Von Willebrand disease

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 dogs (notably Doberman Pinschers), and rarely in swine, cattle, horses, and cats. There are three forms of vWD, inherited, acquired and pseudo or platelet type. There are three types of hereditary vWD, vWD Type I, vWD Type II and vWD III. Within the three inherited types of vWD there are various subtypes. Platelet type vWD is also an inherited condition.

vWD Type I is the most common type of the disorder and those that have it are typically asymptomatic or may experience mild symptoms such as epistaxis although there may be severe symptoms in some cases. There are various factors that affect the presentation and severity of symptoms of vWD such as blood type.

vWD is named after Erik Adolf von Willebrand, a Finnish pediatrician who first described the disease in 1926.

Signs and symptoms
The various types of vWD present with varying degrees of bleeding tendency, usually in the form of easy bruising, nosebleeds and bleeding gums. Women may experience heavy menstrual periods and blood loss during childbirth.

Severe internal or joint bleeding is uncommon (which mostly occurs in type 3 vWD).

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 functionality 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 because 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 and in most cases (but not all) 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 complete 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. Patients with von Willebrand disease will typically display a normal prothrombin time and a variable prolongation of partial thromboplastin time.

The testing for vWD can be influenced by laboratory procedures. There are numerous variables 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 out to an outside facility and the specimen is frozen and transported long distances. Diagnostic errors are not uncommon, and there is a varying rate of testing proficiency amongst laboratories with error rates ranging from 7% to 22% in some studies to as high as 60% in cases of misclassification of vWD sub-type. To increase the probability of a proper diagnosis testing should be done at a facility with immediate on-site processing in their own specialized coagulation laboratory.

Classification
There are inherited and acquired forms of vWD. 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 (ISTH) classification depends on the definition of qualitative and quantitative defects.

Type 1
Type 1 vWD (60-80% of all vWD cases) is a quantitative defect which is heterozygous for the defective gene. Decreased levels of vWF are detected at 10-45% of normal, i.e. 10-45 IU.

Many patients are asymptomatic or may have mild symptoms and not have clearly impaired clotting which might suggest a bleeding disorder. Often times 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 many unaware 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 periods). There are also a minority of cases of Type I which may present with severe symptoms.

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 proteolysis 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 thrombocytopenia 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
Type 2M von willebrands disease is a qualitative deficit in von Willebrand factor. Normal antigen levels are seen, decreased function is observed (reduced RICOF) and, differentiating it from 2A, the functional deficit is not a result of an absence of high molecular weight multimers.

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 hemarthroses (joint bleeding), as in cases of mild hemophilia.

Platelet-type
(also known as pseudo-vWD or platelet-type [pseudo] vWD) 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. 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.

Thrombocythemia is another cause of acquired von Willebrand disease, due to sequestration of von Willebrand factor via the adhesion of vast numbers of platelets.

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

Pathophysiology
vWF is mainly active in conditions of high blood flow and shear stress. Deficiency of vWF therefore shows primarily in organs with extensive small vessels, such as the skin, the gastrointestinal tract and the uterus. In angiodysplasia, a form of telangiectasia of the colon, shear stress is much higher than in average capillaries, and the risk of bleeding is increased concomitantly.

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. 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.

Genetics
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
The prevalence of vWD is about 1 in 100 individuals. However the majority of these people do not have symptoms. The prevalence of clinically significant cases is 1 per 10,000. Because most forms are rather mild, they are detected more often in women, whose bleeding tendency shows during menstruation. 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. For women with heavy menstrual bleeding, the combined oral contraceptive pill may be effective in reducing bleeding or in reducing the length or frequency of periods. 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
In 1924, a 5-year-old girl who lived on the Åland Islands was brought to Deaconess Hospital in Helsinki, Finland, where she was seen by Dr. Erik von Willebrand. He ultimately assessed 66 members of her family and reported in 1926 that this was a previously undescribed bleeding disorder that differed from hemophilia. Dr von Willebrand recognized the autosomal inheritance pattern, and noted that the bleeding symptoms were greater in children and in women of childbearing age. Thus, he stated that patients with this syndrome had (1) mucocutaneous bleeding, (2) normal clotting time, (3) autosomal inheritance rather than being linked to the X chromosome, and (4) prolonged bleeding times by the Duke method (ear lobe bleeding time). He subsequently found that blood transfusions were useful not only to correct the anemia but also to control bleeding.

In the 1950s, it became clear that a "plasma factor," antihemophilic factor (FVIII), 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 "von Willebrand factor" in honor of Dr. Erick von Willebrand.

Variant forms of VWF were recognized in the 1970s, and we now recognize that these variations are 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.