Von Willebrand disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2] Nazia Fuad M.D.

Von Willebrand’s disease is an genetic coagulation disorder with resultant abnormality in platelet adhesion and aggregation. Von Willebrand disease (vWD) is the most common genetic coagulation disorder described in humans. It affects up to 1% of the population, although most cases are mild. Symptomatic vWD is much rare, ~1 in 10000. Von Willebrand disease arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a large glycoprotein protein that is required for platelets to bind to collagen. vWF is therefore important in primary hemostasis. When the disease comes to medical attention, it usually presents in the typical manner for platelet disorders mucosal bleeding and easy bruising. The disease is usually inherited in an autosomal dominant manner, although there are recessive forms as well, and it can also be acquired secondary to another disease.

Von Willebrand’s disease was first described by Erik Adolf von Willebrand, a Finnish pediatrician in 1926. Dr. Erik Adolf von Willebrand was also the first to differentiate Von Willebrand’s disease from hemophilia. Von Willebrand’s disease was initially named hereditary pseudo hemophilia. In the mid 1950s it was recognized that Von Willebrand’s disease was usually accompanied by decreased level of coagulation factor VIII (FVIII) activity. In the early 1970s the immunologic distinction between FVIII and von Willebrand factor was established. In the 1980s, Cloning of the VWF gene was investigated which has facilitated investigation into the genetic basis of VWD.

Von Willebrand disease may be classified as acquired or inherited. There are four hereditary types of vWD described – type 1, type 2, type 3, and platelet-type. Most cases are hereditary, but acquired forms of vWD have been described. The International Society on Thrombosis and Hemostasis’s (ISTH) classification depends on the definition of qualitative and quantitative defects in Von Willebrand factor.

Von Willebrand factor is a glycoprotein present in blood and is involved in hemostasis. Its synthesis takes place in the endothelium (in the Weibel-Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue and are stored there too. The vWF monomer contains a number of specific domains which binds to factor VIII, platelet GPIb-receptor, Heparin, Collagen. Von Willebrand disease is due to an abnormality, either quantitative or qualitative, of the von Willebrand factor. Von Willebrand factor gene mutations results in problems with subunit or multimer formation, storage, secretion, proteolysis, and increased clearance. Von Willebrand’s Disease can also be acquired secondary to another diseases. Acquired VWD is associated with other diseases resulting from different pathological processes. These pathological processes includes Antibody formation resulting in Impaired vWF function and Increased clearance of VWF. Other mechanisms are enhanced proteolysis and decreased synthesis of von Willebrand factor (vWF). Von Willebrand disease types 1 and 2 (except type 2N which is inherited recessively) are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive.

VWD is caused by a quantitative or qualitative defect in vWF. Most cases of vWD are due to inherited mutations that affect production of vWF. There are also acquired forms of vWD where vWF is impaired due to other pathological processes. Acquired defects in vWF can be caused by a number of conditions,for example mitral valve prolapse, ventricular assist device, ventricular septal defect, aortic stenosis, monoclonal gammopathy of undetermined significance, chronic myeloid leukemia and chronic lymphocytic leukemia, wilms tumor, waldenström macroglobulinemia, essential thrombocythemia, multiple myeloma, non-Hodgkin lymphoma, polycythemia vera, valproic acid, ciprofloxacin, griseofulvin, systemic lupus erythematosus,hypothyroidism, uremia, hemoglobinopathies and angiodysplasia.

vWD must be differentiated from platelet disorders, thrombophilias, and hemophilias based on genetic disoder, clinical presentation, laboratory findings and treatment.

The prevalence of von Willebrand’s disease is 0.6 to 1.3%. It is estimated that the referral prevalence of von Willebrand’s disease is approximately 1 case per 10,000 persons. The actual abnormality (which does not necessarily lead to disease) occurs in 0.9-3% of the population. The symptoms of VWD is disproportionately more common in women of child-bearing age. Although autosomal inheritance pattern of disease lead to an equal distribution of male patients and female patients, the disease has female predominance whose bleeding tendency shows during menstruation. There is no racial predilection to vWD however, it may be more severe or apparent in people with blood type O.

Common risk factors in the development of Von Willebrand disease include positive family history and consanguineous relationships. Less common risk factors in the development of Von Willebrand disease include lymphoproliferative disorders and aortic stenosis.

The ISTH-Bleeding Assessment Tool is a validated instrument that is used to screen patients referred for bleeding symptoms for further laboratory testing. The three main screening tests used in the diagnosis of VWD include vonWillebrand Factor (VWF) antigen, platelet-dependent VWF activity, and factor VIII activity

Patients with VWD can become symptomatic at any age. A typical history in a patient with mild to moderate disease includes epistaxis lasting longer than 10 minutes in childhood lifelong easy bruising, bleeding following dental extractions, other invasive dental procedures, or other forms of surgery. Women with VWD usually have a history of heavy menstrual bleeding and may have bleeding during the peripartum period, often at or within hours of delivery and at 5 to 10 days after delivery. Menorrhagia is a major complication. Angiodysplasia is serious, and possibly life-threatening complication. Intraarticular bleeding may be a presenting symptom in those with type 2N or type 3 disease. For some patients, vWD is a mild bleeding disorder and can be managed easily. Patients with mild disease may experience clinically severe hemorrhage following trauma or invasive procedures. Variability of symptoms exists among family members. People with vWD types II and III face severe and potentially life threatening bleeding episodes. Type III disease patients have low FVIII levels and present with arthropathies. Levels of vWF normally increase with age in patients with type I vWD, In patients with type II vWD, vWF levels does not increase with aging.

There is no single diagnostic study of choice for the diagnosis of von Willebrand disease, but von Willebrand disease can be diagnosed based on screening tests followed by confirmatory tests. The screening tests for VWD that are selected by the National Heart, Lung, and Blood Institute include testing for vWF antigen, VWF ristocetin cofactor activityand factor VIII clotting activity. When one of the VWD screening test is abnormal, further confirmatory tests are performed to establish the correct diagnosis and determine the type of VWD. Genotyping is most beneficial for type 1 patients with vWF ≤30 IU/dL and those with type 2 or 3. Genotyping also detects a benign type of vWD the D1472H, It affects ristocetin binding but not vWF function.

Patients with von Willebrand’s disease present with history of mucosal bleeding, recurrent nose bleeds, oral cavity bleeding, and positive family history of similer symptoms among other family members. Adults patients with vWD mainly present with bleeding after dental extraction/ or other surgery. Heavy menstrual periods and postpartum hemorrhage are common among affected females with von Willebrand’s disease. Severe internal or joint bleeding can occur but is usually rare.

Patients with vWD commonly have negative physical examination findings however the findings may include ecchymoses, hematomas with varying sizes and location and evidence of current or recent mucosal bleeding.

The diagnosis of von Willebrand’s disease (VWD) begins with a relevant personal or family history of mucocutaneous bleeding. When VWD is suspected, several levels of testing are needed in order to make diagnosis. Initail tests involve measurement of VWF antigen (VWF:Ag) level, Factor VIII activity (FVIII:C) and VWF–ristocetin cofactor activity [VWF:RCo]. When the results of all first-level tests are normal, VWD is ruled out; because of biologic variability, however, the tests should be repeated if values are at the low end of the normal range or if VWD is strongly suspected. Persons with a bleeding tendency who have VWF levels between 30 and 50 IU per deciliter are classified as having “low VWF” or “possible type 1 disease” but are not classified as having definitive VWD. When von Willebrand factor antigen is undetectable (or the level is <5 IU per deciliter, according to the latest disease classification), type 3 von Willebrand’s disease is diagnosed. If these first-level tests reveal definitive abnormalities, a diagnosis of VWD can be made; if the results are not conclusive, second-level tests are required. Second level testing involves repeating the initial tests and then measurement of VWF multimer distribution using gel electrophoresis and ristocetin-induced platelet aggregation (RIPA). Other tests performed in any patient with bleeding problems include: complete blood count (especially platelet counts), APTT (activated partial thromboplastin time), prothrombin time, thrombin time, fibrinogen level, testing for factor IX if hemophilia B is suspected and other coagulation factor assays may be performed depending on the results of a coagulation screen. Patients with Von Willebrand disease will typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.

There are no imaging findings associated with Von Willebrand disease.

There are no other diagnostic findings associated with Von Willebrand disease.

The mainstay of management of VWD is medical therapy. Medical therapy of von Willebrand’s disease ( vWD) involves normalizing the von Willebrand factor and factor VIIIlevels. Endogenous factor levels can be increased by the use of desmopressin or by infusing exogenous coagulation factors example high-purity or low-purity von Willebrand factor concentrate. Medical therapy depends on the type of von Willebrand’s disease. Desmopressin is used for type 1 and 2 von Willebrand’s disease. von Willebrand factor–factor VIII or von Willebrand factor concentrate is used in some of type 2 von Willebrand’s disease and all of type 3 von Willebrand’s disease. Alternate or additional therapy involves the use of tranexamic acid or aminocaproic acid.

There are no known preventive measures for von Willebrand disease. In families with type 3 disease, genetic analysis may be useful for counseling.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2] Nazia Fuad M.D.

Von Willebrand’s disease was first described by Erik Adolf von Willebrand, a Finnish pediatrician in 1926. Dr. Erik Adolf von Willebrand was also the first to differentiate Von Willebrand’s disease from hemophilia. Von Willebrand’s disease was initially named hereditary pseudo hemophilia. In the mid 1950s it was recognized that Von Willebrand’s disease was usually accompanied by decreased level of coagulation factor VIII (FVIII) activity. In the early 1970s the immunologic distinction between FVIII and von Willebrand factor was established. In the 1980s, cloning of the VWF gene was investigated which has facilitated investigation into the genetic basis of VWD.

• Von Willebrand’s disease was first described by Erik Adolf von Willebrand, a Finnish paediatrician in 1926.^[1][2]
• Dr. Erik Adolf von Willebrand was also the first to differentiate Von Willebrand’s disease from hemophilia.^[2]
• Von Willebrand’s disease was initially named hereditary pseudo hemophilia.^[2]

• In the mid 1950s it was recognized that Von Willebrand’s disease was usually accompanied by the following:^[3]
  • A decreased level of coagulation factor VIII (FVIII) activity
  • Bleeding phenotype could be corrected by the infusion of normal plasma.
• In the early 1970s the immunologic distinction between FVIII and von Willebrand factor was made.^[3]
• In the 1980s, cloning of the VWF gene was investigated which has facilitated investigation into the genetic basis of VWD.^{[3][4][5][6][7]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Nazia Fuad M.D.

Von Willebrand disease may be classified as acquired or inherited. There are four hereditary types of vWD described – type 1, type 2, type 3, and platelet-type. Most cases are hereditary, but acquired forms of vWD have been described. The International Society on Thrombosis and Hemostasis’s (ISTH) classification depends on the definition of qualitative and quantitative defects in Von Willebrand factor.

Classification of von Willebrand disease,

Von Willebrand disease may be classified as inherited and acquired^[1][2][3]

• VWD is caused by mutations at the VWF locus and is usually classified into three main types according to quantitative (Types 1 and 3) or qualitative (Types 2A, 2B, 2M, 2N) abnormalities.^[4]
• Type 1 VWD
  • Refers to partial quantitative deficiency of VWF.
• Type 2 VWD
  • Refers to qualitative deficiency of VWF.

• • Type 2A
    • This is an abnormality of the synthesis or proteolysis of the vWF multimers.
    • This results in the presence of small multimer units in circulation.
    • Factor VIII binding is normal.
    • Ristocetin co-factor activity is low.
  • Type 2B
    • There is a increase binding of vWF to platelets
    • There is rapid clearance of the platelets and the large vWF multimers.
    • A mild thrombocytopenia may occur.
    • The large vWF multimers are absent in the circulation
    • Factor VIII binding is normal.
    • The RiCof:vWF antigen assay is low.
  • Type 2M
    • This is caused by decreased or absent binding of vWF 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 has a normal vWF antigen level and normal functional test results.
    • Factor VIII is low.
    • Patient has the clinical findings of hemophilia A but a pedigree suggesting autosomal, rather than X-linked, inheritance.

• Type 3 VWD
  • Virtually complete deficiency of VWF.^[5]
  • Most severe form of vWD
  • Patients have severe mucosal bleeding.
  • Low levels of factor VIII

• Acquired vWD can occur in patients with autoantibodies.
• In such cases the function of vWF is not inhibited but the vWF-antibody complex is rapidly cleared from the circulation.
• This form of vWD occurs in patients with aortic valve stenosis, leading to gastrointestinal bleeding (Heyde’s syndrome).

• Acquired vWF has also been described in Wilms’ tumour, hypothyroidism and mesenchymal dysplasias.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2] Nazia Fuad M.D.

Von Willebrand factor is a glycoprotein present in blood and is involved in hemostasis. Its synthesis takes place in the endothelium (in the Weibel-Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue and are stored there too. The vWF monomer contains a number of specific domains which binds to factor VIII, platelet GPIb-receptor, Heparin, Collagen. Von Willebrand disease is due to an abnormality, either quantitative or qualitative, of the von Willebrand factor. Von Willebrand factor gene mutations results in problems with subunit or multimer formation, storage, secretion, proteolysis, and increased clearance. Von Willebrand’s Disease can also be acquired secondary to another diseases. Acquired VWD is associated with other diseases resulting from different pathological processes. These pathological processes includes Antibody formation resulting in Impaired vWF function and Increased clearance of VWF. Other mechanisms are enhanced proteolysis and decreased synthesis of von Willebrand factor (vWF). Von Willebrand disease types 1 and 2 (except type 2N which is inherited recessively) are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive.

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

Structure

• It is a glycoprotein present in blood and is involved in hemostasis.
• Its synthesis takes place in the endothelium (in the Weibel-Palade bodies), megakaryocytes (α-granules of platelets), and subendothelial connective tissue.
• The fundamental vWF monomer is a 2050-amino acid protein.

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

• D’/D3 domain, binds to factor VIII
• A1 domain, which binds to:
  • Platelet GPIb-receptor
  • Heparin
  • Collagen
• the A2 domain unfolds and then attach to ADAMTS13 protease that inactivates vWF by making smaller multimers.
• The partial unfolding is affected by shear flow in the blood, by calcium binding, and by the “vicinal disulfide” at the A2-domain C-terminus.
• the A3 domain binds to collagen (Von Willebrand factor type A domain)
• the C1 domain, in which the RGD motif binds to platelet integrin α_IIbβ₃ when this is activated (Von Willebrand factor type C domain)
• Platelet integrin are the transmembrane receptors which facilitate extracellular matrix adhesion.
• The “cystine knot” domain (at the C-terminal end of the protein), which vWF shares with platelet-derived growth factor(PDGF), transforming growth factor-β (TGFβ) and β-human chorionic gonadotropin (βHCG, of pregnancy test fame). (Von Willebrand factor type C domain)

• Monomers are subsequently N-glycosylated, arranged into dimers in the endoplasmic reticulum and into multimers in the Golgi apparatus.
• Multimers of vWF are usually very large, >20,000 kDa, and consist of almost 80 subunits.
• Only the large multimers are functional.
• Some cleavage products from vWF production that are also secreted but serve no function.

Function

• Von Willebrand factor’s main function is binding to other proteins, specially factor VIII.
• It plays an important role in platelet adhesion to wound sites.
• Von Willebrand factor binds to factor VIII while it is inactive in circulation
• Von Willebrand factor protects FVIII from degradation and delivers it to the site of injury
• Factor VIII degrades rapidly when not bound to vWF
• Factor VIII is released from vWF by the action of thrombin.
• In the absence of vWF, factor VIII has a half-life of 1-2 hours
• When it is carried by intact vWF, factor VIII half-life becomes 8-12 hour
• When vWF is exposed in endothelial cells due to damage occurring to the blood vessel, it binds to collagen.
• Endothelium also releases vWF which forms additional links between the platelets’ glycoprotein Ib/IX/V and the collagen fibrils
• Von Willebrand factor attaches to platelets by its specific receptor to glycoprotein Ib on the platelet surface.
• It acts as an adhesive bridge between the platelets and damaged subendothelium at the site of vascular injury
• VWF binds to platelet glycoprotein Ib when it forms a complex with gpIX and gpV
• This binding is most efficient under high shear stress
• When coagulation has been stimulated vWF binds to other platelet receptors that are activated by thrombin.

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

Pathogenetic mechanisms of inherited VWD

Pathogenetic mechanisms of acquired VWD

• Von Willebrand’s Disease can also be acquired secondary to another disease.^{[3][4][5][6][7][8][9][10]}

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

• Antibody formation resulting in:^[11][12]
  • Impaired vWF function
  • Increased clearance of VWF
• Enhanced proteolysis
• Decreased synthesis

Von Willebrand disease types 1 and 2 (except type 2N which is inherited recessively) are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. The diagram below illustrates autosomal dominant inheritance.

von Willebrand disease

• The vWF gene is located on chromosome twelve (12p13.2).
• It has 52 exons spanning 178kbp. *
• VWD Types 1 and 2 are inherited as autosomal dominant traits and type 3 is inherited as autosomal recessive. Occasionally type 2 also inherits recessively.

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

• Mitral valve prolapse
• Ventricular assist device
• Ventricular septal defect
• Aortic stenosis

• Monoclonal gammopathy of undetermined significance
• chronic myeloid leukemia and chronic lymphocytic leukemia
• Wilms tumor
• Waldenström macroglobulinemia
• Essential thrombocythemia
• Multiple myeloma
• Non-Hodgkin lymphoma
• Polycythemia vera

• Valproic acid
• Ciprofloxacin
• Griseofulvin

• Systemic lupus erythematosus

• Hypothyroidism
• Uremia
• Hemoglobinopathies
• Angiodysplasia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2] Nazia Fuad M.D.

VWD is caused by a quantitative or qualitative defect in vWF. Most cases of vWD are due to inherited mutations that affect production of vWF. There are also acquired forms of vWD where vWF is impaired due to other pathological processes. Acquired defects in vWF can be caused by a number of conditions,for example mitral valve prolapse, ventricular assist device, ventricular septal defect, aortic stenosis, monoclonal gammopathy of undetermined significance, chronic myeloid leukemia and chronic lymphocytic leukemia, wilms tumor, waldenström macroglobulinemia, essential thrombocythemia, multiple myeloma, non-Hodgkin lymphoma, polycythemia vera, valproic acid, ciprofloxacin, griseofulvin, systemic lupus erythematosus,hypothyroidism, uremia, hemoglobinopathies and angiodysplasia.

• There are no life-threatening causes of von willebrand disease.

Common causes of von willebrand disease may include:^[1][2]

• Chronic myeloid leukemia
• Chronic lymphocytic leukemia
• Wilms tumor
• Essential thrombocythemia
• Non-Hodgkin lymphoma
• Mitral valve prolapse
• Ventricular assist device
• Ventricular septal defect
• Aortic stenosis
• Valproic acid
• Ciprofloxacin

Less common causes of von Willebrand disease include:^[3]

• Waldenström macroglobulinemia
• Multiple myeloma
• Polycythemia vera
• Wilms tumor
• Systemic lupus erythematosus
• Hypothyroidism
• Uremia
• Hemoglobinopathies
• Angiodysplasia

• The vWF gene is located on the short arm p of chromosome 12 (12p13.2) von Willebrand disease is caused by a mutation in this gene.

List the causes of the disease in alphabetical order:

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

vWD must be differentiated from platelet disorders, thrombophilias, and hemophilias based on genetic disoder, clinical presentation, laboratory findings and treatment.

vWD must be differentiated from platelet disorders, thrombophilias, and hemophilias as shown below:

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

The prevalence of von Willebrand’s disease is 0.6 to 1.3%. It is estimated that the referral prevalence of von Willebrand’s disease is approximately 1 case per 10,000 persons. The actual abnormality (which does not necessarily lead to disease) occurs in 0.9-3% of the population. The symptoms of VWD is disproportionately more common in women of child-bearing age. Although autosomal inheritance pattern of disease lead to an equal distribution of male patients and female patients, the disease has female predominance whose bleeding tendency shows during menstruation. There is no racial predilection to vWD however, it may be more severe or apparent in people with blood type O.

The prevalence of von Willebrand’s disease is 0.6 to 1.3%.^[1][2] It is estimated that the referral prevalence of von Willebrand’s disease is approximately 1 case per 10,000 persons.^[3]

The actual abnormality (which does not necessarily lead to disease) occurs in 0.9-3% of the population.

The symptoms of VWD is disproportionately more common in women of child-bearing age.^[1]

Although autosomal inheritance pattern of disease lead to an equal distribution of male patients and female patients, the disease has female predominance whose bleeding tendency shows during menstruation.^[4][5]

There is no racial predilection to vWD however, it may be more severe or apparent in people with blood type O.^[6]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2] Nazia Fuad M.D.

There are no established risk factors for Von Willebrand disease however, 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. Common risk factors in the development of Von Willebrand disease include positive family history and consanguineous relationships. Less common risk factors in the development of Von Willebrand disease include lymphoproliferative disorders and aortic stenosis.

• Common risk factors in the development of Von Willebrand disease include:^[1]
  • Positive family history
  • Consanguineous relationships

Less common risk factors in the development of Von Willebrand disease include:^[1]

• Lymphoproliferative disorders
• Aortic stenosis
• Myeloproliferative disorders
• Hypothyroidism

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2]

The ISTH-Bleeding Assessment Tool is a validated instrument that is used to screen patients referred for bleeding symptoms for further laboratory testing. The three main screening tests used in the diagnosis of VWD include vonWillebrand Factor (VWF) antigen, platelet-dependent VWF activity, and factor VIII activity.

.

The ISTH-Bleeding Assessment Tool is a validated instrument that is used to screen patients referred for bleeding symptoms for further laboratory testing.^[1]

The three main screening tests used in the diagnosis of VWD include:

• VonWillebrand Factor (VWF) antigen
• Platelet-dependent VWF activity
• Factor VIII activity.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Prince Tano Djan, BSc, MBChB [2] Nazia Fuad M.D.

Patients with VWD can become symptomatic at any age. A typical history in a patient with mild to moderate disease includes epistaxis lasting longer than 10 minutes in childhood lifelong easy bruising, bleeding following dental extractions, other invasive dental procedures, or other forms of surgery. Women with VWD usually have a history of heavy menstrual bleeding and may have bleeding during the peripartum period, often at or within hours of delivery and at 5 to 10 days after delivery. Menorrhagia is a major complication. Angiodysplasia is serious, and possibly life-threatening complication. Intraarticular bleeding may be a presenting symptom in those with type 2N or type 3 disease. For some patients, vWD is a mild bleeding disorder and can be managed easily. Patients with mild disease may experience clinically severe hemorrhage following trauma or invasive procedures. Variability of symptoms exists among family members. People with vWD types II and III face severe and potentially life threatening bleeding episodes. Type III disease patients have low FVIII levels and present with arthropathies. Levels of vWF normally increase with age in patients with type I VWD, In patients with type II VWD, VWF levels does not increase with aging.

• Patients with VWD can become symptomatic at any age.
• A typical history in a patient with mild to moderate disease includes
  • Epistaxis lasting longer than 10 minutes in childhood
  • Lifelong easy bruising
  • Bleeding with or following dental extractions, other invasive dental procedures, or other forms of surgery.

• Women with VWD usually have a history of heavy menstrual bleeding and may have bleeding during the peripartum period, often at or within hours of delivery and at 5 to 10 days after delivery. The bleeding may be delayed until 14 to 21 days postpartum, or persists.

Complications of vWD include the followings:^{[1][2][3][4][5]}

• Menorrhagia is a major complication, which also impairs the quality of life.
• Angiodysplasia is serious, and possibly life-threatening complication.
• Intraarticular bleeding may be a presenting symptom in those with type 2N or type 3 disease.
• Primary and secondary postpartum bleeding is a commmon complication.

• For some patients, VWD is a mild bleeding disorder and can be managed easily.
• Patients with mild disease may experience clinically severe hemorrhage following trauma or invasive procedures.
• Variability of symptomatology exists among family members.
• People with VWD types II and III face severe and potentially life threatening bleeding episodes.
• Patients withType III disease have low FVIII levels and present with arthropathies.

• Levels of VWF normally increase with age in patients with type I VWD,
• Elderly patients with type I exhibit no change in their pattern of bleeding though.^[6]
• In patients with type II VWD, VWF levels does not increase with aging.

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