Von Willebrand disease overview
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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.
Overview
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.
Historical Perspective
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.
Classification
Von Willebrand disease may be classified as acquired or inherited. There are four hereditary types of vWD described - type 1, type 2, type 3, and platelet-type. 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.
Pathophysiology
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.
Causes
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.
Differentiating Von Willebrand disease from other diseases
vWD must be differentiated from platelet disorders, thrombophilias, and hemophilias based on genetic disoder, clinical presentation, laboratory findings and treatment.
Epidemiology and Demographics
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.
Risk Factors
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.
Screening
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
Natural History, Complications, and Prognosis
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.
Diagnosis
Diagnostic Study of Choice
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.
History and Symptoms
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.
Physical Examination
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.
Laboratory Findings
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.
Imaging Findings
There are no imaging findings associated with Von Willebrand disease.
Other Diagnostic Studies
There are no other diagnostic findings associated with Von Willebrand disease.
Treatment
Medical Therapy
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.
Prevention
There are no known preventive measures for von Willebrand disease. In families with type 3 disease, genetic analysis may be useful for counseling.