.

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.

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).

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.

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.

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.

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.

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.

Acquired vWF has also been described in the following disorders: Wilms' tumour, hypothyroidism and mesenchymal dysplasias.

Pathophysiology

For the normal function of the coagulation factor, see von Willebrand factor.

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.

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]

Genetics

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.

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.

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.

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.

History

vWD is named after Erik Adolf von Willebrand, a Finnish paediatrician (1870–1949).^[4] He first described the disease in 1926.

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

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

See also

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

External links

• International repository on vWF mutations (University of Sheffield)
• National Hemophilia Foundation
• The Haemophilia Society
• World Federation of Hemophilia
• Los Bleedos
• UK Haemophilia Centre Directors Organisation
• AllAboutBleeding.com Your Online von Willebrand Disease Resource

Pathology: hematology (primarily C81-C96/200-208, D45-D47, D50-D77/280-289)
WBCs	hematological malignancy (Lymphoma, leukemia) -cytosis (Agranulocytosis, Leukocytosis, Lymphocytosis, Monocytosis) • -penia (Lymphopenia, Neutropenia)
RBCs/anemia/ hemoglobinopathy	nutritional anemia: Iron deficiency anemia, Plummer-Vinson syndrome, Megaloblastic anemia (Pernicious anemia) hereditary hemolytic anemia: G6PD Deficiency, Thalassemia, Sickle-cell disease/trait, Hereditary spherocytosis, Hereditary elliptocytosis, Hereditary stomatocytosis acquired hemolytic anemia: Warm autoimmune hemolytic anemia, HUS, MAHA, PNH aplastic anemia: Acquired PRCA, Diamond-Blackfan anemia, Fanconi anemia • Sideroblastic anemia • Hemochromatosis
Coagulation/platelets	coagulopathy: DIC • Hemophilia (A, B, C, XIII) • Von Willebrand disease Purpura: Henoch-Schönlein, ITP, TTP primary hypercoagulable state: Protein C deficiency - Protein S deficiency - Antithrombin III deficiency other hemorrhagic conditions: Bernard-Soulier syndrome - Glanzmann's thrombasthenia - Grey platelet syndrome
Histiocytosis	WHO-I Langerhans cell histiocytosis - non-Langerhans-cell histiocytosis/WHO-II (Juvenile xanthogranuloma, Hemophagocytic lymphohistiocytosis) - malignant histiocytic disorders/WHO-III (Acute monocytic leukemia, Malignant histiocytosis, Erdheim-Chester disease)
Other	Asplenia/hyposplenism - Methemoglobinemia

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